{"id": "1", "type": "silver", "text": "Outcome definitions\n\nThe primary outcome was the clinical recovery rate at 7 days from the beginning of treatment. Clinical recovery was defined as continuous (>72 hours) recovery of body temperature, respiratory rate, oxygen saturation and cough relief after treatment, with following quantitative criteria: axillary temperature ≤36.6°C; respiratory frequency ≤24 times/min; Oxygen saturation ≥98% without oxygen inhalation; mild or no cough. Secondary outcomes included the latency to pyrexia relief (for patients with pyrexia at the time of enrollment), the latency to cough relief (for patients with moderate or severe cough at the time of enrollment), the rate of AOT or NMV, all-cause mortality, dyspnea, rate of respiratory failure (defined as SPO2 ≤90% without oxygen inhalation or PaO2/FiO2 <300mmHg, requires oxygen therapy or additional respiratory support), and the rate of patients needed to receive intensive care in ICU. Safety outcomes included adverse events occurred during treatment and premature discontinuation.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[49, 71]], "text": "clinical recovery rate"}, {"id": "T2", "type": "TimeFrame", "offsets": [[72, 113]], "text": "at 7 days from the beginning of treatment"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[148, 442]], "text": "continuous (>72 hours) recovery of body temperature, respiratory rate, oxygen saturation and cough relief after treatment, with following quantitative criteria: axillary temperature ≤36.6°C; respiratory frequency ≤24 times/min; Oxygen saturation ≥98% without oxygen inhalation; mild or no cough"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[681, 700]], "text": "all-cause mortality"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[702, 709]], "text": "dyspnea"}, {"id": "T10", "type": "SecondaryOutcome", "offsets": [[878, 934]], "text": "rate of patients needed to receive intensive care in ICU"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[476, 555]], "text": "latency to pyrexia relief (for patients with pyrexia at the time of enrollment)"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[561, 655]], "text": "latency to cough relief (for patients with moderate or severe cough at the time of enrollment)"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[661, 679]], "text": "rate of AOT or NMV"}, {"id": "T11", "type": "OtherOutcome", "offsets": [[961, 1001]], "text": "adverse events occurred during treatment"}, {"id": "T12", "type": "OtherOutcome", "offsets": [[1006, 1031]], "text": "premature discontinuation"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[711, 738]], "text": "rate of respiratory failure"}, {"id": "T13", "type": "OutcomeDefinition", "offsets": [[751, 867]], "text": "SPO2 ≤90% without oxygen inhalation or PaO2/FiO2 <300mmHg, requires oxygen therapy or additional respiratory support"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}, {"id": "R3", "type": "DefinedAs", "arg1": "T9", "arg2": "T13"}]}
{"id": "100", "type": "silver", "text": "Outcomes\nOutcomes were assessed at 28 days after randomisation, with further analyses specified at 6 months. The primary outcome was 28-day all-cause mortality. Secondary outcomes were time to discharge from hospital and, among patients not on invasive mechanical ventilation at randomisation, post-enrolment use of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death. Prespecified subsidiary clinical outcomes were cause-specific mortality, use of haemodialysis or haemofiltration, major cardiac arrhythmia (recorded in a subset), and receipt and duration of ventilation (for which full data are still being collected from relevant routine sources).\nInformation on suspected serious adverse reactions was collected in an expedited fashion to comply with regulatory requirements", "entities": [{"id": "T1", "type": "TimeFrame", "offsets": [[32, 107]], "text": "at 28 days after randomisation, with further analyses specified at 6 months"}, {"id": "T2", "type": "PrimaryOutcome", "offsets": [[140, 159]], "text": "all-cause mortality"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[185, 216]], "text": "time to discharge from hospital"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[294, 404]], "text": "post-enrolment use of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death"}, {"id": "T5", "type": "OtherOutcome", "offsets": [[453, 477]], "text": "cause-specific mortality"}, {"id": "T6", "type": "OtherOutcome", "offsets": [[520, 544]], "text": "major cardiac arrhythmia"}, {"id": "T7", "type": "OtherOutcome", "offsets": [[479, 518]], "text": "use of haemodialysis or haemofiltration"}, {"id": "T8", "type": "OtherOutcome", "offsets": [[703, 738]], "text": "suspected serious adverse reactions"}, {"id": "T9", "type": "OtherOutcome", "offsets": [[573, 608]], "text": "receipt and duration of ventilation"}, {"id": "T10", "type": "TimeFrame", "offsets": [[133, 139]], "text": "28-day"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T3", "arg2": "T1"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T4", "arg2": "T1"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T2", "arg2": "T10"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T5", "arg2": "T1"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T7", "arg2": "T1"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T6", "arg2": "T1"}, {"id": "R7", "type": "MeasuredAt", "arg1": "T9", "arg2": "T1"}, {"id": "R8", "type": "MeasuredAt", "arg1": "T8", "arg2": "T1"}]}
{"id": "101", "type": "silver", "text": "Outcomes\n\nThe primary clinical endpoint was the necessity for intubation and invasive mechanical ventilation. Secondary outcomes were time of invasive mechanical ventilation, admission to the ICU, length of ICU stay, and mortality.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[48, 108]], "text": "necessity for intubation and invasive mechanical ventilation"}, {"id": "T2", "type": "SecondaryOutcome", "offsets": [[134, 173]], "text": "time of invasive mechanical ventilation"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[175, 195]], "text": "admission to the ICU"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[197, 215]], "text": "length of ICU stay"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[221, 230]], "text": "mortality"}], "relations": []}
{"id": "102", "type": "silver", "text": " Outcomes\n\nThe primary outcome was a composite of mechanical ventilation, hospitalization >14 days or in-hospital death.\n\nSecondary outcomes included: days of mechanical ventilation, days of high-flow nasal cannula (HFNC), days of oxygen requirement, time to respiratory failure development (PaO2/FiO2<200), the severity of multiple organ dysfunction (by SOFA score) at day 3 and 7; days in ICU or intermediate care unit, hospital length of stay, and mortality at 30 days. The kinetics of inflammatory biomarkers, including total lymphocyte count, C-reactive protein (CRP), procalcitonin, LDH, D-dimer, ferritin and IL-6 were determined on days 0, 3 and 7; and SARS-CoV-2 RT-PCR in nasopharyngeal swab on days 3 and 7.\n\nRadiological outcomes included the comparison of infiltrates progression on chest CT scans on enrollment and day 5, based on COVID-19 pneumonia severity scores[20–23]. For the combined analysis with portable chest X-rays, a blinded thoracic radiologist expert categorized images as “progression” vs “stable or improved”.\n\nAlso, pre-planned analyses of baseline neutralizing antibodies (NAbs) titers, and anti-SARS-CoV-2 IgG titers were determined in participants from the early plasma group and in the subset of participants from the deferred plasma group who had not yet received plasma on days 0, 3 and 7.\n\nAnalysis of the primary outcome and clinical secondary outcomes was performed by intention-to-treat (ITT). Laboratory and radiology secondary outcomes were analyzed by modified-ITT, excluding a patient who withdrew consent before any intervention.\n\nSafety outcomes were evaluated in all participants.", "entities": [{"id": "T2", "type": "SecondaryOutcome", "offsets": [[151, 181]], "text": "days of mechanical ventilation"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[183, 221]], "text": "days of high-flow nasal cannula (HFNC)"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[223, 249]], "text": "days of oxygen requirement"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[251, 306]], "text": "time to respiratory failure development (PaO2/FiO2<200)"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[312, 366]], "text": "severity of multiple organ dysfunction (by SOFA score)"}, {"id": "T7", "type": "TimeFrame", "offsets": [[367, 381]], "text": "at day 3 and 7"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[383, 421]], "text": "days in ICU or intermediate care unit,"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[422, 445]], "text": "hospital length of stay"}, {"id": "T1", "type": "PrimaryOutcome", "offsets": [[50, 119]], "text": "mechanical ventilation, hospitalization >14 days or in-hospital death"}, {"id": "T10", "type": "SecondaryOutcome", "offsets": [[451, 460]], "text": "mortality"}, {"id": "T11", "type": "TimeFrame", "offsets": [[461, 471]], "text": "at 30 days"}, {"id": "T12", "type": "SecondaryOutcome", "offsets": [[755, 810]], "text": "comparison of infiltrates progression on chest CT scans"}, {"id": "T13", "type": "TimeFrame", "offsets": [[811, 834]], "text": "on enrollment and day 5"}, {"id": "T14", "type": "UnclearOutcome", "offsets": [[1081, 1118]], "text": "neutralizing antibodies (NAbs) titers"}, {"id": "T15", "type": "UnclearOutcome", "offsets": [[1124, 1150]], "text": "anti-SARS-CoV-2 IgG titers"}, {"id": "T16", "type": "TimeFrame", "offsets": [[1311, 1326]], "text": "days 0, 3 and 7"}, {"id": "T17", "type": "SecondaryOutcome", "offsets": [[524, 546]], "text": "total lymphocyte count"}, {"id": "T18", "type": "SecondaryOutcome", "offsets": [[548, 572]], "text": "C-reactive protein (CRP)"}, {"id": "T19", "type": "SecondaryOutcome", "offsets": [[574, 587]], "text": "procalcitonin"}, {"id": "T20", "type": "SecondaryOutcome", "offsets": [[589, 592]], "text": "LDH"}, {"id": "T21", "type": "SecondaryOutcome", "offsets": [[594, 601]], "text": "D-dimer"}, {"id": "T22", "type": "SecondaryOutcome", "offsets": [[603, 611]], "text": "ferritin"}, {"id": "T23", "type": "SecondaryOutcome", "offsets": [[616, 620]], "text": "IL-6"}, {"id": "T24", "type": "TimeFrame", "offsets": [[637, 655]], "text": "on days 0, 3 and 7"}, {"id": "T25", "type": "SecondaryOutcome", "offsets": [[661, 678]], "text": "SARS-CoV-2 RT-PCR"}, {"id": "T26", "type": "TimeFrame", "offsets": [[702, 717]], "text": "on days 3 and 7"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T6", "arg2": "T7"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T10", "arg2": "T11"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T12", "arg2": "T13"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T14", "arg2": "T16"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T15", "arg2": "T16"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T2", "arg2": "T7"}, {"id": "R7", "type": "MeasuredAt", "arg1": "T3", "arg2": "T7"}, {"id": "R8", "type": "MeasuredAt", "arg1": "T4", "arg2": "T7"}, {"id": "R9", "type": "MeasuredAt", "arg1": "T5", "arg2": "T7"}, {"id": "R10", "type": "MeasuredAt", "arg1": "T8", "arg2": "T11"}, {"id": "R11", "type": "MeasuredAt", "arg1": "T9", "arg2": "T11"}, {"id": "R12", "type": "MeasuredAt", "arg1": "T17", "arg2": "T24"}, {"id": "R13", "type": "MeasuredAt", "arg1": "T18", "arg2": "T24"}, {"id": "R14", "type": "MeasuredAt", "arg1": "T19", "arg2": "T24"}, {"id": "R15", "type": "MeasuredAt", "arg1": "T20", "arg2": "T24"}, {"id": "R16", "type": "MeasuredAt", "arg1": "T21", "arg2": "T24"}, {"id": "R17", "type": "MeasuredAt", "arg1": "T22", "arg2": "T24"}, {"id": "R18", "type": "MeasuredAt", "arg1": "T23", "arg2": "T24"}, {"id": "R19", "type": "MeasuredAt", "arg1": "T25", "arg2": "T26"}]}
{"id": "103", "type": "silver", "text": "Outcomes\n\nThe primary outcome was the cumulative lung lesion remission rate (lung CT examination indicated absorption of lung inflammation). Secondary outcomes were the improvement of clinical symptoms (cough, diarrhea, dyspnea, fever, myalgia) before and after treatment; the changes of blood routine test and IL-6; changes of oxygen therapy. In addition, we also analyzed the peripheral blood T lymphocyte subsets (count and proportion) before and after treatment. Safety endpoints were the frequencies of adverse events in each group.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[38, 75]], "text": "cumulative lung lesion remission rate"}, {"id": "T2", "type": "OutcomeDefinition", "offsets": [[77, 138]], "text": "lung CT examination indicated absorption of lung inflammation"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[169, 244]], "text": "improvement of clinical symptoms (cough, diarrhea, dyspnea, fever, myalgia)"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[273, 315]], "text": "the changes of blood routine test and IL-6"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[317, 342]], "text": "changes of oxygen therapy"}, {"id": "T6", "type": "TimeFrame", "offsets": [[245, 271]], "text": "before and after treatment"}, {"id": "T7", "type": "OtherOutcome", "offsets": [[378, 438]], "text": "peripheral blood T lymphocyte subsets (count and proportion)"}, {"id": "T8", "type": "TimeFrame", "offsets": [[439, 465]], "text": "before and after treatment"}, {"id": "T9", "type": "OtherOutcome", "offsets": [[493, 522]], "text": "frequencies of adverse events"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T3", "arg2": "T6"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T7", "arg2": "T8"}]}
{"id": "104", "type": "silver", "text": " Outcomes\n\nThe primary outcome was the variation in gas exchange over time evaluated through the ratio of partial pressure of arterial oxygen (PaO2) to the fraction of inspired oxygen (FiO2) at baseline, 7, and 14 days after randomization. This ratio was blindly calculated using the result of the arterial blood gas (ABG) analysis collected routinely around 6:00 am.\n\nThe secondary outcomes were the time until successful liberation from mechanical ventilation, the ventilator-free days (during the 28 days after inclusion in the study; numbers of days without mechanical ventilation), the variation in D-dimer levels collected at baseline during inclusion in the study and repeated 72–96 h later, all-cause 28-day mortality, in-hospital mortality, and the intensive care unit (ICU)-free days at 28 days.\n\nTo determine the successful liberation from mechanical ventilation, we considered the maintenance of spontaneous ventilation without the need for invasive mechanical ventilation support for a minimum of 72 h. All patients received the lung-protective ventilation strategy with low tidal volume. Each unit used its ventilator liberation protocol. The patients underwent prone positioning of at least 16 h if PaO2/FiO2 ratio < 150 mmHg. Other ventilator adjuncts to improve oxygenation in the setting of severe ARDS, such as inhaled nitric oxide and extracorporeal membrane oxygenation, were not available in our service.\n\nThe D-dimer measurement was performed through the automated assay VIDAS® D-dimer Exclusion II™ (bioMérieux SA, Lyon, France) with a cutoff of 500 μg/L.\n\nThe safety outcome analyzed was the occurrence of bleeding using the Thrombolysis in Myocardial Infarction (TIMI) bleeding criteria, which classified the bleeding in major, minor and requiring medical attention [14]", "entities": [{"id": "T2", "type": "TimeFrame", "offsets": [[191, 238]], "text": "at baseline, 7, and 14 days after randomization"}, {"id": "T1", "type": "PrimaryOutcome", "offsets": [[39, 74]], "text": "variation in gas exchange over time"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[75, 190]], "text": "evaluated through the ratio of partial pressure of arterial oxygen (PaO2) to the fraction of inspired oxygen (FiO2)"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[401, 461]], "text": "time until successful liberation from mechanical ventilation"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[467, 487]], "text": "ventilator-free days"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[591, 618]], "text": "variation in D-dimer levels"}, {"id": "T8", "type": "TimeFrame", "offsets": [[629, 697]], "text": "at baseline during inclusion in the study and repeated 72–96 h later"}, {"id": "T6", "type": "TimeFrame", "offsets": [[489, 536]], "text": "during the 28 days after inclusion in the study"}, {"id": "T9", "type": "OutcomeDefinition", "offsets": [[538, 584]], "text": "numbers of days without mechanical ventilation"}, {"id": "T10", "type": "SecondaryOutcome", "offsets": [[699, 725]], "text": "all-cause 28-day mortality"}, {"id": "T11", "type": "SecondaryOutcome", "offsets": [[727, 748]], "text": "in-hospital mortality"}, {"id": "T12", "type": "SecondaryOutcome", "offsets": [[758, 793]], "text": "intensive care unit (ICU)-free days"}, {"id": "T13", "type": "TimeFrame", "offsets": [[794, 804]], "text": "at 28 days"}, {"id": "T14", "type": "OutcomeDefinition", "offsets": [[893, 1014]], "text": "maintenance of spontaneous ventilation without the need for invasive mechanical ventilation support for a minimum of 72 h"}, {"id": "T15", "type": "OtherOutcome", "offsets": [[1617, 1639]], "text": "occurrence of bleeding"}, {"id": "T16", "type": "OutcomeDefinition", "offsets": [[1650, 1791]], "text": "Thrombolysis in Myocardial Infarction (TIMI) bleeding criteria, which classified the bleeding in major, minor and requiring medical attention"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T5", "arg2": "T6"}, {"id": "R4", "type": "DefinedAs", "arg1": "T5", "arg2": "T9"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T7", "arg2": "T8"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T12", "arg2": "T13"}, {"id": "R7", "type": "DefinedAs", "arg1": "T4", "arg2": "T14"}, {"id": "R8", "type": "DefinedAs", "arg1": "T15", "arg2": "T16"}, {"id": "R9", "type": "MeasuredAt", "arg1": "T11", "arg2": "T13"}, {"id": "R10", "type": "MeasuredAt", "arg1": "T10", "arg2": "T13"}]}
{"id": "105", "type": "silver", "text": " End points\n\nThe primary endpoints were the achievement of two successive negative SARS-CoV-2 PCR analysis tests 48 h apart by nasopharyngeal swab, normalization of body temperature for 48 h, improvement of radiological abnormalities at Day 14 and the hospital discharge rate. The secondary endpoints were the normalization of C-reactive protein (CRP) and serum ferritin levels.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[44, 112]], "text": "achievement of two successive negative SARS-CoV-2 PCR analysis tests"}, {"id": "T2", "type": "PrimaryOutcome", "offsets": [[148, 181]], "text": "normalization of body temperature"}, {"id": "T3", "type": "PrimaryOutcome", "offsets": [[192, 233]], "text": "improvement of radiological abnormalities"}, {"id": "T4", "type": "PrimaryOutcome", "offsets": [[252, 275]], "text": "hospital discharge rate"}, {"id": "T5", "type": "TimeFrame", "offsets": [[113, 123]], "text": "48 h apart"}, {"id": "T6", "type": "TimeFrame", "offsets": [[182, 190]], "text": "for 48 h"}, {"id": "T7", "type": "TimeFrame", "offsets": [[234, 243]], "text": "at Day 14"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[310, 351]], "text": "normalization of C-reactive protein (CRP)"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[356, 377]], "text": "serum ferritin levels"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T5"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T2", "arg2": "T6"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T3", "arg2": "T7"}]}
{"id": "106", "type": "silver", "text": "Outcomes\n 2.8.1. Primary outcome\n\nThe primary endpoint was time to clinical improvement, defined as the days from randomization until normalization. Clinical improvement was assessed by five components including body temperature, respiratory rate, oxygen saturation, alleviation of cough, and absorption of pulmonary infection by chest CT. Normalization was defined as body temperature < 37.0 °C, respiratory rate < 24 times per minute indoors, and oxygen saturation > 94% (fingertip). Alleviation of cough was defined as a reduced severity of cough from a physician-reported scale of severe or moderate to mild condition or absence. Absorption of pulmonary infection was defined as an absorption area > 2/3 by Digital Imaging and Communications in Medicine (DICOM) images on chest CT. Alleviation of these five clinical symptoms were required to stay normal for at least 72 h on all components to fulfill the primary endpoint of clinical improvement.\n 2.8.2. Secondary outcomes\n\nPrespecified secondary outcomes included clinical improvement rate, median time and proportion of defervescence, mean time and proportion of significant inflammatory absorption of lung lesions, a negative conversion rate of the viral nucleic acid test, mortality at day 28, and the conversion from mild or ordinary to severe or critical severe status. The diagnosis and classification of mild, ordinary, severe, and critical severe conditions of this disease were set according to Chinese guidelines for COVID-19 [4], [12].\n\nDefervescence time was defined as the days from randomization to a temperature less than 37.0 °C maintained for at least 24 or 72 h. A throat swab viral nucleic acid test was repeated after 48 h following a negative test result. The conversion rate in severe and critical severe subjects was assessed with a six-point scale. The patient being discharged from the hospital or the score decreasing by two points from the baseline was considered to be conversion.\n 2.8.3. Exploratory outcomes\n\nThe exploratory outcomes were changes in laboratory indicators, including routine blood test, C-reactive protein (CRP), coagulation function, myocardial enzymes, and hepatic and renal functions. The recovery rates of the above indicators from abnormal to normal were also calculated.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[59, 87]], "text": "time to clinical improvement"}, {"id": "T2", "type": "OutcomeDefinition", "offsets": [[100, 147]], "text": "the days from randomization until normalization"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[212, 338]], "text": "body temperature, respiratory rate, oxygen saturation, alleviation of cough, and absorption of pulmonary infection by chest CT"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[1021, 1046]], "text": "clinical improvement rate"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[1048, 1091]], "text": "median time and proportion of defervescence"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[1093, 1172]], "text": "mean time and proportion of significant inflammatory absorption of lung lesions"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[1176, 1231]], "text": "negative conversion rate of the viral nucleic acid test"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[1233, 1242]], "text": "mortality"}, {"id": "T9", "type": "TimeFrame", "offsets": [[1243, 1252]], "text": "at day 28"}, {"id": "T10", "type": "SecondaryOutcome", "offsets": [[1262, 1330]], "text": "conversion from mild or ordinary to severe or critical severe status"}, {"id": "T11", "type": "OutcomeDefinition", "offsets": [[1543, 1636]], "text": "days from randomization to a temperature less than 37.0 °C maintained for at least 24 or 72 h"}, {"id": "T12", "type": "TimeFrame", "offsets": [[1680, 1732]], "text": "repeated after 48 h following a negative test result"}, {"id": "T14", "type": "OtherOutcome", "offsets": [[2026, 2189]], "text": "changes in laboratory indicators, including routine blood test, C-reactive protein (CRP), coagulation function, myocardial enzymes, and hepatic and renal functions"}, {"id": "T13", "type": "OutcomeDefinition", "offsets": [[1448, 1492]], "text": "according to Chinese guidelines for COVID-19"}, {"id": "T15", "type": "OutcomeDefinition", "offsets": [[1834, 1932]], "text": "patient being discharged from the hospital or the score decreasing by two points from the baseline"}, {"id": "T16", "type": "OutcomeDefinition", "offsets": [[1738, 1828]], "text": "conversion rate in severe and critical severe subjects was assessed with a six-point scale"}, {"id": "T17", "type": "OtherOutcome", "offsets": [[2195, 2257]], "text": "recovery rates of the above indicators from abnormal to normal"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T8", "arg2": "T9"}, {"id": "R4", "type": "DefinedAs", "arg1": "T5", "arg2": "T11"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T7", "arg2": "T12"}, {"id": "R6", "type": "DefinedAs", "arg1": "T10", "arg2": "T13"}, {"id": "R7", "type": "DefinedAs", "arg1": "T4", "arg2": "T15"}, {"id": "R8", "type": "DefinedAs", "arg1": "T10", "arg2": "T16"}]}
{"id": "107", "type": "silver", "text": " Primary clinical outcome\nThere was a significant difference in the 28-day mortality, no patient died (0%) in the treatment group, while five patients died (12.8%) in the standard group; P= 0.027 (Fig. 3). Among patients in the treatment arm with bromhexine, two patients were admitted to ICU (5.1%) while in the standard arm, eleven patients (28.2%) were transferred to ICU. There was a significant difference in the ICU admission between the treatment and the standard group (P = 0.006). Moreover, among patients in bromhexine arm, one patient received mechanical ventilation (2.6%), while in the standard arm nine patients (23.1%) were intubated and underwent mechanical ventilation. There was also a highly significant difference in the intubation and mechanical ventilation between the two groups (P = 0.007) as shown in Table 2.\nSecondary clinical outcomes\nThere was also a significant difference in the secondary outcome of this study (Fig. 4). Improvement of cardinal respiratory symptoms such as cough and dyspnea within two weeks among the two groups were assessed:\nDyspnea remained in 3.4% in the treatment group vs 48.3% in the standard group P ≤ 0.001 and cough remained in the treatment group 6.9% vs 40.0% in the standard group, P = 0.003). Similar results for lassitude between the two groups were observed (6.9% vs 34.5%, P = 0.010). At baseline, there was no significant difference in the frequency of fever, headache, and gastrointestinal symptoms between the two groups.\nThe patients in the bromhexine group showed improvement in the level of LDH (363.2±83.6 vs. 445.3±115.2; P = 0.056), NLR [1.7 (1.0) vs. 3.0 (6.3); P=0.052] and CRP [0% vs. 81.8%; P < 0.001)] within two weeks compared to the standard group (Table 2).\nThere was no significant difference in the length of stay in the hospital [from randomization to discharge] between the two groups (treatment 7.6±3.5 days and standard 8.1±5.5 days; P = 0.587).", "entities": [{"id": "T2", "type": "SecondaryOutcome", "offsets": [[952, 1022]], "text": "Improvement of cardinal respiratory symptoms such as cough and dyspnea"}, {"id": "T3", "type": "TimeFrame", "offsets": [[1023, 1039]], "text": "within two weeks"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[1276, 1285]], "text": "lassitude"}, {"id": "T1", "type": "PrimaryOutcome", "offsets": [[75, 84]], "text": "mortality"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[1420, 1425]], "text": "fever"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[1427, 1435]], "text": "headache"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[1441, 1466]], "text": "gastrointestinal symptoms"}, {"id": "T10", "type": "SecondaryOutcome", "offsets": [[1535, 1566]], "text": "improvement in the level of LDH"}, {"id": "T11", "type": "SecondaryOutcome", "offsets": [[1651, 1654]], "text": "CRP"}, {"id": "T12", "type": "SecondaryOutcome", "offsets": [[1608, 1611]], "text": "NLR"}, {"id": "T13", "type": "TimeFrame", "offsets": [[1682, 1698]], "text": "within two weeks"}, {"id": "T15", "type": "SecondaryOutcome", "offsets": [[1784, 1814]], "text": "length of stay in the hospital"}, {"id": "T16", "type": "TimeFrame", "offsets": [[1815, 1848]], "text": "[from randomization to discharge]"}, {"id": "T14", "type": "TimeFrame", "offsets": [[68, 74]], "text": "28-day"}, {"id": "T17", "type": "PrimaryOutcome", "offsets": [[418, 431]], "text": "ICU admission"}, {"id": "T5", "type": "PrimaryOutcome", "offsets": [[741, 778]], "text": "intubation and mechanical ventilation"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T2", "arg2": "T3"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T10", "arg2": "T13"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T12", "arg2": "T13"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T11", "arg2": "T13"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T15", "arg2": "T16"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T1", "arg2": "T14"}]}
{"id": "108", "type": "silver", "text": " Outcomes\n\nThe primary endpoint was the timing to achieve viral RNA negative conversion for SARS-CoV-2 in all three specimens, including nasopharyngeal swabs, throat swabs and stool swabs. When a COVID-19 patient was discharged from hospital, the viral RNA negative conversion of all three specimens needed to be considered. The secondary clinical endpoint was the timing when CT imaging improvement was observed, which was mainly based on the size and density reduction of lesions. Safety data included adverse events during treatment, severe adverse events, and premature discontinuation of treatment. Adverse events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 [23].", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[40, 187]], "text": "timing to achieve viral RNA negative conversion for SARS-CoV-2 in all three specimens, including nasopharyngeal swabs, throat swabs and stool swabs"}, {"id": "T2", "type": "SecondaryOutcome", "offsets": [[365, 399]], "text": "timing when CT imaging improvement"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[424, 481]], "text": "mainly based on the size and density reduction of lesions"}, {"id": "T4", "type": "OtherOutcome", "offsets": [[504, 535]], "text": "adverse events during treatment"}, {"id": "T5", "type": "OtherOutcome", "offsets": [[537, 558]], "text": "severe adverse events"}, {"id": "T6", "type": "OtherOutcome", "offsets": [[564, 602]], "text": "premature discontinuation of treatment"}, {"id": "T7", "type": "OutcomeDefinition", "offsets": [[624, 724]], "text": "classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T2", "arg2": "T3"}, {"id": "R2", "type": "DefinedAs", "arg1": "T4", "arg2": "T7"}]}
{"id": "11", "type": "gold", "text": "Main outcome measure Negative conversion of severe acute respiratory syndrome coronavirus 2 by 28 days, analysed according to the intention to treat principle. Adverse events were analysed in the safety population in which hydroxychloroquine recipients were participants who received at least one dose of hydroxychloroquine and hydroxychloroquine non-recipients were those managed with standard of care alone.\n\nOutcome\n\nThe primary outcomes for this trial were whether patients had negative conversion of SARS-CoV-2 by 28 days and whether patients with severe covid-19 had clinical improvement by 28 days. However, as the trial was stopped early and only two patients with severe disease were enrolled, results on clinical improvement are not presented. We defined negative conversion of SARS-CoV-2 as two consecutive reports of a negative result for SARS-CoV-2 at least 24 hours apart without a subsequent report of a positive result by the end of the study. We considered the date of the first negative report as the date of negative conversion. In the original protocol, the primary endpoint was prespecified as the “Negative conversion rate by Day 10” (approved by the ethics committee on 6 February 2020). However, with the increasing knowledge of covid-19 from our clinical practice, we realised that the duration of SARS-CoV-2 in respiratory samples of many patients was longer than 10 days, recently highlighted by a detailed virological study.14 We therefore modified our primary outcome to test whether patients had a negative conversion of SARS-CoV-2 by 28 days (approved by the ethics committee on 17 February 2020). Probability of negative conversion at day 4, 7, 10, 14, or 21 was specified as a secondary outcome in the protocol, but this does not appear on the trial registration list. The listed secondary outcome in the trial registration was adverse events coded using the latest version of Medical Dictionary for Regulatory Activities coding dictionary, recorded in standard medical terminology and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events.\n\nOther prespecified secondary outcomes not listed in the trial registration but included in the protocol were the probabilities of alleviation of clinical symptoms; improvement of C reactive protein, erythrocyte sedimentation rate, tumour necrosis factor α, interleukin 6, and absolute blood lymphocyte count; improvement of lung lesions on chest radiology; all cause death; and disease progression in patients with mild to moderate disease. The time frame for these secondary outcomes was from randomisation to 28 days. Prespecified secondary outcomes for patients with severe disease are not listed here but are included in the protocol. Owing to the early termination of our study, we could not justify the results from these analyses with an underpowered sample size and therefore decided not to emphasise them in this paper to avoid misinterpretation. The only one presented here is the alleviation of clinical symptoms within 28 days, which is an important outcome of interest prespecified in our protocol. The definition of the alleviation of clinical symptoms was resolving from fever to an axillary temperature of 36.6°C or below, normalisation of SpO2 (>94% on room air), and disappearance of respiratory symptoms including nasal congestion, cough, sore throat, sputum production, and shortness of breath.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[482, 515]], "text": "negative conversion of SARS-CoV-2"}, {"id": "T2", "type": "PrimaryOutcome", "offsets": [[573, 593]], "text": "clinical improvement"}, {"id": "T4", "type": "TimeFrame", "offsets": [[594, 604]], "text": "by 28 days"}, {"id": "T5", "type": "OutcomeDefinition", "offsets": [[802, 958]], "text": "two consecutive reports of a negative result for SARS-CoV-2 at least 24 hours apart without a subsequent report of a positive result by the end of the study"}, {"id": "T6", "type": "PrimaryOutcome", "offsets": [[1120, 1144]], "text": "Negative conversion rate"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[1629, 1663]], "text": "Probability of negative conversion"}, {"id": "T7", "type": "TimeFrame", "offsets": [[1664, 1690]], "text": "at day 4, 7, 10, 14, or 21"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[1861, 1875]], "text": "adverse events"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[2231, 2280]], "text": "probabilities of alleviation of clinical symptoms"}, {"id": "T10", "type": "SecondaryOutcome", "offsets": [[2282, 2315]], "text": "improvement of C reactive protein"}, {"id": "T11", "type": "SecondaryOutcome", "offsets": [[2317, 2347]], "text": "erythrocyte sedimentation rate"}, {"id": "T12", "type": "SecondaryOutcome", "offsets": [[2349, 2373]], "text": "tumour necrosis factor α"}, {"id": "T13", "type": "SecondaryOutcome", "offsets": [[2375, 2388]], "text": "interleukin 6"}, {"id": "T14", "type": "SecondaryOutcome", "offsets": [[2394, 2425]], "text": "absolute blood lymphocyte count"}, {"id": "T15", "type": "SecondaryOutcome", "offsets": [[2427, 2473]], "text": "improvement of lung lesions on chest radiology"}, {"id": "T16", "type": "SecondaryOutcome", "offsets": [[2475, 2490]], "text": "all cause death"}, {"id": "T17", "type": "SecondaryOutcome", "offsets": [[2496, 2557]], "text": "disease progression in patients with mild to moderate disease"}, {"id": "T18", "type": "TimeFrame", "offsets": [[2607, 2636]], "text": "from randomisation to 28 days"}, {"id": "T19", "type": "SecondaryOutcome", "offsets": [[3009, 3041]], "text": "alleviation of clinical symptoms"}, {"id": "T20", "type": "TimeFrame", "offsets": [[3042, 3056]], "text": "within 28 days"}, {"id": "T21", "type": "OutcomeDefinition", "offsets": [[3189, 3431]], "text": "resolving from fever to an axillary temperature of 36.6°C or below, normalisation of SpO2 (>94% on room air), and disappearance of respiratory symptoms including nasal congestion, cough, sore throat, sputum production, and shortness of breath"}, {"id": "T22", "type": "TimeFrame", "offsets": [[516, 526]], "text": "by 28 days"}, {"id": "T23", "type": "TimeFrame", "offsets": [[1145, 1154]], "text": "by Day 10"}, {"id": "T24", "type": "OutcomeDefinition", "offsets": [[1876, 2115]], "text": "coded using the latest version of Medical Dictionary for Regulatory Activities coding dictionary, recorded in standard medical terminology and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events"}, {"id": "T25", "type": "PrimaryOutcome", "offsets": [[1528, 1561]], "text": "negative conversion of SARS-CoV-2"}, {"id": "T26", "type": "TimeFrame", "offsets": [[1562, 1572]], "text": "by 28 days"}, {"id": "T27", "type": "PrimaryOutcome", "offsets": [[21, 91]], "text": "Negative conversion of severe acute respiratory syndrome coronavirus 2"}, {"id": "T28", "type": "TimeFrame", "offsets": [[92, 102]], "text": "by 28 days"}, {"id": "T29", "type": "OtherOutcome", "offsets": [[160, 174]], "text": "Adverse events"}], "relations": [{"id": "R2", "type": "MeasuredAt", "arg1": "T2", "arg2": "T4"}, {"id": "R3", "type": "DefinedAs", "arg1": "T1", "arg2": "T5"}, {"id": "R1", "type": "MeasuredAt", "arg1": "T3", "arg2": "T7"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T8", "arg2": "T18"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T9", "arg2": "T18"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T10", "arg2": "T18"}, {"id": "R7", "type": "MeasuredAt", "arg1": "T11", "arg2": "T18"}, {"id": "R8", "type": "MeasuredAt", "arg1": "T12", "arg2": "T18"}, {"id": "R9", "type": "MeasuredAt", "arg1": "T13", "arg2": "T18"}, {"id": "R10", "type": "MeasuredAt", "arg1": "T14", "arg2": "T18"}, {"id": "R11", "type": "MeasuredAt", "arg1": "T15", "arg2": "T18"}, {"id": "R12", "type": "MeasuredAt", "arg1": "T16", "arg2": "T18"}, {"id": "R13", "type": "MeasuredAt", "arg1": "T17", "arg2": "T18"}, {"id": "R14", "type": "MeasuredAt", "arg1": "T19", "arg2": "T20"}, {"id": "R15", "type": "DefinedAs", "arg1": "T19", "arg2": "T21"}, {"id": "R16", "type": "MeasuredAt", "arg1": "T1", "arg2": "T22"}, {"id": "R17", "type": "MeasuredAt", "arg1": "T6", "arg2": "T23"}, {"id": "R18", "type": "DefinedAs", "arg1": "T8", "arg2": "T24"}, {"id": "R19", "type": "MeasuredAt", "arg1": "T25", "arg2": "T26"}, {"id": "R20", "type": "MeasuredAt", "arg1": "T27", "arg2": "T28"}]}
