STUDY QUESTION Does linzagolix administered orally once daily for up to 3 months at a dose of 75 mg alone or 200 mg in combination with add-back therapy (ABT) (1.0 mg estradiol; 0.5 mg norethindrone acetate, also known as norethisterone acetate [NETA]) demonstrate better efficacy than placebo in the management of endometriosis-related dysmenorrhea and non-menstrual pelvic pain? SUMMARY ANSWER Combining 200 mg linzagolix with ABT was found to significantly reduce dysmenorrhea and non-menstrual pelvic pain at 3 months of therapy, while a daily dose of 75 mg linzagolix yielded a significant decrease only in dysmenorrhea at 3 months. WHAT IS KNOWN ALREADY? A previously published Phase 2, dose-finding study reported that at a dose of 200 mg daily, linzagolix promotes full suppression of estradiol secretion to serum levels below 20 pg/ml and noted that the addition of ABT may be needed to manage hypoestrogenic side effects. At lower doses (75 mg and 100 mg/day), linzagolix maintains estradiol values within the target range of 20–60 pg/ml, which could be ideal to alleviate symptoms linked to endometriosis. STUDY DESIGN, SIZE, DURATION EDELWEISS 3 was a multicenter, prospective, randomized, placebo-controlled, double-blind, double-dummy Phase 3 study to evaluate the safety and efficacy of linzagolix for the treatment of moderate-to-severe endometriosis-associated pain. Treatment was administered orally once daily for up to 6 months. PARTICIPANTS/MATERIALS, SETTING, METHODS In the EDELWEISS 3 trial, 486 subjects with moderate-to-severe endometriosis-associated pain were randomized at a 1:1:1 ratio to one of the three study groups: placebo, 75 mg linzagolix alone or 200 mg linzagolix in association with ABT. Pain was measured daily on a verbal rating scale and recorded in an electronic diary. MAIN RESULTS AND THE ROLE OF CHANCE At 3 months, the daily 200 mg linzagolix dose with ABT met the primary efficacy objective, showing clinically meaningful and statistically significant reductions in dysmenorrhea and non-menstrual pelvic pain, with stable or decreased use of analgesics. The proportion of responders for dysmenorrhea in the 200 mg linzagolix with ABT group was 72.9% compared with 23.5% in the placebo group (P < 0.001), while the rates of responders for non-menstrual pelvic pain were 47.3% and 30.9% (P = 0.007), respectively. The 75 mg linzagolix daily dose demonstrated a clinically meaningful and statistically significant reduction in dysmenorrhea versus placebo at 3 months. The proportion of responders for dysmenorrhea in the 75 mg linzagolix group was 44.0% compared with 23.5% in the placebo group (P < 0.001). Although the 75 mg dose showed a trend toward reduction in non-menstrual pelvic pain at 3 months relative to the placebo, it was not statistically significant (P = 0.279). Significant improvements in dyschezia and overall pelvic pain were observed in both linzagolix groups when compared to placebo. Small improvements in dyspareunia scores were observed in both linzagolix groups but they were not