Trial Outcomes & Findings for Efficacy and Safety of Elagolix in Combination With Estradiol/Norethindrone Acetate for the Management of Heavy Menstrual Bleeding Associated With Uterine Fibroids in Premenopausal Women (Replicate Study) (NCT NCT02691494)

Last Updated: 2021-07-13

Results Overview

Percentage of responders, defined as participants who met the following conditions: * Menstrual blood loss (MBL) volume \< 80 mL during the Final Month (the last 28 days prior to and including the Reference Day, which is defined as the last visit date during the Treatment Period (last treatment visit date) or the last dose date if there are evaluable alkaline hematin data after the last treatment visit date and prior to or on the last dose date), and * ≥ 50% reduction in MBL volume from Baseline to the Final Month. Participants who prematurely discontinued study drug due to "lack of efficacy," "requires surgery or invasive intervention for treatment of uterine fibroids," or "adverse events" were considered non-responders regardless of whether she meets the two aforementioned responder criteria or not.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

378 participants

Primary outcome timeframe

Final Month (the last 28 days prior to and including the Reference Day), up to Month 6

Results posted on

2021-07-13

Participant Flow

Eligible participants were randomized in a 1:1:2 ratio to 1 of 3 treatment groups: placebo, elagolix 300 mg BID, or elagolix 300 mg twice daily (BID) plus estradiol/norethindrone acetate (E2/NETA) once daily (QD).

Participant milestones

Participant milestones
Measure	Placebo Placebo for both elagolix BID and E2/NETA QD	Elagolix Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix + E2/NETA Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
Treatment Period STARTED	94	95	189
Treatment Period COMPLETED	72	69	148
Treatment Period NOT COMPLETED	22	26	41
Post-Treatment Follow-Up Period STARTED	14	25	59
Post-Treatment Follow-Up Period COMPLETED	9	18	42
Post-Treatment Follow-Up Period NOT COMPLETED	5	7	17

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Placebo for both elagolix BID and E2/NETA QD	Elagolix Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix + E2/NETA Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
Post-Treatment Follow-Up Period Withdrawal by Subject	1	2	8
Post-Treatment Follow-Up Period Lost to Follow-up	2	3	4
Post-Treatment Follow-Up Period Other	2	1	1
Post-Treatment Follow-Up Period Required Surgery/Invasive Intervention	0	0	3
Post-Treatment Follow-Up Period Non-Compliance	0	1	1

Baseline Characteristics

Efficacy and Safety of Elagolix in Combination With Estradiol/Norethindrone Acetate for the Management of Heavy Menstrual Bleeding Associated With Uterine Fibroids in Premenopausal Women (Replicate Study)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=94 Participants Placebo for both elagolix BID and E2/NETA QD	Elagolix n=95 Participants Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix + E2/NETA n=189 Participants Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Total n=378 Participants Total of all reporting groups
Age, Continuous	42.5 years STANDARD_DEVIATION 5.43 • n=5 Participants	42.2 years STANDARD_DEVIATION 5.41 • n=7 Participants	42.5 years STANDARD_DEVIATION 5.33 • n=5 Participants	42.4 years STANDARD_DEVIATION 5.36 • n=4 Participants
Sex: Female, Male Female	94 Participants n=5 Participants	95 Participants n=7 Participants	189 Participants n=5 Participants	378 Participants n=4 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	11 Participants n=5 Participants	17 Participants n=7 Participants	31 Participants n=5 Participants	59 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	83 Participants n=5 Participants	78 Participants n=7 Participants	158 Participants n=5 Participants	319 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) Black or African American	63 Participants n=5 Participants	66 Participants n=7 Participants	124 Participants n=5 Participants	253 Participants n=4 Participants
Race (NIH/OMB) White	30 Participants n=5 Participants	27 Participants n=7 Participants	59 Participants n=5 Participants	116 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants	3 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants

PRIMARY outcome

Timeframe: Final Month (the last 28 days prior to and including the Reference Day), up to Month 6

Population: All randomized and treated participants.

Outcome measures

Outcome measures
Measure	Placebo n=94 Participants Placebo for both elagolix BID and E2/NETA QD	Elagolix n=95 Participants Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix + E2/NETA n=189 Participants Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
Percentage of Participants Meeting the Criteria for Responder	10.5 percentage of participants	76.9 percentage of participants	76.5 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Final Month (the last 28 days prior to and including the Reference Day), up to Month 6

Population: All randomized and treated participants.

