Elagolix Treatment for Up to 12 Months in Women With Heavy Menstrual Bleeding and Uterine Leiomyomas

Abstract

Objective: To investigate the safety and efficacy of elagolix, an oral gonadotropin-releasing hormone antagonist, with hormonal add-back therapy for up to 12 months in women with heavy menstrual bleeding associated with uterine leiomyomas.

Methods: Elaris UF-EXTEND was a phase 3 extension study that evaluated an additional 6 months (up to 12 months total) of elagolix 300 mg twice daily with hormonal add-back therapy (estradiol 1 mg and norethindrone acetate 0.5 mg once daily) in women who completed an initial 6 months of the same treatment in one of two preceding phase 3 studies. The primary endpoint was the percentage of women with both less than 80 mL menstrual blood loss during final month and a 50% or greater reduction in menstrual blood loss from baseline to final month. Safety evaluations included adverse events and bone mineral density changes. The planned sample size of UF-EXTEND was based on estimated rollover and discontinuation rates in the two preceding studies.

Results: From September 2016 to March 2019, 433 women were enrolled in UF-EXTEND. Of these women, 218 received up to 12 months of elagolix with add-back therapy; the mean±SD age of this group was 42.4±5.4 years and 67.3% were black. The percentage of women who met the primary endpoint in this elagolix with add-back group was 87.9% (95% CI [83.4-92.3]). The most frequently reported adverse events with up to 12 months of elagolix plus add-back therapy were hot flush (6.9%), night sweats (3.2%), headache (5.5%), and nausea (4.1%). Mean percent decreases in bone mineral density from baseline to extension month 6 were significantly less with elagolix plus add-back therapy than with elagolix alone {between-group difference in lumbar spine: -3.3 (95% CI [-4.1 to -2.5])}.

Conclusion: Up to 12 months of elagolix with add-back therapy provided sustained reduction in menstrual blood loss in women with uterine leiomyomas, with the addition of add-back therapy attenuating the hypoestrogenic effects of elagolix alone. No new or unexpected safety concerns were associated with an additional 6 months of elagolix with addback therapy.

Clinical trial registration: ClinicalTrials.gov, NCT02925494.

Funding source: AbbVie Inc funded this study.

Figures

Fig. 1.. Study design and disposition of women treated with up to 12 months of elagolix. Elagolix alone, elagolix 300 mg twice daily throughout UF-1 and UF-2 and UF-EXTEND; elagolix with add-back therapy, elagolix 300 mg twice daily with add-back therapy (estradiol 1 mg and norethindrone 0.5 mg once daily) throughout UF-1 and UF-2 and UF-EXTEND. *In UF-1 and UF-2 combined, 5 of 150 (3.3%) women treated with elagolix alone and 3 of 312 (1.0%) women treated with elagolix plus add-back therapy did not enter UF-EXTEND because of a dual-energy X-ray absorptiometry scan (DXA) finding of bone mineral density decrease greater than 8% in at least one of the anatomic locations (lumbar spine, total hip, and femoral neck). †The most common other reason was that the extension study was closed to enrollment. ‡Women required surgery or invasive intervention for treatment of uterine leiomyomas. Other reasons for premature discontinuation included moved out of state (n=2), weight exceeded DXA limits, study site closing, participant stopped drug because she thought she was pregnant but was not, did not like bleeding while on medication, personal reasons, and DXA results.

Simon. Twelve Months of Elagolix With Add-Back Therapy. Obstet Gynecol 2020.

Fig. 2.. Percentage of women who met the primary endpoint (A) and mean change from baseline in menstrual blood loss in women treated with up to 12 months of elagolix with add-back therapy (B). Data are % or mean with error bars indicating 95% CI. Baseline was before first dosing in the UF-1 and UF-2 studies. *Mean changes from baseline in menstrual blood loss for UF-1 and UF-2 are presented as least squares means.

Simon. Twelve Months of Elagolix With Add-Back Therapy. Obstet Gynecol 2020.

Fig. 3.. Lumbar spine bone mineral density changes from baseline (A) and bone mineral density Z-scores during treatment and posttreatment periods in women treated with up to 12 months of elagolix (B). Bone mineral density changes are presented as least square mean percent change, with error bars indicating 95% CI. Bone mineral density Z-scores are presented as median, quartile 1, quartile 3, and range. Bone mineral density changes and Z-scores for UF-1 and UF-2 exclude participants who switched machine types. Elagolix alone, elagolix 300 mg twice daily throughout UF-1 and UF-2 and UF-EXTEND; elagolix with add-back therapy, elagolix 300 mg twice daily with add-back therapy (estradiol 1 mg and norethindrone 0.5 mg once daily) throughout UF-1 and UF-2 and UF-EXTEND. Baseline was before first dosing in UF-1 and UF-2 studies. *P≤.05 for test of difference between the elagolix with add-back therapy and elagolix-alone groups using an analysis of covariance model with treatment as the main effect and baseline value as a covariate for extension month 6.

Simon. Twelve Months of Elagolix With Add-Back Therapy. Obstet Gynecol 2020.

Fig. 4.. Total hip bone mineral density changes from baseline (A) and bone mineral density Z-scores during treatment and posttreatment periods in women treated with up to 12 months of elagolix (B). Bone mineral density changes are presented as least square mean percent change with error bars indicating 95% CI. Bone mineral density Z-scores are presented as median, quartile 1, quartile 3, and range. Bone mineral density changes and Z-scores for UF-1 and UF-2 exclude participants who switched machine types. Elagolix alone, elagolix 300 mg twice daily throughout UF-1 and UF-2 and UF-EXTEND; elagolix with add-back therapy, elagolix 300 mg twice daily with add-back therapy (estradiol 1 mg and norethindrone 0.5 mg once daily) throughout UF-1 and UF-2 and UF-EXTEND. Baseline was before first dosing in UF-1 and UF-2 studies. *P≤.05 for test of difference between the elagolix with add-back therapy and elagolix-alone groups using an analysis of covariance model with treatment as the main effect and baseline value as a covariate for extension month 6.

Simon. Twelve Months of Elagolix With Add-Back Therapy. Obstet Gynecol 2020.

Fig. 5.. Femoral neck bone mineral density changes from baseline (A) and bone mineral density Z-scores during treatment and posttreatment periods in women treated with up to 12 months of elagolix (B). Bone mineral density changes are presented as least square mean percent change, with error bars indicating 95% CI. Bone mineral density Z-scores are presented as median, quartile 1, quartile 3, and range. Bone mineral density changes and Z-scores for UF-1 and UF-2 exclude participants who switched machine types. Elagolix alone, elagolix 300 mg twice daily throughout UF-1 and UF-2 and UF-EXTEND; elagolix with add-back therapy, elagolix 300 mg twice daily with add-back therapy (estradiol 1 mg and norethindrone 0.5 mg once daily) throughout UF-1 and UF-2 and UF-EXTEND. Baseline was before first dosing in UF-1 and UF-2 studies. *P≤.05 for test of difference between the elagolix with add-back therapy and elagolix-alone groups using an analysis of covariance model with treatment as the main effect and baseline value as a covariate for extension month 6.

Simon. Twelve Months of Elagolix With Add-Back Therapy. Obstet Gynecol 2020.