Medi.txt

A real-world study of quality of life following treatment with xylometazoline hydrochloride in individuals with common cold
Martina Hagen, Conceptualization, Formal analysis, Writing – review & editing, Kim Clark, Methodology, Writing – review & editing, Pranab Kalita, Conceptualization, Writing – review & editing, Gessica Serra, Methodology, Writing – review & editing, Edwin Sanchez, Formal analysis, Writing – review & editing, Gabor Varbiro, Formal analysis, Methodology, Writing – review & editing, and Mathieu M. Albasser, Formal analysis, Writing – review & editing
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Associated Data
Supplementary Materials
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Abstract
Background:
The common cold is a frequent, acute, and mild upper respiratory human disease. Nasal congestion has been considered the most bothersome symptom in the common cold, impacting quality of life (QoL). Topical decongestants containing steroids benefit QoL in allergic rhinitis, but no published research has assessed the impact of topical decongestants on QoL in the common cold.

Objective:
To evaluate the effects of xylometazoline hydrochloride 0.1% (Otrivin, GSK Consumer Healthcare SARL, Switzerland) for up to 7 days on QoL in participants with nasal congestion associated with the common cold.

Design:
This was a decentralized, longitudinal, open-label study.

Methods:
The study enrolled 136 participants (⩾18 years) with early symptoms of the common cold, of which 102 were included in the modified intention-to-treat (mITT) population. Within 24 h of study product receipt, participants confirmed a ‘plugged nose’ and ⩾1 other common cold symptom. Primary endpoints were Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) total score, total and individual symptom scores, and total QoL score. Secondary endpoints were additional QoL scores. Exploratory and post hoc analyses included median days to resolution for each QoL factor and analyses of five QoL categories.

Results:
Consistent improvements in symptoms and QoL were seen in the mITT population. From day 1, improvements were seen in the ‘plugged nose’ symptom (p = 0.0023), WURSS-21 total QoL score, and all individual QoL scores (p < 0.0001 for all). After the last dose needed, significant improvements were seen in sleep quality (73%), vitality (76%), physical activity (71%), social activity (80%), and sensation (81%). No serious or unexpected adverse events were reported.

Conclusion:
This study is the first to demonstrate in a real-life setting that treating nasal congestion in adults with xylometazoline hydrochloride 0.1% during the common cold positively impacts QoL factors relevant to daily living [Otrivin: Quality of Life (QoL) Impact in a Real-World Setting; https://clinicaltrials.gov/study/NCT05556148].

Keywords: decentralized, nasal congestion, real-world evidence, WURSS-21, xylometazoline nasal decongestant

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Infographic abstract

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Plain language summary
Impact of xylometazoline hydrochloride 0.1% on quality of life in people with blocked nose associated with the common cold

The common cold is a widespread, mild respiratory illness for which a hallmark symptom is a blocked or stuffy nose, which makes breathing and sleeping difficult. This study focused on how a nasal spray called Otrivin (containing xylometazoline hydrochloride 0.1%) impacts the quality of life (QoL) of people suffering from nasal congestion due to the common cold.

Participants answered a questionnaire called the Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21), which helped understand how people experience respiratory symptoms and how different aspects of QoL were impacted. Participants also responded to eight additional QoL questions not covered in the WURSS-21.

The results showed that from the first day of using the nasal spray, participants experienced significant relief from the blocked nose symptom and reported an overall improvement in their QoL and well-being, such as in sleep quality, energy levels, senses, and physical and social activities.

In conclusion, this real-world study demonstrated that using xylometazoline hydrochloride 0.1% nasal spray during the common cold can significantly improve nasal congestion and various aspects of a person’s daily life. These findings provide valuable evidence for using this nasal spray to relieve symptoms and enhance the overall well-being of individuals with the common cold.

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Introduction
The common cold is an acute, mild upper respiratory disease and is considered the most frequent human disease.1,2 Most adults experience at least one episode of the common cold per year 3 with an average of four episodes yearly, 4 although frequency varies with age. 5 It is usually a self-limiting illness caused predominately by a rhinovirus. 1

The common cold is easily self-diagnosed, 6 and can last for 7–10 days. 1 Symptoms typically include nasal congestion, cough, sore throat, sneezing, runny nose, and headaches. 1 In addition, people with the common cold may also experience sleep disruption, 7 fatigue, 6 cognitive impairment,6,8 and reduced alertness. 8 Consequently, these symptoms impact individuals’ quality of life (QoL), such as the performance of daily activities, and individuals’ occupational functions.8,9

Out of all symptoms of the common cold, nasal congestion (also referred to as plugged nose or blocked nose) is a hallmark symptom of the disease that has been reported to be the most bothersome for the majority of people. 1 This symptom is not caused directly by the virus, but by the local inflammatory response to the viral infection. 10 Nasal congestion tends to peak on the second and third days of the illness,11,12 and contributes to sleep disruption 9 which results in daytime somnolence and mood changes. 13

Although there is no cure for the common cold, treatment can relieve the most bothersome symptoms. 1 Nasal congestion, for instance, can be relieved with topical decongestants, such as xylometazoline hydrochloride. 14 Xylometazoline hydrochloride is a nasal decongestant that constricts nasal blood vessels leading to reduction in mucosal swelling and increasing nasal airflow, allowing patients to breathe more easily during episodes of nasal congestion.6,14

Previous studies found that topical decongestants containing glucocorticoids benefit QoL in allergic rhinitis,15,16 but no known published research has assessed the impact of a topical decongestant on the QoL of individuals experiencing the common cold.

This study aimed to evaluate the over-time effects of using xylometazoline hydrochloride 0.1% (Otrivin) nasal spray on QoL among people experiencing nasal congestion associated with the common cold.

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Methods
This study was conducted in compliance with the protocol and in accordance with Good Clinical Practices, Medicines, and Healthcare Products Regulatory Agency regulations, and all applicable local and state regulations. The electronic informed consent (eIC) was made available to participants through the study app. Participants signed the eIC electronically and the date was added automatically. Signature of the eIC was required and obtained from all participants before any study-related activities. The eIC was reviewed by West Midlands, Edgbaston, Research Ethics Committee, Manchester, UK. IRAS project ID 1006069, REC:22/WM/0177. Approved by West Midlands – Edgbaston Research Ethics Committee 25 October 2022.

Study design and participants
This was a fully decentralized, longitudinal, open-label study to evaluate the effect on QoL factors in participants with the common cold using a nasal spray containing xylometazoline hydrochloride 0.1% in a real-world setting across the United Kingdom. No randomization was carried out in this study. The design of this study is not specific to any of the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) Network guidelines.

The study design ensured assessment of eligibility before and after the study product was provided to the participants. A summary of the study design and an overview of the schedule of activities can be found in Figure 1 and Supplemental Table 1, respectively. The first two steps of the study protocol were the pre-screening stage, and the screening stage. At the pre-screening stage, eligible participants were invited via email to download the study app and participants completed an eIC. Participants had an interview phone call with a medically qualified investigator to confirm personal details and medical history (Figure 1 and Supplemental Methods Sections 1 and 2). At the screening stage, participants who provided the eIC were asked to complete the Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) 17 and the additional QoL questions as baseline assessments. Participants also confirmed their medical history, concomitant medication, and completed a product shipping form (Figure 1 and Supplemental Methods Sections 3–5). Participants completed the baseline questionnaires from the 7 November 2022; the last questionnaire was completed on the 20 December 2022.

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Figure 1.
Flowchart of the study design.

eIC, electronic informed consent; QoL, quality of life; WURSS-21, Wisconsin Upper Respiratory Symptom Survey-21.

Enrolled participants were supplied with xylometazoline hydrochloride 0.1% nasal spray (Otrivin) within 1 day of completing screening, and confirmed receipt and usability of the product via the study app. Upon product receipt, participants were required to re-confirm their eligibility by reporting nasal congestion (described as ‘plugged nose’ in the WURSS-21) of at least moderate intensity (score 5) and at least one other common cold symptom of at least mild intensity (score 3) as per the WURSS-21 questionnaire (Table 1). Participants started treatment on day 0 of the study protocol, which was expected to align with a very early stage of disease progression and peak symptom stage (Supplemental Table 1). This was considered a key period to start treatment of the common cold with xylometazoline hydrochloride 0.1% to relieve nasal congestion.

Table 1.
WURSS-21 QoL questionnaire and additional QoL questions answered by participants using a severity scale ranging from 0 to 7.

