Stewart Elizabeth A, Lukes Andrea S, Venturella Roberta, Li Yulan, Hunsche Elke, Wagman Rachel B, Al-Hendy Ayman
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology Mayo Clinic and Mayo Clinic Alix School of Medicine, Rochester, MN.
Carolina Women's Research and Wellness Center, Durham, NC.
Am J Obstet Gynecol. 2023 Mar;228(3):320.e1-320.e11. doi: 10.1016/j.ajog.2022.11.1278. Epub 2022 Nov 9.
Symptomatic uterine fibroids are burdensome to live with; they are associated with symptom-related distress, affect daily activities, and reduce health-related quality of life. The LIBERTY randomized clinical trials showed that oral relugolix combination therapy (40 mg relugolix, 1 mg estradiol, and 0.5 mg norethindrone acetate once daily) markedly improved fibroid-associated symptoms and conditions, including heavy menstrual bleeding, pain, and anemia, and was well-tolerated.
This study aimed to evaluate the effect of relugolix combination therapy on the symptom burden and health-related quality of life among women with uterine fibroids.
Two replicate, multinational, double-blind, 24-week, randomized, placebo-controlled, phase 3 studies, LIBERTY 1 and LIBERTY 2, were conducted in premenopausal women with uterine fibroid-associated heavy menstrual bleeding (≥80 mL per cycle for 2 cycles or ≥160 mL during 1 cycle). The symptom burden and health-related quality of life were secondary endpoints and were assessed using the validated Uterine Fibroid Symptom and Quality of Life questionnaire, which the participants completed at baseline and at week 12 and 24 of treatment. For this secondary analysis, the pooled LIBERTY 1 and LIBERTY 2 data set was used. The Uterine Fibroid Symptom and Quality of Life questionnaire is made up of a Symptom Severity scale and a Health-Related Quality of Life scale, the latter of which includes 6 subscales focusing on the following aspects of daily life: concern, activities, energy or mood, control, self-consciousness, and sexual function. The Revised Activities subscale of the Health-Related Quality of Life scale addresses the impact of uterine fibroids on physical and social activities. Symptom burden was also assessed via the Bleeding and Pelvic Discomfort subscale, a patient-reported outcome measure derived from the Uterine Fibroid Symptom Severity scale that focuses on distress from key uterine fibroid symptoms, which was a key secondary endpoint. Least squares mean changes from baseline to week 24 in the Symptom Severity scale, Bleeding and Pelvic Discomfort subscale, overall Health-Related Quality of Life scale, and the respective subscales were compared between the relugolix combination therapy and placebo groups. Responder analyses of the proportion of women who experienced a clinically meaningful change from baseline to week 24 were conducted for the Bleeding and Pelvic Discomfort and the activity subscales. A stratified Cochran-Mantel-Haenszel test, adjusted for stratification factors (region [North America vs rest of world] and baseline menstrual blood loss volume), was used for treatment comparisons.
Across both trials, 509 women were randomized to the relugolix combination therapy or placebo groups (April 2017-December 2018). Participants on relugolix combination therapy showed a statistically significant reduction in symptom severity (-33.5 vs -12.1; nominal P<.0001) and the Bleeding and Pelvic Discomfort subscale from baseline to week 24 when compared with those on placebo treatment (-48.4 vs -17.4; nominal P<.0001). Overall, the total Health-Related Quality of Life scores improved significantly from baseline to week 24 in the relugolix combination therapy group when compared with the placebo (+37.6 vs +13.1; nominal P<.0001). Responder analyses demonstrated that more women treated with relugolix combination therapy reported a clinically meaningful reduction in the Bleeding and Pelvic Discomfort subscale and an improvement in physical and social activities when compared with those treated with the placebo (nominal P<.0001).
After 24 weeks of treatment with relugolix combination therapy, women with symptomatic uterine fibroids experienced substantial improvements in health-related quality of life with all subscales showing improvement, including emotional well-being, physical and social activities, and sexual function. In addition, women reported substantial reductions in the overall symptom burden and distress caused by key fibroid-associated symptoms.
有症状的子宫肌瘤会给患者的生活带来负担；它们与症状相关的困扰有关，影响日常活动，并降低健康相关生活质量。LIBERTY随机临床试验表明，口服瑞戈非尼联合疗法（每日一次，40毫克瑞戈非尼、1毫克雌二醇和0.5毫克醋酸炔诺酮）可显著改善与肌瘤相关的症状和状况，包括月经过多、疼痛和贫血，且耐受性良好。
本研究旨在评估瑞戈非尼联合疗法对子宫肌瘤女性症状负担和健康相关生活质量的影响。
两项重复、多国、双盲、为期24周的随机、安慰剂对照3期研究，即LIBERTY 1和LIBERTY 2，在患有子宫肌瘤相关月经过多（连续2个周期每个周期≥80毫升或1个周期内≥160毫升）的绝经前女性中进行。症状负担和健康相关生活质量是次要终点，使用经过验证的子宫肌瘤症状与生活质量问卷进行评估，参与者在基线以及治疗的第12周和第24周完成该问卷。对于本次次要分析，使用了LIBERTY 1和LIBERTY 2的汇总数据集。子宫肌瘤症状与生活质量问卷由症状严重程度量表和健康相关生活质量量表组成，后者包括6个分量表，重点关注日常生活的以下方面：担忧、活动、精力或情绪、控制、自我意识和性功能。健康相关生活质量量表的修订活动分量表涉及子宫肌瘤对身体和社交活动的影响。症状负担也通过出血和盆腔不适分量表进行评估，这是一种源自子宫肌瘤症状严重程度量表的患者报告结局指标，重点关注主要子宫肌瘤症状引起的困扰，这是一个关键的次要终点。比较了瑞戈非尼联合疗法组和安慰剂组从基线到第24周症状严重程度量表、出血和盆腔不适分量表、总体健康相关生活质量量表及其各自分量表的最小二乘均值变化。对出血和盆腔不适以及活动分量表进行了从基线到第24周经历临床意义变化的女性比例的反应者分析。使用分层Cochran-Mantel-Haenszel检验，并根据分层因素（地区[北美与世界其他地区]和基线月经失血量）进行调整，以进行治疗比较。
在两项试验中，509名女性被随机分配到瑞戈非尼联合疗法组或安慰剂组（2017年4月至2018年12月）。与接受安慰剂治疗的参与者相比，接受瑞戈非尼联合疗法的参与者从基线到第24周症状严重程度有统计学显著降低（-33.5对-12.1；名义P<.0001），出血和盆腔不适分量表也有显著降低（-48.4对-17.4；名义P<.0001）。总体而言，与安慰剂相比，瑞戈非尼联合疗法组从基线到第24周总体健康相关生活质量得分显著提高（+37.6对+13.1；名义P<.0001）。反应者分析表明，与接受安慰剂治疗的女性相比，接受瑞戈非尼联合疗法治疗的女性报告出血和盆腔不适分量表有临床意义的降低以及身体和社交活动有改善（名义P<.0001）。
在接受瑞戈非尼联合疗法治疗24周后，有症状的子宫肌瘤女性的健康相关生活质量有显著改善，所有分量表均显示改善，包括情绪健康、身体和社交活动以及性功能。此外，女性报告主要肌瘤相关症状引起的总体症状负担和困扰大幅减轻。
