Meta-Analysis of Response Rates Among Placebo-Treated Patients from Five Clinical Trials of Experimental Recurrent Clostridium difficile Therapeutics

Dale Gerding, MD, Courtney Jones, BS, Ken Blount, PhD, Bill Shannon, PhD MBA

Background

• Recurrent Clostridium difficile infections (rCDI) has been recognized as an urgent health threat.
• Numerous therapeutics are being developed to reduce recurrence and have been evaluated in clinical trials.
• RBX2660 is a standardized microbiota-based drug manufactured from live human-derived microbes and was evaluated in PUNCH CD 2, a randomized, placebo-controlled Phase 2b trial for rCDI.
• Twenty (20) PUNCH CD 2 patients in the placebo arm met response criteria of no CDI recurrence within 8 weeks.
• To contextualize this placebo response observation, we conducted a meta-analysis of response rates among placebo-treated patients in additional rCDI trials.

Methods

• Five (5) blinded, randomized, and placebo-controlled trials were included in this meta-analysis ^1-5.
• Studies required patients to have ≥15 or >21-4 prior CDI recurrences.
• All patients completed standard-of-care antibiotic course prior to experimental treatment.
• Four (4) studies tested a vehicle placebo administered by the same route as the active treatment (oral, intravenous, or enema) 1,2,4,5, and 1 study tested an autologous fecal transplant administered via enema.
• Response to treatment was defined as no CDI recurrence within 8-12 weeks.
• The proportional response rates with 95% confidence interval were calculated and compared in aggregate and among studies.

Results

• A total of 154 of 292 placebo-treated patients (53%) met study specific response criteria.
• Placebo response rates ranged from 43%-58%.
• No study group presented a significantly different outcome from the aggregate cohort.
• No correlation of response with placebo administration route was observed.

Conclusions

• This meta-analysis demonstrates that response rates for blinded placebo-treated patients are consistent among 5 trials of experimental rCDI therapeutics, including a phase 2B trial of RBX2660.
• This analysis provides a useful framework for interpreting published rCDI trials, and for designing and interpreting future rCDI therapeutics trials.
• Further evaluation of placebo response in rCDI patients is warranted.

References

1. Dubberke E et al. Presented at Infectious Diseases Week 2016, New Orleans, LA.
2. Seres Therapeutics [news release]. Cambridge, MA: Seres Therapeutics, Inc. communication; July 29, 2016. http://ir.serestherapeutics.com/phoenix.zhtml?c=254006&p=irol-newsArticle&ID=2240833. Accessed May 16, 2017.
3. Kelly CR et al. Ann Intern Med . 2016:165:609-616.
4. Wilcox MH et al. N Engl J Med. 2017;376:305-317.
5. Surawicz CM et al. Clin Infect Dis . 2000;31:1012–7.