WURSS-21 questionnaire
Please fill in one circlea for each of the following items:
1. How sick do you feel today? Not sick (very mildly to severely as the score belowa)
Please rate the average severity of your cold symptoms over the last 24 h for each symptom:
2. Runny nose
3. Plugged nose
4. Sneezing
5. Sore throat
6. Scratchy throat
7. Cough
8. Hoarseness
9. Head congestion
10. Chest congestion
11. Feeling tired
Over the last 24 h, how much has your cold interfered with your ability to:
12. Think clearly
13. Sleep well
14. Breathe easily
15. Walk, climb stairs, exercise
16. Accomplish daily activities
17. Work outside the home
18. Work inside the home
19. Interact with others
20. Live your personal life
Compared to yesterday, I feel that my cold is. . ..
21. Very much better – Somewhat better – A little better – The same – A little worse – Somewhat worse – Very much worse
Additional QoL questionnaire
Considering the past 24 h, please read each question and choose the answera that best reflects your experience with Otrivin use and your nasal congestion:
1. After using Otrivin, is your nasal congestion/cold making you snore during the night? (aFor those with sleeping partners only)
2. After using Otrivin, is your nasal congestion/cold making you slow in your responses?
3. After using Otrivin, is your nasal congestion/cold making you self-conscious about how you sound?
4. After using Otrivin, is your nasal congestion/cold affecting your sense of smell?
5. After using Otrivin, is your nasal congestion/cold affecting your sense of taste?
6. After using Otrivin, is your nasal congestion/cold making you self-conscious around people?
7. After using Otrivin, is your nasal congestion/cold making you less energetic than usual?
8. After using Otrivin, is your nasal congestion/cold making you less motivated than usual?
aSeverity scale:
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QoL, quality of life; WURSS-21, Wisconsin Upper Respiratory Symptom Survey-21.

Every morning, participants’ QoL factors were assessed via completion of the WURSS-21 questionnaire and the additional QoL questions based on the effects of the study product used on the previous day. For example, the scores reported on day 1 show the results from day 0. As per leaflet instructions, xylometazoline hydrochloride 0.1% was used no more than three times a day for up to 7 days and participants had the option to stop treatment at their discretion (Supplemental Methods Section 6) based on their desire to treat nasal congestion. Opting out of the treatment before the completion of 7 days of treatment was possible if participants felt their symptoms did not warrant further treatment, or if their nasal congestion was resolved; both criteria were assessed daily. The last dose was the day of last treatment if before 7 days. On day 7, or on the day after the last dose was used, participants completed an exit survey. Participants who did not satisfy the criteria for participation and treatment compliance (Supplemental Methods Section 7) were considered dropouts.

Endpoints
The primary, secondary, exploratory, safety, and post hoc study objectives are summarized in Table 2.

Table 2.
Summary of the objectives of primary, secondary, exploratory, safety, and post hoc endpoints.

Objectives	Endpoints
Primary
To evaluate the over-time effects of xylometazoline hydrochloride 0.1% on QoL factors and common cold symptoms among individuals experiencing nasal congestion associated with the common cold, following up to 7 days of treatment	• WURSS-21 total score
• WURSS-21 total symptom domains
• WURSS-21 total QoL domains (Q12-think clearly, Q13-sleep well, Q14-breathe easily, Q15-walk, climb, exercise, Q16-accomplishing daily activities, Q17-work outside the home, Q18-work inside the home, Q19-interacting with others, Q20-living your personal life)
• Individual WURSS-21 symptom domains
(Q2-runny nose, Q3-plugged nose, Q4-sneezing, Q5-sore throat, Q6-scratchy throat, Q7-cough, Q8-hoarseness, Q9-head congestion, Q10-chest congestion, Q11-feeling tired)
Secondary
To evaluate, the over-time effects of xylometazoline hydrochloride 0.1% on additional measures of QoL factors among individuals experiencing nasal congestion associated with the common cold, following up to 7 days of treatment	Snoring (Q1), alertness (slow in responses) (Q2), feeling self-conscious about how you sound (Q3), feeling self-conscious around people (Q4), smell (Q5) and taste (Q6), energy (Q7), and motivation (Q8)
Exploratory
To evaluate the median time to resolution of the eight additional QoL factors	
Safety
To record AEs during the study period	Number and percentage of patients reporting AEs or SAEs while on treatment related or not related to the product
Post hoc
• To evaluate the over-time effects of xylometazoline hydrochloride 0.1% on WURSS-21 individual QoL factors among individuals experiencing nasal congestion associated with the common cold, following up to 7 days of treatment
• To assess the median time to resolution of WURSS-21 individual QoL domains
• To determine the correlation between the WURSS-21 plugged nose symptom and the WURSS-21 individual QoL and the additional QoL factors
• To evaluate the over-time effects of xylometazoline hydrochloride 0.1% on five QoL categories (sleep quality, physical activities, sensation, vitality, and social)	• Scores of each individual WURSS-21 QoL factor at baseline and after each day of xylometazoline hydrochloride 0.1% use, up to 7 days
• Median time to resolution of individual WURSS-21 QoL factors
• Correlation between plugged nose symptom and WURSS-21 questions 12–20 and the eight additional QoL questions
• Significance on improvement in five QoL categories that were created by grouping similar WURSS-21 factors and additional QoL factors, where applicable
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AE, adverse event; Q, question; QoL, quality of life; SAE, serious AE; WURSS-21, Wisconsin Upper Respiratory Symptom Survey-21.

The summary of the individual QoL factors grouped to form the five QoL categories bundles are shown in Table 3.

Table 3.
Five additional QoL categories.

QoL category	QoL individual factors
Sleep quality	• Sleep well (WURSS-21 Q13)
• Snoring (QoL Q1)
Vitality	• Less energetic (QoL Q7)
• Less motivated (QoL Q8)
• Feel tired (WURSS-21 Q11)
• Alertness (slow in response, QoL Q2)
Physical activity	• Breathe easily (WURSS-21 Q14)
• Walk, climb stairs, exercise (WURSS-21 Q15)
• Accomplish daily activities (WURSS-21 Q16)
Social activity	• Interact with others (WURSS-21 Q19)
• Self-conscious around people (QoL Q6)
Sensation	• Sense of smell (QoL Q4)
• Sense of taste (QoL Q5)
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Q, question; QoL, quality of life; WURSS-21, Wisconsin Upper Respiratory Symptom Survey-21.

Statistical analysis
Sample size A non-parametric paired Wilcoxon test was performed to determine sample size, which was based on a significance level (α) of 0.05, 80% power (1 – β), and an estimated standardized effect size of 0.27. Using these parameters, a sample size of N = 125 eligible participants to retain 100 completed participants was obtained to be sufficient to observe improvement in QoL. The Full Analysis Set population and the modified intention-to-treat (mITT) population were considered the same in this instance as participants used the study product at least once and had data from at least one post-baseline QoL questionnaire to support at least one of the primary endpoint assessments.
Primary endpoint Primary analyses for QoL and data were summarized using the mITT population. The WURSS-21 questionnaire was completed at baseline, on each day of treatment and at the last dose used to determine the effect of xylometazoline hydrochloride 0.1% on QoL factors and cold symptoms. Daily WURSS-21 scores were calculated by adding each score of the 10 questions related to symptoms and the 9 questions related to QoL, 19 in total (Supplemental Methods Section 3). Two questions not related to specific symptoms or QoL factors, but overall performance, were not included in the total score. The severity scale range of the different WURSS-21 scores was calculated by multiplying the total number of individual symptom and/or QoL factors by the individual lowest (score = 0), very mild (score = 1), mild (score = 3), moderate (score = 5), and highest (score = 7) severity scores. Thus, the WURSS-21 total score severity ranged from 0 to 133, as the WURSS-21 total score included 19 symptoms and QoL factors. The WURSS-21 total symptom domain severity score ranged from 0 to 70, and the WURSS-21 total QoL domain severity score ranged from 0 to 63. The change from baseline in mean WURSS-21 scores were analyzed each day using a Student’s paired t-test, and p-values were assessed to a significance level of α = 0.05 and 95% confidence intervals (CIs).
Secondary endpoint Secondary analyses for QoL and data were summarized using the mITT population. Participants’ baseline scores were used to determine the effect of xylometazoline hydrochloride 0.1% on additional QoL factors. The changes from baseline in mean additional QoL scores were analyzed each day using a Student’s paired t-test, and p-values were assessed to a significance level of α = 0.05. Median post-treatment scores were presented for each day of treatment through day 7 or until data were no longer provided due to nasal symptom resolution, whichever came first.
Safety endpoint Adverse events (AEs) were summarized using the safety population, which included all participants who received at least one dose of the study product. All AEs were coded using the Medical Dictionary for Regulatory Activities (v25.1). The number of AEs and serious AEs (SAEs) and the number of participants with AEs/SAEs were tabulated by System Organ Class and Preferred Team. Causality assessment of the AEs was carried out by the virtual research organization prior to database lock.
Exploratory endpoint The times to resolution of QoL factors were evaluated using Kaplan–Meier curves. Analyses were summarized using the mITT population.
Post hoc analyses Post hoc analyses were evaluated using the mITT population. The changes from baseline in mean WURSS-21 individual QoL scores were analyzed each day using a Student’s paired t-test, and p-values were assessed to a significance level of α = 0.05. The median times to resolution of WURSS-21 individual QoL domains were analyzed using Kaplan–Meier curves. Correlations and significance between the WURSS-21 ‘plugged nose’ symptom, the WURSS-21 individual QoL domains (WURSS-21 questions 12–20), and the eight additional QoL factors were calculated using the Pearson correlation coefficient. The over-time effect of xylometazoline hydrochloride 0.1% was evaluated in five QoL categories (Table 3). The changes from baseline for the mean of each QoL category score were analyzed each day using a Student’s paired t-test, and p-values were assessed to a significance level of α = 0.05.
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Results
Study participants
A total of 172 adults were screened, of which 136 were enrolled in the study (Figure 2). Study documentation did not capture the reasons why 36 participants from the screening were not enrolled. Of the enrolled population, 129 participants reconfirmed eligibility upon study product receipt. Of these, 102 participants were included in the mITT population as they used the study product at least once and completed at least one post-baseline QoL questionnaire. Two participants from the mITT population discontinued the study due to ‘early termination’ for non-compliance reasons after using the study product (Supplemental Results Section 1). Data up to the time of discontinuation were included in the mITT analysis. Figure 2 also shows the number of participants remaining from day 1 through day 7 in the mITT population. A total of 100 participants completed the study, for which the scores of the last dose used were calculated.

