Trial Outcomes & Findings for Efficacy and Safety Study of Elagolix Versus Placebo or Leuprorelin Acetate in Endometriosis (NCT NCT00797225)

Results Overview

The NRS is an 11-point scale used to measure endometriosis pain and was completed at approximately the same time each day using an electronic diary (e-Diary). Participants were instructed to select a single number between 0 (No pain) and 10 (Worst pain ever) that best described their endometriosis pain at its worst over the past day. The monthly mean NRS is the average of the daily values reported during the 4 weeks prior to each visit.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

174 participants

Primary outcome timeframe

Baseline and Weeks 4, 8, and 12

Results posted on

2018-09-10

Participant Flow

The study was conducted from 26 November 2008 to 24 February 2010 at 27 centers in Central Eastern Europe (Bulgaria, Hungary, Poland, Romania, Russia and Ukraine).

Patients were randomized equally to oral elagolix 150 mg or 250 mg once daily, placebo or leuprorelin acetate (LA) 1-month depot 3.75 mg injection for 12 weeks. Thereafter, patients originally randomized to placebo or LA were re-randomized to 1 of the elagolix doses and patients randomized to elagolix continued their assigned dose for 12 weeks.

Participant milestones

Participant milestones
Measure	Placebo Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Placebo / Elagolix 150 mg Participants initially randomized to placebo were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Placebo / Elagolix 250 mg Participants initially randomized to placebo were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Weeks 1 to 12 STARTED	43	43	44	44	0	0	0	0
Weeks 1 to 12 Received Study Drug	43	43	44	44	0	0	0	0
Weeks 1 to 12 COMPLETED	41	42	43	44	0	0	0	0
Weeks 1 to 12 NOT COMPLETED	2	1	1	0	0	0	0	0
Weeks 13 to 24 STARTED	0	42	43	0	20	21	22	22
Weeks 13 to 24 COMPLETED	0	38	41	0	19	21	20	22
Weeks 13 to 24 NOT COMPLETED	0	4	2	0	1	0	2	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Placebo / Elagolix 150 mg Participants initially randomized to placebo were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.
Weeks 1 to 12 Adverse Event	0	0	1	0	0
Weeks 1 to 12 Non-compliance	0	1	0	0	0
Weeks 1 to 12 Lack of Efficacy	1	0	0	0	0
Weeks 1 to 12 Sponsor Decision	1	0	0	0	0
Weeks 13 to 24 Non-compliance	0	2	0	0	0
Weeks 13 to 24 Withdrawal by Subject	0	1	1	0	0
Weeks 13 to 24 Lost to Follow-up	0	0	1	1	0
Weeks 13 to 24 Adverse Event	0	1	0	0	1
Weeks 13 to 24 Sponsor Decision	0	0	0	0	1

Baseline Characteristics

Efficacy and Safety Study of Elagolix Versus Placebo or Leuprorelin Acetate in Endometriosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=43 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=43 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=44 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=44 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Total n=174 Participants Total of all reporting groups
Age, Continuous	31.4 years STANDARD_DEVIATION 0.8 • n=5 Participants	32.1 years STANDARD_DEVIATION 0.9 • n=7 Participants	31.7 years STANDARD_DEVIATION 1.0 • n=5 Participants	31.4 years STANDARD_DEVIATION 0.7 • n=4 Participants	31.7 years STANDARD_DEVIATION 0.4 • n=21 Participants
Sex: Female, Male Female	43 Participants n=5 Participants	43 Participants n=7 Participants	44 Participants n=5 Participants	44 Participants n=4 Participants	174 Participants n=21 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	0 Participants n=21 Participants
Race/Ethnicity, Customized White	43 Participants n=5 Participants	43 Participants n=7 Participants	44 Participants n=5 Participants	44 Participants n=4 Participants	174 Participants n=21 Participants

PRIMARY outcome

Timeframe: Baseline and Weeks 4, 8, and 12

Population: All randomized participants who received at least 1 dose of study drug and had at least 1 evaluable e-Diary report following randomization (intent-to-treat population). The analysis includes participants with non-missing data at each time point.

