Randomized phase II clinical trials of wellmune WGP[R] for immune support during cold and flu season.
Beta-glucan from oats and barley may decrease cardiovascular risk
factors. Beta-glucan from some kinds of mushrooms may have as similar
effect while modulating the immune system. This pilot trial examined
whether beta-glucan derived from Saccharomyces cerevisiae can favorably
decrease the risk of or symptomology associated with upper respiratory
illness. Forty healthy adult subjects (18 to 65 years of age) were
enrolled in a 12-week, randomized, double-blind, placebo-controlled,
parallel-group trial conducted during the cold/flu season. The treatment
arm compared Wellmune WGP[R] (WGP) gluco polysaccharide (beta-glucan)
(500 mg/d) vs a placebo (500 mg rice flour). Cold/flu symptoms were
evaluated by medical staff within 24 hours of onset. There were no
significant differences in the incidence of symptomatic respiratory
infections (SRI's) among the study groups. However, none of
subjects in the WGP group missed work or school due to colds, while
subjects with colds in the placebo group missed an average of 1.38 days
(Intent to Treat: (0.00 [+ or -] 0.00 vs. 1.38 [+ or -] 1.25; p =
0.026). Quality of Life, assessed by the Physical Component Summary
score (SF36v-2), improved significantly in the WPG group vs the placebo
group after 90 days as compared to baseline (Intent to Treat: 0.8 [+ or
-] 5.5 vs. -1.9 [+ or -] 2.8;p=0.042). The WGP group had a significantly
lower average fever score than the placebo group (Per Protocol: 0.00 [+
or -] 0.00 vs. 3.50 [+ or -] 3.42; p = 0.042). No adverse events were
detected and no safety concerns were presented. This preliminary study
suggests 1,3-1,6 beta-glucan from Saccharomyces cerevisiae may modulate
the immune system and reduce some risks associated with upper
respiratory influenza infections.
KEYWORDS: common cold, human influenza, beta-glucans
(Care and treatment)
Cold (Disease) (Research)
Influenza (Care and treatment)
Schwartz, Howard I.
Kalman, Douglas S.
Kohrman, Hannah M.
Krieger, Diane R.
|Publication:||Name: Journal of Applied Research Publisher: Therapeutic Solutions LLC Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 Therapeutic Solutions LLC ISSN: 1537-064X|
|Issue:||Date: March-June, 2009 Source Volume: 9 Source Issue: 1-2|
|Topic:||Event Code: 310 Science & research|
|Geographic:||Geographic Scope: United States Geographic Code: 1USA United States|
The common cold, typically caused by human parainfluenza viruses, remains one of the most frustrating of medical illnesses, given its incidence and prevalence. The common cold has significant effects on health, well-being, and productivity. Each cold experienced by a working adult results in an average of 8.7 lost work hours, and 1.2 lost work hours due to attending to sick children. (1) The economic burden of lost productivity due to colds is approximately $25 billion annually, with lost productivity from missed work days comprising the majority of the financial burden. (2) There are no reliable interventions currently available that significantly protect against influenza infections or prevent the occurrence of this illness. There have been several clinical trials evaluating a variety of dietary supplements for the prevention and treatment of both experimentally induced and naturally occurring colds. Many of those interventions included Echinacea, (3-13) vitamin C, (14-18) probiotics, (19) ginseng, (20) vitamin E, (21,22) and zinc. (20,23-36) Other studies indicate no dietary supplement consistently reduces the risk of the common cold. Some studies suggest vitamin E and ginseng may reduce the incidence of common colds, (20,21) while other investigations report no favorable effects of vitamin E on upper respiratory tract infection. (22) Zinc, from zinc acetate, is reported to reduce the symptom and severity of common colds in healthy adults, (21) while other reports suggest the absence of any effect. (32,33) These apparent discrepancies are due to various study limitations across the literature, such as potential differences in product identity and dose, and small sample size and low statistical power, or lack of a clinical effect. Another possibility may be genetic variations and immunocompetencies among study subjects.