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Figure 2.
Disposition of participants.

aEnrolled population included all subjects who met the inclusion/exclusion criteria and have met the eligibility confirmation criteria (including a plugged nose score ⩾5 and another common cold symptom score ⩾3).

bSubjects who did not use the study product due to eligibility cessation, or participants who were unresponsive and discontinued the study.

cmITT population included all subjects who used the study product at least once and had at least one post-baseline QoL questionnaire. After receiving the study product, participants had to comply with a plugged nose score ⩾5 and another common cold symptom score ⩾3.

mITT, modified intention-to-treat; N, total number of subjects in the screened population and total number of participants who took concomitant medication; n, number of subjects in each subcategory; QoL, quality of life.

Demographics and other baseline characteristics
Baseline characteristics of study participants are shown in Table 4. Most of the participants were female (71.57%), white (76.47%), and the mean age was 35.9 ± 12.04 years old. Medical history of the participants revealed that the most common reported conditions were related to respiratory/thoracic disorders (11.80%) followed by musculoskeletal and connective tissue disorders (7.80%), gastrointestinal disorders (6.90%), and immune system disorders (5.90%). A total of 134 concomitant medications usages were reported by 63 participants (Table 4 and Figure 2). Of these concomitant medications, 15 were reported for cold-related symptoms as defined by questions 2–11 on the WURSS-21 (Table 1); 29 were reported for non-cold related indications that may have affected common cold symptoms; and 90 concomitant medications were reported for indications unrelated to the common cold (Supplemental Table 3).

Table 4.
Demographic and other baseline characteristics.

Characteristic	Participants included in data analyses (N = 102)
Age (mean ± SD)	35.9 ± 12.04 years
Female n (%)	73 (71.57)
Male n (%)	25 (24.51)
Other n (%)	2 (1.96)
Prefer not to tell n (%)	2 (1.96)
Caucasian n (%)	78 (76.47)
Asian or Asian British n (%)	18 (17.65)
Black, Black British, Caribbean, or African n (%)	1 (0.98)
Mixed or multiple ethnic groups n (%)	3 (2.94)
Other n (%)	2 (1.96)
Non-Hispanic/Latino n (%)	99 (97.06)
Hispanic or Latino n (%)	2 (1.96)
Not reported n (%)	1 (0.98)
Respiratory/thoracic disorders n (%)	12 (11.80)
Musculoskeletal and connective tissue disorders n (%)	8 (7.80)
Surgical/medical procedures n (%)	8 (7.80)
GI disorders n (%)	7 (6.90)
Immune system disorders n (%)	6 (5.90)
Concomitant medications	134 (reported by 63 participants)
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GI, gastrointestinal; N, number of subjects in the safety population; n, number of subjects in this category; SD, standard deviation.

WURSS-21 total score
WURSS-21 total score ranges from 0 to 133, in which higher scores indicate higher severity. At baseline, the mean [±standard error (SE)] of the WURSS-21 total score of the mITT population (n = 102) was 75.8 (±2.00), which represents mild (score = 57) to moderate (score = 95) severity level. Statistically significant decreases in the WURSS-21 total score were observed consistently from day 2 to day 7 of treatment with the study product (p < 0.0001 for all). At the last dose administered for all participants that completed the study (n = 100), a statistically significant difference in WURSS-21 total score indicated a significant improvement in symptoms and QoL factors [−51.09 (95% CI: −56.82 to −45.36; p < 0.0001)] compared with baseline [Figure 3(a) and Supplemental Table 2], with a 67.6% improvement from baseline to the last dose (Supplemental Table 2).

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Figure 3.
Over-time mean scores for the primary endpoint measures for the mITT population (N = 102). (a) Total score is the sum of questions 2 through 20, ranging from 0 to 133. (b) Total symptom domain score is a sum of questions 2 through 11 ranging from 0 to 70. (c) Total QoL domain score is a sum of questions 12–20 ranging from 0 to 63. (d) WURSS-21 plugged nose symptom score range from 0 to 7. Last dose refers to all participants’ last day if prior to day 7.

Subjects answered 10 symptom questions and 9 QoL questions scored from 0 (not at all) to 7 (severely). Higher scores indicate more negative impact of symptoms and QoL. Values presented are mean ± SE, and p-value calculated using Student’s paired t-test.

mITT, modified intention-to-treat; QoL, quality of life; SE, standard error; WURSS-21, Wisconsin Upper Respiratory Symptom Survey-21 items. *p < 0.05, **p < 0.01, ***p < 0.0001.

WURSS-21 total symptom domain score
WURSS-21 total symptom domain score ranges from 0 to 70, in which higher scores indicate higher severity. At baseline, the mean (±SE) of the WURSS-21 symptom domain score of the mITT population observed was 38.3 (±1.12), which represents a mild (score = 30) to moderate (score = 50) severity level [Figure 3(b) and Supplemental Table 2]. Statistically significant decreases in the WURSS-21 total symptom domain were observed consistently from day 2 to day 7 (p < 0.0001) (Supplemental Table 2).

At the time of the last dose administered, the difference in WURSS-21 total symptom domain score was −24.7 (95% CI: −27.73 to −21.67; p < 0.0001) compared with baseline, which represents a drop to a severity level between very mild and mild. A 64.8% improvement from baseline in WURSS-21 total symptom domain score was observed at the last dose of treatment needed for all participants completing the study (n = 100) [Figure 3(b) and Supplemental Table 2].

WURSS-21 total QoL domain score
The WURSS-21 total QoL domain score ranges from 0 to 63, in which higher scores indicate higher severity. At baseline, the mean (±SE) of the WURSS-21 total QoL domain score of the mITT population observed was 37.5 (±1.15), which represents a mild (score = 27) to moderate (score = 45) severity level [Figure 3(c) and Supplemental Table 2]. Statistically significant decreases in the WURSS-21 total QoL domain score were observed consistently from day 1 (p = 0.0481) to day 7 (p < 0.0001) (Supplemental Table 2). By the last dose administered, the difference in WURSS-21 QoL domain score was −26.39 (95% CI: −29.75 to −23.03; p < 0.0001) compared with baseline, representing a 70.4% improvement from baseline in WURSS-21 total QoL domain score at the last dose of the treatment needed for all participants who completed the study (n = 100) [Figure 3(c) and Supplemental Table 2].

Individual WURSS-21 symptom domain scores
The individual WURSS-21 symptom domain score ranges from 0 to 7 (Table 1), in which higher scores indicate higher severity. Of the 10 individual symptoms assessed using the WURSS-21 questionnaire, ‘plugged nose’, ‘runny nose’, ‘head congestion’, and ‘feeling tired’ scored a mean baseline score of at least 4, representing a mild (score = 3) to moderate (score = 5) severity level. These individual symptoms generally showed the greatest percentage improvement by the last day of dose administered (Supplemental Table 2). A statistically significant improvement in ‘plugged nose’ (p = 0.0023) was observed from day 1 post-treatment [Figure 3(d) and Supplemental Table 2]. The mean ± SE score for ‘plugged nose’ at baseline was 5.5 (±0.09), which represents a moderate to severe level for this symptom. By the last dose of xylometazoline hydrochloride 0.1% was used, the ‘plugged nose’ symptom improved by 68.1% and dropped to a mean (±SE) score of 1.8 (±0.16), which represents a very mild-to-absent severity level. All 10 symptom scores improved by at least 50% from baseline at the last dose (Supplemental Table 2).

Safety
Treatment-emergent AEs (TEAEs) are shown in Table 5. Six participants reported 10 TEAEs, 5 of which were treatment-related in 5 participants (two events of epistaxis, two events of headache, and one event of sinusitis). No new significant safety information was identified from these AEs. There were no severe TEAEs, and no participants withdrew from the study due to AEs. Participants who reported using the product more than three times a day did not report any safety issues.