{"id": "116", "type": "gold", "text": "Study arms and treatment plans\n\nPatients were randomly divided into two treatment groups, a case group comprising 56 patients and a control group comprising 55 patients. On the first day of admission, laboratory studies including complete blood count and erythrocyte sedimentation rate (ESR) were performed. The case group received oral AZM 500 mg daily, oral LPV/r 400/100 mg twice daily and oral HCQ 400 mg daily. The control group received oral LPV/r 400/100 mg twice daily and oral HCQ 400 mg daily; for both treatment groups, all medications were administered for 5 days.\n\nOn the first day of admission, for patients assigned to the case treatment group, the risk for ventricular arrhythmia in concurrent treatment with HCQ and AZM was calculated based on the proposed guideline by the ACC [23], and patients with a score of ≥7 were excluded from the study.\n\nPatients were assessed by daily measurements of core body temperature, respiratory rate, heart rate and peripheral capillary oxygen saturation (SpO2). Daily electrocardiogram (ECG) studies were also conducted to monitor possible evolution of heart rate-corrected QT (QTc) interval prolongation, in which case, treatment with AZM and HCQ would have been stopped. For correction of the QT interval, Bazett's formula (QTc = QT/√RR) was used [24]. In case of deterioration in general and/or pulmonary condition, methylprednisolone was prescribed [25]. Patients were discharged when they achieved a stable SpO2 > 92%, had no respiratory distress and were afebrile for 3 consecutive days. The primary endpoints in this trial were a decrease in mortality, duration of hospitalisation and need for intensive care unit (ICU) admission. Secondary endpoints were determined as improvements in SpO2 and vital signs as well as the general wellbeing of the patient.\n\nSample size calculation was performed for non-inferiority tests of difference between two group proportions. We assumed an effectiveness of 65% for the intervention group and effectiveness of 50% for the control group. We also assumed a margin of non-inferiority of at least 10% between the two groups. With these assumptions, a sample size of 48 cases in each group was calculated. After consideration of a dropout rate of 10%, the total sample size of 110 cases was calculated. The power of the study was determined as 90% (G*Power, Erdfelder, Faul, & Buchner, 1996).", "entities": [{"id": "T1", "type": "OtherOutcome", "offsets": [[230, 250]], "text": "complete blood count"}, {"id": "T2", "type": "OtherOutcome", "offsets": [[255, 291]], "text": "erythrocyte sedimentation rate (ESR)"}, {"id": "T3", "type": "OtherOutcome", "offsets": [[664, 695]], "text": "risk for ventricular arrhythmia"}, {"id": "T4", "type": "OutcomeDefinition", "offsets": [[741, 861]], "text": "calculated based on the proposed guideline by the ACC [23], and patients with a score of ≥7 were excluded from the study"}, {"id": "T5", "type": "OtherOutcome", "offsets": [[912, 933]], "text": "core body temperature"}, {"id": "T6", "type": "OtherOutcome", "offsets": [[935, 951]], "text": "respiratory rate"}, {"id": "T7", "type": "OtherOutcome", "offsets": [[953, 963]], "text": "heart rate"}, {"id": "T8", "type": "OtherOutcome", "offsets": [[968, 1013]], "text": "peripheral capillary oxygen saturation (SpO2)"}, {"id": "T9", "type": "TimeFrame", "offsets": [[890, 908]], "text": "daily measurements"}, {"id": "T10", "type": "OtherOutcome", "offsets": [[1021, 1044]], "text": "electrocardiogram (ECG)"}, {"id": "T11", "type": "TimeFrame", "offsets": [[1015, 1020]], "text": "Daily"}, {"id": "T12", "type": "OutcomeDefinition", "offsets": [[1093, 1157]], "text": "evolution of heart rate-corrected QT (QTc) interval prolongation"}, {"id": "T13", "type": "PrimaryOutcome", "offsets": [[1590, 1611]], "text": "decrease in mortality"}, {"id": "T14", "type": "PrimaryOutcome", "offsets": [[1613, 1640]], "text": "duration of hospitalisation"}, {"id": "T15", "type": "PrimaryOutcome", "offsets": [[1645, 1689]], "text": "need for intensive care unit (ICU) admission"}, {"id": "T16", "type": "SecondaryOutcome", "offsets": [[1730, 1766]], "text": "improvements in SpO2 and vital signs"}, {"id": "T17", "type": "SecondaryOutcome", "offsets": [[1782, 1814]], "text": "general wellbeing of the patient"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T3", "arg2": "T4"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T5", "arg2": "T9"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T6", "arg2": "T9"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T7", "arg2": "T9"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T8", "arg2": "T9"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T10", "arg2": "T11"}, {"id": "R7", "type": "DefinedAs", "arg1": "T10", "arg2": "T12"}]}
{"id": "117", "type": "gold", "text": " Outcome measures\nThe primary outcome of this study was the rate of hospitalization. Secondary outcomes were clinical improvements (e.g., resolution of fever, cough and dyspnea) and improvement of CT findings at days 14 after initiation of the treatment. Patients were assessed clinically (e.g., temperature, respiratory rate, cough, and dyspnea) and paraclinically (e.g., CBC-diff and C-Reactive Protein) at onset of admission and 5th day of treatment. In addition, the chest CT scans were done at first and 14 days after the onset of treatment. For each patient, the chest CT scan was evaluated for the presence of groundglass opacities and/or consolidation. Each five lobe of the lung was assessed and the overall lung involvement was reached by summing the five lobe scores (range of possible scores, 0 – 20 for each lobe and total lung involvement of possible score of 0-100 percent). The Chest CT was repeated in day 14 and compared with the initial finding. Reduced lung CT involvement; not adjusted\" values were computed according to this equation:\nReduced Lung CT involvement, not adjusted =\nDay 14 total long involvement – Initial total lung involvement\nReduced lung CT involvement; adjusted values was computed with the following equation that included the initial total lung involvement in the denominator:\nReduced lung CT involvement; adjusted value = (Initial total long involvement ― Day 14 total long involvement)\nInitial total lung involvement", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[60, 83]], "text": "rate of hospitalization"}, {"id": "T2", "type": "SecondaryOutcome", "offsets": [[109, 177]], "text": "clinical improvements (e.g., resolution of fever, cough and dyspnea)"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[182, 208]], "text": "improvement of CT findings"}, {"id": "T4", "type": "TimeFrame", "offsets": [[209, 253]], "text": "at days 14 after initiation of the treatment"}, {"id": "T5", "type": "OutcomeDefinition", "offsets": [[569, 659]], "text": "chest CT scan was evaluated for the presence of groundglass opacities and/or consolidation"}, {"id": "T6", "type": "TimeFrame", "offsets": [[406, 452]], "text": "at onset of admission and 5th day of treatment"}, {"id": "T7", "type": "OutcomeDefinition", "offsets": [[661, 888]], "text": "Each five lobe of the lung was assessed and the overall lung involvement was reached by summing the five lobe scores (range of possible scores, 0 – 20 for each lobe and total lung involvement of possible score of 0-100 percent)"}, {"id": "T8", "type": "TimeFrame", "offsets": [[916, 925]], "text": "in day 14"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T2", "arg2": "T4"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T3", "arg2": "T4"}, {"id": "R3", "type": "DefinedAs", "arg1": "T3", "arg2": "T5"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T2", "arg2": "T6"}, {"id": "R5", "type": "DefinedAs", "arg1": "T3", "arg2": "T7"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T3", "arg2": "T8"}]}
{"id": "12", "type": "gold", "text": "Primary outcomes and Secondary outcomes\n\nThe primary outcome of this study was the SOFA Score, and the secondary outcome was the all-cause mortality up to 30 days. All outcomes were determined by an independent clinical endpoint determination committee.\n", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[83, 93]], "text": "SOFA Score"}, {"id": "T2", "type": "SecondaryOutcome", "offsets": [[129, 148]], "text": "all-cause mortality"}, {"id": "T3", "type": "TimeFrame", "offsets": [[149, 162]], "text": "up to 30 days"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T2", "arg2": "T3"}]}
{"id": "126", "type": "gold", "text": " Abstract. The COVID-19 pandemic is showing an exponential growth, mandating an urgent need to develop an effective treatment. Indeed, to date, a well-established therapy is still lacking. We aimed to evaluate the safety and efficacy of hydroxychloroquine (HCQ) added to standard care in patients with COVID-19. This was a multicenter, randomized controlled trial conducted at three major university hospitals in Egypt. One hundred ninety-four patients with confirmed diagnosis of COVID-19 were included in the study after signing informed consent. They were equally randomized into two arms: 97 patients administrated HCQ plus standard care (HCQ group) and 97 patients administered only standard care as a control arm (control group). The primary endpoints were recovery within 28 days, need for mechanical ventilation, or death. The two groups were matched for age and gender. There was no significant difference between them regarding any of the baseline characteristics or laboratory parameters. Four patients (4.1%) in the HCQ group and 5 (5.2%) patients in the control group needed mechanical ventilation (P = 0.75). The overall mortality did not differ between the two groups, as six patients (6.2%) died in the HCQ group and 5 (5.2%) died in the control group (P = 0.77). Univariate logistic regression analysis showed that HCQ treatment was not significantly associated with decreased mortality in COVID-19 patients. So, adding HCQ to standard care did not add significant benefit, did not decrease the need for ventilation, and did not reduce mortality rates in COVID-19 patients", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[763, 771]], "text": "recovery"}, {"id": "T2", "type": "PrimaryOutcome", "offsets": [[788, 819]], "text": "need for mechanical ventilation"}, {"id": "T3", "type": "PrimaryOutcome", "offsets": [[824, 829]], "text": "death"}, {"id": "T4", "type": "TimeFrame", "offsets": [[772, 786]], "text": "within 28 days"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T4"}]}
{"id": "13", "type": "gold", "text": "Clinical study\nPatients\nThe study was initially designed as a multi-center study across hospitals in Changsha city and in other cities of Hunan Province,\nChina. However, per a government order, all patients from hospitals in Changsha city had to be relocated to the First Hospital of Changsha, a designated treatment center for all COVID-19 patients in Changsha city, and hospitals in other cities of Hunan\nProvince were not able to participate due to various reasons. The study was changed to a single-center study. This study was approved by the ethics committee of the First Hospital of Changsha (file number KX-2020002) and was conducted at the hospital. The study was also registered in the Chinese Clinical Trial Registry (http://www.chictr.org.cn/), number ChiCTR2000029496.\nHospitalized COVID-19 patients with confirmed SARS-CoV-2 detection, clinically classified as moderate or severe, at an age over 18 years, and without comorbidity of severe heart, lung, or brain diseases, were eligible for enrolling into this study. Moderate patients were defined as “patients with fever, symptoms of the respiratory system and pneumonia changes in CT images, and severe patients were defined as “patients with any of the following: (1) Respiratory distress, respiratory frequency \u0015 30/ min; (2) Under rest status, arterial oxygen saturation (SaO2 ) \u0014 93%; (3) Arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) \u0014 300 mmHg. In this study, we aimed to observe moderate and severe COVID-19 patients as these patients would likely benefit more from antiviral treatments.\nTrial design and treatments\nThis was a randomized, open-label, parallel-group study.\nPatients eligible for the study were assigned, in a 1:1:1 ratio, to\nNovaferon, Novaferon plus Lopinavir/Ritonavir, or Lopinavir/\nRitonavir group. An SAS generated simple randomization schedule was prepared by a statistician not involved in the trial. Using the order in which they enrolled in the study, patients were assigned to a treatment group that was implemented by a research assistant.\nInformed consent was obtained from all enrolled patients.\nAntiviral effects were assessed on day three, day six, and day nine after starting drug administration.\nThe approved dosage of Novaferon for hepatitis B application is the daily injection of 10 mg of protein in 1.0 ml volume per vial.\nLopinavir/Ritonavir (Kaletra) was manufactured by AbbVie Inc.; each tablet contained 200 mg of Lopinavir and 50 mg of Ritonavir.\nThe total daily doses (40 mg) of Novaferon were administered to patients twice per day by oxygen-driven aerosolized inhalation for 15 min of 20 mg of Novaferon (2 \u0003 1 ml vials) diluted with saline.\nFor patients receiving Lopinavir/Ritonavir (Kaletra), two tablets were orally taken twice per day. The aerosolized inhalation was administrated to hospitalized patients in the negative-pressure wards at the designated COVID-19 center to minimize the risk of disease transmission.\nAssessments\nSamples of nasopharyngeal swabs on day three, day six, and day nine during the seven to ten-day course of antiviral treatment were collected from the patients and tested for SARS-CoV-2 nucleic acids by RT-PCR. SARS-CoV-2 clearance in COVID-19 patients was defined as two consecutive negative-detection of SARS-CoV-2 RNA in nasopharyngeal swab samples with an interval of over 24 h.\nAdverse events were monitored throughout the trial, reported and graded based on the WHO Toxicity Grading Scale for Determining the Severity.\nThe peak levels of the SARS virus were around ten days after onset, and then the viral level began to decrease without effective antiviral treatment in SARS patients (Peiris et al., 2003).\nConsidering the homology of gene sequences of SARS-CoV-2 and SARS was over 90% (Zhu et al., 2020), we assumed that the intervention of antiviral drugs in COVID-19 patients would likely enhance or shorten the time to viral clearance. In this regard, this study's primary endpoint was chosen based on the SARS-CoV-2  clearance rates in COVID-19 patients assessed on day six of antiviral treatment. The secondary endpoint was the median time to SARS-CoV-2 clearance", "entities": [{"id": "T1", "type": "OtherOutcome", "offsets": [[3194, 3235]], "text": "SARS-CoV-2 clearance in COVID-19 patients"}, {"id": "T2", "type": "TimeFrame", "offsets": [[3016, 3051]], "text": "on day three, day six, and day nine"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[3251, 3364]], "text": "two consecutive negative-detection of SARS-CoV-2 RNA in nasopharyngeal swab samples with an interval of over 24 h"}, {"id": "T4", "type": "OtherOutcome", "offsets": [[3366, 3380]], "text": "Adverse events"}, {"id": "T5", "type": "OutcomeDefinition", "offsets": [[3418, 3506]], "text": "reported and graded based on the WHO Toxicity Grading Scale for Determining the Severity"}, {"id": "T6", "type": "PrimaryOutcome", "offsets": [[4000, 4027]], "text": "SARS-CoV-2  clearance rates"}, {"id": "T7", "type": "TimeFrame", "offsets": [[4058, 4091]], "text": "on day six of antiviral treatment"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[4124, 4159]], "text": "median time to SARS-CoV-2 clearance"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}, {"id": "R3", "type": "DefinedAs", "arg1": "T4", "arg2": "T5"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T6", "arg2": "T7"}]}
{"id": "14", "type": "gold", "text": "Outcomes\n\nThe primary clinical endpoint was time to clinical improvement within 28 days after randomisation. Clinical improvement was defined as a two-point reduction in patients' admission status on a six-point ordinal scale, or live discharge from the hospital, whichever came first. The six-point scale was as follows: death=6; hospital admission for extracorporeal membrane oxygenation or mechanical ventilation=5; hospital admission for non-invasive ventilation or high-flow oxygen therapy=4; hospital admission for oxygen therapy (but not requiring high-flow or non-invasive ventilation)=3; hospital admission but not requiring oxygen therapy=2; and discharged or having reached discharge criteria (defined as clinical recovery—ie, normalisation of pyrexia, respiratory rate <24 breaths per minute, saturation of peripheral oxygen >94% on room air, and relief of cough, all maintained for at least 72 h)=1. The six-point scale was modified from the seven-point scale used in our previous COVID-19 lopinavir–ritonavir RCT11 by combining the two outpatient strata into one.\n\nSecondary outcomes were the proportions of patients in each category of the six-point scale at day 7, 14, and 28 after randomisation; all-cause mortality at day 28; frequency of invasive mechanical ventilation; duration of oxygen therapy; duration of hospital admission; and proportion of patients with nosocomial infection. Virological measures included the proportions of patients with viral RNA detected and viral RNA load (measured by quantitative RT-PCR). Safety outcomes included treatment-emergent adverse events, serious adverse events, and premature discontinuations of study drug.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[44, 72]], "text": "time to clinical improvement"}, {"id": "T2", "type": "TimeFrame", "offsets": [[73, 107]], "text": "within 28 days after randomisation"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[145, 284]], "text": "a two-point reduction in patients' admission status on a six-point ordinal scale, or live discharge from the hospital, whichever came first"}, {"id": "T4", "type": "OutcomeDefinition", "offsets": [[286, 912]], "text": "The six-point scale was as follows: death=6; hospital admission for extracorporeal membrane oxygenation or mechanical ventilation=5; hospital admission for non-invasive ventilation or high-flow oxygen therapy=4; hospital admission for oxygen therapy (but not requiring high-flow or non-invasive ventilation)=3; hospital admission but not requiring oxygen therapy=2; and discharged or having reached discharge criteria (defined as clinical recovery—ie, normalisation of pyrexia, respiratory rate <24 breaths per minute, saturation of peripheral oxygen >94% on room air, and relief of cough, all maintained for at least 72 h)=1."}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[1107, 1170]], "text": "proportions of patients in each category of the six-point scale"}, {"id": "T6", "type": "TimeFrame", "offsets": [[1171, 1211]], "text": "at day 7, 14, and 28 after randomisation"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[1213, 1232]], "text": "all-cause mortality"}, {"id": "T8", "type": "TimeFrame", "offsets": [[1233, 1242]], "text": "at day 28"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[1244, 1288]], "text": "frequency of invasive mechanical ventilation"}, {"id": "T10", "type": "SecondaryOutcome", "offsets": [[1290, 1316]], "text": "duration of oxygen therapy"}, {"id": "T11", "type": "SecondaryOutcome", "offsets": [[1318, 1348]], "text": "duration of hospital admission"}, {"id": "T12", "type": "SecondaryOutcome", "offsets": [[1354, 1402]], "text": "proportion of patients with nosocomial infection"}, {"id": "T13", "type": "OtherOutcome", "offsets": [[1438, 1504]], "text": "proportions of patients with viral RNA detected and viral RNA load"}, {"id": "T14", "type": "OtherOutcome", "offsets": [[1565, 1598]], "text": "treatment-emergent adverse events"}, {"id": "T15", "type": "OtherOutcome", "offsets": [[1600, 1622]], "text": "serious adverse events"}, {"id": "T16", "type": "OtherOutcome", "offsets": [[1628, 1668]], "text": "premature discontinuations of study drug"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}, {"id": "R2", "type": "DefinedAs", "arg1": "T1", "arg2": "T4"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T5", "arg2": "T6"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T7", "arg2": "T8"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}]}
{"id": "15", "type": "gold", "text": "Outcomes\nPrimary and Secondary Outcomes\n\nThe primary efficacy end point was the percentage of subjects with viral negative by Day 14 and the time from randomization to clinical improvement, defined as the time from randomization to an improvement of two points (from the status at randomization) on a seven-category ordinal scale or live discharge from the hospital, whichever came first. The ordinal scale, which is refer to National Early Warning Score 2 (NEWS2), have been used as end points in clinical trials in patients hospitalized with COVID-19. Secondary clinical end points included the percentage of subjects with viral negative by Day 7, the incidence of mechanical ventilation by Day 14, ICU admission by Day 14, and all-cause mortality by Day14.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[80, 122]], "text": "percentage of subjects with viral negative"}, {"id": "T2", "type": "TimeFrame", "offsets": [[123, 132]], "text": "by Day 14"}, {"id": "T3", "type": "PrimaryOutcome", "offsets": [[141, 188]], "text": "time from randomization to clinical improvement"}, {"id": "T4", "type": "OutcomeDefinition", "offsets": [[205, 387]], "text": "time from randomization to an improvement of two points (from the status at randomization) on a seven-category ordinal scale or live discharge from the hospital, whichever came first"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[597, 639]], "text": "percentage of subjects with viral negative"}, {"id": "T6", "type": "TimeFrame", "offsets": [[640, 648]], "text": "by Day 7"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[654, 689]], "text": "incidence of mechanical ventilation"}, {"id": "T8", "type": "TimeFrame", "offsets": [[690, 699]], "text": "by Day 14"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[701, 714]], "text": "ICU admission"}, {"id": "T10", "type": "TimeFrame", "offsets": [[715, 724]], "text": "by Day 14"}, {"id": "T11", "type": "SecondaryOutcome", "offsets": [[730, 749]], "text": "all-cause mortality"}, {"id": "T12", "type": "TimeFrame", "offsets": [[750, 758]], "text": "by Day14"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T3", "arg2": "T4"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T5", "arg2": "T6"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T7", "arg2": "T8"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T9", "arg2": "T10"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T11", "arg2": "T12"}]}
{"id": "16", "type": "gold", "text": "Outcomes\nThe primary endpoint was time to achieve a negative RT-PCR result for SARS-CoV-2 in a nasopharyngeal swab sample. Secondary clinical endpoints were time to resolution of symptoms defined as a NEWS2 of 0 maintained for 24 h; daily NEWS2 and sequential organ failure assessment (SOFA) score; length of hospital stay; and 30-day mortality. Other virological endpoints included the time to achieve negative SARS-CoV-2 RT-PCR in all clinical samples, including nasopharyngeal swab, posterior oropharyngeal saliva, throat swab, stool, and urine; daily viral load changes in the first 7 days; and emergence of amino acid mutations in the nsp5 gene encoding a 3C-like protease.\nThe serum cytokine response was also measured.\nSafety endpoints were the frequencies and duration of adverse events", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[34, 121]], "text": "time to achieve a negative RT-PCR result for SARS-CoV-2 in a nasopharyngeal swab sample"}, {"id": "T2", "type": "SecondaryOutcome", "offsets": [[157, 187]], "text": "time to resolution of symptoms"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[199, 231]], "text": "a NEWS2 of 0 maintained for 24 h"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[239, 297]], "text": "NEWS2 and sequential organ failure assessment (SOFA) score"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[299, 322]], "text": "length of hospital stay"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[335, 344]], "text": "mortality"}, {"id": "T7", "type": "OtherOutcome", "offsets": [[387, 453]], "text": "time to achieve negative SARS-CoV-2 RT-PCR in all clinical samples"}, {"id": "T8", "type": "OtherOutcome", "offsets": [[549, 573]], "text": "daily viral load changes"}, {"id": "T9", "type": "TimeFrame", "offsets": [[574, 593]], "text": "in the first 7 days"}, {"id": "T10", "type": "OtherOutcome", "offsets": [[599, 677]], "text": "emergence of amino acid mutations in the nsp5 gene encoding a 3C-like protease"}, {"id": "T11", "type": "OtherOutcome", "offsets": [[752, 794]], "text": "frequencies and duration of adverse events"}, {"id": "T12", "type": "TimeFrame", "offsets": [[328, 334]], "text": "30-day"}, {"id": "T13", "type": "OutcomeDefinition", "offsets": [[465, 547]], "text": "nasopharyngeal swab, posterior oropharyngeal saliva, throat swab, stool, and urine"}, {"id": "T14", "type": "OtherOutcome", "offsets": [[683, 706]], "text": "serum cytokine response"}, {"id": "T15", "type": "TimeFrame", "offsets": [[233, 238]], "text": "daily"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T2", "arg2": "T3"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T8", "arg2": "T9"}, {"id": "R3", "type": "DefinedAs", "arg1": "T7", "arg2": "T13"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T6", "arg2": "T12"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T4", "arg2": "T15"}]}
{"id": "19", "type": "gold", "text": " Outcomes\n\nThe primary outcome was the time to recovery, defined as the first day, during the 28 days after enrollment, on which a patient met the criteria for category 1, 2, or 3 on the eight-category ordinal scale. The categories are as follows: 1, not hospitalized and no limitations of activities; 2, not hospitalized, with limitation of activities, home oxygen requirement, or both; 3, hospitalized, not requiring supplemental oxygen and no longer requiring ongoing medical care (used if hospitalization was extended for infection-control or other nonmedical reasons); 4, hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (related to Covid-19 or to other medical conditions); 5, hospitalized, requiring any supplemental oxygen; 6, hospitalized, requiring noninvasive ventilation or use of high-flow oxygen devices; 7, hospitalized, receiving invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); and 8, death.\n\nThe key secondary outcome was clinical status at day 15, as assessed on the ordinal scale. Other secondary outcomes included the time to improvement of one category and of two categories from the baseline ordinal score; clinical status as assessed on the ordinal scale at days 3, 5, 8, 11, 15, 22, and 29; mean change in status on the ordinal scale from day 1 to days 3, 5, 8, 11, 15, 22, and 29; time to discharge or National Early Warning Score of 2 or less (maintained for 24 hours), whichever occurred first; change in the National Early Warning Score from day 1 to days 3, 5, 8, 11, 15, 22, and 29; number of days with supplemental oxygen, with noninvasive ventilation or high-flow oxygen, and with invasive ventilation or ECMO up to day 29 (if these were being used at baseline); the incidence and duration of new oxygen use, of noninvasive ventilation or high-flow oxygen, and of invasive ventilation or ECMO; number of days of hospitalization up to day 29; and mortality at 14 and 28 days after enrollment. Secondary safety outcome measures included grade 3 and 4 adverse events and serious adverse events that occurred during the trial, discontinuation or temporary suspension of infusions, and changes in assessed laboratory values over time.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[39, 55]], "text": "time to recovery"}, {"id": "T2", "type": "OutcomeDefinition", "offsets": [[68, 215]], "text": "the first day, during the 28 days after enrollment, on which a patient met the criteria for category 1, 2, or 3 on the eight-category ordinal scale"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[1004, 1019]], "text": "clinical status"}, {"id": "T4", "type": "TimeFrame", "offsets": [[1020, 1029]], "text": "at day 15"}, {"id": "T5", "type": "OutcomeDefinition", "offsets": [[1031, 1063]], "text": "as assessed on the ordinal scale"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[1103, 1192]], "text": "time to improvement of one category and of two categories from the baseline ordinal score"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[1194, 1242]], "text": "clinical status as assessed on the ordinal scale"}, {"id": "T8", "type": "TimeFrame", "offsets": [[1243, 1278]], "text": "at days 3, 5, 8, 11, 15, 22, and 29"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[1280, 1322]], "text": "mean change in status on the ordinal scale"}, {"id": "T10", "type": "TimeFrame", "offsets": [[1323, 1369]], "text": "from day 1 to days 3, 5, 8, 11, 15, 22, and 29"}, {"id": "T11", "type": "TimeFrame", "offsets": [[2102, 2118]], "text": "during the trial"}, {"id": "T12", "type": "SecondaryOutcome", "offsets": [[1487, 1529]], "text": "change in the National Early Warning Score"}, {"id": "T13", "type": "TimeFrame", "offsets": [[1530, 1576]], "text": "from day 1 to days 3, 5, 8, 11, 15, 22, and 29"}, {"id": "T14", "type": "SecondaryOutcome", "offsets": [[1578, 1706]], "text": "number of days with supplemental oxygen, with noninvasive ventilation or high-flow oxygen, and with invasive ventilation or ECMO"}, {"id": "T15", "type": "TimeFrame", "offsets": [[1707, 1719]], "text": "up to day 29"}, {"id": "T16", "type": "SecondaryOutcome", "offsets": [[1760, 1889]], "text": "the incidence and duration of new oxygen use, of noninvasive ventilation or high-flow oxygen, and of invasive ventilation or ECMO"}, {"id": "T17", "type": "SecondaryOutcome", "offsets": [[1891, 1924]], "text": "number of days of hospitalization"}, {"id": "T18", "type": "TimeFrame", "offsets": [[1925, 1937]], "text": "up to day 29"}, {"id": "T19", "type": "SecondaryOutcome", "offsets": [[1943, 1952]], "text": "mortality"}, {"id": "T20", "type": "TimeFrame", "offsets": [[1953, 1987]], "text": "at 14 and 28 days after enrollment"}, {"id": "T21", "type": "SecondaryOutcome", "offsets": [[2032, 2060]], "text": "grade 3 and 4 adverse events"}, {"id": "T22", "type": "SecondaryOutcome", "offsets": [[2065, 2087]], "text": "serious adverse events"}, {"id": "T23", "type": "SecondaryOutcome", "offsets": [[2120, 2172]], "text": "discontinuation or temporary suspension of infusions"}, {"id": "T24", "type": "SecondaryOutcome", "offsets": [[2178, 2225]], "text": "changes in assessed laboratory values over time"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T3", "arg2": "T4"}, {"id": "R3", "type": "DefinedAs", "arg1": "T3", "arg2": "T5"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T7", "arg2": "T8"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T9", "arg2": "T10"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T12", "arg2": "T13"}, {"id": "R7", "type": "MeasuredAt", "arg1": "T14", "arg2": "T15"}, {"id": "R8", "type": "MeasuredAt", "arg1": "T17", "arg2": "T18"}, {"id": "R9", "type": "MeasuredAt", "arg1": "T19", "arg2": "T20"}, {"id": "R10", "type": "MeasuredAt", "arg1": "T21", "arg2": "T11"}, {"id": "R11", "type": "MeasuredAt", "arg1": "T22", "arg2": "T11"}]}
{"id": "2", "type": "gold", "text": "A 4.5 mm fibreoptic bronchoscope (UE Medical Company Ltd, Zhejiang, China) loaded with a lubricated reinforced Parker Flex-Tip® tracheal tube (Well Lead Medical Company Ltd., Guangzhou, China) was inserted until the carina was visualised, and the tube was advanced over the bronchoscope into the trachea. During attempts at tracheal intubation, HFNO was maintained for the HFNO group, whereas no oxygen was administered for the SMO group. After removal of the bronchoscope, successful intubation was confirmed by capnography. If Spo2 <90% occurred during intubation, bronchoscopy was terminated and face-mask ventilation was initiated to correct desaturation. The primary endpoint was the total time of intubation, defined as the sum of the time spent from the beginning of bronchoscopy until proper tracheal tube placement was confirmed. The secondary endpoints included the lowest Spo2 during intubation, incidence of mask ventilation for Spo2 <90%, Pao2/Fio2 before intubation, incidence of Spo2 <80% during intubation, incidence of minimum Spo2 >95% during intubation, and 7 day mortality.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[689, 713]], "text": "total time of intubation"}, {"id": "T2", "type": "OutcomeDefinition", "offsets": [[726, 837]], "text": "the sum of the time spent from the beginning of bronchoscopy until proper tracheal tube placement was confirmed"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[876, 905]], "text": "lowest Spo2 during intubation"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[907, 950]], "text": "incidence of mask ventilation for Spo2 <90%"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[952, 979]], "text": "Pao2/Fio2 before intubation"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[981, 1021]], "text": "incidence of Spo2 <80% during intubation"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[1023, 1071]], "text": "incidence of minimum Spo2 >95% during intubation"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[1083, 1092]], "text": "mortality"}, {"id": "T9", "type": "TimeFrame", "offsets": [[1077, 1082]], "text": "7 day"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T8", "arg2": "T9"}]}