Biological response modifiers such as beta-glucan, enhance the innate immune response without inducing damaging pro-inflammatory cytokines, and may represent a novel approach to protect against cold and flu pathogens. (37,38) Beta-glucans are glucose polymers derived from yeast, fungi, or from oats. In vivo studies suggest beta-glucans may enhance the immune system responses to infectious organisms without eliciting a pro-inflammatory cytokine response. (37,39-43) Other in vivo investigations report that oat-derived beta-glucan can decrease increased risk of upper respiratory tract infection as a result of stressful exercise in mice. (44, 45)
In clinical trials, beta-glucan reduces postoperative infection rates and shortens intensive care unit stay duration. (46-48) One study also reported that increasing doses of beta-glucan resulted in fewer infections after surgery. (46)
Beta-glucan from a variety of dietary sources has immunomodulatory properties. The potential immunomodulatory effect of beta-glucan from Saccharomyces cerevisiae has not been evaluated in a structured clinical trial that assesses its efficacy on the prevention and/or treatment of the common cold in a healthy adult population. The current study aimed to determine whether the proprietary beta-glucan extract Wellmune WGP[R] (WGP) can reduce the incidence and/or duration/severity of respiratory illnesses in a healthy population during peak cold/flu season.
MATERIALS AND METHODS
A randomized, double-blind, placebo-controlled, parallel-group trial compared beta-glucan extract Wellmune WGP[R] (WGP) and placebo in healthy community-dwelling subjects. Wellmune WGP, a registered trademark of Biothera, is a functional ingredient for foods, beverages and supplements that is derived from a proprietary strain of yeast (Saccharomyces cerevisiae) . The entire study was conducted at the Miami Research Associates (Miami, FL) facilities. This study was approved by the Copernicus Group, an Independent Review Board located in Cary, North Carolina.
All subjects who were taking immune-modifying dietary supplements prior to enrollement underwent a 4-week washout phase prior to randomization. Subjects were then randomly assigned to trail groups in which they were blinded to intervention. During the 90-day intervention period, subjects consumed 500 mg/d of beta-glucan or a rice-flour placebo. Subjects were evaluated by the medical staff within 24 hours of cold onset.
Endpoints were measured at the onset of symptoms of a respiratory infection, and twice daily for seven days. Endpoints measured were changes from baseline in: number of symptomatic respiratory infections (SRIs) that each subject had during the study, total days of duration of each subject's SRIs, average days of duration of each subject's SRIs, symptom-days total for each SRI symptom based on a self-report daily diary, and average symptom-day total for each subject that included categories SRIs into Colds, Flu, or Pharyngitis. Other endpoints included safety data through laboratory (CBC, kidney, and liver function) and physical testing.
Subjects were screened in January and February of 2006. Subjects were recruited from existing patient populations, physician referrals, subject databases, and community-based local advertising. Approximately 65 potential candidates were telephone screened and 42 were called in for a screening visit (Figure 1). Exclusion and inclusion criteria are provided in Table 1. Out of the 42 potential subjects, two screened subjects did not meet the inclusion/exclusion criteria: one subject had abnormal laboratory results, and another was listed as ineligible in the database.
The remaining 40 healthy community-dwelling adults (28 females, 12 males) between the ages of 18 and 65 were enrolled into the study. There were 12 early terminations: one subject withdrew consent, and 11 subjects were lost to follow-up. The remaining 28 subjects finished the study without protocol deviations. One subject completed all scheduled visits, but was excluded because of inadequate compliance. Subject baseline characteristics are displayed in Table 2. Subjects who qualified based on their screening visit, received $50 for the screening visit, and $50 for completion of each study visit. Total compensation was up to $300 per subject.
Forty subjects were randomly assigned to WGP (Wellmune WGPI beta-glucan) derived from Saccharomyces cerevisiae (250 mg) or a sensory-identical placebo containing rice flour. The intervention subjects consumed two capsules (total=500mg beta-glucan) once daily, 30 minutes before breakfast. The Intent-to-Treat (ITT) population consisted of 33 subjects (17 in the WGP group, and 16 in the placebo group) and defined as only those who received at least one dose of investigational product and returned for at least one visit after baseline. The Per-Protocol (PP) population consisted of 27 subjects (14 in the WGP 3-6 group, and 13 in the placebo group) who completed all visits, and had 80% compliance with the prescribed amount of product.