Table 5.
TEAEs by system organ class and preferred term.

System organ class a
Preferred term b	Overall c , N = 102, n (%)	Total events, M = 10, m (%)
TEAE	6 (5.9)	10 (100)
Respiratory, thoracic, and mediastinal disorders	3 (2.9)	4 (40.0)
 Epistaxis	2 (2.0)	2 (20.0)
 Cough	1 (1.0)	1 (10.0)
 Oropharyngeal pain	1 (1.0)	1 (10.0)
Eye disorders	1 (1.0)	2 (20.0)
 Eye pruritus	1 (1.0)	1 (10.0)
 Lacrimation increased	1 (1.0)	1 (10.0)
Nervous system disorders	2 (2.0)	2 (20.0)
 Headache	2 (2.0)	2 (20.0)
Gastrointestinal disorders	1 (1.0)	1 (10.0)
 Nausea	1 (1.0)	1 (10.0)
Infections and infestations	1 (1.0)	1 (10.0)
 Sinusitis	1 (1.0)	1 (10.0)
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AEs are coded with the MedDRA version 25.1.

aSubjects with multiple occurrences of AEs in the same system organ class are counted only once within that preferred term.
bSubjects with multiple occurrences of AEs in the same preferred term are counted only once within that system organ class.
cOverall is the number of subjects who had at least one TEAE. System organ classes are listed in descending order of frequency and preferred terms are listed in descending order of frequency within each system organ class.
AE, adverse event; M, number of AEs; m (%), number (percentage) of AEs in this category; MedDRA, Medical Dictionary for Regulatory Activities N, number of subjects in the safety population; n (%), number (percentage) of subjects in this category; TEAE, treatment-emergent adverse event.

QoL categories
The over-time effects of xylometazoline hydrochloride 0.1% on five QoL categories were evaluated. Each category grouped similar QoL factors from the WURSS-21 questionnaire and the additional QoL factors. Other QoL factors that were not included in a category were analyzed individually.

Sleep quality
The sleep quality category was defined by grouping the ‘sleep well’ factor from the WURSS-21 questionnaire (Q13) and the ‘snoring’ factor from the additional QoL questions (Q1). The severity scale for sleep quality was calculated by adding the two individual QoL scores included; the resulting range was 0–14, where 14 represented the highest severity. Because the ‘snoring’ factor could only be measured in participants who lived with a partner, the analyses for sleep quality category were assessed on an initial n of 80 participants, and not on the full mITT population (n = 102).

At baseline, the mean (±SE) score for ‘sleep quality’ was 9.7 (±0.30), which was considered a moderate severity level (score = 10). However, a significant improvement was seen on day 1 of treatment (p = 0.0001), with a mean score of 7.3 (±0.37), which was closer to mild severity level (score = 6). At the last dose administered sleep quality improved by 72.5% (Table 6).

Table 6.
Overview of changes observed in the sleep quality category.

QoL category/factor	n a	Baseline	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7	Last dose b
80	73	71	69	61	41	27	25	74
Sleep quality c	Mean ± SE	9.7 ± 0.30	7.3 ± 0.37	6.3 ± 0.39	4.9 ± 0.42	3.7 ± 0.38	3.8 ± 0.42	3.8 ± 0.55	3.0 ± 0.55	2.6 ± 0.34
95% CI		(−3.08 to −1.72)	(−4.17 to −2.81)	(−5.53 to −3.94)	(−6.75 to −5.05)	(−6.45 to −4.53)	(−7.19 to −4.44)	(−7.78 to −4.46)	(−7.85 to −6.18)
Difference		−2.40	−3.49	−4.74	−5.90	−5.49	−5.81	−6.12	−7.01
p-Value		<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		24.75	35.41	48.79	61.46	59.21	60.38	66.81	72.52
Snoring d	Mean ± SE	4.7 ± 0.19	2.8 ± 0.25	2.4 ± 0.24	1.9 ± 0.23	1.4 ± 0.23	1.4 ± 0.25	1.4 ± 0.30	1.2 ± 0.29	0.9 ± 0.19
Difference		−1.88	−2.45	−2.90	−3.30	−2.95	−3.26	−3.12	−3.78
p-Value		<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		39.83	50.88	60.79	70.53	67.98	69.84	72.22	80.00
n	102	99	98	92	82	59	39	30	100
Sleep well e	Mean ± SE	4.9 ± 0.16	4.4 ± 0.17	3.8 ± 0.19	3.0 ± 0.22	2.6 ± 0.21	2.6 ± 0.27	2.2 ± 0.31	1.7 ± 0.30	1.7 ± 0.18
95% CI		(−0.94 to −0.01)	(−1.48 to −0.74)	(−2.40 to −1.45)	(−2.81 to −1.76)	(−2.83 to −1.61)	(−3.37 to −1.81)	(−4.12 to −2.48)	(−3.72 to −2.82)
Difference		−0.57	−1.11	−1.92	−2.28	−2.22	−2.59	−3.30	−3.27
p-Value		0.0039	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		11.45	22.66	39.25	46.87	46.45	53.72	66.0	66.3
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Individual QoL factors scores ranged from 0 (not at all) to 7 (severely). The ‘sleep quality’ category scores were calculated by adding the individual QoL factors scores grouped in this category. Sleeping quality category score ranged from 0 (not at all) to 14 (severely). Higher scores indicate more negative impact of QoL domains. % Improvement is calculated as −100 * (mean change from baseline)/(baseline mean). p-Value presented using Student’s paired t-test.

aNumber of participants who lived with partners and could score the snoring factor.
bLast dose includes all subjects’ last day of treatment regardless of study day.
cPost hoc analysis: QoL category.
dSecondary endpoint: additional QoL factor (Q1).
ePost hoc analysis: WURSS-21 Individual QoL factor (Q13).
CI, confidence interval; n, number of subjects in this category; Q, question; QoL, quality of life; SE, standard error; WURSS-21, Wisconsin Upper Respiratory Symptom Survey-21.

‘Sleep well’ and ‘snoring’ were found to be moderately affected at baseline with a mean score (±SE) of 4.9 (±0.16) and 4.7 (±0.19), respectively. Statistically significant improvements in the ‘sleep well’ factor (p = 0.0039) and ‘snoring’ factor (p < 0.0001) (Table 6) were observed by day 1 following the use of xylometazoline hydrochloride 0.1%. Continued improvements were seen throughout the study for both factor scores (p < 0.0001). By the last dose of treatment, improvements of 66.3% and 80.0% were observed for the ‘sleep well’ and ‘snoring’ scores, respectively (Table 6).

The median days to resolution for ‘snoring’ and ‘sleep well’ were day 4 and day 5, respectively (Figure 4).

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Figure 4.
Median days to resolution for the QoL factors grouped by QoL categories and for other QoL factors for the mITT population.

Symptom resolution occurred when a subject selected ‘0-not at all’ or answered ‘No’ to the question ‘Do you have nasal congestion associated with your cold from which you seek relief?’

mITT, modified intention-to-treat; QoL, quality of life.

The observed improvements may be attributed to the relief of nasal congestion, as shown by a moderate positive correlation observed between the ‘plugged nose’ and ‘sleep well’ factors [Pearson correlation coefficient (r = 0.60; p < 0.0001)] (Table 12).

Table 12.
Correlation analysis of the plugged nose symptom with WURSS-21 QoL individual factors and the additional QoL factors for the mITT population.

Question	Correlation (r)	p-Value
Breathe easily	0.72	<0.0001
Smell	0.61	<0.0001
Sleep well	0.60	<0.0001
Interact with others	0.60	<0.0001
Live your personal life	0.60	<0.0001
Motivation	0.59	<0.0001
Energy	0.58	<0.0001
Accomplish daily activities	0.58	<0.0001
Self-conscious about how you sound	0.57	<0.0001
Think clearly	0.57	<0.0001
Walk, climb stairs, exercise	0.56	<0.0001
Taste	0.56	<0.0001
Self-conscious about people	0.55	<0.0001
Work outside the home	0.53	<0.0001
Work inside the home	0.52	<0.0001
Snoring	0.51	<0.0001
Alertness (slow in your responses)	0.47	<0.0001
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r = Pearson correlation coefficient. A positive correlation indicates the question changes in the same direction as plugged nose.

mITT, modified intention-to-treat; QoL, quality of life; WURSS-21, Wisconsin Upper Respiratory Symptom Survey-21.

Vitality
QoL factors grouped in the vitality category correspond to ‘alertness’ (slow in responses, Q2), ‘energy’ (Q7), ‘motivation’ (Q8) factors of the additional QoL questionnaire, and the ‘feeling tired’ symptom factor (Q11) from the WURSS-21 questionnaire. The score range of the vitality category was calculated by adding the maximum score for each factor resulting in a range of 0–28, where higher scores indicate higher severity.

