METHOD OF TREATMENT
20210379126 · 2021-12-09
Inventors
- David Pyne (Murrumbateman, AU)
- NICOLAS WEST (Queensland, AU)
- ALLAN CRIPPS (Queensland, AU)
- SAMPO LAHTINEN (Lohja, FI)
Cpc classification
International classification
Abstract
The present invention relates to a method of treating or prophlaxis of a respiratory tract illness in a subject comprising administering to said subject a composition comprising Bifidobacterium lactis BL04 and/or fermentation product of Bifidobacterium lactis BL04 and/or a cell lysate of Bifidobacterium lactis BL04.
Claims
1. A method of treating or prophylaxis of a respiratory tract illness in a human, wherein: the method comprises administering to the human a composition comprising Bifidobacterium lactis BL04 and/or a fermentation product of Bifidobacterium lactis BL04 and/or a cell lysate of Bifidobacterium lactis BL04; and the Bifidobacterium lactis BL04 and/or fermentation product of Bifidobacterium lactis BL04 and/or cell lysate of Bifidobacterium lactis BL04 is the only probiotic bacterium, probiotic fermentation product and/or probiotic cell lysate in the composition.
2. A method according to claim 1, wherein: the method comprises administering to the human a composition comprising Bifidobacterium lactis BL04, and the Bifidobacterium lactis BL04 is the only probiotic bacterium in the composition.
3. The method according to claim 1, wherein the respiratory tract illness is an upper respiratory tract illness.
4. The method according to claim 1, wherein the respiratory tract illness is a lower respiratory tract illness.
5. The method according to claim 1, wherein the respiratory tract illness is selected from one or more of the group consisting of tonsillitis, otitis media, rhinitis, rhinosinusitis, sinusitis, nasopharyngitis, rhinopharyngitis, a common cold, pharyngitis, epiglottitis, supraglottitis, laryngitis, laryngotracheitis and tracheitis.
6. The method according to claim 1, wherein the human has displayed symptoms of the respiratory tract illness for more than 7 days.
7. The method according to claim 1, wherein the respiratory tract illness is selected from one or more of the group consisting of throat soreness, sneezing, blocked nose, runny nose and a cough.
8. The method according to claim 1, wherein the respiratory tract illness is selected from one or more of the group consisting of bronchitis, acute bronchitis, pneumonia and a lung abscess.
9. The method according to claim 1, wherein the respiratory tract illness is selected from one or more of the group consisting of coughing with chest congestion and coughing with wheezing.
10. The method according to claim 1, wherein the administration of the Bifidobacterium lactis BL04, fermentation product of Bifidobacterium lactis BL04 and/or cell lysate of Bifidobacterium lactis BL04 increases granulocyte phagocytic activity in the human.
11. The method according to claim 10, wherein the administration of the Bifidobacterium lactis BL04, fermentation product of Bifidobacterium lactis BL04 and/or cell lysate of Bifidobacterium lactis BL04 increases monocyte phagocytic activity in the human.
12. The method according to claim 1, wherein the administration of the Bifidobacterium lactis BL04, fermentation product of Bifidobacterium lactis BL04 and/or cell lysate of Bifidobacterium lactis BL04 increases monocyte phagocytic activity in the human.
13. The method according to claim 1, wherein the method is prophylactic as to the respiratory tract illness.
14. The method according to claim 1, wherein the composition is formulated to provide a dose of 10.sup.8 to 10.sup.12 CFU of Bifidobacterium lactis BL04 per day to the human.
15. The method according to claim 1, wherein the human is at least 18 years old.
16. The method according to claim 1, wherein the human is a healthy, physically active adult.
17. The method according to claim 1, wherein the composition is formulated as a medicament.
18. The method according to claim 1, wherein the composition is formulated as a food product.
19. The method according to claim 1, wherein the composition is formulated as a dietary supplement.
20. The method according to claim 1, wherein: the method is a method of prophylaxis of a respiratory tract illness; the method comprises administering to the human a composition comprising Bifidobacterium lactis BL04; the Bifidobacterium lactis BL04 is the only probiotic bacterium in the composition; and the human is a healthy, physically active adult.
Description
[0247] Examples The present invention will be further described with reference to the following Examples and figures in which:—
[0248]
[0249]
METHODOLOGY
[0250] Experimental approach: The study involved a double-blind placebo-controlled trial of healthy physically active individuals from the community to establish whether 150 days supplementing with a probiotics reduces URTI during the winter period between June and October 2010 (
[0251] Ethics committee clearance was granted by the Ethics Committees of the Australian Institute of Sport (19 Feb. 2010) and Griffith University (11 Mar. 2010).
