Placebo Response in a Randomized Controlled Trial of a Microbiota-based Drug Targeted at Recurrent C. difficile Infection: Results of the PUNCH CD 2

Sahil Khanna, MBBS, MS; Julie Messer, BS; Matt Adams, MS

Background

• Largely uncontrolled studies of microbiota-based therapies for recurrent C. difficile infection (CDI) have demonstrated excellent efficacy.
• Recently reported randomized, double-blinded, placebo-controlled studies of non-antibiotic therapies for multiply recurrent CDI, have found higher than anticipated placebo response rates.

Objective

• To assess predictors of placebo response in a randomized, double-blinded, placebo-controlled trial of RBX2660, a microbiota-based drug targeted at the prevention of recurrent CDI.

Methods

• Patients in the 3-arm PUNCH CD 2 trial were randomized 1:1:1 to receive either: 2 doses of RBX2660 (Group A); 2 doses of placebo (normal saline and cryoprotectant in the same proportions as RBX2660) (Group B); or 1 dose of RBX2660 and 1 dose of placebo (Group C), (Figure 1).
• Therapies were administered via enema with doses 7 days apart.
• Failures could cross over to open-label treatment and receive up to 2 doses of a CDI therapy, administered 7 days apart.
• Success was defined as the absence of C. difficile-associated diarrhea at 8 weeks following completion of the last treatment.
• Failure was defined as recurrence of CDI symptoms; a positive stool test; a need for CDI retreatment; and no other cause for CDI symptoms within 8 weeks.

RBX2660

• Each dose of RBX2660 consisted of 50 gm of human stool/150 mL of suspension in a single-dose ready-to-use enema bag.
• RBX2660 was stored frozen at ≤−80°C in a secure location at the manufacturer and then shipped frozen to the site in a temperature-controlled container.
• RBX2660 was manufactured using standardized, quality-controlled processes.

Results

• In the intention-to-treat population, a total of 44 patients (median age: 62; range: 19-92 years; 68.2% female) were randomized to the placebo arm.
• Of the patients treated with placebo, 45.5% (20/24) responded and 54.5% (24/44) failed.
• There were no significant differences in the age, gender, number of previous CDI episodes, or antibiotics used to control C. difficile symptoms prior to enrollment between patients who responded to placebo and those who did not (Table 1).
• All 24 patients who failed placebo (experienced recurrence) went on to receive open-label treatment with RBX2660. Of these patients, 87.5% (21/24) were successful when treated with RBX2660.

Conclusions

• The placebo response rate in the PUNCH CD 2 was higher than originally anticipated.
• There were no differences in the patient profiles, prior history of CDI and its treatment between the patients in the PUNCH CD 2 who responded to placebo and those who did not.
• 87.5% of patients who failed placebo were successful with open-label RBX2660.
• The placebo response rate in the PUNCH CD 2 study is consistent with other recent studies of drugs and therapies for recurrent CDI (Tables 2 and 3).
• Further studies are needed to explore reasons for the placebo response.

References

1. Kelly CR, Khoruts A, Staley C, et al. Effect of fecal microbiota transplantation on recurrence in multiply recurrent Clostridium difficile infection: A randomized trial. Ann Intern Med. 2016 Aug 23. Epub ahead of print.
2. Seres Therapeutics announces interim results from SER-109 Phase 2 ECOSPOR study in multiply recurrent Clostridium difficile infection [news release]. Cambridge, MA: Seres Therapeutics, Inc. communication; July 29, 2016. http://ir.serestherapeutics.com/phoenix.zhtml?c=254006&p=irol-newsArticle&ID=2190006. Accessed August 8, 2016.
3. Wilcox M, Gerding D, Poxton I, et al. Bezlotoxumab (BEX) alone and with actoxubab (ACT) for prevention of recurrent C. difficile infection (rCDI) in patients on standard of care (SoC) antibiotics: integrated results of 2 Phase 3 Studies (MODIFY 1 and MODIFY II). Abstract presented at ID Week 2015. October 7-11, 2016, San Diego, CA.