A Phase 3, Randomized, Double-Blind, Multicenter Study To Evaluate the Safety and Efficacy of Intravenous Iclaprim versus Vancomycin for Treatment of Acute Bacterial Skin and Skin Structure Infections Suspected or Confirmed To Be Due to Gram-Positive Pathogens (REVIVE-2 Study)

Study design and participants.The REVIVE-2 study was a double-blind, multicenter phase 3 noninferiority trial (ClinicalTrials.gov identifier NCT02600611). Patients were randomized 1:1 to treatment with either iclaprim at 80 mg intravenously (i.v.) every 12 h (q12h) (iclaprim) or vancomycin at 15 mg/kg i.v. q12h (vancomycin). This study design followed both Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidance. Patients were enrolled between April 2016 and August 2017. The institutional review board at each site approved the protocol, and all patients or their authorized representative provided written informed consent.

Male and female patients ≥18 years of age with a suspected or confirmed ABSSSI due to Gram-positive pathogens were eligible for study participation. An ABSSSI was defined as a bacterial infection of the skin with a lesion size of ≥75 cm². ABSSSIs were classified as major cutaneous abscesses, pure cellulitis/erysipelas, and/or wound infections (caused by external trauma [e.g., needle sticks or insect bites]) and had characteristics of the presence of purulent or seropurulent drainage before or after surgical intervention of a wound or at least 3 of the following signs and symptoms: discharge, erythema (extending at least 2 cm beyond a wound edge in one direction), swelling and/or induration, heat and/or localized warmth, and/or pain and/or tenderness to palpation. Key inclusion and exclusion criteria are listed in Table 5.

Iclaprim was administered at 80 mg (no hepatic impairment or a Child-Pugh score of A) or 40 mg i.v. q12h (a Child-Pugh score of B). Patients with a Child-Pugh score of C were excluded. Vancomycin was administered at 15 mg/kg i.v., and the dose was adjusted according to a nomogram with dosing every 12 h (creatinine clearance [CL_CR] ≥ 50 ml/min), every 24 h (CL_CR ≥ 35 to 49 ml/min), every 48 h (CL_CR ≥ 25 to 34 ml/min), or according to vancomycin trough levels (CL_CR < 25 ml/min) or creatinine clearance. The unblind pharmacist prepared the infusions for patients who were assigned to the vancomycin arm, maintaining the same infusion volume used for iclaprim. For each patient, the unblind pharmacist used the creatinine clearance or vancomycin trough levels (to which the investigator was blind) to adjust the vancomycin dosage to maintain a trough concentration of 10 to 15 mg/liter for patients with an organism with an MIC of ≤1 mg/liter or 15 to 20 mg/liter for those with an organism with an MIC of >1 mg/liter. Both iclaprim and vancomycin were infused over 120 min in 500 ml normal saline. Normal saline placebo infusions were used to maintain the blind when vancomycin was dosed at an interval greater than every 12 h.

The protocol permitted concomitant antibiotic treatment with aztreonam or metronidazole for patients in whom Gram staining of culturable material or cultures indicated Gram-negative and anaerobic bacteria, respectively. Systemic antibiotics (other than aztreonam and metronidazole) or topical antibiotics at the site of the ABSSSI under investigation were prohibited.

Patients received their first dose of randomly allocated study medication within 24 h after randomization. Study medications were administered for at least 5 days, with continuation of the treatment for up to 14 days occurring at the discretion of the investigator on the basis of an assessment of the resolution of signs and symptoms of the ABSSSI. This duration of treatment was in accordance with Infectious Diseases Society of America (IDSA) guidelines (11).

Clinical specimens for microbiologic evaluation, including pus from a wound or abscess and aspirate or a skin biopsy specimen from the leading edge of cellulitis, were obtained from patients prior to randomization. At subsequent visits, additional specimens were obtained for patients with persistent clinical signs or symptoms. Specimens were evaluated by the local microbiology laboratory, and the isolates were subcultured and sent to a central microbiology laboratory for confirmation of the pathogen identity and MICs. S. aureus genotyping was not performed for this study. In order to increase the identification of patients with ABSSSIs caused by Streptococcus pyogenes (e.g., cellulitis), the collection of leading-edge punch biopsy specimens was encouraged for patients with pure cellulitis, and serological tests (ASO titer determinations) were performed for all patients at the baseline and at the test of cure (2 to 3 weeks after the baseline). A beta-hemolytic streptococcus was considered present if the patient had an ABSSSI and an elevated titer of ASO at the baseline and/or at the test of cure or a 4-fold rise of the antibody titer at the test of cure from that at the baseline. Two sets of blood samples for aerobic/anaerobic cultures were obtained 10 min apart from different sites peripherally within the 24 h before the first dose of study drug.