[0252] Subjects and Recruitment
[0253] There were 268 healthy, physically active members of the community recruited to the study. Of these, 226 individuals were included in the statistical analysis of the physical activity and illness measures. Subject characteristics of those included in the statistical analysis are detailed in Table 1. There were no substantial differences between the groups.
[0254] Inclusion Criteria:
[0255] Inclusion to the study was determined according to physical activity levels with participants required to be undertaking a minimum of three exercise sessions weekly.
[0256] Exclusion Criteria:
[0257] All participants were required to declare their use of dietary and/or ergogenic aids that may influence underlying immune function. All participants on immuno-modulatory medications were excluded, including those on steroid based anti-asthma treatments. Subjects who were on antibiotic treatments in the previous month were also excluded. Subjects with any symptoms of gastrointestinal disease, such as Crohn's disease, coelic disease and related conditions were excluded.
[0258] Primary Outcome Measures:
[0259] The primary clinical outcome measure was URT illness in the participants over the study period. Subjects were required to record any symptoms of URTI and chest illness on a daily illness log over the study period. Briefly, URTI symptoms included throat soreness, sneezing, a blocked or runny nose and cough. Lower respiratory illness symptoms included coughing with chest congestion and/or wheezing. A classification of an episode of illness was made when two or more symptoms were recorded on consecutive days. The functional impact or severity of symptoms for physically active individuals were self-rated as mild, moderate or severe based on the impact of the symptoms on daily activity for that day: mild—no change, moderate—a reduction in normal activity, and severe—total cessation of activity.
[0260] Secondary Outcome Measures
[0261] Perceived stress and resilience: Participant's perceived stress and resilience were measured by questionnaire pre- and post-supplementation. Psychological and social factors represent a source of stress that may affect immunity and health. All subjects undertook the Connor Davidson Resilience questionnaire prior to and at the end of supplementation.
[0262] A cohort of participants (53 in the B. lactis BL-04 group, 51 in the placebo group) from each of the treatment groups provided samples for the following secondary outcome measures.
[0263] Faecal Microbiology [0264] Total bacterial count (eubacteria): [0265] Quantification of the bacterial groups in fecal samples: [0266] These groups may include, but are not limited to, Bacteroidetes, Enterobacteriaceae, Lactobacillus spp., Bifidobacterium spp. Clostridium cluster XIV and other clostridial clusters, Clostridium difficile, Collinsella, Escherichia coli, Enterococcus spp., Faecalibacterium prausnitzii, Roseburia spp., Veillonella spp., and sulphate reducing bacteria. Bacterial quantification will be carried out with qPCR and/or with other relevant culture-independent methods. Analysis of the throat swab bacteria by qPCR will focus on particularly relevant bacterial groups, which may include, but are not limited to, Staphylococcus aureus, Pneumococcus spp. and Streptococcus spp. [0267] Antibiotic-resistant Escherichia coli: [0268] L. acidophilus NCFM and B. lactis Bi-07 and B. lactis BL-04:
[0269] Serum [0270] Natural killer cell activity [0271] Phagocytosis
[0272] Data Analysis
[0273] A practical approach to making an inference (conclusion) about the clinical and physiological effects of the probiotic treatments was used. This approach has been detailed in several articles (6). This approach is also consistent with the International Committee of Medical Journal Editors guidelines for assessing clinical trials. The merits of this approach to address some of the shortcomings of an approach based on hypothesis testing and statistical significance is well recognised. The approach is based on where the range in uncertainty in the true value of an effect falls in relation to thresholds for values that are clinically important. The uncertainty in the true value is the confidence interval. Because there are a large number of effects in this study, a conservative level of 99% was chosen for the confidence interval; in other words, there is a 99% chance that the true value of each effect falls within the confidence interval that is calculated for it from the data. When the confidence interval includes values that are substantial in some positive and negative sense, such as beneficial and harmful, the effect could be both beneficial and harmful, here it has been inferred that the effect is inconclusive or unclear. Otherwise it is inferred that the effect is clear, and the magnitude assigned to the effect is the observed magnitude, such as a beneficial, trivial or harmful difference.
