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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03378167
Recruitment Status : Recruiting
First Posted : December 19, 2017
Last Update Posted : September 12, 2019
Sponsor:
Collaborators:
Hamilton Health Sciences Corporation
McMaster University
Information provided by (Responsible Party):
Nikhil Pai, McMaster Children's Hospital

Tracking Information
First Submitted Date  ICMJE December 12, 2017
First Posted Date  ICMJE December 19, 2017
Last Update Posted Date September 12, 2019
Actual Study Start Date  ICMJE December 1, 2018
Estimated Primary Completion Date December 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 17, 2017)
  • Monthly Recruitment Rate [ Time Frame: 30 weeks ]
    Assessment of recruitment rate (based on patients meeting all eligibility criteria who were approached for trial entry)
  • Dropout Rate Post Enrolment [ Time Frame: 30 weeks ]
    Rate of patients leaving the trial (patient, or protocol directed exclusion) after enrolment
  • Rate of Patient Protocol Adherence [ Time Frame: 30 weeks ]
    Rate of patients providing all required blood, stool and urine samples per protocol
  • Rate of Adverse Events [ Time Frame: 30 weeks ]
    Rate of patients requiring hospitalization, or experiencing PCDAI increase ≥20 x 2 successive measures
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03378167 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 17, 2017)
  • Clinical: Improvement in Disease Symptoms [ Time Frame: Baseline, Week 6, Week 30 ]
    PCDAI decrease ≥15 from baseline: Week 6, Week 30
  • Clinical: Remission in Disease Symptoms [ Time Frame: Week 6, Week 30 ]
    PCDAI ≤ 10: 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
  • Clinical: Improvement in Mucosal Inflammatory Markers [ Time Frame: Baseline, Week 6, Week 30 ]
    Decrease fecal calprotectin from 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
  • Clinical: Change in Fecal Microbiome [ Time Frame: Baseline, Week 6, Week 30 ]
    Change in fecal 16s rRNA + metagenomics profile baseline: Week 6, Week 30
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE PediCRaFT: Pediatric Crohn's Disease Fecal Transplant Trial
Official Title  ICMJE PediCRaFT: Pediatric Crohn's Disease Fecal Microbiota Transplant Pilot Study
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE 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)
Masking Description:

COLONOSCOPY:

  1. Microbial enemas are drawn up in a 500cc syringe that is concealed with an opaque bag, used to infuse contents through the colonoscope. This will insure contents are blinded to non-study personnel in the room
  2. Patients randomized to the control study arm will have identical concealment of the 500cc syringe used to infuse contents through the colonoscope. For the NS infusion, study personnel will add an additional 0.75 ml of commercially available (Club House® brand), food-grade food coloring (2 drops red, 3 drops green, 7 drops yellow) to confer a brown color to the clear normal saline solution. This step will maintain blinding for the patient and non-study personnel in the room, as the contents of the liquid will be visible endoscopically, but will still retain a similarly-colored brown appearance akin to human stool.

ORAL CAPSULAR THERAPY:

a), b) The opaque color of both the OMC and OPC will insure that blinding is preserved to the study patient.

Primary Purpose: Treatment
Condition  ICMJE
  • Crohn Disease
  • Pediatric Crohns Disease
  • Inflammatory Bowel Diseases
  • Colitis
Intervention  ICMJE
  • 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:
    • RBX2660
    • RBX7455
    • Fecal microbiota transplant
  • 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.

Study Arms  ICMJE
  • 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)
    Intervention: Biological: MICROBIOTA
  • 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)
    Intervention: Biological: PLACEBO
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 1, 2018)
45
Original Estimated Enrollment  ICMJE
 (submitted: December 17, 2017)
28
Estimated Study Completion Date  ICMJE March 31, 2020
Estimated Primary Completion Date December 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 3 Years to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Lee Hill, BSc, PhD(c) 9053087354 hill.lee.devlin@gmail.com
Contact: Nikhil Pai, BSc, MD 9055212100 ext 75637 pain@mcmaster.ca
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03378167
Other Study ID Numbers  ICMJE 0000
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Nikhil Pai, McMaster Children's Hospital
Study Sponsor  ICMJE McMaster Children's Hospital
Collaborators  ICMJE
  • Hamilton Health Sciences Corporation
  • McMaster University
Investigators  ICMJE
Principal Investigator: Nikhil Pai, BSc, MD McMaster Children's Hospital, Division of Pediatric Gastroenterology & Nutrition
PRS Account McMaster Children's Hospital
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP