Bezlotoxumab Alone and With Actoxumab for Prevention of Recurrent Clostridium difficile Infection in Patients on Standard of Care Antibiotics: Integrated Results of 2 Phase 3 Studies (MODIFY I and MODIFY II)

Abstract

Background. Actoxumab ((ACT) MK-3415) and bezlotoxumab ((BEZ) MK- 6072) are human monoclonal antibodies against Clostridium difficile toxins A and B, respectively. Methods. Combined data from 2 double-blind, randomized, phase 3 studies in adult patients receiving oral standard of care (SoC) (metronidazole, vancomycin, or fidaxomi- cin) for primary or recurrent Cd ifficile infection (rCDI), including multiple rCDI. In MODIFY I, patients received a single infusion of ACT + BEZ 10 mg/kg each (MK- 3415A), ACT 10 mg/kg alone, BEZ 10 mg/kg alone, or placebo. In MODIFY II, patients received a single infusion of ACT + BEZ, BEZ alone, or placebo. Entry criteria, study visits/ procedures, and efficacy/safety endpoints were the same for both studies. The rCDI (new episode ofdiarrhea andpositive stooltest fortoxigenic Cd ifficile afterclinical cure ofbase- line CDI episode) was the primary endpoint, and global cure (clinical cure of initial epi- sode and no rCDI) was a secondary endpoint; both were evaluated through week 12. Results. A total of 2655 patients (median age 66 years, 57% female) enrolled in 30 countries and 2580 (97%) received the study infusion. Baseline characteristics were ba- lanced across treatment groups. In MODIFY I, the ACT alone group was stopped for ef- ficacy and safety reasons after interim analysis, based on a predefined adaptive plan. In the full analysis set (N = 2327, ACT alone excluded), 53% of patients were ≥65 years of age, 27% had prior CDI, 17% had severe CDI, and 11% were infected with 027 ribotype. The rCDI rates were significantly lower for ACT+BEZ (15.4%) and for BEZ alone (16.5%) versus placebo (26.6%, both 1-sided, P<.0001) and were reduced relative to placebo in subgroups with risk factors for rCDI, including age ≥65 years, history of CDI, infected with 027 ribotype, and severe CDI. Global cure was superior for BEZ alone (63.5%, 1- sided P=.0001) versus placebo and higher for ACT+BEZ (58.1%, 1-sided P=0.0426) versus placebo (53.7%). Safety endpoints were comparable for ACT + BEZ and BEZ alone versus placebo. The most common adverse events were diarrhea (5.9%), nausea (5.9%), and CDI (4.2%) (table).