The Efficacy of a Probiotic for Antibiotic Associated Gastrointestinal Symptoms

Study Overview
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Brief Summary
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This study evaluates the effect of a multistrain probiotic on gastrointestinal (GI) complaints and diarrhoea in subjects receiving short-term antibiotic (AB) treatment

Detailed Description
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This study aims to investigate the safety and efficacy of live bacteria on gastrointestinal (GI) complaints and diarrhoea in subjects receiving short-term antibiotic (AB) treatment. The trial will be run in Germany and will recruit adult men and women.

Official Title
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A Pilot Clinical Trial Assessing the Effect of Probiotic Supplementation on Antibiotic Associated Gastrointestinal Symptoms and Quality of Life

Conditions
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Antibiotic-associated Diarrhea

Intervention / Treatment
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* Dietary Supplement: Probiotic
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females ≥ 18 years and ≤65 years old Body Mass Index 18.5-30 kg/m2 Generally in good health Use of broad spectrum orally administered AB(s) for no more than 24h prior to V1 (penicillins, cephalosporins, quinolones, tetracyclines and lincomycins) for diagnosed infections other than those of GI, urinary or reproductive tract not requiring hospitalization, with a foreseen total duration of AB intake of 5-7 days Having access to a smartphone/tablet or a computer with an internet access, and familiar with the use thereof (checked during the visit) Readiness to keep dietary habits during the study Readiness to avoid the use of any nutritional (e. g. prebiotic, probiotic), medical and further interventional options for management of GI complaints/diarrhoea (beyond the IP) during the study Women of childbearing potential: commitment to use contraception methods negative pregnancy testing (beta human chorionic gonadotropin test in urine) at V1 Exclusion Criteria: More than 24h from the first dose of AB for diagnosed infections (as per inclusion criterion 4) until screening Intravenously administered antibiotics Taking AB in the last 30 days before starting current AB treatment Taking any probiotic or prebiotic supplements in the last 30 days prior to screening Using antidiarrheal medications / enemas on regular basis Multimedication with microbiome-impacting medications within 30 days before enrolment (e.g. proton pump inhibitors antivirals/immunosuppressants, antidepressants) Clinically relevant (as per investigator judgement) self-reported chronic diseases of GI tract (e.g. inflammatory bowel syndrome, Crohn's disease, ulcerative colitis, celiac disease, diverticulitis, idiopathic esophageal reflux, malabsorption disorder, severe constipation), urinary tract, reproductive tract (e.g. endometriosis, adenomyosis, pelvic inflammatory disease, uterine fibroids) or metabolic (diabetes (type 1 or Type 2), familial hypercholestraemia, hereditary haemachromatosis) diseases Any form of bowel preparation for endoscopy used in the last 3 months Recent GI surgery (within the last 6 months) Women of child-bearing potential: pregnancy, recently gave birth (within the last 6 months) and/or nursing Recent Covid-19 infection (less than 4 weeks since the first negative SARS-CoV-2 (self) test after the infection) Specific dietary restrictions (e.g. active phase of low Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols (FODMAP) diet) Any dietary mode excluding passage of food via GI tract High intake of alcohol (male subjects > 14 units per week, female subjects, >11 (1 unit corresponds to 360 mL beer, 45 mL spirits (40% alcohol) or 150 mL wine) History of confirmed Clostridium difficile infection in the last 6 months Known allergy or hypersensitivity to any ingredients of the IP Previous adverse reactions to antibiotics Artificial or damaged heart valves History and/or presence of other clinically significant known (self-reported) condition/ disorder, which per investigator's judgement could interfere with the results of the study or the safety of the subject, e.g.: acute pancreatitis immunodeficiency eating disorder recurrent diarrhoea History of or current abuse of drugs or medication Inability to comply with study requirements Subjects who are deprived of their freedom by administrative or legal decision or who are in guardianship Participation in another clinical study in the 30 days prior to V1 and during the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Probiotic<br>Participants in this arm will receive a daily dose of 2x10^9 Colony Forming Units (CFU) of a multi strain probiotic (live bacterium), corresponding to 2 capsules twice daily, for the duration of antibiotic therapy, and 14 days thereafter. | Dietary Supplement: Probiotic<br>* Participants in this arm will receive a daily dose of 2x10^9 Colony Forming Units (CFU) of a multi strain probiotic (live bacterium), corresponding to 2 capsules twice daily, for the duration of antibiotic therapy, and 14 days thereafter.<br>|
