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

doi:10.1016/j.ijantimicag.2018.05.012

International Journal of Antimicrobial Agents

Volume 52, Issue 2, August 2018, Pages 233-240

https://doi.org/10.1016/j.ijantimicag.2018.05.012 Get rights and content

Highlights

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Analysis of two phase 3 studies of iclaprim compared with vancomycin (VAN) for treatment of patients with ABSSSIs.
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Iclaprim was non-inferior to VAN for early clinical response at the early time point.
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Iclaprim was active against skin infections caused by MRSA, Streptococcus pyogenes and other Gram-positive pathogens.
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Iclaprim was safe and well tolerated compared with VAN, except for a higher incidence of nephrotoxicity reported for VAN.

ABSTRACT

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.]

Introduction

Up to 1.8% of all hospitalisations are due to acute bacterial skin and skin-structure infections (ABSSSIs) [1]. Often these serious skin infections require intravenous (i.v.) antimicrobials, hospitalisation and/or surgical intervention [2], [3]. The majority of ABSSSIs are caused by Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible S. aureus and β-haemolytic streptococci [3], [4]. Although many antimicrobials are available to treat ABSSSIs, only a few are available for ABSSSI caused by multidrug-resistant bacteria, and some of these are limited by safety, tolerability and dosing issues [5], the need for monitoring plasma concentrations and/or inconvenient dosage regimens [6]. Alternative antimicrobials are needed for ABSSSIs that provide improved efficacy and safety in infections caused by multidrug-resistant bacteria [6], [7].

Iclaprim is a selective inhibitor of bacterial dihydrofolate reductase, the same mechanism of action as trimethoprim (TMP). However, iclaprim is more potent than TMP (i.e. lower MIC₉₀, greater binding affinity to bacteria, better pharmacokinetics/pharmacodynamics) [6]. Iclaprim is rapidly bactericidal and is active against a range of Gram-positive pathogens, including those that are resistant to TMP and other antimicrobials, including vancomycin, linezolid and daptomycin [8], [9], [10], [11]. Unlike trimethoprim/sulfamethoxazole, iclaprim does not need to be combined with a sulfonamide, which are associated with hypersensitivity and/or allergic reactions. Iclaprim has also been shown to supress bacterial toxin production, which may be important in necrotizing skin infections [12]. In two phase 3 studies of patients treated for ABSSSI (REVIVE-1 and REVIVE-2), iclaprim was non-inferior to vancomycin for early clinical response (ECR) at the early time point (ETP) in the intent-to-treat (ITT) population. Here, a pooled analysis was conducted of the two phase 3 REVIVE studies to further evaluate the safety and efficacy of iclaprim for patients with ABSSSI due to Gram-positive pathogens.

Section snippets

Study design

Both REVIVE-1 and REVIVE-2 were phase 3, double-blind, randomised (1:1), multicentre, active-controlled, non-inferiority studies that utilised identical study protocols (NCT02600611 and NCT02607618, respectively). The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) guidance on trials for ABSSSI were incorporated into the study design. Patients were enrolled between March 2016 and January 2017 for REVIVE-1 [13] and between January 2016 and August 2017 for REVIVE-2

Baseline demographics and clinical characteristics

In total, 1198 patients were randomised and met the criteria for the ITT population (Fig. 2). Demographic, clinical characteristics at baseline and type of skin infection generally were comparable between the iclaprim and vancomycin groups and between studies (Table 1). More patients had wound infections (56.9% vs. 43.7%) and fewer patients had cellulitis/erysipelas (27.3% vs. 40.0%) in both treatment groups in REVIVE-1 compared with REVIVE-2. In both REVIVE-1 and REVIVE-2, a large number of

Discussion

This was a pooled analysis of fixed-dose iclaprim compared with vancomycin for patients with ABSSSI. In contrast to weight-based dosing employed in earlier complicated skin and skin-structure infection clinical trials, the REVIVE-1 and REVIVE-2 ABSSSI studies used a fixed dose of iclaprim at 80 mg q12h. The fixed dose was selected because, compared with the weight-based dosing regimen, the fixed-dose regimen increased both the area under the concentration–time curve/MIC ratio (AUC/MIC) by ca.

Acknowledgments

Editorial assistance was provided by Richard Perry, PharmD, and was supported by Motif BioSciences (New York, NY).

Funding

This work was supported by Motif Bio plc (New York, NY).

