Erik R. Dubberke, MD, MSPH; Christine Lee, MD; Robert Orenstein, DO and Sahil Khanna, MBBS, MS; Gail Hecht, MD; Joseph Fraiz, MD
- Experience indicates microbiota-based therapies are highly efficacious at preventing Clostridium difficile (CDI) recurrences.
- There is a need for high-quality data on efficacy and safety.
- The PUNCH CD 2 trial was a randomized, placebo-controlled, double-blinded study to assess the safety and efficacy of RBX2660, a microbiota-based drug targeted at recurrent CDI.
- Patients with recurrent CDI were randomized to: 2 doses of RBX2660 (Group A); 2 doses of placebo (Group B); or 1 dose of RBX2660 and 1 dose of placebo (Group C) via enema with doses 7 days apart.
- Control of CDI symptoms with antibiotics was required prior to enrollment. Antibiotics were discontinued 24-48 hours prior to the first enema.
- Failures could receive up to 2 doses of open-label active treatment, 7 days apart, Figure 1.
- Safety was assessed via a patient diary: in clinic at 1, 4, and 8 weeks and via telephone at 2, 3 and 5-7 weeks and at 3, 6, 12 and 24 months. Durability was assessed concurrently and is on-going until 24 months.
- Assess dosing strategy for RBX2660
- Efficacy of 1 vs. 2 doses; timing of doses
- Long-term safety of RBX2660
Major Inclusion Criteria
- Age ≥ 18 years old
- A positive stool test for Clostridium difficile within 60 days prior to enrollment
- At least two recurrences of CDI after a primary episode
- At least two episodes of severe CDI resulting in hospitalization
Major Exclusion Criteria
- History of inflammatory bowel disease (ulcerative colitis, Crohn’s disease or microscopic colitis); irritable bowel syndrome; chronic diarrhea; celiac disease
- Evidence of active colitis
- Known exposure to antibiotics within 6 months after study enrollment
- Compromised immune system
- White blood cell count <1000 cells/μL
- Microbiota-based drug manufactured from live human-derived microbes using standardized processes and controls.
- Each unit of RBX2660 is identified by a unique batch number and is traceable to a specific donor and recipient.
Definition of Success
- The absence of CDI associated diarrhea -without the need for retreatment with a Clostridium difficile anti-infective therapy or fecal transplant through 8 weeks after administration of the second dose of the assigned treatment in the blinded phase.
Definition of Failure (All 4 Criteria Required)
- Presence of diarrhea, with or without other CDI symptoms, at <8 weeks after last treatment
- A positive stool test for Clostridium difficile
- Need for retreatment for CDI
- No other cause for diarrhea identified
- A total of 127 patients at 21 sites in the U.S. and Canada were enrolled between December 10, 2014 through November 13, 2015 were included in the intent-to-treat analysis:
- Group A (2 doses of RBX2660): n=41
- Group B (2 doses of placebo): n=44
- Group C (1 dose of RBX2660 and 1 dose of placebo: n=42
- The median age was: 63.0, range: 18-92 years; sex: 62% female; median prior CDI episodes (4 range: 2-14), Table 1.
- Group C (1 dose) was superior to Group B (placebo): 66.7%, 28/42 vs. 45.5%, 20/44, P=0.048.
- There was no difference between Group A: 2 doses (61%, 25/41) vs. Group C: 1 dose (66.7%), P=0.589.
- The combined success in Groups A and C (1 or 2 doses) was superior to Group B: placebo, 63.9% vs. 45.5%, P=0.046.
- Of patients in groups A and C who went on to receive open-label treatment, 70% succeeded (21/30).
- 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.
- For all patients who were randomized to receive at least 1 active treatment (Groups A and C), the overall success (blinded and open-label) was 89.2% (n=74/83) compared with a 45.5% (20/44) placebo response, P < 0.0001, Figure 2.
- There were 580 adverse events (AEs) reported in 94 patients and 45 serious AEs in 26 patients with a mean follow-up of 8.3 months, Table 2.
- AEs were primarily gastrointestinal (n=242, 41.7%).
- There were no unanticipated AEs and there was no significant difference in proportion of AEs or serious AEs among the treatment groups.
- Of the patients who received at least 1 active treatment and were successful, the long-term CDI-free rate (median follow-up: 8.3 months; range: 1.6 to 14.9 months) was 95.8%.
- Of these patients, 4.2% developed a new episode of CDI confirmed by a positive test > 8 weeks after that last RBX2660 treatment.
- One recurrence occurred after antibiotics for a dog bite and one during a hospital stay for small bowel obstruction. Reasons were unknown for 2 cases.
- RBX2660 administered via enema is a safe and effective and effective treatment for recurrent CDI.
- Overall efficacy of RBX2660 was 89.2% in a randomized, double-blinded, placebo-controlled study in patients with recurrent CDI.
- AEs were primarily gastrointestinal; there were no unanticipated AEs.
- RBX2660 provided a durable cure.
- The results were consistent with those achieved in the open-label PUNCH CD trial.1
- Orenstein R, Dubberke E, Hardi R, et al. Safety and durability of RBX2660 (microbiota suspension) for recurrent Clostridium difficile infection: results of the PUNCH CD study. Clin Infect Dis. 2016;62:596-602.