Background

Endometriosis is a common cause of pelvic pain in women, for which current treatment options are suboptimal. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, combined with estradiol and a progestin, was evaluated for treatment of endometriosis-associated pain.

Methods

In these two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled trials at 219 community and hospital research centres in Africa, Australasia, Europe, North America, and South America, we randomly assigned women aged 18–50 years with surgically or directly visualised endometriosis with or without histological confirmation, or with histological diagnosis alone. Participants were eligible if they had moderate to severe endometriosis-associated pain and, during the 35-day run-in period, a dysmenorrhoea Numerical Rating Scale (NRS) score of 4·0 or higher on two or more days and a mean non-menstrual pelvic pain NRS score of 2·5 or higher, or a mean score of 1·25 or higher that included a score of 5 or more on 4 or more days. Women received (1:1:1) once-daily oral placebo, relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0·5 mg), or delayed relugolix combination therapy (relugolix 40 mg monotherapy followed by relugolix combination therapy, each for 12 weeks) for 24 weeks. During the double-blind randomised treatment and follow-up period, all patients, investigators, and sponsor staff or representatives involved in the conduct of the study were masked to treatment assignment. The co-primary endpoints were responder rates at week 24 for dysmenorrhoea and non-menstrual pelvic pain, both based on NRS scores and analgesic use. Efficacy and safety were analysed in the modified intent-to-treat population (randomised patients who received ≥1 study drug dose). The studies are registered at ClinicalTrials.gov (SPIRIT 1 [NCT03204318] and SPIRIT 2 [NCT03204331]) and EudraCT (SPIRIT 1 [2017–001588–19] and SPIRIT 2 [2017–001632–19]). Eligible patients who completed the SPIRIT studies could enrol in a currently ongoing 80-week open-label extension study (SPIRIT EXTENSION [NCT03654274, EudraCT 2017-004066-10]). Database lock for the on-treatment duration has occurred, and post-treatment follow-up for safety, specificially for bone mineral density and menses recovery, is ongoing at the time of publication.

Findings

638 patients were enrolled into SPIRIT 1 and randomly assigned between Dec 7, 2017, and Dec 4, 2019, to receive relugolix combination therapy (212 [33%]), placebo (213 [33%]), or relugolix delayed combination therapy (213 [33%]). 623 patients were enrolled into SPIRIT 2 and were randomly assigned between Nov 1, 2017 and Oct 4, 2019, to receive relugolix combination therapy (208 [33%]), placebo (208 [33%]), or relugolix delayed combination therapy (207 [33%]). 98 (15%) patients terminated study participation early in SPIRIT 1 and 115 (18%) in SPIRIT 2. In SPIRIT 1, 158 (75%) of 212 patients in the relugolix combination therapy group met the dysmenorrhoea responder criteria compared with 57 (27%) of 212 patients in the placebo group (treatment difference 47·6% [95% CI 39·3–56·0]; p<0·0001). In SPIRIT 2, 155 (75%) of 206 patients in the relugolix combination therapy group were dysmenorrhoea responders compared with 62 (30%) of 204 patients in the placebo group (treatment difference 44·9% [95% CI 36·2–53·5]; p<0·0001). In SPIRIT 1, 124 (58%) of 212 patients in the relugolix combination therapy group met the non-menstrual pelvic pain responder criteria versus 84 (40%) patients in the placebo group (treatment difference 18·9% [9·5–28·2]; p<0·0001). In SPIRIT 2, 136 (66%) of 206 patients were non-menstrual pelvic pain responders in the relugolix combination therapy group compared with 87 (43%) of 204 patients in the placebo group (treatment difference 23·4% [95% CI 13·9–32·8]; p<0·0001). The most common adverse events were headache, nasopharyngitis, and hot flushes. There were nine reports of suicidal ideation across both studies (two in the placebo run-in, two in the placebo group, two in the relugolix combination therapy group, and three in the delayed relugolix combination therapy group). No deaths were reported. Least squares mean percentage change in lumbar spine bone mineral density in the relugolix combination therapy versus placebo groups was –0·70% versus 0·21% in SPIRIT 1 and –0·78% versus 0·02% in SPIRIT 2, and in the delayed relugolix combination group was –2·0% in SPIRIT 1 and –1·9% in SPIRIT 2. Decreases in opioid use were seen in treated patients as compared with placebo.

Interpretation

Once-daily relugolix combination therapy significantly improved endometriosis-associated pain and was well tolerated. This oral therapy has the potential to address the unmet clinical need for long-term medical treatment for endometriosis, reducing the need for opioid use or repeated surgical treatment.

Funding

Myovant Sciences.

