Preliminary Results From a Multicenter, Randomized Trial Using Fecal Microbiota Transplantation to Induce Remission in Patients With Mild-to-Moderate Crohn's Disease

Abstract

Introduction: Fecal microbiota transplantation (FMT) has shown promise at inducing remission in ulcerative colitis. This study is the first of its kind to evaluate the efficacy and safety of FMT at inducing remission in Crohn's disease (CD).

Methods: This double-blind, placebo-controlled trial was conducted in 3 Canadian academic centers; randomized patients with mild-to-moderate CD received FMT or placebo. The first treatment was administered by colonoscopy followed by weekly oral capsules for 7 weeks. Primary end point was clinical and endoscopic remission at week 8. Secondary outcomes included clinical and endoscopic response, adverse events, and health-related quality of life using generic and disease-specific instruments.

Results: From July 2017 to June 2021, 21 and 13 patients were randomized to FMT and placebo groups, respectively. The trial terminated early due to futility. At week 8, 0% (0/15) of patients in the FMT group versus 8.3% (1/11) in the placebo group reached the primary end point of combined clinical and endoscopic remission as per protocol analysis. There were no differences between the groups in clinical or endoscopic responses. One patient in each group had worsening of CD. Although both groups experienced statistically significant improvements in health-related quality of life, only the FMT group had a significant decrease in activity impairment. Although there were no significant changes in microbial diversity or composition, patients who achieved clinical response became more similar to their donors in stool microbial composition.

Discussion: FMT was not effective at inducing clinical and endoscopic remission in CD using the FMT regimen in this study. Future studies may use other strategies to enhance treatment response, including longer intervention, antibiotic pretreatment, optimized donor-recipient pairing, and concomitant anti-inflammatory diet, and biologic or small molecule therapies.

Trial registration: ClinicalTrials.gov NCT03078803.

Keywords: Crohn's disease; fecal microbiota transplantation; health-related quality of life; microbiome; patient-reported outcome measure.

Graphical abstract

Figure 1.

Consolidated Standards of Reporting Trials diagram. ^aOf the 2 patients who withdrew, 1 was unable to receive treatment due to voluntary donor program suspension as a result of Health Canada safety notice re multi-drug resistant organisms. ^bOf 15 patients who completed week 8 of the FMT-blinded treatment, 1 did not have repeat endoscopy at week 8 due to COVID-related endoscopy unit closure. ^cOf the 15 patients who complete week 8 of the FMT-blinded treatment, I did not complete that 5Q-5D-5L or Short Inflammatory Bowel Disease Questionnaire. ^dOf the 11 patients that completed week 8 of placebo treatment, 1 did not complete the WPAI:CD questionnaire. FMT, fecal microbiota transplantation; SES, simplified endoscopic score; WPAI, work productivity and activity impairment.

Figure 2.

Primary and secondary outcomes at week 8. Primary outcome of combined clinical and endoscopic remission was achieved in 1/11 patients in the placebo group (a). Endoscopic response (b) was achieved in 2/11 patients in the placebo group and endoscopic remission (c) in 1/11 patients in the placebo group. Clinical response (d) was achieved in 11/15 patients in the FMT group and 8/11 patients in the placebo group. Clinical remission was achieved in 9/15 patients in the FMT group and 6/11 patients in the placebo group. There were no significant differences in outcomes between the groups. FMT, n = 15; Placebo, n = 11. FMT, fecal microbiota transplantation.

Figure 3.

There was a significant improvement in HBI (a) between BL and W8 in both groups. There was no change in SES-CD scores in either the placebo or the FMT group (b). Levels of fecal calprotectin (c) and CRP (e) in individual patients at BL, W1, and W8. There were no significant changes in CRP or fecal calprotectin within the FMT or the placebo group between BL, W1, and W8. CRP was higher in the placebo group than in the FMT group at BL and at W8 (e). Delta changes in fecal calprotectin (d) and CRP (f) between BL and W1 and between BL and W8 are shown. Data are shown as individual values and median and were analyzed using 2-way repeated measures or mixed-effect model. FMT, n = 15; Placebo, n = 11. BL, baseline; CRP, C-reactive protein, FMT, fecal microbiota transplantation; HBI, Harvey-Bradshaw Index; SES-CD, simplified endoscopic score for Crohn's disease, W1, week 1; W8, week 8.

Figure 4.

Gut microbial diversity of FMT donors and subjects. Alpha-diversity (a) of fecal microbiota was assessed using the Chao1 and Shannon indices. There was no change in α-diversity between baseline and week 8 in either the FMT or the placebo group. Both baseline and week 8 α-diversity, as assessed by the Shannon index, was lower in the placebo group compared with the donors. Beta diversity (b) was calculated using the Bray-Curtis dissimilarity index. Significant differences were observed in microbial composition between the FMT and placebo groups at week 8 (c). Differences of beta diversity were analyzed via permutational multivariate analysis of variance (n = 999) using the “Adonis” function in “vegan”. for the microbiota compositional features, α-diversity index and centered log-ratio-transformed bacterial taxa counts, repeated measures linear regression, and paired t-tests were applied to compare within-group differences relative to baseline. Between-group differences were assessed by linear regression, and pairwise comparisons used unpaired t-tests. P-values were adjusted by the Benjamin-Hochberg FDR method. FMT, n = 15; Placebo, n = 11. . BL, baseline; DR, donors; FDR, false discovery rate; FMT, fecal microbiota transplantation; W8, week 8.