Effect of Oral Capsule- vs Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent Clostridium difficile Infection: A Randomized Clinical Trial

Abstract

Importance: Fecal microbiota transplantation (FMT) is effective in preventing recurrent Clostridium difficile infection (RCDI). However, it is not known whether clinical efficacy differs by route of delivery.

Objective: To determine whether FMT by oral capsule is noninferior to colonoscopy delivery in efficacy.

Design, setting, and participants: Noninferiority, unblinded, randomized trial conducted in 3 academic centers in Alberta, Canada. A total of 116 adult patients with RCDI were enrolled between October 2014 and September 2016, with follow-up to December 2016. The noninferiority margin was 15%.

Interventions: Participants were randomly assigned to FMT by capsule or by colonoscopy at a 1:1 ratio.

Main outcomes and measures: The primary outcome was the proportion of patients without RCDI 12 weeks after FMT. Secondary outcomes included (1) serious and minor adverse events, (2) changes in quality of life by the 36-Item Short Form Survey on a scale of 0 (worst possible quality of life) to 100 (best quality of life), and (3) patient perception on a scale of 1 (not at all unpleasant) to 10 (extremely unpleasant) and satisfaction on a scale of 1 (best) to 10 (worst).

Results: Among 116 patients randomized (mean [SD] age, 58 [19] years; 79 women [68%]), 105 (91%) completed the trial, with 57 patients randomized to the capsule group and 59 to the colonoscopy group. In per-protocol analysis, prevention of RCDI after a single treatment was achieved in 96.2% in both the capsule group (51/53) and the colonoscopy group (50/52) (difference, 0%; 1-sided 95% CI, -6.1% to infinity; P < .001), meeting the criterion for noninferiority. One patient in each group died of underlying cardiopulmonary illness unrelated to FMT. Rates of minor adverse events were 5.4% for the capsule group vs 12.5% for the colonoscopy group. There was no significant between-group difference in improvement in quality of life. A significantly greater proportion of participants receiving capsules rated their experience as "not at all unpleasant" (66% vs 44%; difference, 22% [95% CI, 3%-40%]; P = .01).

Conclusions and relevance: Among adults with RCDI, FMT via oral capsules was not inferior to delivery by colonoscopy for preventing recurrent infection over 12 weeks. Treatment with oral capsules may be an effective approach to treating RCDI.

Trial registration: clinicaltrials.gov Identifier: NCT02254811.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kao reported receiving grants from Alberta Health Services, University of Alberta Hospital Foundation, and Rebiotix Inc and other funding from Cubist, Actelion, and Merck. Dr Mason reported receiving grants from Alberta Health Services, American Kennel Club, Canine Health Foundation, Canadian Liver Foundation, and Canadian Institutes for Health Research; grants and personal fees from Intercept Pharmaceuticals; grants and nonfinancial support from Merck; and nonfinancial support from Gilead and Abbvie. Dr Wong reported receiving a grant from AITF/iCORE Strategic Chair. Dr Louie reported receiving a grant from Alberta Health Services; grants and personal fees from Actelion Pharmaceuticals; and personal fees from Rebiotix, Davoterra, Pfizer, and Merck. No other disclosures were reported.

Figures

Figure 1.. Flow of Participants in Randomized Clinical Trial Comparing Oral Capsule– or Colonoscopy-Delivered Fecal Microbiota Transplantation (FMT)

CDI indicates Clostridium difficile infection; QOL, quality of life; and UC, ulcerative colitis.

Figure 2.. Shannon Diversity of Taxonomic Data From Patients With Recurrent Clostridium difficile Infection and Donors

The Shannon diversity index represents the relative abundance and evenness of bacterial species in a community. The index is highest in communities with large numbers of species with near equal representation, and lowest in communities with low numbers of species with skewered distribution. Shannon diversity index was significantly different between patients with recurrent C difficile infection in the capsule or colonoscopy groups and the donors before fecal microbiota transplantation (FMT) (P < .001) and between each group of patients before and after FMT at 1, 4, and 12 weeks (P < .01). There was no difference between the capsule and colonoscopy groups at any point. Some donors had provided 2 samples for the microbial composition analysis. Each patient is represented by a single point. The lines within boxes represent medians, while the edges of the boxes represent lower and upper quartiles. The whiskers represent the range of the data set.

Figure 3.. Principal Coordinates Analysis (PCoA) of Taxonomic Data From Patients With Recurrent Clostridium difficile Infection and Donors

PCoA is a method to visualize similarities or dissimilarities in high-dimensional data. In this case, it assigns each patient’s microbial composition to a location in a 2-dimensional graph indicated by principal coordinate 1 (30.9%; x-axis) and principal coordinate 2 (8.4%; y-axis) where the distance between any 2 samples is a measure of their similarity (smaller distance for higher similarity). The microbial composition of patients with recurrent C difficile infection (red circles and triangles) was significantly different from donors (black squares) before fecal microbiota transplantation (FMT) but shifted toward the donor profiles 1 week after FMT (permutational multivariate analysis of variance P = .001). At 12 weeks, a few individuals appeared to revert back toward pre-FMT profiles (gold circles and triangles).