Low-Dose Elagolix for the Treatment of Heavy Menstrual Bleeding in Patients With Uterine Leiomyomas: A Randomized Controlled Trial

This phase 4, randomized, double-blind, placebo-controlled, parallel-group, multicenter study with a 6-month treatment period was conducted from April 12, 2019, to April 28, 2021 (ClinicalTrials.gov identifier: NCT03886220). The study was approved by an independent ethics committee/IRB and conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines and ethical principles of the Declaration of Helsinki. The study consisted of an initial washout period (applicable only for patients taking exclusionary medication at the time of consent) followed by a 1.5- to 2.5-month screening period, 6-month double-blind treatment period, and 1-month follow-up (Appendix 1, available online at http://links.lww.com/AOG/D404). Eligible patients were randomly assigned using an interactive response technology system in a 2:1 ratio to receive either elagolix 150 mg once daily or placebo at the start of the double-blind treatment period. Treatment follow-up was carried out irrespective of whether the patient completed the 6-month treatment period or prematurely discontinued the study drug. Premenopausal patients aged 18–51 years with uterine leiomyomas and heavy menstrual bleeding were eligible for the study. Uterine leiomyomas were confirmed using ultrasonography and met at least one of the following criteria by the central reader: 1) intramural, submucosal, or nonpedunculated uterine leiomyoma with the longest diameter 2 cm or greater; 2) subserosal uterine leiomyoma with the longest diameter 4 cm or greater; or 3) multiple uterine leiomyomas with a total uterine volume between 200 cm3 and 2,500 cm3. Heavy menstrual bleeding was defined as menstrual blood loss greater than 80 mL during one menses, as measured with the alkaline hematin method in the screening period. Other eligibility criteria included experiencing regular menstrual cycles (24–38 days) for 3 consecutive months before screening and no clinically significant abnormalities observed in clinical chemistry, hematology, or urinalysis. Patients with screening hemoglobin levels of 7 g/dL or greater were eligible; patients with screening hemoglobin levels less than 7 g/dL could be prescribed iron supplements and retested before day 1 to confirm eligibility. Patients agreed to use at least two forms of nonhormonal contraception (dual) throughout the washout, screening, treatment, and follow-up periods. Certain medications were prohibited during the study, including hormonal therapies for uterine leiomyomas (eg, GnRH agonists and antagonists) and therapies that were contraindicated per elagolix prescribing information. The primary endpoint was the proportion of patients who were responders, defined as meeting the following two criteria: 1) menstrual blood loss volume less than 80 mL during the final treatment month (last 28 days of treatment) and 2) a reduction in menstrual blood loss volume of 50% or more from baseline to the final month. Additional efficacy endpoints included change and percentage change from baseline in menstrual blood loss volume assessed using the alkaline hematin method in each 28-day interval until the end of treatment. Hemoglobin concentration, proportion of patients with amenorrhea, and proportion of patients with suppression of bleeding were assessed each month during the treatment period. Amenorrhea was defined as no bleeding or spotting during the final month. Suppression of bleeding was defined as no bleeding during the final month with spotting allowed. Health-related quality of life (HRQOL) was assessed using the UFS-QOL (Uterine Fibroid Symptom and Quality of Life) questionnaire, and the PGIC–MB (Patient Global Impression of Change–Menstrual Bleeding) questionnaire evaluated patient perception of change after initiation of treatment. Data on baseline characteristics were collected, including demographic data of age and race and clinical characteristics of menstrual blood loss volume, body mass index, hemoglobin concentration, uterine volume, uterine leiomyoma volume, and International Federation of Gynaecology and Obstetrics primary uterine leiomyoma classification. Safety was evaluated throughout the study. Safety evaluations included adverse event monitoring, physical examinations, vital sign measurements, and clinical laboratory evaluations. The statistical software nQuery Advanced 8.1 was used to determine that approximately 48 patients randomized 2:1 to receive either elagolix 150 mg once daily or placebo would provide at least 80% power to detect a difference in the proportion of patients meeting the primary endpoint. The predicted treatment effect used in the power calculation was based on the clinical judgment of the protocol designers. As with a previous trial of elagolix, the sample size estimation presumed response rates of 10% for the placebo group and 55% for the elagolix group (based on clinical judgment), with two-sided α=0.05. Efficacy analyses were carried out using the full analysis set, and safety was assessed in the safety analysis set. Both the full analysis and safety analysis sets included all randomized patients who received at least one dose of study drug. Analyses of the primary endpoint components were based on a logistic regression model, with treatment as the main effect and baseline menstrual blood loss volume as a covariate, and using multiple imputation to estimate missing final month menstrual blood loss volume (for more details, see Appendix 2, available online at http://links.lww.com/AOG/D404). Change and percentage change in menstrual blood loss from baseline to each month were analyzed using a mixed model for repeated measures, with the fixed categorical effects of treatment, month, and treatment-by-month interaction and the continuous fixed covariate of baseline menstrual blood loss volume. Change and percentage change in menstrual blood loss from baseline to the final month, change and percentage change in hemoglobin concentration (from baseline to months 3 and 6), and change in UFS-QOL (from baseline to months 3 and 6 and the final visit) were analyzed using one-way analysis of covariance, with treatment as the main effect and baseline values of the particular parameter as a covariate. Patients whose primary reason for discontinuing use of the study drug was “lack of efficacy” or “requires surgery or invasive intervention for treatment of uterine leiomyomas” were considered nonresponders for the primary endpoint. Missing final month menstrual blood loss volume data were imputed using multiple imputation.

