Pilot Feasibility Study of Fecal Microbiota Transplant for the Treatment of Small Intestinal Bacterial Overgrowth

Study Overview
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Brief Summary
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The objective of the study is to assess feasibility, and clinical efficacy of a novel Fecal Microbiota Transplantation protocol for the treatment of pediatric small intestinal bacterial overgrowth (SIBO).

Detailed Description
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BACKGROUND AND RATIONALE Fecal microbiota transplant (FMT) is an established treatment for the management of recurrent Clostridioides difficile (CDI) infection in children and adults, including children with underlying immunodeficiency syndromes and extensive surgical resection. While CDI is the most common indication for FMT, this intervention has also been studied for Crohn's disease, ulcerative colitis, autism, and small intestinal bacterial overgrowth (SIBO). SIBO is a disorder in which the small bowel is colonized by excessive aerobic and anaerobic microbes normally present in the colon. This condition may cause malabsorption, bloating, bloodstream infections (BSI), and D-lactic acidosis (DLA). Treatment traditionally involves broad-spectrum antibiotic use yet this approach may promote persistent dysbiosis, multidrug resistant organisms (MDROs), and often lacks clinical efficacy. Patients with short bowel syndrome (SBS), which involves intestinal resection, dysmotility, and altered enteral feeding are at highest risk for SIBO. Pediatric SBS SIBO patients face significant impacts on quality of life, and higher rates of bacteremia and liver disease. Specific Aims i. To determine the feasibility, and safety of administering an FMT based treatment to pediatric SBS patients with SIBO. This aim will include measures of adverse events, acceptability to children and parents, ease of administration and sample collection. ii. To determine short-term clinical efficacy of FMT for the treatment of SIBO. This aim will include measures of time to symptom resolution, completeness of symptom resolution, change in enteral feeding tolerance, and development of any new clinical gastrointestinal symptoms after FMT. Weeks 1-4 after FMT. iii. To determine long-term clinical efficacy of FMT for the treatment of SIBO. This aim will include measures of durability of remission, including time to recurrence of symptom resolution, severity of clinical symptoms if recurrence, sustained changes in feeding tolerance, and efficacy of repeat FMT administration (second treatment). Week 8 after FMT. iv. To assess changes in intestinal microbial composition and function before and after FMT. This aim will attempt to identify functional changes in the intestinal microbiome that correlate with symptom resolution. These data will support future translational and clinical studies with our collaborators and support the development of new therapeutic innovations. D. TRIAL OBJECTIVES Our objectives are to assess feasibility, and clinical efficacy of this intervention in children (Table 2). Feasibility Objectives: Acceptability of this intervention for patients and families, ability of patients and families to conduct the required screening to monitor efficacy and recruitment rate of patients to the study. Clinical Objectives: Clinical efficacy of treating SIBO in our patient population using FMT. These outcomes will be collected at the following timepoints: baseline (pre-FMT), one-, four-, and eight-weeks post-FMT administration E. STUDY DESIGN AND DURATION We will recruit 5-17-year-old patients with intestinal resection (any length), experiencing an active episode of SIBO (diagnosed through lactose breath testing and gastrointestinal symptom scores). Patients will discontinue antibiotics for >1 week prior to FMT. FMT infusions will be administered through patients' enteral tubes (nasogastric, gastrostomy, jejunostomy), or via endoscopy (duodenal infusion). Patients will receive a single FMT (Week 0). They will then have outcomes (including a combination of clinical symptom scores, blood, stool and urine testing) measured one week after FMT, four weeks after FMT, and eight weeks after FMT. As this is an open-label trial, there will be no randomization or blinding required. A placebo / comparative treatment will not be assessed. All FMT treatments will be conducted at MCH, using local pediatric stool bank materials. Patients will have follow-up monitoring, per protocol through their local institution (MCH/HSC). Serial measurements of biological, clinical and microbial outcomes will occur, per protocol.

