Randomised Placebo-controlled Study of FMT to Impact Body Weight and Glycemic Control in Obese Subjects With T2DM

Study Overview
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Brief Summary
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Faecal microbiota transplantation (FMT) represents a clinically feasible way to restore the gut microbial ecology, and has proven to be a breakthrough for the treatment of recurrent Clostridium difficile infection. Early results in human have shown that FMT from lean donor when transplanted into subjects with metabolic syndrome resulted in a significant improvement in insulin sensitivity and an increased in intestinal microbial diversity, including a distinct increase in butyrate-producing bacterial strains. The therapy is generally well tolerated and appeared safe. No clinical studies have assessed the efficacy of FMT in obese subjects with type 2 diabetes mellitus.

Detailed Description
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There is a worldwide epidemic of obesity and type 2 diabetes mellitus. The prevalence of obesity and type 2 diabetes mellitus continues to rise at an alarming rate. Weight loss is associated with reductions in risk of morbidity and mortality from obesity. Conventional non-pharmacological interventions based on diet and exercise showed limited long-term success in producing sustained weight loss. Although obese patients with type 2 diabetes mellitus may be treated by medications or by bariatric surgery, these alternatives are limited by incomplete resolution of the diseases, high cost or potential surgical-related morbidity. Further research focusing on increasing effectiveness of interventions and new ways to achieve weight loss in these individuals are needed. Recently, accumulating evidence supports a role of the enteric microbiota in the pathogenesis of obesity-related insulin resistance. Obesity is associated with changes in the composition of the intestinal microbiota, and the obese microbiome appears to be more efficient in harvesting energy from the diet. Colonization of germ-free mice with an 'obese microbiota' results in a significantly greater increase in total body fat than colonization with a 'lean microbiota', suggesting gut microbiota as an additional contributing factor to the pathophysiology of obesity. Obese and lean phenotypes can also be induced in germ-free mice by transfer of fecal microbiota from human donors. These data have led to the use of microbiota therapeutics as a potential treatment for metabolic syndrome and obesity. Clinical trials are being conducted to evaluate its use for other conditions. Early results in human have shown that FMT from lean donor when transplanted into subjects with metabolic syndrome resulted in a significant improvement in insulin sensitivity and an increased in intestinal microbial diversity, including a distinct increase in butyrate-producing bacterial strains. The therapy is generally well tolerated and appeared safe. No clinical studies have assessed the efficacy of FMT in obese subjects with type 2 diabetes mellitus. No clinical studies have assessed the efficacy of FMT in obese subjects with type 2 diabetes mellitus. A subgroup of 30 subjects will be analyzed at week 24. The difference and proportion in microbiome in different arms, microbial factors, and trans-kingdom correlation of microbial engraftment will be correlated with clinical data in an unblinded manner.

Official Title
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A Randomised Placebo-controlled Study of Fecal Microbiota Transplant (FMT) to Impact Body Weight and Glycemic Control in Obese Subjects With Type 2 Diabetes Mellitus

Conditions
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Type2 Diabetes, Type 2 Diabetes Mellitus, Obese

Intervention / Treatment
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* Procedure: Fecal Microbiota Transplantation
* Behavioral: Lifestyle Modification Program
* Procedure: Sham


