Al‐Hendy, Ayman

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)

INTRODUCTION: Iron-deficiency anemia is common in women with uterine fibroid (UF)-related heavy menstrual bleeding. Severe anemia is defined as hemoglobin (Hb) levels <10g/dL. The effect of linzagolix, an oral GnRH antagonist, on UF-related severe anemia was assessed in two Phase 3 trials. METHODS: PRIMROSE 1 and 2 are randomized, double-blind, placebo-controlled Phase 3 trials investigating the efficacy and safety of linzagolix 100 mg and 200 mg once daily, with or without hormonal add-back therapy (ABT) in the treatment of UF. Subjects were considered responders if an increase of ≥2g/dL from baseline was achieved. Patients with severe anemia were given iron supplements until they reached the Hb levels >12g/dL. RESULTS: In PRIMROSE 1, of 165 subjects with severe anemia, 57.9%, 61.5%, 82.1% and 65.2% of patients were responders at 24 weeks, in the respective treatment groups (100 mg, 100 mg+ABT, 200 mg and 200 mg+ABT), compared to 50% in the placebo group. In PRIMROSE 2, of 93 patients with severe anemia, 62.5%, 75%, 60% and 73.7%, respectively, were responders, compared to 46.2% for placebo. Given the small sample sizes, statistical significance was not reached. Improvements were maintained at week 52: in PRIMROSE 1, 69.2%, 62.5%, 81.3% and 75% of patients were responders in the respective treatment groups, compared to 40% in placebo, in PRIMROSE 2, 66.7%, 100%, 80%, 87% were responders, respectively. CONCLUSION: High and low doses of linzagolix improved Hb levels in patients with UF suffering from severe anemia.

Objective: To assess outcomes of women with uterine fibroids (UFs) and heavy menstrual bleeding (HMB) treated with 300 mg elagolix twice daily plus add-back therapy (E2 1 mg/NETA 0.5 mg once daily) or placebo who were not considered responders in pooled analysis of two phase 3, 6-month randomized clinical trials (Elaris UF-1 and UF-2). Methods: Responders were defined as women who met both primary end point bleeding criteria (<80 mL menstrual blood loss [MBL] during the final month and ≥50% reduction in MBL from baseline to the final month) and either completed the study or discontinued due to predefined reasons. Thus, women termed nonresponders who were analyzed in this study who met neither or one bleeding end point or met both criteria but prematurely discontinued treatment because of adverse events, perceived lack of efficacy, or required surgical or interventional treatment for UFs were analyzed in this study. This post hoc analysis assessed mean changes from baseline in MBL, as well as adverse events. Results: Among 367 women receiving elagolix with add-back with observed data, 89 (24%) were not considered responders. Within this subset, 17 (19%) women met both bleeding criteria but prematurely discontinued treatment for the reasons mentioned above, while 23 (26%) met one bleeding criterion and 49 (55%) met neither bleeding criteria, regardless of discontinuation status. Among all nonresponders, a numerical trend toward greater mean reductions in MBL was observed in those receiving elagolix with add-back, compared with placebo group nonresponders. No differences in adverse events were observed between responders and nonresponders. Conclusion: Forty of 89 (45%) women with HMB and UFs who were classified as nonresponders in the UF-1 or UF-2 trials may have had a clinically meaningful response to elagolix with add-back therapy because they met at least one of the objective bleeding criteria. Clinical Trial Registration: Clinicaltrials.gov, NCT02654054 and NCT02691494. (NEJM 2020; 382:328–340) DOI: 10.1056/NEJMoa1904351

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

INTRODUCTION: Currently, pain (menstrual and non-menstrual), is poorly studied in women with uterine fibroids (UF). Relugolix combination therapy (Relugolix-CT; once-daily relugolix 40 mg, estradiol 1.0 mg, and norethindrone acetate 0.5 mg) significantly improved UF-associated heavy menstrual bleeding in the two LIBERTY randomized phase 3 trials. METHODS: In the LIBERTY 1 and 2 Institutional Review Board-approved studies, a key secondary endpoint was the proportion of women with no/minimal pain (maximal pain score ≤1 on the 0–10 numerical rating scale [NRS] during the last 35 days of treatment) in the pain-evaluable population (women with maximum pain NRS ≥4 during the 35 days prior to randomization). Pain was also evaluated on menstrual bleeding and on non-menstrual days during the last 35 days of treatment. Treatment comparisons were performed in both studies and the pooled dataset using the Cochran–Mantel–Haenszel test stratified by baseline menstrual blood loss volume. RESULTS: After 24 weeks of treatment, a significantly greater proportion of pain-evaluable patients in the Relugolix-CT groups (43.1% and 47.1% in LIBERTY 1 and 2, respectively) had no/minimum UF-associated pain during the last 35 days of treatment compared with placebo (10.1% and 17.1%, respectively; P<.0001). The proportions of women with no/minimum dysmenorrhea and non-menstrual pain were significantly higher with Relugolix-CT (pooled data: 65.0% and 44.6%, respectively) vs placebo (19.3% and 21.6%, respectively). CONCLUSION: Over 24 weeks, once-daily Relugolix-CT reduced UF-associated pain, with a more pronounced effect on menstrual vs non-menstrual pain. Thus, Relugolix-CT improved two common symptoms (menstrual bleeding and pain) associated with UF.