Randomized Trial Comparing Single vs. Maintenance Fecal Microbiota Transplant for Refractory Crohn's Disease in Children

NCT02108821 Detailed Description: Gut microbiome plays a key role in gut immunology and function. A disturbance in the diversity of gut bacterial composition could be linked to several immune mediated diseases including Inflammatory Bowel Diseases IBD. IBD can be classified into Crohn's Disease CD, Ulcerative Colitis UC and indeterminate colitis IC, these diseases occur from an aberrant immune reaction to resident gut bacteria. CD can affect the entire gut in a transmural fashion whereas UC involves primarily the mucosal layer of the colon. The treatment options often overlap in both conditions. It has also been demonstrated that both recurrent Clostridium difficile infection RCDI and IBD are associated with gut dysbiosis. The process of fecal microbiota transplantation FMT, where fecal microbial community from a healthy individual is transferred into a recipient, has been established as an efficacious therapy for RCDI.

The role of FMT in treatment of IBD is still not well established. Recent data on FMT in UC has shown promising results. Three out of the four double blind randomized trials demonstrated superiority of FMT compared to placebo. The first randomized trial was conducted by Moayyedi et al. in which six weekly fecal or water placebo enemas demonstrated a remission rate in 24 percent vs. 5 percent in fecal and placebo group respectively which was found to be statistically significant 1. Similarly FMT was found to be superior to placebo in achieving clinical remission at week 8 2 percent FMT vs. 8 percent placebo by Paramsothy et. al who gave fecal or placebo enemas 5 days a week for 8 weeks 2. Costello et. al used multidonor fecal suspension compared to placebo autologous stool via colonoscopy followed by 2 retention enemas by day 7. They observed a significantly superior rate of remission 32 percent vs. 9 percent with fecal and placebo enemas respectively 3. Rossen et. al reported results of FMT in UC where they used two nasoduodenal infusions, 3 weeks apart with no significant benefit in the group that received fecal infusions compared to the placebo 4. There have been no published randomized trials for CD. An open label study on pediatric CD by Suskind et al showed promising results with response in 7 out of 9 children with a single fecal transplant delivered by nasogastric tube 5. Another open-label study of 30 CD adult patients who received a single FMT into the small bowel demonstrated 86.7 percent clinical improvement in the first month after transplant that was sustained in 66.7 percent patients till 6 months 6. A recent meta-analysis on FMT as a primary or adjunct therapy for IBD in cohort studies showed clinical remission in 22 percent and 60.5 percent patients with UC and CD respectively. It was found to be a safe procedure in both conditions. The authors also speculated that children with IBD might respond better to FMT compared to adult patients 7.

Data on FMT in UC has thus demonstrated better results when multiple enemas are used for induction. So far results from open-label studies on Crohn's disease also look promising. However there is still a gap in knowledge and understanding about the safety, outcome and preferred route of FMT for induction of remission in Crohn's disease. Additionally, the role or frequency of maintenance therapy with retention enemas has not been studied.

In this proposed randomized trial, the investigators will perform an open-label induction with fecal transplantation on the subjects with medically refractory mild to moderately active but Clostridium Difficile CDI negative and otherwise uncomplicated Crohn's disease. Subjects who meet the inclusion criteria will receive the initial FMT into right colon while undergoing a medically indicated colonoscopy. This will be followed by 2 retention enemas at 1 and 2 weeks plus 3 days after colonoscopy as long as they are able to tolerate this treatment. All subjects will then be assessed at 6 weeks for response to FMT that will be defined by a drop in PCDAI by 12.5 points. The responders will be randomized to fecal vs. placebo maintenance retention enemas at 1-monthly intervals for 3 months. The subjects will be followed for 6 months from the initial colonoscopy to assess for medium-term outcome and response.

Primary goal:

-To determine the safety of fecal transplant by colonoscopy and retention enemas for induction followed by maintenance retention fecal vs. placebo enemas in children and young adults with uncomplicated mild-moderately active Crohn's disease.

Secondary goals:

• Assess efficacy of this induction regimen followed by maintenance fecal or placebo transplants in responders. The efficacy will be assessed by clinical evaluation and fecal calprotectin that is a non-invasive biomarker.
• Correlate subject's baseline microbiome findings with likelihood for response to FMT induction therapy.
• Follow the chronological microbiome shifts after transplant and correlate with response using clinical and calprotectin assessment in the two groups.

All subjects will maintain an adverse event diary and will be assessed 1 week after each transplant either on telephone or in the clinic. They will have access to the medical providers for 24 hours a day including weekends. They will also be assessed in the clinic prior to each transplant procedure and at 6 months following colonoscopy. Blood work for blood counts CBC with Diff, erythrocyte sedimentation rate ESR, C reactive protein CRP, liver function tests LFTs If clinically Indicated and fecal calprotectin will be assessed at baseline, as well as at 1.5 and 6 months (+/- 2 weeks) after initial colonoscopy for FMT. Stool collection for microbiome analysis will be performed at baseline and subsequently at 1.5, 3.5 and 6 months (+/- 2 weeks) following initial colonoscopy.

Thirty subjects who are 2-25 years of age at the time of consenting will be enrolled in the trial over a period of 24 months. Subjects with mild-moderate Crohn's disease defined as having Pediatric Crohn's Disease Activity Index PCDAI of 10-37.5 despite standard medical therapy that has been stable for at least 4 weeks and are undergoing a medically indicated colonoscopy will be eligible for screening. All enrolled subjects will get FMT via colonoscopy into the right colon along with routine biopsies. Additional biopsies will be collected from the terminal ileum and rectum for microbiome analysis and also stored for future studies. Microbiota analysis will be performed on the donor at the time of stool collection by Open-Biome and recipient stool sample collected within 7 (+/- 3 days) days prior the scheduled fecal microbiota transplantation. They will be followed for adverse events throughout the duration of the study. The clinical response will be defined as a drop in PCDAI by 12.5 points. The clinical response and fecal microbiome changes will be assessed at 1.5, 2.5, 3.5 and 6 month (+/- 2 weeks) throughout the duration of the study. The subjects assessed as responders at 1.5-month will be randomized to receive monthly maintenance retention fecal or placebo enemas for 3 consecutive months. The enrolled subjects will have blood work CBC with diff, ESR, CRP, LFTs and fecal calprotectin evaluation at baseline, 1.5 and 6 months (+/- 2 weeks). The investigators will utilize the Open-Biome laboratory as the fecal stool bank to supply both placebo and fecal suspension for transplant. The investigators estimate that they will screen up to 100 patients with Crohn's Disease CD over 2 years, to reach our goal of 30 total study participants. Subjects who do not improve at 1.5 month post transplant assessment or require prompt intervention at any time during this study will be offered escalation of medical therapy. All subjects will be clinically assessed at 1.5, 2.5, 3.5, 4.5 and 6 months (+/- 2 weeks) post colonoscopy. A rescue retention enema will be allowed during the study if a subject who was previously responding develops a flare.

The investigators hypothesize that fecal transplant will be a safe therapy in uncomplicated mild-moderate Crohn's disease patients. About 60 percent of the subjects are likely to respond at 1.5 month assessment. Subjects receiving maintenance fecal transplants will have a longer duration of remission compared to those who receive only the induction treatment.