Background: ACT (MK-3415) and BEZ (MK-6072) are human monoclonal antibodies against C. difficile toxins A and B, respectively.
Methods: Combined data from 2 double-blind, randomized, phase 3 studies in adult patients receiving oral SoC (metronidazole, vancomycin, or fidaxomicin) for primary or recurrent CDI, 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. rCDI (new episode of diarrhea and positive stool test for toxigenic C. difficile after clinical cure of baseline CDI episode) was the primary endpoint, and global cure (clinical cure of initial episode and no rCDI) was a secondary endpoint; both were evaluated through Week 12.
Results: 2655 patients (median age 66 years, 57% female) enrolled in 30 countries and 2580 (97%) received the study infusion. Baseline characteristics were balanced across treatment groups. In MODIFY I, the ACT alone group was stopped for efficacy 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. rCDI rates were significantly lower for ACT+BEZ (15.4%) and for BEZ alone (16.5%) vs placebo (26.6%, both 1-sided p<0.0001) 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=0.0001) vs placebo and higher for ACT+BEZ (58.1%, 1-sided p=0.0426) vs placebo (53.7%). Safety endpoints were comparable for ACT+BEZ and BEZ alone vs placebo. The most common adverse events were diarrhea (5.9%), nausea (5.9%), and CDI (4.2%).
Conclusion: In patients receiving SoC therapy for CDI and rCDI, a single infusion of ACT+BEZ or BEZ alone decreased rCDI, both overall and in at-risk subgoups, increased global cure vs placebo over 12 weeks, and was generally well tolerated with a safety profile similar to placebo.
Merck: Scientific Advisor , Research grant
I. Poxton, Merck: Scientific Advisor , Research support
C. Kelly, Merck: Scientific Advisor , Research support
R. Nathan, Merck: Investigator , Research support
O. Cornely, Merck: Investigator , Research support
G. Rahav, Merck: Investigator , Research support
C. Lee, Merck: Investigator , Research support
K. Eves, Merck: Employee and Shareholder , Salary
A. Pedley, Merck: Employee and Shareholder , Salary
R. Tipping, Merck: Employee and Shareholder , Salary
D. Guris, Merck: Employee and Shareholder , Salary
N. Kartsonis, Merck: Employee and Shareholder , Salary
M. B. Dorr, Merck: Employee and Shareholder , Salary
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