significant. In both groups, hypoestrogenic effects were mild, with low rates of hot flushes and bone density loss of <1%. A daily dose of 200 mg linzagolix with ABT or 75 mg linzagolix alone was found to significantly reduce dysmenorrhea and non-menstrual pelvic pain also at 6 months of therapy. LIMITATIONS, REASONS FOR CAUTION Efficacy was compared between linzagolix groups and placebo; however, it would be useful to have results from comparative studies with estro-progestogens or progestogens. It will be important to ascertain whether gonadotropin-releasing hormone antagonists have significant benefits over traditional first-line medications. WIDER IMPLICATIONS OF THE FINDINGS Linzagolix administered orally once daily at a dose of 200 mg in combination with add-back therapy (ABT) demonstrated better efficacy and safety than placebo in the management of moderate-to-severe endometriosis-associated pain. The quality of life was improved and the risks of bone loss and vasomotor symptoms were minimized due to the ABT. The 75 mg dose alone could be suitable for chronic treatment of endometriosis-associated pain without the need for concomitant hormonal ABT, but further research is needed to confirm this. If confirmed, it would offer a viable option for women who do not want to wish to have ABT or for whom it is contraindicated. STUDY FUNDING/COMPETING INTEREST(S) Funding for the EDELWEISS 3 study was provided by ObsEva (Geneva, Switzerland). Analysis of data and manuscript writing were partially supported by ObsEva (Geneva, Switzerland), Theramex (London, UK) and Kissei (Japan) and grant 5/4/150/5 was awarded to M.-M.D. by FNRS. J.D. was a member of the scientific advisory board of ObsEva until August 2022, a member of the scientific advisory board of PregLem, and received personal fees from Gedeon Richter, ObsEva and Theramex. J.D. received consulting fees, speakers’ fees, and travel support from Gedeon Richter, Obseva and Theramex, which was paid to their institution. C.B. has received fees from Theramex, Gedeon Richter, and Myovant, and travel support from Gedeon Richter—all funds went to the University of Oxford. He was a member of the data monitoring board supervising the current study, and served at an advisory board for endometriosis studies of Myovant. H.T. has received grants from Abbvie and was past president of ASRM. F.C.H. has received fees from Gedeon Richter and Theramex. O.D. received fees for lectures from Gedeon Richter and ObsEva and research grants for clinical studies from Preglem and ObsEva independent from the current study. A.H. has received grants from NIHR, UKRI, CSO, Wellbeing of Women, and Roche Diagnostics; he has received fees from Theramex. A.H.’s institution has received honoraria for consultancy from Roche Diagnostics, Gesynta, and Joii. M.P. has nothing to declare. F.P. has received fees from Theramex. S.P.R. has been a member of the scientific advisory board of Gedeon Richter and received fees from Gedeon Richter. A.P. and M.B. are employees of Theramex. E.B. was an employee of ObsEva, sponsor chair of the data monitoring board supervising the current study, and has been working as a consultant for Theramex since December 2022; she owns stock options in ObsEva. M.-M.D. has received fees and travel support from Gedeon Richter and Theramex. TRIAL REGISTRATION NUMBER NCT 03992846. TRIAL REGISTRATION DATE 20 June 2019. DATE OF FIRST PATIENT’S ENROLLMENT 13 June 2019.