The NRS is an 11-point scale used to measure endometriosis pain and was completed at approximately the same time each day using an electronic diary (e-Diary). Participants were instructed to select a single number between 0 (No pain) and 10 (Worst pain ever) that best described their endometriosis pain at its worst over the past day. The monthly mean NRS is the average of the daily values reported during the 4 weeks prior to each visit.

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=43 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=44 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=44 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Change From Baseline in the Monthly Mean Numerical Rating Score (NRS) for Endometriosis Pain Week 4	-0.35 units on a scale Standard Error 0.17	-0.84 units on a scale Standard Error 0.17	-1.00 units on a scale Standard Error 0.17	-0.94 units on a scale Standard Error 0.17	—	—
Change From Baseline in the Monthly Mean Numerical Rating Score (NRS) for Endometriosis Pain Week 8	-0.93 units on a scale Standard Error 0.20	-1.25 units on a scale Standard Error 0.20	-1.57 units on a scale Standard Error 0.20	-1.55 units on a scale Standard Error 0.20	—	—
Change From Baseline in the Monthly Mean Numerical Rating Score (NRS) for Endometriosis Pain Week 12	-1.22 units on a scale Standard Error 0.21	-1.34 units on a scale Standard Error 0.21	-1.47 units on a scale Standard Error 0.21	-1.81 units on a scale Standard Error 0.20	—	—

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 8, and 12

Population: All randomized participants who received at least 1 dose of study drug and had at least 1 evaluable e-Diary report following randomization (intent-to-treat population). The analysis includes participants with non-missing data at each time point.

The NRS is an 11-point scale used to measure endometriosis pain and was completed at approximately the same time each day using an electronic diary (e-Diary). Participants were instructed to select a single number between 0 (No pain) and 10 (Worst pain ever) that best described their endometriosis pain at its worst over the past day. The monthly peak NRS is the maximum of the daily values reported during the 4 weeks prior to each visit.

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=43 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=44 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=44 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Change From Baseline in the Monthly Peak Numerical Rating Score (NRS) for Endometriosis Pain Week 8	-0.89 units on a scale Standard Error 0.34	-2.23 units on a scale Standard Error 0.34	-2.96 units on a scale Standard Error 0.33	-3.62 units on a scale Standard Error 0.33	—	—
Change From Baseline in the Monthly Peak Numerical Rating Score (NRS) for Endometriosis Pain Week 12	-1.67 units on a scale Standard Error 0.34	-2.62 units on a scale Standard Error 0.34	-3.05 units on a scale Standard Error 0.34	-3.99 units on a scale Standard Error 0.33	—	—
Change From Baseline in the Monthly Peak Numerical Rating Score (NRS) for Endometriosis Pain Week 4	-0.20 units on a scale Standard Error 0.34	-1.82 units on a scale Standard Error 0.34	-1.83 units on a scale Standard Error 0.33	-1.48 units on a scale Standard Error 0.33	—	—

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 8, and 12

Population: All randomized participants who received at least 1 dose of study drug and had at least 1 evaluable e-Diary report following randomization (intent-to-treat population). The analysis includes participants with non-missing data at each time point.

Participants assessed their pelvic pain not related to menses and its impact on their daily activities at approximately the same time every day in an e-Diary according to the following response options: * 0 = No pelvic pain * 1 = Mild pelvic pain; subject could not do some of the things she usually does * 2 = Moderate pelvic pain; subject could not do many of the things she usually does * 3 = Severe pelvic pain; subject could not do most or all of the things she usually does. The monthly mean non-menstrual pelvic pain score is the average of the daily values reported during the 4 weeks prior to each visit.