All 82 patients randomized at 23 sites in the United States received at least one dose of study drug; 54 patients received elagolix 150 mg once daily and 28 received placebo (Fig. 1). Overall, 42 patients in the elagolix group (77.8%) and 23 patients in the placebo group (82.1%) completed the 6-month treatment period. The most frequently reported primary reasons for premature discontinuation were “withdrew consent,” “lost to follow-up,” and “other.” Baseline demographic and clinical characteristics were balanced between groups (Table 1). In the primary efficacy analysis, a significantly greater proportion of patients treated with elagolix met the primary endpoint compared with patients treated with placebo (49.4% [95% CI 35.1–63.8%] vs 23.3% [95% CI 7.2–39.5%], respectively, with a difference between treatment groups [elagolix minus placebo] of 26.1% [95% CI 4.4–47.8%], odds ratio 3.2 [95% CI 1.1–9.5], P=.035) (Table 2). Both mean and median menstrual blood loss volumes in the elagolix group were lower than in the placebo group from the first postbaseline assessment to the end of the treatment period (Fig. 2). As early as month 1, the least-squares mean reduction in menstrual blood loss volume from baseline was significantly greater in the elagolix group compared with the placebo group (P<.05 for months 1, 2, 3, and 5; Fig. 3). Patients in the elagolix group also experienced improvements in other efficacy endpoints, including a significantly greater proportion of patients with suppression of bleeding (P=.036) and numerical improvements in amenorrhea (month 6) and hemoglobin concentration (months 3 and 6) compared with placebo (Table 2). In a sensitivity analysis in which patients with missing final month data were classified as nonresponders, patients with total menstrual blood loss volume less than 80 mL at the final month and menstrual blood loss volume reduction 50% or greater from baseline comprised 44.4% (95% CI 31.2–57.7%) with elagolix compared with 21.4% (95% CI 6.2–36.6%) with placebo, with a treatment difference of 23.0% (95% CI 2.9–43.2%) and an odds ratio of 2.9 (95% CI 1.0–8.4; P=.047). Also observed were improvements in patient-reported outcomes. Significantly greater improvements from baseline were observed in the symptom severity score, five of six UFS-QOL HRQOL subscales, and the HRQOL total score at month 6 in the elagolix group compared with the placebo group (Table 3). Additionally, a significantly larger proportion of patients in the elagolix group than in the placebo group marked “very much improved” or “much improved” in the PGIC–MB at every month, including month 6 (67.5% vs 33.3%, respectively; P=.011) and the final visit (56.9% vs 29.6%, respectively; P=.023). A total of 28 patients (51.9%) in the elagolix group and 11 (39.3%) in the placebo group reported adverse events (Table 4). Of the reported adverse events, 17 (31.5%) in the elagolix group and three (10.7%) in the placebo group were determined by investigators to have a reasonable possibility of being related to the study drug. The most common adverse events that occurred in 5% or more of patients in either group were headache and hot flush, both of which were reported more frequently in the elagolix group (Table 4). All three patients (5.6%) who discontinued use of the study drug because of adverse events (anger, alopecia, or hot flush) were in the elagolix group, whereas both patients (7.1%) who reported a serious adverse events (enlarged uvula and coronavirus disease 2019 [COVID-19], n=1 each) were in the placebo group. No adverse event–related deaths occurred in either group.