{"id": "23", "type": "gold", "text": " End Points\n\nThe primary efficacy end point was clinical status assessed on day 14 on a 7-point ordinal scale consisting of the following categories: 1, death; 2, hospitalized, receiving invasive mechanical ventilation or ECMO; 3, hospitalized, receiving noninvasive ventilation or high-flow oxygen devices; 4, hospitalized, requiring low-flow supplemental oxygen; 5, hospitalized, not requiring supplemental oxygen but receiving ongoing medical care (related or not related to Covid-19); 6, hospitalized, requiring neither supplemental oxygen nor ongoing medical care (other than that specified in the protocol for remdesivir administration); and 7, not hospitalized (see Table S1 in the Supplementary Appendix, available at NEJM.org).\n\nThe secondary end point of the trial was the proportion of patients with adverse events that occurred on or after the first dose of remdesivir for up to 30 days after the last dose. Prespecified exploratory end points included the time to clinical improvement (defined as an improvement of at least 2 points from baseline on the 7-point ordinal scale), the time to recovery (defined by the National Institute of Allergy and Infectious Diseases [NIAID] as an improvement from a baseline score of 2 to 5 to a score of 6 or 7), the time to modified recovery (defined as an improvement from a baseline score of 2 to 4 to a score of 5 to 7 or from a score of 5 to a score of 6 or 7), and death from any cause.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[48, 63]], "text": "clinical status"}, {"id": "T2", "type": "TimeFrame", "offsets": [[73, 82]], "text": "on day 14"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[83, 735]], "text": "on a 7-point ordinal scale consisting of the following categories: 1, death; 2, hospitalized, receiving invasive mechanical ventilation or ECMO; 3, hospitalized, receiving noninvasive ventilation or high-flow oxygen devices; 4, hospitalized, requiring low-flow supplemental oxygen; 5, hospitalized, not requiring supplemental oxygen but receiving ongoing medical care (related or not related to Covid-19); 6, hospitalized, requiring neither supplemental oxygen nor ongoing medical care (other than that specified in the protocol for remdesivir administration); and 7, not hospitalized (see Table S1 in the Supplementary Appendix, available at NEJM.org)"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[783, 825]], "text": "proportion of patients with adverse events"}, {"id": "T5", "type": "TimeFrame", "offsets": [[840, 918]], "text": "on or after the first dose of remdesivir for up to 30 days after the last dose"}, {"id": "T6", "type": "OtherOutcome", "offsets": [[969, 997]], "text": "time to clinical improvement"}, {"id": "T7", "type": "OutcomeDefinition", "offsets": [[1010, 1088]], "text": "an improvement of at least 2 points from baseline on the 7-point ordinal scale"}, {"id": "T8", "type": "OtherOutcome", "offsets": [[1095, 1111]], "text": "time to recovery"}, {"id": "T9", "type": "OutcomeDefinition", "offsets": [[1113, 1260]], "text": "defined by the National Institute of Allergy and Infectious Diseases [NIAID] as an improvement from a baseline score of 2 to 5 to a score of 6 or 7"}, {"id": "T10", "type": "OtherOutcome", "offsets": [[1267, 1292]], "text": "time to modified recovery"}, {"id": "T11", "type": "OutcomeDefinition", "offsets": [[1305, 1414]], "text": "an improvement from a baseline score of 2 to 4 to a score of 5 to 7 or from a score of 5 to a score of 6 or 7"}, {"id": "T12", "type": "OtherOutcome", "offsets": [[1421, 1441]], "text": "death from any cause"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T4", "arg2": "T5"}, {"id": "R3", "type": "DefinedAs", "arg1": "T6", "arg2": "T7"}, {"id": "R4", "type": "DefinedAs", "arg1": "T8", "arg2": "T9"}, {"id": "R5", "type": "DefinedAs", "arg1": "T10", "arg2": "T11"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}]}
{"id": "24", "type": "gold", "text": " Outcomes\n\nThe primary efficacy end point was the time to clinical improvement, defined as the time from randomization (D0) to an improvement of 2 points on a 7-category ordinal scale or live discharge from the hospital (Dend), and improvement rate of follow-up CT scans at D14. The 7-category ordinal scale has been used in other COVID-19 randomized controlled trials31 and also recommended by the World Health Organization R&D Blueprint expert group32 (see this article’s Methods section in the Online Repository). Other clinical outcomes included clinical improvement rate as assessed with the 7-category ordinal scale on D7, D14, D21, and D28, time from randomization to lymphocyte recovery and to invasive mechanical ventilation, the duration of hospitalization in survivors, and the time from treatment initiation to death and virus clearance time. The primary safety end point was the incidence of serious adverse events occurring up to 28 days. Safety outcomes included adverse events and serious adverse events that occurred during treatment. Particularly, the eventual negative impact of ruxolitinib on SARS-CoV-2 virus clearance and its specific IgM and/or IgG-antibody formation and/or lymphocyte recovery was also included in the safety profile. Lymphopenia was defined as peripheral absolute lymphocytes less than 1.0 × 109/L. Lymphocyte recovery time was defined as the first day at which lymphocytes returned to the normal levels within the observation period. The virus clearance time was defined as the time from randomization to the first day of at least 2 consecutive negative RT-PCR assays separated by 24 hours apart. The secondary end point is the overall mortality at D28. The investigational outcomes included the dynamic changes in the virus copies, cytokine profile, SARS-CoV-2–speicific antibody, and its correlation with clinical treatment response.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[50, 78]], "text": "time to clinical improvement"}, {"id": "T2", "type": "OutcomeDefinition", "offsets": [[95, 270]], "text": "time from randomization (D0) to an improvement of 2 points on a 7-category ordinal scale or live discharge from the hospital (Dend), and improvement rate of follow-up CT scans"}, {"id": "T3", "type": "TimeFrame", "offsets": [[271, 277]], "text": "at D14"}, {"id": "T4", "type": "OtherOutcome", "offsets": [[550, 575]], "text": "clinical improvement rate"}, {"id": "T5", "type": "OutcomeDefinition", "offsets": [[576, 621]], "text": "as assessed with the 7-category ordinal scale"}, {"id": "T6", "type": "TimeFrame", "offsets": [[622, 646]], "text": "on D7, D14, D21, and D28"}, {"id": "T7", "type": "OtherOutcome", "offsets": [[648, 733]], "text": "time from randomization to lymphocyte recovery and to invasive mechanical ventilation"}, {"id": "T8", "type": "OtherOutcome", "offsets": [[739, 779]], "text": "duration of hospitalization in survivors"}, {"id": "T9", "type": "OtherOutcome", "offsets": [[789, 828]], "text": "time from treatment initiation to death"}, {"id": "T10", "type": "PrimaryOutcome", "offsets": [[892, 927]], "text": "incidence of serious adverse events"}, {"id": "T11", "type": "TimeFrame", "offsets": [[938, 951]], "text": "up to 28 days"}, {"id": "T12", "type": "OtherOutcome", "offsets": [[997, 1019]], "text": "serious adverse events"}, {"id": "T13", "type": "OtherOutcome", "offsets": [[1079, 1139]], "text": "negative impact of ruxolitinib on SARS-CoV-2 virus clearance"}, {"id": "T14", "type": "OtherOutcome", "offsets": [[1157, 1190]], "text": "IgM and/or IgG-antibody formation"}, {"id": "T15", "type": "OtherOutcome", "offsets": [[1198, 1217]], "text": "lymphocyte recovery"}, {"id": "T16", "type": "OutcomeDefinition", "offsets": [[1381, 1475]], "text": "the first day at which lymphocytes returned to the normal levels within the observation period"}, {"id": "T17", "type": "OutcomeDefinition", "offsets": [[1517, 1639]], "text": "the time from randomization to the first day of at least 2 consecutive negative RT-PCR assays separated by 24 hours apart."}, {"id": "T18", "type": "SecondaryOutcome", "offsets": [[1671, 1688]], "text": "overall mortality"}, {"id": "T19", "type": "TimeFrame", "offsets": [[1689, 1695]], "text": "at D28"}, {"id": "T21", "type": "OtherOutcome", "offsets": [[1833, 1877]], "text": "correlation with clinical treatment response"}, {"id": "T22", "type": "OtherOutcome", "offsets": [[833, 853]], "text": "virus clearance time"}, {"id": "T20", "type": "OtherOutcome", "offsets": [[1739, 1774]], "text": "dynamic changes in the virus copies"}, {"id": "T23", "type": "OtherOutcome", "offsets": [[1776, 1792]], "text": "cytokine profile"}, {"id": "T24", "type": "OtherOutcome", "offsets": [[1794, 1823]], "text": "SARS-CoV-2–speicific antibody"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T1", "arg2": "T3"}, {"id": "R3", "type": "DefinedAs", "arg1": "T4", "arg2": "T5"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T4", "arg2": "T6"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T10", "arg2": "T11"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T12", "arg2": "T11"}, {"id": "R7", "type": "DefinedAs", "arg1": "T15", "arg2": "T16"}, {"id": "R8", "type": "DefinedAs", "arg1": "T13", "arg2": "T17"}, {"id": "R9", "type": "MeasuredAt", "arg1": "T18", "arg2": "T19"}]}
{"id": "25", "type": "silver", "text": "ABSTRACT \nTo the best of our knowledge, there is no published study on the use of interferon-1a (IFN-1a) in the treatment of severe COVID-19. In this randomized clinical trial, the efficacy and safety of IFN-1a were evaluated in patients with severe COVID-19. Forty-two patients in the interferon group received IFN-1a in addition to the national protocol medications (hydroxychloroquine plus lopinavirritonavir or atazanavir-ritonavir). Each 44g/ml (12 million IU/ml) dose of interferon-1a was subcutaneously injected three times weekly for two consecutive weeks.\nThe control group consisted of 39 patients who received only the national protocol medications. The primary outcome of the study was time to reach clinical response.\nSecondary outcomes were duration of hospital stay, length of intensive care unit stay, 28-day mortality, effect of early or late administration of IFN on mortality, adverse effects, and complications during the hospitalization. Between 29 February and 3 April 2020, 92 patients were recruited, and a total of 42 patients in the IFN group and 39 patients in the control group completed the study. As the primary outcome, time to the clinical response was not significantly different between the IFN and the control groups (9.7  5.8 versus 8.3  4.9 days, respectively, P  0.95). On day 14, 66.7% versus 43.6% of patients in the IFN group and the control group, respectively, were discharged (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.05 to 6.37). The 28-day overall mortality was significantly lower in the IFN than the control group (19% versus 43.6%, respectively, P  0.015). Early administration significantly reduced mortality (OR, 13.5; 95% CI, 1.5 to 118). Although IFN did not change the time to reach the clinical response, adding it to the national protocol significantly increased discharge rate on day 14 and decreased 28-day mortality. (This study is in the Iranian Registry of Clinical Trials under identifier IRCT20100228003449N28.)", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[698, 729]], "text": "time to reach clinical response"}, {"id": "T2", "type": "SecondaryOutcome", "offsets": [[755, 780]], "text": "duration of hospital stay"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[782, 816]], "text": "length of intensive care unit stay"}, {"id": "T4", "type": "TimeFrame", "offsets": [[818, 824]], "text": "28-day"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[825, 834]], "text": "mortality"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[836, 894]], "text": "effect of early or late administration of IFN on mortality"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[896, 911]], "text": "adverse effects"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[917, 957]], "text": "complications during the hospitalization"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T5", "arg2": "T4"}]}
{"id": "26", "type": "gold", "text": " Main Outcomes and Measures  Primary outcome was time to clinical improvement within 28 days, defined as patient discharged alive or reduction of 2 points on a 6-point disease severity scale (ranging from 1 [discharge] to 6 [death]). Secondary outcomes included 28-day mortality, time to discharge, and the rate of viral polymerase chain reaction (PCR) results turned from positive at baseline to negative at up to 72 hours.\n\n\nOutcome Measures\n\nThe primary end point was time to clinical improvement within a 28-day period. Clinical improvement was defined as patient discharge or a reduction of 2 points on a 6-point disease severity scale.13 The scale was defined as follows: 6 points, death; 5 points, hospitalization plus extracorporeal membrane oxygenation (ECMO) or invasive mechanical ventilation; 4 points, hospitalization plus noninvasive ventilation or high-flow supplemental oxygen; 3 points, hospitalization plus supplemental oxygen (not high-flow or noninvasive ventilation); 2 points, hospitalization with no supplemental oxygen; 1 point, hospital discharge.\n\nPatient discharge criteria included body temperature returned to normal for longer than 3 days, respiratory symptoms significantly improved without the need for oxygen support, and 2 consecutive negative PCR test results from nasopharyngeal swabs at least 24 hours apart.\n\nSecondary clinical outcomes were as follows: (1) 28-day mortality, including analysis of time from randomization to death; (2) duration of hospitalization, including analyses of time from randomization to discharge, time from admission to discharge, and 28-day discharge rates; and (3) conversion of nasopharyngeal swab viral PCR results from positive at baseline to negative at follow-up assessed at 24, 48, and 72 hours. Once nasopharyngeal swab viral PCR testing yielded negative results 2 times consecutively, no further testing was performed.  A post hoc analysis was added to compare rates of improvement at days 7, 14, and 28.\n\nThis clinical trial was an open-label, randomized clinical study. To avoid assessment bias, the evaluation of clinical outcomes was performed by an investigator who was blind to the study group allocation.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[49, 77]], "text": "time to clinical improvement"}, {"id": "T2", "type": "TimeFrame", "offsets": [[78, 92]], "text": "within 28 days"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[105, 232]], "text": "patient discharged alive or reduction of 2 points on a 6-point disease severity scale (ranging from 1 [discharge] to 6 [death])"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[269, 278]], "text": "mortality"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[280, 297]], "text": "time to discharge"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[307, 405]], "text": "rate of viral polymerase chain reaction (PCR) results turned from positive at baseline to negative"}, {"id": "T7", "type": "TimeFrame", "offsets": [[406, 423]], "text": "at up to 72 hours"}, {"id": "T8", "type": "OutcomeDefinition", "offsets": [[1110, 1344]], "text": "body temperature returned to normal for longer than 3 days, respiratory symptoms significantly improved without the need for oxygen support, and 2 consecutive negative PCR test results from nasopharyngeal swabs at least 24 hours apart"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[1403, 1412]], "text": "mortality"}, {"id": "T10", "type": "SecondaryOutcome", "offsets": [[1474, 1501]], "text": "duration of hospitalization"}, {"id": "T11", "type": "SecondaryOutcome", "offsets": [[1633, 1735]], "text": "conversion of nasopharyngeal swab viral PCR results from positive at baseline to negative at follow-up"}, {"id": "T12", "type": "TimeFrame", "offsets": [[1745, 1768]], "text": "at 24, 48, and 72 hours"}, {"id": "T13", "type": "OutcomeDefinition", "offsets": [[1414, 1468]], "text": "including analysis of time from randomization to death"}, {"id": "T14", "type": "OutcomeDefinition", "offsets": [[1503, 1623]], "text": "including analyses of time from randomization to discharge, time from admission to discharge, and 28-day discharge rates"}, {"id": "T15", "type": "TimeFrame", "offsets": [[262, 268]], "text": "28-day"}, {"id": "T16", "type": "OtherOutcome", "offsets": [[1937, 1957]], "text": "rates of improvement"}, {"id": "T17", "type": "TimeFrame", "offsets": [[1958, 1979]], "text": "at days 7, 14, and 28"}, {"id": "T18", "type": "TimeFrame", "offsets": [[1396, 1402]], "text": "28-day"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T6", "arg2": "T7"}, {"id": "R4", "type": "DefinedAs", "arg1": "T5", "arg2": "T8"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T11", "arg2": "T12"}, {"id": "R6", "type": "DefinedAs", "arg1": "T9", "arg2": "T13"}, {"id": "R7", "type": "DefinedAs", "arg1": "T10", "arg2": "T14"}, {"id": "R8", "type": "MeasuredAt", "arg1": "T4", "arg2": "T15"}, {"id": "R9", "type": "MeasuredAt", "arg1": "T16", "arg2": "T17"}, {"id": "R10", "type": "MeasuredAt", "arg1": "T9", "arg2": "T18"}]}
{"id": "3", "type": "gold", "text": "Outcomes\nThe primary outcome was the rate of positive-to-negative conversion of SARS-CoV-2 nucleic acid from the initiation of treatment to day 21, with the enrollment day as the first day of treatment. The secondary outcomes were: 1) the rate of positive-to-negative conversion of SARS-CoV-2 nucleic acid at day 14; 2) the rate of antipyresis (defined as axillary temperature ≤37.3°C for more than 72 hours) from the first day of treatment; 3) the rate of cough alleviation from initiation; 4) the improvement rate of chest CT at days 7 and 14; 5) the deterioration rate of clinical status from mild/moderate to severe/critical status during the study period. The severe status was defined as meeting any of the following criteria: experiencing respiratory distress, RR≥30 times/minute; oxygen saturation ≤93% in the resting state; arterial blood oxygen partial pressure (PaO2)/oxygen concentration (FiO2) ≤300 mmHg (1mmHg = 0.133kPa).5 The critical status was defined as meeting any of the following criteria: development of respiratory failure requiring mechanical ventilation; occurrence of shock; requirement for ICU monitoring and treatment because of complications with other organ failures.5\nSpecimens from pharyngeal swabs were tested every 2 to 3 days. Negative conversion of nucleic acid was defined as negative detection of SARS-CoV-2 nucleic acid for two consecutive instances separated by more than 24 hours.\nCriteria of chest CT improvement included: 1) no new exudative lesions; 2) decreasing size of exudative lesions; 3) decreasing densities of lesions.\nAll participants were monitored for adverse events. Safety outcomes were assessed from serious adverse event reports. Any unexpected medical occurrence resulting in death, prolonged hospitalization, persistent or significant disability or incapacity, which was judged to be causally related to the study intervention, would be reported as a serious adverse event to the\nInstitutional Review Board. Potential adverse events for the study were defined as follows (1) anaphylaxis; (2) elevation of ALT or AST to more than 2.5-fold the upper normal limit or elevation of TBIL to more than 1.5-fold the upper normal limit; (3) acute pancreatitis; and (4) diarrhea.\n", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[37, 103]], "text": "rate of positive-to-negative conversion of SARS-CoV-2 nucleic acid"}, {"id": "T2", "type": "TimeFrame", "offsets": [[104, 146]], "text": "from the initiation of treatment to day 21"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[239, 305]], "text": "rate of positive-to-negative conversion of SARS-CoV-2 nucleic acid"}, {"id": "T4", "type": "TimeFrame", "offsets": [[306, 315]], "text": "at day 14"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[320, 343]], "text": "the rate of antipyresis"}, {"id": "T6", "type": "OutcomeDefinition", "offsets": [[356, 407]], "text": "axillary temperature ≤37.3°C for more than 72 hours"}, {"id": "T7", "type": "TimeFrame", "offsets": [[409, 440]], "text": "from the first day of treatment"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[449, 490]], "text": "rate of cough alleviation from initiation"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[499, 527]], "text": "improvement rate of chest CT"}, {"id": "T10", "type": "TimeFrame", "offsets": [[528, 544]], "text": "at days 7 and 14"}, {"id": "T11", "type": "SecondaryOutcome", "offsets": [[553, 635]], "text": "deterioration rate of clinical status from mild/moderate to severe/critical status"}, {"id": "T12", "type": "TimeFrame", "offsets": [[636, 659]], "text": "during the study period"}, {"id": "T13", "type": "OutcomeDefinition", "offsets": [[694, 935]], "text": "meeting any of the following criteria: experiencing respiratory distress, RR≥30 times/minute; oxygen saturation ≤93% in the resting state; arterial blood oxygen partial pressure (PaO2)/oxygen concentration (FiO2) ≤300 mmHg (1mmHg = 0.133kPa)"}, {"id": "T14", "type": "OutcomeDefinition", "offsets": [[1314, 1421]], "text": "negative detection of SARS-CoV-2 nucleic acid for two consecutive instances separated by more than 24 hours"}, {"id": "T15", "type": "OutcomeDefinition", "offsets": [[1423, 1570]], "text": "Criteria of chest CT improvement included: 1) no new exudative lesions; 2) decreasing size of exudative lesions; 3) decreasing densities of lesions"}, {"id": "T16", "type": "OtherOutcome", "offsets": [[1608, 1622]], "text": "adverse events"}, {"id": "T17", "type": "OtherOutcome", "offsets": [[1659, 1680]], "text": "serious adverse event"}, {"id": "T18", "type": "OutcomeDefinition", "offsets": [[2033, 2230]], "text": "(1) anaphylaxis; (2) elevation of ALT or AST to more than 2.5-fold the upper normal limit or elevation of TBIL to more than 1.5-fold the upper normal limit; (3) acute pancreatitis; and (4) diarrhea"}, {"id": "T19", "type": "OutcomeDefinition", "offsets": [[973, 1197]], "text": "meeting any of the following criteria: development of respiratory failure requiring mechanical ventilation; occurrence of shock; requirement for ICU monitoring and treatment because of complications with other organ failures"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T3", "arg2": "T4"}, {"id": "R3", "type": "DefinedAs", "arg1": "T5", "arg2": "T6"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T5", "arg2": "T7"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T9", "arg2": "T10"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T11", "arg2": "T12"}, {"id": "R7", "type": "DefinedAs", "arg1": "T11", "arg2": "T13"}, {"id": "R8", "type": "DefinedAs", "arg1": "T1", "arg2": "T14"}, {"id": "R9", "type": "DefinedAs", "arg1": "T9", "arg2": "T15"}, {"id": "R10", "type": "DefinedAs", "arg1": "T16", "arg2": "T18"}, {"id": "R11", "type": "DefinedAs", "arg1": "T11", "arg2": "T19"}]}
{"id": "34", "type": "gold", "text": " Outcome Measures\n\nThe primary outcome was all-cause mortality within 28 days after randomization; further analyses were specified at 6 months. Secondary outcomes were the time until discharge from the hospital and, among patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death. Other prespecified clinical outcomes included cause-specific mortality, receipt of renal dialysis or hemofiltration, major cardiac arrhythmia (recorded in a subgroup), and receipt and duration of ventilation. Among those receiving invasive mechanical ventilation at the time of randomization, the outcome of successful cessation of invasive mechanical ventilation was defined as cessation within (and survival to) 28 days. All information presented in this report is based on a data cutoff of December 14, 2020. Information regarding the primary and secondary outcomes is complete for 99.9% of trial participants.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[43, 62]], "text": "all-cause mortality"}, {"id": "T2", "type": "TimeFrame", "offsets": [[63, 142]], "text": "within 28 days after randomization; further analyses were specified at 6 months"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[172, 210]], "text": "time until discharge from the hospital"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[307, 417]], "text": "subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death"}, {"id": "T6", "type": "OtherOutcome", "offsets": [[465, 489]], "text": "cause-specific mortality"}, {"id": "T7", "type": "OtherOutcome", "offsets": [[491, 534]], "text": "receipt of renal dialysis or hemofiltration"}, {"id": "T8", "type": "OtherOutcome", "offsets": [[536, 560]], "text": "major cardiac arrhythmia"}, {"id": "T9", "type": "OtherOutcome", "offsets": [[591, 626]], "text": "receipt and duration of ventilation"}, {"id": "T10", "type": "OutcomeDefinition", "offsets": [[798, 840]], "text": "cessation within (and survival to) 28 days"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R3", "type": "DefinedAs", "arg1": "T5", "arg2": "T10"}]}
{"id": "37", "type": "gold", "text": " Outcomes\n\nThe primary outcome measurement for this study was time to clinical recovery (TTCR), defined as the number of days from randomization to clinical recovery. Maximum TTCR was 28 days. Patients were considered to have achieved clinical recovery when they had met all of the following criteria for at least 48 hours: 1. axillary body temperature ≤36.9°C or oral body temperature ≤37.2°C; 2. complete relief of all symptoms other than cough; 3. cough graded as mild or absent on a patient-reported scale of severe, moderate, mild, absent.\n\nSecondary outcome measurements included (up to 28 days): 1. time to SARS-CoV-2 RNA negativity, defined as the time from randomization to the day of the first test in two consecutive tests of nasopharyngeal or oropharyngeal swabs with negative SARS-CoV-2 RNA; 2. length of hospital stay, defined as the number of days from randomization to discharge; 3. Changes on chest CT scan; 4. duration (days) of supplemental oxygenation; 5. frequency of adverse events; 6. clinical status; 7. all-cause mortality; 8. duration (days) of supplemental oxygenation; 9. vital signs; 10. results of laboratory testing.\n\nWe used a semi-quantitative scoring system similar to the method reported by Pan et al. to estimate the pulmonary manifestations on CT scan [16]. The five lobes of the lungs were assigned a total score of 20 points, based on the volume of tissue affected. The score was given based on the overall affected areas of each side of the lung. Every 10% of affected areas from each lung can be recorded 1 point. Changes in cytokine levels and COVID-19-specific IgG/IgM levels were measured during the first week of hospitalization.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[62, 94]], "text": "time to clinical recovery (TTCR)"}, {"id": "T2", "type": "OutcomeDefinition", "offsets": [[107, 165]], "text": "the number of days from randomization to clinical recovery"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[267, 544]], "text": "met all of the following criteria for at least 48 hours: 1. axillary body temperature ≤36.9°C or oral body temperature ≤37.2°C; 2. complete relief of all symptoms other than cough; 3. cough graded as mild or absent on a patient-reported scale of severe, moderate, mild, absent."}, {"id": "T4", "type": "TimeFrame", "offsets": [[587, 600]], "text": "up to 28 days"}, {"id": "T5", "type": "TimeFrame", "offsets": [[167, 191]], "text": "Maximum TTCR was 28 days"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[606, 639]], "text": "time to SARS-CoV-2 RNA negativity"}, {"id": "T7", "type": "OutcomeDefinition", "offsets": [[652, 803]], "text": "the time from randomization to the day of the first test in two consecutive tests of nasopharyngeal or oropharyngeal swabs with negative SARS-CoV-2 RNA"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[808, 831]], "text": "length of hospital stay"}, {"id": "T9", "type": "OutcomeDefinition", "offsets": [[844, 894]], "text": "the number of days from randomization to discharge"}, {"id": "T10", "type": "SecondaryOutcome", "offsets": [[899, 923]], "text": "Changes on chest CT scan"}, {"id": "T11", "type": "SecondaryOutcome", "offsets": [[928, 971]], "text": "duration (days) of supplemental oxygenation"}, {"id": "T12", "type": "SecondaryOutcome", "offsets": [[976, 1003]], "text": "frequency of adverse events"}, {"id": "T13", "type": "SecondaryOutcome", "offsets": [[1008, 1023]], "text": "clinical status"}, {"id": "T14", "type": "SecondaryOutcome", "offsets": [[1028, 1047]], "text": "all-cause mortality"}, {"id": "T15", "type": "SecondaryOutcome", "offsets": [[1052, 1095]], "text": "duration (days) of supplemental oxygenation"}, {"id": "T16", "type": "SecondaryOutcome", "offsets": [[1100, 1111]], "text": "vital signs"}, {"id": "T17", "type": "SecondaryOutcome", "offsets": [[1117, 1146]], "text": "results of laboratory testing"}, {"id": "T18", "type": "OutcomeDefinition", "offsets": [[1159, 1288]], "text": "semi-quantitative scoring system similar to the method reported by Pan et al. to estimate the pulmonary manifestations on CT scan"}, {"id": "T19", "type": "OtherOutcome", "offsets": [[1555, 1581]], "text": "Changes in cytokine levels"}, {"id": "T20", "type": "OtherOutcome", "offsets": [[1586, 1618]], "text": "COVID-19-specific IgG/IgM levels"}, {"id": "T21", "type": "TimeFrame", "offsets": [[1633, 1673]], "text": "during the first week of hospitalization"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T1", "arg2": "T5"}, {"id": "R4", "type": "DefinedAs", "arg1": "T6", "arg2": "T7"}, {"id": "R5", "type": "DefinedAs", "arg1": "T8", "arg2": "T9"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T6", "arg2": "T4"}, {"id": "R7", "type": "MeasuredAt", "arg1": "T8", "arg2": "T4"}, {"id": "R8", "type": "MeasuredAt", "arg1": "T10", "arg2": "T4"}, {"id": "R9", "type": "MeasuredAt", "arg1": "T11", "arg2": "T4"}, {"id": "R10", "type": "MeasuredAt", "arg1": "T12", "arg2": "T4"}, {"id": "R11", "type": "MeasuredAt", "arg1": "T13", "arg2": "T4"}, {"id": "R12", "type": "MeasuredAt", "arg1": "T14", "arg2": "T4"}, {"id": "R13", "type": "MeasuredAt", "arg1": "T15", "arg2": "T4"}, {"id": "R14", "type": "MeasuredAt", "arg1": "T16", "arg2": "T4"}, {"id": "R15", "type": "MeasuredAt", "arg1": "T17", "arg2": "T4"}, {"id": "R16", "type": "DefinedAs", "arg1": "T10", "arg2": "T18"}, {"id": "R17", "type": "MeasuredAt", "arg1": "T19", "arg2": "T21"}, {"id": "R18", "type": "MeasuredAt", "arg1": "T20", "arg2": "T21"}]}
{"id": "4", "type": "gold", "text": "Outcome Measures\n\nThe primary end point was the time to clinical improvement, defined as the time from randomization to an improvement of two points (from the status at randomization) on a seven-category ordinal scale or live discharge from the hospital, whichever came first. The end point of clinical improvement was used in our previous influenza study17 and was also recommended by the WHO R&D Blueprint expert group.18 Ordinal scales have been used as end points in clinical trials in patients hospitalized with severe influenza.16-19 The seven-category ordinal scale consisted of the following categories: 1, not hospitalized with resumption of normal activities; 2, not hospitalized, but unable to resume normal activities; 3, hospitalized, not requiring supplemental oxygen; 4, hospitalized, requiring supplemental oxygen; 5, hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both; 6, hospitalized, requiring ECMO, invasive mechanical ventilation, or both; and 7, death.\n\nOther clinical outcomes included clinical status as assessed with the seven-category ordinal scale on days 7 and 14, mortality at day 28, the duration of mechanical ventilation, the duration of hospitalization in survivors, and the time (in days) from treatment initiation to death. Virologic measures included the proportions with viral RNA detection over time and viral RNA titer area-under-the-curve (AUC) measurements.\n\nSafety outcomes included adverse events that occurred during treatment, serious adverse events, and premature discontinuation of treatment. Adverse events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[48, 76]], "text": "time to clinical improvement"}, {"id": "T2", "type": "OutcomeDefinition", "offsets": [[93, 275]], "text": "time from randomization to an improvement of two points (from the status at randomization) on a seven-category ordinal scale or live discharge from the hospital, whichever came first"}, {"id": "T3", "type": "OtherOutcome", "offsets": [[1058, 1073]], "text": "clinical status"}, {"id": "T4", "type": "OutcomeDefinition", "offsets": [[1077, 1123]], "text": "assessed with the seven-category ordinal scale"}, {"id": "T5", "type": "TimeFrame", "offsets": [[1124, 1140]], "text": "on days 7 and 14"}, {"id": "T6", "type": "OtherOutcome", "offsets": [[1142, 1151]], "text": "mortality"}, {"id": "T7", "type": "TimeFrame", "offsets": [[1152, 1161]], "text": "at day 28"}, {"id": "T8", "type": "OtherOutcome", "offsets": [[1167, 1201]], "text": "duration of mechanical ventilation"}, {"id": "T9", "type": "OtherOutcome", "offsets": [[1207, 1247]], "text": "duration of hospitalization in survivors"}, {"id": "T10", "type": "OtherOutcome", "offsets": [[1257, 1306]], "text": "time (in days) from treatment initiation to death"}, {"id": "T11", "type": "OtherOutcome", "offsets": [[1340, 1386]], "text": "proportions with viral RNA detection over time"}, {"id": "T12", "type": "OtherOutcome", "offsets": [[1391, 1433]], "text": "viral RNA titer area-under-the-curve (AUC)"}, {"id": "T13", "type": "OtherOutcome", "offsets": [[1474, 1488]], "text": "adverse events"}, {"id": "T14", "type": "OtherOutcome", "offsets": [[1521, 1543]], "text": "serious adverse events"}, {"id": "T15", "type": "OtherOutcome", "offsets": [[1549, 1587]], "text": "premature discontinuation of treatment"}, {"id": "T16", "type": "OutcomeDefinition", "offsets": [[1609, 1722]], "text": "classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T3", "arg2": "T4"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T3", "arg2": "T5"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T6", "arg2": "T7"}, {"id": "R5", "type": "DefinedAs", "arg1": "T13", "arg2": "T16"}]}
{"id": "43", "type": "gold", "text": " Main Outcomes and Measures  Primary end points were (1) maximum high-sensitivity cardiac troponin level; (2) time for C-reactive protein to reach more than 3 times the upper reference limit; and (3) time to deterioration by 2 points on a 7-grade clinical status scale, ranging from able to resume normal activities to death. Secondary end points were (1) the percentage of participants requiring mechanical ventilation, (2) all-cause mortality, and (3) number, type, severity, and seriousness of adverse events. The primary efficacy analysis was performed on an intention-to-treat basis.\n\n\nEnd Points\n\nStudy end point analysis was planned to be performed in 2 phases, an early biochemical phase and a later clinical phase. The coprimary end points of the biochemical phase were the difference in maximal high-sensitivity cardiac troponin (hs cTn) levels between the 2 groups and the time for C-reactive protein to reach levels greater than 3 times the upper reference limit. The primary end point of the clinical phase was the time from baseline to clinical deterioration, defined as a 2-grade increase on an ordinal clinical scale, based on the World Health Organization R&D Blueprint Ordinal Clinical Scale,9 as used in previously published studies,10 within a time frame of 3 weeks after randomization or until hospital discharge (whichever occurred first). The 7-grade ordinal scale consisted of the following levels: 1, ambulatory, normal activities; 2, ambulatory but unable to resume normal activities; 3, hospitalized, not requiring supplemental oxygen; 4, hospitalized, requiring supplemental oxygen; 5, hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both; 6, hospitalized, requiring extracorporeal membrane oxygenation, invasive mechanical ventilation, or both; and 7, death. Secondary end points were the percentage of participants requiring mechanical ventilation, all-cause mortality at the end of follow-up, and the number, type, severity, and seriousness of total adverse events and treatment-related adverse events.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[57, 104]], "text": "maximum high-sensitivity cardiac troponin level"}, {"id": "T2", "type": "PrimaryOutcome", "offsets": [[110, 190]], "text": "time for C-reactive protein to reach more than 3 times the upper reference limit"}, {"id": "T3", "type": "PrimaryOutcome", "offsets": [[200, 268]], "text": "time to deterioration by 2 points on a 7-grade clinical status scale"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[356, 419]], "text": "the percentage of participants requiring mechanical ventilation"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[425, 444]], "text": "all-cause mortality"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[454, 511]], "text": "number, type, severity, and seriousness of adverse events"}, {"id": "T7", "type": "PrimaryOutcome", "offsets": [[783, 875]], "text": "difference in maximal high-sensitivity cardiac troponin (hs cTn) levels between the 2 groups"}, {"id": "T8", "type": "PrimaryOutcome", "offsets": [[884, 974]], "text": "time for C-reactive protein to reach levels greater than 3 times the upper reference limit"}, {"id": "T10", "type": "SecondaryOutcome", "offsets": [[1865, 1924]], "text": "percentage of participants requiring mechanical ventilation"}, {"id": "T11", "type": "SecondaryOutcome", "offsets": [[1926, 1945]], "text": "all-cause mortality"}, {"id": "T12", "type": "TimeFrame", "offsets": [[1946, 1969]], "text": "at the end of follow-up"}, {"id": "T13", "type": "SecondaryOutcome", "offsets": [[1979, 2079]], "text": "number, type, severity, and seriousness of total adverse events and treatment-related adverse events"}, {"id": "T14", "type": "PrimaryOutcome", "offsets": [[1028, 1072]], "text": "time from baseline to clinical deterioration"}, {"id": "T15", "type": "OutcomeDefinition", "offsets": [[1087, 1251]], "text": "2-grade increase on an ordinal clinical scale, based on the World Health Organization R&D Blueprint Ordinal Clinical Scale,9 as used in previously published studies"}, {"id": "T9", "type": "TimeFrame", "offsets": [[1278, 1360]], "text": "3 weeks after randomization or until hospital discharge (whichever occurred first)"}], "relations": [{"id": "R2", "type": "MeasuredAt", "arg1": "T11", "arg2": "T12"}, {"id": "R1", "type": "DefinedAs", "arg1": "T14", "arg2": "T15"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T14", "arg2": "T9"}]}
