Pediatric FEcal Microbiota Transplant for Ulcerative Colitis
Condition: Inflammatory Bowel Disease; Ulcerative Colitis
MeSH terms: Colitis; Colitis, Ulcerative; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer
Study type: Interventional
Phase: Phase 1

Summary: 
      The PediFETCh study is a pilot trial designed to assess the feasibility of fecal microbiota
      transplants for the therapy of pediatric ulcerative colitis (UC) and pediatric inflammatory
      bowel disease-unclassified (IBD-U). Investigators will test the hypothesis that a protocol of
      twice-weekly retention enemas delivered over six weeks, using fecal transplant material from
      a healthy donor, will improve clinical and biological disease markers in patients with
      pediatric UC or IBD-U.
    

Detailed description: 
      BACKGROUND:

      Approximately 104,000 Canadians are affected by ulcerative colitis (UC), an inflammatory
      bowel disease characterized by immune dysregulation. Ontario, Canada has some of the highest
      rates of childhood-onset UC in the world and this disease can be particularly debilitating in
      childhood. Effects on growth and development are profound in pediatric onset disease, and
      existing treatments, which include long-term immunosuppression, carry short and long-term
      risks of infection, malignancy, and toxicity.

      The intestinal bacteria has a critical role in the regulation of the immune system. Fecal
      microbiota transplantation (FMT), the transfer of intestinal bacteria from a healthy donor to
      a recipient, has been shown to treat recurrent Clostridium difficile intestinal infections.
      The therapeutic potential of FMT for UC has been demonstrated in a recent adult UC trial at
      our institution (primary investigator: Dr. Paul Moayyedi; collaborator on the PediFETCh
      trial). Randomized, placebo-controlled trials of FMT in pediatric inflammatory bowel disease
      are nonexistent. FMT may present a valuable, safer therapeutic option for pediatric UC and a
      randomized-controlled trial is needed.

      Four small case-series have demonstrated success of FMT for pediatric inflammatory bowel
      disease (IBD). Protocols and response rates varied across each study, but lower
      gastrointestinal tract administration yielded clinical response rates in 67-100% of patients.
      Two single--center pediatric case reports have been recently published showing marked
      clinical improvement in two patients with severe colitis. A 2015 case report described an 18
      -month old female presenting with an early -onset colitis with UC- like presentation. She
      responded after 7 serial FMT infusions with donor stool from an age-matched niece and older
      brother. A 2016 case report described an 11 -year old female with steroid dependent UC who
      responded after serial FMT infusions every 2 to 4 weeks over a 10 month period. The patient
      remained in clinical remission at 40 weeks post final FMT, and showed complete endoscopic
      healing. A further 2016 case report described a 3-year old female with acute severe UC who
      was refractory to aminosalicylates and all immunosuppressive drugs. She received 6 successive
      FMT enemas and 4 FMT via nasoduodenal tube over 10 days. While this patient ultimately
      required colectomy, she did not show any significant long-term side effects as a result of
      the trial of FMT.

      Strong evidence exists in adult studies to support the use of FMT in UC treatment. Four
      randomized-controlled trials (RCTs), considered one of the highest qualities of clinical
      trial evidence, have been published to date. Slight variations in protocol existed across all
      four studies, but taken together, the overall clinical and endoscopic remission rates in
      patients who received FMT were an impressive: 42.1% and 26.4%, respectively.

      OBJECTIVES:

      Our objective is to determine whether FMT can improve clinical, biological, and mucosal
      disease status in pediatric UC and IBD Unclassified (IBD-U). This pilot study will provide
      access to FMT treatment and demonstrate the feasibility of our study design in order to
      establish a framework for future studies for assessing the effectiveness of FMT intervention.

      HYPOTHESES:

      Based on previously published case series in pediatrics, single-patient case reports, and a
      recent randomized controlled trial in adults, we hypothesize that patients receiving fecal
      microbiota enemas containing healthy donor bacteria will experience clinical remission,
      improvement in inflammatory markers, and a longer duration of remission compared to patients
      receiving the placebo.