At Visit 1 (Screening), subjects provided informed consent. Assessments at this visit were demographic and anthropomorphic, physical examination, vital signs, urine pregnancy test (females) medical history, current medication history, Quality of Life via the SF36v-2 questionnaire, and standard blood panel (CBC, kidney, and liver function).
Supplementation and Follow-up
At Visit 2 (Randomization, Day 0), subjects who met the inclusion/exclusion criteria were randomized and dispensed a 4-week supply of study product or placebo. Randomization was determined by atmospheric noise entropy (www.Random. org). Block randomization was utilized to insure uniform allocation of WGP and placebo. At Visit 3 (Day 30), subjects returned for blood draws, vital signs measurements, Quality of Life via the SF36v-2 questionnaire, interim medical history, compliance assessment, and adverse events review. Participants were then dispensed another 4-week supply of study product or placebo. These same procedures were completed at Visit 4 (Day 60) and Visit 5 (Day 90).
All subjects were contacted by phone at weeks 2, 6, and 10 to assess compliance. In addition, subjects' compliance with the prescribed amount of product was determined by the returned pill-count method at the 30-, 60-, and 90-day visits, and expressed as a fraction.
Subjects were instructed to page a member of the study team as soon as they felt symptoms of a respiratory illness. Subjects were examined by a qualified member of the study team within 24 hours of the onset of any SRI. The examination focused on SRI history, physical examination, standardized diagnosis (Clinical Diagnostic Criteria), baseline symptoms, and blood analysis. These subjects were provided symptom diaries, and instructed on their use. At 7 to 10 days following the SRI baseline visit, subjects returned for the following evaluations: SRI history, physical examination, collection of symptom diaries, and blood analysis.
Self-report adverse events (AEs) were listed, Medical Dictionary for Regulatory Activities (MedDRA) encoded, grouped by general type of event (e.g., gastrointestinal, neurological, cardiac, or dermatologic), and cross-tabulated by event type and product dosing level. Potential differences in AE patterns between products were tested by the Fisher's Exact test. Significance was assigned at p <0.05.
There appears to be a dearth of information on the prevention or treatment of upper respiratory tract infections that included 1-3,1-6 beta glucan. Limited information on the use of dietary supplements directed to cold/flu prevention indicated that community-based trials had sample sizes ranging from 126 to 668 subjects. The duration of these studies ranged from 30 days to several years. Inoculation and severity trials tended to have smaller sample sizes. Given the lack of data to calculate an effect size, the current investigation was undertaken as a pilot study intended to provide critical data for future studies. Power calculations based on the cold/flu literature supported a sample size of 40.
The primary endpoint changes from baseline values were analyzed using a repeated measures analysis of variance (ANOVA). Two approaches to the analysis were performed. Analysis of the primary efficacy endpoints were performed in Intent-to-Treat (ITT) patients as well as Per-Protocol (PP) patients. The Intent-to-Treat analysis was considered primary. All data were transferred into the 'R' statistical system version 2.5.1 (R foundation for Statistical Computing, Vienna, Austria, http://www.R-project.org) for subsequent statistical analysis. Specially-created R programs were used to generate the descriptive tables and statistical tests. For the Intent-to-Treat efficacy analysis, missing efficacy endpoints were imputed with the last available value (last observation carried forward (LOCF) imputation). All descriptive data are expressed as mean [+ or -] SD. Significance level was set at p < 0.05.
There were no significant differences between the treatment and placebo groups in the number of SRI episodes (6 vs. 5, WGP and placebo, respectively, p = 1.00), number of SRI's per subject (0.41 WGP vs. 0.44 placebo, p = 0.948), or number of subjects with SRI (Table 3). There were no significant differences between the groups in the duration of SRI episodes, or in the total daily symptom score of SRI's for seven days after the onset of symptoms. None of the WGP subjects missed work or school due to colds, while subjects in the placebo group with colds missed an average of 1.38 days. This was statistically significant in both the ITT and PP populations (p = 0.026 and p = 0.042, respectively).
