PediCRaFT: Pediatric Crohn's Disease Fecal Transplant Trial (PediCRaFT)

October 17, 2023 updated by: Nikhil Pai, McMaster Children's Hospital

PediCRaFT: Pediatric Crohn's Disease Fecal Microbiota Transplant Pilot Study

The objective of this study is to assess the feasibility of a novel colonic and oral fecal microbiota transplantation protocol for the treatment of active pediatric Crohn's disease (CD). Specifically, we will test the hypothesis that a protocol of combination fecal microbiota colonoscopic infusion and oral microbiota capsules (OMC), using live fecal material from anonymous unrelated donors, can improve the disease activity of pediatric CD patients.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Several recent studies have assessed the role of fecal microbiota transplantation (FMT) in the treatment of inflammatory bowel disease (IBD). IBD is a chronic autoimmune gastrointestinal disorder that has been associated with disease-specific microbial signatures in the host. The vast majority of literature on the therapeutic role of FMT has assessed its role in the treatment of acute Clostridium difficile colitis, but its effectiveness at treating this disease condition suggests a central role of the microbiome in host immune tolerance.

A. Alterations in the IBD Microbiome Investigators have characterized specific alterations of the gut microbiota in ulcerative colitis and Crohn's disease, compared to healthy controls. Patients with active IBD may have a relative depletion in anaerobic microbes, such as Bacteroides vulgatus, Lachnospiraceae (p: Firmicutes), and an increase in Proteobacteria and Bacillus (p: Firmicutes). These microbial signatures of IBD have led to several hypotheses about the protective, and pathological roles of different resident intestinal bacterial species. Conte et al have suggested that B. vulgatus may have a protective role against colitis, downregulating inflammation. Other studies have suggested that dysbiosis in IBD leads to decreased production of key short-chain fatty acids, such as butyric acid metabolized by Faecalibacterium prausnitzii. Directly, butyric acid and other short-chain fatty acids are key substrates absorbed by colonocytes, and indirectly, butyrate may inhibit inflammatory processes in the intestinal mucosa by suppressing cytokines, like interleukin-8. These studies have attempted to define canonical "intestinal-microbial-immune axes," supporting the hypothesis that IBD may occur secondary to an altered microbiome in a genetically, immunologically susceptible host. This constant host-microbial cross-talk may thus be altered by the introduction of key bacterial species that are otherwise absent, or decreased as a consequence of active mucosal inflammation, in the IBD gut. While FMT would not provide targeted, species-specific inoculations, whole stool transplant would theoretically introduce a broad range of bacteria, including those that are theoretically "favorable" to the host.

B. The Pediatric Microbiome Pediatric IBD, and the pediatric microbiome, have several unique features that suggest microbial-based therapies could be particularly effective. Crohn's disease and ulcerative colitis typically have a much more aggressive course in the pediatric age group, suggesting that the pediatric IBD phenotype may have a pathophysiology that is distinct from adult-onset IBD. In pediatric IBD, the early age of onset makes the cumulative burden of medications, nutritional impairment, and surgery greater. Several standard IBD medication therapies have unique, age-specific toxicities in children. The overlap of pediatric chronic disease with critical periods of growth, bone accretion, and psychosocial development can make disease exacerbations disproportionately affect a child's long-term outcome. The pediatric microbiome itself has key differences. The shorter latency of disease may offer a unique window to reverse an underlying state of "dysbiosis." The pediatric microbiome may be more malleable than a fully defined adult microbiome, and the relatively immature immune system of children may be more influenced by FMT.

