Wagman, Rachel B.

Uterine fibroids are a common cause of heavy menstrual bleeding and pain. Treatment with the combination of relugolix (an oral gonadotropin-releasing hormonereceptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects. Methods. We conducted two replicate international, double-blind, 24-week, phase 3 trials involving women with fibroid-associated heavy menstrual bleeding. Participants were randomly assigned in a 1:1:1 ratio to receive once-daily placebo, relugolix combination therapy (40 mg of relugolix, 1 mg of estradiol, and 0.5 mg of norethindrone acetate), or delayed relugolix combination therapy (40 mg of relugolix monotherapy, followed by relugolix combination therapy, each for 12 weeks). The primary efficacy end point in each trial was the percentage of participants with a response (volume of menstrual blood loss <80 ml and a ≥50% reduction in volume from baseline) in the relugolix combination therapy group, as compared with the placebo group. Key secondary end points were amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, fibroid volume, and uterine volume. Safety and bone mineral density were assessed.Result. A total of 388 women in trial L1 and 382 in trial L2 underwent randomization. A total of 73% of the participants in the relugolix combination therapy group in trial L1 and 71% of those in trial L2 had a response (primary end point), as compared with 19% and 15%, respectively, of those in the placebo groups (P<0.001 for both comparisons). Both relugolix combination therapy groups had significant improvements, as compared with the placebo groups, in six of seven key secondary end points, including measures of menstrual blood loss (including amenorrhea), pain, distress from bleeding and pelvic discomfort, anemia, and uterine volume, but not fibroid volume. The incidence of adverse events was similar with relugolix combination therapy and placebo. Bone mineral density was similar with relugolix combination therapy and placebo but decreased with relugolix monotherapy.Conclusions. Once-daily relugolix combination therapy resulted in a significant reduction in menstrual bleeding, as compared with placebo, and preserved bone mineral density in women with uterine fibroids.

What is this summary about? This is a summary of findings from two research studies (known as clinical trials). The studies looked at how well a medicine called relugolix combination therapy worked in women with heavy menstrual bleeding (heavy bleeding during a period) with uterine fibroids (noncancerous or benign growths in the uterus). In this analysis of the studies, researchers looked at how patients self-reported their uterine fibroid symptoms before and after taking relugolix combination therapy. Researchers also looked at how patients self-reported the impact of uterine fibroids on their health-related quality of life before and after taking relugolix combination therapy. What were the results? Women took either relugolix combination therapy or placebo (a pill that contains no medicine) by mouth once daily for 24 weeks. Women completed the Uterine Fibroid Symptom and Quality of Life questionnaire (where “quality of life” refers to the women's health-related quality of life related to uterine fibroids) before, during, and after treatment. The questionnaire let researchers see if the women felt that relugolix combination therapy decreased the burden of uterine fibroid symptoms and improved the women's health-related quality of life related to uterine fibroids. More women said that they felt less distress due to their uterine fibroid symptoms and that their health-related quality of life related to uterine fibroids was better after taking relugolix combination therapy compared with women who took placebo. What do the results mean? Relugolix combination therapy may lessen distress associated with uterine fibroid symptoms and improve health-related quality of life related to uterine fibroids.

What is this summary about? This is a summary of a research study (known as a clinical trial) called the LIBERTY extension study. The LIBERTY extension study is a long-term study looking at how well a medicine called relugolix combination therapy worked in reducing blood loss during menstrual periods in women with uterine fibroids with heavy menstrual periods. Women were included in the extension study if they finished the 24-week LIBERTY 1 or LIBERTY 2 studies. Heavy menstrual periods were considered to be menstrual blood loss of about one-third of a cup of blood (80 ml) per cycle for two cycles or about two-thirds of a cup of blood (160 ml) during one cycle. The LIBERTY extension study also looked at whether relugolix combination therapy was safe to take for up to 1 year. What were the results? Out of 770 total women with uterine fibroids with heavy menstrual bleeding who took part in the LIBERTY 1 and LIBERTY 2 studies, 476 took part in the LIBERTY extension study. From the start of the LIBERTY 1 and LIBERTY 2 studies through the end of the LIBERTY extension: 163 women took relugolix combination therapy for 52 weeks 149 women took relugolix alone for 12 weeks followed by relugolix combination therapy for 40 weeks 164 women took placebo for 24 weeks followed by relugolix combination therapy for 28 weeks The LIBERTY extension study showed that most women in all three treatment groups responded to relugolix combination therapy by having less bleeding during their menstrual periods, having improved anemia symptoms, and having stable bone mineral loss. Side effects were similar across treatment groups, and the most common side effects were headaches and hot flushes. What do the results mean? Women with uterine fibroids with heavy menstrual bleeding taking relugolix combination therapy may have fewer uterine fibroid bleeding symptoms for up to 1 year of treatment. Clinical Trial Registration: NCT03049735 ( ClinicalTrials.gov ) (LIBERTY 1) Clinical Trial Registration: NCT03103087 ( ClinicalTrials.gov ) (LIBERTY 2) Clinical Trial Registration: NCT03412890 ( ClinicalTrials.gov ) (LIBERTY extension study)