Baseline MBL volume was defined as the mean of total MBL volume from all the qualified menstrual cycles during the Screening Period, in which the total MBL volume is from all validated and non-validated sanitary products and the MBL volume of validated sanitary products only (excluding non-validated sanitary products) was greater than 80 mL. The Reference Day is defined as the last visit date during the Treatment Period (last treatment visit date) or the last dose date if there are evaluable alkaline hematin data after the last treatment visit date and prior to or on the last dose date.

Outcome measures

Outcome measures
Measure	Placebo n=94 Participants Placebo for both elagolix BID and E2/NETA QD	Elagolix n=95 Participants Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix + E2/NETA n=189 Participants Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
Change From Baseline in MBL Volume to the Final Month	-4.3 mL Standard Error 15.44	-198.8 mL Standard Error 15.44	-168.8 mL Standard Error 10.72

SECONDARY outcome

Timeframe: Final Month (the last 28 days prior to and including the Reference Day), up to Month 6

Population: All randomized and treated participants with an assessment

Suppression of bleeding is defined as having 0 days of bleeding (spotting is allowed) during the Final Month with the interval starting from Study Day 11. The Reference Day is defined as the last visit date during the Treatment Period (last treatment visit date) or the last dose date if there are evaluable alkaline hematin data after the last treatment visit date and prior to or on the last dose date.

Outcome measures

Outcome measures
Measure	Placebo n=85 Participants Placebo for both elagolix BID and E2/NETA QD	Elagolix n=81 Participants Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix + E2/NETA n=172 Participants Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
Percentage of Participants With Suppression of Bleeding at the Final Month	4.7 percentage of participants	88.9 percentage of participants	61.0 percentage of participants

SECONDARY outcome

Timeframe: Month 0 (Baseline), Month 6

Population: All randomized and treated participants with an assessment at given time point.

Outcome measures

Outcome measures
Measure	Placebo n=64 Participants Placebo for both elagolix BID and E2/NETA QD	Elagolix n=53 Participants Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix + E2/NETA n=124 Participants Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
Change From Baseline in MBL Volume to Month 6	28.5 mL Standard Error 16.68	-223.7 mL Standard Error 17.98	-198.1 mL Standard Error 11.89

SECONDARY outcome

Timeframe: Month 0 (Baseline), Month 3

Population: All randomized and treated participants with an assessment at given time point.

Outcome measures

Outcome measures
Measure	Placebo n=78 Participants Placebo for both elagolix BID and E2/NETA QD	Elagolix n=72 Participants Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix + E2/NETA n=157 Participants Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
Change From Baseline in MBL Volume to Month 3	-14.2 mL Standard Error 11.57	-211.1 mL Standard Error 11.96	-200.3 mL Standard Error 8.17

SECONDARY outcome

Timeframe: Month 0 (Baseline), Month 6

Population: All randomized and treated participants with baseline hemoglobin \<= 10.5 g/dL and an assessment at Month 6.

Outcome measures

Outcome measures
Measure	Placebo n=24 Participants Placebo for both elagolix BID and E2/NETA QD	Elagolix n=25 Participants Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix + E2/NETA n=48 Participants Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
Percentage of Participants With Baseline Hemoglobin <= 10.5 g/dL Who Have an Increase in Hemoglobin > 2 g/dL at Month 6	20.8 percentage of participants	40.0 percentage of participants	50.0 percentage of participants

SECONDARY outcome

Timeframe: Month 0 (Baseline), Month 1

Population: All randomized and treated participants with an assessment at given time point.

Outcome measures

Outcome measures
Measure	Placebo n=88 Participants Placebo for both elagolix BID and E2/NETA QD	Elagolix n=83 Participants Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix + E2/NETA n=175 Participants Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
Change From Baseline in MBL Volume to Month 1	-2.1 mL Standard Error 14.31	-196.6 mL Standard Error 14.74	-127.0 mL Standard Error 10.14