SRI symptoms are shown in Table 4. None of the WGP subjects presented a fever, whereas the subjects in the control group became febrile (2.0 [+ or -] 4.8) in the PP group (p = 0.068). There was no significant effect of WGP on fever in the ITT analysis (0.6 [+ or -] 2.4 in WGP subjects and 1.6 [+ or -] 4.3 in the placebo group; p = 0.295). There were no other apparent trends or significant differences in any other SRI symptom between the two treatment groups (Table 4).
The WGP group exhibited a significantly greater "General Health" summary score over the 90 days (58.7 [+ or -] 7.0 vs. 52.0 [+ or -] 14.6; p = 0.038) with a concomitant significant comparative improvement in the Physical Component Summary (WGP: 57.5 [+ or -] 4.5; Placebo: 55.5 [+ or -] 3.5; p = 0.029). There were no other significant differences between the two groups for any other 'quality of life' measures from the SF-36v2 questionnaire.
Compliance and Side Effects
Overall compliance was nearly 90% in the ITT population, and approximately 95% in the PP population. One subject who had completed all scheduled visits was excluded from the PP population because of inadequate compliance.
[FIGURE 1 OMITTED]
A total of 43 adverse events (AEs) were reported by 20 subjects during this study. Twenty-two events were recorded by 11 subjects in the WGP group, whereas 21 events among 9 control subjects were documented. All events were of mild to moderate severity. All were judged by the principal investigator to be probably not related to each other or as a consequence of the study product. None of the events contributed the subject's self-discontinuance or withdrawal from the study. The number and types of adverse events were distributed evenly between WGP and placebo groups. There was no tendency for AEs to occur more frequently in one study group vs the other (p = 0.728). There were no safety concerns in the study (Table 5).
This is the first clinical study to assess the efficacy of Saccharomyces cerevisiae derived beta-glucan on incidence, duration, and severity of SRI in a healthy, adult, community-dwelling population. Importantly, none of the subjects from the WGP group missed work or school during the 90-day study. In addition, the WGP group's physical component summary score improved more than the placebo group, and the WGP group had a significantly lower fever score. However, there were no significant differences between WGP and placebo on SRI incidence.
Beta-glucan from other sources appears to improve immune function in a variety of animal models, without increasing pro-inflammatory cytokines or inducing a febrile response. (37,42,49,50) Other in vivo models indicate that oat-derived beta-glucan, a linear molecule, can prevent increased risk of URTI as a result of stressful exercise in mice. (44,45) It appears that beta-glucan may be a powerful immune stimulator, as evidenced by its ability to activate macrophages and stimulate positive immune actions on B lymphocytes, natural killer cells, and suppressor T cells in the immune system. (51-53) Many in vitro studies have shown that beta-glucan significantly increases microbiocidal activity of human neutrophils and macrophages against a variety of pathogens without directly stimulating synthesis of the cytokines, IL-1 or TNF. The exact pathway through which beta-glucans interact with the immune system is unknown. One proposed mechanism is the activation of dectin-1 pattern recognition receptor on blood peripheral mononuclear cells. (54,55)
Other dietary supplements are reported to reduce upper respiratory tract infection symptoms in humans. (14) For example, zinc acetate treatment (12.8 mg q3h 12d) reduced severity and duration of cold symptoms. (30) A highly purified beta-glucan (0.1-1.0 mg/kg bw) from Saccharomyces cerevisiae helped to reduce post-surgical infections and decrease intensive care unit stay length. (46-48) A more recent study reported no change in self-reported upper respiratory tract infection symptoms or the average number of sick days in endurance athletes given a beta-glucan supplement for 18 days. (56) In this report, beta-glucan was administered at 5.6 g/day in a 600 ml beverage containing Gatorade[R] and Oatvantage[R], a 54% oat beta-glucan concentrate. Subjects ingested the supplements in two 300 mL doses each day before their first and last meals on an empty stomach. Nieman et al (56) also reported no changes in natural killer cell activity, polymorphonuclear respiratory burst activity, phytohemagglutinin-stimulated lymphocyte proliferation, plasma interleukin 6 (IL-6), IL-10, IL-1 receptor agonist (IL-1ra), and IL-8, and blood leukocyte IL10, IL-8, and IL-Ira mRNA expression. This study is different from our current study in several aspects. The study reported here included both male and female healthy community dwelling adults, while Nieman et al (56) studied male endurance athletes. The chemical composition of the beta-glucan and its dosage differed between the two studies, thus making direct comparisons difficult. Soluble and insoluble beta-glucans may stimulate the immune system differently . Higher doses of oat-derived beta-glucan may also be required to see any effects on SRI incidence such as those reported in rodent studies [44,45].