The vitality category mean score (±SE) at baseline was 19.1 (±0.50) and considered as moderate severity level (score = 20). The individual factors had mean scores within the range of 3.8–5.2, indicating a moderate severity level (score = 5) for each score at baseline (Table 7). The overall vitality category and its corresponding QoL factors showed a statistically significant improvement from day 1 (p < 0.0001). ‘Feeling tired’, which is one of the WURSS-21 symptom factor, significantly improved by day 2 (p = 0.0364). At the time of the observed significance, the scores had dropped from moderate severity to a mild severity level. By the last dose used for all participants, ‘motivation’ improved by 83.2%, ‘energy’ by 83.1%, ‘alertness’ by 85.9%, and ‘feeling tired’ improved by 53.6%. By the last dose of treatment, the vitality category score improved by 76.1% (Table 7).

Table 7.
Overview of changes observed in the vitality category.

QoL category/factor	n a	Baseline	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7	Last dose b
102	98	97	92	82	59	39	30	100
Vitality c	Mean ± SE	19.1 ± 0.50	13.2 ± 0.63	11.2 ± 0.62	9.3 ± 0.66	7.7 ± 0.68	6.5 ± 0.65	6.3 ± 0.77	5.3 ± 0.94	4.6 ± 0.50
95% CI		(−6.96 to −4.67)	(−9.19 to −6.67)	(−11.32 to −8.61)	(−13.16 to −9.99)	(−14.22 to −11.07)	(−15.01 to −11.60)	(−16.77 to −11.89)	(−15.86 to −13.28)
Difference		−5.82	−7.93	−9.97	−11.57	−12.64	−13.31	−14.33	−14.57
p-Value		<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		30.63	41.43	51.60	59.95	66.19	67.84	72.88	76.12
Energy d	Mean ± SE	5.2 ± 0.14	3.1 ± 0.20	2.5 ± 0.21	2.1 ± 0.20	1.8 ± 0.21	1.4 ± 0.20	1.2 ± 0.23	1.0 ± 0.24	0.9 ± 0.15
Difference		−2.07	−2.76	−3.21	−3.49	−3.83	−4.05	−4.13	−4.37
p-Value		<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		39.73	52.76	60.70	66.36	73.86	76.70	81.05	83.08
Motivation d	Mean ± SE	5.2 ± 0.14	2.9 ± 0.22	2.4 ± 0.19	2.0 ± 0.20	1.7 ± 0.21	1.4 ± 0.21	1.2 ± 0.25	1.1 ± 0.27	0.9 ± 0.14
Difference		−2.21	−2.73	−3.16	−3.52	−3.73	−4.00	−4.07	−4.30
p-Value		<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		43.23	53.21	60.75	68.0	72.85	76.85	78.71	83.17
Alertness d	Mean ± SE	3.8 ± 0.17	2.1 ± 0.20	1.8 ± 0.18	1.6 ± 0.19	1.1 ± 0.18	0.8 ± 0.15	0.8 ± 0.18	0.8 ± 0.21	0.5 ± 0.11
Difference		−1.72	−2.12	−2.30	−2.76	−2.85	−3.18	−3.17	−3.28
p-Value		<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		45.31	54.64	59.55	71.52	77.06	78.98	79.17	85.86
n e	102	99	98	92	82	59	39	30	100
Feeling tired f	Mean ± SE	4.9 ± 0.16	5.1 ± 0.17	4.5 ± 0.17	3.7 ± 0.20	3.2 ± 0.20	2.9 ± 0.24	3.0 ± 0.33	2.4 ± 0.41	2.3 ± 0.20
Difference		0.20	−0.35	−1.29	−1.80	−2.24	−2.08	−2.97	−2.62
p-Value		0.1074	0.0364	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		4.16	7.13	26.10	36.01	43.85	40.70	54.94	53.58
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Individual scores ranged from 0 (not at all) to 7 (severely). The scores of the ‘vitality’ category were calculated by adding the scores of the individual QoL factors grouped in this category. The ‘vitality’ category score ranged from 0 (not at all) to 28 (severely). Higher scores indicate more negative impact of QoL domains. % Improvement is calculated as −100 * (mean change from baseline)/(baseline mean). p-Value presented using Student’s paired t-test.

aNumber of participants who answered the additional QoL questionnaire.
bLast dose includes all subjects’ last day of treatment regardless of study day.
cPost hoc analysis: QoL categories.
dSecondary endpoint: additional QoL factors [Q2 (slow in response) and Q7–8].
eNumber of participants who answered the WURSS-21 questionnaire.
fPost hoc analysis: WURSS-21 individual symptom factor (Q11).
CI, confidence interval; n, number of subjects in this category; Q, question; QoL, quality of life; SE, standard error; WURSS-21, Wisconsin Upper Respiratory Symptom Survey-21.

The median time to resolution for ‘alertness’ (slow in response) was day 2, followed by ‘motivation’ with a median time to resolution by day 3 and ‘energy’ with a median time to resolution by day 4 (Figure 4).

Physical activity
The QoL factors under the physical activity category were ‘breathe easily’ (Q14), ‘walk, climb stairs exercise’ (Q15), and ‘accomplish daily activities’ (Q16) from the WURSS-21 questionnaire. The score range for the physical activity category was calculated by adding the maximum score of each factor, resulting in a range of 0–21. At baseline, the physical activity mean (±SE) score was 13.1 (±0.36), which was considered mild (score = 9) to moderate (score = 15) in severity level.

Significant improvement in physical activity was observed by day 2 (p < 0.0001) (Table 8). The ‘breathe easily’ factor was found to significantly improve by day 1 (p = 0.0449) and had the strongest correlation with nasal congestion (‘plugged nose’ symptom) factor (r = 0.72; p < 0.0001) (Table 12). The other two QoL factors ‘walk, climb stairs, exercise’ and ‘accomplish daily activities’, improved significantly by day 2 (Table 8). At the last dose administered for all participants who completed the study, physical activity improved significantly by 70.7% to a mean (±SE) score of 3.8 (±0.46), which indicates an impact closer to a very mild (score = 3) severity level. After last dose, the percentage of improvement in ‘breathe easily’, ‘walk, climb stairs, exercise’, and ‘accomplish daily activities’ was >70% for all (Table 8). The median time to resolution was day 4 for ‘walk, climb stairs, exercise’, and ‘accomplish daily activities’ and day 5 for ‘breathe easily’ (Figure 4).

Table 8.
Overview of changes observed in the physical activity category.

QoL category/factor	n a	Baseline	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7	Last dose b
102	99	98	92	82	59	39	30	100
Physical activity c	Mean ± SE	13.1 ± 0.36	12.4 ± 0.43	9.8 ± 0.44	7.6 ± 0.53	6.3 ± 0.54	5.9 ± 0.65	5.5 ± 0.80	3.9 ± 0.79	3.8 ± 0.46
95% CI		(−1.37 to −0.08)	(−4.22 to −2.37)	(−6.61 to −4.37)	(−8.16 to −5.60)	(−8.58 to −5.39)	(−9.48 to −5.81)	(−11.51 to −8.09)	(−10.40 to −8.12)
Difference		−0.65	−3.30	−5.49	−6.88	−6.98	−7.64	−9.80	−9.26
p-Value		0.0808	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		4.94	25.14	41.87	52.32	54.14	58.09	71.53	70.74
Breathe easily d	Mean ± SE	5.3 ± 0.14	4.9 ± 0.15	4 ± 0.15	3 ± 0.19	2.5 ± 0.18	2.3 ± 0.23	2.2 ± 0.27	1.6 ± 0.32	1.6 ± 0.17
95% CI		(−0.64 to −0.01)	(−1.66 to −0.87)	(−2.73 to −1.80)	(−3.20 to −2.21)	(−3.51 to −2.19)	(−3.51 to −2.24)	(−4.30 to −2.83)	(−4.18 to −3.26)
Difference		−0.32	−1.27	−2.26	−2.71	−2.85	−2.87	−3.57	−3.72
p-Value		0.0449	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		6.13	24.03	43.06	51.99	55.26	56.28	68.59	70.45
Walk, climb stairs, exercise d	Mean ± SE	3.9 ± 0.16	3.7 ± 0.19	2.9 ± 0.18	2.3 ± 0.19	2.0 ± 0.21	1.8 ± 0.25	1.7 ± 0.31	1.2 ± 0.30	1.2 ± 0.17
95% CI		(−0.56 to 0.04)	(−1.43 to −0.71)	(−2.05 to −1.19)	(−2.51 to −1.51)	(−2.70 to −1.50)	(−3.15 to −1.68)	(−3.92 to −2.34)	(−3.20 to −2.32)
Difference		−0.26	−1.07	−1.62	−2.01	−2.10	−2.41	−3.13	−2.76
p-Value		0.0851	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		6.70	27.20	41.05	50.77	53.22	58.39	72.87	70.41
Accomplish daily activities d	Mean ± SE	3.9 ± 0.16	3.8 ± 0.17	2.9 ± 0.19	2.3 ± 0.19	1.8 ± 0.19	1.8 ± 0.23	1.6 ± 0.29	1.1 ± 0.27	1.1 ± 0.15
95% CI		(−0.40 to −0.28)	(−1.32 to −0.60)	(−2.02 to −1.20)	(−2.61 to −1.71)	(−2.57 to −1.50)	(−3.08 to −1.64)	(−3.75 to −2.45)	(−3.19 to −2.37)
Difference		−0.06	−0.96	−1.61	−2.16	−2.03	−2.36	−3.10	−2.78
p-Value		0.7256	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		1.56	24.54	41.11	54.29	53.57	60.13	73.81	71.47
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Individual scores ranged from 0 (not at all) to 7 (severely). The ‘physical activity’ category scores were calculated by adding the individual QoL factors scores grouped in this category. The ‘physical activity’ category score ranged from 0 (not at all) to 21 (severely). Higher scores indicate more negative impact of QoL domains. % Improvement is calculated as −100 * (mean change from baseline)/(baseline mean). p-Value presented using Student’s paired t-test.