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-70; and BMI >=28 kg/m2 and < 45 kg/m2; and A diagnosis of Type 2 diabetes mellitus for >=3 months; and Written informed consent obtained Exclusion Criteria: Current pregnancy Use of any weight loss medications in the preceding 1 year Known history or concomitant significant gastrointestinal disorders (including Inflammatory Bowel Disease, current colorectal cancer, current GI infection) Known history or concomitant significant food allergies Immunosuppressed subjects Known history of severe organ failure (including decompensated cirrhosis), inflammatory bowel disease, kidney failure, epilepsy, acquired immunodeficiency syndrome Current active sepsis Active malignant disease in recent 2 years Known contraindications to oesophago-gastro-duodenoscopy (OGD) Use of probiotic or antibiotics in recent 3 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FMT + LMP<br>FMT and lifestyle modification program | Procedure: Fecal Microbiota Transplantation<br>* FMT<br>Behavioral: Lifestyle Modification Program<br>* Lifestyle<br>|
| Experimental: FMT alone<br>Fecal Microbiota Transplantation | Procedure: Fecal Microbiota Transplantation<br>* FMT<br>|
| Sham Comparator: Sham + LMP<br>Sham and lifestyle modification program | Behavioral: Lifestyle Modification Program<br>* Lifestyle<br>Procedure: Sham<br>* Sham<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects with at least 20% lean-associated microbiota in recipients after FMT compared with subjects receiving lifestyle intervention alone up to week 24 | Proportion of subjects with at least 20% lean-associated microbiota in recipients after FMT compared with subjects receiving lifestyle intervention alone up to week 24. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in microbial composition (including bacteriome and virome), function and metabolite | Changes in microbial composition (including bacteriome and virome), function and metabolite at weeks 4, 16, 20 and 24 compared with baseline | 4, 16, 20, 24 week | 
| Changes in microbiome of stool (including bacteriome and virome) | Changes in microbiome of stool (including bacteriome and virome) at weeks 4, 16 and 24 compared with baseline | 4, 16, 24 week | 
| Difference in microbiome (including bacteriome and virome) compared between subjects in different treatment arm | Compare the difference in microbiome among different treatment arms | 24 week and 52 week | 
| Proportion of microbiome (including bacteriome and virome) derived from recipient, donor or both in subjects who received FMT | Proportion of microbiome (including bacteriome and virome) derived from recipient, donor or both in subjects who received FMT | weeks 4, 8, 12, 16, 20, 24 and 52 | 
| Difference in microbiome (including bacteriome and virome) compared between subjects who have weight loss and those do not have weight loss | Difference in microbiome (including bacteriome and virome) compared between subjects who have weight loss and those do not have weight loss | weeks 4, 8, 12, 16, 20, 24 and 52 | 
| Microbial factors (including bacteriome and virome) that are associated with percentage of body weight loss | Microbial factors (including bacteriome and virome) that are associated with percentage of body weight loss | weeks 4, 8, 12, 16, 20, 24 and 52 | 
| Trans-kingdom correlation of microbial engraftment | Trans-kingdom correlation of microbial engraftment after FMT between bacteriome, and virome | weeks 4, 8, 12, 16, 20, 24 and 52 | 
| Proportion of subjects with serious adverse events compared between treatment arm, especially those related to FMT | Proportion of subjects with serious adverse events compared between treatment arm, especially those related to FMT | weeks 4, 8, 12, 16, 20, 24 and 52 | 
| Explore changes in fungome microbiota | Explore changes in fungome microbiota | weeks 4, 8, 12, 16, 20, 24 and 52 | 
| Proportion of subjects achieving at least 10% reduction in weight compared with baseline | Proportion of subjects achieving at least 10% reduction in weight at 52 weeks | 52 weeks | 
| Proportion of subjects achieving at least 10% reduction in weight compared with baseline | Proportion of subjects achieving at least 10% reduction in weight at 24 weeks | 24 weeks | 
| Changes in body weight to calculate body mass index (BMI) at weeks 24 and 52 compared with baseline | Compare the change in weight to calculate the BMI among different treatment arms | 24 week and 52 week | 
| Changes in biochemical parameters | Changes in liver biochemistry, fasting glucose, fasting lipids, fasting insulin, HbA1C at weeks 24 and 52 compared with baseline | 24 week and 52 week | 
| A 30% decrease in insulin resistance at weeks 24 compared with baseline | A 30% decrease in insulin resistance at weeks 24 compared with baseline | week 24 | 
| Changes in liver stiffness to assess improvement of other metabolic disease weeks 24 compared with baseline | Changes in liver stiffness to assess improvement of other metabolic disease weeks 24 compared with baseline | week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fecal Microbiota Transplant