IGNITE4: Results of a Phase 3, Randomized, Multicenter, Prospective Trial of Eravacycline vs Meropenem in the Treatment of Complicated Intraabdominal Infections

Abstract

Background Increasing antimicrobial resistance among pathogens that cause complicated intraabdominal infections (cIAIs) supports the development of new antimicrobials. Eravacycline, a novel member of the fluorocycline family, is active against multidrug-resistant bacteria including extended-spectrum β-lactamase (ESBL) and carbapenem-resistant Enterobacteriaceae. Methods IGNITE4 was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either eravacycline 1 mg/kg every 12 hours or meropenem 1 g every 8 hours intravenously for 4–14 days. The primary objective was to demonstrate statistical noninferiority (NI) in clinical cure rates at the test-of-cure visit (25–31 days from start of therapy) in the microbiological intent-to-treat population using a NI margin of 12.5%. Microbiological outcomes and safety were also evaluated. Results Eravacycline was noninferior to meropenem in the primary endpoint (177/195 [90.8%] vs 187/205 [91.2%]; difference, –0.5%; 95% confidence interval [CI], –6.3 to 5.3), exceeding the prespecified margin. Secondary endpoints included clinical cure rates in the modified ITT population (231/250 [92.4%] vs 228/249 [91.6%]; difference, 0.8; 95% CI, –4.1, 5.8) and the clinically evaluable population (218/225 [96.9%] vs 222/231 [96.1%]; (difference, 0.8; 95% CI –2.9, 4.5). In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 87.5% (14/16) and 84.6% (11/13) in the eravacycline and meropenem groups, respectively. Eravacycline had relatively low rates of adverse events for a drug of this class, with less than 5%, 4%, and 3% of patients experiencing nausea, vomiting, and diarrhea, respectively. Conclusions Treatment with eravacycline was noninferior to meropenem in adult patients with cIAI, including infections caused by resistant pathogens. Clinical Trials Registration NCT01844856.

Evaluation of Eravacycline: A Novel Fluorocycline

“…The efficacy and safety of ERV in management of cIAI were evaluated in one phase II and two phase III, randomized, double‐blind, active controlled trials: the IGNITE1 and the IGNITE4 trials Table . The phase II study evaluated the efficacy and safety of two ERV dosing regimens, 1.5 mg/kg every 24 hours and 1 mg/kg every 12 hours, compared to ertapenem 1 g every 24 hours for 4–14 days.…”

“…Randomized, Double‐blind, Double‐dummy, Comparative, Noninferiority, Multicenter, multinational (N=500) , …”

“…When clinical outcomes were evaluated in high‐risk subgroups (i.e., patients with advanced age, APACHE II score ≥ 10, complicated appendicitis, and open surgical procedures) from these trials, ERV remained effective in managing cIAI . Notably, carbapenemase‐producing pathogens only occurred in the meropenem group, but not the ERV group . Hence, this challenges the definite utility of ERV among CRE isolates, particularly with low numbers of these isolates in all clinical studies.…”

“…The FDA‐approved ERV dose is 1 mg/kg by intravenous infusion every 12 hours for 4–14 days. The dosing weight is the actual body weight . This dosing weight was based on a pooled analysis of the IGNITE1 and IGNITE4 trials, where patients were classified into six categories based on their body mass index (BMI) .…”

“…The dosing weight is the actual body weight . This dosing weight was based on a pooled analysis of the IGNITE1 and IGNITE4 trials, where patients were classified into six categories based on their body mass index (BMI) . Obese subjects comprised 32% of the overall population, and overweight subjects composed 35% .…”