Safety of Fezolinetant for Vasomotor Symptoms Associated With Menopause: A Randomized Controlled Trial.
Safety of Fezolinetant for Vasomotor Symptoms Associated With Menopause: A Randomized Controlled Trial.
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DOI：
10.1097/aog.0000000000005114
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发表时间：
2023-04-01
影响因子：
7.2
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SKYLIGHT 4（研究发现Fezolinetant长期治疗更年期潮热女性的安全性）证明了Fezolinetant的52周安全性和耐受性及其用于治疗与更年期相关的血管炎症状。评价52周内fezolinetant的安全性、耐受性和对子宫内膜健康的影响。我们进行了一项III期、随机、双盲、52周的安全性研究（SKYLIGHT 4 [研究，以了解长期使用Fezolinetant治疗更年期潮热女性的安全性]），安慰剂、Fezolinetant 30 mg和Fezolinetant 45 mg每日一次（1：1：1）。受试者均为绝经后患者，正在寻求与绝经相关的血管扩张症状的治疗。主要终点是治疗后出现的不良事件，子宫内膜增生的参与者百分比和子宫内膜恶性肿瘤的百分比。根据美国食品药品监督管理局指南（点估计值≤ 1%，单侧95% CI上限≤ 4%）评价子宫内膜增生或恶性肿瘤。次要终点包括骨矿物质密度（BMD）和骨小梁评分的变化。计算样本量为1，740，以观察到一个或多个事件（背景发生率小于1%的事件的概率为80%）。共有1，830名参与者被随机分配并服用一种或多种药物剂量（2019年7月至2022年1月）。安慰剂组64.1%（391/610）、非唑来坦30 mg组67.9%（415/611）和非唑来坦45 mg组63.9%（389/609）发生治疗后出现的不良事件。导致停药的治疗后出现的不良事件在各组之间相似（安慰剂组，26/610 [4.3%];非唑林坦30 mg组，34/611 [5.6%];非唑林坦45 mg组，28/609 [4.6%]）。在599名参与者中评估了子宫内膜安全性。在非唑来坦45 mg组中，1/203例受试者有子宫内膜增生（0.5%;单侧95% CI上限2.3%）;安慰剂组（0/186）或非唑来坦30 mg组（0/210）无病例。非唑林坦30 mg组210例患者中有1例发生子宫内膜恶性肿瘤（0.5%; 95% CI 2.2%），其他组无病例。583名安慰剂组受试者中有6名、590名30 mg非唑林奈坦组受试者中有8名和589名45 mg非唑林奈坦组受试者中有12名出现肝酶升高超过正常上限的3倍;无海氏法则病例报告（即，没有严重的药物-丙氨酸氨基转移酶或天冬氨酸氨基转移酶超过正常值上限的3倍，总胆红素超过2倍正常值上限，碱性磷酸酶无升高，且无其他原因可解释该组合）。各组间BMD和骨小梁评分的变化相似。SKYLIGHT 4的结果证实了非唑来坦的52周安全性和耐受性，并支持其继续开发。Astellas Pharma Inc. ClinicalTrials.gov，NCT 04003389。
SKYLIGHT 4 (Study to Find Out How Safe Long-term Treatment With Fezolinetant is in Women With Hot Flashes Going Through Menopause) demonstrates the 52-week safety and tolerability of fezolinetant and its use for the treatment of vasomotor symptoms associated with menopause. To evaluate the safety, tolerability, and effect of fezolinetant on endometrial health over 52 weeks. We conducted a phase 3, randomized, double-blind, 52-week safety study (SKYLIGHT 4 [Study to Find Out How Safe Long-term Treatment With Fezolinetant is in Women With Hot Flashes Going Through Menopause]) of placebo, fezolinetant 30 mg, and fezolinetant 45 mg once daily (1:1:1). Participants were postmenopausal and seeking treatment for vasomotor symptoms associated with menopause. Primary endpoints were treatment-emergent adverse events, percentage of participants with endometrial hyperplasia, and percentage with endometrial malignancy. Endometrial hyperplasia or malignancy was evaluated according to U.S. Food and Drug Administration guidance (point estimate of 1% or less with an upper bound of one-sided 95% CI of 4% or less). Secondary endpoints included change in bone mineral density (BMD) and trabecular bone score. A sample size of 1,740 was calculated to enable observation of one or more events (≈80% probability for events with background rate of less than 1%). A total of 1,830 participants were randomized and took one or more medication dose (July 2019–January 2022). Treatment-emergent adverse events occurred in 64.1% (391/610) of the placebo group, 67.9% (415/611) of the fezolinetant 30-mg group, and 63.9% (389/609) of the fezolinetant 45-mg group. Treatment-emergent adverse events leading to discontinuation were similar across groups (placebo, 26/610 [4.3%]; fezolinetant 30 mg, 34/611 [5.6%]; fezolinetant 45 mg, 28/609 [4.6%]). Endometrial safety was assessed in 599 participants. In the fezolinetant 45-mg group, 1 of 203 participants had endometrial hyperplasia (0.5%; upper limit of one-sided 95% CI 2.3%); there were no cases in the placebo (0/186) or fezolinetant 30 mg (0/210) group. Endometrial malignancy occurred in 1 of 210 in the fezolinetant 30-mg group (0.5%; 95% CI 2.2%) with no cases in the other groups. Liver enzyme elevations more than three times the upper limit of normal occurred in 6 of 583 placebo, 8 of 590 fezolinetant 30 mg, and 12 of 589 fezolinetant 45 mg participants; no Hy's law cases were reported (ie, no severe drug-induced liver injury with alanine aminotransferase or aspartate aminotransferase more than three times the upper limit of normal and total bilirubin more than two times the upper limit of normal, with no elevation of alkaline phosphatase and no other reason to explain the combination). Changes in BMD and trabecular bone score were similar across groups. Results from SKYLIGHT 4 confirm the 52-week safety and tolerability of fezolinetant and support its continued development. Astellas Pharma Inc. ClinicalTrials.gov, NCT04003389.