背景:Elagolix,经批准的子宫内膜异位症相关疼痛的口服治疗,当用作单一疗法时,与低雌激素作用有关。激素补充疗法有可能减轻这些影响。
目的:为了评估疗效,耐受性,与安慰剂相比,在患有中度至重度子宫内膜异位症相关疼痛的绝经前女性中,每天2次elagolix200mg,每天1mg雌二醇/0.5mg醋酸炔诺酮(补充)治疗的骨密度结局.
方法:这个正在进行的,48个月,第三阶段研究包括12个月,双盲期,随机分为4:1:2,每天两次给elagolix200毫克,并进行补充治疗,elagolix200毫克每日两次单药治疗6个月,然后用elagolix补充治疗,或安慰剂。共同主要终点是在第6个月时痛经和非经期盆腔疼痛的临床改善患者(称为“应答者”)的比例。我们报告了elagolix与补充治疗相比安慰剂在减少痛经方面的疗效的12个月结果,非月经盆腔疼痛,性交困难,和疲劳。耐受性评估包括不良事件和骨矿物质密度相对于基线的变化。
结果:总共679例患者被随机分配到elagolix并进行补充治疗(n=389),elagolix单药治疗(n=97),或安慰剂(n=193)。与随机接受安慰剂治疗的患者相比,在6个月时,随机接受elagolix加补治疗的患者中,痛经(62.8%vs23.7%;P≤.001)和非经期盆腔疼痛(51.3%vs36.8%;P≤.001)的临床改善比例显著更高.与安慰剂相比,elagolix与补充治疗相比,在包括痛经在内的7个分级次要终点(12、6、3个月)中,基线显着改善。非月经盆腔疼痛(12、6、3个月),和疲劳(6个月)(所有P<0.01)。总的来说,使用elagolix+回加治疗的不良事件发生率为73.8%,使用安慰剂的不良事件发生率为66.8%.严重和严重不良事件的发生率在治疗组之间没有显著差异。与不良事件相关的研究药物停药率在接受elagolix加回治疗(12.6%)和接受安慰剂(9.8%)的患者中很低。随机接受elagolix单药治疗的患者骨矿物质密度从基线下降-2.43%(腰椎),-1.54%(全髋关节),6个月时为-1.78%(股骨颈)。当在第6个月向elagolix添加反向治疗时,骨矿物质密度从基线的变化在第12个月时保持在-1.58%至-1.83%的相似范围内。然而,在第6个月和第12个月时,从基线开始接受elagolix加补充治疗的患者的骨矿物质密度与基线相比几乎没有变化(<1%变化).
结论:与安慰剂相比,elagolix与补充疗法导致显著,对痛经有临床意义的改善,非月经盆腔疼痛,和疲劳在6个月持续到12个月的痛经和非经期盆腔疼痛。Elagolix与补充治疗通常耐受性良好。接受elagolix补充治疗的患者在12个月时的骨矿物质密度损失大于接受安慰剂的患者。然而,elagolix+回加治疗的骨矿物质密度变化<1%,与elagolix单药治疗的骨丢失相比,骨矿物质密度变化减弱.
BACKGROUND: Elagolix, an approved oral treatment for endometriosis-associated pain, has been associated with hypoestrogenic effects when used as monotherapy. Hormonal add-back therapy has the potential to mitigate these effects.
OBJECTIVE: To evaluate efficacy, tolerability, and bone density outcomes of elagolix 200 mg twice daily with 1 mg estradiol/0.5 mg norethindrone acetate (add-back) therapy once daily compared with placebo in premenopausal women with moderate-to-severe endometriosis-associated pain.
METHODS: This ongoing, 48-month, phase 3 study consists of a 12-month double-blind period, with randomization 4:1:2 to elagolix 200 mg twice daily with add-back therapy, elagolix 200 mg twice daily monotherapy for 6 months followed by
elagolix with add-back therapy, or placebo. The coprimary endpoints were proportion of patients with clinical improvement (termed \"responders\") in dysmenorrhea and nonmenstrual pelvic pain at month 6. We report 12-month results on efficacy of elagolix with add-back therapy vs placebo in reducing dysmenorrhea, nonmenstrual pelvic pain, dyspareunia, and fatigue. Tolerability assessments include adverse events and change from baseline in bone mineral density.
RESULTS: A total of 679 patients were randomized to elagolix with add-back therapy (n=389),
elagolix monotherapy (n=97), or placebo (n=193). Compared with patients randomized to placebo, a significantly greater proportion of patients randomized to elagolix with add-back therapy responded with clinical improvement in dysmenorrhea (62.8% vs 23.7%; P≤.001) and nonmenstrual pelvic pain (51.3% vs 36.8%; P≤.001) at 6 months. Compared with placebo, elagolix with add-back therapy produced significantly greater improvement from baseline in 7 hierarchically ranked secondary endpoints including dysmenorrhea (months 12, 6, 3), nonmenstrual pelvic pain (months 12, 6, 3), and fatigue (months 6) (all P<.01). Overall, the incidence of adverse events was 73.8% with elagolix plus add-back therapy and 66.8% with placebo. The rate of severe and serious adverse events did not meaningfully differ between treatment groups. Study drug discontinuations associated with adverse events were low in patients receiving elagolix with add-back therapy (12.6%) and those receiving placebo (9.8%). Patients randomized to elagolix monotherapy exhibited decreases from baseline in bone mineral density of -2.43% (lumbar spine), -1.54% (total hip), and -1.78% (femoral neck) at month 6. When add-back therapy was added to elagolix at month 6, the change from baseline in bone mineral density remained in a similar range of -1.58% to -1.83% at month 12. However, patients who received elagolix plus add-back therapy from baseline exhibited little change from baseline in bone mineral density (<1% change) at months 6 and 12.
CONCLUSIONS: Compared with placebo, elagolix with add-back therapy resulted in significant, clinically meaningful improvement in dysmenorrhea, nonmenstrual pelvic pain, and fatigue at 6 months that continued until month 12 for both dysmenorrhea and nonmenstrual pelvic pain.
Elagolix with add-back therapy was generally well tolerated. Loss of bone mineral density at 12 months was greater in patients who received elagolix with add-back therapy than those who received placebo. However, the change in bone mineral density with elagolix plus add-back therapy was <1% and was attenuated compared with bone loss observed with
elagolix monotherapy.