{"id": "45", "type": "gold", "text": " Intervention, primary and secondary endpoints\nPatients were randomly assigned via a web-based system at a 1:1 ratio to the current standard of care at each hospital with or without the addition of 300ml of ConvP, the standard volume of one plasma unit produced by Sanquin Blood Supply, was administered intravenously on the day of inclusion. Patients without a clinical response and a persistently positive RT-PCR could receive a second plasma unit after five days. Off-label use of EMA-approved drugs (e.g. chloroquine, azithromycin, lopinavir/ritonavir, tocilizumab, anakinra) as a treatment for COVID-19 was allowed in hospitals were this was part of the standard of care. We scored the clinical status with the ordinal 8-point WHO COVID-19 disease severity scale on days 1, 15 and 30. 16 Serum samples and nasopharyngeal swabs were collected at inclusion preceding treatment and thereafter. The primary endpoint of the study was overall mortality until discharge from the hospital or a maximum of 60 days after admission whichever came first.\nKey secondary clinical endpoint we describe here are the improvement on the 8-point WHO COVID-19 disease severity scale from inclusion to day 15, hospital length of stay and safety.\n", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[934, 951]], "text": "overall mortality"}, {"id": "T2", "type": "TimeFrame", "offsets": [[952, 1046]], "text": "until discharge from the hospital or a maximum of 60 days after admission whichever came first"}, {"id": "T4", "type": "TimeFrame", "offsets": [[1168, 1192]], "text": "from inclusion to day 15"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[1105, 1167]], "text": "improvement on the 8-point WHO COVID-19 disease severity scale"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[1194, 1217]], "text": "hospital length of stay"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[1222, 1228]], "text": "safety"}, {"id": "T3", "type": "OtherOutcome", "offsets": [[691, 767]], "text": "clinical status with the ordinal 8-point WHO COVID-19 disease severity scale"}, {"id": "T8", "type": "TimeFrame", "offsets": [[768, 788]], "text": "on days 1, 15 and 30"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T5", "arg2": "T4"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T3", "arg2": "T8"}]}
{"id": "47", "type": "silver", "text": " End Points\nThe primary end point was viral clearance rate at day 7 after randomization. After randomization, respiratory samples were collected every 1–2 days until viral clearance. Viral clearance was defined as reverse transcriptase polymerase chain reaction (RT-PCR) negative on at least 2 consecutive oropharyngeal swabs collected at least 1–2 days apart. Secondary end points included viral clearance at day 3 and day 5, the critical illness rate of subjects during the 14 days after randomization, the mortality rate of subjects at day 14, and the number of participants with treatment-related adverse events.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[38, 58]], "text": "viral clearance rate"}, {"id": "T2", "type": "TimeFrame", "offsets": [[59, 87]], "text": "at day 7 after randomization"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[214, 359]], "text": "reverse transcriptase polymerase chain reaction (RT-PCR) negative on at least 2 consecutive oropharyngeal swabs collected at least 1–2 days apart"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[391, 406]], "text": "viral clearance"}, {"id": "T5", "type": "TimeFrame", "offsets": [[407, 425]], "text": "at day 3 and day 5"}, {"id": "T6", "type": "PrimaryOutcome", "offsets": [[431, 464]], "text": "critical illness rate of subjects"}, {"id": "T7", "type": "TimeFrame", "offsets": [[465, 503]], "text": "during the 14 days after randomization"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[505, 535]], "text": "the mortality rate of subjects"}, {"id": "T9", "type": "TimeFrame", "offsets": [[536, 545]], "text": "at day 14"}, {"id": "T10", "type": "SecondaryOutcome", "offsets": [[551, 615]], "text": "the number of participants with treatment-related adverse events"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T4", "arg2": "T5"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T6", "arg2": "T7"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T8", "arg2": "T9"}]}
{"id": "48", "type": "silver", "text": "Outcome measures\nOutcomes were assessed at 28 days after randomization, with further analyses specified at 6 months. The primary outcome was all-cause mortality. Secondary outcomes were time to discharge from hospital and, among patients not on invasive mechanical ventilation at randomization, invasive mechanical ventilation (including extra-corporal membrane oxygenation) or death. Subsidiary clinical outcomes included cause-specific mortality, use of hemodialysis or hemofiltration, major cardiac arrhythmia (recorded in a subset), and receipt and duration of ventilation", "entities": [{"id": "T1", "type": "TimeFrame", "offsets": [[40, 115]], "text": "at 28 days after randomization, with further analyses specified at 6 months"}, {"id": "T3", "type": "PrimaryOutcome", "offsets": [[141, 160]], "text": "all-cause mortality"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[186, 217]], "text": "time to discharge from hospital"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[223, 383]], "text": "among patients not on invasive mechanical ventilation at randomization, invasive mechanical ventilation (including extra-corporal membrane oxygenation) or death"}, {"id": "T6", "type": "OtherOutcome", "offsets": [[423, 447]], "text": "cause-specific mortality"}, {"id": "T7", "type": "OtherOutcome", "offsets": [[449, 486]], "text": "use of hemodialysis or hemofiltration"}, {"id": "T8", "type": "OtherOutcome", "offsets": [[488, 512]], "text": "major cardiac arrhythmia"}, {"id": "T9", "type": "OtherOutcome", "offsets": [[541, 576]], "text": "receipt and duration of ventilation"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T3", "arg2": "T1"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T4", "arg2": "T1"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T5", "arg2": "T1"}, {"id": "R7", "type": "MeasuredAt", "arg1": "T6", "arg2": "T1"}, {"id": "R9", "type": "MeasuredAt", "arg1": "T7", "arg2": "T1"}, {"id": "R11", "type": "MeasuredAt", "arg1": "T8", "arg2": "T1"}, {"id": "R13", "type": "MeasuredAt", "arg1": "T9", "arg2": "T1"}]}
{"id": "49", "type": "silver", "text": " Outcomes\n\nThe primary outcome was the reduction of viral RNA load in nasopharyngeal swabs at days 3 and 7 after treatment start. The secondary outcomes were clinical progression measured using a simplified version of the WHO progression scale [17] (1, not hospitalized with or without resumption of normal activities; 2, hospitalized, requiring supplemental oxygen; 3, hospitalized, requiring invasive mechanical ventilation; and 4, death) and time from randomization to complete resolution of symptoms within the 28-day follow-up period. Resolution of symptoms was assessed sequentially using a symptoms questionnaire designed to gather information on the type of symptom and last day experienced; complete resolution was considered when no COVID-19–related symptoms were reported at all. Safety outcomes included AEs that occurred during treatment, SAEs, AEs of special interest (ie, cardiac), and premature discontinuation of therapy. AEs were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. All unexpected SAEs were notified through Eudravigilance.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[39, 66]], "text": "reduction of viral RNA load"}, {"id": "T2", "type": "TimeFrame", "offsets": [[91, 128]], "text": "at days 3 and 7 after treatment start"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[158, 178]], "text": "clinical progression"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[445, 503]], "text": "time from randomization to complete resolution of symptoms"}, {"id": "T5", "type": "TimeFrame", "offsets": [[504, 538]], "text": "within the 28-day follow-up period"}, {"id": "T6", "type": "OutcomeDefinition", "offsets": [[540, 698]], "text": "Resolution of symptoms was assessed sequentially using a symptoms questionnaire designed to gather information on the type of symptom and last day experienced"}, {"id": "T7", "type": "OtherOutcome", "offsets": [[816, 850]], "text": "AEs that occurred during treatment"}, {"id": "T8", "type": "OtherOutcome", "offsets": [[852, 856]], "text": "SAEs"}, {"id": "T9", "type": "OtherOutcome", "offsets": [[858, 895]], "text": "AEs of special interest (ie, cardiac)"}, {"id": "T10", "type": "OtherOutcome", "offsets": [[901, 937]], "text": "premature discontinuation of therapy"}, {"id": "T11", "type": "OutcomeDefinition", "offsets": [[948, 1048]], "text": "classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events"}, {"id": "T12", "type": "OutcomeDefinition", "offsets": [[222, 243]], "text": "WHO progression scale"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T4", "arg2": "T5"}, {"id": "R3", "type": "DefinedAs", "arg1": "T4", "arg2": "T6"}, {"id": "R4", "type": "DefinedAs", "arg1": "T7", "arg2": "T11"}, {"id": "R5", "type": "DefinedAs", "arg1": "T3", "arg2": "T12"}]}
{"id": "5", "type": "silver", "text": "Abstract  \n\nObjective: To evaluate the efficacy and safety of hydroxychloroquine (HCQ) in the treatment of patients with moderate coronavirus disease 2019 (COVID-19). Methods: We prospectively enrolled 30 treatment-naïve patients with confirmed COVID-19 after informed consent at Shanghai Public Health Clinical Center. The patients were randomized 1:1 to HCQ group and the control group. Patients in HCQ group were given HCQ 400 mg per day for 5 days plus conventional treatments, while those in the control group were given conventional treatment only. The primary endpoint was negative conversion rate of SARS-CoV-2 nucleic acid in respiratory pharyngeal swab on days 7 after randomization. This study has been approved by the Ethics Committee of Shanghai Public Health Clinical Center and registered online (NCT04261517). Results: One patient in HCQ group developed to severe during the treatment. On day 7, nucleic acid of throat swabs was negative in 13 (86.7%) cases in the HCQ group and 14 (93.3%) cases in the control group (P>0.05). The median duration from hospitalization to virus nucleic acid negative conservation was 4 (1, 9) days in HCQ group, which is comparable to that in the control group [2 (1, 4) days, Z=1.27, P>0.05]. The median time for body temperature normalization in HCQ group was 1 (0, 2) day after hospitalization, which was also comparable to that in the control group [1 (0, 3) day]. Radiological progression was shown on CT images in 5 cases (33.3%) of the HCQ group and 7 cases (46.7%) of the control group, and all patients showed improvement in follow-up examinations. Four cases (26.7%) of the HCQ group and 3 cases (20%) of the control group had transient diarrhea and abnormal liver function (P>0.05). Conclusions: The prognosis of COVID-19 moderate patients is good. Larger sample size study are needed to investigate the effects of HCQ in the treatment of COVID-19. Subsequent research should determine better endpoint and fully consider the feasibility of experiments such as sample size.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[582, 628]], "text": "negative conversion rate of SARS-CoV-2 nucleic"}, {"id": "T2", "type": "TimeFrame", "offsets": [[665, 694]], "text": "on days 7 after randomization"}, {"id": "T3", "type": "OtherOutcome", "offsets": [[1049, 1085]], "text": "median duration from hospitalization"}, {"id": "T4", "type": "OtherOutcome", "offsets": [[1248, 1294]], "text": "median time for body temperature normalization"}, {"id": "T5", "type": "OtherOutcome", "offsets": [[1419, 1466]], "text": "Radiological progression was shown on CT images"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}]}
{"id": "50", "type": "silver", "text": "Measurements:\n\nSymptoms and severity at baseline and then at days 3, 5, 10, and 14 using a 10-point visual analogue scale. The primary end point was change in overall symptom severity over 14 days.\n\nStudy End Points\n\nThe initial primary outcome was an ordinal outcome by day 14 of not hospitalized, hospitalized, or intensive care unit stay or death. Secondary end points were symptom severity at day 5 and day 14 by 10-point visual analogue scale, nominal incidence of all hospitalizations and deaths, and incidence of study medicine withdrawal.\n\nChanges in End Point and Sample Sizes\n\nBefore the first interim analysis on 24 April 2020, it became apparent that the pooled event rate of hospitalization or death was substantially lower than our initial 10% expectation (original sample size calculations as described in Statistical Analysis section). Without unblinding of treatment allocation or analysis of the data, the principal investigator proposed to the data and safety monitoring board (DSMB) that we modify the primary end point to the change in overall symptom severity over 14 days as longitudinally measured on a 10-point visual analogue scale. The DSMB approved the change on 24 April 2020. The change was necessary because the low event rate of hospitalizations or deaths in the trial would have required increasing the sample size to 6000 participants, which was not attainable. With enrollment of at least 200 participants per group, we determined that the revised trial would have 90% power (with a 2-sided α level of 0.05) to detect a statistically significant difference between the groups for a change in symptom severity score as small as 0.25 point on the 10-point visual analogue scale. The trial halted at the second DSMB meeting on 6 May 2020, when the DSMB determined that sufficient statistical power had been achieved to evaluate the primary outcome.\n\nOutcomes and Follow-up\n\nWe collected self-reported survey data using the Research Electronic Data Capture (REDCap) system (13). We e-mailed participants follow-up surveys on days 1 (medication start date), 3, 5 (medication stop date), 10, and 14 to assess study medication adherence, adverse effects, presence and severity of COVID-19 symptoms, COVID-19 test results, and hospitalization status. If participants were hospitalized within 14 days, we continued follow-up past study completion to assess outcomes. We assessed symptom severity on a 10-point visual analogue scale, where 0 indicated no symptoms and 10 indicated severe symptoms (Supplement). Medication-related adverse events were collected with directed questioning on the most common adverse effects and an open-ended free-text field. For participants who did not respond to follow-up surveys, investigators used text messages, e-mails, or telephone calls to ascertain outcomes from them or their designated third-party contacts. If this was unsuccessful, investigators searched the internet for obituaries or other evidence of vital status.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[1047, 1081]], "text": "change in overall symptom severity"}, {"id": "T2", "type": "TimeFrame", "offsets": [[1082, 1094]], "text": "over 14 days"}, {"id": "T3", "type": "PrimaryOutcome", "offsets": [[281, 349]], "text": "not hospitalized, hospitalized, or intensive care unit stay or death"}, {"id": "T4", "type": "TimeFrame", "offsets": [[268, 277]], "text": "by day 14"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[377, 393]], "text": "symptom severity"}, {"id": "T6", "type": "TimeFrame", "offsets": [[394, 413]], "text": "at day 5 and day 14"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[449, 501]], "text": "nominal incidence of all hospitalizations and deaths"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[507, 545]], "text": "incidence of study medicine withdrawal"}, {"id": "T9", "type": "OtherOutcome", "offsets": [[2144, 2164]], "text": "medication adherence"}, {"id": "T10", "type": "OtherOutcome", "offsets": [[2166, 2181]], "text": "adverse effects"}, {"id": "T11", "type": "OtherOutcome", "offsets": [[2183, 2225]], "text": "presence and severity of COVID-19 symptoms"}, {"id": "T12", "type": "OtherOutcome", "offsets": [[2227, 2248]], "text": "COVID-19 test results"}, {"id": "T13", "type": "OtherOutcome", "offsets": [[2254, 2276]], "text": "hospitalization status"}, {"id": "T14", "type": "TimeFrame", "offsets": [[2053, 2127]], "text": "on days 1 (medication start date), 3, 5 (medication stop date), 10, and 14"}, {"id": "T15", "type": "OtherOutcome", "offsets": [[2536, 2569]], "text": "Medication-related adverse events"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T3", "arg2": "T4"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T5", "arg2": "T6"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T9", "arg2": "T14"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T10", "arg2": "T14"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T11", "arg2": "T14"}, {"id": "R7", "type": "MeasuredAt", "arg1": "T12", "arg2": "T14"}, {"id": "R8", "type": "MeasuredAt", "arg1": "T13", "arg2": "T14"}]}
{"id": "51", "type": "silver", "text": " Outcomes\n\nThe primary outcome was clinical status at 15 days, evaluated with the use of a seven-level ordinal scale. Scores on the scale were defined as follows: a score of 1 indicated not hospitalized with no limitations on activities; 2, not hospitalized but with limitations on activities; 3, hospitalized and not receiving supplemental oxygen; 4, hospitalized and receiving supplemental oxygen; 5, hospitalized and receiving oxygen supplementation administered by a high-flow nasal cannula or noninvasive ventilation; 6, hospitalized and receiving mechanical ventilation; and 7, death.\n\nSecondary outcomes included clinical status at 7 days, evaluated with the use of a six-level ordinal scale (see below and see the Supplementary Appendix); an indication for intubation within 15 days; the receipt of supplemental oxygen administered by a high-flow nasal cannula or noninvasive ventilation between randomization and 15 days; duration of hospital stay; in-hospital death; thromboembolic complications; acute kidney injury; and the number of days alive and free from respiratory support up to 15 days. A day alive and free from respiratory support was defined as any day in which the patient did not receive supplemental oxygen or invasive or noninvasive mechanical ventilation, from randomization to day 15. Patients who died during the 15-day window were assigned a value of 0 days alive and free from respiratory support in this assessment. Safety outcomes are listed in the Supplementary Appendix. All the trial outcomes were assessed by the site investigators, who were aware of the trial-group assignments (except as noted above for patients who had been discharged before day 15 and who were assessed for the primary outcome by means of a blinded telephone interview). No formal adjudication of trial outcomes was performed.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[35, 50]], "text": "clinical status"}, {"id": "T2", "type": "TimeFrame", "offsets": [[51, 61]], "text": "at 15 days"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[63, 589]], "text": "evaluated with the use of a seven-level ordinal scale. Scores on the scale were defined as follows: a score of 1 indicated not hospitalized with no limitations on activities; 2, not hospitalized but with limitations on activities; 3, hospitalized and not receiving supplemental oxygen; 4, hospitalized and receiving supplemental oxygen; 5, hospitalized and receiving oxygen supplementation administered by a high-flow nasal cannula or noninvasive ventilation; 6, hospitalized and receiving mechanical ventilation; and 7, death"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[620, 635]], "text": "clinical status"}, {"id": "T5", "type": "TimeFrame", "offsets": [[636, 645]], "text": "at 7 days"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[750, 775]], "text": "indication for intubation"}, {"id": "T7", "type": "TimeFrame", "offsets": [[776, 790]], "text": "within 15 days"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[796, 826]], "text": "receipt of supplemental oxygen"}, {"id": "T9", "type": "TimeFrame", "offsets": [[896, 929]], "text": "between randomization and 15 days"}, {"id": "T10", "type": "SecondaryOutcome", "offsets": [[931, 956]], "text": "duration of hospital stay"}, {"id": "T11", "type": "SecondaryOutcome", "offsets": [[958, 975]], "text": "in-hospital death"}, {"id": "T12", "type": "SecondaryOutcome", "offsets": [[977, 1005]], "text": "thromboembolic complications"}, {"id": "T13", "type": "SecondaryOutcome", "offsets": [[1007, 1026]], "text": "acute kidney injury"}, {"id": "T14", "type": "SecondaryOutcome", "offsets": [[1036, 1090]], "text": "number of days alive and free from respiratory support"}, {"id": "T15", "type": "TimeFrame", "offsets": [[1091, 1104]], "text": "up to 15 days"}, {"id": "T16", "type": "OutcomeDefinition", "offsets": [[1156, 1311]], "text": "defined as any day in which the patient did not receive supplemental oxygen or invasive or noninvasive mechanical ventilation, from randomization to day 15"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T4", "arg2": "T5"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T6", "arg2": "T7"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T8", "arg2": "T9"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T14", "arg2": "T15"}, {"id": "R7", "type": "DefinedAs", "arg1": "T14", "arg2": "T16"}]}
{"id": "52", "type": "silver", "text": " Abstract\nBackground. Interventions mitigating progression to mechanical ventilation in COVID 19 would markedly improve outcome and reduce healthcare utilization. We hypothesized that immunomodulation with IVIG would improve oxygenation and reduce length of hospital stay and progression to mechanical ventilation in COVID 19 pneumonia.\nMethods. Patients with COVID 19 were randomized 1:1 to prospectively receive standard of care (SOC) plus IVIG 0.5 g/kg/day x 3 days with methylprednisolone 40 mg 30 minutes before infusion versus SOC alone.\n\nClinical data extraction and analysis. Relevant clinical and laboratory information was captured to allow for group comparisons, including the calculation of Charlson comorbidity index (https://www.mdcalc.com/charlson comorbidity index cci) and APACHE II acute illness severity score (https://www.mdcalc.com/apache ii score#next steps). The alveolar arterial (A a) gradient was calculated (https://www.mdcalc.com/a a o2 gradient) for each subject at the time of enrollment based on arterial blood gases when available or based on PaO2 extrapolated SpO2 and fraction of inspired oxygen (FiO2). Interleukin 6 was measured from blood 24 48 hours after enrollment (https://ltd.aruplab.com/Tests/Pub/0051537).\n\nClinical outcomes. The two patient groups were well matched with respect to their\nCharlson comorbidity index and severity of illness APACHE 2 scores (Figure 2). Median\nCharlson index was 2 for both groups. Median APACHE 2 score was 7 for SOC and 7.5 the IVIG study group. Figure 2 demonstrates the subjects in the control SOC and treatment IVIG group that developed a need for mechanical ventilation after study enrollment, denoted as the red data points. An overall trend is for receipt of mechanical ventilation in the IVIG group in the 2 patients with highest comorbidity and illness severity scores, whereas in the SOC group mechanical ventilation requirement developed across the entire spectrum of scores.\nAmong the entire enrolled and evaluated subjects in each arm, 2 patients in the IVIG arm and 7 patients in the control SOC arm developed a need for mechanical ventilation.\nAmong these 7 SOC patients, 6 received ventilation and 1 was made a ‘do not intubate’ and the patient expired within 24 hours. The difference in receipt of mechanical ventilation was not statistically significant between the two groups (p=0.12, Fisher exact test). Among subjects whose respiratory failure progressed to the need for mechanical ventilation, 1 of 2 IVIG subjects and 2 of 3 control subjects also received concomitant convalescent plasma. Concomitant glucocorticoid therapy was given to 5 of the 7 control subjects who progressed to mechanical ventilation. The use of remdesivir was .CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)\nThe copyright holder for this preprintthis version posted July 25, 2020.;https://doi.org/10.1101/2020.07.20.20157891doi:medRxiv preprint 11 dependent on its availability after May 13, 2020 and therefore all patients admitted after that date whose respiratory failure progressed to needing mechanical ventilation received it. This resulted in 1 of 2 IVIG patients and 3 of 7 SOC subjects that required ventilation receiving remdesivir.\nAlveolar arterial (A a) gradients were calculated directly from arterial blood gas or estimated based on PaO2 and FiO2 measurement. Based on an increase in APACHE II severity of illness scoring associated with achieving and A a gradient of > 200 mm Hg (+2 points), subjects were stratified into those with A a gradient < 200 mm Hg or >200 mm Hg, corresponding to a PaO2/FiO2 of <140, or the approximate requirement of 6 liters O2 by nasal cannula for a PaO2 of <92%. As shown in Figure 3A, none of the 7 subjects (5 SOC, 2 IVIG) with A a gradient < 200 mm Hg progressed to mechanical ventilation, but for subjects with A a gradient of > 200 mm Hg at enrollment, the progression to mechanical ventilation was 7/12 (58%) in the SOC control arm vs 2/14 (14%) in the IVIG, a difference that was statistically significant (p=0.038, Fisher Exact test).\nEvaluation of overall hospital course, including length of hospital stay and length of ICU stay also was highly dependent on A a gradient stratification. Among the 7 patients with A a gradient < 200 mm Hg, no patient required ICU stay during their illness and length of hospital stay were 3 8 days. However, for the subjects with A a gradient > 200 at enrollment, median length of hospital stay was 19 (range 4 30) and 11 (range 5 22) days for SOC and IVIG groups, respectively (p=0.013, Mann Whitney U test, Figure 3B).\nMedian ICU stay were 12.5 days (range 1 29) and 2.5 days (range 0 16) for SOC and IVIG, respectively (p=0.006, Mann Whitney U test, Figure 3C). Total ventilator patient .CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)\nThe copyright holder for this preprintthis version posted July 25, 2020.;https://doi.org/10.1101/2020.07.20.20157891doi:medRxiv preprint 12 days were 98 days for SOC (5.8 days/patient enrolled) and 23 days for the IVIG group (1.4 days/patient enrolled). The supplementary Figure shows schematically the hospital stays from the time of admission of the 33 enrolled patients with respect to medical floor and ICU stays with and without mechanical ventilation.\nImprovement in oxygenation was evaluated by examining the PaO2/FiO2 ratio at the day of enrollment and 7 days after enrollment in individual subjects for SOC (Figure 4A) and IVIG (Figure 4B). Differences in day 7 PaO2/FiO2 minus enrollment PaO2/FiO2 are shown in Figure 4C for both groups, with negative numbers representing worsening in oxygenation. Among the entire subject population, median improvement PaO2/FiO2 for IVIG was +153 (range +35 to + 330) and was better than SOC +90 (range 115 to\n+280), but did not reach statistical significance (p=0·057, Mann Whitney U test).\nHowever, when refocusing on the higher risk patients with A a gradient >200 at enrollment, median improvement of PaO2/FiO2 for IVIG was significantly greater than SOC, with median (range) of +131 (+35 to +330) versus +44·5 ( 115 to +157) (p=0·01,\nMann Whitney U test).\nFigure 4C denotes subjects in the SOC group who did not receive any glucocorticoid therapy as red data points. Seven subjects in SOC did not receive glucocorticoids, 4 of whom were in the low risk group with A a gradient < 200. Of the remaining 3 patients, 2 progressed to requiring mechanical ventilation, one of which was made do not intubate and died. PaO2/FiO2 changes between enrollment and day 7 of the 10 SOC patients who received glucocorticoid therapy (median 11 days) was median +53 (range 115 to\n+216), a difference that remained significantly lower than the IVIG group (p=0.0057,\nMann Whiney U test). .CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)\nThe copyright holder for this preprintthis version posted July 25, 2020.;https://doi.org/10.1101/2020.07.20.20157891doi:medRxiv preprint\n\n", "entities": [{"id": "T1", "type": "OtherOutcome", "offsets": [[1628, 1650]], "text": "mechanical ventilation"}, {"id": "T2", "type": "OtherOutcome", "offsets": [[3369, 3402]], "text": "Alveolar arterial (A a) gradients"}, {"id": "T4", "type": "OtherOutcome", "offsets": [[4737, 4752]], "text": "Median ICU stay"}, {"id": "T5", "type": "OtherOutcome", "offsets": [[4580, 4610]], "text": "median length of hospital stay"}, {"id": "T3", "type": "OtherOutcome", "offsets": [[5566, 5592]], "text": "Improvement in oxygenation"}, {"id": "T6", "type": "OtherOutcome", "offsets": [[6471, 6505]], "text": "receive any glucocorticoid therapy"}], "relations": []}
{"id": "53", "type": "silver", "text": " Outcomes assessment: The primary outcomes included virological and clinical evaluations.\nTime to SARS-CoV-2 RNA negativization (absence of the virus according to the RT-PCR) in positive patients after starting antiviral therapy was the virological endpoint. It was expressed as the percentage of patients negative to SARS-CoV-2 by RT-PCR in throat exudate tissue calculated at 48, 72, 96 and 120 hours. Days to reach the viral negativization were analyzed by Kaplan-Meier plots and compared with a Log-rank test. Hazard Ratio with 95% CI of ratio was also calculated.\nThe clinical evaluation considered the time to progression to severe COVID-19 and it was calculated by the percentage of patients who became severely ill after the end of the antiviral treatment under investigation.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[90, 127]], "text": "Time to SARS-CoV-2 RNA negativization"}, {"id": "T2", "type": "OutcomeDefinition", "offsets": [[128, 173]], "text": "(absence of the virus according to the RT-PCR"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[283, 363]], "text": "percentage of patients negative to SARS-CoV-2 by RT-PCR in throat exudate tissue"}, {"id": "T4", "type": "TimeFrame", "offsets": [[375, 402]], "text": "at 48, 72, 96 and 120 hours"}, {"id": "T5", "type": "PrimaryOutcome", "offsets": [[573, 592]], "text": "clinical evaluation"}, {"id": "T6", "type": "OutcomeDefinition", "offsets": [[608, 646]], "text": "time to progression to severe COVID-19"}, {"id": "T7", "type": "OutcomeDefinition", "offsets": [[676, 783]], "text": "percentage of patients who became severely ill after the end of the antiviral treatment under investigation"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T1", "arg2": "T4"}, {"id": "R4", "type": "DefinedAs", "arg1": "T5", "arg2": "T6"}, {"id": "R5", "type": "DefinedAs", "arg1": "T5", "arg2": "T7"}]}
{"id": "54", "type": "silver", "text": "The objective of the pilot stage of the study was a preliminary assessment of the efficacy and safety of AVIFAVIR, and to select the optimal dosing regimen for further evaluation at the pivotal stage (Phase III). The primary efficacy endpoint at the pilot stage was the elimination of SARS-CoV-2 by Day 10 (defined as two negative PCR tests with at least a 24-hour interval). Qualitative Real-Time RT-PCR tests were performed at local laboratories of the clinical sites or in the central laboratory of Rospotrebnadzor.\n\nThe study assessments included daily vital signs, SpO2 and WHO Ordinal Scale for Clinical Improvement (WHO-OSCI); PCR for SARS-CoV-2 detection in nasopharyngeal and/or oropharyngeal swabs at baseline and on Days 5, 10, and 15; chest computed tomography (CT) scan at baseline and on Day 15; physical examination, complete blood count, biochemistry, C-reactive protein (CRP), urinalysis, and electrocardiogram at baseline and on Days 5 and 15. If not discharged from the hospital earlier, the patients attended follow-up visits on Day 22 and Day 29. All patients were followed until Day 29.\n\nThe “go-no-go” decision to start the pivotal stage of the study was based on the exact single-stage Phase II assessment at one-sided α = 0.05 and 80% power [8]. 13/18 (72.2%) or more patients would have been sufficient to demonstrate that the viral clearance in 80% of patients by Day 10 was plausible, and that the response was greater than the presumably noneffective level of 50%. The secondary endpoints that were assessed during the interim analysis were the rate of viral clearance by Day 5, time to normalization of clinical symptoms (ie, body temperature), changes on CT scan by Day 15, and incidence and severity of adverse events related to the study drug. ", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[270, 295]], "text": "elimination of SARS-CoV-2"}, {"id": "T2", "type": "TimeFrame", "offsets": [[296, 305]], "text": "by Day 10"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[307, 373]], "text": "defined as two negative PCR tests with at least a 24-hour interval"}, {"id": "T4", "type": "OtherOutcome", "offsets": [[551, 568]], "text": "daily vital signs"}, {"id": "T5", "type": "OtherOutcome", "offsets": [[570, 632]], "text": "SpO2 and WHO Ordinal Scale for Clinical Improvement (WHO-OSCI)"}, {"id": "T6", "type": "OtherOutcome", "offsets": [[634, 662]], "text": "PCR for SARS-CoV-2 detection"}, {"id": "T7", "type": "TimeFrame", "offsets": [[724, 745]], "text": "on Days 5, 10, and 15"}, {"id": "T8", "type": "OtherOutcome", "offsets": [[747, 782]], "text": "chest computed tomography (CT) scan"}, {"id": "T9", "type": "TimeFrame", "offsets": [[783, 808]], "text": "at baseline and on Day 15"}, {"id": "T10", "type": "OtherOutcome", "offsets": [[810, 830]], "text": "physical examination"}, {"id": "T11", "type": "OtherOutcome", "offsets": [[832, 852]], "text": "complete blood count"}, {"id": "T12", "type": "OtherOutcome", "offsets": [[854, 866]], "text": "biochemistry"}, {"id": "T13", "type": "OtherOutcome", "offsets": [[868, 892]], "text": "C-reactive protein (CRP)"}, {"id": "T14", "type": "OtherOutcome", "offsets": [[894, 904]], "text": "urinalysis"}, {"id": "T15", "type": "OtherOutcome", "offsets": [[910, 927]], "text": "electrocardiogram"}, {"id": "T16", "type": "TimeFrame", "offsets": [[928, 960]], "text": "at baseline and on Days 5 and 15"}, {"id": "T17", "type": "SecondaryOutcome", "offsets": [[1574, 1597]], "text": "rate of viral clearance"}, {"id": "T18", "type": "TimeFrame", "offsets": [[1598, 1606]], "text": "by Day 5"}, {"id": "T19", "type": "SecondaryOutcome", "offsets": [[1608, 1673]], "text": "time to normalization of clinical symptoms (ie, body temperature)"}, {"id": "T20", "type": "SecondaryOutcome", "offsets": [[1675, 1693]], "text": "changes on CT scan"}, {"id": "T21", "type": "TimeFrame", "offsets": [[1694, 1703]], "text": "by Day 15"}, {"id": "T22", "type": "SecondaryOutcome", "offsets": [[1709, 1775]], "text": "incidence and severity of adverse events related to the study drug"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T6", "arg2": "T7"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T8", "arg2": "T9"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T15", "arg2": "T16"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T17", "arg2": "T18"}, {"id": "R7", "type": "MeasuredAt", "arg1": "T20", "arg2": "T21"}]}