Endpoints.The primary efficacy endpoint of the study was the proportion of patients who achieved an early clinical response (ECR), defined as a ≥20% reduction in lesion size compared with that at the baseline at the early time point (ETP) of 48 to 72 h after the start of administration of the study drug in the intent-to-treat (ITT) population. The secondary endpoints of the study included (i) the clinical cure rate at the test of cure (TOC), which was at 7 to 14 days after the last dose of study drug, as measured by both the traditional and modified composite TOC assessments in the ITT population (see below), and (ii) the safety and tolerability of iclaprim compared with those of vancomycin.

Clinical cure at the TOC visit, determined 7 to 14 days after the EOT, was evaluated using two prespecified definitions. First, clinical cure at the TOC visit was defined as the complete resolution of all signs and symptoms of ABSSSIs, such that no further antibiotic treatment or surgical procedure was needed. This definition of clinical cure is used for pivotal phase 3 studies of ABSSSIs (18). Second, a modified clinical cure at the TOC was also evaluated as a ≥90% reduction in the lesion size compared with that at the baseline, no increase in lesion size since the ETP, and no requirement for additional antibiotics (except aztreonam or metronidazole for polymicrobial infections) or unplanned significant surgical procedures after the ETP. This modified clinical cure was intended to allow for an additional measure (i.e., a 90% reduction in lesion size), similar to the early clinical response (ECR; i.e., a 20% reduction in lesion size).

Patients were evaluated at a baseline assessment, then evaluated daily through ETP, and then evaluated every 48 to 72 h through the EOT. The treatment duration was 5 to 14 days and was based on investigator assessment. Patients were then evaluated at the TOC assessment, conducted 7 to 14 days after the EOT, followed by a late follow-up phone call conducted 28 to 32 days after the first dose (Fig. 1).

Safety was assessed by the use of common terminology criteria for reported adverse events (AEs), serious adverse events (SAEs), hematology, clinical chemistry, liver function tests, coagulation, urinalysis, vital signs, physical examinations, and electrocardiograms (ECGs).

Statistical analysis.The statistical analyses evaluated the efficacy and safety of iclaprim compared with those of vancomycin. Statistical tests for efficacy analyses were two-sided and at a level of significance with an alpha value of 0.05. Confidence intervals (CIs) were calculated as a two-sided 95% confidence interval. Continuous data were summarized by treatment group using the number of patients in the analysis population (n), mean, standard deviation (SD), median, and range, and categorical data were summarized by treatment group using n and the percentage of patients. Demographics and baseline characteristics were summarized using descriptive statistics. The primary efficacy analysis was performed in the ITT population. Secondary analyses were performed in the ITT predefined populations that included patients with diabetes and mild, moderate, and severe renal impairment. By-patient and by-pathogen bacteriological outcomes at the EOT and TOC were presented as frequency distributions of outcomes by treatment group for patients with a confirmed Gram-positive pathogen at the baseline. The safety population was defined as all randomized patients who received at least one dose of study medication. The incidence of AEs was summarized at the overall patient level, the Medical Dictionary for Regulatory Activities (MedDRA; version 20.0) system organ class level, and preferred term level. Separate tabulations were provided by severity and relationship to the study medication and for SAEs. Laboratory data, vital signs, and ECGs were evaluated by presentation of summary statistics of raw data and changes from the baseline.

Six hundred patients (approximately 300 per treatment group) randomized 1:1 were targeted for this study. Using Farrington and Manning's method for noninferiority (NI) testing with a one-sided alpha value of 0.025, assuming a 75% ECR rate in each group, and a 10% noninferiority-bound delta value, a sample size of 295 ITT patients per treatment group was required for 80% power.