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Safety and Efficacy of Fecal Microbiome Transplantation (FMT) in the Treatment of Antibiotic Dependent Pouchitis (ADP)

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02782325
Recruitment Status : Terminated (Due low efficacy of FMT in interim analysis.)
First Posted : May 25, 2016
Results First Posted : May 14, 2019
Last Update Posted : May 14, 2019
Sponsor:
Collaborators:
OpenBiome
Crohn's and Colitis Foundation
The Broad Foundation
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

Tracking Information
First Submitted Date  ICMJE May 12, 2016
First Posted Date  ICMJE May 25, 2016
Results First Submitted Date  ICMJE February 18, 2019
Results First Posted Date  ICMJE May 14, 2019
Last Update Posted Date May 14, 2019
Actual Study Start Date  ICMJE June 1, 2017
Actual Primary Completion Date December 3, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 23, 2019)
Number of Patients With FMT Related Adverse Event [ Time Frame: 24 weeks ]
Number of patients with FMT related adverse event (classified according to MedDRA; lowest level term) and categorized according to CTCAE Version 4.0. The safety was assessed in the randomized placebo controlled segment of the study over 24 weeks after initial endoscopic FMT weeks and if the patient should enter the open label extension part of the study also for 24 weeks after initial open label FMT. 6 patients participated in the randomized arm and 5 patients in the open label extension arm.
Original Primary Outcome Measures  ICMJE
 (submitted: May 20, 2016)
Incidence of Treatment Emergent Adverse Events [ Time Frame: 16 weeks in the randomized placebo controlled study segment and 22 weeks in the open label FMT extension segment ]
Number of patients with FMT related adverse event (classified according to MEDRAS LLT; lowest level term) and categorized according to CTCAE Version 4.0. The safety will be assessed in the randomized placebo controlled segment of the study over 16 weeks and if the patient should enter the open label extension part of the study over 22 weeks.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 23, 2019)
  • Number of Patients in Clinical Remission Week 4 After Endoscopic and Oral FMT [ Time Frame: 4 weeks ]
    Clinical remission as defined by a composite assessment, of which all criteria need to be met: Clinical modified pouch diseases activity index (mPDAI) score ≤4 points and no need for antibiotic therapy at week 4.
  • Number of Patients in Clinical Remission Week 16 [ Time Frame: 16 weeks ]
    Clinical remission as defined by a composite assessment, of which all criteria need to be met: Clinical mPDAI score ≤4 points and no need for antibiotic therapy at week 16.
  • Number of Patients With Endoscopic Improvement Week 4 After Endoscopic and Oral FMT [ Time Frame: 4 weeks ]
    Endoscopic improvement of active pouchitis (decrease from baseline in modified pouch disease activity index endoscopic subscore > 2 points) at week 4.
  • Number of Patients With Clinical Response at Week 4 in Patients Entering the Trial With Active Pouchitis Symptoms [ Time Frame: 4 weeks ]
    This outcome measure is for patients with active pouchitis symptoms entering the trial. Since all patients entered with inactive pouchitis no patient could be evaluated for this outcome. Response as defined by a composite assessment of which both criteria has to be met: Decrease from baseline mPDAI clinical subscore > 2 points and no need for antibiotic therapy at week 4.
  • Number of Patients With Clinical Response Week 8 and Active Pouchitis at Baseline [ Time Frame: 8 weeks ]
    Response as defined by a composite assessment of which both criteria has to be met: Decrease from baseline mPDAI clinical subscore > 2 points and no need for antibiotic therapy at week 8 of the randomized phase.
  • Number of Patients With Clinical Response i at Week 16 and Active Pouchitis at Baseline [ Time Frame: 16 weeks ]
    This outcome measure is for patients with active pouchitis symptoms entering the trial. Response as defined by a composite assessment of which both criteria has to be met: Decrease from baseline mPDAI clinical subscore > 2 points and no need for antibiotic therapy at week 16.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 20, 2016)
  • Clinical Remission week 4 [ Time Frame: Week 4 ]
    Clinical remission as defined by a composite assessment, of which all criteria need to be met: Clinical mPDAI score ≤4 points and decrease from the baseline mPDAI > 2 points and no need for antibiotic therapy at week 4.
  • Clinical remission week 16 [ Time Frame: Week 16 ]
    Clinical remission as defined by a composite assessment, of which all criteria need to be met: Clinical mPDAI score ≤4 points and decrease from the baseline mPDAI > 2 points and no need for antibiotic therapy at week 16.
  • Endoscopic improvement week 4 [ Time Frame: Week 4 ]
    Endoscopic improvement of active pouchitis (decrease from baseline in mPDAI endoscopic subscore > 2 points) at week 4.
  • Clinical Response week 4 [ Time Frame: Week 4 ]
    Response as defined by a composite assessment of which both criteria has to be met: Decrease from baseline mPDAI clinical subscore > 2 points and no need for antibiotic therapy at week 4.
  • Clinical Response week 8 [ Time Frame: Week 8 ]
    Response as defined by a composite assessment of which both criteria has to be met: Decrease from baseline mPDAI clinical subscore > 2 points and no need for antibiotic therapy at week 8.
  • Clinical Response week 16 [ Time Frame: Week 16 ]
    Response as defined by a composite assessment of which both criteria has to be met: Decrease from baseline mPDAI clinical subscore > 2 points and no need for antibiotic therapy at week 16.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy of Fecal Microbiome Transplantation (FMT) in the Treatment of Antibiotic Dependent Pouchitis (ADP)
Official Title  ICMJE Safety and Efficacy of Fecal Microbiome Transplantation (FMT) in the Treatment of Antibiotic Dependent Pouchitis (ADP)
Brief Summary Antibiotic dependent pouchitis (ADP) is predestined to benefit from FMT, since bacterial dysbiosis, which can only be controlled with antibiotics, appears to be the major driver of the clinical symptoms. This is a proof of concept randomized placebo controlled trial, in which 50% of the patients will receive FMT and 50% will receive a placebo FMT. Additionally the trial offers an open label extension period.
Detailed Description