Abstract Study question What is the effect of relugolix combination therapy (Relugolix-CT) on symptom burden and health-related quality-of-life (HR-QoL) in patients with uterine fibroids (UF) over 52 weeks? Summary answer Relugolix-CT demonstrated sustained, clinically meaningful improvement in patient-reported symptom severity and HR-QoL over 52 weeks in women with UF. What is known already In LIBERTY 1 and 2 randomized clinical trials, once-daily Relugolix-CT (40 mg relugolix, an oral gonadotropin-releasing hormone receptor antagonist, estradiol 1 mg, norethindrone acetate 0.5 mg) significantly reduced menstrual blood loss (MBL) and UF-associated pain versus placebo in women with UF and heavy menstrual bleeding (HMB), and was well tolerated, with bone mineral density (BMD) preservation through 24 weeks. In the LIBERTY long-term extension study, a sustained reduction in MBL was observed along with no new safety signals and BMD maintenance through 52 weeks. Relugolix-CT was previously shown to significantly improve patient-reported symptom severity and HR-QoL through 24 weeks. Study design, size, duration In the LIBERTY 1 and 2 studies, 770 premenopausal women with ultrasound-documented clinically significant UF and alkaline-hematin documented HMB were randomized 1:1:1 to Relugolix-CT for 24 weeks, relugolix 40 mg for 12 weeks followed by Relugolix-CT for 12 weeks, or placebo for 24 weeks. Women who completed the pivotal studies were eligible to enroll in the 28-week extension study (N = 477 enrolled). Patients included in the extension study received open-label once-daily Relugolix-CT. Participants/materials, setting, methods Changes from baseline to Weeks 24 and 52 in the Uterine Fibroid Symptom (UFS)-QoL symptom severity scale, Bleeding and Pelvic Discomfort scale (BPD; assessing distress due to HMB, passing blood clots, pelvic pressure/tightness); and HR-QoL (sub)scales were assessed. Higher symptom severity and BPD scores reflect higher severity and distress, respectively; higher HR-QoL scores indicate better outcomes. Least-squares mean changes were provided for the original pivotal-study randomized treatment groups Relugolix-CT and placebo. Main results and the role of chance A sustained improvement in symptom severity was observed for the Relugolix-CT group from baseline to Weeks 24 and 52, with LS mean changes of –36.9 and –37.3 points, respectively. In patients initially treated with placebo, small changes were observed at Week 24 (–10.8 points), whereas a greater reduction from baseline was demonstrated at Week 52 (–35.0 points) after transitioning to Relugolix-CT. Considering the BPD, measuring distress from key UF symptoms, LS mean changes of –50.9 and –51.3 points were observed in the Relugolix-CT group from baseline to Week 24 and 52, respectively. In patients initially treated with placebo, small changes were observed at Week 24 (–15.9 points), whereas a greater reduction from baseline was demonstrated at Week 52 (–48.6 points) after transitioning to Relugolix-CT. Treatment with Relugolix-CT also resulted in a sustained improvement in different aspects of HR-QoL. LS mean total HR-QoL score increased from baseline to Weeks 24 and 52 by 40.8 and 40.4 points, respectively. In patients initially treated with placebo, small changes were observed at Week 24 (11.4 points), whereas a greater increase from baseline was demonstrated at Week 52 (39.0 points) after transitioning to Relugolix-CT at Week 24. Limitations, reasons for caution The 28-week LIBERTY long-term extension study was non-comparative. Analyses were performed in a subset of patients who completed the LIBERTY pivotal studies and were eligible for the extension study. However, it is important to note that the demographic and baseline disease characteristics were similar between pivotal and long-term extension populations. Wider implications of the findings Relugolix-CT resulted in a sustained reduction in UF symptom burden, particularly in terms of distress from key UF symptoms, and a sustained improvement of HR-QoL over 52 weeks. Improvements observed after transitioning from placebo to Relugolix-CT at 24 weeks confirmed the positive effect of Relugolix-CT on UF-associated symptoms and HR-QoL. Trial registration number NCT03412890