 Procedures and Outcomes
Patients 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-
CoV-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).

at day 15 of the study

mean change in the ordinal scale

at day 29

mortality

at days 15 and 29

duration of hospital stay

Serious adverse events (AE)

grade 3 or 4 AE

infusion related AE

within 24 hours after administration

at days 3, 5, 8, 11, 15 and 29


 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.

Outcomes

The 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.

Prespecified 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.

ventilator-free days

during the first 28 days

all-cause mortality

at 28 days

clinical status of patients

at day 15

ICU-free days

during the first 28 days

mechanical ventilation duration

at 28 days

at 48 hours, 72 hours, and 7 days

ventilator-free days

during the first 28 days

all-cause mortality

during 28 days

clinical status of patients

at day 15

using a 6-point ordinal scale

ICU-free days

during the first 28 days

mechanical ventilation duration

at 28 days

at 48 hours, 72 hours, and 7 days

components of ventilator-free days

during the first 28 days

at 15 days

discharge from hospital alive

within 28 days


Outcomes
The 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.
Other 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.

clinical status

at 15 days

mortality

at 29 days after randomisation

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

number of ventilator-free days

by day 29.


Outcomes
Time 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.
Side effects related to IFN therapy and other adverse events during the study period were monitored and recorded as the safety outcomes.
Categorization of adverse events was done according to the common terminology criteria for adverse events (CTCAE), National Institutes of Health and National Cancer Institute, 2017.
Also 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.

Time to clinical improvement

clinical status of patients

at day 7, 14 and 28

ICU admission and intubation rates

length of hospitalization and ICU stay

mortality

Side effects

adverse events

serious complications


Outcomes

Outcomes 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.

rate of ICU admission

deaths


 Outcome Measures
The 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.

clinical status

at day 28

clinical status

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

time to clinical failure

duration of ICU stay

Adverse events


 Main endpoints
The 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.

time of hospitalization

death rate and causes of mortality

measures of serum CRP

from day zero to day 7

frequency of QT interval above 450 ms


Outcomes
The 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.

cure rate of the enrolled patients

recovery rate of hypoxia

over 14 days

the duration of hospital stay

time to negative virus load

treatment -emergent adverse events

serious adverse events


 Outcomes
The 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.
Primary 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.
The 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.
Safety 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
Aronson.

any time within 28 days of enrolment

all-cause mortality

at 28 days

on day 7

on days 1, 3, 5, 7 and 14

on days 3 and 7

levels of biomarkers

requirement of vasopressor support

on day 0,1,3,5,7,14 and 28 days

within 6 hours of CP transfusion

serious adverse event


Outcome Measures

The 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.

Secondary 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.

time to clinical improvement

lymphocyte cell counts

on day 5 posttreatment

mortality

at day 21

viral loads

at day 21

adverse events

serious adverse events

premature discontinuation of treatment


Outcomes

The 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.

The 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.

The 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.

Chest 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).

All 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.

14 days

time to clinical recovery

virologic clearance

during the study period

clinical follow‐up

within 20 days

occurrence of side effects


Study sample

Patients 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).

Inadequate 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.

Conclusions

The 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.

after 48 h of commencing treatment

mortality rates

clinical outcomes

involvement of lungs in lung CT scan


  Outcomes:

The 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.

mortality rate

blood O2 saturation,

need for further oxygen therapy.

Creatine phosphokinase (CPK)

lactate dehydrogenase (LDH)

serum creatinine (SrCr)


Procedures and Outcome
The 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.
All 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.

heart rate

body temperature

blood pressure

oxygen saturation (SO2)

dyspnea

cough

myalgia

chest pain

BORG score

CT scan findings

mortality rate

Laboratory test results

Clinical signs of the improved patients


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.

CT-based radiological pulmonary changes

from baseline to 7 days

disease progression from mild to severe

on the day 7

radiological pulmonary changes


Outcome Measures and Follow-up

There 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).

hospitalization or death

Patient Acceptable Symptom State (PASS)

Treatment success

on days 3, 5, or 7 of follow-up

Dyspnea

Nausea

vomiting

diarrhea

dizziness

conjunctivitis

rhinorrhea

exanthema

skin rash

loss of sense of smell or taste

Adverse events


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.

Bronchoalveolar-lavage PCR results

On the 6th day


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.

Outcomes

Safety 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.

reduction in lethality by at least 50%

on day 13

participant clinical status

laboratory examinations

to day 28

on days 0 and 4

serious adverse events

electrocardiogram

on days 13 and 28

supplementary oxygen (if applicable)

lethality

participant clinical status

laboratory examinations

on day 13


 Main outcomes

The 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.

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

14 days after randomization

at 96 hours after randomization


 Repeat Nasopharyngeal and Throat Swab PCR
All 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.
Endpoints 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

negative PCR

resolution of symptoms

Adverse effects


 Outcome Measures

The 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.

duration of viral shedding

syndromes

peripheral blood cells

biochemical parameters

length of hospital stay

adverse events (AEs)

serious AEs

premature discontinuation of treatment


 Outcome measures

The 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.
The 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.

We 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.

We 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.

We 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.

clinical improvement

7 days after admission

relief of cough, dyspnea, and fever

duration of hospitalization

Time to relieving fever

death

during the 30 days of treatment

duration of hospitalization

changing laboratory tests

during 7 days

changing of CT findings

after 30 days

Fever

cough

dyspnea

nausea and vomiting

diarrhea

fatigue and weakness

loss of appetite

taste

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

thyroid stimulating hormone (TSH)

at the first day of admission

CT scan

chest X-ray

at admission and the time of discharge

PCR test


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).
The 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 (37.5°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.
Neither 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.)

viral clearance

by day 6

change in viral load

by day 6

time to defervescence

hyperuricemia

resolution of symptoms


 Outcomes

The 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.

Secondary 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].

at day 14

at day 30

hospital length of stay (LOS)

fever-free days

oxygen-free days

hepatic and hematology labs


 Outcome measures

The 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.

on day 10


 Primary outcome

The 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.

Secondary outcomes

Secondary 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.

time to clinical improvement

time to radiological improvement

on days 7, 14, and 28

on chest CT scans

on days 7, 14, and 28

rates of deterioration or death

on day 28


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.

Length of hospitalization

symptoms

Co-existed disease

examined 2 weeks after discharge

mortality and morbidity

re-admission

symptoms


Primary and exploratory efficacy end points

The 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.
The 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).
The 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).
The 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.
Representative chest-CT images from one patient in the CIGB-325 group at day 0 and 7.
We 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.

at 0, 3, 7, and 14 days

clinical status

followed up until ending

chest-CT analysis

at day 0 and after treatment (day 7)