C. FMT for the Treatment of Pediatric IBD Four case series have been published for the treatment of pediatric ulcerative colitis (UC) and CD using FMT. Protocols varied between all studies, and three main routes of administration were used: serial enemas, serial enemas with supplementary colonoscopic administration, and nasogastric tube. The first published study, involved five enemas administered daily to 9 UC patients, ages 7-21. Outcomes included clinical improvement from baseline using Pediatric Ulcerative Colitis Activity Index (PUCAI) scores, at one-week, and one-month post-treatment. 6/9 patients maintained clinical response at their one-month follow-up assessment. In 2015, two case series of FMT for CD and UC patients were published. A single FMT infusion was administered via nasogastric tube (NGT) to 4 UC, and 9 CD patients. No clinical response was seen in UC through NGT administration. In contrast, remission was induced in 7/9 CD patients within 2-weeks post-treatment, with 5/9 maintaining remission at week 6 and week 12. The most recent pediatric case series from 2015 included a cohort of pediatric UC patients treated with oral 5-ASA monotherapy, who received a combination of serial FMT enemas and colonoscopic infusions. 3 patients were included; 100% went into clinical remission at week 2, sustained clinical remission at week 4, and had complete withdrawal of immunotherapy at time of publication. Within the limitations of this small case series, there was a correlation between the number of FMT administrations, and the duration of remission.

Two single-center pediatric case reports have recently been published showing marked clinical improvement in two patients with severe colitis. A 2015 case report describes a 4-month old female presenting with an early-onset colitis with UC-like phenotype. The patient was refractory to treatment with azathioprine and corticosteroids, and did not respond to further treatment with probiotics, a trial of amino-acid based formula, or infliximab. 2 serial FMT infusions with anonymous donor stool were administered via colonoscope, and a subsequent 5 infusions via nasoduodenal tube. These interventions led to clinical improvement, and complete resolution of histopathologic changes 6-months post FMT. A recent, 2016 case report describes an 11-year old female with corticosteroid-dependent UC who was unresponsive to treatment with 5-aminosalicylic acid and tacrolimus14. An initial FMT using her father's donor stool was performed via colonoscopy, and subsequent daily FMTs via fecal retention enema over the next 4 days, followed by 11 additional FMTs via retention enema every 2 to 4 weeks over 10 months. The patient remained in clinical remission at 40 weeks post final FMT, and showed complete endoscopic healing.

D. Clinical Observations from Published Pediatric IBD FMT Studies Despite promising results, major drawbacks to these four pediatric studies include small sample sizes and their open label study design. Studies of clinical response demand a blinded study protocol, particularly given that many patients who enrol in FMT studies are a self-selected group, who already believe in the therapeutic value of "natural" treatments. Further, inflammatory bowel disease has well-described associations between clinical symptoms, mucosal disease activity and underlying stressors; thus, patient bias may have a significant influence on self-reported PUCAI/PCDAI (Pediatric Crohn's Disease Activity Index) scores when measuring clinical response. In addition, it is also important to note that success of FMT for IBD reflected in the aforementioned studies may reflect a propensity for studies with positive results to be published and unreported, unsuccessful studies may exist.

Study Type

Interventional

Enrollment (Actual)

17

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Nikhil Pai, BSc, MD
  • Phone Number: 75637 9055212100
  • Email: pain@mcmaster.ca

Study Locations

  • Canada
    • Ontario
      • Hamilton, Ontario, Canada, M8V1A4
        • McMaster Children's Hospital
    • Quebec
      • Montréal, Quebec, Canada, H3T 1C5
        • Centre Hospitalier Universitaire Sainte-Justine, University of Montreal

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

3 years to 17 years (Child)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Pediatric patients
  • ≥3yo
  • Crohn's disease, or IBD-Unclassified favoring Crohn's disease (as deemed by the patient's primary pediatric gastroenterologist)
  • Active symptoms

Exclusion Criteria:

  • Currently enrolled in another clinical trial
  • Unable to give informed consent or assent
  • Severe comorbid medical illness (at discretion of patient's primary pediatric gastroenterologist)
  • Concomitant Clostridium difficile infection
  • Severe Crohn's disease flare requiring hospitalization
  • Commenced new, or temporary medical therapies (ie. corticosteroids, antibiotics, prebiotics) within 4 weeks prior to commencing the trial; NB: Weaning doses of corticosteroid will be permitted (≤ 0.25mg/kg/day)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: MICROBIOTA
Patients randomized to the INTERVENTION arm will receive a baseline fecal microbiota transplant (FMT) colonoscopic infusion at Week 0, followed by twice-weekly oral microbiota capsule (OMC) therapy for 6 weeks (including Week 0). (n = 30)
Biological: MICROBIOTA
Fecal microbiota enema (RBX2660) infused via colonoscope x 1 + oral microbiota capsules (RBX7455) x 6 weeks. The fecal microbiota enema (RBX2660) prepared by Rebiotix has received Health Canada Clinical Trials Application (CTA), and U.S. Food and Drug Administration Investigational New Drug Application (IND) approval for clinical trials in patients with recurrent Clostridium difficile infection, and pediatric inflammatory bowel disease. The human-derived fecal oral microbiota capsule (RBX7455) has received U.S. Food and Drug Administration Investigational New Drug Application (IND) approval for clinical trials in patients with recurrent Clostridium difficile infection.
Other Names:
  • RBX7455
  • RBX2660
  • Fecal microbiota transplant
Placebo Comparator: PLACEBO
Patients randomized to the CONTROL arm will receive a baseline normal saline (NS) colonoscopic infusion at Week 0, followed by twice-weekly dextrose-containing oral placebo capsule (OPC) therapy for 6 weeks (including Week 0). (n = 15)
Biological: PLACEBO

Placebo enema (Normal Saline) infused via colonoscope x 1 + oral placebo capsules (dextrose-containing capsules) x 6 weeks.

NOTE: Patients randomized to the control group will be given the option of receiving open-label treatment, with the intervention therapy, either: upon completion of the trial, or if they are removed from the trial due to disease exacerbation or other adverse event, at the discretion of their primary gastroenterologist.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Monthly Recruitment Rate
Time Frame: 30 weeks
Assessment of recruitment rate (based on patients meeting all eligibility criteria who were approached for trial entry)
30 weeks
Dropout Rate Post Enrolment
Time Frame: 30 weeks
Rate of patients leaving the trial (patient, or protocol directed exclusion) after enrolment
30 weeks
Rate of Patient Protocol Adherence
Time Frame: 30 weeks
Rate of patients providing all required blood, stool and urine samples per protocol
30 weeks
Rate of Adverse Events
Time Frame: 30 weeks
Rate of patients requiring hospitalization, or experiencing PCDAI increase ≥20 x 2 successive measures
30 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinical: Improvement in Disease Symptoms
Time Frame: Baseline, Week 6, Week 30
PCDAI decrease ≥15 from baseline: Week 6, Week 30
Baseline, Week 6, Week 30
Clinical: Remission in Disease Symptoms
Time Frame: Week 6, Week 30
PCDAI ≤ 10: Week 6, Week 30
Week 6, Week 30
Clinical: Improvement in Serum Inflammatory Markers
Time Frame: Baseline, Week 6, Week 30
Decrease C-reactive protein from baseline: Week 6, Week 30
Baseline, Week 6, Week 30
Clinical: Improvement in Mucosal Inflammatory Markers
Time Frame: Baseline, Week 6, Week 30
Decrease fecal calprotectin from baseline: Week 6, Week 30
Baseline, Week 6, Week 30
Clinical: Change in Urine Metabolomics
Time Frame: Baseline, Week 6, Week 30
Change in urine metabolite profile from baseline: Week 6, Week 30
Baseline, Week 6, Week 30
Clinical: Change in Fecal Microbiome
Time Frame: Baseline, Week 6, Week 30
Change in fecal 16s rRNA + metagenomics profile baseline: Week 6, Week 30
Baseline, Week 6, Week 30

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

McMaster Children's Hospital

Collaborators

St. Justine's Hospital

Investigators

  • Principal Investigator: Nikhil Pai, BSc, CNSC, MD, FRCPC, McMaster Children's Hospital, Division of Pediatric Gastroenterology & Nutrition

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 1, 2018

Primary Completion (Actual)

September 30, 2023

Study Completion (Actual)

September 30, 2023

Study Registration Dates

First Submitted

December 12, 2017

First Submitted That Met QC Criteria

December 17, 2017

First Posted (Actual)

December 19, 2017

Study Record Updates

Last Update Posted (Actual)

October 19, 2023

Last Update Submitted That Met QC Criteria

October 17, 2023

Last Verified

October 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 0000 (Centre for care Science, KI, Norrbacka Eugeniastiftelsen)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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