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=43 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=44 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=44 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Change From Baseline in the Monthly Mean Non-menstrual Pelvic Pain Score Week 4	-0.05 units on a scale Standard Error 0.06	-0.22 units on a scale Standard Error 0.06	-0.21 units on a scale Standard Error 0.06	-0.27 units on a scale Standard Error 0.06	—	—
Change From Baseline in the Monthly Mean Non-menstrual Pelvic Pain Score Week 8	-0.18 units on a scale Standard Error 0.06	-0.34 units on a scale Standard Error 0.06	-0.36 units on a scale Standard Error 0.06	-0.46 units on a scale Standard Error 0.06	—	—
Change From Baseline in the Monthly Mean Non-menstrual Pelvic Pain Score Week 12	-0.30 units on a scale Standard Error 0.06	-0.35 units on a scale Standard Error 0.06	-0.34 units on a scale Standard Error 0.06	-0.55 units on a scale Standard Error 0.06	—	—

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 8, and 12

Population: All randomized participants who received at least 1 dose of study drug and had at least 1 evaluable e-Diary report following randomization (intent-to-treat population). The analysis includes participants with non-missing data at each time point.

Participants assessed dysmenorrhea (pain during menstruation) and its impact on their daily activities at approximately the same time each day of their period in an e-Diary according to the following response options: * Subject is not having her period * 0 = No pain related to period * 1 = Mild pain related to period; subject could not do some of the things she usually does * 2 = Moderate pain related to period; subject could not do many of the things she usually does * 3 = Severe pain related to period; subject could not do most of or all of the things she usually does. The monthly mean dysmenorrhea score is the average of the daily values reported during the 4 weeks prior to each visit.

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=43 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=44 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=44 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Change From Baseline in the Monthly Mean Dysmenorrhea Score Week 4	-0.17 units on a scale Standard Error 0.08	-0.64 units on a scale Standard Error 0.08	-0.67 units on a scale Standard Error 0.08	-0.65 units on a scale Standard Error 0.08	—	—
Change From Baseline in the Monthly Mean Dysmenorrhea Score Week 8	-0.40 units on a scale Standard Error 0.08	-0.86 units on a scale Standard Error 0.08	-1.04 units on a scale Standard Error 0.08	-1.22 units on a scale Standard Error 0.08	—	—
Change From Baseline in the Monthly Mean Dysmenorrhea Score Week 12	-0.35 units on a scale Standard Error 0.08	-0.76 units on a scale Standard Error 0.08	-0.87 units on a scale Standard Error 0.08	-1.14 units on a scale Standard Error 0.08	—	—

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 8, and 12

Population: All randomized participants who received at least 1 dose of study drug and had at least 1 evaluable e-Diary report following randomization (intent-to-treat population). The analysis includes participants with non-missing data at each time point.

Participants assessed dysmenorrhea and pelvic pain not related to menses and their impact on daily activities at approximately the same time every day on a 4-point scale (0 = none, 1 = mild, 2 = moderate, and 3 = severe) in an e-Diary. The dysmenorrhea scale included an option for participants who were not having their period. The sum of the dysmenorrhea and non-menstrual pelvic pain scores on each day were calculated to create a daily total score. On days the participant was not having her period, the dysmenorrhea score was not defined; hence, the total score was equal to the non-menstrual pelvic pain score (range 0 to 3). On days where the participant recorded menstruation the total score ranged from 0 to 6, where higher scores indicate more severe pain. The monthly mean sum of dysmenorrhea and non-menstrual pelvic pain scores is the average of the daily values reported during the 4 weeks prior to each visit.

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=43 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=44 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=44 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Change From Baseline in the Monthly Mean Sum of Dysmenorrhea and Non-menstrual Pelvic Pain Scores Week 12	-0.40 units on a scale Standard Error 0.07	-0.55 units on a scale Standard Error 0.07	-0.63 units on a scale Standard Error 0.07	-0.87 units on a scale Standard Error 0.07	—	—
Change From Baseline in the Monthly Mean Sum of Dysmenorrhea and Non-menstrual Pelvic Pain Scores Week 4	-0.12 units on a scale Standard Error 0.07	-0.43 units on a scale Standard Error 0.07	-0.44 units on a scale Standard Error 0.07	-0.50 units on a scale Standard Error 0.07	—	—
Change From Baseline in the Monthly Mean Sum of Dysmenorrhea and Non-menstrual Pelvic Pain Scores Week 8	-0.24 units on a scale Standard Error 0.07	-0.58 units on a scale Standard Error 0.07	-0.67 units on a scale Standard Error 0.07	-0.78 units on a scale Standard Error 0.07	—	—

SECONDARY outcome

Timeframe: Baseline, Weeks 4, 8 and 12

Population: All randomized participants who received at least 1 dose of study drug and had at least 1 evaluable e-Diary report following randomization (intent-to-treat population). The analysis includes participants with non-missing data at each time point.

