Sahil Khanna MBBS, MS, Ken Blount PhD, Courtney Jones BS, Bill Shannon PhD MBA, Sharina Carter PhD
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Infectious Diseases Week (ID Week)
October 4-8, 2017, San Diego, CA
Background
- Recurrent Clostridium difficile infections (rCDI) are associated with decreased taxonomic diversity in patients’ intestinal microbiome compared to healthy microbiomes
- RBX2660 is a standardized microbiota-based drug designed to rehabilitate a patient’s intestinal microbiome
- The effect of RBX2660 on rCDI patient microbiomes was evaluated by comparing pre- and post-treatment samples collected from PUNCH CD 2—a multicenter, randomized, double-blind, placebo-controlled study
- Microbiome profiles from RBX2660 responders (Successes) were compared to those from non-responders (Failures)
Methods
- Patients with rCDI were enrolled in the PUNCH CD2 trial and randomized to receive blinded treatment by enema of 2 doses of RBX2660 (GroupA), 2 doses of placebo (Group B), or 1 dose of RBX2660 and 1 dose of placebo(Group C), with doses 7 days apart (Figure 1)
- Success was defined as the absence of CDI at 8 weeks following completion of the last treatment. Patients were classified as a treatment failure if all four(4) of the following criteria were met: recurrence of diarrhea less than 8 weeks after administration of the last assigned study enema, a positive laboratory diagnosis of C. dfficile as conducted and reported by the study investigator, a need for retreatment for CDI, and no other cause for diarrhea
- Patients voluntarily submitted stool samples at baseline (pre-treatment) 7, 30, and 60 days after treatment
- 16s rRNA analysis using the Illumina MiSeq platform was performed on stool samples collected from patients who received at least one dose of RBX2660 (Groups A & C)
- The variable region V4 was targeted to identify the operational taxonomic units (OTUs) in each sample
- Relative abundance data from subject samples were grouped longitudinally and compared among groups using a Bray-Curtis dissimilarity calculation with non-metric multi-dimensional scaling. Additional analyses were performed based on the Dirichlet-Multinomial distribution to compare group mean relative taxonomic abundances (pi) and within group over dispersion (theta)
- The microbial diversity was analyzed based on Shannon and Simpson indices
- Differentiation between sample communities were visualized using a Kullback-Leibler (KL) divergence analysis model (BioRankings, St. Louis, MO), a measure of the difference between microbial diversity at different time points or between different samples
Results Summary
- RBX2660 successes have different microbiota composition at 7 and 30 daysrelative to baseline (Figure 3)
- RBX2660 failures have similar microbiota composition at 7 and 30 daysrelative to baseline (Figure 3)
- RBX2660 treatment increased Shannon and Simpson diversity at 7 dayspost-treatment in successes but not in failures (p<0.05; Figure 4)
- Taxonomic classes that diverged the most at baseline showed the largestlongitudinal post-treatment change (Figure 5)
Results
- 140 stool samples collected from 58 patients who received at least one dose of RBX2660 (Groups A and C) were analyzed (Table 1)
Conclusion
- We observe a general trend of the microbiomes among RBX2660 Successes toward a healthier composition, with higher Bacteroidia and Clostridia and lower Gammaproteobacteria and Bacilli
- RBX2660 treatment appears to increase microbiome diversity
- For this trial, there do not appear to be differences at baseline that predict response or failure