[0274] The thresholds chosen as clinically important differ for the different kinds of outcome variable in the study. For variables such as the intensity of a symptom on a 3-point scale, the effect of the probiotic treatment was analyzed as a simple difference of the means: probiotic mean minus placebo mean. For this kind of effect the default thresholds are a positive and negative difference in the means equal to 0.20 of the pooled between-subject standard deviation in the two groups. This approach to smallest important effects is known as standardization, and provides thresholds for moderate, large and very large effects (0.60, 1.20 and 2.0 standard deviations). Other variables for which we chose magnitude thresholds in this manner were the number of medications taken per 100 days, the intensity of physical activity, the number of exercise days per week, total exercise hours per week, total activity load per week (sum of the product of exercise intensity and number of exercise days per week), and the variables in saliva samples that were measured for their potential role as mechanisms of any effect of the treatment. The measures of training hours and training load were log-transformed before analysis to permit the effect of the treatment to be properly analyzed as a percent, but magnitude of the effect was determined for the log-transformed variable. The saliva measures were also log transformed before analysis, but variability and effects for these variables were generally much larger than for the training variables and were therefore expressed as factors.
[0275] Magnitude thresholds for variables representing or involving the presence or count of a symptom had to be determined in a different manner, because use of a standard deviation for such variables is not appropriate. The variables in question were number of episodes of a given symptom per 100 days, total number of days of the symptom per 100 days, and total load of the symptom per 100 days (sum of the product of symptom intensity and number of days of the symptom per 100 days). The effect of the probiotic treatment on all these variables was analyzed as a ratio: the mean of the probiotic group divided by the mean of the placebo group. We regarded a ratio of 1.10 (that is, a 10% larger mean value of the variable in the probiotic group) as the threshold for a substantial increase. For statistical reasons, the threshold for a substantial decrease in the probiotic group was therefore a ratio of 1/1.2, or 0.83. These ratios are similar to the risk ratios for illness and injury in studies of public health, epidemiologists consider a risk ratio of 1.1-1.3 to represent substantial increase in risk. Unfortunately there is as yet no consensus about thresholds representing moderate, large and very large increases and decreases in risk.
[0276] The data from the “shoulder” periods defined as 2 weeks following the start and end of supplementation were analysed using a linear weighting factor to assign an appropriate proportion of the training and symptom scores to the baseline and full treatment periods. Thus, on the first day following the start of treatment, 13/14th of a subject's values were assigned to the baseline period and 1/14th was assigned to the treatment period. On the second day of the shoulder, the fractions were 12/14th and 2/14, and so on.
[0277] Data from the baseline was also taken into account. When baseline values are recorded, it is usual to adjust for differences between subjects at baseline by subtracting baseline scores from treatment scores. This strategy usually results in greater precision of the effect of a treatment than that provided by an analysis of the treatment scores alone, and it thereby permits the use of smaller sample sizes. However, it is not generally appreciated that adjusting for a baseline score in this manner results in better precision only when the variable being analyzed is reasonably reliable (that is, subjects' scores tend to be consistently different from each others' in pre and post treatment trials). In this study the symptom and training variables as treatment-only scores were analysed. It was clear that the effect of the treatment on symptoms was more precise for the treatment-only analysis, whereas the effect on training was more precise for the treatment-baseline changes: evidently the subjects' training was more reliable and well defined by the baseline monitoring than their illness symptoms. Therefore, the treatment-only analyses is presented for the symptoms and the treatment-baseline analyses for training. In making the decision about using treatment-only vs treatment-baseline analyses, examining the magnitude of the effect was deliberately avoided, focus was only on comparing the precision of the estimate of the effect of the treatment. The saliva variables have also been presented as treatment-baseline analyses.
[0278] Confidence limits for the symptom scores were estimated by an empirical method known as bootstrapping, because the usual analytical approaches involve assumptions that are difficult to justify for measures involving duration of the symptom. Bootstrapping was also used with the training measures. These analyses were performed using programs written in the Statistical Analysis System.
[0279] Treatments
[0280] Supplement Z contained a combined Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07—the dosage was 5×10.sup.9 CFU/day for each bacterium, therefore a total dosage of 10.sup.9 CFU/day.
[0281] Supplement X contained Bifidobacterium lactis BL-04—the dosage was 2×10.sup.9 CFU/day.
[0282] The placebo supplement Y contained sucrose.
[0283] Supplements Z and X were freeze dried bacteria mixed into a cold drink (no alcohol was to be consumed and the drink was not hot).