Official Title
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Pilot Feasibility Study of Fecal Microbiota Transplant for the Treatment of Small Intestinal Bacterial Overgrowth

Conditions
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Small Intestinal Bacterial Overgrowth

Intervention / Treatment
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* Biological: Fecal Microbiota Transplant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 3-18 years old Patients will discontinue antibiotics for at least 1 week prior to FMT A diagnosis of SIBO established through lactose breath test (LBT), and showing of symptoms of SIBO Exclusion Criteria: Participants will not be permitted to start any new treatments (including antibiotics, probiotics, antacid treatments, or antimotility treatments) until Week 8, unless clinically indicated We will exclude participants <3yo to avoid potential concerns of microbial transmission in young children, and to ensure participants are developmentally able to perform LBT

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fecal Microbiota Transpant<br>Participants will receive a Fecal Microbiota transplant Infusion via participants' existing enteral feeding tubes or via elective upper endoscopy (with infusion into the duodenum). Most patients with SBS at MCH and HSC have an existing enteral feeding tube (gastrostomy or jejunostomy tube). | Biological: Fecal Microbiota Transplant<br>* Participants will receive approximately 50 grams of human stool/150mL (approximately 107 microbes/mL of suspension) in saline, prepared as per standard collection, preparation, and screening protocols for FMT infusion developed by our institutional stool bank in accordance with recognized standards. Fecal microbiota transplant infused via existing enteral feeding tube or upper elective endoscopy (with infusion into the duodenum) x1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Clinical Symptoms (pre/post fecal microbiota transplant) | SIBO Clinical Symptom Scores will be measured using the PedsQL Gastrointestinal Symptoms Scale. This validated instrument has strong age-specific test-retest properties and has been used for functional GI disorders, which have symptoms that strongly overlap with SIBO. Participants will also report symptoms using a Likert scale (Izumo scale). Results of both will be compared. | Baseline (pre-fecal microbiota transplant), one-, four-, and eight-weeks post-fecal microbiota transplant administration. | 
| Rate of Clinical Remission (post fecal microbiota transplant) | Absence of SIBO symptoms | Baseline (pre-fecal microbiota transplant), one-, four-, and eight-weeks post-fecal microbiota transplant administration. | 
| Urine Metabolomics Analysis | Collected urine will be assessed by multisegment injection-capillary electrophoresis-mass spectrometry (MSI-CE-MS), using previously described protocols. This technique will offer additional data on microbiome functional changes. Samples will be measured centrally through the Britz-McKibbin laboratory (PBM). Urine metabolomics outcomes are exploratory. | Baseline (pre-fecal microbiota transplant), one-, four-, and eight-weeks post-fecal microbiota transplant administration. | 
| Change in Microbiome Composition, Function (pre/post fecal microbiota transplant) | Stool will be collected for microbiome 16S rRNA and shotgun metagenomic sequencing. Samples will be obtained from either stool (per rectum), or distal ostomy outputs (ostomy in continuity with proximal bowel). All samples will be sequenced centrally through the McMaster Genomics Centre (MGC). Samples will be stored in -80 freezers. Participants unable to bring stool samples to MCH or HSC will receive funding support for temperature-controlled courier services from home. Costs of microbiome analyses will be partially subsidized by collaborators (MS). | Baseline (pre-fecal microbiota transplant), one-, four-, and eight-weeks post-fecal microbiota transplant administration. | 
| Change in Breath Test Results (pre/post fecal microbiota transplant) | Lactulose breath test | Baseline (pre-fecal microbiota transplant), one-, four-, and eight-weeks post-fecal microbiota transplant administration. | 
| Bloodwork | Bloodwork will include complete blood count (CBC), C-reactive protein (CRP), ferritin, folic acid, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), serum cytokine profiles (including IL-2, IL-6, IL10, IL-18, TNF) and serum bile acids. Routine institutional testing protocols will be followed at MCH and HSC. Bloodwork outcomes are exploratory. Data will support the development of primary and secondary objectives for future studies. | Baseline and Week 8 (post-FMT) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Monthly Rate of Recruitment | Recruitment/month. ≥2 participants/month. | 30 weeks | 
| Adverse Events | Adverse and serious events will be recorded using the Common Terminology Criteria for Adverse Events. <10% participants | 30 Weeks | 
| Blood, stool specimens, breath tests, clinical symptom scores | Participant provides all required blood, stool, lactulose breath tests, and symptom scores per protocol. >80% participants | 30 Weeks |