Panay Nick, Joffe Hadine, Maki Pauline M, Nappi Rossella E, Pinkerton JoAnn V, Simon James A, Soares Claudio N, Thurston Rebecca C, Francuski Maja, Caetano Cecilia, Genga Kelly, Haberland Claudia, Haseli Mashhadi Nazanin, Laapas Kaisa, Parke Susanne, Seitz Christian, Schwarz Judith, Zuurman Lineke
Queen Charlotte's and Chelsea Hospital, Imperial College London, London, England.
Department of Psychiatry and Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
JAMA Intern Med. 2025 Sep 8. doi: 10.1001/jamainternmed.2025.4421.
There is an unmet need for long-term, safe, effective, and hormone-free treatments for menopausal symptoms, including vasomotor symptoms (VMS) and sleep disturbances.
To evaluate the 52-week efficacy and safety of elinzanetant, a dual neurokinin-targeted therapy, for treating moderate to severe VMS associated with menopause.
DESIGN, SETTING, AND PARTICIPANTS: OASIS-3 was a double-blind, placebo-controlled, randomized phase 3 clinical trial that was conducted at 83 sites in North America and Europe from August 27, 2021, to February 12, 2024, and included postmenopausal women aged 40 to 65 years who were seeking treatment for moderate to severe VMS (no requirement for a minimum number of VMS events per week). The data were analyzed on March 11, 2024.
Once-daily oral elinzanetant, 120 mg, or matching placebo for 52 weeks.
The primary outcome was mean change from baseline to week 12 in the frequency of daily moderate to severe VMS, which was analyzed using a mixed model with repeated measures. Secondary end points included changes over 52 weeks in measures evaluating sleep disturbance and the effect on menopause-related quality of life. Exploratory end points included mean changes over 50 weeks in frequency and severity of daily moderate to severe VMS. Exploratory and secondary end points were analyzed using descriptive statistics. Safety was also assessed.
Overall, 313 women (mean [SD] age, 54.6 [4.7] years; 51 [16.3%] were Black or African American, and 240 [76.7%] were White individuals; 34 [10.9%] were Hispanic or Latina) were randomized to receive elinzanetant and 315 (mean [SD] age, 54.9 [5.0] years; 44 [14.0%] Black or African American, 34 [10.8%] Hispanic or Latina, and 253 [80.3%] White individuals) to receive placebo. At week 12, the mean change from baseline in daily moderate to severe VMS frequency was -5.4 (95% CI, -6.3 to -4.5) for elinzanetant and -3.5 (95% CI, -4.1 to -2.9) for placebo; the least-squares mean difference for elinzanetant vs placebo was -1.6 (95% CI, -2.0 to -1.1; P < .001). Although no statistical hypotheses were defined, nor was the study powered to detect between-group differences for the secondary and exploratory end points, descriptive analyses showed numerical advantages for elinzanetant vs placebo for improving VMS frequency and severity over 50 weeks and sleep disturbances and menopause-related quality of life over 52 weeks. Regarding safety, elinzanetant was not associated with hepatotoxic effects, endometrial hyperplasia, or meaningful changes in bone density or bone turnover markers. Treatment-related adverse events were more common with elinzanetant than placebo (30.4% vs 14.6%); the most frequent were somnolence, fatigue, and headache.
The OASIS-3 randomized clinical trial expanded on findings from the 26-week OASIS-1 and OASIS-2 trials, exploring the use of elinzanetant over a longer duration and in a broader population. Elinzanetant shows promise as a treatment for moderate to severe VMS.
ClinicalTrials.gov Identifier: NCT05030584.
对于更年期症状，包括血管舒缩症状（VMS）和睡眠障碍，长期、安全、有效且无激素的治疗方法仍未得到满足。
评估elinzanetant（一种双重神经激肽靶向疗法）治疗与更年期相关的中度至重度VMS的52周疗效和安全性。
设计、设置和参与者：OASIS-3是一项双盲、安慰剂对照、随机3期临床试验，于2021年8月27日至2024年2月12日在北美和欧洲的83个地点进行，纳入了年龄在40至65岁之间、寻求治疗中度至重度VMS（对每周VMS事件的最低数量无要求）的绝经后女性。数据于2024年3月11日进行分析。
每日口服一次120mg的elinzanetant或匹配的安慰剂，持续52周。
主要结局是从基线到第12周每日中度至重度VMS频率的平均变化，使用重复测量的混合模型进行分析。次要终点包括52周内评估睡眠障碍的指标变化以及对更年期相关生活质量的影响。探索性终点包括50周内每日中度至重度VMS频率和严重程度的平均变化。探索性和次要终点使用描述性统计进行分析。同时也评估了安全性。
总体而言，313名女性（平均[标准差]年龄，54.6[4.7]岁；51名[16.3%]为黑人或非裔美国人，240名[76.7%]为白人；34名[10.9%]为西班牙裔或拉丁裔）被随机分配接受elinzanetant，315名（平均[标准差]年龄，54.9[5.0]岁；44名[14.0%]为黑人或非裔美国人，34名[10.8%]为西班牙裔或拉丁裔，253名[80.3%]为白人）接受安慰剂。在第12周时，elinzanetant组每日中度至重度VMS频率从基线的平均变化为-5.4（95%CI，-6.3至-4.5），安慰剂组为-3.5（95%CI，-4.1至-2.9）；elinzanetant与安慰剂的最小二乘平均差异为-1.6（95%CI，-2.0至-1.1；P < .001）。尽管未定义统计假设，且该研究也没有足够的效力检测次要和探索性终点的组间差异，但描述性分析显示，在改善50周内的VMS频率和严重程度以及52周内的睡眠障碍和更年期相关生活质量方面，elinzanetant相对于安慰剂在数值上具有优势。关于安全性，elinzanetant与肝毒性、子宫内膜增生或骨密度或骨转换标志物的有意义变化无关。与治疗相关的不良事件在elinzanetant组比安慰剂组更常见（30.4%对14.6%）；最常见的是嗜睡、疲劳和头痛。
OASIS-3随机临床试验扩展了26周的OASIS-1和OASIS-2试验的结果，探索了elinzanetant在更长时间和更广泛人群中的使用。Elinzanetant显示出作为中度至重度VMS治疗方法的前景。
ClinicalTrials.gov标识符：NCT05030584。
