Study population and investigational product
Two hundred and twenty-four healthy subjects with recurring common colds were included in the study. They had to meet the following inclusion criteria: age ≥ 18–70 years, written consent to participate, and at least three common cold infections within the last 6 months. The main exclusion criteria were as follows: acute or chronic upper airways disease, chronic cough, chronic rhinitis (e.g. allergic rhinitis) or asthma, severe organ or systemic disorders, stomach or intestinal diseases, congenital or acquired immunodeficiency diseases, vaccination against influenza or swine flu within 21 days before the study start, suspected swine flu or influenza, body temperature ≥38 °C, known sensibility to one of the ingredients of the study product, pregnancy or nursing, use of immunosuppressants or stimulants, use of pre- and probiotics.
The sample size calculation was determined by the previously observed effect size and the requirements of a significance level of 5.0 % (two-sided) and a power of 80 % . One study site missed the predetermined difference of the average cold incidence between study groups and, thus, was excluded from further analysis. From the remaining 164 subjects, two were excluded from the intention to treat (ITT) population due to absence of available values after baseline leaving 162 subjects for the ITT analysis. Furthermore, 16 subjects were excluded from the per protocol (PP) analysis, either due to early termination (n = 5) or due to poor compliance (n = 11), resulting in 146 subjects. Hence, 146 subjects remained for PP analysis.
The beta-glucan preparation is an insoluble (1,3)-(1,6)-beta-glucan made from brewers’ yeast (S. cerevisiae), with a purity of at least 85 % on dry matter (branching factor approximately: 1,3 [backbone]: 1,6 [side chain]: 1,3/1,6 [branching] = 10:1:0.6). Moreover, it contains <2 % α-d-Mannan, <3 % fat, <2 % protein and <2 % ash on dry matter. The dry matter is more than 94 %.
Subjects were randomly assigned to receive a total of 900 mg of either insoluble yeast beta-glucan (Yestimun® provided by Leiber GmbH, Germany) or placebo, each provided in two capsules per day, which were consumed at breakfast and supper. Detection of clinical effects like a reduction in common cold infections was demonstrated recently at a daily dosage of 900 mg insoluble beta-glucan .
The placebo product was maltodextrin. Verum and placebo capsules were identical in shape, colour, size and taste. The randomization code was created by an independent statistician prior to study start. The random numbers in blocks of 4 were randomized in a 1:1 ratio to the two study groups.
The study was approved by the Ethic Committee of the Charité, Berlin, Germany and was carried out in accordance with the Helsinki declaration and ICH GCP E6. Participants gave written informed consent prior to the study. The study was registered in the International Standard Randomized Controlled Trial Number Register (http://www.isrctn.org/) as ISRCTN16094368.
The study was a multi-centric, randomized, double-blind, placebo-controlled study with two parallel arms in healthy subjects with recurring common cold episodes. The study was performed between October 2010 and May 2011. The subjects were enrolled at 7 study sites. During the study period of 16 weeks, a total of 3 routine visits were performed: at baseline, after 8 weeks and at the end after 16 weeks. In addition, one episode visit was conducted on the 5th day of each cold episode. Hence, the total number of visits per subject varies depended on the number of common cold episodes. During an infection, the subjects were instructed to record and assess their cold symptoms for a period of 14 days for each occurring episode.
Compliance was determined by counting returned capsules. Sufficient compliance was considered if >75 and <125 % of the capsules were consumed.
The primary objective of the present study, the incidence of common cold episodes, was defined as the number of common cold infections during the study period. Further, severity and duration of cold episodes were assessed.
A cold episode was defined by the occurrence of at least two of the following cold symptoms: sore throat, feeling of lump in the throat/difficulty swallowing, hoarseness, cough, rhinorrhea or nasal congestion. These symptoms had to be rated with at least one point. Upon occurrence of the cold episode, the subjects had to document ten predefined common cold symptoms (headache, joint pain, sore throat, feeling of lump in the throat/difficulty swallowing, hoarseness, cough, rhinorrhea, nasal congestion, cold-related sleeping difficulties, fever) in an episode diary. The evaluation was carried out on a rating scale (0 points = symptom free, 1 point = mild symptoms, 2 points = moderate symptoms, 3 points = severe symptoms). The occurrence of fever was rated three points. By summation of the scores of the individual symptoms, a sum of scores (=total score) was calculated. All episodes were documented by the participants in a diary and confirmed by an investigator during the episode visit on the 5th day of each cold episode. The investigators examination includes the auscultation of the lungs, the control of the subject’s diary, the recording of possible vaccination against influenza/swine flu, the assessment and documentation of cold symptoms, any use of antibiotics as well as any changes in the concomitant illness and medications and the recording of sick leave days.
In seven cases, a cold episode occurred within first 4 days of treatment. Due to the presumed date of infection prior to intake of the investigational product (prophylactic effect not assessable), these episodes were not considered in the analysis.
As concurrent variables, the efficacy and tolerability of the investigational product was evaluated by both the subjects and the investigators at the end of the study. The following ratings were used for it: “very good” “good”, “moderate” or “poor”. The safety and tolerability of the product was additionally evaluated by the documentation of adverse events.
All the variables contained in the data collection were presented descriptively using their statistical key data or their frequency distribution and statistically analysed in view of the group specific differences (p
χ-value). The Mann–Whitney U test was employed to test for between-groups comparison (p
u). All statistical analyses were carried out on both the ITT and PP collective. Statistical analyses were performed with SPSS (SPSS for windows, Release 19, LEAD Technologies Inc). Values of p < 0.05 were considered significant.