Faecal Microbiota Transplantation for Patients With Diabetes Mellitus Type 1 and Severe Gastrointestinal Neuropathy

Study Overview
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Brief Summary
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A randomised, double-blinded and placebo-controlled intervention study. The study aim to evaluate the feasibility, safety and pilot-efficacy of faecal microbiota transplantation as a treatment of severe gastrointestinal neuropathy in patients with diabetes mellitus type 1.

Detailed Description
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Diabetes type 1 may cause damage to nerve cells in the gut causing neuropathy that leads to changes in gastric and intestinal motility. This change predisposes to an abnormal amounts and composition of bacteria in the gut, probably leading to uncontrollable diarrhea and severely impaired quality of life. Transferal of intestinal microbiota from a healthy donor to a patient is called faecal microbiota transplantation (FMT). FMT may potentially change the bacteria in the gut and reduce gastrointestinal symptoms. However, FMT may also have potential side effects, especially in persons with autonomic neuropathy and delayed transit through the gut.

Official Title
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Faecal Microbiota Transplantation for Patients With Diabetes Mellitus Type 1 and Severe Gastrointestinal Neuropathy: a Randomised, Double-blinded Safety and Pilot-efficacy Study

Conditions
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Faecal Microbiota Transplantation (FMT), Diabetes Mellitus, Type 1, Gastrointestinal Neuropathy

Intervention / Treatment
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* Other: Faecal microbiota transplantation (FMT) capsules
* Other: Placebo capsules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult (≥ 18 years old), male or female patients with DM1 for at least 5 years and average of or above 40 points in the questionnaire: Gastrointestinal syndrome rating scale - irritable bowel syndrome version (GSRS-IBS). Exclusion Criteria: Inability to understand Danish or the trial procedures Known or anticipated pregnancy Known severe renal insufficiency Antibiotic use in the prior 4 weeks Treatment with morphine Ongoing infection with Clostridioides difficile or pathogenic intestinal bacteria or parasites Known gastrointestinal disease or GI infection Patients diagnosed with intestinal stricture Patients with other known disorder that can cause gastroparesis Patients with planned MR scan within 4 weeks Patients with pacemaker/ICD Previous abdominal surgery Changes in medicine that affects the GI tract in the prior 4 weeks

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Crossover Assignment
Interventional Model Description: The study is a 8-week, randomised, double-blinded, placebo-controlled pilot trial of oral FMT versus placebo in patients with DM1 and severe GI neuropathy. The intervention period consists of a first 4 weeks where patients receive either FMT or placebo and a second 4 weeks where all patients receive FMT. The patients will undergo the investigations before and after each 4-week period.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Faecal microbiota transplantation (FMT)<br>Donor faeces is obtained from thoroughly screened healthy blood donors and processed in compliance with the European Tissue and Cells Directive. | Other: Faecal microbiota transplantation (FMT) capsules<br>* The faeces is minimally processed through a series of centrifugation steps and dispensed into double-coated, acid resistant enterocapsules. A single treatment includes approximately 22 capsules ( 50 grams of original donor faeces).<br>|
| Placebo Comparator: Placebo<br>Placebo capsules will be identical in terms of visual appearance, weight, and vials and number | Other: Placebo capsules<br>* The placebo capsules are produced from a suspension of 50% glycerol, 40% sterile saline and 10% food coloring in enterocapusles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse events of severity grade 2 or more assessed by CTCAE v5.0 during the first week after first intervention (FMT or placebo). | Patient-reported measures from the schedule of side effects and telephone call 1 week after each intervention. | One week after the first intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient-reported outcomes obtained from the bowel habit diary. | Stool consistency measured by the Bristol scale from 1(severe constipation) to 7 (severe diarrhea) | Each patient fills out the diary every day for one week at baseline, for one week starting at each day of the two interventions and for one week at the long term follow-up at week 26 | 
| Patient-reported outcomes obtained from the bowel habit diary. | Median number of bowel openings per 24 hours. | Each patient fills out the diary every day for one week at baseline, for one week starting at each day of the two interventions and for one week at the long term follow-up at week 26 | 
| Patient-reported outcomes obtained from the bowel habit diary. | Number of nightly bowel openings (from bedtime until morning). | Each patient fills out the diary every day for one week at baseline, for one week starting at each day of the two interventions and for one week at the long term follow-up at week 26 | 
| Patient-reported outcomes obtained from the bowel habit diary. | Number of episodes with involuntary defaecation. | Each patient fills out the diary every day for one week at baseline, for one week starting at each day of the two interventions and for one week at the long term follow-up at week 26 | 
| Patient-reported outcomes obtained from the bowel habit diary. | Glycemic control measured by patient reported use of insulin (IE). | Each patient fills out the diary every day for one week at baseline, for one week starting at each day of the two interventions and for one week at the long term follow-up at week 26 | 
| Patient-reported measures from the schedule of side effects and telephone call 1 week after each intervention. | Mild adverse events (grade 1) following FMT or placebo assessed by CTCAE v5.0. | One week after each intervention | 
| Patient-reported outcomes from questionnaires. | Change in Gastrointestinal syndrome rating scale - irritable bowel version questionnaire (GSRS-IBS) | at baseline and 4 weeks after each intervention period and at long term follow-up at week 26 | 
| Patient-reported outcomes from questionnaires. | Change in patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM) | at baseline and 4 weeks after each intervention period and at long term follow-up at week 26 | 
| Patient-reported outcomes from questionnaires. | Change in irritable bowel syndrome impact scale (IBS-IS) | at baseline and 4 weeks after each intervention period and at long term follow-up at week 26 | 
| Objective measures from the wireless motility capsule. | Transit time through the small intestine. | at baseline and 4 weeks after each intervention period | 
| Objective measures from the wireless motility capsule. | Colonic transit time. | at baseline and 4 weeks after each intervention period | 
| Objective measures from the wireless motility capsule. | pH drop from the small intestine to the colon. | at baseline and 4 weeks after each intervention period | 
| Objective measures from the low-dose CT scan. | Volume of the a) small intestine and b) the colon. Volume of gas in a) the small intestine and b) the colon. | at baseline and 4 weeks after the first intervention | 
| Objective measures from the breath test. | Rise in hydrogen PPM measured in breath test for small intestinal bacterial overgrowth. | at baseline and 4 weeks after the first intervention | 
| Microbiota analysis on faecal samples. | Alpha-diversity of faecal microbiota, 16S. Dysbiosis index. | at baseline and 4 weeks after each intervention period | 
| Microbiota analysis on faecal samples. | Dysbiosis index. | at baseline and 4 weeks after each intervention period | 
| Blood samples. | Glycemic control measured by HbA1C levels. | at baseline and 4 weeks after each intervention period |