Dataset Information

Systematic Review and Meta-Analysis to Estimate the Treatment Effect and Inform a Noninferiority Margin for a Phase 3 Noninferiority Trial in Uncomplicated Urogenital Gonorrhea.

ABSTRACT:

Background

Active-controlled noninferiority studies are used to investigate novel agents for uncomplicated urogenital gonorrhea (uUGC) as placebo-controlled trials are unethical. A systematic literature review and meta-analysis were conducted to estimate the ceftriaxone and proxy-for-placebo microbiological treatment effect and determine an appropriate noninferiority margin for phase 3 trials.

Methods

Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. To account for interstudy variability, a weighted, noniterative random-effects model was fitted using "R" software to estimate the microbiological response rate and 95% confidence intervals (CIs) for ceftriaxone and proxy-for-placebo (treatment with an antibiotic the isolate was subsequently confirmed resistant to, or spontaneous resolution without treatment). I2 , τ2 , and P values were computed and included in the meta-analysis forest plot.

Results

Seventeen studies were included in the meta-analysis; 14 reported ceftriaxone response in micro-intent-to-treat and microbiologically evaluable populations, and 3 reported proxy-for-placebo treatment response in uUGC (microbiologically evaluable population only). Microbiological treatment effect was estimated by subtracting the upper end of the CI for placebo from the lower end of the CI for ceftriaxone. Overall microbiological response was 98% (95% CI, 97-99) for ceftriaxone and 44% (95% CI, 34-54) for proxy-for-placebo, resulting in a microbiological treatment effect of 43%. A noninferiority margin of 15% preserved 65% of the ceftriaxone treatment effect, exceeding the 50% recommended per US Food and Drug Administration guidance for noninferiority studies.

Conclusions

Results of this systematic literature review and meta-analysis could help inform the design, conduct, and analysis of future clinical studies in uUGC.

SUBMITTER: Mitrani-Gold FS

PROVIDER: S-EPMC9377503 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Publications

Systematic Review and Meta-Analysis to Estimate the Treatment Effect and Inform a Noninferiority Margin for a Phase 3 Noninferiority Trial in Uncomplicated Urogenital Gonorrhea.

Mitrani-Gold Fanny S FS Fix Jonathan J Donald Alison A

Sexually transmitted diseases 20220608 9

<h4>Background</h4>Active-controlled noninferiority studies are used to investigate novel agents for uncomplicated urogenital gonorrhea (uUGC) as placebo-controlled trials are unethical. A systematic literature review and meta-analysis were conducted to estimate the ceftriaxone and proxy-for-placebo microbiological treatment effect and determine an appropriate noninferiority margin for phase 3 trials.<h4>Methods</h4>Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines we ...[more]

PMID: 35675712

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Project description:IntroductionGonorrhea, caused by Neisseria gonorrhoeae (NG), is the second most common bacterial sexually transmitted infection (STI). Rates of antimicrobial resistance to standard care are increasing worldwide, with many antibiotic classes now ineffective against NG. Gepotidacin is a first-in-class, bactericidal, triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by inhibition of two enzymes, where a single target-specific mutation does not significantly impact susceptibility. Gepotidacin confers activity against NG, including most strains resistant to marketed antibiotics. Here, we describe the design of a phase 3 clinical trial (EAGLE-1; NCT04010539) evaluating gepotidacin for the treatment of uncomplicated urogenital gonorrhea.MethodsThis phase 3, randomized, multicenter, sponsor-blinded, noninferiority study across six countries is comparing the efficacy of gepotidacin with ceftriaxone plus azithromycin in 400 patients with uncomplicated urogenital gonorrhea (microbiological intent-to-treat population) and assessing the safety of gepotidacin in approximately 600 patients (intent-to-treat population). Eligible participants 12 years of age or older with clinical suspicion of urogenital gonococcal infection and a NG-positive urogenital sample and/or purulent discharge are randomized 1:1 to receive oral gepotidacin (2 × 3000 mg 10-12 h apart) or ceftriaxone (500 mg, intramuscular) plus azithromycin (1 g, oral). The primary endpoint is culture-confirmed bacterial eradication of NG from the urogenital site at the test-of-cure (days 4-8) visit.Planned outcomesThis trial was designed in accordance with US Food and Drug Administration (2015) and European Medicines Agency (2011) guidance, particularly the primary endpoint and microbiological evaluability requirements. This study will help characterize the risk-benefit profile of gepotidacin for treating uncomplicated urogenital gonorrhea. Gepotidacin is an important potential treatment for gonorrhea to help address the urgent unmet need of multidrug resistance and the increasingly limited number of oral treatment options.Trial registrationClinicalTrials.gov identifier, NCT04010539.