In this randomized, double-blind, placebo-controlled trial, a significantly greater percentage of patients receiving elagolix 150 mg once daily met the primary endpoint compared with patients receiving placebo. A reduction in mean menstrual blood loss volume occurred as early as month 1, with lower menstrual blood loss volume at all time points for patients receiving elagolix 150 mg once daily compared with those receiving placebo (Fig. 2). Greater proportions of patients in the elagolix group experienced amenorrhea, suppression of bleeding, and increases in hemoglobin concentration during the treatment period. In addition, significantly more patients in the elagolix group reported better outcomes in symptom severity and overall quality of life compared with those in the placebo group. Improvements in patient-reported outcomes of symptom severity, concern, activities, energy and mood, control, self-consciousness, and sexual function with elagolix were also clinically meaningful to patients. Overall, efficacy and improved quality of life were sustained over the 6-month elagolix treatment period. In this study, treatment with elagolix 150 mg once daily was well-tolerated. No serious or severe adverse events were reported, and the overall safety profile observed in this study was consistent with previously reported safety results in patients who received elagolix 150 mg once daily for endometriosis pain. In this study, the reduction in the effect of elagolix on mean menstrual blood loss volume toward the end of treatment is likely due to the decrease in the number of patients remaining in the study (ie, from month 5 to month 6, the number of patients taking elagolix decreased from 42 to 25 and those receiving placebo decreased from 22 to 15). This reduction in patients on treatment may have led to a consequent increase in variability of the estimates with clinically meaningful reduction (Fig. 2A). This artifact of reduced efficacy on mean menstrual blood loss volume toward the end of the study was not observed in median menstrual blood loss volume (Fig. 2B). In addition, study drug compliance could be a contributing factor based on study fatigue of a 6-month treatment study. In the prior studies of Elaris UF-1 and Elaris UF-2, no apparent reductions in treatment efficacy on menstrual blood loss volume were observed. At 6 months of treatment, 84.1% (Elaris UF-1) and 77% (Elaris UF-2) of patients receiving elagolix monotherapy (vs 8.7% and 10% of the placebo cohort, respectively) achieved the primary endpoint of menstrual blood loss volume less than 80 mL with at least a 50% reduction from baseline in menstrual blood loss volume. This study has some limitations that should be taken into consideration. The eligibility criterion for heavy menstrual bleeding was defined in this study as greater than 80 mL of menstrual blood loss per menstrual cycle for at least one cycle. However, in a previously published phase 3 study of elagolix 300 mg twice daily with 1 mg estradiol and 0.5 mg norethindrone acetate add-back, patients needed to experience greater than 80 mL of menstrual blood loss per cycle for at least two separate cycles for eligibility. Hence, the higher placebo responder rate observed in this study (23%) than in the previously published study (8.7–10%) may have been a result of the more lenient eligibility guideline in this study, because participants in this study may have had a tendency to experience some menses with less than 80 mL menstrual blood loss. Although the observed response rate for the primary endpoint in our study with elagolix (49%) was comparable with the estimated response rate used for the sample size estimation (55%), the higher placebo response (23% observed vs 10% estimated) could partly explain the smaller treatment difference in the primary efficacy result than hypothesized (Table 2). In addition, one criterion for patients to be selected for study eligibility was presence of heavy menstrual bleeding determined using the alkaline hematin method. Use of a single month of the alkaline hematin method to assess heavy menstrual bleeding at screening could have resulted in some patients regressing to the mean in subsequent months during the study, leading to less than the study-qualifying menstrual blood loss of greater than 80 mL. Unlike previous elagolix studies, this study did not use dual-energy X-ray absorptiometry scans to monitor bone mineral density. Nevertheless, there is a sufficient body of evidence to support bone safety from previous elagolix studies at a dosage of 150 mg once daily. Please refer to the package insert for elagolix with add-back for additional information on bone mineral density and safety (Oriahnn [elagolix, estradiol, and norethindrone acetate capsules; elagolix capsules]. Prescribing information. Accessed May 8, 2023. https://www.rxabbvie.com/pdf/oriahnn_pi.pdf). The results of this study show that a statistically significantly larger proportion of patients receiving elagolix 150 mg once daily than those receiving placebo met the primary efficacy endpoint of a reduction in menstrual blood loss volume to less than 80 mL and by 50% or greater from baseline at the final month during a 6-month treatment period (P<.05). Treatment with elagolix 150 mg once daily was generally well-tolerated, and no new safety concerns or trends were identified in this study compared with the overall safety profile of low-dose monotherapy elagolix 150 mg once daily that has been established in women with endometriosis pain. Elagolix 150 mg once daily also was shown to improve overall patient satisfaction and quality of life. This regimen may be considered in patients with contraindications to hormonal add-back therapy or who prefer a nonhormonal therapy with once-daily dosing. Authors' Data Sharing Statement Will individual participant data be available (including data dictionaries)? Yes, anonymized individual patient data can be made available, as long as the trials are not part of an ongoing or planned regulatory submission. What data in particular will be shared? Trial-level data (analysis data sets) can be shared, as long as the trials are not part of an ongoing or planned regulatory submission. What other documents will be available? Protocols, clinical study reports, or analysis plans can be made available, as long as the trials are not part of an ongoing or planned regulatory submission. When will data be available (start and end dates)? Data requests can be submitted at any time after approval in the United States and Europe and after acceptance of this manuscript for publication. These data will be accessible for 12 months, with possible extensions considered. By what access criteria will data be shared (including with whom, for what types of analyses, and by what mechanism)? AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal, Statistical Analysis Plan (SAP), and execution of a Data Sharing Agreement (DSA). For more information on the process or to submit a request, visit the following link: https://vivli.org/ourmember/abbvie/, then select “Home”

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