Elagolix Alone or With Add-Back Therapy in Women With Heavy Menstrual Bleeding and Uterine Leiomyomas: A Randomized Controlled Trial

Abstract

Objective: To evaluate elagolix, an oral gonadotropin-releasing hormone receptor antagonist, alone or with add-back therapy, in premenopausal women with heavy menstrual bleeding (greater than 80 mL per month) associated with uterine leiomyomas.

Methods: This double-blind, randomized, placebo-controlled, parallel-group study evaluated efficacy and safety of elagolix in cohorts 1 (300 mg twice daily) and 2 (600 mg daily) with four arms per cohort: placebo, elagolix alone, elagolix with 0.5 mg estradiol/0.1 norethindrone acetate, and elagolix with 1.0 mg estradiol/0.5 mg norethindrone acetate. A sample size of 65 per group was planned to compare elagolix with add-back to placebo on the primary end point: the percentage of women who had less than 80 mL menstrual blood loss and 50% or greater reduction in menstrual blood loss from baseline to the last 28 days of treatment. Safety assessments included changes in bone mineral density.

Results: From April 8, 2013, to December 8, 2015, 571 women were enrolled, 567 were randomized and treated (cohort 1=259; cohort 2=308), and 80% and 75% completed treatment, respectively. Participants had a mean±SD age of 43±5 years (cohort 2, 42±5 years), and 70% were black (cohort 2, 74%). Primary end point responder rates in cohort 1 (cohort 2) were 92% (90%) for elagolix alone, 85% (73%) for elagolix with 0.5 mg estradiol/0.1 mg norethindrone acetate, 79% (82%) for elagolix with 1.0 mg estradiol/0.5 mg norethindrone acetate, and 27% (32%) for placebo (all P<.001 vs placebo). Elagolix groups had significant decreases compared with placebo in lumbar spine bone mineral density, which was attenuated by adding 1.0 mg estradiol/0.5 mg norethindrone acetate.

Conclusion: Elagolix with and without add-back significantly reduced menstrual blood loss in women with uterine leiomyomas. Add-back therapy reduced hypoestrogenic effects on bone mineral density.

Clinical trial registration: ClinicalTrials.gov, NCT01817530; EU Clinical Trial Register, 2013-000082-37.

Fig. 1.

Study design. BID, twice daily; E2, estradiol; NETA, norethindrone acetate; QD, daily.

Fig. 2.

Cohort 1 patient disposition. *Two women were randomized but not treated. ^†Women may have listed more than one reason for premature discontinuation, but only the primary reasons are included. ^‡Other category is a combination of pregnancy, exclusionary medication received, and other categories. BID, twice daily; 0.5/0.1, 0.5 mg estradiol/0.1 mg norethindrone acetate; 1.0/0.5, 1.0 mg estradiol/0.5 mg norethindrone acetate.

Fig. 3.

Fig. 4.

Percentage of women who met the composite primary end point (A) and mean menstrual blood loss at baseline and final month (B). Menstrual blood loss was measured from sanitary products by the alkaline hematin method. A. *Statistical significance vs placebo is indicated for P<.001. B. Arrows indicate the mean percent change from baseline to final month in menstrual blood loss. *Significance vs placebo is indicated for P<.001. BID, twice daily; QD, daily; 0.5/0.1, 0.5 mg estradiol/0.1 mg norethindrone acetate; 1.0/0.5, 1.0 mg estradiol/0.5 mg norethindrone acetate.

Fig. 5.

Mean percent change from baseline to month 6 in bone mineral density. Cohort 1 (A) and cohort 2 (B). *Significance vs placebo is indicated for P≤.05 using observed data. Error bars indicate 95% CI. BID, twice daily; E2, estradiol; NETA, norethindrone acetate; QD, daily.