[0284] Results
[0285] A Consort Flow Chart is presented in
[0286] Subjects Details
[0287] Physical and Physiological Characteristics: Details of subject characteristics included for analysis are detailed in Table 1 for each of the groups. There were no substantial differences between the groups in gender, age or body mass index.
TABLE-US-00001 TABLE 1 Characteristics of the individuals included for analysis in each of the groups. Mean ± SD. Variable Group Sex Number Mean SD Min Max Age BL-04 female 65 39.2 11.1 19.3 61.2 Age Placebo female 66 37.2 12 19.5 64.4 Age BL-04 male 72 36 11.4 18.9 65.5 Age Placebo male 65 37.7 10.1 19 55.6 BMI BL-04 female 62 24.1 3.1 18.8 32.4 BMI Placebo female 63 23.5 3.4 17.4 32.6 BMI BL-04 male 68 24.8 2.9 14.2 31.6 BMI Placebo male 61 25.3 2.6 20.1 32.2 ExerciseHoursPerWk BL-04 female 29 9.6 5.6 2 25 ExerciseHoursPerWk Placebo female 34 7 3.4 3 16 ExerciseHoursPerWk BL-04 male 36 7.7 3.2 2.5 15.5 ExerciseHoursPerWk Placebo male 31 7.9 3 3.5 14
[0288] Compliance
[0289] Compliance details and the mean number of supplement days completed by participants in each group are detailed in Table 2.
TABLE-US-00002 TABLE 2 The degree of compliance and the mean number of supplement days completed by participants in each of the three treatment groups over the course of the study. Variable Group Sex Mean SD Min Max % sachets left BL-04 female 13.5 17.9 0 100 % sachets left Placebo female 11.6 12.7 0 55 % sachets left BL-04 male 7.3 12.1 0 75 % sachets left Placebo male 15.1 16.1 0 80 Supplement days (%) BL-04 female 95.7 5.8 70.6 100 Supplement days (%) Placebo female 94.4 7.5 71.8 100 Supplement days (%) BL-04 male 95.2 8.4 60.5 100 Supplement days (%) Placebo male 95 6.5 73.8 100
[0290] Adverse Effects
[0291] Four subjects experience diarrheoa and cramps at the onset of supplementation. Three of these subjects withdrew and the symptoms settled in the third. One subject withdrew due to headaches that started with supplementation, including after a break from taking the supplement assigned. One subject experienced urticaria after starting supplementation and withdrew. One subject experienced bowel pain after travelling to Asia. The date of travel coincided with taking the supplement and the subject withdrew.
[0292] Dietary Information
[0293] Dietary information regarding fibre intake in each of the treatment groups is in Table 3. There were no substantial differences between the groups in fibre serves.
TABLE-US-00003 TABLE 3 Number of standard serves of fibre per day by treatment group and gender at the midpoint (Mid), end of the study (End) and mean of both time points (Mean). Variable Treatment Sex N Nmiss Mean SD Min Max FiberServesPerDayMid BL-04 female 48 17 4.0 6.1 0.3 31.8 FiberServesPerDayMid BL-04 male 55 17 2.9 1.6 0.3 7.3 FiberServesPerDayMid Pla female 56 10 4.8 8.3 0.6 46.7 FiberServesPerDayMid Pla male 48 17 4.9 8.1 0.4 56.5 FiberServesPerDayEnd BL-04 female 52 13 3.3 4.5 0.2 32.4 FiberServesPerDayEnd BL-04 male 55 17 4.0 5.5 0.3 40.8 FiberServesPerDayEnd Pla female 56 10 4.4 6.4 0.3 40.8 FiberServesPerDayEnd Pla male 53 12 3.7 3.5 0.0 23.4 FiberServesPerDayMean BL-04 female 55 10 3.6 4.6 0.3 31.4 FiberServesPerDayMean BL-04 male 60 12 3.4 3.0 0.3 22.4 FiberServesPerDayMean Pla female 62 4 5.0 7.4 0.8 40.8 FiberServesPerDayMean Pla male 57 8 4.3 4.6 0.6 30.0 Pla-placebo;
[0294] Physical Activity Information
[0295] Participant training details by treatment group during the study are presented in Table 4. There were no substantial differences between the groups in physical activity patterns.