The daily use of endometriosis analgesics was reported by participants daily using the e-Diary. Participants reported whether the medication was over-the-counter (OTC) or prescription, and, if prescription, whether the medication was a narcotic. The percentage of days of any analgesic use is defined as the number of days in the 4 weeks prior to each study visit that the participant reported the use of an analgesic, divided by the number of study days in the interval that the participant provided an e-Diary report regarding the use of endometriosis analgesics (including a response of "none").

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=43 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=44 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=44 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Change From Baseline in the Percentage of Days of Any Analgesic Use Week 8	-6.2 percentage of days Standard Error 2.0	-3.4 percentage of days Standard Error 2.0	-9.1 percentage of days Standard Error 2.0	-10.2 percentage of days Standard Error 2.0	—	—
Change From Baseline in the Percentage of Days of Any Analgesic Use Week 12	-6.2 percentage of days Standard Error 2.0	-4.4 percentage of days Standard Error 2.0	-8.3 percentage of days Standard Error 2.0	-10.5 percentage of days Standard Error 2.0	—	—
Change From Baseline in the Percentage of Days of Any Analgesic Use Week 4	-5.2 percentage of days Standard Error 2.0	-1.1 percentage of days Standard Error 2.0	-8.4 percentage of days Standard Error 2.0	-8.7 percentage of days Standard Error 2.0	—	—

SECONDARY outcome

Timeframe: Baseline, Weeks 4, 8 and 12

Population: All randomized participants who received at least 1 dose of study drug and had at least 1 evaluable e-Diary report following randomization (intent-to-treat population). The analysis includes participants with non-missing data at each time point.

The daily use of endometriosis analgesics was reported by participants daily using the e-Diary. Participants reported whether the medication was over-the-counter (OTC) or prescription, and, if prescription, whether the medication was a narcotic. The percentage of days of prescription analgesic use is defined as the number of days in the 4 weeks prior to each study visit that the participant reported the use of a prescription analgesic, divided by the number of study days in the interval that the participant provided an e-Diary report regarding the use of endometriosis analgesics (including a response of "none").

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=43 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=44 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=44 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Change From Baseline in the Percentage of Days of Prescription Analgesic Use Week 12	-1.8 percentage of days Standard Error 1.4	0.7 percentage of days Standard Error 1.4	-1.9 percentage of days Standard Error 1.4	-2.8 percentage of days Standard Error 1.3	—	—
Change From Baseline in the Percentage of Days of Prescription Analgesic Use Week 4	-0.3 percentage of days Standard Error 1.8	3.4 percentage of days Standard Error 1.8	-1.2 percentage of days Standard Error 1.7	-2.5 percentage of days Standard Error 1.7	—	—
Change From Baseline in the Percentage of Days of Prescription Analgesic Use Week 8	-1.3 percentage of days Standard Error 1.6	1.3 percentage of days Standard Error 1.6	-2.8 percentage of days Standard Error 1.6	-2.6 percentage of days Standard Error 1.6	—	—

SECONDARY outcome

Timeframe: Baseline, Weeks 4, 8 and 12

Population: All randomized participants who received at least 1 dose of study drug and had at least 1 evaluable e-Diary report following randomization (intent-to-treat population). The analysis includes participants with non-missing data at each time point.