Adverse Events

Placebo

Serious events: 1 serious events

Other events: 34 other events

Deaths: 0 deaths

Elagolix

Serious events: 4 serious events

Other events: 58 other events

Deaths: 0 deaths

Elagolix + E2-NETA

Serious events: 7 serious events

Other events: 80 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=94 participants at risk Placebo for both elagolix BID and E2/NETA QD	Elagolix n=95 participants at risk Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix + E2-NETA n=189 participants at risk Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
Blood and lymphatic system disorders ANAEMIA	0.00% 0/94 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.00% 0/95 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.53% 1/189 • Number of events 1 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Endocrine disorders HYPERTHYROIDISM	0.00% 0/94 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.00% 0/95 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.53% 1/189 • Number of events 1 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Gastrointestinal disorders SMALL INTESTINAL OBSTRUCTION	0.00% 0/94 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	1.1% 1/95 • Number of events 1 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.00% 0/189 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Hepatobiliary disorders CHOLELITHIASIS	0.00% 0/94 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	1.1% 1/95 • Number of events 1 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.53% 1/189 • Number of events 1 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Infections and infestations APPENDICITIS	0.00% 0/94 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	1.1% 1/95 • Number of events 1 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.00% 0/189 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Infections and infestations CELLULITIS	0.00% 0/94 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.00% 0/95 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.53% 1/189 • Number of events 1 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Metabolism and nutrition disorders OBESITY	0.00% 0/94 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.00% 0/95 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.53% 1/189 • Number of events 1 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Pregnancy, puerperium and perinatal conditions ABORTION COMPLETE	1.1% 1/94 • Number of events 1 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.00% 0/95 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.00% 0/189 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Psychiatric disorders ANXIETY	0.00% 0/94 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.00% 0/95 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.53% 1/189 • Number of events 1 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Reproductive system and breast disorders DYSFUNCTIONAL UTERINE BLEEDING	0.00% 0/94 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.00% 0/95 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.53% 1/189 • Number of events 1 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Reproductive system and breast disorders DYSMENORRHOEA	0.00% 0/94 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.00% 0/95 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.53% 1/189 • Number of events 1 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Reproductive system and breast disorders MENORRHAGIA	0.00% 0/94 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.00% 0/95 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.53% 1/189 • Number of events 1 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Reproductive system and breast disorders PELVIC PAIN	0.00% 0/94 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	1.1% 1/95 • Number of events 1 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.00% 0/189 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.

Other adverse events

Other adverse events
Measure	Placebo n=94 participants at risk Placebo for both elagolix BID and E2/NETA QD	Elagolix n=95 participants at risk Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix + E2-NETA n=189 participants at risk Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
Gastrointestinal disorders NAUSEA	9.6% 9/94 • Number of events 11 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	4.2% 4/95 • Number of events 4 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	7.4% 14/189 • Number of events 15 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
General disorders FATIGUE	5.3% 5/94 • Number of events 5 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	3.2% 3/95 • Number of events 3 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	5.3% 10/189 • Number of events 10 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Infections and infestations NASOPHARYNGITIS	8.5% 8/94 • Number of events 9 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	4.2% 4/95 • Number of events 4 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	5.3% 10/189 • Number of events 11 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Infections and infestations URINARY TRACT INFECTION	5.3% 5/94 • Number of events 6 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	2.1% 2/95 • Number of events 2 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	6.3% 12/189 • Number of events 12 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Musculoskeletal and connective tissue disorders ARTHRALGIA	2.1% 2/94 • Number of events 2 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	5.3% 5/95 • Number of events 5 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	4.8% 9/189 • Number of events 10 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Nervous system disorders HEADACHE	5.3% 5/94 • Number of events 6 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	13.7% 13/95 • Number of events 14 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	10.6% 20/189 • Number of events 21 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Psychiatric disorders LIBIDO DECREASED	2.1% 2/94 • Number of events 2 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	3.2% 3/95 • Number of events 3 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	5.3% 10/189 • Number of events 10 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Psychiatric disorders MOOD SWINGS	2.1% 2/94 • Number of events 2 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	6.3% 6/95 • Number of events 6 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	3.2% 6/189 • Number of events 8 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Reproductive system and breast disorders DYSMENORRHOEA	6.4% 6/94 • Number of events 6 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	0.00% 0/95 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	3.2% 6/189 • Number of events 6 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Skin and subcutaneous tissue disorders NIGHT SWEATS	5.3% 5/94 • Number of events 6 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	25.3% 24/95 • Number of events 24 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	10.6% 20/189 • Number of events 21 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.
Vascular disorders HOT FLUSH	4.3% 4/94 • Number of events 4 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	43.2% 41/95 • Number of events 41 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.	19.6% 37/189 • Number of events 37 • From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively Treatment-emergent adverse events are presented.

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