aNumber of participants in this category.
bLast dose includes all subjects’ last day of treatment regardless of study day.
cPost hoc analysis: QoL categories.
dPost hoc analysis: WURSS-21 individual QoL factors (Q14–Q16).
CI, confidence interval; Q, question; QoL, quality of life; SE, standard error; WURSS-21, Wisconsin Upper Respiratory Symptom Survey-21.

Social activity
The social activity category grouped the ‘interact with others’ factor from the WURSS-21 questionnaire (Q19) and ‘being self-conscious around people’ from the additional QoL questions (Q6). The sum of the individual scores determined the range of severity for the social activity category of 0–14. The individual QoL factors were both mildly (score = 3) to moderately (score = 5) impacted at baseline (Table 9).

Table 9.
Overview of changes observed in the social activity category.

QoL category/factor	n a	Baseline	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7	Last dose b
102	98	97	92	82	59	39	30	100
Social activity c	Mean ± SE	8.2 ± 0.32	5.9 ± 0.30	4.4 ± 0.32	3.8 ± 0.33	2.8 ± 0.32	2.7 ± 0.36	2.8 ± 0.48	1.8 ± 0.48	1.6 ± 0.24
95% CI		(−2.75 to −1.64)	(−4.442 to −3.13)	(−5.05 to −3.58)	(−6.06 to −4.50)	(−6.20 to −4.44)	(−6.47 to −4.25)	(−7.80 to −5.13)	(−7.31 to −5.85)
Difference		−2.19	−3.78	−4.32	−5.28	−5.32	−5.36	−6.47	−6.58
p-Value		<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		29.94	46.16	52.93	65.31	65.97	65.52	78.23	80.05
Self-conscious around people d	Mean ± SE	4.3 ± 0.20	2.3 ± 0.20	1.7 ± 0.18	1.6 ± 0.18	1.1 ± 0.18	1.0 ± 0.18	1.0 ± 0.24	0.8 ± 0.25	0.7 ± 0.13
Difference		−1.93	−2.60	−2.65	−3.07	−3.25	−3.41	−3.47	−3.63
p-Value		<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		45.76	60.72	62.72	73.68	76.19	76.88	80.62	84.81
n e	102	99	98	92	82	59	39	30	100
Interact with others f	Mean ± SE	3.9 ± 0.17	3.7 ± 0.17	2.7 ± 0.19	2.3 ± 0.19	1.7 ± 0.19	1.7 ± 0.23	1.8 ± 0.30	1.0 ± 0.29	1.0 ± 0.15
95% CI		(−0.56 to −0.06)	(−1.58 to −0.81)	(−2.09 to −1.23)	(−2.69 to −1.73)	(−2.60 to −1.53)	(−2.64 to −1.26)	(−3.73 to −2.27)	(−3.40 to −2.50)
Difference		−0.25	−1.19	−1.66	−2.21	−2.07	−1.95	−3.00	−2.95
p-Value		0.1106	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		6.41	30.55	42.38	56.39	54.46	52.05	75.63	74.87
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Individual scores ranged from 0 (not at all) to 7 (severely). The ‘social activity category’ scores were calculated by adding the individual QoL factors grouped in this category. The ‘social activity’ category score ranged from 0 (not at all) to 14 (severely). Higher scores indicate more negative impact of QoL domains. % Improvement is calculated as −100 * (mean change from baseline)/(baseline mean). p-Value presented using Student’s paired t-test.

aNumber of participants in this category who answered the additional QoL questionnaire.
bLast dose includes all subjects’ last day of treatment regardless of study day.
cPost hoc analysis: QoL categories.
dSecondary endpoint: additional QoL factor (Q6).
eNumber of participants who answered the WURSS-21 questionnaire.
fPost hoc analysis: WURSS-21 individual QoL factor (Q19).
CI, confidence interval; Q, question; QoL, quality of life; SE, standard error; WURSS-21, Wisconsin Upper Respiratory Symptom Survey-21.

Significant improvement in ‘being self-conscious around people’ was observed from day 1 (p < 0.0001). The social activity category score and the individual factor of ‘interacting with others’ score significantly improved from day 1 (p < 0.0001) (Table 9). The time to resolution was day 3 for ‘being self-conscious around people’ and the median time to resolution for the ‘interact with others’ factor was day 4 (Figure 4). At last dose, social activity and both individual factors improved by at least by 70% (Table 9). Finally, the individual factor of ‘interacting with others’ showed a positive correlation with relief of nasal congestion (‘plugged nose’ symptom) (r = 0.60; p < 0.0001) (Table 12).

Sensation
The QoL category of sensation incorporates the senses of ‘smell’ (Q4) and ‘taste’ (Q5) from the additional QoL questions (Table 10). The sum of the individual scores determined the range of severity for the sensation category of 0–14. The ‘smell’ factor had a baseline mean (±SE) score of 4.8 (±0.16), considered to be moderate in severity level. The ‘taste’ factor had a mean (±SE) score of 4.2 (±0.19), considered mild (score = 3) to moderate (score = 5) in severity level. After day 1 of xylometazoline hydrochloride 0.1% use, the ‘smell’ and ‘taste’ senses improved significantly (p < 0.0001) (Table 10). Significant improvements continued throughout the study, and, at the last dose of treatment, the category of sensation had an improvement of 81%; the sense of ‘smell’ and the sense of ‘taste’ improved by 82.2% and 79.7%, respectively. The median time to resolution was day 3 for the sense of ‘taste’ and day 4 for the sense of ‘smell’ (Figure 4). A positive correlation with the symptom of ‘plugged nose’ and the sense of ‘smell’ was also observed (r = 0.61; p < 0.0001) (Table 12).

Table 10.
Overview of changes observed in the sensation category.

QoL category/factor	n a	Baseline	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7	Last dose b
102	98	97	92	82	59	39	30	100
Sensation c	Mean ± SE	9.0 ± 0.33	5.2 ± 0.38	4.5 ± 0.40	3.6 ± 0.38	2.8 ± 0.36	2.5 ± 0.41	2.8 ± 0.57	2.6 ± 0.61	1.7 ± 0.27
95% CI		(−4.47 to −2.96)	(−5.28 to −3.75)	(−6.21 to −4.55)	(−6.98 to −5.19)	(−7.07 to −5.10)	(−7.38 to −4.83)	(−8.41 to −5.39)	(−8.08 to −6.54)
Difference		−3.71	−4.52	−5.38	−6.09	−6.08	−6.10	−6.90	−7.31
p-Value		<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		41.60	50.17	59.93	68.36	71.09	68.39	72.38	81.04
Smell d	Mean ± SE	4.8 ± 0.16	2.8 ± 0.19	2.4 ± 0.20	1.8 ± 0.19	1.5 ± 0.18	1.2 ± 0.21	1.5 ± 0.29	1.3 ± 0.31	0.9 ± 0.14
Difference		−1.96	−2.42	−2.97	−3.34	−3.36	−3.23	−3.70	−3.98
p-Value		<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		40.94	50.54	61.76	69.72	73.33	68.48	74.00	82.23
Taste d	Mean ± SE	4.2 ± 0.19	2.4 ± 0.20	2.1 ± 0.21	1.8 ± 0.20	1.4 ± 0.18	1.3 ± 0.21	1.3 ± 0.29	1.3 ± 0.30	0.9 ± 0.14
Difference		−1.76	−2.09	−2.41	−2.74	−2.73	−2.87	−3.20	−3.33
p-Value		<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		42.36	49.75	57.81	66.77	68.51	68.29	70.59	79.67
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Individual scores ranged from 0 (not at all) to 7 (severely). The ‘sensation category’ scores were calculated by adding the individual QoL factors grouped in this category. The ‘sensation activity’ category score ranged from 0 (not at all) to 14 (severely). Higher scores indicate more negative impact of QoL domains. % Improvement is calculated as −100 * (mean change from baseline)/(baseline mean). p-Value presented using Student’s paired t-test.

aNumber of participants in this category.
bLast dose includes all subjects’ last day of treatment regardless of study day.
cPost hoc analysis: QoL category.
dSecondary endpoint: additional QoL factors (Q4, Q5).
CI, confidence interval; Q, question; QoL, quality of life; SE, standard error; WURSS-21, Wisconsin Upper Respiratory Symptom Survey-21.

