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

Small Intestinal Bacterial Overgrowth Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05967871
• Other study ID #: 16581
• Status: Recruiting
• Phase: Phase 1
• Start date: March 11, 2024
• Est. completion date: November 2026

Study information

• Verified date: March 2024
• Source: McMaster Children's Hospital
• Contact: Nikhil Pai, MD
• Phone: 905-521-2100
• Email: pain[@]mcmaster.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: November 2026
• Est. primary completion date: November 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Small Intestinal Bacterial Overgrowth

Intervention

Biological:
• Fecal Microbiota Transplant
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.

Locations

Country	Name	City	State
Canada	McMaster Children's Hospital	Hamilton	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
McMaster Children's Hospital	The Hospital for Sick Children

Country where clinical trial is conducted

Canada, 

References & Publications (26)

Allegretti JR, Kassam Z, Chan WW. Small Intestinal Bacterial Overgrowth: Should Screening Be Included in the Pre-fecal Microbiota Transplantation Evaluation? Dig Dis Sci. 2018 Jan;63(1):193-197. doi: 10.1007/s10620-017-4864-8. Epub 2017 Nov 29. — View Citation

Bakker GJ, Nieuwdorp M. Fecal Microbiota Transplantation: Therapeutic Potential for a Multitude of Diseases beyond Clostridium difficile. Microbiol Spectr. 2017 Aug;5(4). doi: 10.1128/microbiolspec.BAD-0008-2017. — View Citation

Bulik-Sullivan EC, Roy S, Elliott RJ, Kassam Z, Lichtman SN, Carroll IM, Gulati AS. Intestinal Microbial and Metabolic Alterations Following Successful Fecal Microbiota Transplant for D-Lactic Acidosis. J Pediatr Gastroenterol Nutr. 2018 Oct;67(4):483-487. doi: 10.1097/MPG.0000000000002043. — View Citation

Cammarota G, Ianiro G, Tilg H, Rajilic-Stojanovic M, Kump P, Satokari R, Sokol H, Arkkila P, Pintus C, Hart A, Segal J, Aloi M, Masucci L, Molinaro A, Scaldaferri F, Gasbarrini G, Lopez-Sanroman A, Link A, de Groot P, de Vos WM, Hogenauer C, Malfertheiner P, Mattila E, Milosavljevic T, Nieuwdorp M, Sanguinetti M, Simren M, Gasbarrini A; European FMT Working Group. European consensus conference on faecal microbiota transplantation in clinical practice. Gut. 2017 Apr;66(4):569-580. doi: 10.1136/gutjnl-2016-313017. Epub 2017 Jan 13. — View Citation

Conover KR, Absah I, Ballal S, Brumbaugh D, Cho S, Cardenas MC, Knackstedt ED, Goyal A, Jensen MK, Kaplan JL, Kellermayer R, Kociolek LK, Michail S, Oliva-Hemker M, Reed AW, Weatherly M, Kahn SA, Nicholson MR. Fecal Microbiota Transplantation for Clostridioides difficile Infection in Immunocompromised Pediatric Patients. J Pediatr Gastroenterol Nutr. 2023 Apr 1;76(4):440-446. doi: 10.1097/MPG.0000000000003714. Epub 2023 Jan 31. — View Citation

Davidovics ZH, Michail S, Nicholson MR, Kociolek LK, Pai N, Hansen R, Schwerd T, Maspons A, Shamir R, Szajewska H, Thapar N, de Meij T, Mosca A, Vandenplas Y, Kahn SA, Kellermayer R; FMT Special Interest Group of the North American Society of Pediatric Gastroenterology Hepatology, Nutrition, the European Society for Pediatric Gastroenterology Hepatology, Nutrition. Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection and Other Conditions in Children: A Joint Position Paper From the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2019 Jan;68(1):130-143. doi: 10.1097/MPG.0000000000002205. — View Citation

Davidovics ZH, Vance K, Etienne N, Hyams JS. Fecal Transplantation Successfully Treats Recurrent D-Lactic Acidosis in a Child With Short Bowel Syndrome. JPEN J Parenter Enteral Nutr. 2017 Jul;41(5):896-897. doi: 10.1177/0148607115619931. Epub 2015 Nov 29. — View Citation

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Food and Drug Adminstration. Guidance for Industry: Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium Difficile Infection Not Responsive to Standard Therapies.; 2016.

Furuta K, Ishihara S, Sato S, Miyake T, Ishimura N, Koshino K, Tobita H, Moriyama I, Amano Y, Adachi K, Ohta A, Kinoshita Y. [Development and verification of the Izumo Scale, new questionnaire for quality of life assessment of patients with gastrointestinal symptoms]. Nihon Shokakibyo Gakkai Zasshi. 2009 Oct;106(10):1478-87. Japanese. — View Citation

Gu L, Ding C, Tian H, Yang B, Zhang X, Hua Y, Zhu Y, Gong J, Zhu W, Li J, Li N. Serial Frozen Fecal Microbiota Transplantation in the Treatment of Chronic Intestinal Pseudo-obstruction: A Preliminary Study. J Neurogastroenterol Motil. 2017 Apr 30;23(2):289-297. doi: 10.5056/jnm16074. — View Citation

