目的:linzagolix每天一次口服给药,剂量为75mg单独或200mg联合补充治疗(ABT)(1.0mg雌二醇;0.5mg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痛经和非月经性盆腔疼痛方面比安慰剂更好?
结论:发现200mglinzagolix与ABT联合治疗3个月时可显著减少痛经和非月经性盆腔疼痛,而每日剂量75mglinzagolix仅在3个月时痛经显着减少。
背景:先前发表的第2阶段,剂量发现研究报告说,每天200毫克的剂量,linzagolix促进雌二醇分泌的完全抑制至低于20pg/ml的血清水平,并指出可能需要添加ABT以控制雌激素副作用。在较低剂量(75毫克和100毫克/天),linzagolix将雌二醇值保持在20-60pg/ml的目标范围内,这可能是缓解子宫内膜异位症相关症状的理想选择。
方法:EDELWEISS3是一个多中心,prospective,随机化,安慰剂对照,双盲,评估linzagolix治疗中重度子宫内膜异位症相关性疼痛的安全性和有效性的双模拟3期研究。治疗每天口服一次,持续6个月。
方法:在EDELWEISS3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,75mglinzagolix单独或200mglinzagolix与ABT联合使用。每天用口头评定量表测量疼痛,并记录在电子日记中。
结果:在3个月时,每日200mglinzagolix剂量与ABT符合主要疗效目标,显示痛经和非月经性盆腔疼痛的临床意义和统计学上的显着减少,稳定或减少使用镇痛药。200mglinzagolix与ABT组的痛经应答者比例为72.9%,而安慰剂组为23.5%(P<0.001),而非月经性盆腔疼痛的应答者发生率分别为47.3%和30.9%(P=0.007),分别。75mglinzagolix每日剂量显示3个月时痛经与安慰剂相比有临床意义和统计学意义的显著减少。75mglinzagolix组的痛经应答者比例为44.0%,而安慰剂组为23.5%(P<0.001)。尽管75mg剂量在3个月时相对于安慰剂显示出减少非月经性盆腔疼痛的趋势,无统计学意义(P=0.279)。与安慰剂相比,在两个linzagolix组中都观察到了明显的改善,改善了呼吸困难和整体盆腔疼痛。在两个linzagolix组中观察到性交困难评分的微小改善,但并不显著。在这两组中,低雌激素作用轻微,潮热率低,骨密度损失<1%。发现每日剂量200mglinzagolix与ABT或单独75mglinzagolix在治疗6个月时也显着减少痛经和非月经性盆腔疼痛。
结论:比较了linzagolix组和安慰剂组的疗效;然而,这将是有用的,从比较研究的结果与雌激素或孕激素。重要的是要确定促性腺激素释放激素拮抗剂是否比传统的一线药物具有显著的益处。
结论:Linzagolix在治疗中度至重度子宫内膜异位症相关疼痛时,每天一次口服200mg剂量联合补充治疗(ABT)显示出比安慰剂更好的疗效和安全性。由于ABT,生活质量得到改善,骨丢失和血管舒缩症状的风险降至最低。单独的75mg剂量可适用于子宫内膜异位症相关疼痛的慢性治疗,而不需要伴随激素ABT,但是需要进一步的研究来证实这一点。如果确认,它将为不想拥有ABT或禁忌ABT的女性提供可行的选择。
背景:EDELWEISS3研究的资金由ObsEva提供(日内瓦,瑞士)。对数据和手稿写作的分析得到了ObsEva的部分支持(日内瓦,瑞士),Theramex(伦敦,英国)和Kissei(日本),5/4/150/5被FNRS授予M.-M.D.。J.D.是ObsEva科学顾问委员会的成员,直到2022年8月,PregLem科学顾问委员会的成员。收到了GedeonRichter的个人费用,ObsEva和Theramex.J.D.收到咨询费,演讲者的费用,以及GedeonRichter的旅行支持,Obseva和Theramex,支付给他们的机构。C.B.已收到Theramex的费用,GedeonRichter,和Myovant,GedeonRichter的旅行支持-所有资金都流向了牛津大学。他是监督当前研究的数据监测委员会的成员,并在Myovant子宫内膜异位症研究顾问委员会任职。H.T.已获得Abbvie的资助,曾任ASRM总裁。F.C.H.已收到GedeonRichter和Theramex的费用。O.D.获得了GedeonRichter和ObsEva的讲座费用,以及Preglem和ObsEva独立于当前研究的临床研究研究资助。A.H.收到了NIHR的资助,UKRI,CSO,妇女的幸福,和罗氏诊断;他已经收到了Theramex的费用。A.H.的机构已收到罗氏诊断公司的酬金,Gesynta,还有Joii.M.P.没有什么要申报的。F.P.已收到Theramex的费用。S.P.R.一直是GedeonRichter科学顾问委员会的成员,并从GedeonRichter获得了费用。A.P.和M.B.是Theramex的雇员。E.B.是ObsEva的雇员,数据监测委员会主席监督当前研究,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.-M.D.已从GedeonRichter和Theramex获得费用和旅行支持。
背景:NCT03992846。
■2019年6月20日。
■2019年6月13日。
OBJECTIVE: 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?
CONCLUSIONS: 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.
BACKGROUND: 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.
METHODS: 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.
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.
RESULTS: 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.
CONCLUSIONS: 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.
CONCLUSIONS: 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.
BACKGROUND: 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.
BACKGROUND: NCT03992846.
UNASSIGNED: 20 June 2019.
UNASSIGNED: 13 June 2019.