Elagolix，一种口服 GnRH 拮抗剂，治疗子宫内膜异位症相关疼痛。

Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist.

机构信息

From Yale School of Medicine, New Haven, CT (H.S.T.); University of California, San Francisco, San Francisco (L.C.G.); Greenville Health System, Greenville, SC (B.A.L.); University of São Paulo and Sirio Libanes Hospital, São Paulo (M.S.A.); Medical University, Lublin, Poland (J.K.); Eastern Virginia Medical School, Norfolk (D.F.A.); Augusta University, Augusta, GA (M.P.D.); Colorado Center for Reproductive Medicine, Lone Tree (E.S.); Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia (N.P.J.); Repromed Auckland, Auckland, New Zealand (N.P.J.); Mercy Health Osteoporosis and Bone Health Services, Cincinnati (N.B.W.); Creighton University School of Medicine, Omaha, NE (J.C.G.); George Washington University, Washington, DC (J.A.S.); University of Texas Southwestern Medical Center, Dallas (B.C.); Institute for the Study and Treatment of Endometriosis, Oak Brook (W.P.D.), and AbbVie, North Chicago (J.P.R., W.R.D., J.N., B.S., J.W.T., R.I.J., K.C.) - both in Illinois; and McMaster University, Hamilton, ON, Canada (N.L.).

出版信息

N Engl J Med. 2017 Jul 6;377(1):28-40. doi: 10.1056/NEJMoa1700089. Epub 2017 May 19.

DOI:10.1056/NEJMoa1700089

PMID:28525302

Abstract

BACKGROUND

Endometriosis is a chronic, estrogen-dependent condition that causes dysmenorrhea and pelvic pain. Elagolix, an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist, produced partial to nearly full estrogen suppression in previous studies.

METHODS

We performed two similar, double-blind, randomized, 6-month phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II]) to evaluate the effects of two doses of elagolix - 150 mg once daily (lower-dose group) and 200 mg twice daily (higher-dose group) - as compared with placebo in women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain. The two primary efficacy end points were the proportion of women who had a clinical response with respect to dysmenorrhea and the proportion who had a clinical response with respect to nonmenstrual pelvic pain at 3 months. Each of these end points was measured as a clinically meaningful reduction in the pain score and a decreased or stable use of rescue analgesic agents, as recorded in a daily electronic diary.

RESULTS

A total of 872 women underwent randomization in Elaris EM-I and 817 in Elaris EM-II; of these women, 653 (74.9%) and 632 (77.4%), respectively, completed the intervention. At 3 months, a significantly greater proportion of women who received each elagolix dose met the clinical response criteria for the two primary end points than did those who received placebo. In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P<0.001 for all comparisons). In Elaris EM-I, the percentage of women who had a clinical response with respect to nonmenstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P<0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P=0.003 and P<0.001, respectively). The responses with respect to dysmenorrhea and nonmenstrual pelvic pain were sustained at 6 months. Women who received elagolix had higher rates of hot flushes (mostly mild or moderate), higher levels of serum lipids, and greater decreases from baseline in bone mineral density than did those who received placebo; there were no adverse endometrial findings.

CONCLUSIONS

Both higher and lower doses of elagolix were effective in improving dysmenorrhea and nonmenstrual pelvic pain during a 6-month period in women with endometriosis-associated pain. The two doses of elagolix were associated with hypoestrogenic adverse effects. (Funded by AbbVie; Elaris EM-I and EM-II ClinicalTrials.gov numbers, NCT01620528 and NCT01931670 .).

摘要

背景

子宫内膜异位症是一种慢性、雌激素依赖性疾病，可导致痛经和盆腔疼痛。在之前的研究中，口服非肽类促性腺激素释放激素（GnRH）拮抗剂 Elagolix 可产生部分至几乎完全的雌激素抑制作用。

方法

我们进行了两项相似的、双盲、随机、6 个月的 3 期试验（Elaris 子宫内膜异位症 I 和 II [EM-I 和 EM-II]），以评估两种剂量的 Elagolix（每日一次 150mg 低剂量组和每日两次 200mg 高剂量组）与安慰剂相比，在经手术诊断为子宫内膜异位症且伴有中度或重度与子宫内膜异位症相关的疼痛的女性中的疗效。主要的两个疗效终点是：在痛经方面有临床缓解的女性比例，以及在非经期盆腔疼痛方面有临床缓解的女性比例，这两个终点都通过每日电子日记记录的疼痛评分降低和/或救援止痛药物使用减少来衡量。

结果

共有 872 名女性在 Elaris EM-I 中接受了随机分组，817 名女性在 Elaris EM-II 中接受了随机分组；其中，分别有 653 名（74.9%）和 632 名（77.4%）女性完成了干预。在 3 个月时，与接受安慰剂的女性相比，接受 Elagolix 各剂量的女性在两个主要终点的临床缓解标准上有更高的比例符合要求。在 Elaris EM-I 中，低剂量 Elagolix 组和高剂量 Elagolix 组痛经方面有临床缓解的女性比例分别为 46.4%和 75.8%，而安慰剂组为 19.6%（所有比较均 P<0.001）；在 Elaris EM-II 中，相应的百分比分别为 43.4%和 72.4%，而安慰剂组为 22.7%（所有比较均 P<0.001）。在 Elaris EM-I 中，低剂量 Elagolix 组和高剂量 Elagolix 组非经期盆腔疼痛方面有临床缓解的女性比例分别为 50.4%和 54.5%，而安慰剂组为 36.5%（所有比较均 P<0.001）；在 Elaris EM-II 中，相应的百分比分别为 49.8%和 57.8%，而安慰剂组为 36.5%（P=0.003 和 P<0.001）。痛经和非经期盆腔疼痛的缓解在 6 个月时持续存在。与接受安慰剂的女性相比，接受 Elagolix 的女性更易出现热潮红（多为轻度或中度）、血清脂质水平升高以及骨密度从基线的更大下降，而子宫内膜无不良反应。

结论

在 6 个月的时间内，高剂量和低剂量的 Elagolix 均能有效改善与子宫内膜异位症相关的疼痛患者的痛经和非经期盆腔疼痛。两种剂量的 Elagolix 均与雌激素减少相关的不良反应有关。（由 AbbVie 资助；Elaris EM-I 和 EM-II 的临床试验注册号为 NCT01620528 和 NCT01931670）。