{"id": "55", "type": "silver", "text": " Outcome measurement\nThe primary endpoint was to evaluate the efficacy of HCQ with respect to time to negative rRT-PCR assessments from randomization up to 14 days. The secondary endpoints were to evaluate the proportion of negative viral rRT-PCR on hospital day 14, the resolution of clinical symptoms (time to clinical recovery), the proportion of discharges by day 14, and the mortality rate. HCQ safety and tolerability were also evaluated.\n\n", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[62, 130]], "text": "efficacy of HCQ with respect to time to negative rRT-PCR assessments"}, {"id": "T2", "type": "TimeFrame", "offsets": [[131, 163]], "text": "from randomization up to 14 days"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[210, 246]], "text": "proportion of negative viral rRT-PCR"}, {"id": "T4", "type": "TimeFrame", "offsets": [[247, 265]], "text": "on hospital day 14"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[271, 330]], "text": "resolution of clinical symptoms (time to clinical recovery)"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[336, 360]], "text": "proportion of discharges"}, {"id": "T7", "type": "TimeFrame", "offsets": [[361, 370]], "text": "by day 14"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[380, 394]], "text": "mortality rate"}, {"id": "T9", "type": "OtherOutcome", "offsets": [[396, 406]], "text": "HCQ safety"}, {"id": "T10", "type": "OtherOutcome", "offsets": [[411, 423]], "text": "tolerability"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T3", "arg2": "T4"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T6", "arg2": "T7"}]}
{"id": "56", "type": "silver", "text": "Outcomes\n\nThe primary outcome was the difference in the interval from baseline (initiation of antiviral treatment) to SARS-CoV-2 nucleic acid negativity by nasopharyngeal swab among the three antiviral treatment groups, with each of these two tests at least 24 h apart. The secondary outcomes included the differences among the three groups in the proportion of patients with SARS-CoV-2 nucleic acid negativity at day 14, the mortality rate at day 28, the proportion of patients re-classified as severe cases during the study period, the incidence of adverse events during the study period, and the proportion of therapeutic discontinuations due to adverse events during the study period.  SARS-CoV-2 nucleic acid negativity was defined as the presence of negative SARS-COV-2 results in at least two consecutive nasopharyngeal swabs by reverse transcriptase polymerase chain reaction (RT-PCR), with an interval of at least 24 h between the two time points of swab-taking. Of the two consecutive negative RT-PCR test results, the first negative result was used to calculate the interval between baseline and SARS-COV-2 nucleic acid negativity.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[38, 218]], "text": "difference in the interval from baseline (initiation of antiviral treatment) to SARS-CoV-2 nucleic acid negativity by nasopharyngeal swab among the three antiviral treatment groups"}, {"id": "T2", "type": "SecondaryOutcome", "offsets": [[306, 410]], "text": "differences among the three groups in the proportion of patients with SARS-CoV-2 nucleic acid negativity"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[426, 440]], "text": "mortality rate"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[456, 532]], "text": "proportion of patients re-classified as severe cases during the study period"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[538, 589]], "text": "incidence of adverse events during the study period"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[599, 687]], "text": "proportion of therapeutic discontinuations due to adverse events during the study period"}, {"id": "T7", "type": "TimeFrame", "offsets": [[411, 420]], "text": "at day 14"}, {"id": "T8", "type": "TimeFrame", "offsets": [[441, 450]], "text": "at day 28"}, {"id": "T9", "type": "OutcomeDefinition", "offsets": [[729, 970]], "text": "defined as the presence of negative SARS-COV-2 results in at least two consecutive nasopharyngeal swabs by reverse transcriptase polymerase chain reaction (RT-PCR), with an interval of at least 24 h between the two time points of swab-taking"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T2", "arg2": "T7"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T3", "arg2": "T8"}, {"id": "R3", "type": "DefinedAs", "arg1": "T1", "arg2": "T9"}]}
{"id": "57", "type": "silver", "text": " Methods:\nTrial Design and Participants:\nIt is an open label, randomized clinical trial conducted at Bahria International Hospital, Lahore, to evaluate the effects of a combination therapy including Dexamethasone and Aprepitant in hospitalized patients with Covid-19. The trial was conducted in accordance with the principles of the\nInternational Conference on Harmonization Good Clinical Practice guidelines and approved by the\nBahria International Hospital Ethic Committee and informed consent was obtained from the patients.\nRandomization:\nCase report form included demographics, major comorbidities, medication already being administered. Patients were divided randomly into two arms Control (A) and Interventioanl (B). Both the arms received routine management including Dexamethasone 20mg, but one arm received\nAprepitant capsule 80mg once a day as an addition for 3-5 days depending on the condition of patient.\nInclusion criteria was admitted patients above 18 years, both genders, lab confirmed Covid-19 positive based on PCR, more than 72 hours since the appearance of first symptoms. Patients with moderate to critical stages were included. Patients with respiratory diseases other than Covid-19 infection and pregnant females were excluded. Primary endpoint was total in hospital days and the duration of disease. Patients and care givers were not blinded to the allocated treatment. Lab investigations including total blood cell count, total leukocyte count, C-reactive protein, D-dimers, lactate dehydrogenase, oxygen saturation was performed on daily basis to monitor the status of patient.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[1274, 1296]], "text": "total in hospital days"}, {"id": "T2", "type": "PrimaryOutcome", "offsets": [[1305, 1324]], "text": "duration of disease"}, {"id": "T3", "type": "OtherOutcome", "offsets": [[1425, 1447]], "text": "total blood cell count"}, {"id": "T4", "type": "OtherOutcome", "offsets": [[1449, 1470]], "text": "total leukocyte count"}, {"id": "T5", "type": "OtherOutcome", "offsets": [[1472, 1490]], "text": "C-reactive protein"}, {"id": "T6", "type": "OtherOutcome", "offsets": [[1492, 1500]], "text": "D-dimers"}, {"id": "T7", "type": "OtherOutcome", "offsets": [[1502, 1523]], "text": "lactate dehydrogenase"}, {"id": "T8", "type": "OtherOutcome", "offsets": [[1525, 1542]], "text": "oxygen saturation"}], "relations": []}
{"id": "59", "type": "silver", "text": " Outcomes\n\nThe primary outcome was 28-day mortality. Secondary endpoints included early mortality (Days 7 and 14), the need for orotracheal intubation by Day 7, and the proportion of patients with an oxygenation index (PaO2/FiO2) < 100 by Day 7. Post hoc exploratory analyses were for mortality rates in subgroups (whether enrolled already in IMV or not, age, and some laboratorial predictors of severity). Subgroup analyses were based on the same direction of prespecified hypotheses (benefit of MP), consistency across other studies, and a strong preexisting biological rationale supporting the apparent subgroup effect [18]. We also analyzed the length of hospitalization, the radiological presence of fibrosis or Bronchiolitis Obliterans with Organizing Pneumonia (BOOP) after Day 7 [19], a need for insulin or an increase in the dosage in diabetic patients, a positive blood culture (Bactec), and the presence of viral RNA in the naso-/oropharyngeal swab at Day 7. As per protocol, the Day 120 visit will focus on the respiratory sequelae of surviving patients; therefore, those data will not be presented here.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[42, 51]], "text": "mortality"}, {"id": "T2", "type": "SecondaryOutcome", "offsets": [[82, 97]], "text": "early mortality"}, {"id": "T3", "type": "TimeFrame", "offsets": [[99, 112]], "text": "Days 7 and 14"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[119, 150]], "text": "need for orotracheal intubation"}, {"id": "T5", "type": "TimeFrame", "offsets": [[151, 159]], "text": "by Day 7"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[169, 235]], "text": "proportion of patients with an oxygenation index (PaO2/FiO2) < 100"}, {"id": "T7", "type": "TimeFrame", "offsets": [[236, 244]], "text": "by Day 7"}, {"id": "T8", "type": "OtherOutcome", "offsets": [[649, 674]], "text": "length of hospitalization"}, {"id": "T9", "type": "OtherOutcome", "offsets": [[680, 774]], "text": "radiological presence of fibrosis or Bronchiolitis Obliterans with Organizing Pneumonia (BOOP)"}, {"id": "T10", "type": "TimeFrame", "offsets": [[775, 786]], "text": "after Day 7"}, {"id": "T11", "type": "OtherOutcome", "offsets": [[795, 861]], "text": "need for insulin or an increase in the dosage in diabetic patients"}, {"id": "T12", "type": "OtherOutcome", "offsets": [[863, 896]], "text": "a positive blood culture (Bactec)"}, {"id": "T13", "type": "OtherOutcome", "offsets": [[906, 959]], "text": "presence of viral RNA in the naso-/oropharyngeal swab"}, {"id": "T14", "type": "TimeFrame", "offsets": [[960, 968]], "text": "at Day 7"}, {"id": "T15", "type": "TimeFrame", "offsets": [[35, 41]], "text": "28-day"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T2", "arg2": "T3"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T4", "arg2": "T5"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T6", "arg2": "T7"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T9", "arg2": "T10"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T13", "arg2": "T14"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T1", "arg2": "T15"}]}
{"id": "6", "type": "silver", "text": "Endpoints\n 5 days after enrollment or severe adverse reactions appeared was the observation endpoint. Changes in time to clinical recovery (TTCR) and clinical characteristics of patients were evaluated after administration. TTCR is defined as the return of body temperature and cough relief, maintained for more than 72 h. Normalization and mitigation criteria included the following: a. Body temperature ≤ 36.6 °C on the surface, ≤ 37.2 °C under the armpit and mouth or ≤ 37.8 °C in the rectum and tympanic membrane; b. Cough from patients’ reports, slight or no cough was in the asymptomatic range. Body temperature, cough check three times daily to calculate the average level. For radiological changes, the chest CT results in one day before (Day 0) and one day after (Day 6) the study for evaluation. Pulmonary recovery is defined as three levels: exacerbated, unchanged, and improved, moderately improved when less than 50 % of pneumonia were absorbed, and more than 50 % means significantly improved.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[11, 71]], "text": "5 days after enrollment or severe adverse reactions appeared"}, {"id": "T2", "type": "OtherOutcome", "offsets": [[102, 145]], "text": "Changes in time to clinical recovery (TTCR)"}, {"id": "T3", "type": "OtherOutcome", "offsets": [[150, 186]], "text": "clinical characteristics of patients"}, {"id": "T4", "type": "OutcomeDefinition", "offsets": [[232, 321]], "text": "defined as the return of body temperature and cough relief, maintained for more than 72 h"}, {"id": "T5", "type": "OtherOutcome", "offsets": [[711, 727]], "text": "chest CT results"}, {"id": "T6", "type": "TimeFrame", "offsets": [[731, 804]], "text": "one day before (Day 0) and one day after (Day 6) the study for evaluation"}, {"id": "T7", "type": "OutcomeDefinition", "offsets": [[839, 1006]], "text": "three levels: exacerbated, unchanged, and improved, moderately improved when less than 50 % of pneumonia were absorbed, and more than 50 % means significantly improved"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T2", "arg2": "T4"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T5", "arg2": "T6"}, {"id": "R3", "type": "DefinedAs", "arg1": "T5", "arg2": "T7"}]}
{"id": "60", "type": "silver", "text": " \nOutcomes\n\nThe primary outcomes were the rate of nucleic acid negativity conversion of SARS-CoV-2 and the negativity conversion time. Nucleic acid conversion rate was defined as the ratio of patients with negativity nucleic acid testing in FNC group to all patients in FNC group at a certain point in the follow-up process. Secondary outcomes were the improvement rate of chest CT images, the time required for the body temperature returning to normal and the improvement in respiratory symptoms and signs. The improvement of chest CT images was defined as a significant reduction in the range of lesions and inflammation. The results for this outcome were double-checked by two radiologists.\n\nSafety was regularly assessed by monitoring vital signs (heart rate, respiratory rate, systolic pressure, diastolic pressure), changes in laboratory values (liver function, renal function), and adverse events (including type, incidence, severity, time and drug correlation, and assessment of severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], version 5.0).\n", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[42, 98]], "text": "rate of nucleic acid negativity conversion of SARS-CoV-2"}, {"id": "T2", "type": "PrimaryOutcome", "offsets": [[107, 133]], "text": "negativity conversion time"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[168, 323]], "text": "defined as the ratio of patients with negativity nucleic acid testing in FNC group to all patients in FNC group at a certain point in the follow-up process"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[353, 388]], "text": "improvement rate of chest CT images"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[394, 452]], "text": "time required for the body temperature returning to normal"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[461, 506]], "text": "improvement in respiratory symptoms and signs"}, {"id": "T7", "type": "OutcomeDefinition", "offsets": [[547, 623]], "text": "defined as a significant reduction in the range of lesions and inflammation."}, {"id": "T8", "type": "OtherOutcome", "offsets": [[739, 820]], "text": "vital signs (heart rate, respiratory rate, systolic pressure, diastolic pressure)"}, {"id": "T9", "type": "OtherOutcome", "offsets": [[822, 883]], "text": "changes in laboratory values (liver function, renal function)"}, {"id": "T10", "type": "OtherOutcome", "offsets": [[889, 1111]], "text": "adverse events (including type, incidence, severity, time and drug correlation, and assessment of severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], version 5.0)"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}, {"id": "R2", "type": "DefinedAs", "arg1": "T4", "arg2": "T7"}]}
{"id": "61", "type": "silver", "text": " End points\nAll AEs, serious and non-serious, were to be reported. Immediately reportable serious adverse events included adverse events that resulted in death and new life-threatening events. The primary outcome was defined as relative change (%) from baseline (day 1 prior to study drug administration at ± 1h of randomization) in PaO2/FiO2 ratio in supine position at day five. During the study it became clear that several patients in prone position could not be assessed regularly in supine position because of severe hypoxemia. It was therefore decided to focus on all\nPaO2/FiO2 ratioassessments (irrespective of position) and perform an analysis of supine position values for sensitivity. Various additional secondary and other outcomes were pre-defined in line with the exploratory nature of the initial phase of the clinical study. Subgroup and sensitivity analyses for patients intubated at or within six hours after randomization was performed.", "entities": [{"id": "T1", "type": "OtherOutcome", "offsets": [[12, 44]], "text": "All AEs, serious and non-serious"}, {"id": "T2", "type": "PrimaryOutcome", "offsets": [[228, 367]], "text": "relative change (%) from baseline (day 1 prior to study drug administration at ± 1h of randomization) in PaO2/FiO2 ratio in supine position"}, {"id": "T3", "type": "TimeFrame", "offsets": [[368, 379]], "text": "at day five"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T2", "arg2": "T3"}]}
{"id": "62", "type": "silver", "text": " Outcomes\nReductions of C reactive protein levels at day 5 and 8 after randomization were chosen as primary outcome. Secondary outcomes included admission to ICU within 15 and 30 days from randomization, occurrence of mechanical ventilation within 15 and 30 days from randomization, death within 15 and 30 days from randomization, composite occurrence of admission to ICU, mechanical ventilation or death within 15 and 30 days from randomization, proportion of patients requiring supplemental oxygen at day 15 (or with an oxygen saturation lower than 96% while breathing room air), time from randomization to discharge up to day 15 from randomization, and significative differences in serum lactate dehydrogenase levels at day 5 and 8. All the trial outcomes were assessed by the site investigators, who were aware of the trial-group assignments.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[10, 49]], "text": "Reductions of C reactive protein levels"}, {"id": "T2", "type": "TimeFrame", "offsets": [[50, 84]], "text": "at day 5 and 8 after randomization"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[145, 161]], "text": "admission to ICU"}, {"id": "T4", "type": "TimeFrame", "offsets": [[162, 202]], "text": "within 15 and 30 days from randomization"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[204, 240]], "text": "occurrence of mechanical ventilation"}, {"id": "T6", "type": "TimeFrame", "offsets": [[241, 281]], "text": "within 15 and 30 days from randomization"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[283, 288]], "text": "death"}, {"id": "T8", "type": "TimeFrame", "offsets": [[289, 329]], "text": "within 15 and 30 days from randomization"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[331, 404]], "text": "composite occurrence of admission to ICU, mechanical ventilation or death"}, {"id": "T10", "type": "TimeFrame", "offsets": [[405, 445]], "text": "within 15 and 30 days from randomization"}, {"id": "T11", "type": "SecondaryOutcome", "offsets": [[447, 499]], "text": "proportion of patients requiring supplemental oxygen"}, {"id": "T12", "type": "TimeFrame", "offsets": [[500, 509]], "text": "at day 15"}, {"id": "T13", "type": "SecondaryOutcome", "offsets": [[582, 618]], "text": "time from randomization to discharge"}, {"id": "T14", "type": "TimeFrame", "offsets": [[619, 650]], "text": "up to day 15 from randomization"}, {"id": "T15", "type": "SecondaryOutcome", "offsets": [[656, 719]], "text": "significative differences in serum lactate dehydrogenase levels"}, {"id": "T16", "type": "TimeFrame", "offsets": [[720, 734]], "text": "at day 5 and 8"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T3", "arg2": "T4"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T5", "arg2": "T6"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T7", "arg2": "T8"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T9", "arg2": "T10"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T11", "arg2": "T12"}, {"id": "R7", "type": "MeasuredAt", "arg1": "T13", "arg2": "T14"}, {"id": "R8", "type": "MeasuredAt", "arg1": "T15", "arg2": "T16"}]}
{"id": "63", "type": "silver", "text": " Outcomes. The primary outcome was the time to clinical improvement (TTCI) as defined by the Cap-China Network 57, which was employed in the LOTUS China trial 11 and recommended by the World Health Organization. TTCI refers to the time from randomization to an improvement of two points on the seven-category ordinal scale as follows 58 (or discharge alive from the hospital): 1, not hospitalized with resumption of normal activities; 2, not hospitalized, but unable to resume normal activities; 3, hospitalized, not requiring supplemental oxygen; 4, hospitalized, requiring supplemental oxygen; 5, hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation; 6, hospitalized, requiring ECMO, invasive mechanical ventilation, or both; or 7, death. The secondary outcomes were as follows: percentage of patients on seven-category scale on days 7, 14 and 21; time on mechanical ventilation; time of hospitalization of survivors; time on oxygen support; time from randomization to hospital discharge; time from randomization to death; and frequency of severe adverse events as defined by National Cancer Institute Common\n", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[39, 74]], "text": "time to clinical improvement (TTCI)"}, {"id": "T2", "type": "OutcomeDefinition", "offsets": [[78, 777]], "text": "defined by the Cap-China Network 57, which was employed in the LOTUS China trial 11 and recommended by the World Health Organization. TTCI refers to the time from randomization to an improvement of two points on the seven-category ordinal scale as follows 58 (or discharge alive from the hospital): 1, not hospitalized with resumption of normal activities; 2, not hospitalized, but unable to resume normal activities; 3, hospitalized, not requiring supplemental oxygen; 4, hospitalized, requiring supplemental oxygen; 5, hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation; 6, hospitalized, requiring ECMO, invasive mechanical ventilation, or both; or 7, death"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[819, 865]], "text": "percentage of patients on seven-category scale"}, {"id": "T4", "type": "TimeFrame", "offsets": [[866, 886]], "text": "on days 7, 14 and 21"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[888, 918]], "text": "time on mechanical ventilation"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[920, 956]], "text": "time of hospitalization of survivors"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[958, 980]], "text": "time on oxygen support"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[982, 1027]], "text": "time from randomization to hospital discharge"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[1029, 1061]], "text": "time from randomization to death"}, {"id": "T10", "type": "SecondaryOutcome", "offsets": [[1067, 1101]], "text": "frequency of severe adverse events"}, {"id": "T11", "type": "OutcomeDefinition", "offsets": [[1116, 1148]], "text": "National Cancer Institute Common"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T3", "arg2": "T4"}, {"id": "R3", "type": "DefinedAs", "arg1": "T10", "arg2": "T11"}]}
{"id": "64", "type": "silver", "text": " Main Outcomes and Measures  The primary end point was clinical status on day 11 on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7). Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicates difference in clinical status distribution toward category 7 for the remdesivir group vs the standard care group.\n\n\nEnd Points\n\nThe primary efficacy end point was the distribution of clinical status assessed on the 7-point ordinal scale on study day 11. If remdesivir treatment improves outcomes, the distribution of scores among patients who received remdesivir should shift more toward the higher values of the scale than the distribution of scores among patients who received standard care.\n\nThe secondary end point was the proportion of patients with adverse events throughout the duration of the study. Prespecified exploratory end points were (1) time to recovery (improvement from a baseline score of 2-5 to a score of 6 or 7 or from a baseline score of 6 to a score of 7); (2) time to modified recovery (improvement from a baseline score of 2-4 to a score of 5-7, improvement from a baseline score of 5 to a score of 6-7, or improvement from a baseline score of 6 to a score of 7); (3) time to clinical improvement (≥2-point improvement from baseline on the 7-point ordinal scale); (4) time to 1-point or larger improvement; and (5) time to discontinuation of any oxygen support. The proportion of patients with these end points was also assessed on days 5, 7, and 11. Other exploratory end points were duration of hospitalization, duration of different modes of respiratory support, and all-cause mortality. Due to logistical issues at the time of study implementation, virological and pharmacokinetic measurements were limited, including SARS-CoV-2 polymerase chain reaction tests on day 5 and day 10, and are not presented.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[55, 70]], "text": "clinical status"}, {"id": "T2", "type": "TimeFrame", "offsets": [[71, 80]], "text": "on day 11"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[81, 166]], "text": "on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7)"}, {"id": "T4", "type": "PrimaryOutcome", "offsets": [[517, 586]], "text": "distribution of clinical status assessed on the 7-point ordinal scale"}, {"id": "T5", "type": "TimeFrame", "offsets": [[587, 602]], "text": "on study day 11"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[877, 919]], "text": "proportion of patients with adverse events"}, {"id": "T7", "type": "TimeFrame", "offsets": [[920, 956]], "text": "throughout the duration of the study"}, {"id": "T8", "type": "OtherOutcome", "offsets": [[1003, 1019]], "text": "time to recovery"}, {"id": "T9", "type": "OutcomeDefinition", "offsets": [[1021, 1128]], "text": "improvement from a baseline score of 2-5 to a score of 6 or 7 or from a baseline score of 6 to a score of 7"}, {"id": "T10", "type": "OtherOutcome", "offsets": [[1135, 1160]], "text": "time to modified recovery"}, {"id": "T11", "type": "OutcomeDefinition", "offsets": [[1162, 1337]], "text": "improvement from a baseline score of 2-4 to a score of 5-7, improvement from a baseline score of 5 to a score of 6-7, or improvement from a baseline score of 6 to a score of 7"}, {"id": "T12", "type": "OtherOutcome", "offsets": [[1344, 1372]], "text": "time to clinical improvement"}, {"id": "T13", "type": "OutcomeDefinition", "offsets": [[1373, 1437]], "text": "(≥2-point improvement from baseline on the 7-point ordinal scale"}, {"id": "T14", "type": "OtherOutcome", "offsets": [[1444, 1481]], "text": "time to 1-point or larger improvement"}, {"id": "T15", "type": "OtherOutcome", "offsets": [[1491, 1536]], "text": "time to discontinuation of any oxygen support"}, {"id": "T16", "type": "OtherOutcome", "offsets": [[1661, 1688]], "text": "duration of hospitalization"}, {"id": "T17", "type": "TimeFrame", "offsets": [[1605, 1625]], "text": "on days 5, 7, and 11"}, {"id": "T18", "type": "OtherOutcome", "offsets": [[1690, 1740]], "text": "duration of different modes of respiratory support"}, {"id": "T19", "type": "OtherOutcome", "offsets": [[1746, 1765]], "text": "all-cause mortality"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T4", "arg2": "T5"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T6", "arg2": "T7"}, {"id": "R5", "type": "DefinedAs", "arg1": "T8", "arg2": "T9"}, {"id": "R6", "type": "DefinedAs", "arg1": "T10", "arg2": "T11"}, {"id": "R7", "type": "DefinedAs", "arg1": "T12", "arg2": "T13"}, {"id": "R8", "type": "MeasuredAt", "arg1": "T8", "arg2": "T17"}, {"id": "R9", "type": "MeasuredAt", "arg1": "T10", "arg2": "T17"}, {"id": "R10", "type": "MeasuredAt", "arg1": "T12", "arg2": "T17"}, {"id": "R11", "type": "MeasuredAt", "arg1": "T14", "arg2": "T17"}, {"id": "R12", "type": "MeasuredAt", "arg1": "T15", "arg2": "T17"}]}
{"id": "65", "type": "silver", "text": " Methods  A randomized, controlled, open-label study of Auxora was conducted in adults with severe or critical COVID-19 pneumonia. Patients were randomized 2:1 to receive three doses of once-daily Auxora versus standard of care (SOC) alone. The primary objective was to assess the safety and tolerability of Auxora. Following FDA guidance, study enrollment was halted early to allow for transition to a randomized, blinded, placebo-controlled study.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[281, 314]], "text": "safety and tolerability of Auxora"}], "relations": []}
{"id": "66", "type": "silver", "text": " Outcomes\n\nThe primary endpoint of this trial was clinical recovery within 14 days of enrolment. Clinical recovery was defined as normalization of fever (≤37.2°C), respiratory rate (≤24/min) and oxygen saturation (≥94%) without supplementary oxygen therapy sustained for at least 24 h. If patients maintained these criteria for over 24 h they were safely discharged from hospital. Other secondary endpoints included all-cause mortality, requirement for mechanical ventilation, duration of hospital stay and time to hospital discharge. Safety endpoints were measured as frequencies of serious adverse events. Outcomes were extracted from patient files and medical progress notes by a researcher blinded to the allocation of patients.\n", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[50, 67]], "text": "clinical recovery"}, {"id": "T2", "type": "TimeFrame", "offsets": [[68, 95]], "text": "within 14 days of enrolment"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[119, 284]], "text": "defined as normalization of fever (≤37.2°C), respiratory rate (≤24/min) and oxygen saturation (≥94%) without supplementary oxygen therapy sustained for at least 24 h"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[416, 435]], "text": "all-cause mortality"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[437, 475]], "text": "requirement for mechanical ventilation"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[477, 502]], "text": "duration of hospital stay"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[507, 533]], "text": "time to hospital discharge"}, {"id": "T8", "type": "OtherOutcome", "offsets": [[569, 606]], "text": "frequencies of serious adverse events"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}]}
{"id": "67", "type": "silver", "text": " Outcome\nThe primary outcome measure was a composite endpoint that included in-hospital all-cause mortality, escalation to ICU admission, or progression of respiratory insufficiency that required non-invasive ventilation (NIV).\nThe secondary outcomes were the effects on the individual components of the composite endpoint and laboratory biomarkers at baseline and 6 days after inclusion (time window 4-8 days).", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[76, 226]], "text": "in-hospital all-cause mortality, escalation to ICU admission, or progression of respiratory insufficiency that required non-invasive ventilation (NIV)"}, {"id": "T2", "type": "SecondaryOutcome", "offsets": [[260, 322]], "text": "effects on the individual components of the composite endpoint"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[327, 348]], "text": "laboratory biomarkers"}, {"id": "T4", "type": "TimeFrame", "offsets": [[349, 411]], "text": "at baseline and 6 days after inclusion (time window 4-8 days)."}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T3", "arg2": "T4"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T2", "arg2": "T4"}]}
{"id": "68", "type": "silver", "text": " Clinical outcome assessment\n\nThe patients were observed for 2 weeks after hUC-MSC infusion, and clinical symptoms, laboratory tests, and radiological results were recorded and confirmed by experienced physicians. The primary clinical outcomes included the incidence of progression from severe to critical illness and the time to a clinical improvement of two points on a seven-category ordinal scale that has been used widely in clinical symptom assessment or discharge from the hospital [27]. In our study, the NEWS2 score and seven-category ordinal scale were used to assess the clinical symptoms and conditions of the enrolled patients [28]. The secondary clinical outcomes included patient status at days 7 and 14 assessed with a seven-category ordinal scale, hospital stay, changes in oxygenation index, hematological inflammatory factors, and imaging.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[257, 313]], "text": "incidence of progression from severe to critical illness"}, {"id": "T2", "type": "PrimaryOutcome", "offsets": [[322, 394]], "text": "time to a clinical improvement of two points on a seven-category ordinal"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[687, 701]], "text": "patient status"}, {"id": "T4", "type": "TimeFrame", "offsets": [[702, 718]], "text": "at days 7 and 14"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[765, 778]], "text": "hospital stay"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[780, 808]], "text": "changes in oxygenation index"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[810, 844]], "text": "hematological inflammatory factors"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[850, 857]], "text": "imaging"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T3", "arg2": "T4"}]}
{"id": "69", "type": "silver", "text": " Outcomes\n\nThe primary outcome of the study was length of hospital stay. Secondary outcomes included the frequency of ICU admission, invasive mechanical ventilation, duration of ICU admission, mechanical ventilation and, finally, the frequency and time to recovery, defined as hospital discharge alive.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[48, 71]], "text": "length of hospital stay"}, {"id": "T2", "type": "SecondaryOutcome", "offsets": [[105, 131]], "text": "frequency of ICU admission"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[133, 164]], "text": "invasive mechanical ventilation"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[166, 191]], "text": "duration of ICU admission"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[193, 215]], "text": "mechanical ventilation"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[234, 264]], "text": "frequency and time to recovery"}, {"id": "T7", "type": "OutcomeDefinition", "offsets": [[266, 301]], "text": "defined as hospital discharge alive"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T6", "arg2": "T7"}]}
