Randomized, Double-Blind, Phase II, Multicenter Study Evaluating the Safety/Tolerability and Efficacy of JNJ-Q2, a Novel Fluoroquinolone, Compared with Linezolid for Treatment of Acute Bacterial Skin and Skin Structure Infection

Covington, Paul S.; Davenport, James M.; Andrae, David; O’Riordan, William; Liverman, Lisa C.; McIntyre, Gail; Almenoff, June

doi:10.1128/aac.05044-11

Cited by 38 publications

(45 citation statements)

References 24 publications

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“…JNJ-Q2 possesses desirable drug-like properties, including acceptable solubility and lipophilicity. In a phase 2 clinical trial comparing efficacy, safety, and tolerability to those of linezolid, it was found to be statistically noninferior for early clinical response and well tolerated, with a favorable safety profile (32). However, primary intent-to-treat analysis was unable to declare noninferiority based on a 15% delta (a measure of comparison between arms of a controlled clinical trial that is related to a confidence interval); additional clinical data will be required for further development.…”

Section: Quinolonesmentioning

confidence: 99%

Investigational Antimicrobial Agents of 2013

Pucci

Bush

2013

Clin Microbiol Rev

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SUMMARY New antimicrobial agents are always needed to counteract the resistant pathogens that continue to be selected by current therapeutic regimens. This review provides a survey of known antimicrobial agents that were currently in clinical development in the fall of 2012 and spring of 2013. Data were collected from published literature primarily from 2010 to 2012, meeting abstracts (2011 to 2012), government websites, and company websites when appropriate. Compared to what was reported in previous surveys, a surprising number of new agents are currently in company pipelines, particularly in phase 3 clinical development. Familiar antibacterial classes of the quinolones, tetracyclines, oxazolidinones, glycopeptides, and cephalosporins are represented by entities with enhanced antimicrobial or pharmacological properties. More importantly, compounds of novel chemical structures targeting bacterial pathways not previously exploited are under development. Some of the most promising compounds include novel β-lactamase inhibitor combinations that target many multidrug-resistant Gram-negative bacteria, a critical medical need. Although new antimicrobial agents will continue to be needed to address increasing antibiotic resistance, there are novel agents in development to tackle at least some of the more worrisome pathogens in the current nosocomial setting.

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Section: Quinolonesmentioning

confidence: 99%

Investigational Antimicrobial Agents of 2013

Pucci

Bush

2013

Clin Microbiol Rev

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“…In conclusion, three (5%) and zero patients discontinued the study drug because of adverse reactions attributable to GSK1322322 and linezolid, respectively. In comparison, 0.6 to 2.6% of the patients treated with linezolid were discontinued from other previous phase II or III trials (5,24,25). Therefore, the frequency of withdrawal observed in this study suggests that the tolerability of the 1,500-mg b.i.d.…”

Section: Discussionmentioning

confidence: 74%

Safety, Tolerability, and Efficacy of GSK1322322 in the Treatment of Acute Bacterial Skin and Skin Structure Infections

Corey

Naderer

O’Riordan

et al. 2014

Antimicrob Agents Chemother

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GSK1322322 represents a new class of antibiotics that targets an essential bacterial enzyme required for protein maturation, peptide deformylase. This multicenter, randomized, phase IIa study compared the safety, tolerability, and efficacy of GSK1322322 at 1,500 mg twice daily (b.i.d.) with that of linezolid at 600 mg b.i.d. in patients suspected of having Gram-positive acute bacterial skin and skin structure infections (ABSSSIs). The primary endpoint was assessment of the safety of GSK1322322, and a key secondary endpoint was the number of subjects with a >20% decrease in lesion area from the baseline at 48 and 72 h after treatment initiation. GSK1322322 administration was associated with mild-to-moderate drug-related adverse events, most commonly, nausea, vomiting, diarrhea, and headache. Adverse events (86% versus 74%) and withdrawals (28% versus 11%) were more frequent in the GSK1322322-treated group. Treatment with GSK1322322 and linezolid was associated with >20% decreases from the baseline in the lesion area in 73% (36/49) and 92% (24/26) of the patients, respectively, at the 48-h assessment and in 96% (44/46) and 100% (25/25) of the patients, respectively, at the 72-h assessment. Reductions in exudate/pus, pain, and skin infection scores were comparable between the GSK1322322 and linezolid treatments. The clinical success rates within the intent-to-treat population and the per-protocol population that completed this study were 67 and 91%, respectively, in the GSK1322322-treated group and 89 and 100%, respectively, in the linezolid-treated group. These results will be used to guide dose selection in future studies with GSK1322322 to optimize its tolerability and efficacy in patients with ABSSSIs. (This study has been registered at ClinicalTrials.gov under registration no. NCT01209078 and at http://www.gsk-clinicalstudyregister.com [PDF113414].)