| Placebo Comparator: Placebo<br>Participants in this arm will receive an equivalent placebo for the duration of antibiotic therapy, and 14 day thereafter. | Dietary Supplement: Placebo<br>* Participants in this arm will receive an equivalent placebo for for the duration of antibiotic therapy, and 14 day thereafter.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Gastrointestinal Symptom Rating Score - Irritable Bowel Syndrome (GSRS-IBS) | Change in Gastrointestinal Symptom Rating Score - Irritable Bowel Syndrome total score (max 78) from baseline (V1) to Day 6 - 11 (V2), where higher scores mean worse symptoms | Baseline (V1), Day 6 - 11 (V2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in the Gastrointestinal Symptom Rating Score - Irritable Bowel Syndrome (GSRS-IBS) | Difference in Gastrointestinal Symptom Rating Score - Irritable Bowel Syndrome (GSRS-IBS) total score (max 78) between day 6 - 11 (V2) and day 20 - 25 (V3), where higher scores mean worse symptoms | Day 6 - 11 (V2), Day 20 - 25 (V3) | 
| Difference in the Gastrointestinal Symptom Rating Score - Irritable Bowel Syndrome (GSRS-IBS) | Difference in Gastrointestinal Symptom Rating Score - Irritable Bowel Syndrome (GSRS-IBS) total score (max 78) from baseline (V1) to day 20 - 25 (V3) between intervention and placebo, where higher scores mean worse symptoms | Baseline (V1), Day 20 - 25 (V3) | 
| Incidence of antibiotic-associated diarrhoea (AAD) | Total incidence rate of antibiotic-associated diarrhoea (AAD) between intervention and placebo, defined as 2 or more days with a stool frequency of 3 or more a day and/or a stool consistency of 5 or more on the Bristol Stool Form Scale (BSFS), throughout the period between baseline (V1) and Day 20 - 25 (V3). The BSFS max score is 7, where lower scores indicate constipation and higher scores indicate diarrhoea | Through study completion, an expected average of 21 days | 
| Duration of antibiotic associated diarrhoea (AAD) | Difference in the average continuous days of antibiotic associated diarrhoea (defined as 2 or more days with a stool frequency of 3 or more a day and/or a stool consistency of 5 or more on the Bristol Stool Form Scale (BSFS)) in the intervention and placebo arms between baseline (V1) and day 20 - 25 (V3). The BSFS max score is 7, lower scores indicate constipation and higher scores indicate diarrhoea. | Through study completion, an expected average of 21 days | 
| Difference in individual scores of Gastrointestinal Symptom Rating Score - Irritable Bowel Syndrome (GSRS-IBS) | Difference in average individual Gastrointestinal Symptom Rating Score - Irritable Bowel Syndrome scores (max 7) from Day 6 - 11 (V2) to Day 20 - 25 (V3) where higher scores mean worse symptoms | Day 6 - 11 (V2), Day 20 - 25 (V3) | 
| Difference in individual scores of Gastrointestinal Symptom Rating Score - Irritable Bowel Syndrome (GSRS-IBS) | Difference in average individual Gastrointestinal Symptom Rating Score - Irritable Bowel Syndrome (GSRS-IBS) scores (max 7) from Baseline (V1) to Day 6 - 11 (V2), and from Baseline (V1) to Day 20 - 25 (V3) where higher scores mean worse symptoms | Baseline (V1), Day 6 - 11 (V2), Day 20 - 25 (V3) | 
| Difference in Stool Consistency | Difference in weekly stool consistency, as measured by the Bristol Stool Form Scale (BSFS) on a daily basis throughout the period between baseline (V1) and Day 20 - 25 (V3). BSFS max score 7 - lower scores indicate constipation, higher scores indicate diarrhea. | Through study completion, an expected average of 21 days | 
| Difference in Stool Frequency | Difference in weekly average stool frequency throughout the period between baseline (V1) and day 20 - 25 (V3). | Through study completion, an expected average of 21 days | 
| Percentage with diarrhoea | Percentage of participants who have developed diarrhoea (defined as proportion of subjects with stool classified on the Bristol Stool Form Scale (BSFS) as 5-7) throughout the period between baseline (V1) and day 20 - 25 (V3). BSFS max score is 7 - lower scores indicate constipation, higher scores indicate diarrhoea. | Through study completion, an expected average of 21 days | 
| Duration of diarrhoea | Duration of diarrhoea (defined as proportion of subjects with Bristol Stool Form Scale (BSFS) of 5-7/day) throughout the period between baseline (V1) and day 20 - 25 (V3). BSFS max score is 7 - lower scores indicate constipation, higher scores indicate diarrhoea. | Through study completion, an expected average of 21 days | 
| Metabolomic Analysis of Faecal Samples | Targeted metabolomic analysis of faecal samples using liquid chromatography - mass spectrometry (LC-MS) for differences between baseline (V1), Day 6 - 11 (V2) and Day 20 - 25 (V3) including, but not restricted to succinate | Baseline (V1), Day 6 - 11 (V2), Day 20 - 25 (V3) | 
| Difference in Short Form 12 (SF-12) - Mental Component Score | Difference in Short Form-12 (SF-12) mental component score at Day 6 - 11 (V2) and Day 20 - 25 (V3). Higher scores indicate better mental health functioning (max score 100) | Day 6 - 11 (V2), Day 20 - 25 (V3) | 
| Difference in Short Form 12 (SF-12) - Physical Component Score | Difference in Short Form-12 (SF-12) physical component score at Day 6 - 11 (V2) and Day 20 - 25 (V3). Higher scores indicate better physical health (max score 100) | Day 6 - 11 (V2), Day 20 - 25 (V3) | 
| Difference in Short Form 12 (SF-12) - Mental Component Score (MCS) | Difference in Short Form-12 (SF-12) mental component score (MCS) from baseline (V1) to Day 6 - 11 (V2) and baseline (V1) to Day 20 - 25 (V3). Higher scores indicate better mental health (max score 100) | Baseline (V1), Day 6 - 11 (V2), Day 20 - 25 (V3) | 
| Difference in Short Form 12 (SF-12) - Physical Component Score (PCS) | Difference in Short Form-12 (SF-12) physical component score (PCS) from baseline (V1) to Day 6 - 11 (V2) and baseline (V1) to Day 20 - 25 (V3). Higher scores indicate better physical health (max score 100) | Baseline (V1), Day 6 - 11 (V2), Day 20 - 25 (V3) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Probiotic, Antibiotic-associated Diarrhea, GI microbiome, Lactobacillus, Bifidobacterium