OBJECTIVE: To evaluate the safety and efficacy of elagolix vs. placebo and 
elagolix with low-dose E2/progestogen add-back therapy.
DESIGN: Proof-of-concept, dose-ranging, multiple-cohort study.
SETTING: Clinics.
PATIENT(S): Premenopausal women with fibroids and heavy menstrual bleeding 
(menstrual blood loss [MBL] >80 mL per cycle).
INTERVENTION(S): Three months' treatment with elagolix alone: 100 mg twice daily 
(BID), 200 mg BID, 300 mg BID, 400 mg once daily (QD), or 600 mg QD (all but the 
600 mg QD arm were placebo controlled); or elagolix plus add-back therapy: 
200 mg BID plus continuous low-dose E2 0.5 mg/norethindrone acetate 0.1 mg or 
elagolix 300 mg BID plus E2 1 mg continuously and cyclical P 200 mg.
MAIN OUTCOME MEASURE(S): Least-squares mean percentage change in MBL; adverse 
events (AEs).
RESULT(S): Mean age was 41.8 years; 73.8% were black; mean baseline MBL was 
267 mL. Of randomized women (elagolix alone, n = 160; placebo, n = 50; elagolix 
with add-back therapy, n = 61), 228 of 271 completed the 3-month treatment 
period. The MBL percentage change from baseline to last 28 days was 
significantly greater with elagolix alone (range, -72% to -98%; dose-dependent 
reduction was highest with 300 mg BID) vs. placebo (range, -8% to -41%); mean 
percentage changes with add-back regimens were -80% to -85%. Overall AEs were 
dose independent (elagolix alone, 70.0%-81.3%) but lower with placebo (56.0%) 
and add-back regimens (55.6%-70.6%). Hot flush was the most common AE (elagolix 
alone, 45.5%-62.5%; placebo, 12.0%; add-back regimens, 18.5%-26.5%).
CONCLUSION(S): Elagolix significantly reduced heavy menstrual bleeding in women 
with fibroids. Low-dose add-back regimens substantially reduced flushing.
CLINICAL TRIAL REGISTRATION NUMBER: NCT01441635.