Clinical trial NCT03378167: PediCRaFT: Pediatric Crohn's Disease Fecal Transplant Trial
Official title: PediCRaFT: Pediatric Crohn's Disease Fecal Microbiota Transplant Pilot Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Crohn Disease
Pediatric Crohns Disease
Inflammatory Bowel Diseases
Colitis
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
Lead sponsor: McMaster Children's Hospital
Sponsor class: OTHER
Collaborators: name: St. Justine's Hospital
First posted: 2017-12-19
Enrollment: 17
Sex: ALL
Minimum age (years): 3
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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.
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Monthly Recruitment Rate
timeFrame: 30 weeks
measure: Dropout Rate Post Enrolment
timeFrame: 30 weeks
measure: Rate of Patient Protocol Adherence
timeFrame: 30 weeks
measure: Rate of Adverse Events
timeFrame: 30 weeks
Secondary outcomes:
measure: Clinical: Improvement in Disease Symptoms
timeFrame: Baseline, Week 6, Week 30
measure: Clinical: Remission in Disease Symptoms
timeFrame: Week 6, Week 30
measure: Clinical: Improvement in Serum Inflammatory Markers
timeFrame: Baseline, Week 6, Week 30
measure: Clinical: Improvement in Mucosal Inflammatory Markers
timeFrame: Baseline, Week 6, Week 30
measure: Clinical: Change in Urine Metabolomics
timeFrame: Baseline, Week 6, Week 30
measure: Clinical: Change in Fecal Microbiome
timeFrame: Baseline, Week 6, Week 30
Other outcomes:
Locations:
city: Hamilton
country: Canada
facility: McMaster Children's Hospital
state: Ontario
city: Montréal
country: Canada
facility: Centre Hospitalier Universitaire Sainte-Justine, University of Montreal
state: Quebec
Study officials:
affiliation: McMaster Children's Hospital, Division of Pediatric Gastroenterology & Nutrition
name: Nikhil Pai, BSc, CNSC, MD, FRCPC
role: PRINCIPAL_INVESTIGATOR
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