{"id": "70", "type": "silver", "text": " Data collection and management\n\nBaseline data, which included demographics, anthropometrics, comorbid conditions, vital signs, Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, and Glasgow coma scale (GCS) scores, were obtained on the day of randomization. Laboratory data, sequential organ failure assessment (SOFA) scores, PaO2/FiO2, and other treatments used were monitored on days 1, 3, and 7 (day 1 was defined as the day of the first administration of vitamin C).\n\nThe primary outcome of the study was IMV- free days in 28 days (IMVFD28). Secondary outcomes included 28-day mortality, organ functions and inflammatory parameters, including white blood cell counts, neutrophil counts, lymphocyte counts, procalcitonin, interleukin-6 (IL-6), and C-reactive protein (CRP). Multi-organ dysfunction was assessed using SOFA scores.Additionally, vasopressor days, respiratory support days, invasive mechanical ventilation (IMV)-free days, patient condition improvement rate, patient condition deterioration rate, length of ICU and hospital stay, ICU and in-hospital mortality were recorded as additional secondary outcomes of this research. IMV-free days were defined as the number of days a patient was extubated after recruitment to day 28. If the patient died with MV, a value of zero was assigned. Deterioration of the patient’s condition was defined as the patient requiring HFNC or NIV on day 1 and requiring ECMO or IMV, or dying, after 7 days of treatment. Improvement of the patient’s condition was defined as the patient requiring ECMO or IMV on day 1 and switching to HFNC, NIV, or discharged from the ICU after 7 days of treatment. The P/F was calculated based on the PaO2/FiO2, and we choose the lowest values recorded on the specific day. All the data were collected from the clinical information system of three ICUs.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[529, 543]], "text": "IMV- free days"}, {"id": "T2", "type": "TimeFrame", "offsets": [[544, 554]], "text": "in 28 days"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[601, 610]], "text": "mortality"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[612, 627]], "text": "organ functions"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[632, 795]], "text": "inflammatory parameters, including white blood cell counts, neutrophil counts, lymphocyte counts, procalcitonin, interleukin-6 (IL-6), and C-reactive protein (CRP)"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[866, 882]], "text": "vasopressor days"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[884, 908]], "text": "respiratory support days"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[910, 957]], "text": "invasive mechanical ventilation (IMV)-free days"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[959, 993]], "text": "patient condition improvement rate"}, {"id": "T10", "type": "SecondaryOutcome", "offsets": [[995, 1031]], "text": "patient condition deterioration rate"}, {"id": "T11", "type": "SecondaryOutcome", "offsets": [[1033, 1064]], "text": "length of ICU and hospital stay"}, {"id": "T12", "type": "SecondaryOutcome", "offsets": [[1066, 1095]], "text": "ICU and in-hospital mortality"}, {"id": "T13", "type": "OutcomeDefinition", "offsets": [[1195, 1233]], "text": "number of days a patient was extubated"}, {"id": "T14", "type": "OutcomeDefinition", "offsets": [[1367, 1483]], "text": "defined as the patient requiring HFNC or NIV on day 1 and requiring ECMO or IMV, or dying, after 7 days of treatment"}, {"id": "T15", "type": "OutcomeDefinition", "offsets": [[1528, 1662]], "text": "defined as the patient requiring ECMO or IMV on day 1 and switching to HFNC, NIV, or discharged from the ICU after 7 days of treatment"}, {"id": "T16", "type": "TimeFrame", "offsets": [[594, 600]], "text": "28-day"}, {"id": "T17", "type": "TimeFrame", "offsets": [[1234, 1261]], "text": "after recruitment to day 28"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T8", "arg2": "T13"}, {"id": "R3", "type": "DefinedAs", "arg1": "T10", "arg2": "T14"}, {"id": "R4", "type": "DefinedAs", "arg1": "T9", "arg2": "T15"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T3", "arg2": "T16"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T8", "arg2": "T17"}]}
{"id": "71", "type": "silver", "text": "Main Outcomes and Measures  The primary outcome, treatment failure on day 21, was defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy. Prespecified secondary outcomes included the need for tracheal intubation (among patients not intubated at baseline); cumulative incidences (until day 21) of prone position sessions, extracorporeal membrane oxygenation, and inhaled nitric oxide; Pao2:Fio2 ratio measured daily from day 1 to day 7, then on days 14 and 21; and the proportion of patients with secondary infections during their ICU stay.\n\n\nOutcome Measures and Data Collection\n\nThe primary outcome was treatment failure on day 21, defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy.\n\nPrespecified secondary outcomes included the use of tracheal intubation (for patients not intubated at inclusion); the use of prone position (with the number of sessions), extracorporeal membrane oxygenation or inhaled nitric oxide (with the number of days the treatment was used); the Pao2:Fio2 ratio recorded daily from day 1 to day 7 and then on days 14 and 21; and the proportion of patients with and the number of episodes of nosocomial infections recorded during the ICU stay. Because some patients were still hospitalized in the ICU when the data were analyzed, nosocomial infections were recorded up to day 28 (which was a post hoc decision). The diagnosis of nosocomial infection was made by the clinician in charge and provided that an antibiotic therapy had been prescribed.\n\nDeath on day 21 and status on day 21 (determined using a 5-item scale: death, presence in the ICU on mechanical ventilation, high-flow or low-flow oxygen therapy, ICU discharge) were post hoc outcomes.\n\nApart from death, the adverse events expected in this context (such as the need for intubation in a patient breathing spontaneously at baseline) were only reported if the clinician thought they might be related to the study treatment.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[49, 66]], "text": "treatment failure"}, {"id": "T2", "type": "TimeFrame", "offsets": [[67, 76]], "text": "on day 21"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[82, 177]], "text": "defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[224, 252]], "text": "need for tracheal intubation"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[297, 423]], "text": "cumulative incidences (until day 21) of prone position sessions, extracorporeal membrane oxygenation, and inhaled nitric oxide"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[425, 440]], "text": "Pao2:Fio2 ratio"}, {"id": "T7", "type": "TimeFrame", "offsets": [[450, 499]], "text": "daily from day 1 to day 7, then on days 14 and 21"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[509, 557]], "text": "proportion of patients with secondary infections"}, {"id": "T9", "type": "OtherOutcome", "offsets": [[1559, 1564]], "text": "Death"}, {"id": "T10", "type": "TimeFrame", "offsets": [[1565, 1574]], "text": "on day 21"}, {"id": "T11", "type": "OtherOutcome", "offsets": [[1579, 1585]], "text": "status"}, {"id": "T12", "type": "TimeFrame", "offsets": [[1586, 1595]], "text": "on day 21"}, {"id": "T13", "type": "OutcomeDefinition", "offsets": [[1597, 1735]], "text": "determined using a 5-item scale: death, presence in the ICU on mechanical ventilation, high-flow or low-flow oxygen therapy, ICU discharge"}, {"id": "T14", "type": "UnclearOutcome", "offsets": [[1784, 1798]], "text": "adverse events"}, {"id": "T15", "type": "TimeFrame", "offsets": [[558, 579]], "text": "during their ICU stay"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T6", "arg2": "T7"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T9", "arg2": "T10"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T11", "arg2": "T12"}, {"id": "R6", "type": "DefinedAs", "arg1": "T11", "arg2": "T13"}, {"id": "R7", "type": "MeasuredAt", "arg1": "T8", "arg2": "T15"}]}
{"id": "72", "type": "silver", "text": " Main Outcomes and Measures  The primary end point was organ support–free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned –1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%).\n\n\nOutcomes\n\nThe primary outcome was respiratory and cardiovascular organ support–free days up to day 21, an ordinal end point with death within the hospital as the worst outcome (labeled –1), then the length of time free of both respiratory and cardiovascular organ support, such that the best outcome would be 21 organ support–free days. Organ support was defined using the same criteria as those for study entry. This outcome was used in a recent registration trial in septic shock approved by the Food and Drug Administration (although up to 28 days), with a 1.5-day difference (7.5%-15% relative difference) considered to be the minimal clinically important difference.18\n\nSecondary outcomes were in-hospital mortality, ICU and hospital length of stay, respiratory support–free days, cardiovascular organ support–free days, a composite outcome of progression to invasive mechanical ventilation, extracorporeal membrane oxygenation (ECMO) or death among those not ventilated at baseline, and the WHO ordinal scale (range, 0-8, where 0 = no illness, 1-7 = increasing level of care, and 8 = death) assessed at day 14.19,20 This scale was used in a recent COVID-19 RCT of remdesivir, where an odds ratio of 1.32 was considered clinically important, although few data support that assumption.20", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[55, 78]], "text": "organ support–free days"}, {"id": "T2", "type": "OutcomeDefinition", "offsets": [[80, 150]], "text": "days alive and free of ICU-based respiratory or cardiovascular support"}, {"id": "T3", "type": "TimeFrame", "offsets": [[152, 166]], "text": "within 21 days"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[1309, 1330]], "text": "in-hospital mortality"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[1332, 1363]], "text": "ICU and hospital length of stay"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[1365, 1394]], "text": "respiratory support–free days"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[1396, 1434]], "text": "cardiovascular organ support–free days"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[1459, 1597]], "text": "progression to invasive mechanical ventilation, extracorporeal membrane oxygenation (ECMO) or death among those not ventilated at baseline"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[1607, 1624]], "text": "WHO ordinal scale"}, {"id": "T10", "type": "TimeFrame", "offsets": [[1716, 1731]], "text": "at day 14.19,20"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T1", "arg2": "T3"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T9", "arg2": "T10"}]}
{"id": "73", "type": "silver", "text": " Procedures and Outcomes\nPatients were registered, after giving informed consent to participate, in a web-based eCRF (ORACLE clinical), their baseline clinical data collected and then randomly assigned 1:1 to the investigational treatment, stratified by study site. CP had to be administered immediately after randomization (day 1). Inpatients were assessed daily until hospital discharge and at days 15 and 29. Assessments in discharged patients were performed either as outpatient consultations or by phone. The patient’s clinical status was recorded using the seven-category ordinal COVID-19 scale: 1, not hospitalized, no limitations on activities; 2, not hospitalized, limitation on activities; 3, hospitalized, not requiring supplemental oxygen; 4, hospitalized, requiring supplemental oxygen; 5, hospitalized, on non-invasive ventilation or high flow oxygen devices; 6, hospitalized, on invasive mechanical ventilation or ECMO and 7, death. The primary outcome was the proportion of patients in categories 5, 6 or 7 at day 15 of the study. Key secondary outcomes were time to improvement of one category on the ordinal scale; mean change in the ordinal scale from baseline to days 3, 5, 8, 11, 15 and 29; proportion of patients in categories 5, 6 or 7 at day 29; mortality at days 15 and 29; duration of hospital stay; number of days alive and free from oxygen support; number of days alive and free from mechanical ventilation. Serial naso/oropharyngeal swabs and blood samples were collected at days 3, 5, 8, 11, 15 and 29, and tested for SARS-CoV- 2 RNA by RT-PCR assay. Serum samples were tested at the same time points for anti SARS-\nCoV-2 IgG. Neutralizing antibody titers were determined at baseline in those patients with positive IgG results. Serious adverse events (AE), grade 3 or 4 AE and infusion related AE (within 24 hours after administration) were collected. Investigators were instructed to actively monitor for the appearance of predefined AE of Special Interest: TRALI and ADE (antibody-dependent enhancement of infection).\n", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[976, 1022]], "text": "proportion of patients in categories 5, 6 or 7"}, {"id": "T2", "type": "TimeFrame", "offsets": [[1023, 1045]], "text": "at day 15 of the study"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[524, 946]], "text": "clinical status was recorded using the seven-category ordinal COVID-19 scale: 1, not hospitalized, no limitations on activities; 2, not hospitalized, limitation on activities; 3, hospitalized, not requiring supplemental oxygen; 4, hospitalized, requiring supplemental oxygen; 5, hospitalized, on non-invasive ventilation or high flow oxygen devices; 6, hospitalized, on invasive mechanical ventilation or ECMO and 7, death"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[1075, 1131]], "text": "time to improvement of one category on the ordinal scale"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[1133, 1165]], "text": "mean change in the ordinal scale"}, {"id": "T6", "type": "TimeFrame", "offsets": [[1166, 1210]], "text": "from baseline to days 3, 5, 8, 11, 15 and 29"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[1212, 1258]], "text": "proportion of patients in categories 5, 6 or 7"}, {"id": "T8", "type": "TimeFrame", "offsets": [[1259, 1268]], "text": "at day 29"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[1270, 1279]], "text": "mortality"}, {"id": "T10", "type": "TimeFrame", "offsets": [[1280, 1297]], "text": "at days 15 and 29"}, {"id": "T11", "type": "SecondaryOutcome", "offsets": [[1299, 1324]], "text": "duration of hospital stay"}, {"id": "T12", "type": "SecondaryOutcome", "offsets": [[1326, 1375]], "text": "number of days alive and free from oxygen support"}, {"id": "T13", "type": "SecondaryOutcome", "offsets": [[1377, 1435]], "text": "number of days alive and free from mechanical ventilation."}, {"id": "T14", "type": "OtherOutcome", "offsets": [[1759, 1786]], "text": "Serious adverse events (AE)"}, {"id": "T15", "type": "OtherOutcome", "offsets": [[1788, 1803]], "text": "grade 3 or 4 AE"}, {"id": "T16", "type": "OtherOutcome", "offsets": [[1808, 1827]], "text": "infusion related AE"}, {"id": "T17", "type": "TimeFrame", "offsets": [[1829, 1865]], "text": "within 24 hours after administration"}, {"id": "T18", "type": "TimeFrame", "offsets": [[1501, 1531]], "text": "at days 3, 5, 8, 11, 15 and 29"}, {"id": "T19", "type": "OtherOutcome", "offsets": [[1436, 1485]], "text": "Serial naso/oropharyngeal swabs and blood samples"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T16", "arg2": "T17"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T7", "arg2": "T8"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T9", "arg2": "T10"}, {"id": "R7", "type": "MeasuredAt", "arg1": "T5", "arg2": "T6"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T19", "arg2": "T18"}]}
{"id": "74", "type": "silver", "text": " Main Outcomes and Measures  The primary outcome was ventilator-free days during the first 28 days, defined as being alive and free from mechanical ventilation. Secondary outcomes were all-cause mortality at 28 days, clinical status of patients at day 15 using a 6-point ordinal scale (ranging from 1, not hospitalized to 6, death), ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, and Sequential Organ Failure Assessment (SOFA) scores (range, 0-24, with higher scores indicating greater organ dysfunction) at 48 hours, 72 hours, and 7 days.\n\n\nOutcomes\n\nThe primary outcome was ventilator-free days during the first 28 days, defined as the number of days alive and free from mechanical ventilation for at least 48 consecutive hours.20 Patients discharged from the hospital before 28 days were considered alive and free from mechanical ventilation at 28 days. Nonsurvivors at day 28 were considered to have no ventilator-free days. More details on the definitions are provided in the eMethods section of Supplement 3.\n\nPrespecified secondary outcomes were all-cause mortality during 28 days, clinical status of patients at day 15 using a 6-point ordinal scale adapted from the World Health Organization R&D Blueprint expert group21—(1) not hospitalized, (2) hospitalized, not requiring supplemental oxygen, (3) hospitalized, requiring supplemental oxygen, (4) hospitalized, requiring noninvasive ventilation or nasal high-flow oxygen therapy, (5) hospitalized, requiring invasive mechanical ventilation or ECMO, and (6) death; ICU-free days during the first 28 days; mechanical ventilation duration at 28 days; and Sequential Organ Failure Assessment (SOFA) scores, which range from 0 to 24, with higher scores indicating greater dysfunction, at 48 hours, 72 hours, and 7 days. For post hoc analyses, we evaluated the components of ventilator-free days during the first 28 days, the cumulative proportions of the 6-point ordinal scale at 15 days, and the outcome of discharge from hospital alive within 28 days. For patients who died, the number of ventilator-free days was 0; for patients who were alive, the ventilator-free days were the days they did not require mechanical ventilation.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[53, 73]], "text": "ventilator-free days"}, {"id": "T2", "type": "TimeFrame", "offsets": [[74, 98]], "text": "during the first 28 days"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[111, 159]], "text": "being alive and free from mechanical ventilation"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[185, 204]], "text": "all-cause mortality"}, {"id": "T5", "type": "TimeFrame", "offsets": [[205, 215]], "text": "at 28 days"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[217, 244]], "text": "clinical status of patients"}, {"id": "T7", "type": "TimeFrame", "offsets": [[245, 254]], "text": "at day 15"}, {"id": "T8", "type": "OutcomeDefinition", "offsets": [[255, 331]], "text": "using a 6-point ordinal scale (ranging from 1, not hospitalized to 6, death)"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[333, 346]], "text": "ICU-free days"}, {"id": "T10", "type": "TimeFrame", "offsets": [[347, 371]], "text": "during the first 28 days"}, {"id": "T11", "type": "SecondaryOutcome", "offsets": [[373, 404]], "text": "mechanical ventilation duration"}, {"id": "T12", "type": "TimeFrame", "offsets": [[405, 415]], "text": "at 28 days"}, {"id": "T13", "type": "SecondaryOutcome", "offsets": [[421, 541]], "text": "Sequential Organ Failure Assessment (SOFA) scores (range, 0-24, with higher scores indicating greater organ dysfunction)"}, {"id": "T14", "type": "TimeFrame", "offsets": [[542, 575]], "text": "at 48 hours, 72 hours, and 7 days"}, {"id": "T15", "type": "PrimaryOutcome", "offsets": [[613, 633]], "text": "ventilator-free days"}, {"id": "T16", "type": "TimeFrame", "offsets": [[634, 658]], "text": "during the first 28 days"}, {"id": "T17", "type": "OutcomeDefinition", "offsets": [[675, 766]], "text": "number of days alive and free from mechanical ventilation for at least 48 consecutive hours"}, {"id": "T18", "type": "SecondaryOutcome", "offsets": [[1090, 1109]], "text": "all-cause mortality"}, {"id": "T19", "type": "TimeFrame", "offsets": [[1110, 1124]], "text": "during 28 days"}, {"id": "T20", "type": "SecondaryOutcome", "offsets": [[1126, 1153]], "text": "clinical status of patients"}, {"id": "T21", "type": "TimeFrame", "offsets": [[1154, 1163]], "text": "at day 15"}, {"id": "T22", "type": "OutcomeDefinition", "offsets": [[1164, 1193]], "text": "using a 6-point ordinal scale"}, {"id": "T23", "type": "SecondaryOutcome", "offsets": [[1561, 1574]], "text": "ICU-free days"}, {"id": "T24", "type": "TimeFrame", "offsets": [[1575, 1599]], "text": "during the first 28 days"}, {"id": "T25", "type": "SecondaryOutcome", "offsets": [[1601, 1632]], "text": "mechanical ventilation duration"}, {"id": "T26", "type": "TimeFrame", "offsets": [[1633, 1643]], "text": "at 28 days"}, {"id": "T27", "type": "SecondaryOutcome", "offsets": [[1649, 1698]], "text": "Sequential Organ Failure Assessment (SOFA) scores"}, {"id": "T28", "type": "TimeFrame", "offsets": [[1777, 1810]], "text": "at 48 hours, 72 hours, and 7 days"}, {"id": "T29", "type": "OutcomeDefinition", "offsets": [[1706, 1775]], "text": "range from 0 to 24, with higher scores indicating greater dysfunction"}, {"id": "T30", "type": "OtherOutcome", "offsets": [[1852, 1886]], "text": "components of ventilator-free days"}, {"id": "T31", "type": "TimeFrame", "offsets": [[1887, 1911]], "text": "during the first 28 days"}, {"id": "T32", "type": "OtherOutcome", "offsets": [[1917, 1968]], "text": "cumulative proportions of the 6-point ordinal scale"}, {"id": "T33", "type": "TimeFrame", "offsets": [[1969, 1979]], "text": "at 15 days"}, {"id": "T34", "type": "OtherOutcome", "offsets": [[2000, 2029]], "text": "discharge from hospital alive"}, {"id": "T35", "type": "TimeFrame", "offsets": [[2030, 2044]], "text": "within 28 days"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T4", "arg2": "T5"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T6", "arg2": "T7"}, {"id": "R5", "type": "DefinedAs", "arg1": "T6", "arg2": "T8"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T11", "arg2": "T12"}, {"id": "R7", "type": "MeasuredAt", "arg1": "T9", "arg2": "T10"}, {"id": "R8", "type": "MeasuredAt", "arg1": "T13", "arg2": "T14"}, {"id": "R9", "type": "MeasuredAt", "arg1": "T15", "arg2": "T16"}, {"id": "R10", "type": "DefinedAs", "arg1": "T15", "arg2": "T17"}, {"id": "R11", "type": "MeasuredAt", "arg1": "T18", "arg2": "T19"}, {"id": "R12", "type": "MeasuredAt", "arg1": "T20", "arg2": "T21"}, {"id": "R13", "type": "DefinedAs", "arg1": "T20", "arg2": "T22"}, {"id": "R14", "type": "MeasuredAt", "arg1": "T23", "arg2": "T24"}, {"id": "R15", "type": "MeasuredAt", "arg1": "T25", "arg2": "T26"}, {"id": "R16", "type": "DefinedAs", "arg1": "T27", "arg2": "T29"}, {"id": "R17", "type": "MeasuredAt", "arg1": "T27", "arg2": "T28"}, {"id": "R18", "type": "MeasuredAt", "arg1": "T30", "arg2": "T31"}, {"id": "R19", "type": "MeasuredAt", "arg1": "T32", "arg2": "T33"}, {"id": "R20", "type": "MeasuredAt", "arg1": "T34", "arg2": "T35"}]}
{"id": "75", "type": "silver", "text": "Outcomes\nThe primary outcome was clinical status, measured at 15 days using a six-level ordinal scale as follows: (1) not admitted to hospital; (2) admitted to hospital and not using supplemental oxygen; (3) admitted to hospital and using supplemental oxygen; (4) admitted to hospital and using non-invasive positive-pressure ventilation or high-flow nasal cannula; (5) admitted to hospital and on mechanical ventilation or extracorporeal membrane oxygen support; or (6) death. The key secondary outcome was mortality at 29 days after randomisation.\nOther secondary outcomes were clinical status assessed by the six-point ordinal scale at 7 days and 29 days; length of hospital stay among survivors; incidence of secondary infection (ie, new infections arising after randomisation, whether nosocomial or not); and number of ventilator-free days by day 29. Safety outcomes were prolongation of the QTc interval (defined as QTc ≥470 ms for women or ≥450 ms for men, in patients whose baseline QTc was below those thresholds, or QTc ≥480 ms if baseline QTc was above those thresholds); gastrointestinal intolerance (meaning diarrhoea, nausea, abdominal pain, or vomiting); laboratory changes in blood counts and bilirubin levels; acute kidney failure (as reported by site investigators); and overall serious adverse events.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[33, 48]], "text": "clinical status"}, {"id": "T2", "type": "TimeFrame", "offsets": [[59, 69]], "text": "at 15 days"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[70, 476]], "text": "using a six-level ordinal scale as follows: (1) not admitted to hospital; (2) admitted to hospital and not using supplemental oxygen; (3) admitted to hospital and using supplemental oxygen; (4) admitted to hospital and using non-invasive positive-pressure ventilation or high-flow nasal cannula; (5) admitted to hospital and on mechanical ventilation or extracorporeal membrane oxygen support; or (6) death"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[508, 517]], "text": "mortality"}, {"id": "T5", "type": "TimeFrame", "offsets": [[518, 548]], "text": "at 29 days after randomisation"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[580, 595]], "text": "clinical status"}, {"id": "T7", "type": "OutcomeDefinition", "offsets": [[596, 635]], "text": "assessed by the six-point ordinal scale"}, {"id": "T8", "type": "TimeFrame", "offsets": [[636, 657]], "text": "at 7 days and 29 days"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[659, 698]], "text": "length of hospital stay among survivors"}, {"id": "T10", "type": "SecondaryOutcome", "offsets": [[700, 732]], "text": "incidence of secondary infection"}, {"id": "T11", "type": "OutcomeDefinition", "offsets": [[738, 807]], "text": "new infections arising after randomisation, whether nosocomial or not"}, {"id": "T12", "type": "SecondaryOutcome", "offsets": [[814, 844]], "text": "number of ventilator-free days"}, {"id": "T13", "type": "TimeFrame", "offsets": [[845, 855]], "text": "by day 29."}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T4", "arg2": "T5"}, {"id": "R4", "type": "DefinedAs", "arg1": "T6", "arg2": "T7"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T6", "arg2": "T8"}, {"id": "R6", "type": "DefinedAs", "arg1": "T10", "arg2": "T11"}, {"id": "R7", "type": "MeasuredAt", "arg1": "T12", "arg2": "T13"}]}
{"id": "76", "type": "silver", "text": "Outcomes\nTime to clinical improvement was considered as primary outcome of study. Clinical improvement was defined as improvement of at least two points from the baseline status on the six-category ordinal scale [18]. This scale contains the subsequent categories: (1) death (2) hospital admission requiring invasive mechanical ventilation (3) hospital admission, requiring non-invasive positive pressure ventilation (4) hospital admission, requiring oxygen (5) hospital admission, not requiring oxygen (6) discharge. Secondary outcomes were clinical status of patients at day 7, 14 and 28, ICU admission and intubation rates, length of hospitalization and ICU stay, and 28-day mortality.\nSide effects related to IFN therapy and other adverse events during the study period were monitored and recorded as the safety outcomes.\nCategorization of adverse events was done according to the common terminology criteria for adverse events (CTCAE), National Institutes of Health and National Cancer Institute, 2017.\nAlso serious complications during the hospitalization course such as acute respiratory distress syndrome (ARDS), nosocomial infections, septic shock, acute kidney injury (AKI) and acute hepatic injury (AHI) were considered.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[9, 37]], "text": "Time to clinical improvement"}, {"id": "T2", "type": "OutcomeDefinition", "offsets": [[91, 211]], "text": "improvement was defined as improvement of at least two points from the baseline status on the six-category ordinal scale"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[223, 516]], "text": "scale contains the subsequent categories: (1) death (2) hospital admission requiring invasive mechanical ventilation (3) hospital admission, requiring non-invasive positive pressure ventilation (4) hospital admission, requiring oxygen (5) hospital admission, not requiring oxygen (6) discharge"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[542, 569]], "text": "clinical status of patients"}, {"id": "T5", "type": "TimeFrame", "offsets": [[570, 589]], "text": "at day 7, 14 and 28"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[591, 625]], "text": "ICU admission and intubation rates"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[627, 665]], "text": "length of hospitalization and ICU stay"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[678, 687]], "text": "mortality"}, {"id": "T9", "type": "TimeFrame", "offsets": [[671, 677]], "text": "28-day"}, {"id": "T10", "type": "OtherOutcome", "offsets": [[689, 701]], "text": "Side effects"}, {"id": "T11", "type": "OtherOutcome", "offsets": [[735, 749]], "text": "adverse events"}, {"id": "T12", "type": "OutcomeDefinition", "offsets": [[868, 1006]], "text": "according to the common terminology criteria for adverse events (CTCAE), National Institutes of Health and National Cancer Institute, 2017"}, {"id": "T13", "type": "OtherOutcome", "offsets": [[1013, 1034]], "text": "serious complications"}, {"id": "T14", "type": "OutcomeDefinition", "offsets": [[1069, 1214]], "text": "such as acute respiratory distress syndrome (ARDS), nosocomial infections, septic shock, acute kidney injury (AKI) and acute hepatic injury (AHI)"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T4", "arg2": "T5"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T8", "arg2": "T9"}, {"id": "R5", "type": "DefinedAs", "arg1": "T11", "arg2": "T12"}, {"id": "R6", "type": "DefinedAs", "arg1": "T13", "arg2": "T14"}]}
{"id": "77", "type": "silver", "text": "Outcomes\n\nOutcomes of effectiveness included rate of ICU admission and deaths. The working hypothesis of this pilot trial was that calcifediol treatment would decrease the need for ICU admissions and the potential risk of death associated with these admissions.", "entities": [{"id": "T1", "type": "OtherOutcome", "offsets": [[45, 66]], "text": "rate of ICU admission"}, {"id": "T2", "type": "OtherOutcome", "offsets": [[71, 77]], "text": "deaths"}], "relations": []}
{"id": "78", "type": "silver", "text": " Outcome Measures\nThe primary efficacy outcome was clinical status assessed on a 7-category ordinal scale (1, discharged or ready for discharge; 2, non–intensive care unit [ICU] hospital ward, not requiring supplemental oxygen; 3, non–ICU hospital ward, requiring supplemental oxygen; 4, ICU or non–ICU hospital ward, requiring noninvasive ventilation or high-flow oxygen; 5, ICU, requiring intubation and mechanical ventilation; 6, ICU, requiring extracorporeal membrane oxygenation or mechanical ventilation and additional organ support; 7, death) at day 28. Clinical status was recorded at baseline and every day during hospitalization. Key secondary efficacy endpoints were clinical status at day 14 on the 7-category ordinal scale, mortality at day 28, ventilator-free days to day 28, time to improvement from baseline in ≥2 categories on the 7-category ordinal scale, and time to hospital discharge (or ready for discharge [defined as normal body temperature and respiratory rate and stable oxygen saturation on ambient air or ≤2 L supplemental oxygen]). Other secondary endpoints included time to clinical failure defined as death, withdrawal during hospitalization, mechanical ventilation, or ICU transfer (for patients intubated or in the ICU at baseline, a 1-category worsening of clinical status was considered clinical failure); incidence of mechanical ventilation (among those not mechanically ventilated at randomization); incidence of ICU transfer (among those not in ICUs at baseline); and duration of ICU stay. Adverse events were recorded according to Medical Dictionary for Regulatory Activities system organ class and preferred term.\n", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[51, 66]], "text": "clinical status"}, {"id": "T2", "type": "OutcomeDefinition", "offsets": [[67, 549]], "text": "assessed on a 7-category ordinal scale (1, discharged or ready for discharge; 2, non–intensive care unit [ICU] hospital ward, not requiring supplemental oxygen; 3, non–ICU hospital ward, requiring supplemental oxygen; 4, ICU or non–ICU hospital ward, requiring noninvasive ventilation or high-flow oxygen; 5, ICU, requiring intubation and mechanical ventilation; 6, ICU, requiring extracorporeal membrane oxygenation or mechanical ventilation and additional organ support; 7, death)"}, {"id": "T3", "type": "TimeFrame", "offsets": [[550, 559]], "text": "at day 28"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[678, 693]], "text": "clinical status"}, {"id": "T5", "type": "OtherOutcome", "offsets": [[561, 576]], "text": "Clinical status"}, {"id": "T6", "type": "TimeFrame", "offsets": [[590, 638]], "text": "at baseline and every day during hospitalization"}, {"id": "T7", "type": "TimeFrame", "offsets": [[694, 703]], "text": "at day 14"}, {"id": "T8", "type": "OutcomeDefinition", "offsets": [[704, 735]], "text": "on the 7-category ordinal scale"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[737, 746]], "text": "mortality"}, {"id": "T10", "type": "TimeFrame", "offsets": [[747, 756]], "text": "at day 28"}, {"id": "T11", "type": "SecondaryOutcome", "offsets": [[758, 778]], "text": "ventilator-free days"}, {"id": "T12", "type": "TimeFrame", "offsets": [[779, 788]], "text": "to day 28"}, {"id": "T13", "type": "SecondaryOutcome", "offsets": [[790, 809]], "text": "time to improvement"}, {"id": "T14", "type": "TimeFrame", "offsets": [[810, 823]], "text": "from baseline"}, {"id": "T15", "type": "OutcomeDefinition", "offsets": [[824, 872]], "text": "in ≥2 categories on the 7-category ordinal scale"}, {"id": "T17", "type": "OutcomeDefinition", "offsets": [[941, 1057]], "text": "normal body temperature and respiratory rate and stable oxygen saturation on ambient air or ≤2 L supplemental oxygen"}, {"id": "T19", "type": "SecondaryOutcome", "offsets": [[1096, 1120]], "text": "time to clinical failure"}, {"id": "T20", "type": "OutcomeDefinition", "offsets": [[1132, 1339]], "text": "death, withdrawal during hospitalization, mechanical ventilation, or ICU transfer (for patients intubated or in the ICU at baseline, a 1-category worsening of clinical status was considered clinical failure)"}, {"id": "T21", "type": "SecondaryOutcome", "offsets": [[1341, 1435]], "text": "incidence of mechanical ventilation (among those not mechanically ventilated at randomization)"}, {"id": "T22", "type": "SecondaryOutcome", "offsets": [[1437, 1500]], "text": "incidence of ICU transfer (among those not in ICUs at baseline)"}, {"id": "T23", "type": "SecondaryOutcome", "offsets": [[1506, 1526]], "text": "duration of ICU stay"}, {"id": "T24", "type": "OtherOutcome", "offsets": [[1528, 1542]], "text": "Adverse events"}, {"id": "T25", "type": "OutcomeDefinition", "offsets": [[1557, 1652]], "text": "according to Medical Dictionary for Regulatory Activities system organ class and preferred term"}, {"id": "T16", "type": "SecondaryOutcome", "offsets": [[878, 928]], "text": "time to hospital discharge (or ready for discharge"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T1", "arg2": "T3"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T5", "arg2": "T6"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T4", "arg2": "T7"}, {"id": "R5", "type": "DefinedAs", "arg1": "T4", "arg2": "T8"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T9", "arg2": "T10"}, {"id": "R7", "type": "MeasuredAt", "arg1": "T11", "arg2": "T12"}, {"id": "R8", "type": "MeasuredAt", "arg1": "T13", "arg2": "T14"}, {"id": "R9", "type": "DefinedAs", "arg1": "T13", "arg2": "T15"}, {"id": "R11", "type": "DefinedAs", "arg1": "T19", "arg2": "T20"}, {"id": "R12", "type": "DefinedAs", "arg1": "T24", "arg2": "T25"}, {"id": "R10", "type": "DefinedAs", "arg1": "T16", "arg2": "T17"}]}
{"id": "79", "type": "silver", "text": " Main endpoints\nThe primary endpoints were clinical parameters, such as the time of need for supplemental oxygen; time of hospitalization; need for admission and length of stay in ICU; and death rate and causes of mortality. As secondary endpoints we assessed clinical and laboratory parameters: measures of serum CRP, serum LDH and relation neutrophil to lymphocyte of peripheral blood samples from day zero to day 7; the number, type, and severity of adverse events; frequency of interruption of the study protocol due to adverse events; and frequency of QT interval above 450 ms.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[43, 112]], "text": "clinical parameters, such as the time of need for supplemental oxygen"}, {"id": "T2", "type": "PrimaryOutcome", "offsets": [[114, 137]], "text": "time of hospitalization"}, {"id": "T3", "type": "PrimaryOutcome", "offsets": [[139, 183]], "text": "need for admission and length of stay in ICU"}, {"id": "T5", "type": "PrimaryOutcome", "offsets": [[189, 223]], "text": "death rate and causes of mortality"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[296, 317]], "text": "measures of serum CRP"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[319, 394]], "text": "serum LDH and relation neutrophil to lymphocyte of peripheral blood samples"}, {"id": "T8", "type": "TimeFrame", "offsets": [[395, 417]], "text": "from day zero to day 7"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[419, 467]], "text": "the number, type, and severity of adverse events"}, {"id": "T10", "type": "SecondaryOutcome", "offsets": [[469, 538]], "text": "frequency of interruption of the study protocol due to adverse events"}, {"id": "T11", "type": "SecondaryOutcome", "offsets": [[544, 581]], "text": "frequency of QT interval above 450 ms"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T7", "arg2": "T8"}]}
