Phase 2/3, Open-label, Randomized, Active-controlled Clinical Trial Evaluating the Safety and Efficacy of Imipenem/Cilastatin/Relebactam in Pediatric Patients From Birth to Less Than 18 Years With Gram-negative Bacterial Infections

BACKGROUND: Imipenem/cilastatin/relebactam (IMI/REL), a fixed-dose combination of imipenem/cilastatin with the β-lactamase inhibitor relebactam, has broad gram-negative coverage. Prospectively obtained safety and efficacy data in neonates and children are needed. METHODS: Children (birth to <18 years old) with hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), complicated intra-abdominal infection (cIAI) and complicated urinary tract infection (cUTI), including pyelonephritis, were enrolled in an open-label, randomized, active-controlled, multinational phase 2/3 trial (ClinicalTrials.gov: NCT03969901). Participants were randomized 3:1 to IMI/REL or active-control, standard-of-care antibacterial therapy for 7-14 days (HABP/VABP; intravenous [IV] only) or 5-14 days (cIAI, cUTI; with oral step-down permitted after 3 days of IV). The primary endpoint was safety, assessed through 14 days after the end of therapy (EOT) as adverse events (AEs) and AE-related discontinuations of IV therapy. Clinical and microbiologic responses were also assessed at EOT and follow-up visits. This was an estimation study without hypothesis testing. RESULTS: Eighty-six children were randomized to IMI/REL and 29 to active control. AEs were reported in 67.1% of IMI/REL versus 50.0% of active control arm participants (treatment difference: 17.1% [95% confidence interval: -3.5, 37.2]), leading to 3 versus 0 discontinuations of IV therapy, respectively. Treatment outcomes were generally comparable at all time points; at EOT, clinical response was 78.8% versus 75.0% and microbiologic response 95.6% versus 90.9% with IMI/REL and active control, respectively, with no mortality in either arm. CONCLUSIONS: IMI/REL was generally well tolerated in neonates and older pediatric patients with HABP/VABP, cIAI, or cUTI, with safety and efficacy profiles comparable to standard-of-care antibacterial therapy.