Tolerability and Risk of Adverse Events With a Probiotic Supplement

Study Overview
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Brief Summary
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The butyrate-producing bacterium Faecalibacterium prausnitzii is abundant in the human bowel and can make up to 5% of the gastrointestinal flora in healthy individuals. A reduced presence of it has been associated with an imbalance in the gastrointestinal flora of metabolic syndromes such as type 2 diabetes, fat liver, and in inflammatory bowel disease. The present double-blind, placebo-controlled, randomized study is designed to investigate if dietary supplementation with F.prausnitzii (combined with D. piger) once a day for 8 consecutive weeks is tolerated compared to placebo and if it can affect the metabolism in a positive way.

Detailed Description
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The understanding of the role of the gastrointestinal microbes for human health has gained considerable interest in recent years. The butyrate-producing bacterium Faecalibacterium prausnitzii is a naturally occurring bacterial species in the human gut that can make up to 5% of the gastrointestinal flora in healthy individuals. Several studies have shown that the presence of butyrate producing bacteria, including F. prausnitzii, is lower in patients with inflammatory bowel disease; Crohn's disease and ulcerative colitis. Furthermore, lower levels of short fatty acids have been found in people with ulcerative colitis as compared to healthy individuals. Similar results have been obtained from studies about Crohn's disease, where people with a low abundance of F. prausnitzii run a higher risk of post-operative recurrence of their disease. It has become evident that bacteria in the human gastrointestinal tract are symbiotic and dependent on each other's metabolism. Studies conducted by the sponsor (Metabogen AB) have shown that butyrate production from F. prausnitzii increases in the presence of Desulfovibrio piger, a common sulphate-reducing bacterium present in the human intestine. The symbiotic relationship between F. prausnitzii and D. piger can be utilised by combining these bacterial species into a probiotic dietary supplement, thus maintaining butyrate production in the intestine. In animal models, who received approximately 5,000 times higher doses per kilogram of body weight than the highest dose scheduled in the proposed study, the intake of F. prausnitzii has shown anti-inflammatory effects as well as positive effects on the metabolism. The present study is a double-blind, placebo-controlled, randomized, study in 48 healthy individuals (men and women) between 20 and 40 years old recruited from the general population. These volunteers will either receive F. prausnitzii and D. piger (in two different doses) or placebo orally once a day for 8 consecutive weeks. The investigators will assess how well treatment with the study product compared to placebo is tolerated (termination due to adverse events within 8 weeks of treatment) and if it can cause gastrointestinal symptoms (measured with The Gastrointestinal Symptom Rating Scale). The investigators will also assess if the intake of the study product can potentially give positive effects in the metabolism (blood glucose, fatty acids, protein ect).

Official Title
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Tolerability and Risk of Adverse Events With a Probiotic Supplement: A Randomised and Placebo Controlled Study in Healthy Individuals

Conditions
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Healthy Individuals

Intervention / Treatment
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* Dietary Supplement: Placebo
* Dietary Supplement: High dose F. prausnitzii and D. piger
* Dietary Supplement: Low dose F. prausnitzii and D. piger


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 20 to 40 years old Signed consent for participation Healthy individuals without any known diseases Willingness and ability to attend to planned visits, participate in telephone interviews and follow study instructions Understanding the Swedish language in spoken and written terms Exclusion Criteria: Ongoing treatment with prescription drugs Regular or sporadic intake of probiotic products (foods with probiotics are allowed) Treated with antibiotics during the last 3 months Pregnancy Have experienced gastrointestinal tract symptoms (during the last month), which could affect study participation, as deemed by study physician. Current tobacco use (smoking or snuff) Participation in another clinical study