Other QoL factors
The five remaining QoL factors were assessed individually; these were ‘think clearly’ (Q12), ‘work outside home’(Q17), ‘work inside the home’ (Q18), and ‘live your personal life’ (Q20) from the WURSS-21 questionnaire, and ‘being self-conscious about how you sound’ (Q3) from the additional QoL questionnaire. The mean (±SE) scores for each individual QoL factor at baseline are shown in Table 11. All ranged between 3.5 and 4.2, which could be considered mild (score = 3) to moderate (score = 5) in severity level. After treatment with xylometazoline hydrochloride 0.1%, significant improvements from day 1 were seen in ‘live your personal life’ and ‘being self-conscious about how you sound’ factors. ‘Work inside the home’ and ‘work outside the home’ showed a significant improvement from day 2 (Table 11). ‘Think clearly’ improved from day 3, a day later to the ‘head congestion’ symptom, which improved from day 2 (Supplemental Table 2).

Table 11.
Overview of changes observed in other WURSS-21 individual QoL and additional QoL factors.

QoL factor	n a	Baseline	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7	Last dose b
102	98	97	92	82	59	39	30	100
Self-conscious about how you sound c	Mean ± SE	4.2 ± 0.19	2.2 ± 0.19	2.0 ± 0.20	1.6 ± 0.18	1.4 ± 0.19	1.1 ± 0.20	1.3 ± 0.27	0.9 ± 0.23	0.6 ± 0.12
95% CI		(−2.39 to −1.57)	(−2.66 to −1.81)	(−3.14 to −2.32)	(−3.40 to −2.43)	(−3.68 to −2.66)	(−4.02 to −2.54)	(−4.24 to −2.70)	(−4.05 to −3.25)
p-Value		<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		46.97	52.42	63.38	68.29	73.62	71.91	78.79	85.48
n d	102	99	98	92	82	59	39	30	100
Think clearly e	Mean ± SE	3.9 ± 0.17	4.2 ± 0.18	3.6 ± 0.19	2.7 ± 0.20	2.3 ± 0.21	2.0 ± 0.23	1.9 ± 0.31	1.5 ± 0.31	1.4 ± 0.18
95% CI		(0.10–0.55)	(−0.66 to 0.01)	(−1.62 to −0.86)	(−2.03 to −1.04)	(−2.34 to −1.35)	(−2.62 to −1.22)	(−3.22 to −1.64)	(−2.87 to −2.05)
Difference		0.32	−0.33	−1.24	−1.54	−1.85	−1.92	−2.43	−2.46
p-Value		0.0051	0.0572	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		NI	8.40	31.84	39.75	48.44	50.0	62.39	63.24
Work inside the home e	Mean ± SE	3.5 ± 0.18	3.5 ± 0.19	2.7 ± 0.19	2.2 ± 0.20	1.8 ± 0.20	1.6 ± 0.23	1.6 ± 0.29	1.0 ± 0.28	1.0 ± 0.16
95% CI		(−0.23 to 0.41)	(−1.19 to −0.36)	(−1.69 to −0.79)	(−2.14 to −1.11)	(−2.39 to −1.14)	(−2.43 to −1.06)	(−3.14 to −1.66)	(−2.87 to −1.95)
Difference		0.09	−0.78	−1.24	−1.62	−1.76	−1.74	−2.40	−2.41
p-Value		0.5711	0.0004	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		NI	22.55	35.85	47.67	51.74	52.71	70.59	70.06
Work outside the home e	Mean ± SE	4.0 ± 0.19	3.6 ± 0.20	2.8 ± 0.19	2.3 ± 0.21	1.8 ± 0.21	1.7 ± 0.22	1.5 ± 0.27	0.9 ± 0.27	1.1 ± 0.15
95% CI		(−0.63 to 0.05)	(−1.45 to −0.67)	(−2.19 to −1.20)	(−2.73 to −1.64)	(−2.66 to −1.48)	(−3.00 to −1.41)	(−3.77 to −2.50)	(−3.36 to −2.42)
Difference		−0.29	−1.06	−1.70	−2.18	−2.07	−2.21	−3.13	−2.89
p-Value		0.0892	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		7.47	27.15	42.51	55.08	54.46	59.31	77.05	73.35
Live your personal life e	Mean ± SE	4.2 ± 0.16	3.8 ± 0.17	2.8 ± 0.18	2.3 ± 0.19	1.9 ± 0.20	1.9 ± 0.23	1.7 ± 0.28	1.0 ± 0.29	1.1 ± 0.17
95% CI		(−0.80 to −0.17)	(−1.77 to −0.99)	(−2.36 to −1.46)	(−2.87 to −1.86)	(−2.67 to −1.53)	(−2.95 to −1.56)	(−3.90 to −2.37)	(−3.61 to −2.69)
Difference		−0.48	−1.38	−1.91	−2.37	−2.10	−2.26	−3.13	−3.15
p-Value		0.0030	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
% Improvement		11.43	32.77	45.24	55.91	52.32	57.14	75.20	74.29
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Individual scores ranged from 0 (not at all) to 7 (severely). Higher scores indicate more negative impact of QoL domains. % Improvement is calculated as −100 * (mean change from baseline)/(baseline mean). p-Value presented using Student’s paired t-test.

aNumber of participants in this category who answered the additional QoL questionnaire.
bLast dose includes all subjects’ last day of treatment regardless of study day.
cSecondary endpoint: additional QoL factor (Q3).
dNumber of participants in this category who answered the WURSS-21 questionnaire.
ePost hoc analysis: individual QoL factors (Q12, Q17–18, Q20).
CI, confidence interval; NI, no improvement; Q, question; QoL, quality of life; SE, standard error; WURSS-21, Wisconsin Upper Respiratory Symptom Survey-21.

By the last dose, the highest percentage of improvement was seen in ‘being self-conscious about how you sound’ by 85.5%; ‘live your personal life’ improved by 74.3%; ‘work inside the home’ and ‘work outside the home’ improved by 70.1% and 73.4%, respectively, and ‘think clearly’ improved by 63.2% (Table 11).

Median time to resolution for ‘being conscious about how you sound’ was day 3; median time for resolution for ‘live your personal life’, ‘work inside the home’, and ‘work outside of the home’ was day 4; and mean time to resolution for ‘think clearly’ was day 5 (Figure 4).

A positive correlation was found between the plugged nose symptom and all QoL factors; one of the strongest correlations was with the ‘live your personal life’ factor (r = 0.6, p < 0.0001) (Table 12).

Satisfaction
At the exit survey, participants were asked to report their satisfaction with the treatment and if they would use the study product again based on their experience in this study. Most participants (n = 91) were satisfied [n = 35 (34.31%)] or very satisfied [n = 59 (57.84%)] with treatment, and 93% of participants reported that they would use xylometazoline hydrochloride 0.1% again.

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Discussion
The common cold can be caused by a plethora of different viruses.1,5 Due to the involvement of different pathologic mechanisms and the fact that the disease is acute and self-limited, there is no cure and it is usually managed through symptomatic treatment.5,18 Despite being a generally mild disease, the symptom severity of the common cold manifests widely among individuals9,19 and can impact QoL in terms of productivity9,20 and sleep quality, 9 among other factors. In particular, nasal congestion contributes significantly to sleep disturbances, absences from work, and general activity impairment.21,22

Assessment of QoL measures in similar non-life threatening conditions that rely on symptomatic management has been valuable in understanding the benefit–risk ratio of treatment options. 23 QoL analyses are now standard practice in clinical research in chronic conditions, such as allergic rhinitis, for which standard questionnaires have been developed to assess the effectiveness of symptom relief on the patient’s QoL.24–26 Similar to the common cold, nasal congestion is one of the most bothersome symptoms of allergic rhinitis.27–29 Although the common cold is not a chronic disease, the frequency of viral infections per adult and the associated symptoms can place a burden on the QoL of people experiencing a common cold.19,20

Xylometazoline hydrochloride has been established as a safe and efficacious nasal decongestant in the treatment of the common cold. 14 Combined with existing knowledge on the natural disease course, the present study was designed to gather insights on QoL data from a real-world setting, given that real-world data have the potential to supplement existing findings from randomized controlled trials. 30

To reflect how common cold sufferers experiencing a blocked nose use xylometazoline nasal spray in everyday life, a fully decentralized, longitudinal, real-world, open-label study design was chosen. The study was the first to demonstrate the effectiveness of a nasal decongestant on the common cold to improve QoL factors. WURSS-21 total score and total symptom score improved significantly from moderate to mild severity by day 2 of the study, whereas the WURSS-21 total QoL score significantly improved from day 1. These results suggest that although participants were still experiencing moderate symptoms, nasal decongestion may have helped them to resume their daily living at an earlier stage of the common cold compared with the natural course of the disease.

