A phase-3, double-blind, placebo-controlled study of the effectiveness and safety of single oral doses of secnidazole 2 g for the treatment of women with bacterial vaginosis

Abstract

A novel single oral dose granule formulation of secnidazole 2 g, a 5-nitroimidazole with a longer half-life (∼17 hours) than metronidazole (∼8 hours), is being developed to treat bacterial vaginosis. We sought to evaluate the effectiveness and safety of single-dose secnidazole 2 g compared to placebo for the treatment of women with bacterial vaginosis. In all, 189 women with bacterial vaginosis were randomized 2:1 to receive a single oral dose of secnidazole 2 g (N= 125) or matched placebo (N= 64) at 21 centers in the United States. The primary endpoint was the proportion of clinical outcome responders, defined as those with: (1) normal vaginal discharge; (2) negative 10% potassium hydroxide whiff test; and (3) <20% clue cells of total epithelial cell count on microscopic examination of the vaginal wet mount, using saline at the test of cure/end of study visit (study days 21-30). Secondary efficacy analyses included clinical cure rates, defined as: (1) responders with normal vaginal discharge; (2) negative potassium hydroxide whiff tests; and (3) clue cells <20% assessed at the interim visit (study days 7-14), and test of cure/end of study (study days 21-30). In addition, based on the 2016 US Food and Drug Administration draft guidance, patients with baseline Nugent scores 7-10 were evaluated for clinical cure using the following clinical assessments on study days 7-14: (1) resolution of the abnormal vaginal discharge; (2) a negative potassium hydroxide whiff test; and (3) clue cells <20%. The study was designed and powered todemonstrate the efficacy of single-dose secnidazole 2 g compared toplacebo; safety and tolerability were also assessed. Due to a prespecified institutional review board-approved protocol calling for withdrawal of randomized, treated patients with a Nugent score <4 or with a separate sexually transmitted infection, this modified intent-to-treat population was the primary analysis population. Statistical comparisons used a stratified Cochran-Mantel-Haenszel test with a .05 level of significance (2-sided). Single-dose secnidazole 2 g was superior to placebo for the primary and all secondary efficacy measures in the modified intent-to-treat population, with clinical outcome responder rates of 53.3% (57/107) vs 19.3% (11/57; P < .001). Clinical cure rates, based on an alternate definition of responder, which accounted for resolution of abnormal discharge consistent with bacterial vaginosis, were consistent with the clinical outcome responder rate analysis (58.9% vs 24.6%; P < .001) for single-dose secnidazole 2 g vs placebo. Clinical cure rates based on the 2016 US Food and Drug Administration guidance were 64.0% vs 26.4% for single-dose secnidazole 2 g vs placebo. Based on the investigator's clinical assessment at the test of cure/end of study visit, significantly more patients receiving single-dose secnidazole 2 g vs placebo required noadditional bacterial vaginosis treatment (68.0% [68/100] vs 29.6% [16/54]; P < .001). Adverse events considered by the investigator to be related to study drug occurred in only 20.0% of single-dose secnidazole 2 g-treated patients vs 10.9% of placebo patients, and they included diarrhea (4.0% vs 1.6%), headache (4.0% vs 3.1%), nausea (4.8% vs 1.6%), and vulvovaginal candidiasis (4.0% vs 3.1%). Single-dose secnidazole 2 g was superior to placebo on all primary and secondary outcomes and was well tolerated; these results support its role for the treatment of women with bacterial vaginosis.