PediCRaFT: Pediatric Crohn's Disease Fecal Transplant Trial
Condition: Crohn Disease; Pediatric Crohns Disease; Inflammatory Bowel Diseases; Colitis
MeSH terms: Crohn Disease; Colitis; Intestinal Diseases; Inflammatory Bowel Diseases
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

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.
    

Intervention name(s): MICROBIOTA; PLACEBO
Intervention type(s): Biological; Biological
Intervention description(s): 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.; 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.
Other intervention name(s): RBX2660; RBX7455; Fecal microbiota transplant
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Patients will be randomized 2:1 to one of two groups upon consent: intervention or control. 30 patients will be randomized to receive an FMT via colonoscopy + oral microbiota capsular (OMC) therapy (INTERVENTION), and 15 patients will be randomized to receive normal saline (NS) via colonoscopy + dextrose-containing oral capsules (oral placebo capsule, OPC) (CONTROL). Randomization will occur through a computer-generated block-randomization pattern (block size = 6 participants).
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.
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Paediatrics; Pediatrics; Crohn's; Crohn; Microbiome; Microbiota; FMT; Fecal Transplant; Fecal Microbiota Transplant; IBD-U; Inflammatory Bowel Disease Unclassified; Inflammatory Bowel Disease Indeterminate; IBD; Colitis