Kang DW, Adams JB, Gregory AC, Borody T, Chittick L, Fasano A, Khoruts A, Geis E, Maldonado J, McDonough-Means S, Pollard EL, Roux S, Sadowsky MJ, Lipson KS, Sullivan MB, Caporaso JG, Krajmalnik-Brown R. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome. 2017 Jan 23;5(1):10. doi: 10.1186/s40168-016-0225-7. — View Citation

Kuehnbaum NL, Kormendi A, Britz-McKibbin P. Multisegment injection-capillary electrophoresis-mass spectrometry: a high-throughput platform for metabolomics with high data fidelity. Anal Chem. 2013 Nov 19;85(22):10664-9. doi: 10.1021/ac403171u. Epub 2013 Nov 6. — View Citation

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Maeda Y, Murakami T. Diagnosis by Microbial Culture, Breath Tests and Urinary Excretion Tests, and Treatments of Small Intestinal Bacterial Overgrowth. Antibiotics (Basel). 2023 Jan 28;12(2):263. doi: 10.3390/antibiotics12020263. — View Citation

McGrath KH, Pitt J, Bines JE. Small intestinal bacterial overgrowth in children with intestinal failure on home parenteral nutrition. JGH Open. 2019 Apr 4;3(5):394-399. doi: 10.1002/jgh3.12174. eCollection 2019 Oct. — View Citation

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Nicholson MR, Alexander E, Ballal S, Davidovics Z, Docktor M, Dole M, Gisser JM, Goyal A, Hourigan SK, Jensen MK, Kaplan JL, Kellermayer R, Kelsen JR, Kennedy MA, Khanna S, Knackstedt ED, Lentine J, Lewis JD, Michail S, Mitchell PD, Oliva-Hemker M, Patton T, Queliza K, Sidhu S, Solomon AB, Suskind DL, Weatherly M, Werlin S, de Zoeten EF, Kahn SA; North American Society of Pediatric Gastroenterology and Nutrition Faecal Microbiota Transplantation Special Interest Group. Efficacy and Outcomes of Faecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection in Children with Inflammatory Bowel Disease. J Crohns Colitis. 2022 Jun 24;16(5):768-777. doi: 10.1093/ecco-jcc/jjab202. Erratum In: J Crohns Colitis. 2023 Jan 04;: — View Citation

Nicholson MR, Mitchell PD, Alexander E, Ballal S, Bartlett M, Becker P, Davidovics Z, Docktor M, Dole M, Felix G, Gisser J, Hourigan SK, Jensen MK, Kaplan JL, Kelsen J, Kennedy M, Khanna S, Knackstedt E, Leier M, Lewis J, Lodarek A, Michail S, Oliva-Hemker M, Patton T, Queliza K, Russell GH, Singh N, Solomon A, Suskind DL, Werlin S, Kellermayer R, Kahn SA. Efficacy of Fecal Microbiota Transplantation for Clostridium difficile Infection in Children. Clin Gastroenterol Hepatol. 2020 Mar;18(3):612-619.e1. doi: 10.1016/j.cgh.2019.04.037. Epub 2019 Apr 19. — View Citation

Pai N, Popov J, Hill L, Hartung E, Grzywacz K, Moayyedi P; McMaster Pediatric Fecal Microbiota Transplant Research Collaboration. Results of the First Pilot Randomized Controlled Trial of Fecal Microbiota Transplant In Pediatric Ulcerative Colitis: Lessons, Limitations, and Future Prospects. Gastroenterology. 2021 Aug;161(2):388-393.e3. doi: 10.1053/j.gastro.2021.04.067. Epub 2021 May 4. No abstract available. — View Citation

Pai N, Popov J, Hill L, Hartung E. Protocol for a double-blind, randomised, placebo-controlled pilot study for assessing the feasibility and efficacy of faecal microbiota transplant in a paediatric Crohn's disease population: PediCRaFT Trial. BMJ Open. 2019 Nov 28;9(11):e030120. doi: 10.1136/bmjopen-2019-030120. — View Citation

Pai N, Popov J. Protocol for a randomised, placebo-controlled pilot study for assessing feasibility and efficacy of faecal microbiota transplantation in a paediatric ulcerative colitis population: PediFETCh trial. BMJ Open. 2017 Aug 21;7(8):e016698. doi: 10.1136/bmjopen-2017-016698. — View Citation

Podlesny D, Durdevic M, Paramsothy S, Kaakoush NO, Hogenauer C, Gorkiewicz G, Walter J, Fricke WF. Identification of clinical and ecological determinants of strain engraftment after fecal microbiota transplantation using metagenomics. Cell Rep Med. 2022 Aug 16;3(8):100711. doi: 10.1016/j.xcrm.2022.100711. Epub 2022 Aug 4. — View Citation

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* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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	Monthly Rate of Recruitment	Recruitment/month. =2 participants/month.	30 weeks
Secondary	Adverse Events	Adverse and serious events will be recorded using the Common Terminology Criteria for Adverse Events. <10% participants	30 Weeks
Secondary	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

External Links

•   US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE). Published 2017.