Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy.
Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy.
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DOI：
10.1056/nejmoa2008283
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发表时间：
2021-02-18
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影响因子：
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通讯作者：
Stewart EA
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作者：
Al-Hendy A;Lukes AS;Poindexter AN 3rd;Venturella R;Villarroel C;Critchley HOD;Li Y;McKain L;Arjona Ferreira JC;Langenberg AGM;Wagman RB;Stewart EA
子宫肌瘤是月经大量出血和疼痛的常见原因。Relugolix（一种口服促性腺激素释放激素受体拮抗剂）、雌二醇和醋酸炔诺酮每日一次联合给药可能在子宫肌瘤和大出血女性中具有疗效，同时避免了雌激素水平低下效应。我们进行了两个重复的国际，双盲，24周，3期临床试验，涉及子宫肌瘤相关的大量月经出血的妇女。受试者以1：1：1的比例随机分配接受每日一次安慰剂、Relugolix联合治疗（40 mg Relugolix、1 mg雌二醇和0.5 mg醋酸炔诺酮）或延迟Relugolix联合治疗（40 mg Relugolix单药治疗，随后Relugolix联合治疗，各持续12周）。每项试验的主要疗效终点是Relugolix联合治疗组与安慰剂组相比出现缓解（月经失血量<80 ml且月经量较基线减少≥50%）的受试者百分比。关键的次要终点是闭经、月经失血量、出血引起的痛苦和盆腔不适、贫血、疼痛、肌瘤体积和子宫体积。评估安全性和骨密度。试验L1中共有388名女性和试验L2中共有382名女性接受了随机化。试验L1中Relugolix联合治疗组共有73%的受试者和试验L2中共有71%的受试者出现缓解（主要终点），而安慰剂组分别为19%和15%（两项比较均P<0.001）。与安慰剂组相比，两个Relugolix联合治疗组的7个关键次要终点中有6个显著改善，包括月经失血量（包括闭经）、疼痛、出血和盆腔不适引起的痛苦、贫血和子宫体积，但非肌瘤体积。Relugolix联合治疗组和安慰剂组的不良事件发生率相似。Relugolix联合治疗组和安慰剂组的骨密度相似，但Relugolix单药治疗组骨密度降低。与安慰剂相比，Relugolix每日一次联合治疗可显著减少子宫肌瘤女性的月经出血，并保持骨密度。（由Myovant Sciences资助; LIBERTY 1 [L1]和LIBERTY 2 [L2] Clinicaltrials.gov编号分别为NCT 03049735和NCT 03103087。）
Uterine fibroids are a common cause of heavy menstrual bleeding and pain. Treatment with the combination of relugolix (an oral gonadotropin-releasing hormone-receptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects. We conducted two replicate international, double-blind, 24-week, phase 3 trials involving women with fibroid-associated heavy menstrual bleeding. Participants were randomly assigned in a 1:1:1 ratio to receive once-daily placebo, relugolix combination therapy (40 mg of relugolix, 1 mg of estradiol, and 0.5 mg of norethindrone acetate), or delayed relugolix combination therapy (40 mg of relugolix monotherapy, followed by relugolix combination therapy, each for 12 weeks). The primary efficacy end point in each trial was the percentage of participants with a response (volume of menstrual blood loss <80 ml and a ≥50% reduction in volume from baseline) in the relugolix combination therapy group, as compared with the placebo group. Key secondary end points were amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, fibroid volume, and uterine volume. Safety and bone mineral density were assessed. A total of 388 women in trial L1 and 382 in trial L2 underwent randomization. A total of 73% of the participants in the relugolix combination therapy group in trial L1 and 71% of those in trial L2 had a response (primary end point), as compared with 19% and 15%, respectively, of those in the placebo groups (P<0.001 for both comparisons). Both relugolix combination therapy groups had significant improvements, as compared with the placebo groups, in six of seven key secondary end points, including measures of menstrual blood loss (including amenorrhea), pain, distress from bleeding and pelvic discomfort, anemia, and uterine volume, but not fibroid volume. The incidence of adverse events was similar with relugolix combination therapy and placebo. Bone mineral density was similar with relugolix combination therapy and placebo but decreased with relugolix monotherapy. Once-daily relugolix combination therapy resulted in a significant reduction in menstrual bleeding, as compared with placebo, and preserved bone mineral density in women with uterine fibroids. (Funded by Myovant Sciences; LIBERTY 1 [L1] and LIBERTY 2 [L2] Clinicaltrials.gov numbers, NCT03049735 and NCT03103087, respectively.)