Temporary or chronic impairment of sleep quality results in fatigue, irritability, slowed responses, and general daytime dysfunction. 31 In the common cold, nasal congestion and cough are the most commonly reported disruptive symptoms causing reduced sleep quality.32,33 Studies in allergic rhinitis have demonstrated that relief of nasal congestion improves sleep quality,34,35 and efficient symptom relief significantly improved the difficulty of falling asleep or waking up at night.28,36 In this study, participants who experienced nasal congestion due to the common cold reported improvements in sleep quality from day 1 after xylometazoline hydrochloride 0.1% usage, with similar findings for the associated QoL factors ‘sleep well’ and ‘snoring’. Analysis of individual symptom scores showed that nasal congestion (‘plugged nose’) positively correlates with the ‘sleep well’ factor (r = 0.60). These data suggest that alleviating nasal congestion during the early stages of the common cold is associated with improved sleep quality, thereby improving overall QoL.

Sleep has also been shown to impact QoL factors related to vitality, such as ‘energy’, ‘motivation’, and ‘alertness’ (being slow in response).31,37 In this study, all QoL factors for vitality had improved from day 1, corroborating findings from the sleep quality category. A previous study showed that nasal decongestion with intranasal corticosteroids in allergic rhinitis was associated with improved sleep and reduced daytime fatigue. 28 In this study, the symptom of ‘plugged nose’ from the WURSS-21 questionnaire significantly improved from day 1, and the WURSS-21 individual symptom factor of ‘feeling tired’ showed a significant improvement from day 2, suggesting that xylometazoline hydrochloride 0.1% decongestion effect may also benefit patients experiencing the common cold.

In terms of physical activity, these results suggest that once participants were able to breathe easily, they were able to increase their daily activities and even perform mild exercise after 2 days of treatment. The ‘walk, climb stairs, exercise’ factor and ‘accomplish daily activities’ both had a severity level of mild-to-moderate at baseline. After treatment with xylometazoline hydrochloride 0.1%, a significant improvement was observed from day 2, correlating with the symptom of ‘feeling tired’ from the vitality category. Furthermore, the QoL factor ‘breathe easily’ showed significant improvement on day 1 and demonstrated the strongest positive correlation with nasal congestion (‘plugged nose’ symptom) (r = 0.72).

It was observed that ‘being conscious around people’ and ‘interacting with others’ were mildly affected at baseline and significantly improved from day 1 and day 2, respectively. It may be expected that the fatigue or irritability experienced during a common cold episode drive social withdrawal. However, early intervention to relieve nasal congestion with xylometazoline hydrochloride 0.1% may help people to carry out daily activities requiring social exposure sooner.

This study also showed that xylometazoline hydrochloride 0.1% significantly improved the senses of ‘smell’ and ‘taste’ from day 1. As the olfactory and gustatory systems are central to the process of food consumption, 38 these results suggest that xylometazoline hydrochloride 0.1% usage may have made it easier for participants to enjoy food and ensure necessary nutritional uptake during the early stages of the common cold.

Other QoL parameters, such as ‘being self-conscious around people’ and ‘being self-conscious about how you sound’, may be related to negative feelings (embarrassment or negative self-judgments) that could be a cause of anxiety. 39 In this study, nasal congestion relief improved the self-consciousness QoL factors assessed from day 1, suggesting that during the early stages of the common cold, the disease burden may have reduced when using xylometazoline hydrochloride 0.1%.

Some QoL factors assessed in this study were not expected to be affected by the alleviation of nasal congestion. Instead, these factors were likely resolved on their own through the natural disease course, such as the ‘think clearly’ factor, which we found to significantly improve from day 3. The effect of the common cold on ‘thinking clearly’ is not well understood. However, the combined effects of sleep disruption, 40 and the underlying mechanism of inflammation may impact neurotransmitter function, 10 may cause irritability and mild cognitive impairment during a common cold episode.8,41

This study showed a significant improvement in all symptoms and QoL factors evaluated. More than 90% of participants in this study reported product satisfaction and would use xylometazoline hydrochloride 0.1% again. As participants were recruited at an early stage of the common cold and started treatment by the peak symptom stage, changes in symptom severity during this study may be attributed to xylometazoline hydrochloride 0.1% treatment. Given the well-known natural history of the common cold, 12 and that xylometazoline hydrochloride 0.1% efficiently reduces nasal congestion, 14 these data suggest that nasal congestion relief may positively impact participants’ QoL.

Nevertheless, a limitation of this study is the single-arm and open-label design, which does not include a direct comparison with a control group. Furthermore, as the study design focused on real-world evidence, the use of concomitant medications was permitted, apart from other types of decongestants. Therefore, some of the observed symptomatic improvements may not be solely due to treatment with the study drug. Additionally, as the common cold is a self-limiting disease, it is also important to delineate which symptomatic improvements can be attributed to the effectiveness of xylometazoline hydrochloride 0.1% treatment, compared with symptomatic resolution during the natural course of disease.

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Conclusion
This study is the first to demonstrate that treating nasal congestion with xylometazoline hydrochloride 0.1% during the common cold positively impacts QoL factors relevant to daily living in a real-life setting. Findings from this study suggest that xylometazoline hydrochloride 0.1% usage during the common cold helps improve breathing, may have positive implications on sleep quality, general performance, and enable individuals to feel better during an episode of the common cold. The results presented in this real-world study provide a broader perspective on symptom relief during the common cold and the positive impact this has on QoL, which may inform healthcare decision making for patients and providers alike.

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Supplemental Material
sj-docx-1-tar-10.1177_17534666241228927 – Supplemental material for A real-world study of quality of life following treatment with xylometazoline hydrochloride in individuals with common cold:
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sj-tif-2-tar-10.1177_17534666241228927 – Supplemental material for A real-world study of quality of life following treatment with xylometazoline hydrochloride in individuals with common cold:
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Acknowledgments
The authors would like to thank all participants and everyone involved in conducting the studies and analyzing the data. The authors would like to thank Yoshita Anandarajah and Mizpah Lamptey for their contributions during study design, study execution, and reporting of data. Medical writing assistance was provided by Sandra Malagon and Shuang Song of Nucleus Global, UK, which was funded by Haleon in accordance with Good Publication Practice (GPP2022) guidelines.

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Footnotes
ORCID iD: Martina Hagen An external file that holds a picture, illustration, etc.
Object name is 10.1177_17534666241228927-img1.jpg https://orcid.org/0009-0004-9542-630X

Supplemental material: Supplemental material for this article is available online.

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Contributor Information
Martina Hagen, Haleon CH SARL, Route de l’Etraz 2, Nyon 1279, 1260, Switzerland.

Kim Clark, Haleon, Weybridge, Surrey, UK.

Pranab Kalita, Haleon, Weybridge, Surrey, UK.

Gessica Serra, Haleon, Weybridge, Surrey, UK.

Edwin Sanchez, Haleon, Warren, NJ, USA.

Gabor Varbiro, Haleon, Weybridge, Surrey, UK.

Mathieu M. Albasser, Haleon CH SARL, Nyon, Switzerland.

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Declarations
Ethics approval and consent to participate: This study was conducted in compliance with the protocol and in accordance with Good Clinical Practices Medicines and Healthcare products Regulatory Agency regulations, and all applicable local and state regulations. Signature of the eIC was required and obtained from all participants before any study-related activities. The eIC was reviewed by West Midlands, Edgbaston, Research Ethics Committee, Manchester, UK. IRAS project ID 1006069, REC:22/WM/0177. Approved by West Midlands – Edgbaston Research Ethics Committee 25 October 2022.

Consent for publication: Consent for publication was provided by participants through the eIC form.

Contributed by
Author contributions: Martina Hagen: Conceptualization; Formal analysis; Writing – review & editing.

Kim Clark: Methodology; Writing – review & editing.
Pranab Kalita: Conceptualization; Writing – review & editing.

Gessica Serra: Methodology; Writing – review & editing.

Edwin Sanchez: Formal analysis; Writing – review & editing.

Gabor Varbiro: Formal analysis; Methodology; Writing – review & editing.

Mathieu M. Albasser: Formal analysis; Writing – review & editing.

Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored by Haleon.

Competing interests: All authors are employees of Haleon.

Availability of data and materials: Anonymized individual participant data and study documents can be requested for further research from https://haleon-study-register.idea-point.com. Clinical trial details can be found on Study Record | Beta ClinicalTrials.gov.

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References