Objectives To assess the efficacy and safety of the non-hormonal, neurokinin 3 receptor antagonist, fezolinetant, to treat moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy. Design Phase 3b randomised controlled trial. Setting 16 countries. Participants 453 individuals aged 40-65 years with moderate-severe vasomotor symptoms associated with menopause who were considered unsuitable candidates for hormone therapy (contraindicated, caution (based on medical history), stoppers (previous discontinuation of hormone therapy), or averse (informed choice not to use hormone therapy)) were randomised to receive fezolinetant (n=227) or placebo (n=226). Intervention Fezolinetant 45 mg or placebo once daily for 24 weeks. Main outcome measures The primary endpoint was mean change in daily frequency of moderate-severe vasomotor symptoms from baseline to week 24. Secondary endpoints were mean change in symptom severity, sleep disturbance using the Patient-Reported Outcome Measurement Information System Sleep Disturbance Short Form (PROMIS SD-SF) 8b total score, and safety. Results 370 (81.7%) participants completed the study (fezolinetant=195, placebo group=175). The safety and full analysis sets comprised 452 participants who received at least one dose of study drug. Mean age was 54.5 (standard deviation 4.7) years and most of the participants (435 (96.7%) were white and categorised as either hormone therapy averse (168 (37.2%)) or caution (165 (36.5%)). At week 24, fezolinetant significantly reduced the frequency (least squares mean difference –1.93, 95% confidence interval (CI) –2.64 to –1.22; P<0.001) and severity of vasomotor symptoms (–0.39, –0.57 to –0.21; P<0.001). At week 24, the fezolinetant group had a greater reduction in sleep disturbance (PROMIS SD-SF 8b total score) compared with placebo (–2.5, –3.9 to –1.1; P<0.001). Improvements over placebo were observed as early as week 1. Both groups showed similar incidences of treatment emergent adverse events (TEAEs, 147 (65.0%) in the fezolinetant group, 138 (61.1%) in the placebo group) and serious TEAEs (10 (4.4%) and 8 (3.5%), respectively). The most common TEAEs in the fezolinetant group were covid-19 (30 (13.3%)), headache (20 (8.8%)), and fatigue (13 (5.8%)). Conclusions Fezolinetant was efficacious and well tolerated over a six month period for treating moderate-severe vasomotor symptoms in individuals considered unsuitable for hormone therapy. These results highlight the utility of fezolinetant as an effective treatment option for those who have contraindications to or choose not to use hormone therapy. Trial registration ClinicalTrials.gov [NCT05033886][1]; EudraCT 2021-001685-38. Researchers may request access to anonymised participant level data, trial level data, and protocols from Astellas sponsored clinical trials at [www.clinicalstudydatarequest.com][2]. For the Astellas criteria on data sharing, see . [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05033886&atom=%2Fbmj%2F387%2Fbmj-2024-079525.atom [2]: http://www.clinicalstudydatarequest.com

中文翻译：

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Fezolinetant 治疗不适合激素治疗的个体与绝经相关的中重度血管舒缩症状的疗效和安全性： 3b 期随机对照试验


目的 评估非激素神经激肽 3 受体拮抗剂 fezolinetant 治疗不适合激素治疗的个体与更年期相关的中度至重度血管舒缩症状的有效性和安全性。设计 3b 期随机对照试验。设置 16 个国家/地区。参与者 453 名年龄在 40-65 岁之间、患有与更年期相关的中重度血管舒缩症状且被认为不适合激素治疗（禁忌、谨慎（基于病史）、停止者（既往停止激素治疗）或厌恶（知情选择不使用激素治疗））的个体被随机分配接受非唑利坦 （n=227） 或安慰剂 （n=226）。干预 Fezolinetant 45 mg 或安慰剂，每天一次，持续 24 周。主要结局指标 主要终点是从基线到第 24 周中重度血管舒缩症状的每日频率的平均变化。次要终点是症状严重程度的平均变化、使用患者报告结果测量信息系统睡眠障碍简表 （PROMIS SD-SF） 8b 总分的睡眠障碍和安全性。结果 370 名 （81.7%） 参与者完成了研究 （fezolinetant=195，安慰剂组=175）。安全性和完整分析集包括 452 名至少接受一剂研究药物的参与者。平均年龄为 54.5 （标准差 4.7） 岁，大多数参与者 （435 （96.7%） 是白人，并被归类为厌恶激素治疗 （168 （37.2%）） 或谨慎 （165 （36.5%））。在第 24 周，fezolinetant 显著降低频率（最小二乘均数差 -1.93,95% 置信区间 （CI） -2.64 至 -1.22;P<0.001）和血管舒缩症状的严重程度（-0.39、-0.57 至 -0.21;P<0.001）。 在第 24 周，与安慰剂组相比，fezolinetant 组的睡眠障碍减少幅度更大 （PROMIS SD-SF 8b 总分） （-2.5， -3.9 至 -1.1;P<0.001）。早在第 1 周就观察到与安慰剂相比的改善。两组均显示出相似的治疗紧急不良事件 （TEAEs，fezolinetant 组 147 例 （65.0%），安慰剂组 138 例 （61.1%））和严重 TEAEs （分别为 10 例 （4.4%） 和 8 例 （3.5%））。fezolinetant 组中最常见的 TEAE 是 covid-19 （30 （13.3%））、头痛 （20 （8.8%） 和疲劳 （13 （5.8%））。结论 Fezolinetant 在 6 个月内治疗被认为不适合激素治疗的个体的中重度血管舒缩症状有效且耐受性良好。这些结果强调了 fezolinetant 作为有激素治疗禁忌症或选择不使用激素治疗的患者的有效治疗选择的效用。试验注册 ClinicalTrials.gov [NCT05033886][1];EudraCT公司 2021-001685-38。研究人员可以请求访问安斯泰来赞助的临床试验的匿名参与者水平数据、试验水平数据和方案，网址为 [www.clinicalstudydatarequest.com][2]。有关 Astellas 关于数据共享的标准，请参阅。[1]： /lookup/external-ref？link_type=CLINTRIALGOV&access_num=NCT05033886&atom=%2Fbmj%2F387%2Fbmj-2024-079525.atom [2]： http://www.clinicalstudydatarequest.com