Pediatric FEcal Microbiota Transplant for Ulcerative Colitis (PediFETCh)

A Single-Blind, Randomized, Placebo-Controlled Trial of Human Fecal Microbiota Transplantation for the Therapy of Pediatric Ulcerative Colitis and Inflammatory Bowel Disease Unclassified

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.

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: Primary outcomes for this pilot trial are measures of feasibility. 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.

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

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.

Patients will not be aware of which type of enema they have been randomized to receive (fecal microbial enema, or normal saline enema). Patients who were randomized to the normal saline enema will still be eligible to receive the fecal microbial enema when they finish the trial; these patients will know what they are receiving and no longer need masking.

Live, healthy, human donor stool prepared as fecal enemas. Fecal enemas are prepared and collected by Rebiotix(®) (RBX2660), using extensively screened donor stool. Enemas will be administered on site at one of the participating trial sites by trained study investigators. Enemas are given: 2x per week for 6 weeks (total = 12 enemas over 6 weeks). Patients will be masked to enema contents.

Normal saline enemas will be administered on site at one of the participating trial sites by trained study investigators. Enemas are given: 2x per week for 6 weeks (total = 12 enemas over 6 weeks). Patients will be masked to enema contents.

Inclusion Criteria: 3yo to 17yo at start of trial Followed at a participating clinical trial site: a) McMaster Children's Hospital, b) Children's Hospital at London Health Sciences Centre, c) Centre Hospitalier Universitaire Sainte-Justine Ulcerative colitis (UC) or Inflammatory bowel disease unclassified (IBD-U) Evidence of active clinical, biological, or mucosal disease Ongoing treatment is acceptable provided the patient has had no significant changes to medications, or medication dose for at least 4 weeks prior to starting the trial Exclusion Criteria: Active participation in another therapeutic trial Unable to give informed consent, or assent Active Clostridium difficile infection Significant change in medication type, or medication dose within the preceding 4 weeks prior to starting the trial Starting new treatments, or having a significant change in medication dosing during the trial Significant, consecutive rise in PUCAI score during the trial Hospitalization during trial

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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