1. In this pair of identical phase 3 trials involving premenopausal women with uterine fibroids, both elagolix with and without add-back therapy was more effective in reducing heavy menstrual bleeding than placebo.
2. Significant decreases in bone mineral density were observed in the group that received elagolix without add-back therapy, but the hypoestrogenic effects of elagolix were successfully attenuated in the treatment group that also received add-back therapy.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Uterine fibroids can cause heavy menstrual bleeding along with a host of symptoms including pelvic pain, gastrointestinal upset, and infertility. Current non-surgical options including progestins, tranexamic acid, and uterine-artery embolization have demonstrated only limited effectiveness and can carry long-lasting hypoestrogenic side effects such as decreased bone density and vasomotor symptoms. Elagolix is a reversible nonpeptide gonadotropin-releasing hormone (GnRH) antagonist that is currently approved for endometriosis-associated pain and was also efficacious in reducing menstrual bleeding in a phase 2b trial involving women with uterine fibroids. This study combined two identical phase 3 trials with the objective of assessing the safety and efficacy of elagolix as well as the impact of add-back hormone therapy on hypoestrogenic effects. Menstrual blood loss was found to be significantly lower in women who received elagolix with add-back therapy than in those who received placebo, with suppression of bleeding in the final month in over half of the group. Patients who received elagolix without add-back therapy also reaped these benefits but faced greater decreases from baseline in bone mineral density. Most adverse events in both elagolix groups were mild or moderate, the most common being hot flushes, and all serious events were resolved by the end of the trial.
Relevant Reading: Uterine Fibroids: Burden and Unmet Medical Need
In-Depth [randomized controlled trial]: In these two identical, double-blind, 6-month phase 3 trials, 412 women in UF-1 and 378 in UF-2 were randomly assigned in a 2:1:1 ratio to receive elagolix at a dose of 300 mg twice daily with add-back therapy (estradiol, 1 mg, and norethindrone acetate, 0.5 mg, once daily), elagolix at a dose of 300 mg twice daily alone, or placebo. Some exclusion criteria were pregnancy, a persistent or complex ovarian cyst, cancer, pelvic inflammatory disease, and a history of osteoporosis. The primary endpoint, defined as menstrual blood loss of less than 80 ml during the final month and at least a 50% reduction in menstrual blood loss from baseline to the final month, was met by significantly higher percentages of women who received elagolix with add-back therapy (68.5% of 206 women in UF-1 and 76.5% of 189 women in UF-2) compared with women who received placebo (8.7% of 102 women in UF-1 and 10% of 94 women in UF-2). An even greater percentage of women who received elagolix alone met the primary endpoint (84.1% of 104 women in UF-1 and 77% of 95 women in UF-2), but these groups also had significantly greater decreases in bone mineral density compared to placebo at the lumbar spine, total hip, and femoral neck. In contrast, there were no significant differences in bone mineral density between the elagolix with add-back and placebo groups in either trial.
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