A phase 2, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy and safety of orally administered VT-1161 in the treatment of recurrent vulvovaginal candidiasis
A phase 2, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy and safety of orally administered VT-1161 in the treatment of recurrent vulvovaginal candidiasis
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DOI：
10.1016/j.ajog.2018.03.001
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发表时间：
2018-06-01
影响因子：
9.8
通讯作者：
Tavakkol, Amir
中科院分区：
文献类型：
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作者：
Brand, Stephen R.;Degenhardt, Thorsten P.;Tavakkol, Amir
背景：羊毛甾醇脱甲基酶是真菌生长所必需的一种酶，它催化麦角甾醇生物合成途径的早期步骤，麦角甾醇是真菌细胞膜形成和完整性所必需的一种甾醇。羊毛甾醇去甲基酶是一类被称为“唑类抗真菌药”的药物的分子靶标。VT-1161是一种新型的、口服的、选择性的真菌羊毛甾醇脱甲基酶抑制剂，正在被开发用于治疗复发性外阴阴道念珠菌病。目的：我们评估了4种口服VT-1161方案与安慰剂治疗复发性外阴阴道念珠菌病的有效性和安全性，其定义为在12个月内至少有3次急性外阴阴道念珠菌病的症状发作。STUDY设计：215名有复发性外阴阴道念珠菌病病史的妇女，她们在筛查时经历了急性外阴阴道念珠菌病(急性外阴阴道念珠菌病；复合外阴阴道体征和症状评分>=3，酵母菌氢氧化钾试验阳性)。在用氟康唑治疗急性感染后，受试者被随机分为5种治疗方案：(1)VT-1161 150 mg每日1次，连续7天，然后每周150 mg，连续11周，然后每周服用安慰剂1次，共12周；(2)VT-1161每天1次，连续7天，然后每周300 mg，连续11周，然后每周1次安慰剂，共12周；(3)VT-1161 150 mg，每天1次，连续7天，然后每周150 mg，连续23周；(4)VT-1161 300 mg每日一次，连续7天，然后每周300 mg，连续23周；或(5)匹配的安慰剂方案，持续24周。结果：在意向治疗人群中，发生>；=1次急性外阴阴道念珠菌病的受试者比例在4个VT-1161组中为0e7%，在安慰剂组中为52%，与安慰剂组相比均有统计学意义。VT-1161具有良好的耐受性和良好的安全性，与安慰剂相比，所有VT-1161组的不良事件发生率都较低。此外，任何VT-1161组的患者都没有因为不良事件或实验室异常而提前终止研究。结论：本研究表明VT-1161治疗复发性外阴阴道念珠菌病安全有效。这些数据有力地支持了VT-1161治疗复发性外阴阴道念珠菌病的进一步临床研究。
BACKGROUND: Lanosterol demethylase is an enzyme that is essential for fungal growth and catalyzes an early step in the biosynthetic pathway of ergosterol, which is a sterol that is required for fungal cell membrane formation and integrity. Lanosterol demethylase is the molecular target of the class of drugs referred to as "azole antifungals." VT-1161 is a novel, oral, selective inhibitor of fungal lanosterol demethylase and is being developed for the treatment of recurrent vulvovaginal candidiasis.OBJECTIVE: We evaluated the efficacy and safety of 4 dosing regimens of oral VT-1161 compared with placebo in women with recurrent vulvovaginal candidiasis, which was defined as at least 3 symptomatic episodes of acute vulvovaginal candidiasis within a 12-month period.STUDY DESIGN: Two hundred fifteen women with a documented history of recurrent vulvovaginal candidiasis and who, at screening, were experiencing an episode of acute vulvovaginal candidiasis (acute vulvovaginal candidiasis; composite vulvovaginal signs and symptoms score of >= 3 and a positive potassium hydroxide test for yeast) were enrolled. After treatment of the acute infection with fluconazole, subjects were assigned randomly to 1 of 5 treatment regimens: (1) VT-1161 150 mg once daily for 7 days, then 150 mg once weekly for 11 weeks, followed by a once-weekly dose of placebo for 12 weeks; (2) VT-1161 300 mg once daily for 7 days, then 300 mg once weekly for 11 weeks, followed by a once-weekly dose of placebo for 12 weeks; (3) VT-1161 150 mg once daily for 7 days, then 150 mg once weekly for 23 weeks; (4) VT-1161 300 mg once daily for 7 days, then 300 mg once weekly for 23 weeks; or (5) a matching placebo regimen for 24 weeks. The primary efficacy outcome was the proportion of subjects with >= 1 culture-verified acute vulvovaginal candidiasis episodes through week 48.RESULTS: In the intent-to-treat population, the proportion of subjects with >= 1 acute vulvovaginal candidiasis episodes ranged from 0e7% across the 4 VT-1161 arms vs 52% in the placebo arm, with all arms achieving statistical significance vs placebo. VT-1161 was well-tolerated with a favorable safety profile, and the incidence of adverse events was lower in all VT-1161 arms compared with placebo. In addition, no patient in any VT-1161 arm discontinued the study early because of an adverse event or laboratory abnormality. There was also no evidence of an adverse effect of VT-1161 on liver function or electrocardiogram recordings.CONCLUSION: In this study, VT-1161 was shown to be efficacious and safe in the treatment of patients with recurrent vulvovaginal candidiasis. These data strongly support further clinical investigation of VT-1161 for the treatment of recurrent vulvovaginal candidiasis.