The current pilot study reported results from 27 participants who reported 11 colds. The small sample size may be insufficient to detect possible therapeutic or prophylactic effects of betaglucan from Saccharomyces cerevisiae. Given the economic burden of the common cold, alternative approaches that can lessen the financial impact on society and health burden on individuals should be investigated. Further research in larger groups is needed to determine if this type of beta-glucan, (1-3,1-6) linked from Saccharomyces cerevisiae can modulate the immune system to reduce the risk of developing seasonal cold and flu illness in healthy people across the age spectrum
This study was funded by a research grant from Biothera. Authors Feldman, Schwartz, Kalman, Mayers, Kohrman, and Krieger do not have any additional conflicts of interest to report. Author Clemens is the consulting scientific advisor to ETHorn, distributor of the Biothera product.
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Howard I. Schwartz (2)
Douglas S. Kalman (1)
Athena Mayers (1)
Hannah M. Kohrman
Roger Clemens (3)
Diane R. Krieger (1)
Affiliation: Miami Research Associates, Department of Nutrition & Endocrinology, South Miami, FL 33143
(2) Affiliation: Miami Research Associates Department of Gastroenterology, South Miami, FL 33143
Table 1. Inclusion and Exclusion Criteria Criteria Inclusion criteria Age [greater than or equal to] 18 and [less than or equal to] 65 Generally healthy BMI > 25 kg/m2 and < 40 kg/m2 at screening Agree to all study visits and visit procedures Females must agree to use appropriate birth control methods during the study Community dwelling At least 1 self-reported cold in the last 12 months prior to screening Exclusion criteria Cigarette smoking Current respiratory illness Temperature > 38.3[degrees]C at screening Immune modifying medications: Anti-inflammatory agents, Antibiotics, Steroids Subjects with any history of immune system disorder or auto-immune disorder including but not limited to the following: * AIDS, HIV, * Ankylosing Spondylitis, Chronic Fatigue Syndrome, CREST Syndrome, Crohn's Disease, Dermatomyositis, Fibromyalgia, Grave's Disease, Hashimoto's Thyroiditis, Lupus, Myasthenia Gravis, Pernicious Anemia, Polyarteritis Nodosa, Primary Biliary Cirrhosis, Psoriasis, Reynaud's Disease, Rheumatoid Arthritis, Sarcoidosis, Scleroderma, Sjogren's Syndrome, Temporal Arthritis, Ulcerative Colitis, and Vitiligo Use of any immunosuppressive drugs in the last 5 years (Steroids, Biologics, etc.) History of Splenectomy History of Tuberculosis Diabetes (Type I and II) Untreated Hypothyroidism Active Liver Disease with liver function tests > 2X upper limit of normal (ULN) Active Renal Disease with Cr > 1.5 ULN Active Asthma requiring ongoing treatment Weight loss of ? 