TABLE-US-00004 TABLE 4 Subject training during the study. Intensity scored on a 1-10 scale; Training load is the sum of the product of training intensity and training duration in arbitrary units. Variable Group Sex Number Mean SD Min Max Training intensity BL-04 female 65 5.7 1.4 1.8 8.6 Training intensity Placebo female 66 5.8 1.4 1.3 8.9 Training intensity BL-04 male 72 6.1 1.3 2.9 9 Training intensity Placebo male 65 6.1 1.1 2.6 8.5 TrainingDaysPerWeek BL-04 female 65 4.5 1.3 2.1 6.9 TrainingDaysPerWeek Placebo female 66 4.1 1.2 1.4 6.9 TrainingDaysPerWeek BL-04 male 72 3.9 1.3 1.6 6.3 TrainingDaysPerWeek Placebo male 65 4 1.4 0.6 6.9 TrainingHoursPerWeek BL-04 female 65 5.9 2.6 2 14.6 TrainingHoursPerWeek Placebo female 66 5.4 2.9 1.5 18.2 TrainingHoursPerWeek BL-04 male 72 5.9 3.7 1.5 24.2 TrainingHoursPerWeek Placebo male 65 5.7 4 1 19.5 TrainingLoadPerWeek BL-04 female 65 34 16 8.2 79.9 TrainingLoadPerWeek Placebo female 66 31.7 17.8 4.2 98.8 TrainingLoadPerWeek BL-04 male 72 35.2 19.8 4.9 119.2 TrainingLoadPerWeek Placebo male 65 33.7 21.9 6.3 119.3
[0296] Episodes of Illness
[0297] Upper Respiratory Tract Illness
[0298] The effect of probiotic supplementation on the number of episodes of respiratory tract illness of varying duration is at in Table 5a. B. lactis BL04 reduced the number of respiratory tract illnesses of longer duration.
[0299] Furthermore, this effect was more pronounced as episodes of illness became longer.
TABLE-US-00005 TABLE 5a The effect of probiotic treatment on symptoms of upper respiratory tract symptoms. Effect of probiotic Length Probiotic Placebo treatment of group group relative to placebo Clinical P- illness (Mean ± SD) (Mean ± SD) (Mean; 99% Cl) inference value 1 day 1.93 1.93 1.00 (0.74 to 1.72) Unclear 0.9 3 day 0.6 0.75 0.80 (0.52 to 1.21) Possible 0.16 ↓ 5 day 0.22 0.33 0.65 (0.33 to 1.29) Likely ↓ 0.11 7 day 0.09 0.16 0.54 (0.21 to 1.30) Likely ↓ 0.09
[0300] Chest infection (Lower respiratory tract infection)
[0301] The effect of B. lactis on chest infection is in Table 5b. Similar to the effects of B. lactis BL04 on URTI, supplementation reduced the number of episodes of chest infection that lasted for 5 days compared to episodes that lasted of shorter duration.
TABLE-US-00006 TABLE 5b The effect of probiotic treatment on symptoms of chest symptoms. Effect of Length Probiotic Placebo probiotic treatment of group group relative to placebo Clinical P- illness (Mean ± SD) (Mean ± SD) (Mean; 99% Cl) inference value 1 day 1.41 1.49 0.94 (0.67 to 1.33) Unclear 0.7 3 day 0.39 0.48 0.81 (0.48 to 1.38) Unclear 0.3 5 day 0.11 0.19 0.55 (0.24 to 1.27) Likely ↓ 0.06
[0302] Patterns of Illness
[0303] The difference in the frequency, duration, severity and combined load of upper respiratory illness between probiotic and placebo groups during the treatment period is shown in Table 6. There was a substantially lower illness load and duration in those taking BL-04 compared to placebo. On a gender basis these reductions were also more pronounced in females than in men.
