Donors are Universal in the Fight Against Clostridium difficile: Results from Two Trials Investigating the Safety and Efficacy of RBX2660, a Microbiota-based Drug

Arnab Ray, MD, Courtney Jones, BS, Bill Shannon, PhD, MBA, Sharina Carter, BSr

Donors are Universal in the Fight Against Clostridium difficile: Results from Two Trials Investigating the Safety and Efficacy of RBX2660, a Microbiota-based Drug DDW 2017 poster image

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Digestive Diseases Week
May 6-9, 2017, Chicago, IL

Background

  • Live microbial therapies are becoming an increasingly accepted treatment for recurrent Clostridium difficile infection (CDI).
  • Questions remain regarding factors contributing to therapeutic success, including donor influence on patient outcome.
  • RBX2660 is a microbiota-based drug derived from healthy human donors.
  • The impact of donor on clinical outcome following RBX2660 treatment was evaluated in two clinical trials: PUNCH CD, an open label clinical trial, and the blinded phase of PUNCH CD 2, a randomized, double-blind, placebo-controlled trial.

Methods

Donor Sourcing and Traceability

  • Donors underwent pre-enrollment blood and stool pathogen screening as well as extensive health history reviews prior to acceptance into the program.
  • All drug product associated with that donor during a cycle is destroyed if a positive result is detected for any test.
  • Four donors were used to prepare the RBX2660 used in the PUNCH CD study. Seventeen donors were used to prepare the RBX2660 used in the PUNCH CD 2 study.
  • Donations were made on site at Rebiotix Inc., Roseville, MN.
  • Donations were not pooled allowing for direct donor to patient traceability.
  • Donors were randomized to patients for both the first and second doses.

RBX2660

  • Each dose of RBX2660 is 150 mL of microbial suspension is packaged in a ready-to-use enema format.
  • Manufactured using standardized, quality-controlled processes with guaranteed minimum quantity of microbes.
  • In both studies, donor batches were randomized to the patient, and randomized again for the second dose. Patients could receive product from the same or different donors.

Clinical Studies

  • Patients in the PUNCH CD (Phase 2) – an open label study where patients received 1 dose of RBX2660, with opportunity to receive a second dose.
  • Patients in the PUNCH CD 2 (Phase 2B) trial were randomized to receive either: 2 doses of RBX2660; 2 doses of placebo; or 1 dose of RBX2660 followed by 1 dose of placebo. Therapies were administered via enema with doses 7 days apart.
  • Success was defined as the absence of C. difficile-associated diarrhea at 8 weeks following completion of the last treatment.

Mathematical Model

  • For each clinical study, a mixed model was used to predict treatment success taking into account donors and dose number.
  • Repeated measures data was included to account for patients who received 2 doses of RBX2660. A patient was classified as either a success or failure for each dose.
  • P<0.05 indicates statistical significance; all analyses were done using the R statistical package.

Results

Results from PUNCH CD1

  • A total of 34 patients enrolled in the PUNCH CD Phase 2 trial (mean age 68.8 years, 67.6% female) were treated with at least one dose of RBX2660. Fifteen patients received a second dose.
  • Success was not impacted by the donor or the dose order.

Results from PUNCH CD 22

  • A total of 83 patients enrolled in the PUNCH CD 2 Phase 2B trial (mean age 62 years; 59% female) received at least one dose of RBX2660 in the blinded arm of the study. Forty-one patients received 2 doses of RBX2660.
  • Success was not impacted by the donor or the dose order.
  • The donor was not significant (P>0.99).
  • The variance estimate refers to variation in outcome between donors. Variance = 0 indicates no difference in outcome based on donor.
  • One outcome (patient) may be associated with up to two different donors. Therefore, patients that received two doses of RBX2660 are represented twice.
  • RBX2660 generated from Donor 1 was administered in both clinical trials.
  • Successes and failures per Donor 1 were consistent across donors.

Conclusions

  • RBX2660 success in preventing recurrent CDI is not determined by specific donor.
  • Data from two separate clinical studies demonstrate that preparation of RBX2660 from a universal group of screened donors does not impact patient outcomes.
  • A super donor was not identified.
  • The role of donor in RBX2660 success for treatment of other clinical indications requires further study.

References

  1. Ray A, Jones C. Does the donor matter? Donor vs patient effects in the outcome of a next-generation microbiota-based drug trial for recurrent Clostridium difficile infection. Future Microbiol. 2016; 11:611-6.
  2. Ray A, Jones C, Shannon B, Carter S. Does the donor matter? Results from PUNCH CD 2, a Randomized Controlled Trial of a Microbiota-based Drug for Recurrent Clostridium difficile Infection, ACG 2016 Annual Scientific Meeting October 15-19, 2016, Las Vegas, NV.