中文翻译：

---

每天一次口服 relugolix 联合治疗与安慰剂治疗子宫内膜异位症相关疼痛患者：两个重复的 3 期、随机、双盲研究（SPIRIT 1 和 2）

背景

子宫内膜异位症是女性盆腔疼痛的常见原因，目前的治疗选择并不理想。Relugolix 是一种口服促性腺激素释放激素受体拮抗剂，联合雌二醇和孕激素，用于治疗子宫内膜异位症相关疼痛。

方法

在这两项在非洲、大洋洲、欧洲、北美和南美的 219 个社区和医院研究中心进行的多中心、多中心、随机、双盲、安慰剂对照试验中，我们随机分配了 18-50 岁的女性手术或直接可见的子宫内膜异位症，有或没有组织学确认，或仅有组织学诊断。如果参与者有中度至重度子宫内膜异位症相关疼痛，并且在 35 天的磨合期，两天或更多天的痛经数字评定量表 (NRS) 得分为 4·0 或更高，并且平均非经期盆腔痛 NRS 评分为 2·5 或更高，或平均评分为 1·25 或更高，其中包括 4 天或更长时间的评分为 5 或更高。女性接受 (1:1:1) 每日一次口服安慰剂、relugolix 联合治疗（relugolix 40 mg、雌二醇 1 mg，醋酸炔诺酮 0·5 mg），或延迟 relugolix 联合治疗（relugolix 40 mg 单药治疗，随后 relugolix 联合治疗，每次 12 周）持续 24 周。在双盲随机治疗和随访期间，所有参与研究的患者、研究人员和申办者工作人员或代表都被掩盖了治疗分配。共同主要终点是第 24 周痛经和非经期盆腔疼痛的反应率，均基于 NRS 评分和镇痛药的使用。在改良的意向治疗人群（接受≥1次研究药物剂量的随机患者）中分析了疗效和安全性。这些研究已在 ClinicalTrials.gov（SPIRIT 1 [NCT03204318] 和 SPIRIT 2 [NCT03204331]）和 EudraCT（SPIRIT 1 [2017-001588-19] 和 SPIRIT 2 [2017-001632-19]）注册。完成 SPIRIT 研究的合格患者可以参加目前正在进行的为期 80 周的开放标签扩展研究（SPIRIT EXTENSION [NCT03654274，EudraCT 2017-004066-10]）。治疗持续时间的数据库锁定已经发生，并且在出版时正在进行治疗后的安全性随访，特别是骨矿物质密度和月经恢复。

发现

638 名患者被纳入 SPIRIT 1，并在 2017 年 12 月 7 日至 2019 年 12 月 4 日期间随机分配接受 relugolix 联合治疗（212 [33%]）、安慰剂（213 [33%]）或 relugolix 延迟联合治疗（ 213 [33%]）。623 名患者被纳入 SPIRIT 2，并在 2017 年 11 月 1 日至 2019 年 10 月 4 日期间被随机分配接受 relugolix 联合治疗（208 [33%]）、安慰剂（208 [33%]）或 relugolix 延迟联合治疗（ 207 [33%]）。98 名（15%）患者在 SPIRIT 1 中提前终止了研究参与，115 名（18%）在 SPIRIT 2 中终止了研究参与。在 SPIRIT 1 中，relugolix 联合治疗组的 212 名患者中有 158 名（75%）符合痛经反应者标准，而 57 名（ 27%）安慰剂组 212 名患者（治疗差异 47·6% [95% CI 39·3–56·0]；p<0·0001）。在精神 2 中，relugolix 联合治疗组 206 名患者中有 155 名（75%）对痛经有反应，而安慰剂组 204 名患者中有 62 名（30%）（治疗差异 44·9% [95% CI 36·2–53·5] ; p<0·0001)。在 SPIRIT 1 中，relugolix 联合治疗组的 212 名患者中有 124 名 (58%) 符合非经期盆腔疼痛反应者标准，而安慰剂组为 84 名 (40%) 患者（治疗差异 18·9% [9·5– 28·2]；p<0·0001)。在 SPIRIT 2 中，relugolix 联合治疗组 206 名患者中有 136 名（66%）是非经期盆腔疼痛反应者，而安慰剂组 204 名患者中有 87 名（43%）（治疗差异 23·4% [95% CI 13·9–32·8]；p<0·0001)。最常见的不良事件是头痛、鼻咽炎和潮热。两项研究共有 9 例自杀意念报告（安慰剂组 2 例，安慰剂组 2 例，relugolix 联合治疗组 2 例，延迟 relugolix 联合治疗组 3 例）。没有死亡报告。relugolix 联合治疗与安慰剂组相比，腰椎骨密度的最小二乘平均百分比变化在 SPIRIT 1 中为 –0·70% 与 0·21%，在 SPIRIT 2 中为 –0·78% 与 0·02%，在延迟 relugolix 联合组在 SPIRIT 1 中为 –2·0%，在 SPIRIT 2 中为 –1·9%。与安慰剂相比，治疗患者的阿片类药物使用减少。

解释

每天一次的 relugolix 联合疗法显着改善了子宫内膜异位症相关的疼痛并且耐受性良好。这种口服疗法有可能解决子宫内膜异位症长期药物治疗未满足的临床需求，减少对阿片类药物使用或重复手术治疗的需求。

资金

Myovant 科学。