{"id": "80", "type": "silver", "text": "Outcomes\nThe primary end point was the cure rate of the enrolled patients. The definition for cure followed the standard given by the “Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (5th or update version)” as 1) fever attenuated for continuously 7 days, 2) twice COVD-19 nucleolus acid detections negative, 3) CT scan shows chest effusion absorbed more than 50% percent when the patient is discharged from hospital. Secondary outcomes were the recovery rate of hypoxia over 14 days, the worsening rate of hypoxia during hospitalization, the duration of hospital stay, and the time to negative virus load. Hypoxia was defined as when inhaling room air, the peripheral oxygen saturation was less than 93%. Hypoxia recovery was defined as the patient's fingertip oxygen saturation was ≥ 93% when inhaling room air. Hypoxia worsening is defined as the patient's inhaling oxygen concentration must be upregulated so as to maintain normal oxygen saturation levels. Safety outcomes included treatment -emergent adverse events, serious adverse events.\n\n", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[39, 73]], "text": "cure rate of the enrolled patients"}, {"id": "T2", "type": "OutcomeDefinition", "offsets": [[112, 433]], "text": "standard given by the “Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (5th or update version)” as 1) fever attenuated for continuously 7 days, 2) twice COVD-19 nucleolus acid detections negative, 3) CT scan shows chest effusion absorbed more than 50% percent when the patient is discharged from hospital"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[463, 487]], "text": "recovery rate of hypoxia"}, {"id": "T4", "type": "TimeFrame", "offsets": [[488, 500]], "text": "over 14 days"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[506, 554]], "text": "worsening rate of hypoxia during hospitalization"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[556, 585]], "text": "the duration of hospital stay"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[595, 622]], "text": "time to negative virus load"}, {"id": "T8", "type": "OutcomeDefinition", "offsets": [[759, 829]], "text": "patient's fingertip oxygen saturation was ≥ 93% when inhaling room air"}, {"id": "T9", "type": "OutcomeDefinition", "offsets": [[867, 976]], "text": "patient's inhaling oxygen concentration must be upregulated so as to maintain normal oxygen saturation levels"}, {"id": "T10", "type": "OtherOutcome", "offsets": [[1003, 1037]], "text": "treatment -emergent adverse events"}, {"id": "T11", "type": "OtherOutcome", "offsets": [[1039, 1061]], "text": "serious adverse events"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T3", "arg2": "T8"}, {"id": "R3", "type": "DefinedAs", "arg1": "T5", "arg2": "T9"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T3", "arg2": "T4"}]}
{"id": "81", "type": "silver", "text": " Outcomes\nThe primary outcome of the study was a composite measure of progress to severe disease (PaO2/FiO2 ratio <100) any time within 28 days of enrolment or all-cause mortality at 28 days.\nPrimary outcome was considered as “good” if the progress to severe disease or all-cause mortality could be prevented in the 28 days post enrolment and “poor” if not.\nThe secondary outcomes were clinical improvement and symptom resolution on day 7; variation in fraction of inspired oxygen (Fio2%) on days 1, 3, 5, 7 and 14; total duration of respiratory support during hospitalization and post enrolment duration of respiratory support till day 28 or discharge whichever is earlier; negative conversion of SARS-CoV-2 viral RNA on days 3 and 7; levels of biomarkers on days 3 and 7 post enrolment compared to baseline; requirement of vasopressor support; and clinical improvement on WHO ordinal scale on day 0,1,3,5,7,14 and 28 days. 22 The WHO ordinal scale was not mentioned in the initial study protocol but was added midway through the trial as it was felt that it will be a key endpoint in any future meta-analysis.\nSafety outcomes were frequency of minor and serious adverse event (death and invasive mechanical ventilation, hemodynamic instability) within 6 hours of CP transfusion. Relatedness of a serious adverse event with the trial was assessed as per the definitions given by Edwards and\nAronson.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[70, 119]], "text": "progress to severe disease (PaO2/FiO2 ratio <100)"}, {"id": "T2", "type": "TimeFrame", "offsets": [[120, 156]], "text": "any time within 28 days of enrolment"}, {"id": "T3", "type": "PrimaryOutcome", "offsets": [[160, 179]], "text": "all-cause mortality"}, {"id": "T4", "type": "TimeFrame", "offsets": [[180, 190]], "text": "at 28 days"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[386, 429]], "text": "clinical improvement and symptom resolution"}, {"id": "T6", "type": "TimeFrame", "offsets": [[430, 438]], "text": "on day 7"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[440, 488]], "text": "variation in fraction of inspired oxygen (Fio2%)"}, {"id": "T8", "type": "TimeFrame", "offsets": [[489, 514]], "text": "on days 1, 3, 5, 7 and 14"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[516, 627]], "text": "total duration of respiratory support during hospitalization and post enrolment duration of respiratory support"}, {"id": "T10", "type": "SecondaryOutcome", "offsets": [[675, 718]], "text": "negative conversion of SARS-CoV-2 viral RNA"}, {"id": "T12", "type": "TimeFrame", "offsets": [[719, 734]], "text": "on days 3 and 7"}, {"id": "T13", "type": "SecondaryOutcome", "offsets": [[736, 756]], "text": "levels of biomarkers"}, {"id": "T14", "type": "TimeFrame", "offsets": [[757, 808]], "text": "on days 3 and 7 post enrolment compared to baseline"}, {"id": "T15", "type": "SecondaryOutcome", "offsets": [[810, 844]], "text": "requirement of vasopressor support"}, {"id": "T16", "type": "SecondaryOutcome", "offsets": [[850, 891]], "text": "clinical improvement on WHO ordinal scale"}, {"id": "T17", "type": "TimeFrame", "offsets": [[892, 923]], "text": "on day 0,1,3,5,7,14 and 28 days"}, {"id": "T18", "type": "OtherOutcome", "offsets": [[1133, 1246]], "text": "frequency of minor and serious adverse event (death and invasive mechanical ventilation, hemodynamic instability)"}, {"id": "T19", "type": "TimeFrame", "offsets": [[1247, 1279]], "text": "within 6 hours of CP transfusion"}, {"id": "T20", "type": "OtherOutcome", "offsets": [[1298, 1319]], "text": "serious adverse event"}, {"id": "T11", "type": "TimeFrame", "offsets": [[628, 673]], "text": "till day 28 or discharge whichever is earlier"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T5", "arg2": "T6"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T7", "arg2": "T8"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T10", "arg2": "T12"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T13", "arg2": "T14"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T16", "arg2": "T17"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T18", "arg2": "T19"}, {"id": "R7", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R8", "type": "MeasuredAt", "arg1": "T3", "arg2": "T4"}, {"id": "R9", "type": "MeasuredAt", "arg1": "T9", "arg2": "T11"}]}
{"id": "82", "type": "silver", "text": " \nOutcome Measures\n\nThe primary end point was the time to clinical improvement,18 ie, the duration from randomization to the improvement of at least 1 point on a 7-category ordinal scale (adopted from a scale for hospitalized patients with severe influenza)19 or discharge from hospital, whichever occurred first. The 7-category ordinal scale was graded based on the following scheme: 1 for nonhospitalized with normal activities; 2 for nonhospitalized but unable to resume normal activities; 3 for hospitalized but not requiring supplemental oxygen; 4 for hospitalized and requiring supplemental oxygen; 5 for hospitalized and requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both; 6 for hospitalized and requiring extracorporeal membrane oxygenation, invasive ventilation, or both; and 7 for death.\n\nSecondary outcomes included lymphocyte cell counts on day 5 posttreatment, mortality at day 21, the proportions of patients progressing to critical conditions (eg, acute respiratory distress syndrome, sepsis, or septic shock), and viral loads (reflected by the Ct values as measured with real-time RT-PCR assays) at day 21. Safety outcomes included adverse events, serious adverse events, and premature discontinuation of treatment. Classifications were based on National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[50, 78]], "text": "time to clinical improvement"}, {"id": "T2", "type": "OutcomeDefinition", "offsets": [[86, 831]], "text": "the duration from randomization to the improvement of at least 1 point on a 7-category ordinal scale (adopted from a scale for hospitalized patients with severe influenza)19 or discharge from hospital, whichever occurred first. The 7-category ordinal scale was graded based on the following scheme: 1 for nonhospitalized with normal activities; 2 for nonhospitalized but unable to resume normal activities; 3 for hospitalized but not requiring supplemental oxygen; 4 for hospitalized and requiring supplemental oxygen; 5 for hospitalized and requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both; 6 for hospitalized and requiring extracorporeal membrane oxygenation, invasive ventilation, or both; and 7 for death"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[862, 884]], "text": "lymphocyte cell counts"}, {"id": "T4", "type": "TimeFrame", "offsets": [[885, 907]], "text": "on day 5 posttreatment"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[909, 918]], "text": "mortality"}, {"id": "T6", "type": "TimeFrame", "offsets": [[919, 928]], "text": "at day 21"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[934, 992]], "text": "proportions of patients progressing to critical conditions"}, {"id": "T8", "type": "OutcomeDefinition", "offsets": [[998, 1058]], "text": "acute respiratory distress syndrome, sepsis, or septic shock"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[1065, 1076]], "text": "viral loads"}, {"id": "T10", "type": "OutcomeDefinition", "offsets": [[1078, 1145]], "text": "reflected by the Ct values as measured with real-time RT-PCR assays"}, {"id": "T11", "type": "TimeFrame", "offsets": [[1147, 1156]], "text": "at day 21"}, {"id": "T12", "type": "OtherOutcome", "offsets": [[1183, 1197]], "text": "adverse events"}, {"id": "T13", "type": "OtherOutcome", "offsets": [[1199, 1221]], "text": "serious adverse events"}, {"id": "T14", "type": "OtherOutcome", "offsets": [[1227, 1265]], "text": "premature discontinuation of treatment"}, {"id": "T15", "type": "OutcomeDefinition", "offsets": [[1297, 1382]], "text": "National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T3", "arg2": "T4"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T5", "arg2": "T6"}, {"id": "R3", "type": "DefinedAs", "arg1": "T7", "arg2": "T8"}, {"id": "R4", "type": "DefinedAs", "arg1": "T9", "arg2": "T10"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T9", "arg2": "T11"}, {"id": "R6", "type": "DefinedAs", "arg1": "T12", "arg2": "T15"}]}
{"id": "83", "type": "silver", "text": "Outcomes\n\nThe study objective was to evaluate the efficacy and safety of BRH at a dose of 32 mg three times per day in patients with moderate COVID‐19. The primary and secondary outcomes were assessed during the study period of 14 days.\n\nThe primary end points were the time to clinical recovery and the deterioration rate after initiation of medications. Clinical recovery was defined as clinical symptoms (fever and respiratory symptoms) returning to normal over 48 hours. Disease deterioration was defined as the presence of respiratory distress, respiratory rate ≥ 30 times/minute, oxygen saturation ≤ 93% in the resting state, and oxygenation index ≤ 300 mmHg.\n\nThe secondary outcomes assessed the virologic clearance during the study period (SARS‐CoV‐2‐negative conversion within 20 days, rate of SARS‐CoV‐2‐negative conversion), clinical follow‐up (clinical remission rate, time to fever remission, rate of significant improvement in chest CT, percentage of patients requiring oxygen therapy, and discharge rate within 20 days), and the occurrence of side effects. Deteriorated patients who progressed to severe or critical condition were withdrawn from the study.\n\nChest CT was blindly interpreted at the baseline (7 days before randomization) and after randomization (7 days ± 1 day) by two experienced radiologists. A semiquantitative scoring system was used to quantitatively assess the pulmonary improvement, and the cases were divided into the following five categories: no improvement (< 10% absorption), mild improvement (10–30% absorption), improvement (30–60% absorption), remarkable improvement (60–90% absorption), and complete improvement (> 90% absorption).\n\nAll AEs reported during the study were recorded and graded according to the Common Terminology Criteria for Adverse Events, version 5.0. Assessments of laboratory parameters, physical condition, chest images, and nucleic acid test results were performed at baseline, during the study period, and at the 3‐week follow‐up. Assessments were also conducted at the end of the study period or the time of withdrawal, as appropriate.", "entities": [{"id": "T1", "type": "TimeFrame", "offsets": [[228, 235]], "text": "14 days"}, {"id": "T2", "type": "PrimaryOutcome", "offsets": [[270, 295]], "text": "time to clinical recovery"}, {"id": "T3", "type": "PrimaryOutcome", "offsets": [[304, 354]], "text": "deterioration rate after initiation of medications"}, {"id": "T4", "type": "OutcomeDefinition", "offsets": [[389, 473]], "text": "clinical symptoms (fever and respiratory symptoms) returning to normal over 48 hours"}, {"id": "T5", "type": "OutcomeDefinition", "offsets": [[516, 665]], "text": "presence of respiratory distress, respiratory rate ≥ 30 times/minute, oxygen saturation ≤ 93% in the resting state, and oxygenation index ≤ 300 mmHg."}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[703, 722]], "text": "virologic clearance"}, {"id": "T7", "type": "TimeFrame", "offsets": [[723, 746]], "text": "during the study period"}, {"id": "T8", "type": "OutcomeDefinition", "offsets": [[748, 833]], "text": "SARS‐CoV‐2‐negative conversion within 20 days, rate of SARS‐CoV‐2‐negative conversion"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[836, 854]], "text": "clinical follow‐up"}, {"id": "T10", "type": "OutcomeDefinition", "offsets": [[856, 1018]], "text": "clinical remission rate, time to fever remission, rate of significant improvement in chest CT, percentage of patients requiring oxygen therapy, and discharge rate"}, {"id": "T11", "type": "TimeFrame", "offsets": [[1019, 1033]], "text": "within 20 days"}, {"id": "T12", "type": "SecondaryOutcome", "offsets": [[1044, 1070]], "text": "occurrence of side effects"}, {"id": "T13", "type": "OutcomeDefinition", "offsets": [[1732, 1815]], "text": "graded according to the Common Terminology Criteria for Adverse Events, version 5.0"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T2", "arg2": "T1"}, {"id": "R3", "type": "DefinedAs", "arg1": "T2", "arg2": "T4"}, {"id": "R4", "type": "DefinedAs", "arg1": "T3", "arg2": "T5"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T3", "arg2": "T1"}, {"id": "R5", "type": "DefinedAs", "arg1": "T9", "arg2": "T10"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T9", "arg2": "T11"}, {"id": "R7", "type": "MeasuredAt", "arg1": "T6", "arg2": "T7"}, {"id": "R8", "type": "DefinedAs", "arg1": "T6", "arg2": "T8"}, {"id": "R9", "type": "DefinedAs", "arg1": "T12", "arg2": "T13"}, {"id": "R10", "type": "MeasuredAt", "arg1": "T12", "arg2": "T1"}]}
{"id": "84", "type": "silver", "text": "Study sample\n\nPatients were included if they had acute respiratory syndrome and a definitive diagnosis of COVID-19, made based on real-time reverse transcription-polymerase chain reaction (RT-PCR) and chest computed tomography scan findings from an undisclosed teaching hospital. The name of the teaching hospital was hidden due to blind peer-review protocol. Patients consecutively were recruited between May 9th, 2020 and June 9th, 2020. Inclusion criteria included being over 18 years of age, possessing a PCR-confirmed COVID-19 diagnosis, involvement of > than 30% of both lungs (ground-glass opacity) in high-resolution computed tomography (HRCT) (confirmed by two radiologists), O2 saturation (satO2) of < 90%, and a lack of adequate response to initial treatment including at least both one antiviral and one chloroquine-class drug. Exclusion criteria, in addition to an age of less than 18 years, included pregnancy, coagulation disorders (such as hemophilia, Von Willebrand disease, other clotting factor deficiencies), history of hypersensitivity to IVIg, advanced heart failure (defined as a left ventricular ejection fraction less than 35%), pulmonary fibrosis/history of lung surgery, and the presence of either sarcoidosis or tuberculosis (that may interfere with an accurate estimation of the severity of pulmonary interference by COVID-19).\n\nInadequate response to initial treatment was defined as the lack of improvement of dyspnea, fever, and hypoxemia (satO2 less than 90%), as well as the need for oxygenation to maintain satO2 above 90% after 48 h of commencing treatment.\n\nConclusions\n\nThe results of our study suggest that the administration of IVIg in patients with severe COVID-19 infection who did not respond to initial treatments could improve clinical outcomes and thus reduce mortality rates. Regarding high price of IVIg, we suggest that it should be considered in patients with > 30% involvement of lungs in lung CT scan, whom their dyspnea do not improve with standard treatment, those with persistent satO2 under 90%, and those who develop aggravation of lung involvement in serial lung CT scans, especially in younger adults.", "entities": [{"id": "T1", "type": "UnclearOutcome", "offsets": [[1418, 1557]], "text": "lack of improvement of dyspnea, fever, and hypoxemia (satO2 less than 90%), as well as the need for oxygenation to maintain satO2 above 90%"}, {"id": "T2", "type": "TimeFrame", "offsets": [[1558, 1592]], "text": "after 48 h of commencing treatment"}, {"id": "T3", "type": "UnclearOutcome", "offsets": [[1806, 1821]], "text": "mortality rates"}, {"id": "T4", "type": "UnclearOutcome", "offsets": [[1772, 1789]], "text": "clinical outcomes"}, {"id": "T5", "type": "UnclearOutcome", "offsets": [[1916, 1952]], "text": "involvement of lungs in lung CT scan"}, {"id": "T6", "type": "UnclearOutcome", "offsets": [[2035, 2040]], "text": "satO2"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}]}
{"id": "85", "type": "silver", "text": "  Outcomes:\n\nThe primary objective of this study was to investigate the efficacy of methylprednisolone pulse on mortality rate, blood O2 saturation, and need for further oxygen therapy. Sequential Organ Failure Assessment (SOFA) Score changes were assessed before and during the study. Moreover radiographic and laboratory parameters including Creatine phosphokinase (CPK), lactate dehydrogenase (LDH), and serum creatinine (SrCr), Total and Direct bilirubin were studied.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[112, 126]], "text": "mortality rate"}, {"id": "T2", "type": "PrimaryOutcome", "offsets": [[128, 148]], "text": "blood O2 saturation,"}, {"id": "T3", "type": "PrimaryOutcome", "offsets": [[153, 185]], "text": "need for further oxygen therapy."}, {"id": "T4", "type": "OtherOutcome", "offsets": [[344, 372]], "text": "Creatine phosphokinase (CPK)"}, {"id": "T5", "type": "OtherOutcome", "offsets": [[374, 401]], "text": "lactate dehydrogenase (LDH)"}, {"id": "T6", "type": "OtherOutcome", "offsets": [[407, 430]], "text": "serum creatinine (SrCr)"}], "relations": []}
{"id": "86", "type": "silver", "text": "Procedures and Outcome\nThe clinical and demographic characteristics of the study participants were obtained before enrolled in the study. All patients were followed-up from day 0 to day 3, improvement, hospital discharge, or death, and one week after hospital discharge, which was scheduled at three or four consecutive visit points. Clinical signs of the patients including heart rate, body temperature, blood pressure, oxygen saturation (SO2), and, dyspnea, cough, gastrointestinal involvement (GI) symptoms, myalgia, chest pain, and BORG score were assessed before and after treatment (by 3 days of treatment and discharge time). The need on oxygen therapy (nasal cannula, mask oxygen, reserve mask, noninvasive ventilation (NIV), and invasive ventilation) was recorded before and after treatment (by 3 days of treatment and discharge time). CT scan findings were also assessed before and one week after treatment only in patients agreed to give informed consent. Other clinical outcomes including mortality rate, the duration of hospitalization in improved patients, and the time (in days) from the initiation of treatment to death were assessed in each group. Laboratory test results including complete blood count (CBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), vein blood gas analysis (VBG) including PH, Bicarbonate (HCO3), and partial pressure of carbon dioxide (PCO2), IL-6, Ferritin, Troponin, D-dimer, lactic acid dehydrogenase (LDH), and creatine phosphokinase (CPK) were recorded before and after treatment (by 3 days of treatment and discharge time). Clinical signs of the improved patients, including cough, GI symptoms, myalgia, chest pain, and BORG score, were assessed one-week after discharge time.\nAll data were considered during the study and follow-up time and recorded on case report forms (CRFs) and the Excel database. The primary endpoint was the time of clinical improvement and discharge from the hospital or death whichever came first. Hospital discharge was determined according to the patients clinical and laboratory findings. Improvement was defined as BORG score>3, improved dyspnea, stopped fever for 72 hours, SO2> 93%, tolerated oral regimen (PO), normal urinary output and reduced CRP level without any treatment side effects.\n", "entities": [{"id": "T1", "type": "UnclearOutcome", "offsets": [[375, 385]], "text": "heart rate"}, {"id": "T2", "type": "UnclearOutcome", "offsets": [[387, 403]], "text": "body temperature"}, {"id": "T3", "type": "UnclearOutcome", "offsets": [[405, 419]], "text": "blood pressure"}, {"id": "T4", "type": "UnclearOutcome", "offsets": [[421, 444]], "text": "oxygen saturation (SO2)"}, {"id": "T5", "type": "UnclearOutcome", "offsets": [[451, 458]], "text": "dyspnea"}, {"id": "T6", "type": "UnclearOutcome", "offsets": [[460, 465]], "text": "cough"}, {"id": "T7", "type": "UnclearOutcome", "offsets": [[467, 509]], "text": "gastrointestinal involvement (GI) symptoms"}, {"id": "T8", "type": "UnclearOutcome", "offsets": [[511, 518]], "text": "myalgia"}, {"id": "T9", "type": "UnclearOutcome", "offsets": [[520, 530]], "text": "chest pain"}, {"id": "T10", "type": "UnclearOutcome", "offsets": [[536, 546]], "text": "BORG score"}, {"id": "T11", "type": "UnclearOutcome", "offsets": [[637, 758]], "text": "need on oxygen therapy (nasal cannula, mask oxygen, reserve mask, noninvasive ventilation (NIV), and invasive ventilation"}, {"id": "T12", "type": "UnclearOutcome", "offsets": [[845, 861]], "text": "CT scan findings"}, {"id": "T13", "type": "UnclearOutcome", "offsets": [[1001, 1015]], "text": "mortality rate"}, {"id": "T14", "type": "UnclearOutcome", "offsets": [[1021, 1069]], "text": "duration of hospitalization in improved patients"}, {"id": "T15", "type": "UnclearOutcome", "offsets": [[1079, 1135]], "text": "time (in days) from the initiation of treatment to death"}, {"id": "T16", "type": "UnclearOutcome", "offsets": [[1165, 1188]], "text": "Laboratory test results"}, {"id": "T17", "type": "OutcomeDefinition", "offsets": [[1208, 1502]], "text": "blood count (CBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), vein blood gas analysis (VBG) including PH, Bicarbonate (HCO3), and partial pressure of carbon dioxide (PCO2), IL-6, Ferritin, Troponin, D-dimer, lactic acid dehydrogenase (LDH), and creatine phosphokinase (CPK)"}, {"id": "T18", "type": "UnclearOutcome", "offsets": [[1589, 1628]], "text": "Clinical signs of the improved patients"}, {"id": "T19", "type": "OutcomeDefinition", "offsets": [[1630, 1695]], "text": "including cough, GI symptoms, myalgia, chest pain, and BORG score"}, {"id": "T20", "type": "PrimaryOutcome", "offsets": [[1897, 1987]], "text": "time of clinical improvement and discharge from the hospital or death whichever came first"}, {"id": "T21", "type": "OutcomeDefinition", "offsets": [[1989, 2287]], "text": "Hospital discharge was determined according to the patients clinical and laboratory findings. Improvement was defined as BORG score>3, improved dyspnea, stopped fever for 72 hours, SO2> 93%, tolerated oral regimen (PO), normal urinary output and reduced CRP level without any treatment side effects"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T16", "arg2": "T17"}, {"id": "R2", "type": "DefinedAs", "arg1": "T18", "arg2": "T19"}, {"id": "R3", "type": "DefinedAs", "arg1": "T20", "arg2": "T21"}]}
{"id": "87", "type": "silver", "text": "A total of 21 mild patients with COVID-19 were enrolled in this pilot RCT from February 2020 through March 2020 (Trial Registration: ChiCTR2000029431). Patients were considered eligible in this study on the basis of the WHO interim guidance3 and they were laboratory-confirmed positive on by the means of real-time reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. Randomization was performed and ensured with the use of Web-based randomization system. Patients were assigned, in a 1:1 ratio, into control (11 patients) and 99mTc-MDP group (10 patients). Patients in the control group received routine treatment according to Diagnostic of COVID-19 criteria issued by National Health Commission of China. Patients assigned to the 99mTc-MDP group received a combination of routine treatment and an administration of 99mTc-MDP injection of 5ml/day. Both of the patients in the control and 99mTc-MDP groups were treated for 7 days. The primary end point was the CT-based radiological pulmonary changes from baseline to 7 days. The secondary end points were disease progression from mild to severe on the day 7, as well as radiological pulmonary changes during 7 days to 14 days after treatment.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[1011, 1050]], "text": "CT-based radiological pulmonary changes"}, {"id": "T2", "type": "TimeFrame", "offsets": [[1051, 1074]], "text": "from baseline to 7 days"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[1106, 1145]], "text": "disease progression from mild to severe"}, {"id": "T4", "type": "TimeFrame", "offsets": [[1146, 1158]], "text": "on the day 7"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[1171, 1201]], "text": "radiological pulmonary changes"}, {"id": "T6", "type": "TimeFrame", "offsets": [[1202, 1242]], "text": "during 7 days to 14 days after treatment"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T3", "arg2": "T4"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T5", "arg2": "T6"}]}
{"id": "88", "type": "silver", "text": "\nOutcome Measures and Follow-up\n\nThere were 3 co-primary endpoints. The first was the number of patients with disease progression, defined as hospitalization or death. The second primary end point was the Patient Acceptable Symptom State (PASS), defined as the value of symptoms the patient considered to be well-being thresholds of pain and function. Our study incorporated the most widely used anchoring question to identify PASS cut-off points, which was: “Taking into account all your daily activities, do you consider your current state satisfactory in relation to pain level and functional impairment?” The response options were “Yes” or “No” [35][36](34)[37]. Treatment success was defined as no disease progression, or a PASS answered in the affirmative on days 3, 5, or 7 of follow-up. The third endpoint was the change from the baseline in the patient overall self-assessment, which was determined by the response to the question: Considering all the ways in which illness and health conditions may affect you at this time, please indicate below how you are doing? The response options were measured on the 0–10 VAS, from ‘very well’ (score of 0) to ‘very poorly’ (score of 10). That question is validated in the Routine Assessment of Patient Index Data 3 (RAPID3), which is a pooled index of the three patient-reported Core Data Set measures of the American College of Rheumatology, and it has previously been used to determine the activity of autoimmune diseases, degenerative diseases, such as osteoarthritis (18), and infectious diseases with a strong component of general malaise, such as chikungunya fever (37). That end point is similar to the symptom severity score (self-assessed using a 10-point VAS) recently used in a clinical trial that evaluated the efficacy of hydroxychloroquine in non-hospitalized patients with COVID-19 [38]. The secondary endpoints were changes from the baseline in different types of body pain (arthralgia, myalgia, headache, and sore throat), or more exactly, the difference between the values at enrollment and on days 3, 5, and 7 of follow-up. Pain was measured on the 0–10 VAS (27). Intensity of pain was recorded, from ‘no pain’ (score of 0) to ‘worst imaginable pain’ (score of 10). The VAS was selected because it is the validated scale that best evaluates pain in diseases (28,29), at present, and because it has also been used as a primary endpoint in other clinical trials (30). Patients completed the previously validated fatigue VAS (0–10 scale) [37], which states: “How much of a problem has unusual fatigue or tiredness been for you today” and was anchored from 0 (fatigue is not a problem) to 10 (fatigue is a major problem). Daily coughing episodes were reported by the patient on a numerical scale from 0 to 20. If there were more than 20 episodes, they were registered as 20. Dyspnea was determined once a day through the Borg scale, from 0 to 10, in which 0 is no dyspnea and 10 is extremely severe dyspnea [37]. Nausea, vomiting, diarrhea, dizziness, conjunctivitis, rhinorrhea, exanthema, skin rash, and loss of sense of smell or taste were catalogued as present or absent for each day of follow-up. Adverse events were monitored by the researchers through anamnesis and abnormal routine laboratory test results. Follow-up was carried out for at least 20 days or until patient outcome (cure or death). Daily follow-up was suspended in the hospitalized patients, and from the day of hospital admission, their registers were considered lost data and were not considered in the analysis from that day forward, with the exception of the PASS, in which its subsequent registers were reported as a negative acceptable symptom state. Nevertheless, the general aspects of those patients were registered, such as hospitalization and outcome (cure or death).\n", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[86, 129]], "text": "number of patients with disease progression"}, {"id": "T2", "type": "OutcomeDefinition", "offsets": [[142, 166]], "text": "hospitalization or death"}, {"id": "T3", "type": "PrimaryOutcome", "offsets": [[205, 244]], "text": "Patient Acceptable Symptom State (PASS)"}, {"id": "T4", "type": "OutcomeDefinition", "offsets": [[261, 350]], "text": "value of symptoms the patient considered to be well-being thresholds of pain and function"}, {"id": "T5", "type": "OtherOutcome", "offsets": [[667, 684]], "text": "Treatment success"}, {"id": "T6", "type": "OutcomeDefinition", "offsets": [[700, 761]], "text": "no disease progression, or a PASS answered in the affirmative"}, {"id": "T7", "type": "TimeFrame", "offsets": [[762, 793]], "text": "on days 3, 5, or 7 of follow-up"}, {"id": "T8", "type": "PrimaryOutcome", "offsets": [[822, 885]], "text": "change from the baseline in the patient overall self-assessment"}, {"id": "T9", "type": "OutcomeDefinition", "offsets": [[915, 1853]], "text": "response to the question: Considering all the ways in which illness and health conditions may affect you at this time, please indicate below how you are doing? The response options were measured on the 0–10 VAS, from ‘very well’ (score of 0) to ‘very poorly’ (score of 10). That question is validated in the Routine Assessment of Patient Index Data 3 (RAPID3), which is a pooled index of the three patient-reported Core Data Set measures of the American College of Rheumatology, and it has previously been used to determine the activity of autoimmune diseases, degenerative diseases, such as osteoarthritis (18), and infectious diseases with a strong component of general malaise, such as chikungunya fever (37). That end point is similar to the symptom severity score (self-assessed using a 10-point VAS) recently used in a clinical trial that evaluated the efficacy of hydroxychloroquine in non-hospitalized patients with COVID-19 [38]."}, {"id": "T10", "type": "SecondaryOutcome", "offsets": [[1883, 2092]], "text": "changes from the baseline in different types of body pain (arthralgia, myalgia, headache, and sore throat), or more exactly, the difference between the values at enrollment and on days 3, 5, and 7 of follow-up"}, {"id": "T11", "type": "OutcomeDefinition", "offsets": [[2094, 2687]], "text": "Pain was measured on the 0–10 VAS (27). Intensity of pain was recorded, from ‘no pain’ (score of 0) to ‘worst imaginable pain’ (score of 10). The VAS was selected because it is the validated scale that best evaluates pain in diseases (28,29), at present, and because it has also been used as a primary endpoint in other clinical trials (30). Patients completed the previously validated fatigue VAS (0–10 scale) [37], which states: “How much of a problem has unusual fatigue or tiredness been for you today” and was anchored from 0 (fatigue is not a problem) to 10 (fatigue is a major problem)."}, {"id": "T12", "type": "OtherOutcome", "offsets": [[2688, 2774]], "text": "Daily coughing episodes were reported by the patient on a numerical scale from 0 to 20"}, {"id": "T13", "type": "OtherOutcome", "offsets": [[2841, 2848]], "text": "Dyspnea"}, {"id": "T14", "type": "OutcomeDefinition", "offsets": [[2864, 2972]], "text": "once a day through the Borg scale, from 0 to 10, in which 0 is no dyspnea and 10 is extremely severe dyspnea"}, {"id": "T15", "type": "OtherOutcome", "offsets": [[2979, 2985]], "text": "Nausea"}, {"id": "T16", "type": "OtherOutcome", "offsets": [[2987, 2995]], "text": "vomiting"}, {"id": "T17", "type": "OtherOutcome", "offsets": [[2997, 3005]], "text": "diarrhea"}, {"id": "T18", "type": "OtherOutcome", "offsets": [[3007, 3016]], "text": "dizziness"}, {"id": "T19", "type": "OtherOutcome", "offsets": [[3018, 3032]], "text": "conjunctivitis"}, {"id": "T20", "type": "OtherOutcome", "offsets": [[3034, 3044]], "text": "rhinorrhea"}, {"id": "T21", "type": "OtherOutcome", "offsets": [[3046, 3055]], "text": "exanthema"}, {"id": "T22", "type": "OtherOutcome", "offsets": [[3057, 3066]], "text": "skin rash"}, {"id": "T23", "type": "OtherOutcome", "offsets": [[3072, 3103]], "text": "loss of sense of smell or taste"}, {"id": "T24", "type": "OtherOutcome", "offsets": [[3168, 3182]], "text": "Adverse events"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T3", "arg2": "T4"}, {"id": "R3", "type": "DefinedAs", "arg1": "T5", "arg2": "T6"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T5", "arg2": "T7"}, {"id": "R5", "type": "DefinedAs", "arg1": "T8", "arg2": "T9"}, {"id": "R6", "type": "DefinedAs", "arg1": "T10", "arg2": "T11"}, {"id": "R7", "type": "DefinedAs", "arg1": "T13", "arg2": "T14"}]}
{"id": "89", "type": "silver", "text": " The COVID-19 virus has spread rapidly around the world and there are many patients in multiple countries. Great efforts have been made to find effective medications against the COVID-19. This study aims to compare the effectiveness of LINCOCIN® and AZITRO® in the treatment of COVID-19 associated pneumonia. A total of 24 hospitalized patients aged between 30-80 years who were admitted to the Tarsus Medical Park Hospital between February to March 2020 was included in the study. The patients were divided into LINCOCIN® and AZITRO® treatment groups. Bronchoalveolar-lavage PCR results were compared after treatment. The mean age was 58.4±15.4 years in the LINCOCIN® group and 59.1±16.6 years in the AZITRO® group. In the LINCOCIN® group, the rate of males was 66.7% and it was 58.3% in the AZITRO® group. There were no statistical differences in terms of age and gender between the groups. On the 6th day after starting treatment, negative bronchoalveolar PCR result was 83.3% in the LINCOCIN® group and 33.3% in the AZITRO® group. The negative bronchoalveolar PCR proportion was significantly higher in the LINCOCIN® group than in the AZITRO® group. LINCOCIN® usage may be more appropriate in the treatment of COVID-19 associated pneumonia. Further studies with a large sample size should clarify these results.", "entities": [{"id": "T1", "type": "UnclearOutcome", "offsets": [[553, 587]], "text": "Bronchoalveolar-lavage PCR results"}, {"id": "T2", "type": "TimeFrame", "offsets": [[893, 907]], "text": "On the 6th day"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}]}