中文翻译：

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Linzagolix 疗法与安慰剂治疗子宫内膜异位症相关疼痛患者：一项前瞻性、随机、双盲 3 期研究 (EDELWEISS 3)

研究问题 林扎戈利是否可以单独口服 75 mg 剂量，每日一次，持续长达 3 个月，或 200 mg 联合反加疗法 (ABT)（1.0 mg 雌二醇；0.5 mg 醋酸炔诺酮，也称为醋酸炔诺酮 [NETA]） ]）在治疗子宫内膜异位症相关的痛经和非经期盆腔疼痛方面表现出比安慰剂更好的疗效？摘要：在治疗 3 个月时，将 200 mg 林扎戈利与 ABT 联合使用可显着减少痛经和非经期盆腔疼痛，而每天服用 75 mg 林扎戈利仅在 3 个月时显着减少痛经。目前已知什么？先前发表的第 2 期剂量探索研究报告称，每日 200 mg 的剂量下，林扎戈利可促进雌二醇分泌的完全抑制，使血清水平低于 20 pg/ml，并指出可能需要添加 ABT 来控制低雌激素副作用。在较低剂量（75 毫克和 100 毫克/天）下，林扎戈利将雌二醇值维持在 20-60 pg/ml 的目标范围内，这可能是缓解与子宫内膜异位症相关症状的理想选择。研究设计、规模、持续时间 EDELWEISS 3 是一项多中心、前瞻性、随机、安慰剂对照、双盲、双模拟 3 期研究，旨在评估林扎戈利治疗中重度子宫内膜异位症相关的安全性和有效性疼痛。治疗每天口服一次，持续长达 6 个月。参与者/材料、环境、方法 在 EDELWEISS 3 试验中，486 名患有中度至重度子宫内膜异位症相关疼痛的受试者以 1:1:1 的比例随机分配到三个研究组之一：安慰剂组、单用 75 mg 林扎戈利或200 mg 林扎戈利与 ABT 联合使用。每天通过口头评定量表测量疼痛并记录在电子日记中。主要结果和机会的作用 3 个月时，每日 200 mg 林扎戈利剂量联合 ABT 达到了主要疗效目标，显示出具有临床意义和统计学意义的痛经和非经期盆腔疼痛的减少，镇痛药的使用稳定或减少。 200 mg 林扎戈利联合 ABT 组中对痛经有反应的比例为 72.9%，而安慰剂组为 23.5%（P < 0.001），而对非经期盆腔疼痛有反应的比例分别为 47.3% 和 30.9%（ P = 0.007），分别。 3 个月后，与安慰剂相比，每天服用 75 毫克林扎戈利可显着减少痛经，具有临床意义和统计学意义。 75 mg 林扎戈利组中对痛经有反应的比例为 44.0%，而安慰剂组为 23.5%（P < 0.001）。尽管与安慰剂相比，75 mg 剂量在 3 个月时显示出非经期盆腔疼痛减少的趋势，但并不具有统计学意义（P = 0.279）。与安慰剂相比，林扎戈利组的排便困难和整体骨盆疼痛都有显着改善。在两个林扎戈利组中均观察到性交困难评分略有改善，但并不显着。在两组中，低雌激素作用都很轻微，潮热和骨密度损失的发生率较低，<1%。研究发现，每日服用 200 mg 林扎戈利联合 ABT 或单独服用 75 mg 林扎戈利在治疗 6 个月时也能显着减轻痛经和非经期盆腔疼痛。局限性、注意原因 比较林扎戈利组和安慰剂组之间的疗效；然而，获得与雌孕激素或孕激素的比较研究结果将是有用的。确定促性腺激素释放激素拮抗剂是否比传统一线药物具有显着益处非常重要。研究结果的更广泛意义 在治疗中度至重度子宫内膜异位症相关疼痛方面，每日一次口服林扎戈利 (200 mg) 与反加疗法 (ABT) 相结合，显示出比安慰剂更好的疗效和安全性。 ABT 提高了生活质量，并将骨质流失和血管舒缩症状的风险降至最低。单独使用 75 毫克剂量可能适合慢性治疗子宫内膜异位症相关疼痛，无需同时使用激素 ABT，但需要进一步研究来证实这一点。如果得到证实，它将为那些不想进行 ABT 或禁忌 ABT 的女性提供一个可行的选择。研究经费/竞争利益 EDELWEISS 3 研究的经费由 ObsEva（瑞士日内瓦）提供。数据分析和手稿写作得到了 ObsEva（瑞士日内瓦）、Theramex（英国伦敦）和 Kissei（日本）的部分支持，FNRS 向 M.-MD 授予了 5/4/150/5 拨款。 JD 一直是 ObsEva 科学顾问委员会的成员，直至 2022 年 8 月，也是 PregLem 科学顾问委员会的成员，并从 Gedeon Richter、ObsEva 和 Theramex 收取个人费用。 JD 从 Gedeon Richter、Obseva 和 Theramex 获得咨询费、演讲费和差旅支持，这些费用均支付给他们的机构。 CB 已从 Theramex、Gedeon Richter 和 Myovant 收取费用，并从 Gedeon Richter 获得旅行支持——所有资金都捐给了牛津大学。他是监督当前研究的数据监测委员会成员，并在 Myovant 子宫内膜异位症研究顾问委员会任职。 HT 已获得艾伯维 (Abbvie) 的资助，并曾担任 ASRM 前任主席。 FCH 已从 Gedeon Richter 和 Theramex 收取费用。 OD 从 Gedeon Richter 和 ObsEva 获得讲座费用，并从 Preglem 和 ObsEva 获得独立于当前研究的临床研究资助。 AH 已获得 NIHR、UKRI、CSO、Wellbeing of Women 和 Roche Diagnostics 的资助；他已从 Theramex 收取费用。 AH 机构已获得罗氏诊断公司、Gesynta 和 Joii 的咨询酬金。国会议员没有什么可宣布的。 FP 已从 Theramex 收取费用。表面等离子体共振曾担任 Gedeon Richter 科学顾问委员会成员，并从 Gedeon Richter 收取费用。 AP 和 MB 是 Theramex 的员工。 EB 是 ObsEva 的员工，也是监督当前研究的数据监测委员会的发起人主席，并自 2022 年 12 月以来一直担任 Theramex 的顾问；她拥有 ObsEva 的股票期权。 M.-MD 已获得 Gedeon Richter 和 Theramex 的费用和差旅支持。试验注册号 NCT 03992846。试验注册日期 2019 年 6 月 20 日。第一位患者入组日期 2019 年 6 月 13 日。