TABLE-US-00007 TABLE 6 The effect of probiotic treatment on the number, duration, sever and combined load of respiratory tract infection. Observed values (mean ± SD) Effect of BL-04 vs Placebo BL-04 Placebo Mean; Cl Inference All # of episodes 1.93 ± 1.90 1.93 ± 1.90 Ratio 1.0; Unclear (/100 days) 0.74 to 1.34 Duration 2.9 ×/÷ 3.8 3.9 ×/÷ 3.4 Difference Possible ↓ (/100 days) (%) 25 −52 to 17 Severity 1.47 ± 0.42 1.48 ± 0.36 Difference Unclear (1-3 scale) −0.01 −0.15 to 0.12 Illness Load 4.1 ×/÷ 4.1 5.7 ×/÷ 5.7 Difference Possible ↓ (%) −27; −55 to 18 Females # of episodes 2.01 ± 1.96 2.28 ± 1.96 Ratio 0.88; Unclear (/100 days) 0.59 to 1.32 Duration 2.7 ×/÷ 4.6 3.0 ×/÷ 3.1 Difference Likely ↓ (/100 days) (%) −44; −71 to 10 Severity 1.43 ± 0.43 1.44 ± 0.45 Difference Unclear (1-3 scale) −0.01; −0.18 to 0.17 Illness Load 3.5 ×/÷ 5.2 6.3 ×/÷ 3.5 Difference Likely ↓ (%) −45; −73 to 14 Males # of episodes 1.84 ± 1.84 1.63 ± 1.69 Ratio 1.13; Unclear (/100 days) 0.74 to 1.72 Duration 3.4 ×/÷ 3.0 3.4 ×/÷ 3.4 Difference Unclear (/100 days) (%) −1; −46 to 83 Severity 1.51 ± 0.41 1.53 ± 0.61 Difference Unclear (1-3 scale) −0.02; −0.23 to 0.19 Illness Load 4.9 ×/÷ 3.3 5.1 ×/÷ 3.4 Difference Unclear (%) −4; −50 to 84
[0304] The difference in the frequency, duration, severity and combined load of chest illness (lower respiratory illness) between probiotic and placebo groups over the treatment period is shown in Table 7. There is a reduction in severity of chest infection symptoms in BL-04 compared to placebo.
TABLE-US-00008 TABLE 7 The effect of probiotic treatment on the number, duration, severity and combined load of Chest infection. Observed values (mean ± SD) Effect of BL-04 vs Placebo BL-04 Placebo Mean; Cl Inference All # of episodes 1.41 ± 1.62 1.49 ± 1.70 Ratio 0.94; Unclear (/100 days) 0.67 to 1.33 Duration 2.6 ×/÷ 2.9 2.8 ×/÷ 3.1 Difference (%) Unclear (/100 days) −9 −40 to 38 Severity 1.42 ± 0.42 1.51 ± 0.53 Difference Possible (1-3 scale) −0.09 ↓ −0.27 to 0.09 Illness Load 3.5 ×/÷ 3.2 4.0 ×/÷ 3.3 Difference (%) Unclear −12; 43 to 36 Females # of episodes 1.44 ± 1.66 1.80 ± 1.96 Ratio 0.80; Unclear (/100 days) 0.50 to 1.29 Duration 2.7 ×/÷ 2.7 3.0 ×/÷ 3.1 Difference (%) Unclear (/100 days) −11; −49 to 55 Severity 1.44 ± 0.43 1.46 ± 0.45 Difference Unclear (1-3 scale) −0.01; −0.24 to 0.21 Illness Load 3.8 ×/÷ 3.0 4.2 ×/÷ 3.3 Difference (%) Unclear −9.8; −50 to 63 Males # of episodes 1.37 ± 1.59 1.24 ± 1.48 Ratio 1.10; Unclear (/100 days) 0.68 to 1.81 Duration 2.5 ×/÷ 3.2 2.7 ×/÷ 3.2 Difference (%) Unclear (/100 days) −7; −50 to 74 Severity 1.40 ± 0.41 1.57 ± 0.61 Difference Unclear (1-3 scale) −0.17; −0.45 to 0.11 Illness Load 3.3 ×/÷ 3.5 3.9 ×/÷ 3.3 Difference (%) Unclear −14; −55 to 65
[0305] The difference in the frequency, duration, severity and combined load of medication usage between the groups over the treatment period is shown in Table 8. Briefly, participants on BL-04 had a substantially lower total number of medications and total days of medications compared to those on the placebo. When examined by gender the effect was maintained in the men but less so in women.