20 pounds in the last 3 months Untreated or unstable Hypothyroidism Abnormal physical examination Subjects with active eating disorder including anorexia nervosa, bulimia, and/or obsessive compulsive eating disorders Table 2. Baseline Characteristics Subject Demographics Variables WGP 3-6 (n=21) Placebo (n= 19) Total (%) Total (%) Age (years) 30.3 [+ or -] 11.4 36.4 [+ or -] 16.2 Sex: Female 14 (67) 14(74 Male 7(33) 5 (26) Race: Asian 1(5) 0 (0) Caucasian 18(86) 19 (100) Other 1 (5) 0 (0) Unknown 1 (5) 0 (0) Hispanic: No 5 (24) 6 (32) Yes 16 (76) 13 (68) Consent Language: English 21 (100) 19 (100) Morphometry and Vital Signs WGP 3-6 (n=21) Placebo (n=19) Total (%) Total (%) Height (cm) 167.4 [+ or -] 9.7 166.8 [+ or -] 10.1 Weight (kg) 66.3 [+ or -] 11.8 70.2 [+ or -] 14.9 BMI (kg/[m.sup.2]) 23.6 [+ or -] 2.5 25.1 [+ or -] 4.3 Body temperature ([degrees]F) 98.16 [+ or -] 0.48 98.22 [+ or -] 0.60 Heart Rate (beats/minute) 81.7 [+ or -] 16.6 72.5 [+ or -] 10.7 SBP (mm Hg) 112.3 [+ or -] 12.9 112.7 [+ or -] 8.0 DBP (mm Hg) 71.8 [+ or -] 10.8 74.1 [+ or -] 6.2 Flu Vaccine: No 14 (67) 15 (79) Yes 7 (33) 4 (21) Subject Demographics Variables p-value Age (years) 0.248 Sex: Female 0.736 Male Race: Asian 1.000 Caucasian Other Unknown Hispanic: No 0.727 Yes Consent Language: English Morphometry and Vital Signs p-value Height (cm) 0.851 Weight (kg) 0.486 BMI (kg/[m.sup.2]) 0.258 Body temperature ([degrees]F) 0.531 Heart Rate (beats/minute) 0.098 SBP (mm Hg) 0.919 DBP (mm Hg) 0.433 Flu Vaccine: No 0.488 Yes BMI: Body Mass Index. SBP: Systolic Blood Pressure. DBP: Diastolic Blood Pressure Table 3. Symptomatic Respiratory Episodes Intent-to-Treat Population WGP 3-6 Placebo p-value (n=17) (n=16) Total % Total % Total % Any Colds During the Study? No 11 (65) 11 (69) 1.000 Yes 6 (35) 5 (31) Number of Colds 0.41 [+ or -] 0.62 0.44 [+ or -] 0.73 0.948 Average Duration of a Cold 12.9 [+ or -] 12.4 7.5 [+ or -] 2.0 0.592 Average Number of Missed Days of School or Work per Cold 0.00 [+ or -] 0.00 * 1.38 [+ or -] 1.25 0.026 Number of SRI Episodes 0.41 [+ or -] 0.62 0.44 [+ or -] 0.73 0.948 Number of Cold Episodes 0.29 [+ or -] 0.59 0.38 [+ or -] 0.72 0.866 Number of Flu Episodes 0.059 [+ or -] 0.243 0.000 [+ or -] 0.00 0.363 Number of Pharyngitis Episodes 0.059 [+ or -] 0.243 0.000 [+ or -] 0.00 0.363 Number of URI Episodes 0.00 [+ or -] 0.00 0.063 [+ or -] 0.250 0.332 Total Duration of SRI Episodes 5.1 [+ or -] 9.9 3.0 [+ or -] 6.2 0.580 Total Missed Days of School or Work per Subject 0.00 [+ or -] 0.00 0.50 [+ or -] 1.10 0.071 Per-Protocol Population WGP 3-6 Placebo p-value (n=14) (n=13) Total % Total Any Colds During the Study? No 9 (64) 9 (69) 1.000 Yes 5 (36) 4 (31) Number of Colds 0.43 [+ or -] 0.65 0.46 [+ or -] 0.78 0.953 Average Duration of a Cold 13.5 [+ or -] 13.8 7.5 [+ or -] 2.0 0.902 Average Number of Missed Days of School or Work per Cold 0.00 [+ or -] 0.00 * 1.38 [+ or -] 1.25 0.042 Number of SRI Episodes 0.43 [+ or -] 0.65 0.46 [+ or -] 0.78 0.953 Number of Cold