A phase 3 randomized trial of sulopenem vs. ertapenem in patients with complicated intra-abdominal infections.

Objective: To demonstrate the non-inferiority of intravenous (IV) sulopenem to IV ertapenem, each followed by an oral regimen, in adults with complicated intra-abdominal infections (cIAI).

Methods: Hospitalized adults with cIAI were randomly assigned to 5 days of IV sulopenem followed by oral sulopenem etzadroxil/probenecid twice daily or 5 days of IV ertapenem followed by oral ciprofloxacin/metronidazole or amoxicillin-clavulanate depending on baseline pathogen susceptibility. The target treatment duration was 7-10 days. The primary (FDA [Food and Drug Administration]-specified) endpoint was clinical response at day 28 (test-of-cure) in the micro-modified intent-to-treat (micro-MITT) population.

Results: A total of 674 patients were randomly assigned. The two treatment arms were well balanced. Escherichia coli (395 patients) and Bacteroides fragilis (111 patients) were the most frequently isolated pathogens. Clinical success rates in the micro-MITT population were 81.9% (204/249) for sulopenem-treated patients and 87.9% (233/265) for ertapenem-treated patients. The lower bound of the CI for the treatment difference of the primary endpoint was below the pre-specified non-inferiority margin of -10.0 (treatment difference -6.0%, 95% CI, [-12.2 to 0.2]). In all other analysis populations, the lower limit of the 95% CI was above -10.0. Treatment-emergent adverse events (all, 26.0% [87/335] vs. 23.4% [78/333]; related, 6.0% [20/335] vs. 5.1% [17/333]) were similar for sulopenem and ertapenem, respectively. Most events were mild to moderate in severity. There were more serious adverse events in the sulopenem arm (7.5% [25/335] vs. 3.6% [12/333]), only two of which were considered possibly drug-related.

Discussion: Sulopenem IV followed by oral sulopenem etzadroxil/probenecid was not non-inferior to ertapenem followed by oral step-down in treating cIAI in the micro-MITT population. This finding should be interpreted in the context of country regulations, as endpoint timing, primary analysis population and non-inferiority margin may vary regionally. Both IV and oral sulopenem were well-tolerated; the oral formulation allowed patients with resistant pathogens to step-down from IV therapy.