Pooled analysis of the phase 3 REVIVE trials: randomised, double-blind studies to evaluate the safety and efficacy of iclaprim versus vancomycin for treatment of acute bacterial skin and skin-structure infections

• Published in: International journal of antimicrobial agents 2018-08, Vol.52 (2), p.233-240
• Main Authors: Huang, David B., Corey, G. Ralph, Holland, Thomas L., Lodise, Thomas, O'Riordan, William, Wilcox, Mark H., File, Thomas M., Dryden, Matthew, Balser, Barbara, Desplats, Eve, Torres, Antoni
• Format: Article
• Language: English
• Subjects: Acute bacterial skin and skin-structure infection; Acute Disease; Adult; Anti-Bacterial Agents - therapeutic use; Creatinine - blood; Double-Blind Method; Drug Administration Schedule; Female; Humans; Iclaprim; Male; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - growth & development; Microbial Sensitivity Tests; Middle Aged; Patient Safety; Pyrimidines - therapeutic use; Skin Diseases, Bacterial - drug therapy; Skin Diseases, Bacterial - microbiology; Staphylococcal Infections - drug therapy; Staphylococcal Infections - microbiology; Staphylococcus aureus - drug effects; Staphylococcus aureus - growth & development; Streptococcal Infections - drug therapy; Streptococcal Infections - microbiology; Streptococcus pyogenes - drug effects; Streptococcus pyogenes - growth & development; Treatment Outcome; Vancomycin; Vancomycin - therapeutic use
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2018.05.012

•Analysis of two phase 3 studies of iclaprim compared with vancomycin (VAN) for treatment of patients with ABSSSIs.•Iclaprim was non-inferior to VAN for early clinical response at the early time point.•Iclaprim was active against skin infections caused by MRSA, Streptococcus pyogenes and other Gram-positive pathogens.•Iclaprim was safe and well tolerated compared with VAN, except for a higher incidence of nephrotoxicity reported for VAN. Iclaprim, a diaminopyrimidine antimicrobial, was compared with vancomycin for treatment of patients with acute bacterial skin and skin-structure infections (ABSSSIs) in two studies (REVIVE-1 and REVIVE-2). Here, the efficacy and tolerability of iclaprim in a pooled analysis of results from both studies was explored. REVIVE-1 and REVIVE-2 were phase 3, double-blind, randomised, multicentre, active-controlled, non-inferiority (margin of 10%) trials, each designed to enrol 600 patients with ABSSSI using identical study protocols. Iclaprim 80 mg and vancomycin 15 mg/kg were administered intravenously every 12 h for 5–14 days. The primary endpoint was a ≥20% reduction from baseline in lesion size [early clinical response (ECR)] at the early time point (ETP) (48–72 h after starting study drug) in the intent-to-treat population. In REVIVE-1, ECR at the ETP was 80.9% with iclaprim versus 81.0% with vancomycin (treatment difference −0.13%, 95% CI −6.42% to 6.17%). In REVIVE-2, ECR was 78.3% with iclaprim versus 76.7% with vancomycin (treatment difference 1.58%, 95% CI –5.10% to 8.26%). The pooled ECR was 79.6% with iclaprim versus 78.8% with vancomycin (treatment difference 0.75%, 95% CI –3.84 to 5.35%). Iclaprim and vancomycin were comparable for the incidence of mostly mild adverse events, except for a higher incidence of elevated serum creatinine with vancomycin (n = 7) compared with iclaprim (n = 0). Iclaprim achieved non-inferiority compared with vancomycin for ECR at the ETP and secondary endpoints with a similar safety profile in two phase 3 studies for treatment of ABSSSI suspected or confirmed as caused by Gram-positive pathogens. [Clinical Trials Registration. NCT02600611 and NCT02607618.]