Results of phase III trial of the efficacy and safety of Recarbrio v. piperacillin and tazobactam in adult patients with HABP/VABP .- Merck Inc.,

Merck Inc., announced results from RESTORE-IMI 2, a randomized, controlled, double-blind Phase III clinical trial evaluating Recarbrio (imipenem, cilastatin, and relebactam) for the treatment of adults with hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP). The results demonstrated non-inferiority of Recarbrio compared to piperacillin and tazobactam (PIP/TAZ), the active comparator, in the primary and key secondary endpoints of the study, 28-day all-cause mortality and clinical response, respectively.

In February 2020, the FDA accepted for review a supplemental New Drug Application (sNDA) for use of Recarbrio in this patient population. The FDA Prescription Drug User Fee Act (PDUFA) goal date is June 4, 2020. Phase III trial data are now available in a compendium of presentations posted by Merck, coinciding with publication of study abstracts by the 30th European Congress of Clinical Microbiology & Infectious Diseases (ECCMID).

RESTORE-IMI 2 Design : RESTORE-IMI 2 was a Phase III multinational, randomized, double-blind, non-inferiority trial evaluating the efficacy and safety of Recarbrio versus PIP/TAZ in adult patients with HABP/VABP. In the study, 537 patients at 113 clinical trial sites were randomized 1:1 to receive a dose of Recarbrio (imipenem 500 mg/cilastatin 500 mg/relebactam 250 mg) or PIP/TAZ (piperacillin 4000 mg/tazobactam 500 mg), each given intravenously every six hours for seven to 14 days. Patients in both treatment groups also received open label empiric linezolid (600 mg) until baseline cultures confirmed absence of methicillin-resistant Staphylococcus aureus (MRSA). The primary endpoint was Day 28 all-cause mortality and the key secondary endpoint was clinical response at early follow-up (seven to 14 days after completing therapy).

RESTORE-IMI 2 Results : Recarbrio met its primary and key secondary endpoints, demonstrating non-inferiority compared to PIP/TAZ. For patients treated with Recarbrio, Day 28 all-cause mortality (primary endpoint) was 15.9% (42/264) compared with 21.3% (57/267) in those treated with PIP/TAZ (adjusted treatment difference: 5.3%, 95% confidence interval [CI]: -11.9, 1.2). For patients treated with REcarbrio, a favorable clinical response at early follow-up (key secondary endpoint) was observed in 60.9% (161/264) compared with 55.8% (149/267) in the PIP/TAZ group (adjusted treatment difference: 5%, 95% CI: -3.2, 13.2). Rates of overall adverse events (AEs) were similar between treatment groups, with 84.9% (226/266) in the Recarbrio arm vs. 86.6% (233/269) in the PIP/TAZ arm, reporting at least one AE.

AEs classified as drug-related by the investigator were 12% (31/266) in the Recarbrio arm vs. 10% (26/269) in the PIP/TAZ arm. Additionally, therapy discontinuations due to any AE were similar in both groups, with 6% (15/266) in the Recarbrio arm vs. 8% (22/269) in the PIP/TAZ arm. Therapy discontinuations due to drug-related AEs were also similar: 2.3% (6/266) in the Recarbrio arm vs. 1.5% (4/269) in the PIP/TAZ arm. The most frequently reported (>5 patients) drug-related AEs in the Recarbrio arm were diarrhea and elevated levels of the liver function biomarkers alanine aminotransferase and aspartate aminotransferase (2% each [6/266]).