TABLE-US-00009 TABLE 8 The effect of probiotic treatment on the number, duration, severity and combined load of Medication episodes. Observed values (mean ± SD) Effect of BL-04 vs Placebo BL-04 Placebo Mean; Cl Inference All # of med 1.04 ± 1.27 1.19 ± 1.39 Ratio 0.88; Unclear episodes 0.62 to 1.25 (/100 days) Total days of 2.7/ ÷ 3.0 4.0 /÷3.0 Difference Likely small medications (%) −31; ↓ (/100days) −55 to 4.4 Mean #of 1.30 ± 0.56 1.28 ± 0.44 Difference Unclear medication 0.01; per episode −0.19 to 0.21 Total # of 3.4/ ÷ 3.4 5.0/ ÷ 3.3 Difference Likely ↓ medications (%) −32; −57 to 9 Females # of med 1.32 ± 1.50 1.43 ± 1.58 Ratio 1.08; Unclear episodes 0.67 to 1.73 (/100 days) Total days of 3.5/ ÷ 2.6 4.2/ ÷ 3.5 Difference Unclear medications (%) −15; (/100days) −54 to 58 Mean # of 1.32 ± 0.40 1.31 ± 0.35 Difference Unclear medication 0.01; per episode 0.21 to −0.20 Total # of 4.6/ ÷ 3.0 5.5/ ÷ 4.0 Difference Unclear medications (%) −16; −58 to 68 Males # of med 0.82 ± 1.08 0.99 ± 1.23 Ratio 0.83; Unclear episodes 0.49 to 1.40 (/100 days) Total days of 2.1/ ÷ 3.2 3.8/ ÷ 2.4 Difference Very likely medications (%) −44; ↓ (/100 days) −68 to −2 Mean # of 1.27 ± 0.69 1.25 ± 0.52 Difference Unclear medication 0.02; per episode −0.32 to 0.36 Total # of 2.5/ ÷ 3.5 4.5/ ÷ 2.6 Difference Likely ↓ medications (%) −44; −70 to 5
CONCLUSIONS
[0306] The results show that supplementing with B. lactis BL-04 elicited a substantial decrease in the number of upper and lower respiratory illnesses and a decrease in the severity and duration of URTI and lower respiratory tract symptoms.
[0307] Full Data Analysis
[0308] Interim data analysis at 99% confidence interval suggested that B. lactis BL-04 may be effective in preventing respiratory tract infections and reduce the need of medications associated with respiratory infections (see Tables 5a, 5b, 6, 7 and 8). The encouraging interim results warranted full data analysis, as shown below.
[0309] The full data analysis (n=399) was based on the determination of both clinical significance as well as statistical significance testing. The statistical significance was determined using the traditional 95% confidence intervals. For the clinical significance testing, the pre-defined threshold for clinical relevancy was set at 20% reduction of symptoms as compared to the placebo group.
[0310] As shown in Table 9, the treatment with B. lactis BI-04 reduced the symptoms of upper respiratory tract illness markedly. The reducing effect was stronger for the illnesses with longer duration, i.e. the more severe episodes of illness. The illnesses with duration of 7 days or more were reduced by 46% as compared to placebo. In all categories of illness duration (3 d, 5 d, and 7 day or more), the reduction was equal or more than the pre-defined cut-off value of clinical significance. Surprisingly, the effects of BL-04 on upper respiratory illness were stronger than for the combination of NCFM and Bi-07. This was particularly surprising because the BL-04 probiotic was administered at lower dose than the probiotic combination.
[0311] Both BL-04 and the combination of NCFM and Bi-07 were equally effective in reducing the lower respiratory chest infections (see Table 9). A separate analysis also showed that both the combined NCFM+Bi-07 as well as BL-04 as single strain had a significant reducing effect on the duration of the illness episodes.
TABLE-US-00010 TABLE 9 BI-04 vs NCFM + Bi07 vs Placebo (%) placebo Duration Mean; 95% Cl Mean; 95% Cl % reduction Rate ratios Upper respiratory tract illness 3 day 20% (−10 to 42%) 16% (−15 to 39%) 5 day 35% (−9 to 61%) 19% (−27 to 48%) 7 day 46% (−7 to 73%) 33% (−57 to 71%) Chest illness 3 day 19% (−21 to 44%) 33% (−17 to 49%) 5 day 45% (−4 to 71%) 53% (6 to 79%) Cold and flu medication usage 3 day 28% (0 to 49%) 33% (−7 to 45%) 5 day 45% (13 to 65%) 35% (−3 to 76%)
[0312] Table 9: The effect of probiotic supplements on the rate of upper and lower respiratory tract illnesses, and cold and flu medication usage, stratified by illness duration. Effects exceeding the pre-defined cut-off value of clinical significance (20% reduction) are marked in bold. The Bl-04 group had higher reduction of the illness rate vs placebo than the combined NCFM+Bi-07 group vs placebo.
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