Fanny S Mitrani-Gold1, Aparna Raychaudhuri2, Sapna Rao3. 1. GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426, USA. Electronic address: fanny.s.mitrani-gold@gsk.com. 2. GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426, USA; CSL Behring, 500 North Gulph Road, King of Prussia, PA 19406, USA. 3. University of North Carolina at Chapel Hill, Gilling's School of Global Public Heath, 135 Dauer Drive, Chapel Hill, NC 27599, USA.
Abstract
OBJECTIVES: Active-comparator, non-inferiority study designs are used in uncomplicated urinary tract infection (uUTI) to establish the efficacy of a new antibacterial, given the availability of effective antibiotics. Here we estimated the treatment effect of a planned antimicrobial comparator (nitrofurantoin) from historical trial data to properly design an upcoming non-inferiority trial in uUTI. METHODS: A systematic literature review and meta-analysis was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, which incorporate recommendations for standardised data quality assessment, reporting of results, risk of bias assessment and sensitivity analyses. To account for interstudy variability, a weighted, non-iterative, random-effects model was fit using R software to obtain estimates of the microbiological response rate and corresponding 95% confidence interval (CI) for nitrofurantoin and placebo treatment. Interstudy heterogeneity was assessed with Cochran's χ2 test for interstudy heterogeneity; I2 statistic and P-values were computed and included in the forest plot of the meta-analysis. RESULTS: Twelve unique studies met the final eligibility criteria for meta-analysis inclusion; three trials assessed placebo efficacy, eight trials assessed nitrofurantoin efficacy, and one study assessed both nitrofurantoin and placebo efficacy in uUTI. The overall microbiological response (95% CI) was 0.766 (0.665-0.867) for nitrofurantoin and 0.342 (0.288-0.397) for placebo. CONCLUSION: The corresponding treatment effect estimate for nitrofurantoin was 26.8%, which supports a conservative non-inferiority margin of 12.5% and is consistent with the recently published draft FDA guidance. The findings from this systematic review and meta-analysis may inform future antibacterial trials by providing non-inferiority margin justification.
OBJECTIVES: Active-comparator, non-inferiority study designs are used in uncomplicated urinary tract infection (uUTI) to establish the efficacy of a new antibacterial, given the availability of effective antibiotics. Here we estimated the treatment effect of a planned antimicrobial comparator (nitrofurantoin) from historical trial data to properly design an upcoming non-inferiority trial in uUTI. METHODS: A systematic literature review and meta-analysis was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, which incorporate recommendations for standardised data quality assessment, reporting of results, risk of bias assessment and sensitivity analyses. To account for interstudy variability, a weighted, non-iterative, random-effects model was fit using R software to obtain estimates of the microbiological response rate and corresponding 95% confidence interval (CI) for nitrofurantoin and placebo treatment. Interstudy heterogeneity was assessed with Cochran's χ2 test for interstudy heterogeneity; I2 statistic and P-values were computed and included in the forest plot of the meta-analysis. RESULTS: Twelve unique studies met the final eligibility criteria for meta-analysis inclusion; three trials assessed placebo efficacy, eight trials assessed nitrofurantoin efficacy, and one study assessed both nitrofurantoin and placebo efficacy in uUTI. The overall microbiological response (95% CI) was 0.766 (0.665-0.867) for nitrofurantoin and 0.342 (0.288-0.397) for placebo. CONCLUSION: The corresponding treatment effect estimate for nitrofurantoin was 26.8%, which supports a conservative non-inferiority margin of 12.5% and is consistent with the recently published draft FDA guidance. The findings from this systematic review and meta-analysis may inform future antibacterial trials by providing non-inferiority margin justification.