Episodes 0.36 [+ or -] 0.63 0.46 [+ or -] 0.78 0.832 Number of Flu Episodes 0.00 [+ or -] 0.00 0.00 [+ or -] 0.00 Number of Pharyngitis Episodes 0.071 [+ or -] 0.02670.00 [+ or -] 0.00 0.374 Number of URI Episodes 0.00 [+ or -] 0.00 0.00 [+ or -] 0.00 Total Duration of SRI Episodes 5.4 [+ or -] 10.7 3.7 [+ or -] 6.8 0.862 Total Missed Days of School or Work per Subject 0.00 [+ or -] 0.00 0.62 [+ or -] 1.19 0.068 * p < 0.05 Table 4. Symptom Severity from Diary Intent-to-Treat Population (ITT) WGP 3-6 Placebo p-value (n=17) (n=16) WGP3-6 Total Tiredness 6.9 [+ or -] 12.3 6.8 [+ or -] 13.2 0.611 Total Stuff Nose 8.8 [+ or -] 15.6 7.6 [+ or -] 15.1 0.642 Total Runny Nose 8.1 [+ or -] 15.5 7.1 [+ or -] 12.9 0.580 Total Scratchy/Sore 8.8 [+ or -] 18.9 7.1 [+ or -] 14.6 0.674 Throat Total Headache 3.1 [+ or -] 5.7 3.9 [+ or -] 7.6 0.963 Total Muscle Ache 3.5 [+ or -] 6.5 2.8 [+ or -] 6.6 0.565 Total Earache 1.12 [+ or -] 3.87 0.38 [+ or -] 1.50 0.357 Total Fever 0.6 [+ or -] 2.4 1.6 [+ or -] 4.3 0.295 Total Sneezing 6.1 [+ or -] 10.9 5.2 [+ or -] 10.1 0.658 Total Hoarse Voice 8.2 [+ or -] 19.3 5.7 [+ or -] 12.0 1.000 Total Cough Frequency 7.7 [+ or -] 15.7 6.3 [+ or -] 11.6 0.783 Total Cough Intensity 6.8 [+ or -] 14.1 6.1 [+ or -] 11.3 0.872 Total Phlegm/Mucous 8.1 [+ or -] 14.1 8.9 [+ or -] 17.9 0.740 Total Sleeplessness 5.3 [+ or -] 9.7 4.6 [+ or -] 9.1 0.854 Per-Protocol Population (PP) WGP 3-6 Placebo p-value (n=14) (n=13) Total Tiredness 6.4 [+ or -] 12.1 8.3 [+ or -] 14.3 0.954 Total Stuff Nose 7.3 [+ or -] 13.2 9.4 [+ or -] 16.4 1.000 Total Runny Nose 6.4 [+ or -] 13.0 8.7 [+ or -] 13.9 0.954 Total Scratchy/Sore 9.2 [+ or -] 20.4 8.8 [+ or -] 15.8 0.954 Throat Total Headache 3.4 [+ or -] 6.2 4.8 [+ or -] 8.2 0.810 Total Muscle Ache 3.6 [+ or -] 6.9 3.4 [+ or -] 7.3 0.850 Total Earache 1.2 [+ or -] 4.3 0.5 [+ or -] 1.7 0.625 Total Fever 0.0 [+ or -] 0.0 2.0 [+ or -] 4.8 0.068 Total Sneezing 4.9 [+ or -] 8.6 6.4 [+ or -] 10.9 0.977 Total Hoarse Voice 8.3 [+ or -] 20.8 7.0 [+ or -] 13.1 0.659 Total Cough Frequency 7.5 [+ or -] 16.3 7.7 [+ or -] 12.5 0.928 Total Cough Intensity 6.9 [+ or -] 15.1 7.5 [+ or -] 12.2 0.928 Total Phlegm/Mucous 7.7 [+ or -] 14.1 11.0 [+ or -] 19.4 0.954 Total Sleeplessness 5.9 [+ or -] 10.5 5.6 [+ or -] 9.9 0.952 Table 5. Adverse Events (MedDRA coded) Number of Subjects WGP 3-6 Placebo p-value Ear and lahyrinth disorders 0 1 1.000 Eye disorders 1 0 1.000 Gastrointestinal disorders 1 1 1.000 General disorders and 1 0 1.000 administration site conditions Infections and infestations 9 5 0.296 Injury, poisoning and procedural 0 2 0.485 complications Musculoskeletal and connective 1 0 1.000 tissue disorders Nervous system disorders 1 3 0.601 Psychiatric disorders 1 1 1.000 Respiratory, thoracic and 1 1 1.000 mediastinal disorders Surgical and medical procedures 1 0 1.000 All Events 11 9 0.728
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