Competing interests

DBH is an employee of Motif BioSciences; TLH has received consultancy fees from Basilea Pharmaceutica, Genentech, The Medicines Company and Motif Biosciences, and grant support from Basilea and Achaogen; TMF has served as a consultant for Motif BioSciences, GSK, Meiji, Merck, Nabriva, Paratek, Cempra and Shionogi; AT has served

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Cited by (16)

Worldwide surveillance of Iclaprim activity: In Vitro susceptibility of gram-positive pathogens collected from patients with skin and skin structure infections from 2013 to 2017
2020, Diagnostic Microbiology and Infectious Disease
Citation Excerpt :
In an in vitro study, iclaprim suppressed toxin production, which contributes to the pathogenesis of S. aureus infections (Bryant et al., 2019). Two Phase 3 clinical trials among patients treated for acute bacterial skin and skin structure infections have been completed (Huang et al., 2018a). 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%).
Iclaprim is a novel diaminopyrimidine, which inhibits bacterial dihydrofolate reductase, and it is active against Gram-positive pathogens including emerging drug-resistant pathogens. In vitro activity of iclaprim and comparators against 1365 Gram-positive clinical isolates from patients with skin and skin structure infections (SSSI) from the United States, Asia Pacific, Latin America, Europe, Africa or Middle East collected between 2013 and 2017 were tested. Susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) interpretations were based on CLSI criteria. MIC₉₀ for all S.aureus, methicillin-susceptible S. aureus, methicillin-resistant S. aureus, Streptococcus pyogenes, S. agalactiae, S. anginosus, S. constellatus, S. dysgalactiae and S. intermedius were 0.12, 0.12, 0.5, 0.03, 0.5, ≤0.004, ≤0.004, 0.12, and 0.008 μg/ml, respectively. The MIC for iclaprim was 8 to 32-fold lower than trimethoprim, the only FDA approved dihydrofolate reductase inhibitor, against all Gram-positive isolates including resistant phenotypes. Iclaprim demonstrated lower MICs than trimethoprim against a collection (2013–2017) of Gram-positive clinical isolates from patients with SSSI from the United States, Asia Pacific, Latin America, and Europe.
A Pooled Analysis of the Safety and Efficacy of Iclaprim Versus Vancomycin for the Treatment of Acute Bacterial Skin and Skin Structure Infections in Patients With Intravenous Drug Use: Phase 3 REVIVE Studies
2019, Clinical Therapeutics
Citation Excerpt :
The mean lesion size for ABSSSI was similar in patients who were or were not IVDUs (320 vs 350 cm2).12 Although some ABSSSIs may be treated with topical (if minor) or oral antibacterial agents, the mean lesion size of the ABSSSI in the REVIVE trials12 was approximately 300 cm2, which is substantial and commensurate with a need for intravenous therapy. In addition, IVDUs may be less adherent with use of topical or oral antibacterial agents, which may lead to increased selective pressure from nonadherence with the duration of outpatient treatment.
This analysis evaluates the efficacy and safety of iclaprim versus vancomycin for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in patients who were intravenous drug users (IVDUs).
A total of 621 patients who were IVDUs from 2 parallel Phase III, double-blind, randomized (1:1), active-controlled, multinational, multicenter trials (REVIVE-1 and REVIVE-2) were analyzed separately and pooled. This post hoc analysis summarizes the efficacy and safety profile of iclaprim 80 mg fixed dose compared with vancomycin 15 mg/kg administered intravenously during 2 h every 12 h for 5–14 days among this population. The primary end point of these studies was to determine whether iclaprim was noninferior (10% margin) to vancomycin in achieving a ≥20% reduction in lesion size at 48–72 h after initiation of treatment with the study drug (early clinical response) in the intent-to-treat population. The safety profile was assessed based on adverse events and laboratory parameters.
Iclaprim had higher early clinical response rates (85.8%; 95% CI, 81.5%–89.4%) compared with vancomycin (79.8%; 95% CI, 74.8%–84.2%) among patients with ABSSSIs who were IVDUs, with a treatment difference of +6.00% (95% CI, 0.06–12.0). The safety profile was similar in the iclaprim and vancomycin arms, with 3.7% and 5.0%, respectively, of patients discontinuing study therapy because of adverse events and 1.9% and 3.4%, respectively, of patients developing serious adverse events.
Iclaprim had a higher early clinical response rate and favorable safety profile compared with vancomycin for the treatment of ABSSSIs in patients who were IVDUs. Iclaprim may be a valuable treatment option for ABSSSIs in this patient population.
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Therapeutics for Vancomycin-Resistant Enterococcal Bloodstream Infections
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Efficacy and Safety of Iclaprim for the Treatment of Skin Structures and Soft Tissue Infections: A Methodological Framework
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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

Highlights

ABSTRACT

Introduction

Section snippets

Study design

Baseline demographics and clinical characteristics

Discussion

Acknowledgments

Funding

Competing interests

J Emerg Med

Curr Opin Pharmacol

Bioorg Med Chem Lett

Diagn Microbiol Infect Dis

Rising United States hospital admissions for acute bacterial skin and skin structure infections: recent trends and economic impact

PLoS One

Multistate point-prevalence survey of health care-associated infections

N Engl J Med

Microbiology and initial antibiotic therapy for injection drug users and non-injection drug users with cutaneous abscesses in the era of community-associated methicillin-resistant Staphylococcus aureus

Acad Emerg Med

New therapeutic options for skin and soft tissue infections

Curr Opin Infect Dis