CHICAGO – Results were negative from the first randomized placebo-controlled trial of fecal microbiota transplant in ulcerative colitis, but enthusiasm remains for this newly regulated and trendy therapy.
"We need to get more data and we need to understand how better to use this approach, but I don’t think this study is telling us we should stop exploring. I still think it is an interesting avenue that we need to evaluate," study author Dr. Paul Moayyedi said during a late-breaking abstract session at Digestive Disease Week.
Part of the enthusiasm for what was described as "the new kid on the block for altering gut flora," has been fueled by a roughly 90% success rate for fecal transplant in treating Clostridium difficile infection.
Dr. Moayyedi also showcased a success story from the trial that "typifies a few patients in this study." The patient had ulcerative colitis for almost 20 years that was unresponsive to steroids and 5-aminosalicylic acid for 2 years before the study and so severe it caused bloody diarrhea 10-20 times per day. No improvement was seen after 6 weeks of placebo therapy and his Mayo Clinic score was "about as bad as it can be" at 12.
After crossing over to 6 weeks of open-label fecal microbiota transplantation (FMT), symptoms were much improved and his Mayo score dropped to 5. After 20 weeks, mucosa healed throughout the colon, his Mayo score reached 0, and he was "fine" on no medication.
"What we’re finding is that 6 weeks is usually not enough and that if you continue longer, you can get remission in some patients," said Dr. Moayyedi, the Richard Hunt-Astra Zeneca Chair in Gastroenterology, McMaster University, Hamilton, Ontario.
He went on to say, "I’m a very big proponent of evidenced-based medicine, but cases like these make you think something must be going on in some patients, but we don’t have the funding to do the 500-patient trial you need to get that signal."
Dr. Moayyedi and his associates enrolled ambulatory patients with active ulcerative colitis, defined as a Mayo score of at least 4 and an endoscopic Mayo score of at least 1, who tested negative for the C. difficile gene. Patients could be on ulcerative colitis medications, if doses were stable for at least 12 weeks but had to be off antibiotics for 30 days.
Patients were randomly assigned to receive a 50-mL retention enema containing fecal microbiota from an anonymous donor or water, once per week for 6 weeks. The primary outcome was remission of ulcerative colitis, defined as a Mayo score of 2 or less and an endoscopic Mayo score of 0 at week 7. Patients, clinicians, and investigators were blinded to therapy.
The 31 FMT and 30 placebo patients were well matched at baseline, except for significantly more pancolitis in the FMT group (64% vs. 36%).
Remission was achieved by seven FMT patients (23%) and two placebo patients (7%), which was not significantly different (P = .15), Dr. Moayyedi said.
There also were no differences between the FMT and placebo groups in any of the secondary outcomes: 6-week Mayo score (6.36 vs. 6.30; P = .95), 6-week Inflammatory Bowel Disease Questionnaire (148.4 vs. 146.4; P = .85), and 6-week EQ-5D health questionnaire (61.0 vs. 66.2; P = .34).
Based on these findings, the study is being stopped for futility, he said.
There were no major adverse events, although the diagnosis changed to Crohn’s colitis for two patients given FMT and one on placebo.
This was "much bigger than you’d expect," Dr. Moayyedi said. "We’re not sure why, and of course the worry is that FMT may change the phenotype, which would not be good."
If FMT is to succeed in ulcerative colitis, he suggested more data will be needed on the fecal microbiome and the best approach to administer FMT, including donor selection, timing, preparation, and duration of treatment. The group has not done an analysis of enema dwell time and response, and no signal was seen that FMT is more effective in left-sided disease.
More detailed microbiome analyses of the patient highlighted during the talk, however, revealed the man had a "very diverse and unstable" microbiome at baseline that gradually became more stable, "with a loss of Ruminococcus that seems to be a feature of improvement and a movement toward the phenotype of the donor," Dr. Moayyedi said.
During a discussion of the results, some audience members expressed concern that FMT might change the phenotype, while others were more enthusiastic about the therapy.