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 40 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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>One capsule containing placebo (identical to the capsule with active product (F. prausnitzii and D. piger) in taste and appearance but without the active component) taken orally once a day (morning), one hour before breakfast on empty stomach, for 8 consecutive weeks. | Dietary Supplement: Placebo<br>* Dietary supplementation with placebo once a day for 8 consecutive weeks<br>|
| Active Comparator: High dose F. prausnitzii and D. piger<br>One capsule (containing F. prausnitzii and D. piger at a dose of 1E9-5x1E9 colony forming units per bacterial strain) taken orally once a day (morning), one hour before breakfast on empty stomach, for 8 consecutive weeks. | Dietary Supplement: High dose F. prausnitzii and D. piger<br>* Dietary supplementation with high dose F. prausnitzii and D. piger once a day for 8 consecutive weeks<br>|
| Active Comparator: Low dose F. prausnitzii and D. piger<br>One capsule (containing F. prausnitzii and D. piger at a dose of 1E8-5x1E8 colony forming units per bacterial strain) taken orally once a day (morning), one hour before breakfast on empty stomach, for 8 consecutive weeks. | Dietary Supplement: Low dose F. prausnitzii and D. piger<br>* Dietary supplementation with low dose F. prausnitzii and D. piger once a day for 8 consecutive weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability of the oral intake of F. prausnitzii and D. piger, defined as study discontinuation due to adverse events under 8 weeks of treatment. | How well treatment with the study product compared to placebo is tolerated, which is primarily defined as termination due to adverse events under 8 weeks of treatment. | 0-8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gastrointestinal side effects, measured using the Gastrointestinal Symptom Rating Scale (GSRS) | Gastrointestinal symptoms are measured with The Gastrointestinal Symptom Rating Scale (GSRS), which includes 15 items combined into five symptom clusters measuring 1) reflux, 2) abdominal pain, 3) indigestion, 4) diarrhoea and 5) constipation. GSRS has a seven-point graded Likert-type scale, in which 1 represents absence of troublesome symptoms and 7 represents very troublesome symptoms. The total score is derived from all subclasses, resulting in a score between 0 and 45. | 0-8 weeks | 
| Effects on inflammation - erythrocyte sedimentation rate (safety parameters ) | Change in erythrocyte sedimentation rate in blood. Significant change in erythrocyte sedimentation rate before and after the 8-week treatment period. | 0-8 weeks | 
| Effects on inflammation - CRP (safety parameters ) | Change in C-reactive protein (CRP) level in blood. Significant change in CRP before and after the 8-week treatment period. | 0-8 weeks | 
| Effect on hematopoiesis - red blood cells (safety parameters) | Changes in red blood cells count. Significant change in red blood cell count before and after the 8-week treatment period. | 0-8 weeks | 
| Effect on hematopoiesis - white blood cells (safety parameters) | Changes in white blood cells count. Significant change in white blood cells count before and after the 8-week treatment period. | 0-8 weeks | 
| Effect on hematopoiesis - platelets (safety parameters) | Changes in platelets count. Significant change in platelets count before and after the 8-week treatment period. | 0-8 weeks | 
| Effects on liver enzymes - ALAT (safety parameters) | Changes in liver enzyme ALAT (Alanine transaminase). Significant changes before baseline and after 8 weeks of treatment. | 0-8 weeks | 
| Effects on liver enzymes - ASAT (safety parameters) | Changes in liver enzyme ASAT (Aspartate transaminase). Significant changes before baseline and after 8 weeks of treatment. | 0-8 weeks | 
| Effects on liver enzymes - ALP (safety parameters) | Changes in liver enzyme, ALP (Alkaline phosphatase). Significant changes before baseline and after 8 weeks of treatment. | 0-8 weeks | 
| Effects on serum bilirubin (safety parameters) | Changes in serum bilirubin. Significant changes before baseline and after 8 weeks of treatment. | 0-8 weeks | 
| Effects on the blood glucose | Changes (in percent) in levels of fasting blood glucose and HbA1c before and after the 8 week treatment period. | 0-8 weeks | 
| Effects on abundance of short-chain fatty acids | Changes in short-chain fatty acids in stool from baseline to week 10. | 0-10 weeks | 
| Colonization with F. prausnitzii | Colonization of the intestine with the total amount of F. prausnitzii bacteria. Measured in stool. | 0-8 weeks | 
| Effect on renal function(safety parameter) | Change in calculated eGFR (Glomerular Filtration Rate, based on serum creatinine) | 0-8 weeks | 
| Effect on serum total protein (safety parameter) | Change in serum total protein | 0-8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Faecalibacterium prausnitzii, Desulfovibrio piger, tolerability, blood glucose levels