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.

Figure 1

Flowchart depicting the systematic literature search for treatment effect estimation in uUGC: publication identification, screening, eligibility, and meta-analysis inclusion. *The 11 additional records were identified from the referenced literature cited in the publications identified by the primary searches. ^†Reasons for exclusion were as follows: narrative reviews (gonorrhea, STDs, PID, HIV; n = 36); unrelated to gonorrhea and no information on primary objectives (n = 33); microbiology surveillance in vitro gonorrhea susceptibility (n = 17); HIV/STD studies and not informing on primary objectives (n = 17); STD/gonorrhea prevention studies (n = 13); STD mathematical modeling studies (n = 8); case reports for other STDs (n = 7); gonorrhea RCTs not reporting on efficacy of ceftriaxone, placebo, or proxy-for-placebo (n = 5); observational studies for STDs, not gonorrhea-specific (Mycoplasma genitalium and bacterial vaginosis; n = 4); RCTs unrelated to gonorrhea (n = 3); complicated gonorrhea case reports (n = 3); gonorrhea antibody study and adherence to treatment guidelines (n = 2); STD surveillance studies (n = 2); PID etiology/microstudy (n = 1); STD case series, not gonorrhea (n = 1); systematic review and meta-analysis not reporting on efficacy of ceftriaxone, placebo, or proxy-for-placebo (n = 1); and letter to the editor (n = 1). HIV, human immunodeficiency virus; PID, pelvic inflammatory disease; RCT, randomized controlled trial; STD, sexually transmitted disease; uUGC, uncomplicated urogenital gonorrhea.

Figure 2

Forest plot of the meta-analysis for microbiological response for (A) ceftriaxone and (B) proxy-for-placebo in uUGC among the ME study population. CI, confidence interval; I², percentage of variation across studies due to heterogeneity rather than chance (total heterogeneity/total variability); ME, microbiologically evaluable population; τ², estimate of the degree of heterogeneity (heterogeneity variance); uUGC, uncomplicated urogenital gonorrhea.