      STUDY DESIGN:

      The proposed study is a multicenter, randomized, controlled, single-blind trial. Pediatric
      patients with a diagnosis of UC, or IBD-U will be enrolled and randomized to receive 6 weeks
      of bi-weekly fecal microbiota enemas or normal saline enemas (placebo). Fecal enemas will
      contain healthy donor stool that has been extensively safety-screened and provided by
      Rebiotix® (RBX-2660).

      Patients may continue taking their existing UC medical treatments (probiotics, 5-ASAs,
      immunomodulators, anti-TNF) while enrolled in the trial. However, no significant changes in
      dosing or the introduction of new therapies will be permitted over the study period. All
      fecal enemas will be delivered at the study site by investigators to ensure consistency in
      technique and viability of fecal transplant material. Patients will have clinical disease
      activity scores measured at each enema administration (6 weeks), and at weeks 18 and 30.
      Stool samples will be collected at time points throughout the trial for microbiome analyses
      and fecal calprotectin measurements, with support from the Farncombe Family Digestive Health
      Research Institute. Bloodwork will be collected throughout the trial to further measure
      change in biological disease activity.

      Patients participating in the trial will be offered an opportunity to be re-enrolled in the
      fecal microbiota arm if they were initially randomized to the normal saline (placebo) arm of
      the study.

      SAMPLE SIZE:

      50 patients will be recruited for the trial across all participating study sites. Patients
      will be single-blinded, and randomized to placebo or treatment arms.

      SAFETY MONITORING:

      Study risks include complications of fecal microbiota transplants (infection, mild
      gastrointestinal symptoms, fever). Based on results of previous studies, and existing safety
      data of the fecal enema preparation (RBX2660) from previously conducted trials, the risks of
      infection, adverse gastrointestinal symptoms, or other adverse events are extremely low. The
      fecal enema preparation used in this trial (RBX2660) by Rebiotix(®) has received FDA IND and
      Health Canada approvals for clinical trials in recurrent C. difficile. Donors are initially
      prescreened, and donor blood and stool are extensively screened at additional time points
      prior to administration. We will be providing close follow-up of our patients throughout the
      trial and in followup.

      OUTCOMES:

        1. Primary outcomes for this pilot trial are measures of feasibility.

        2. Secondary outcomes are measures of clinical response to fecal microbiota transplant
           treatments. These include: clinical response (based on Pediatric Ulcerative Colitis
           Activity Index [PUCAI] scores), biological response (serum bloodwork measures), mucosal
           healing (fecal calprotectin levels), and change in fecal microbiome (change in 16s rRNA,
           inferred metagenome, metabolome). Patients enrolled in the open-label portion of the
           trial will also have urine metabolomics measured. We will not be assessing other indices
           of mucosal healing, such as performing endoscopy or magnetic resonance enterography in
           this trial.
    

Intervention name(s): Fecal Microbiota Enema; Normal Saline Enema
Intervention type(s): Biological; Biological
Intervention description(s): Active intervention.; Placebo comparator.
Other intervention name(s): FMT; RBX2660; Rebiotix; Fecal microbial enema
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Patients will be randomized to receive either the fecal microbial enema containing healthy donor stool OR the normal saline enema placebo. Patients who receive the normal saline enema placebo may be eligible to still receive the fecal microbial enema when they finish the trial.
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Microbiome; Microbiota; Fecal Microbial Transplant; Fecal Microbiota Transplant; FMT; Gastroenterology; IBD; Inflammatory Bowel Disease; Ulcerative Colitis; UC; Inflammatory Bowel Disease Unclassified; IBD-U; Rebiotix; RBX2660; Pediatrics; McMaster Children's Hospital; Centre Hospitalier Universitaire Sainte-Justine; Children's Hospital at London Health Sciences Centre