FMT for ADP is a promising approach, given the documented role of bacteria in the pathogenesis. In contrast to patients with C. difficile colitis, in whom a single FMT is highly effective, in patients with Inflammatory Bowel Disease (IBD) an intensified therapy with daily or repeated FMT may be more beneficial. Whereas repeated endoscopic application are not feasible and repeated enema applications are not favored by patients a combination of endoscopic FMT and consecutive maintenance therapy with oral FMT using the FMT capsule G3 produced by OpenBiome to help establish the donor microbiome in the host seems to be the most promising approach. The objective of this trial is to evaluate the safety of FMT in patients with ADP and to estimate the effect size to be achieved from FMT therapy in patients with ADP for subsequent evaluation in a large definitive trial. A secondary objective is to study the microbial engraftment of donor FMT in the recipients.

This proof of concept randomized placebo controlled trial with an open label extension period will evaluate the safety and efficacy of an initial endoscopic FMT followed by 14 days of oral FMT. The study has two distinct outcomes, a clinical and translational aim, to investigate the effect of FMT in patients with ADP.

Aim1: Evaluation of safety, tolerability and clinical effectiveness (measured as clinical response or remission and discontinuation of antibiotic therapy) of FMT in patients with ADP.

Aim 2: Evaluation of the impact of FMT on the fecal bacterial microbiome in patients with ADP, which will provide functional data about possible mechanisms of this therapy.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Pouchitis
Intervention  ICMJE
  • Biological: Active FMT, then open label FMT
    Endoscopic application of OpenBiome FMT Lower Delivery followed by 2 weeks of treatment with OpenBiome FMT Capsules G3 with follow-up at week 4, 8, 16 and 24 after inclusion. In case the study patient does not achieve clinical remission at week 4 or experiences a flare of disease on day 15-28 after start of the study he/she will be offered the possibility to participate in open label extension after at least 10 day of antibiotic therapy with an additional endoscopic FMT followed by 2 weeks of oral FMT. Follow-up will occur in open label at week 4, 8, 16 and 24 after open label FMT.
    Other Name: Active FMT
  • Biological: Placebo FMT, then open label FMT
    Endoscopic application of Placebo FMT Lower Delivery followed by 2 weeks of treatment with Placebo FMT Capsules G3 with follow-up at week 4, 8, 16 and 24 after inclusion. In case the study patient does not achieve clinical remission at week 4 or experiences a flare of disease on day 15-28 after start of the study he/she will be offered the possibility to participate in open label extension after at least 10 day of antibiotic therapy with an additional endoscopic FMT followed by 2 weeks of oral FMT. Follow-up will occur in open label at week 4, 8, 16 and 24 after open label FMT.
    Other Name: Placebo FMT
Study Arms  ICMJE
  • Active Comparator: Active FMT, then open label FMT
    Endoscopic application of OpenBiome FMT Lower Delivery followed by 2 weeks of treatment with OpenBiome FMT Capsules G3 with follow-up at week 4, 8, 16 and 24 after inclusion. In case the study patient does not achieve clinical remission at week 4 or experiences a flare of disease on day 15-28 after start of the study he/she will be offered the possibility to participate in open label extension after at least 10 day of antibiotic therapy with an additional endoscopic FMT followed by 2 weeks of oral FMT. Follow-up will occur in open label at week 4, 8, 16 and 24 after open label FMT.
    Intervention: Biological: Active FMT, then open label FMT
  • Placebo Comparator: Placebo FMT, then open label FMT
    Endoscopic application of Placebo FMT Lower Delivery followed by 2 weeks of treatment with Placebo FMT Capsules G3 with follow-up at week 4, 8, 16 and 24 after inclusion. In case the study patient does not achieve clinical remission at week 4 or experiences a flare of disease on day 15-28 after start of the study he/she will be offered the possibility to participate in open label extension after at least 10 day of antibiotic therapy with an additional endoscopic FMT followed by 2 weeks of oral FMT. Follow-up will occur in open label at week 4, 8, 16 and 24 after open label FMT.
    Intervention: Biological: Placebo FMT, then open label FMT
Publications * Not Provided

*   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 Terminated
Actual Enrollment  ICMJE
 (submitted: April 23, 2019)
6
Original Estimated Enrollment  ICMJE
 (submitted: May 20, 2016)
20
Actual Study Completion Date  ICMJE December 3, 2018
Actual Primary Completion Date December 3, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Signed informed consent.
  • Man or woman between 18 and 70 years of age.
  • Ileal Pouch-Anal Anastomosis (IPAA) after colectomy for ulcerative colitis
  • Active pouchitis, defined as a modified pouch disease activity index (mPDAI) ≥ 5 and a history of ≥ 4 antibiotic therapies for pouchitis in the last 12 months

or

- Need for ongoing antibiotic therapy (> 4 weeks) to maintain clinical remission and a history of at least 2 attempts in the last 24 months to stop antibiotic therapy resulting in pouchitis episodes.

Exclusion Criteria:

  • Treatment with biologics (e.g. infliximab, adalimumab, golimumab, vedolizumab)
  • Treatment with immunomodulators (azathioprine, 6-mercaptopurine (6-MP), methotrexate), steroids or any investigational drugs
  • Use of cholestyramine
  • Crohn's disease of the pouch
  • Known cytomegalovirus infection of the pouch
  • Clostridium difficile infection
  • Isolated cuffitis
  • Clinical significant strictures of the pouch inlet or outlet
  • Concurrent intestinal obstruction
  • History of familial adenomatous polyposis
  • History of uncontrolled lactose intolerance
  • History of confirmed (serological test and/or histology) celiac disease
  • Pregnancy, breast feeding, or planning to become pregnant during the trial
  • Non - steroidal inflammatory medications (NSAIDs) as long-term treatment, defined as use for at least 4 days a week each month
  • Dysphagia (oropharyngeal, esophageal, functional, neuromuscular)
  • History of recurrent aspiration episodes
  • Proven Gastroparesis
  • Allergy to the following generally regarded as safe ingredients (GRAS): glycerol, acid resistant hypromellose (HPMC), gellan gum, cocoa butter, titanium dioxide
  • Adverse event attributable to previous FMT
  • Allergy/intolerance to pump inhibitor therapy
  • Any condition for which the investigator thinks the FMT treatment may pose a health risk (e.g. severely immunocompromised)
  • Participation in another clinical trial within the last 30 days, simultaneous participation in another clinical trial, or previous participation in this trial
  • During the trial period until one week after the trial end: Non-use of appropriate contraceptives in females of childbearing potential (e.g. condoms, intrauterine device (IUD), hormonal contraception, or other means considered adequate by the responsible investigator) or in males with a child-fathering potential (condoms, or other means considered adequate by the responsible investigator during treatment - Well-founded doubt about the patient's cooperation
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02782325
Other Study ID Numbers  ICMJE 16-1310
FMTADP ( Other Identifier: UNC-CH )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: The final results of the trial will be posted on clinical trials.gov. No individual patient data will be posted.
Responsible Party University of North Carolina, Chapel Hill
Study Sponsor  ICMJE University of North Carolina, Chapel Hill
Collaborators  ICMJE
  • OpenBiome
  • Crohn's and Colitis Foundation
  • The Broad Foundation
Investigators  ICMJE
Principal Investigator: Hans Herfarth, MD, PhD University of North Carolina
PRS Account University of North Carolina, Chapel Hill
Verification Date December 2018

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