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“…No early clinical treatment response was reported in the proxy for placebo uSSTI trials. The early clinical treatment response for linezolid in the ITT population was reported in three trials, with a pooled estimate of 78.7% (95% CI, 61.1% to 96.3%); a high variance across trials (I 2 ϭ 96.7%, P Ͻ 0·0001) was evident (39,41,42). This response rate approximated the early clinical treatment response rate of 79.4% (95% CI, 75.1% to 83.7%) reported in the most robust of the three linezolid trials with these data, as well as the early clinical treatment response of ceftaroline at 74.0% (95% CI, 69.7% to 78.3%) reported in one trial (39,54).…”

Section: Iii) Nonantibacterial Treatment Trials (Search C)mentioning

confidence: 99%

“…These trials, published over a 13-year interval, had evidence of clinical and methodological heterogeneity for lesion size, type of infection, geographic region, MRSA etiology, per-protocol treatment duration, definition of clinical success, and timing of TOC assessment (Tables 2 and 3). For the meta-analysis, the selection of the three linezolid trials comprised subjects with total surface area lesion size of Ն75 cm 2 , non-MRSA-specific populations, and Ͻ50% of subjects with abscesses (39,41,42). The pooled linezolid TOC clinical treatment response rate was 88.1% (95% CI, 81.0% to 95.1%) (Fig.…”

Section: Iii) Nonantibacterial Treatment Trials (Search C)mentioning

confidence: 99%

“…2a) (36)(37)(38). Eleven of the 12 linezolid trials reported TOC clinical treatment response rates ranging from 50% to 95% (Table 2) (39)(40)(41)(42)(43)(44)(46)(47)(48)(49)(50). These trials, published over a 13-year interval, had evidence of clinical and methodological heterogeneity for lesion size, type of infection, geographic region, MRSA etiology, per-protocol treatment duration, definition of clinical success, and timing of TOC assessment (Tables 2 and 3).…”

Section: Iii) Nonantibacterial Treatment Trials (Search C)mentioning

confidence: 99%

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Systematic Review and Meta-Analysis To Estimate Antibacterial Treatment Effect in Acute Bacterial Skin and Skin Structure Infection

Cates

Mitrani-Gold

et al. 2015

Antimicrob Agents Chemother

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A systematic literature review and meta-analysis were conducted to estimate the antibacterial treatment effect for linezolid and ceftaroline to inform on the design of acute bacterial skin and skin structure infection (ABSSSI) noninferiority trials. The primary endpoints included an early clinical treatment response (ECTR) defined as cessation of lesion spread at 48 to 72 h postrandomization and the test-of-cure (TOC) response defined as total resolution of the infection at 7 to 14 days posttreatment. The systematic review identified no placebo-controlled trials in ABSSSI, 4 placebo-controlled trials in uncomplicated skin and soft tissue infection as a proxy for placebo in ABSSSI, 12 linezolid trials in ABSSSI, 3 ceftaroline trials in ABSSSI, and 2 trials for nonantibacterial treatment. The ECTR rates at 48 to 72 h and corresponding 95% confidence intervals (CI) were 78.7% (95% CI, 61.1 to 96.3%) for linezolid, 74.0% (95% CI, 69.7 to 78.3%) for ceftaroline, and 59.0% (95% CI, 52.8 to 65.3%) for nonantibacterial treatment. The early clinical treatment effect could not be estimated, given no available placebo or proxy for placebo data for this endpoint. Clinical, methodological, and statistical heterogeneity influenced the selection of trials for the meta-analysis of the TOC treatment effect estimation. The pooled estimates of the TOC treatment response were 31.0% (95% CI, 6.2 to 55.9%) for the proxy for placebo, 88.1% (95% CI, 81.0 to 95.1%) for linezolid, and 86.1% (95% CI, 83.7 to 88.6%) for ceftaroline. The TOC clinical treatment effect estimation was 25.1% for linezolid and 27.8% for ceftaroline. The antibacterial treatment effect estimation at TOC will inform on the design and analysis of future noninferiority ABSSSI clinical trials. Over the past decade, robust clinical, scientific, and regulatory debate has emerged for initiatives to improve the design, execution, and analysis of antibacterial clinical trials (1-4). New trials for acute bacterial skin and skin structure infections (ABSSSI), previously referred to as complicated skin and skin structure infections (cSSTI), remain important, given the rise in incidence of methicillin-resistant Staphylococcus aureus infections and reports of treatment failure (5-8). Per guidance from the U.S. Food and Drug Administration (FDA), patient eligibility for enrollment in ABSSSI trials should be restricted to those with erysipelas, cellulitis, major cutaneous abscesses, and wound infections having a minimal lesion surface area involvement of 75 cm 2 (9). For trial endpoints, the traditional test-of-cure (TOC) endpoint, with the treatment success defined as total resolution of the infection at 7 to 14 days posttreatment, remains aligned with the European regulatory guidance, yet the treatment success for the primary efficacy endpoint aligned with the FDA guidance is defined as cessation of lesion spread after 48 to 72 h of treatment (9-11). Revisions to the enrollment and endpoint criteria in recent regulatory guidance for ABSSSI trials necessitate reevaluation of the...

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Randomized, Double-Blind, Phase II, Multicenter Study Evaluating the Safety/Tolerability and Efficacy of JNJ-Q2, a Novel Fluoroquinolone, Compared with Linezolid for Treatment of Acute Bacterial Skin and Skin Structure Infection

Cited by 38 publications

References 24 publications

Investigational Antimicrobial Agents of 2013

Investigational Antimicrobial Agents of 2013

Safety, Tolerability, and Efficacy of GSK1322322 in the Treatment of Acute Bacterial Skin and Skin Structure Infections

Systematic Review and Meta-Analysis To Estimate Antibacterial Treatment Effect in Acute Bacterial Skin and Skin Structure Infection

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