Project description:We evaluated microbiological correlates for the successful treatment of Neisseria gonorrhoeae isolates from a phase 2 study of gepotidacin, a novel triazaacenaphthylene antibacterial, for therapy of uncomplicated urogenital gonorrhea. Culture, susceptibility testing, genotypic characterization, and frequency of resistance (FoR) were performed for selected isolates. Microbiological success was defined as culture-confirmed eradication of N. gonorrhoeae Against 69 baseline urogenital isolates, gepotidacin MICs ranged from ≤0.06 to 1 µg/ml (MIC90 = 0.5 µg/ml). For gepotidacin, the ratio of the area under the free-drug concentration-time curve to the MIC (fAUC/MIC) was associated with therapeutic success. Success was 100% (61/61) at fAUC/MICs of ≥48 and decreased to 63% (5/8) for fAUC/MICs of ≤25. All 3 isolates from microbiological failures were ciprofloxacin resistant, had a baseline gepotidacin MIC of 1 µg/ml, and carried a preexisting ParC D86N mutation, a critical residue for gepotidacin binding. In a test-of-cure analysis, the resistance to gepotidacin emerged in 2 isolates (MICs increased ≥32-fold) with additional GyrA A92T mutations, also implicated in gepotidacin binding. Test-of-cure isolates had the same sequence type as the corresponding baseline isolates. For 5 selected baseline isolates, all carrying a ParC D86N mutation, the in vitro FoR to gepotidacin was low (10-9 to 10-10); the resistant mutants had the same A92T mutation as the 2 isolates in which resistance emerged. Five participants with isolates harboring the ParC D86N mutation were treatment successes. In summary, fAUC/MICs of ≥48 predicted 100% microbiological success, including 3 isolates with the ParC D86N mutation (fAUC/MICs ≥ 97). Pharmacokinetic/pharmacodynamic determinations may help to evaluate new therapies for gonorrhea; further study of gepotidacin is warranted. (This study has been registered at ClinicalTrials.gov under identifier NCT02294682.).

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Project description:ObjectivesTo review the literature for non-standard treatment options for uncomplicated Chlamydia trachomatis (CT) infections in adolescents and adults.DesignSystematic review.Data sourcesOvid MEDLINE/PubMed, Ovid EMBASE, Cochrane Trials & Systematic Review Databases, CINAHL Plus with Full Text, Web of Science Core Collection, Scopus, ProQuest Dissertations & Theses Global, ClinicalTrials.gov and Health Canada Trials Database were searched for studies in English or French from 1 January 2006 to 6 August 2017. Keywords included CT, anti-infective or anti-bacterial agents, therapy/pharmacotherapy/management.Review methodsIncluded were primary research studies. Outcome measures included clinical or microbiological cure, treatment failure and adverse events. We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies were assessed for risk of bias using the Revised Cochrane Risk of Bias V.2.0 tool for randomised and the Newcastle-Ottawa Quality Assessment Scale for non-randomised studies.Funding sourcePublic Health Agency of Canada.ResultsOf the 6899 records identified through the database search, 11 studies were included. One randomised controlled trial reported that delayed release doxycycline was non-inferior to azithromycin. Two studies examined higher doses of azithromycin but reported no additional benefit. One study looked at a 5-day azithromycin treatment regimen and reported a high cure rate. Two studies reported efficacy of sitafloxacin, and a single study supports the use of levofloxacin. Two phase 2 studies reported efficacy of single-dose rifalazil in both men and women. Only one retrospective study was identified that examined treatment in pregnant women and reported that efficacy with single-dose azithromycin exceeded that of amoxicillin and erythromycin. A single study examining the efficacy of a beta-lactam antibiotic was stopped early due to high treatment failures.ConclusionsThe paucity of existing data highlights the need for further adequately powered studies to evaluate rifalazil, delayed release doxycycline, levofloxacin and other agents for the treatment of uncomplicated CT infections.Prospero registration numberCRD42017073096.

Project description:ObjectivesWe used modified contingent valuation methodology to determine how noninferiority margin sizes influence clinicians' willingness to accept clinical trial results that compare mortality in critically ill children.MethodsWe surveyed pediatric infectious diseases and critical care clinicians in Canada, Australia, and New Zealand and randomized respondents to review 1 of 9 mock abstracts describing a noninferiority trial of bacteremic critically ill children assigned to 7 or 14 d of antibiotics. Each scenario showed higher mortality in the 7-d group but met noninferiority criterion. We explored how noninferiority margins and baseline mortality rates influenced respondent acceptance of results.ResultsThere were 106 survey respondents: 65 (61%) critical care clinicians, 28 (26%) infectious diseases physicians, and 13 (12%) pharmacists. When noninferiority margins were 5% and 10%, 73% (24/33) and 79% (27/33) respondents would accept shorter treatment, compared with 44% (17/39) when the margin was 20% (P = 0.003). Logistic regression adjusted for baseline mortality showed 5% and 10% noninferiority margins were more likely to be associated with acceptance of shorter treatment compared with 20% margins (odds ratio [OR] 3.5, 95% confidence interval [CI]: 1.3-9.6, P = 0.013; OR 5.1, 95% CI: 1.8-14.6, P = 0.002). Baseline mortality was not a significant predictor of acceptance of shorter treatment.ConclusionsClinicians are more likely to accept shorter treatment when noninferiority margins are ≤10%. However, nearly half of respondents who reviewed abstracts with 20% margins were still willing to accept shorter treatment. This is a novel application of contingent valuation methodology to elicit acceptance of research results among end users of the medical literature.HighlightsClinicians are more likely to accept shorter treatment durations based on noninferior mortality results when the noninferiority margin is 5% or 10% than if the margin is 20%.However, nearly half of clinicians would still accept shorter-duration treatment as noninferior with margins of 20%.Baseline mortality does not independently predict acceptance of shorter-duration treatment.Contingent valuation is a novel approach to elicit the acceptance of research design parameters from the perspective of endusers of the medical literature.

Dataset Information

Systematic Review and Meta-Analysis to Estimate the Treatment Effect and Inform a Noninferiority Margin for a Phase 3 Noninferiority Trial in Uncomplicated Urogenital Gonorrhea.

Background

Methods

Results

Conclusions

Publications

Systematic Review and Meta-Analysis to Estimate the Treatment Effect and Inform a Noninferiority Margin for a Phase 3 Noninferiority Trial in Uncomplicated Urogenital Gonorrhea.

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