Phase 2, dose-ranging study of relebactam with imipenem

Abstract

Relebactam (REL, MK-7655) is a novel class A/C ß-lactamase inhibitor intended for use with imipenem for the treatment of Gram-negative bacterial infections. REL restores imipenem activity against some resistant strains of Klebsiella and Pseudomonas. In this multicenter, double-blind, controlled trial (NCT01506271), subjects ≥18 years of age with complicated intra-abdominal infection were randomly assigned (1:1:1) to receive REL 250 mg, REL 125 mg, or placebo, each given IV with imipenem/cilastatin 500 mg (IMI) every 6 hours for 4-14 days. The primary efficacy endpoint was the proportion of microbiologically evaluable (ME) subjects with a favorable clinical response at discontinuation of IV therapy (DCIV). A total of 351 subjects were randomized, 347 (99%) were treated, and 255 (73%) were ME at DCIV (55% male, mean age 49 years). The most common diagnoses were complicated appendicitis (53%) and complicated cholecystitis (17%). Thirty-six subjects (13%) had imipenem-resistant Gram-negative infections at baseline. Both REL doses + IMI were generally well tolerated and demonstrated safety profiles similar to that of IMI alone. Clinical response rates at DCIV were similar in subjects who received REL 250 mg + IMI (96.3%) or REL 125 mg + IMI (98.8%), and both were non-inferior to IMI alone (95.2%; one-sided p<0.001). The treatment groups were also similar with respect to clinical response at early and late follow-up, and microbiological response at all visits. PK/PD simulations show that imipenem exposures at the proposed dose of IMI 500 mg with REL 250 mg q6h provide coverage of >90% of carbapenem-resistant bacterial strains.