Clinical efficacy of RECARBRIO™ (imipenem, cilastatin, and relebactam)
Supporting the case for RECARBRIOTM (imipenem, cilastatin, and relebactam)
A multinational, randomized, double-blind, active-controlled phase 3 trial in adult patients with HABP or VABP1
aMITT population is defined as all randomized participants who received at least 1 dose of trial treatment and did not have only Gram-positive cocci on Gram stain of the baseline lower respiratory tract specimen.
The mean age was 60 and 43% were 65 years of age or older. The mean APACHE II score was 15 and 47% of the population had an APACHE II score of ≥15. At randomization, 66% of patients were admitted to the ICU, 77% had been in the hospital for ≥5 days, and 48% had a creatinine clearance of <90 mL/min. Concurrent bacteremia was present at baseline in 5.8% of patients.
Day 28 all-cause mortality in MITT population
RECARBRIO achieved primary endpoint of noninferiority vs piperacillin/tazobactam in day 28 all-cause mortality1
RECARBRIO demonstrated a favorable response in certain high-risk subgroups1
- Ventilated HABP and VABP patients
- Patients with APACHE II scores ≥15
Additional clinical data2
In a noninferential trial vs colistin + imipenem…
- A noninferential, prospective, randomized, double-blind trial compared RECARBRIO as monotherapy (imipenem/relebactam) to dose-optimized colistin (loading dose to achieve 300 mg colistin base activity, followed by maintenance doses up to 150 mg colistin base activity, every 12 hours) + imipenem (500 mg every 6 hours) in hospitalized adult patients
- Patients had bacterial infections that were imipenem nonsusceptible but susceptible to imipenem plus relebactam as well as to colistin
- Primary analysis population: microbiological modified intent-to-treat, determined by meeting microbiological entry criteria, receiving ≥1 dose of study drug, and cultures collected within 1 week of enrollment confirming ≥1 qualifying Gram-negative pathogen from the primary infection site
This was a noninferential, descriptive, estimation trial without formal statistical testing for efficacy endpoints. The trial had several limitations, including the small sample size. Sample size was based on logistical feasibility and not statistical considerations. The trial was intended to generate limited clinical data in target population as part of a streamlined drug development program.
- All-cause mortality through day 28 postrandomization in patients with HABP/VABP
- Clinical response at day 28 postrandomization for patients with complicated intra-abdominal infection (cIAI)
- The composite clinical and microbiological response 5-9 days after therapy for patients with complicated urinary tract infection (cUTI)
Secondary endpoints include
- All-cause mortality: RECARBRIO 9.5% (n=2/21); colistin 30.0% (n=3/10)
- Clinical response at day 28: RECARBRIO 71.4% (n=15/21); colistin 40.0% (n=4/10)
- Treatment-emergent nephrotoxicity: RECARBRIO 10.3% (n=3/29); colistin 56.3% (n=9/16)
In patients with normal baseline renal function (serum creatinine <1.2 mg/dL), nephrotoxicity was defined as serum creatinine doubling (to >1.2 mg/dL) or ≥50% CLcr reduction. In patients with preexisting renal dysfunction (serum creatinine ≥1.2 mg/dL), nephrotoxicity was defined as serum creatinine increases ≥1 mg/dL, ≥20% CLcr reduction, or need for renal replacement therapy.
Adverse reactions in this noninferential study
The most frequently reported adverse events occurring in 2 or more patients treated with RECARBRIO were pyrexia, increased AST, increased ALT, nausea, and decreased CLcr.
The safety population comprised all randomized patients with ≥1 dose of study treatment according to the actual treatment received.
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1. Titov I et al. Clin Infect Dis. Published online August 12, 2020. doi.org/10.1093/cid/ciaa803 2. Motsch J et al. Clin Infect Dis. 2020;70(9):1799-1808.
APACHE II, Acute Physiology and Chronic Health Evaluation II; BLI, beta-lactamase inhibitor; HABP, hospital-acquired bacterial pneumonia; ICU, intensive care unit; IV, intravenous; MITT, modified intent-to-treat; Q6H, every 6 hours; VABP, ventilator-associated bacterial pneumonia; vHABP, ventilated hospital-acquired bacterial pneumonia.