Comparison of Treatment Outcomes between Analysis Populations in the RESTORE-IMI 1 Phase 3 Trial of Imipenem-Cilastatin-Relebactam versus Colistin plus Imipenem-Cilastatin in Patients with Imipenem-Nonsusceptible Bacterial Infections

Abstract

The RESTORE-IMI 1 phase 3 trial demonstrated the efficacy and safety of imipenem-cilastatin (IMI) combined with relebactam (REL) for treating imipenem-nonsusceptible infections. The objective of this analysis was to compare the outcomes among patients meeting eligibility requirements based on central laboratory susceptibility versus local laboratory susceptibility. Patients with serious infections caused by imipenem-nonsusceptible, colistin-susceptible, and imipenem-REL-susceptible pathogens were randomized 2:1 to IMI-REL plus placebo or colistin plus IMI for 5 to 21 days. The primary endpoint was a favorable overall response. Key endpoints included the clinical response and all-cause mortality. We compared outcomes between the primary microbiological modified intent-to-treat (mMITT) population, where eligibility was based on central laboratory susceptibility testing, and the supplemental mMITT (SmMITT) population, where eligibility was based on local, site-level testing. The SmMITT (n = 41) and MITT (n = 31) populations had similar baseline characteristics, including sex, age, illness severity, and renal function. In both analysis populations, favorable overall response rates in the IMI-REL treatment group were >70%. Favorable clinical response rates at day 28 were 71.4% for IMI-REL and 40.0% for colistin plus IMI in the mMITT population, whereas they were 75.0% for IMI-REL and 53.8% for colistin plus IMI in the SmMITT population. Day 28 all-cause mortality rates were 9.5% for IMI-REL and 30.0% for colistin plus IMI in the mMITT population, whereas they were 10.7% for IMI-REL and 23.1% for colistin plus IMI in the SmMITT population. The outcomes in the SmMITT population were generally consistent with those in the mMITT population, suggesting that outcomes may be applicable to the real-world use of IMI-REL for treating infections caused by imipenem-nonsusceptible Gram-negative pathogens. (This study has been registered at ClinicalTrials.gov under identifier NCT02452047.).

Keywords: carbapenem resistant; local microbiology data; supplemental analysis population; β-lactamase inhibitor.

FIG 1

Trial enrollment and summary of patients in analysis populations. IMI, imipenem-cilastatin; mMITT, microbiological modified intent-to-treat; REL, relebactam; SmMITT, supplemental microbiological modified intent-to-treat.

FIG 2

Assessment schedule. ^a, from specimen types of interest: blood, urinary, intra-abdominal, or lower respiratory tract sources. CST, colistin; EFU, early follow-up; EOT, end of therapy; IMI, imipenem-cilastatin; i.v., intravenous; REL, relebactam; SOP, standard operating procedure.