{"id": "9", "type": "silver", "text": "Main Outcomes and Measures  Primary outcome was reduction in lethality by at least 50% in the high-dosage group compared with the low-dosage group. Data presented here refer primarily to safety and lethality outcomes during treatment on day 13. Secondary end points included participant clinical status, laboratory examinations, and electrocardiogram results. Outcomes will be presented to day 28. Viral respiratory secretion RNA detection was performed on days 0 and 4.\n\n\nOutcomes\n\nSafety outcomes included adverse events that occurred during treatment, serious adverse events, and premature or temporary discontinuation of treatment. Adverse events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events. The working hypothesis of this trial was that the lethality rate in the high-dosage group would be half that of the low-dosage group by day 28. Thus, the primary end point was lethality by day 28. Secondary end points included lethality on day 13, participant clinical status, laboratory examinations, electrocardiogram on days 13 and 28, daily clinical status during hospitalization, duration of mechanical ventilation (if applicable) and supplementary oxygen (if applicable), and the time (in days) from treatment initiation to death. Here we present analyses until day 13, with lethality as the primary outcome. A subgroup of patients enrolled when already admitted to the intensive care unit was analyzed separately. Virologic measures included viral RNA detection on days 0 and 4.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[48, 86]], "text": "reduction in lethality by at least 50%"}, {"id": "T2", "type": "TimeFrame", "offsets": [[234, 243]], "text": "on day 13"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[275, 302]], "text": "participant clinical status"}, {"id": "T4", "type": "SecondaryOutcome", "offsets": [[304, 327]], "text": "laboratory examinations"}, {"id": "T6", "type": "TimeFrame", "offsets": [[387, 396]], "text": "to day 28"}, {"id": "T7", "type": "OtherOutcome", "offsets": [[398, 439]], "text": "Viral respiratory secretion RNA detection"}, {"id": "T8", "type": "TimeFrame", "offsets": [[454, 469]], "text": "on days 0 and 4"}, {"id": "T9", "type": "OtherOutcome", "offsets": [[508, 553]], "text": "adverse events that occurred during treatment"}, {"id": "T10", "type": "OtherOutcome", "offsets": [[555, 577]], "text": "serious adverse events"}, {"id": "T11", "type": "OtherOutcome", "offsets": [[583, 634]], "text": "premature or temporary discontinuation of treatment"}, {"id": "T12", "type": "OutcomeDefinition", "offsets": [[656, 756]], "text": "classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[1060, 1077]], "text": "electrocardiogram"}, {"id": "T13", "type": "TimeFrame", "offsets": [[1078, 1095]], "text": "on days 13 and 28"}, {"id": "T14", "type": "SecondaryOutcome", "offsets": [[1097, 1141]], "text": "daily clinical status during hospitalization"}, {"id": "T15", "type": "SecondaryOutcome", "offsets": [[1143, 1193]], "text": "duration of mechanical ventilation (if applicable)"}, {"id": "T16", "type": "SecondaryOutcome", "offsets": [[1198, 1234]], "text": "supplementary oxygen (if applicable)"}, {"id": "T17", "type": "SecondaryOutcome", "offsets": [[1244, 1293]], "text": "time (in days) from treatment initiation to death"}, {"id": "T18", "type": "SecondaryOutcome", "offsets": [[985, 994]], "text": "lethality"}, {"id": "T19", "type": "SecondaryOutcome", "offsets": [[1006, 1033]], "text": "participant clinical status"}, {"id": "T20", "type": "SecondaryOutcome", "offsets": [[1035, 1058]], "text": "laboratory examinations"}, {"id": "T21", "type": "TimeFrame", "offsets": [[995, 1004]], "text": "on day 13"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T3", "arg2": "T6"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T4", "arg2": "T6"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T7", "arg2": "T8"}, {"id": "R6", "type": "DefinedAs", "arg1": "T9", "arg2": "T12"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T5", "arg2": "T13"}, {"id": "R7", "type": "MeasuredAt", "arg1": "T18", "arg2": "T21"}]}
{"id": "90", "type": "silver", "text": " Main outcomes\n\nThe primary endpoint of the study is the rate of decline in SARS-CoV-2 viral load in oropharyngeal samples as assessed by RT-PCR in samples collected at baseline, 48 and 96 hours after randomization and administration of drug for the intervention arm. Secondary endpoints include change in NEWS2 at 96 hours after randomisation, admission to intensive care unit, mortality (in-hospital, and at 30 and 90 days), duration of hospital admission, clinical status on a 7-point ordinal scale 14 days after randomization ([1] Death [2] Hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation [3] Hospitalised, on non-invasive ventilation or high flow oxygen devices [4] Hospitalized, requiring supplemental oxygen [5] Hospitalised, not requiring supplemental oxygen [6] Not hospitalized, but unable to resume normal activities [7] Not hospitalised, with resumption of normal activities), and improvement in protein biomarker profiles (C-reactive protein, markers of renal and hepatic injury, and established cardiac biomarkers like cardiac troponin and B-type natriuretic peptide) at 96 hours after randomization.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[57, 155]], "text": "rate of decline in SARS-CoV-2 viral load in oropharyngeal samples as assessed by RT-PCR in samples"}, {"id": "T2", "type": "TimeFrame", "offsets": [[166, 266]], "text": "at baseline, 48 and 96 hours after randomization and administration of drug for the intervention arm"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[296, 311]], "text": "change in NEWS2"}, {"id": "T4", "type": "TimeFrame", "offsets": [[312, 343]], "text": "at 96 hours after randomisation"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[345, 377]], "text": "admission to intensive care unit"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[379, 388]], "text": "mortality"}, {"id": "T7", "type": "TimeFrame", "offsets": [[390, 424]], "text": "in-hospital, and at 30 and 90 days"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[427, 457]], "text": "duration of hospital admission"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[459, 501]], "text": "clinical status on a 7-point ordinal scale"}, {"id": "T10", "type": "TimeFrame", "offsets": [[502, 529]], "text": "14 days after randomization"}, {"id": "T11", "type": "OutcomeDefinition", "offsets": [[531, 926]], "text": "[1] Death [2] Hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation [3] Hospitalised, on non-invasive ventilation or high flow oxygen devices [4] Hospitalized, requiring supplemental oxygen [5] Hospitalised, not requiring supplemental oxygen [6] Not hospitalized, but unable to resume normal activities [7] Not hospitalised, with resumption of normal activities"}, {"id": "T12", "type": "SecondaryOutcome", "offsets": [[933, 974]], "text": "improvement in protein biomarker profiles"}, {"id": "T13", "type": "OutcomeDefinition", "offsets": [[976, 1120]], "text": "C-reactive protein, markers of renal and hepatic injury, and established cardiac biomarkers like cardiac troponin and B-type natriuretic peptide"}, {"id": "T14", "type": "TimeFrame", "offsets": [[1122, 1153]], "text": "at 96 hours after randomization"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T3", "arg2": "T4"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T6", "arg2": "T7"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T9", "arg2": "T10"}, {"id": "R5", "type": "DefinedAs", "arg1": "T9", "arg2": "T11"}, {"id": "R6", "type": "DefinedAs", "arg1": "T12", "arg2": "T13"}, {"id": "R7", "type": "MeasuredAt", "arg1": "T12", "arg2": "T14"}]}
{"id": "91", "type": "silver", "text": " Repeat Nasopharyngeal and Throat Swab PCR\nAll subjects underwent repeat nasopharyngeal and throat swab PCR for SARS-CoV2 every other day until their PCR was negative. These repeat PCR tests began on the fifth day after taking the medication for subjects who began the study and remained symptom-free. The PCR repeat testing began on the second symptom-free day onward for subjects who began the study with symptoms or developed symptoms. The investigators had telephone contact with all the subjects every three days throughout the study to determine any therapy's adverse effects. A re-evaluation PCR was performed after seven days following the first negative PCR.\nEndpoints were a negative PCR and resolution of symptoms. The duration from the first day of drug intake to the negative PCR was counted as the recovery period. The duration from the first day of drug intake to the disappearance of symptoms was counted as the period to symptomatic recovery. \"Adverse effects\" were determined by the existence of the pharmacological side effects of the particular drug during treatment. A detailed history of adverse effects (other than previous disease symptoms) experienced by each participant was collected during the follow-up sample collection. An asymptomatic participant presented with no symptom of COVID-19 and remained the same until the negative PCR", "entities": [{"id": "T1", "type": "OtherOutcome", "offsets": [[685, 697]], "text": "negative PCR"}, {"id": "T2", "type": "OtherOutcome", "offsets": [[702, 724]], "text": "resolution of symptoms"}, {"id": "T3", "type": "OtherOutcome", "offsets": [[961, 976]], "text": "Adverse effects"}, {"id": "T4", "type": "OutcomeDefinition", "offsets": [[1018, 1086]], "text": "pharmacological side effects of the particular drug during treatment"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T3", "arg2": "T4"}]}
{"id": "92", "type": "silver", "text": " Outcome Measures\n\nThe primary endpoint was the duration of viral shedding, which was defined as the time from randomization to the first negative nucleic acid test of 5 consecutive RT-PCR results. Other clinical outcomes included clinical status (ie, progressive rate to severe illness), syndromes, peripheral blood cells, and biochemical parameters, C-reactive protein and inflammatory cytokines, and length of hospital stay. Safety outcomes included adverse events (AEs) that occurred during treatment, serious AEs, and premature discontinuation of treatment.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[48, 74]], "text": "duration of viral shedding"}, {"id": "T2", "type": "OutcomeDefinition", "offsets": [[101, 196]], "text": "time from randomization to the first negative nucleic acid test of 5 consecutive RT-PCR results"}, {"id": "T3", "type": "OtherOutcome", "offsets": [[231, 287]], "text": "clinical status (ie, progressive rate to severe illness)"}, {"id": "T4", "type": "OtherOutcome", "offsets": [[289, 298]], "text": "syndromes"}, {"id": "T5", "type": "OtherOutcome", "offsets": [[300, 322]], "text": "peripheral blood cells"}, {"id": "T6", "type": "OtherOutcome", "offsets": [[328, 350]], "text": "biochemical parameters"}, {"id": "T7", "type": "OtherOutcome", "offsets": [[352, 397]], "text": "C-reactive protein and inflammatory cytokines"}, {"id": "T8", "type": "OtherOutcome", "offsets": [[403, 426]], "text": "length of hospital stay"}, {"id": "T9", "type": "OtherOutcome", "offsets": [[453, 473]], "text": "adverse events (AEs)"}, {"id": "T10", "type": "OtherOutcome", "offsets": [[506, 517]], "text": "serious AEs"}, {"id": "T11", "type": "OtherOutcome", "offsets": [[523, 561]], "text": "premature discontinuation of treatment"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T2"}]}
{"id": "93", "type": "silver", "text": " Outcome measures\n\nThe research objective of this study was the assessment of potential superiority of ARB compared to KALETRA on management of patients with COVID-19. The primary outcome was duration of hospitalization and clinical improvement 7 days after admission. The criteria of improvement were relief of cough, dyspnea, and fever. Time to relieving fever was also assessed across the two groups.\nThe secondary outcomes were death during the 30 days of treatment, duration of hospitalization, changing laboratory tests during 7 days, changing of CT findings after 30 days, and the need for invasive mechanical ventilation.\n\nWe documented the age, gender, job, education status, underlying disease (history of diabetes, ischemic heart disease, hypertension, asthma,) and smoking status, as demographic variables. Fever, cough, dyspnea, nausea and vomiting, diarrhea, fatigue and weakness, loss of appetite, and taste were also documented at the first day of admission. The saturation of peripheral oxygen, C-reactive protein (CRP), complete blood cell count (CBC), erythrocyte sedimentation rate (ESR), aspartate transaminase (AST), alanine aminotransferase (ALT), white blood cell count (WBC), lymphocyte and neutrophil count, neutrophil lymphocyte ratio, total bilirubin, blood Na and K, creatinine and thyroid stimulating hormone (TSH) were measured at the first day of admission and 7 days after. The CT scan and chest X-ray were taken at the first day of admission and 30 days after. The PCR test was taken at admission and the time of discharge.\n\nWe considered the following criteria for discharge from hospital: Resolution of fever at least for 72 h and decreasing trend in LDH and CRP and lymphocytosis significant and having normal saturation of peripheral oxygen.\n\nWe categorized the patients to three groups based on severity of disease according to the CT scan and chest X-ray findings. Mild, moderate and severe categories were defined as involvement of base, less and more than 50% of the lung field respectively in CXR and CT scan.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[224, 244]], "text": "clinical improvement"}, {"id": "T2", "type": "TimeFrame", "offsets": [[245, 267]], "text": "7 days after admission"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[302, 337]], "text": "relief of cough, dyspnea, and fever"}, {"id": "T4", "type": "PrimaryOutcome", "offsets": [[192, 219]], "text": "duration of hospitalization"}, {"id": "T5", "type": "OtherOutcome", "offsets": [[339, 362]], "text": "Time to relieving fever"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[432, 437]], "text": "death"}, {"id": "T7", "type": "TimeFrame", "offsets": [[438, 469]], "text": "during the 30 days of treatment"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[471, 498]], "text": "duration of hospitalization"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[500, 525]], "text": "changing laboratory tests"}, {"id": "T10", "type": "TimeFrame", "offsets": [[526, 539]], "text": "during 7 days"}, {"id": "T11", "type": "SecondaryOutcome", "offsets": [[541, 564]], "text": "changing of CT findings"}, {"id": "T12", "type": "TimeFrame", "offsets": [[565, 578]], "text": "after 30 days"}, {"id": "T13", "type": "SecondaryOutcome", "offsets": [[588, 628]], "text": "need for invasive mechanical ventilation"}, {"id": "T14", "type": "OtherOutcome", "offsets": [[819, 824]], "text": "Fever"}, {"id": "T15", "type": "OtherOutcome", "offsets": [[826, 831]], "text": "cough"}, {"id": "T16", "type": "OtherOutcome", "offsets": [[833, 840]], "text": "dyspnea"}, {"id": "T17", "type": "OtherOutcome", "offsets": [[842, 861]], "text": "nausea and vomiting"}, {"id": "T18", "type": "OtherOutcome", "offsets": [[863, 871]], "text": "diarrhea"}, {"id": "T19", "type": "OtherOutcome", "offsets": [[873, 893]], "text": "fatigue and weakness"}, {"id": "T20", "type": "OtherOutcome", "offsets": [[895, 911]], "text": "loss of appetite"}, {"id": "T21", "type": "OtherOutcome", "offsets": [[917, 922]], "text": "taste"}, {"id": "T22", "type": "OtherOutcome", "offsets": [[979, 1010]], "text": "saturation of peripheral oxygen"}, {"id": "T23", "type": "OtherOutcome", "offsets": [[1012, 1036]], "text": "C-reactive protein (CRP)"}, {"id": "T24", "type": "OtherOutcome", "offsets": [[1038, 1069]], "text": "complete blood cell count (CBC)"}, {"id": "T25", "type": "OtherOutcome", "offsets": [[1071, 1107]], "text": "erythrocyte sedimentation rate (ESR)"}, {"id": "T26", "type": "OtherOutcome", "offsets": [[1109, 1137]], "text": "aspartate transaminase (AST)"}, {"id": "T27", "type": "OtherOutcome", "offsets": [[1139, 1169]], "text": "alanine aminotransferase (ALT)"}, {"id": "T28", "type": "OtherOutcome", "offsets": [[1171, 1199]], "text": "white blood cell count (WBC)"}, {"id": "T29", "type": "OtherOutcome", "offsets": [[1201, 1232]], "text": "lymphocyte and neutrophil count"}, {"id": "T30", "type": "OtherOutcome", "offsets": [[1234, 1261]], "text": "neutrophil lymphocyte ratio"}, {"id": "T31", "type": "OtherOutcome", "offsets": [[1263, 1278]], "text": "total bilirubin"}, {"id": "T32", "type": "OtherOutcome", "offsets": [[1280, 1294]], "text": "blood Na and K"}, {"id": "T33", "type": "OtherOutcome", "offsets": [[1296, 1306]], "text": "creatinine"}, {"id": "T34", "type": "OtherOutcome", "offsets": [[1311, 1344]], "text": "thyroid stimulating hormone (TSH)"}, {"id": "T35", "type": "TimeFrame", "offsets": [[1359, 1405]], "text": "at the first day of admission and 7 days after"}, {"id": "T36", "type": "TimeFrame", "offsets": [[944, 973]], "text": "at the first day of admission"}, {"id": "T37", "type": "OtherOutcome", "offsets": [[1411, 1418]], "text": "CT scan"}, {"id": "T38", "type": "OtherOutcome", "offsets": [[1423, 1434]], "text": "chest X-ray"}, {"id": "T39", "type": "TimeFrame", "offsets": [[1446, 1493]], "text": "at the first day of admission and 30 days after"}, {"id": "T40", "type": "TimeFrame", "offsets": [[1518, 1556]], "text": "at admission and the time of discharge"}, {"id": "T41", "type": "OtherOutcome", "offsets": [[1499, 1507]], "text": "PCR test"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T4", "arg2": "T2"}, {"id": "R3", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T6", "arg2": "T7"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T11", "arg2": "T12"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T22", "arg2": "T35"}, {"id": "R7", "type": "MeasuredAt", "arg1": "T23", "arg2": "T35"}, {"id": "R8", "type": "MeasuredAt", "arg1": "T24", "arg2": "T35"}, {"id": "R9", "type": "MeasuredAt", "arg1": "T25", "arg2": "T35"}, {"id": "R10", "type": "MeasuredAt", "arg1": "T26", "arg2": "T35"}, {"id": "R11", "type": "MeasuredAt", "arg1": "T27", "arg2": "T35"}, {"id": "R12", "type": "MeasuredAt", "arg1": "T28", "arg2": "T35"}, {"id": "R13", "type": "MeasuredAt", "arg1": "T29", "arg2": "T35"}, {"id": "R14", "type": "MeasuredAt", "arg1": "T30", "arg2": "T35"}, {"id": "R15", "type": "MeasuredAt", "arg1": "T31", "arg2": "T35"}, {"id": "R16", "type": "MeasuredAt", "arg1": "T32", "arg2": "T35"}, {"id": "R17", "type": "MeasuredAt", "arg1": "T33", "arg2": "T35"}, {"id": "R18", "type": "MeasuredAt", "arg1": "T34", "arg2": "T35"}, {"id": "R19", "type": "MeasuredAt", "arg1": "T14", "arg2": "T36"}, {"id": "R20", "type": "MeasuredAt", "arg1": "T15", "arg2": "T36"}, {"id": "R21", "type": "MeasuredAt", "arg1": "T16", "arg2": "T36"}, {"id": "R22", "type": "MeasuredAt", "arg1": "T17", "arg2": "T36"}, {"id": "R23", "type": "MeasuredAt", "arg1": "T18", "arg2": "T36"}, {"id": "R24", "type": "MeasuredAt", "arg1": "T19", "arg2": "T36"}, {"id": "R25", "type": "MeasuredAt", "arg1": "T20", "arg2": "T36"}, {"id": "R26", "type": "MeasuredAt", "arg1": "T21", "arg2": "T36"}, {"id": "R27", "type": "MeasuredAt", "arg1": "T9", "arg2": "T10"}, {"id": "R28", "type": "MeasuredAt", "arg1": "T37", "arg2": "T39"}, {"id": "R29", "type": "MeasuredAt", "arg1": "T38", "arg2": "T39"}, {"id": "R30", "type": "MeasuredAt", "arg1": "T41", "arg2": "T40"}]}
{"id": "94", "type": "silver", "text": "ABSTRACT Favipiravir is an oral broad-spectrum inhibitor of viral RNA-dependent RNA polymerase that is approved for treatment of influenza in Japan. We conducted a prospective, randomized, open-label, multicenter trial of favipiravir for the treatment of COVID-19 at 25 hospitals across Japan. Eligible patients were adolescents and adults admitted with COVID-19 who were asymptomatic or mildly ill and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned at a 1:1 ratio to early or late favipiravir therapy (in the latter case, the same regimen starting on day 6 instead of day 1).\nThe primary endpoint was viral clearance by day 6. The secondary endpoint was change in viral load by day 6. Exploratory endpoints included time to defervescence and resolution of symptoms. Eighty-nine patients were enrolled, of whom 69 were virologically evaluable. Viral clearance occurred within 6 days in 66.7% and 56.1% of the early and late treatment groups (adjusted hazard ratio [aHR], 1.42; 95% confidence interval [95% CI], 0.76 to 2.62). Of 30 patients who had a fever (\u000237.5°C) on day 1, times to defervescence were 2.1 days and 3.2 days in the early and late treatment groups (aHR, 1.88; 95% CI, 0.81 to 4.35). During therapy, 84.1% developed transient hyperuricemia. Favipiravir did not significantly improve viral clearance as measured by reverse transcription-PCR (RT-PCR) by day 6 but was associated with numerical reduction in time to defervescence.\nNeither disease progression nor death occurred in any of the patients in either treatment group during the 28-day participation. (This study has been registered with the Japan Registry of Clinical Trials under number jRCTs041190120.)", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[667, 682]], "text": "viral clearance"}, {"id": "T2", "type": "TimeFrame", "offsets": [[683, 691]], "text": "by day 6"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[720, 740]], "text": "change in viral load"}, {"id": "T4", "type": "TimeFrame", "offsets": [[741, 749]], "text": "by day 6"}, {"id": "T5", "type": "OtherOutcome", "offsets": [[782, 803]], "text": "time to defervescence"}, {"id": "T7", "type": "UnclearOutcome", "offsets": [[1308, 1321]], "text": "hyperuricemia"}, {"id": "T8", "type": "OtherOutcome", "offsets": [[808, 830]], "text": "resolution of symptoms"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T3", "arg2": "T4"}]}
{"id": "95", "type": "silver", "text": " Outcomes\n\nThe primary efficacy outcome was the proportion of subjects meeting a severe COVID-19 progression composite end point (death, ICU admission, mechanical ventilation, ECMO, and/or vasopressor use) at day 14. The primary safety outcome was the cumulative incidence of serious adverse events (SAEs), grade 3 or 4 adverse events, and/or discontinuation of therapy at day 30.\n\nSecondary clinical outcomes included changes in an 8-point ordinal COVID-19 clinical severity score (defined in Table 2), the primary composite outcome and mortality at day 30, hospital length of stay (LOS), fever-free days, and oxygen-free days (defined as 7 [the maximum number of days with vital signs captured] minus the number of days with temperature ≥100.4°F or requiring supplemental oxygen). Secondary laboratory outcomes included SARS-CoV-2 viral clearance on nasopharyngeal PCR, clinically significant changes from baseline to follow-up (day 6, or day 3 if day 6 was unavailable) creatinine [25], hepatic and hematology labs [26], and changes in inflammatory markers (C-reactive protein, lactic acid dehydrogenase, ferritin, interleukin-6) and coagulation factors (D-dimer) associated with severe COVID-19 [27, 28].", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[48, 205]], "text": "proportion of subjects meeting a severe COVID-19 progression composite end point (death, ICU admission, mechanical ventilation, ECMO, and/or vasopressor use)"}, {"id": "T2", "type": "TimeFrame", "offsets": [[206, 215]], "text": "at day 14"}, {"id": "T3", "type": "OtherOutcome", "offsets": [[252, 369]], "text": "cumulative incidence of serious adverse events (SAEs), grade 3 or 4 adverse events, and/or discontinuation of therapy"}, {"id": "T4", "type": "TimeFrame", "offsets": [[370, 379]], "text": "at day 30"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[419, 481]], "text": "changes in an 8-point ordinal COVID-19 clinical severity score"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[508, 557]], "text": "primary composite outcome and mortality at day 30"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[559, 588]], "text": "hospital length of stay (LOS)"}, {"id": "T8", "type": "SecondaryOutcome", "offsets": [[590, 605]], "text": "fever-free days"}, {"id": "T9", "type": "SecondaryOutcome", "offsets": [[611, 627]], "text": "oxygen-free days"}, {"id": "T10", "type": "OutcomeDefinition", "offsets": [[628, 780]], "text": "(defined as 7 [the maximum number of days with vital signs captured] minus the number of days with temperature ≥100.4°F or requiring supplemental oxygen"}, {"id": "T11", "type": "OtherOutcome", "offsets": [[822, 870]], "text": "SARS-CoV-2 viral clearance on nasopharyngeal PCR"}, {"id": "T12", "type": "OtherOutcome", "offsets": [[872, 983]], "text": "clinically significant changes from baseline to follow-up (day 6, or day 3 if day 6 was unavailable) creatinine"}, {"id": "T13", "type": "OtherOutcome", "offsets": [[990, 1017]], "text": "hepatic and hematology labs"}, {"id": "T14", "type": "OtherOutcome", "offsets": [[1028, 1198]], "text": "changes in inflammatory markers (C-reactive protein, lactic acid dehydrogenase, ferritin, interleukin-6) and coagulation factors (D-dimer) associated with severe COVID-19"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T3", "arg2": "T4"}, {"id": "R3", "type": "DefinedAs", "arg1": "T9", "arg2": "T10"}]}
{"id": "96", "type": "silver", "text": " Outcome measures\n\nThe outcome end point was the time needed for resolution of fever, cough, shortness of breath and finally, full recovery from all symptoms and the negative result of repeat RT-PCR on day 10. Recovery time was defined as time required for the resolution of symptom(s) from the date of enrolment in the study as well as from the onset of initial illness. ", "entities": [{"id": "T1", "type": "UnclearOutcome", "offsets": [[49, 198]], "text": "time needed for resolution of fever, cough, shortness of breath and finally, full recovery from all symptoms and the negative result of repeat RT-PCR"}, {"id": "T2", "type": "TimeFrame", "offsets": [[199, 208]], "text": "on day 10"}, {"id": "T3", "type": "OutcomeDefinition", "offsets": [[239, 370]], "text": "time required for the resolution of symptom(s) from the date of enrolment in the study as well as from the onset of initial illness"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T1", "arg2": "T3"}]}
{"id": "97", "type": "silver", "text": " Primary outcome\n\nThe primary outcome was the time to clinical improvement, defined as the time from enrollment to an improvement of two points on a seven-category ordinal scale33 (Supplementary Table 4) or live discharge from the hospital, whichever came first.\n\nSecondary outcomes\n\nSecondary outcomes included the time to radiological improvement defined as the time from enrollment to radiological improvement on chest CT scans, the time to virus nucleic acid negative conversion defined as the time from enrollment to two consecutive negative tests for SARS-CoV-2 via qRT-PCR on nasopharyngeal swabs samples, the overall rate of clinical improvement assessed on day 28. Safety outcomes included treatment-emergent AEs and SAEs, classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. AEs and SAEs were assessed and recorded once daily by trained researchers from day 0 to day 28. Other secondary outcomes included overall rates of radiological improvement on days 7, 14, and 28 on chest CT scans, overall rates of virus nucleic acid negative conversion via qRT-PCR on nasopharyngeal swabs samples on days 7, 14, and 28,  and the rates of deterioration or death on day 28.", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[46, 74]], "text": "time to clinical improvement"}, {"id": "T2", "type": "OutcomeDefinition", "offsets": [[91, 261]], "text": "time from enrollment to an improvement of two points on a seven-category ordinal scale33 (Supplementary Table 4) or live discharge from the hospital, whichever came first"}, {"id": "T3", "type": "SecondaryOutcome", "offsets": [[316, 348]], "text": "time to radiological improvement"}, {"id": "T4", "type": "OutcomeDefinition", "offsets": [[364, 430]], "text": "time from enrollment to radiological improvement on chest CT scans"}, {"id": "T5", "type": "OtherOutcome", "offsets": [[699, 845]], "text": "treatment-emergent AEs and SAEs, classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0"}, {"id": "T6", "type": "TimeFrame", "offsets": [[887, 941]], "text": "once daily by trained researchers from day 0 to day 28"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[977, 1018]], "text": "overall rates of radiological improvement"}, {"id": "T8", "type": "TimeFrame", "offsets": [[1019, 1040]], "text": "on days 7, 14, and 28"}, {"id": "T9", "type": "OutcomeDefinition", "offsets": [[1041, 1058]], "text": "on chest CT scans"}, {"id": "T10", "type": "SecondaryOutcome", "offsets": [[1060, 1159]], "text": "overall rates of virus nucleic acid negative conversion via qRT-PCR on nasopharyngeal swabs samples"}, {"id": "T11", "type": "TimeFrame", "offsets": [[1160, 1181]], "text": "on days 7, 14, and 28"}, {"id": "T12", "type": "SecondaryOutcome", "offsets": [[1192, 1223]], "text": "rates of deterioration or death"}, {"id": "T13", "type": "TimeFrame", "offsets": [[1224, 1233]], "text": "on day 28"}], "relations": [{"id": "R1", "type": "DefinedAs", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T3", "arg2": "T4"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T5", "arg2": "T6"}, {"id": "R4", "type": "DefinedAs", "arg1": "T7", "arg2": "T9"}, {"id": "R5", "type": "MeasuredAt", "arg1": "T7", "arg2": "T8"}, {"id": "R6", "type": "MeasuredAt", "arg1": "T10", "arg2": "T11"}]}
{"id": "98", "type": "silver", "text": " Methods: In this prospective, open-label, randomized and double blind clinical trial, 100 patients hospitalized with COVID-19 were randomized in a 1:1 allocation from May 21 to June 20, 2020, to either standard medical treatment (Hydroxychloroquine) or colchicine with standard medical treatment. The study took place in Imam Reza hospital of Ardabil city in Iran, with trial registration ID: 47707 (irct.ir). Colchicine group were received 1 mg tablet of colchicine daily alongside the Hydroxychloroquine for 6 days. Primary end points were (1) Length of hospitalization; (2) symptoms and (3) Co-existed disease. Secondary end points were examined 2 weeks after discharge and included (1) mortality and morbidity; (2) re-admission and (3) symptoms. ", "entities": [{"id": "T1", "type": "PrimaryOutcome", "offsets": [[547, 572]], "text": "Length of hospitalization"}, {"id": "T2", "type": "PrimaryOutcome", "offsets": [[578, 586]], "text": "symptoms"}, {"id": "T3", "type": "PrimaryOutcome", "offsets": [[595, 613]], "text": "Co-existed disease"}, {"id": "T4", "type": "TimeFrame", "offsets": [[641, 673]], "text": "examined 2 weeks after discharge"}, {"id": "T5", "type": "SecondaryOutcome", "offsets": [[691, 714]], "text": "mortality and morbidity"}, {"id": "T6", "type": "SecondaryOutcome", "offsets": [[720, 732]], "text": "re-admission"}, {"id": "T7", "type": "SecondaryOutcome", "offsets": [[741, 749]], "text": "symptoms"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T5", "arg2": "T4"}, {"id": "R2", "type": "MeasuredAt", "arg1": "T6", "arg2": "T4"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T7", "arg2": "T4"}]}
{"id": "99", "type": "silver", "text": "Primary and exploratory efficacy end points\n\nThe dynamic conversion from positive to negative of SARS-Cov2 RT-PCR results was analyzed in both groups of treatments at 0, 3, 7, and 14 days. No significant differences were observed in the median time, 11 days ± 8.0 for CIGB-325 plus standard care and 12 days ± 6 for standard care alone (p = 0.614). Thus, time to SARS-Cov2 viral clearance in the nasopharynx swabs behaved similarly for both treatments over the time.\nThe clinical status was classified in categories of asymptomatic, mild, moderate or severe disease and it was followed up until ending treatment and thereafter for both groups. In the intent-to-treat population of CIGB-325 group at day 6 there were 2/10 patients that remained asymptomatic since initiation of treatment, 2/10 changed from severe to moderate, 1/10 from moderate to asymptomatic, 1/10 from mild to asymptomatic and 4/10 did not change their clinical status during the treatment. Otherwise, in the control 6/10 patients remained asymptomatic since initiation of treatment, 1/10 changed from mild to asymptomatic and 3/10 did not change their clinical status during the treatment. Additionally, chest-CT analysis was performed to investigate the effect of CIGB-325 over the Covid-19 pulmonary lesions. For that purpose, both number and lesion’s extent at day 0 and after treatment (day 7) were compared just in those patients analyzed per protocol (Table 1). Importantly, CIGB-325 treatment significantly reduced the median number of pulmonary lesions from 9.5 ± 10 (day 0) to 5.5 ± 10 (day 7) (p = 0.042). Conversely, no substantial change was observed in the control group. Proportion of patients with reduction of pulmonary lesions was higher in the CIGB-325 group compared with control according to the Bayesian analysis (pDif > 0; 0.951) (Table 1).\nThe effect over lesion’s extent showed in Supp. 2 including those patients analyzed per protocol indicates that CIGB-325 treatment also reduced the median of lesion’s extent after consecutive-5 day regimen although not significantly. Otherwise, any kind of reduction was observed in the control group. Importantly, proportion of patients with reduction of lesion’s extent was higher in the CIGB-325 group (4/7) compared with control (1/9) (pDif > 0; 0.982) (Bayesian analysis).\nThe overall chest-CT response was also analyzed considering the lesion’s extent and the pattern of Covid-19 typical chest-CT abnormalities (Supp. 3). The analysis per protocol showed that 50% (3/6) of patients in the CIGB-325 group had a favorable overall chest-CT response compared with 28.6% (2/7) in the control (pDif > 0; 0.796) (Bayesian analysis). Importantly, any patient had progression in the CIGB-325 group and 28.6% (2/7) in the control group did it. Representative images of chest-CT evolution from one CIGB-325 treated patient are shown in Fig. 2.\nRepresentative chest-CT images from one patient in the CIGB-325 group at day 0 and 7.\nWe also investigated the levels of Creatinine Phospho Kinase (CPK), Reactive C-Protein (RCP), and Lactate dehydrogenase (LDH) in plasma. Of note, data from Supp. 4 shows that CIGB-325 treatment significantly reduced the CPK (p = 0.007) and LDH (p = 0.028) serum levels. Also, the RCP values were lowered by CIGB-325 although with no statistical difference.", "entities": [{"id": "T1", "type": "UnclearOutcome", "offsets": [[49, 121]], "text": "dynamic conversion from positive to negative of SARS-Cov2 RT-PCR results"}, {"id": "T2", "type": "TimeFrame", "offsets": [[164, 187]], "text": "at 0, 3, 7, and 14 days"}, {"id": "T3", "type": "UnclearOutcome", "offsets": [[471, 486]], "text": "clinical status"}, {"id": "T4", "type": "OutcomeDefinition", "offsets": [[502, 565]], "text": "in categories of asymptomatic, mild, moderate or severe disease"}, {"id": "T5", "type": "TimeFrame", "offsets": [[577, 601]], "text": "followed up until ending"}, {"id": "T6", "type": "UnclearOutcome", "offsets": [[1175, 1192]], "text": "chest-CT analysis"}, {"id": "T7", "type": "TimeFrame", "offsets": [[1332, 1368]], "text": "at day 0 and after treatment (day 7)"}, {"id": "T8", "type": "UnclearOutcome", "offsets": [[2984, 3094]], "text": "levels of Creatinine Phospho Kinase (CPK), Reactive C-Protein (RCP), and Lactate dehydrogenase (LDH) in plasma"}], "relations": [{"id": "R1", "type": "MeasuredAt", "arg1": "T1", "arg2": "T2"}, {"id": "R2", "type": "DefinedAs", "arg1": "T3", "arg2": "T4"}, {"id": "R3", "type": "MeasuredAt", "arg1": "T3", "arg2": "T5"}, {"id": "R4", "type": "MeasuredAt", "arg1": "T6", "arg2": "T7"}]}