SYN-004 (Ribaxamase), an Orally Administered β-Lactamase for Prevention of Clostridium Difficile Infection in Patients Treated with Intravenous β-Lactam Antibiotics: A Randomized, Double-Blind, Placebo-Controlled Phase 2b Study

Background: Clostridium difficile infection (CDI) is an urgent public health threat, yet there is no product currently licensed for its prevention. The use of intravenous β-lactam antibiotics are considered high risk for the development of CDI due to their biliary excretion into the GI tract and disruption of the gut microbiome. SYN-004 (ribaxamase) is an orally-administered β-lactamase, designed to be given with IV β-lactam antibiotics to degrade excess antibiotics in the upper GI tract before they can disrupt the gut microbiome leading to CDI. Methods: A parallel-group, double-blind, placebo-controlled, multi-center, study evaluating the effectiveness of ribaxamase for prevention of CDI was conducted in 412 hospitalized patients > 50 years of age who received intravenous ceftriaxone for a lower respiratory tract infection (LRTI). Patients were randomized 1:1 to receive either 150 mg of ribaxamase or placebo four times per day during and for 72 hours after ceftriaxone treatment. The primary endpoint was the incidence of CDI through 4 weeks post-treatment in the ribaxamase vs. the placebo group. Secondary endpoints included resolution of the LRTI, new colonization by certain opportunistic pathogens, and microbiome-focused exploratory endpoints. Findings: Of 412 patients (mean age ~69·5), 206 each received ceftriaxone plus ribaxamase or ceftriaxone plus placebo. By 4 weeks post-antibiotics, the incidence of CDI in the placebo group was 3·4% while the incidence of C. difficile infection in the ribaxamase group was only 1·0% which corresponds to a 71% reduction in the incidence of C. difficile infection (one-sided, P=0·045). Patients who received ribaxamase also had a lower incidence of new fecal colonization with C. difficile and vancomycin resistant enterococci. Interpretation: In patients being treated with intravenous ceftriaxone for a LRTI, oral ribaxamase significantly reduced the incidence of CDI as compared with placebo. Ribaxamase has the potential to become the first product licensed for prevention of CDI. Trial registration number: The trial was registered at clinicaltrials.gov: NCT02563106. Funding: Synthetic Biologics, Inc. Declaration of Interest: All authors are employees or paid consultants of Synthetic Biologics, Inc. Ethical Approval: The study protocol was approved by the appropriate institutional review boards or ethics committees at the corresponding institutions or countries. All study patients provided written informed consent to participate in the study.