The daily use of endometriosis analgesics was reported by participants daily using the e-Diary. Participants reported whether the medication was over-the-counter (OTC) or prescription, and, if prescription, whether the medication was a narcotic. The percentage of days of narcotic analgesic use is defined as the number of days in the 4 weeks prior to each study visit that the participant reported the use of a narcotic analgesic, divided by the number of study days in the interval that the participant provided an e-Diary report regarding the use of endometriosis analgesics (including a response of "none").

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=43 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=44 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=44 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Change From Baseline in the Percentage of Days of Narcotic Analgesic Use Week 4	0.0 percentage of days Standard Error 0.1	-0.1 percentage of days Standard Error 0.1	0.0 percentage of days Standard Error 0.1	-0.1 percentage of days Standard Error 0.1	—	—
Change From Baseline in the Percentage of Days of Narcotic Analgesic Use Week 8	-0.1 percentage of days Standard Error 0.1	-0.1 percentage of days Standard Error 0.1	-0.1 percentage of days Standard Error 0.1	-0.1 percentage of days Standard Error 0.1	—	—
Change From Baseline in the Percentage of Days of Narcotic Analgesic Use Week 12	0.0 percentage of days Standard Error 0.1	0.1 percentage of days Standard Error 0.1	0.1 percentage of days Standard Error 0.1	0.3 percentage of days Standard Error 0.1	—	—

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 8, and 12

Population: All randomized participants who received at least 1 dose of study drug and had at least 1 evaluable e-Diary report following randomization (intent-to-treat population). The analysis includes participants with non-missing data at baseline and at each time point.

The CPSSS consists of 5 components that address dysmenorrhea, dyspareunia, non-menstrual pelvic pain, pelvic tenderness, and pelvic induration. To assess dyspareunia (painful intercourse) participants were asked to select the best description of pain during sexual intercourse over the past 28 days using the following response categories: * 0 = Absent; No discomfort during sexual intercourse. * 1 = Mild; I can tolerate the discomfort during sexual intercourse. * 2 = Moderate; Intercourse is sometime interrupted due to pain. * 3 = Severe; I prefer to avoid intercourse because of pain. * Not applicable. I am not sexually active for reasons other than my endometriosis symptoms.

Outcome measures

Outcome measures
Measure	Placebo n=40 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=38 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=40 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=41 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Change From Baseline in Dyspareunia Component of the Composite Pelvic Signs and Symptoms Score (CPSSS) Week 4	-0.33 units on a scale Standard Error 0.11	-0.46 units on a scale Standard Error 0.11	-0.49 units on a scale Standard Error 0.11	-0.55 units on a scale Standard Error 0.11	—	—
Change From Baseline in Dyspareunia Component of the Composite Pelvic Signs and Symptoms Score (CPSSS) Week 8	-0.72 units on a scale Standard Error 0.11	-0.68 units on a scale Standard Error 0.11	-0.77 units on a scale Standard Error 0.11	-0.76 units on a scale Standard Error 0.11	—	—
Change From Baseline in Dyspareunia Component of the Composite Pelvic Signs and Symptoms Score (CPSSS) Week 12	-0.60 units on a scale Standard Error 0.11	-0.84 units on a scale Standard Error 0.12	-0.89 units on a scale Standard Error 0.11	-1.04 units on a scale Standard Error 0.11	—	—

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: All randomized participants who received at least 1 dose of study drug and had at least 1 evaluable e-Diary report following randomization (intent-to-treat population). Data collection for this endpoint was added via a protocol amendment; therefore, the analysis only includes the subset of participants affected by the protocol amendment.

The CPSSS consists of 5 components that address dysmenorrhea, dyspareunia, non-menstrual pelvic pain, pelvic tenderness, and pelvic induration. To assess dysmenorrhea (pain during menstruation), participants were asked to select the best description of painful menstruation over the past 28 days using the following response categories: * 0 = Absent; Amenorrhea (no bleeding) or no discomfort. * 1 = Mild; Some loss of work efficiency; occasional use of analgesics. * 2 = Moderate; In bed part of one day, occasional loss of work; regular use of analgesics. * 3 = Severe; In bed ≥ 1 day, incapacitation; requirement for strong analgesics.

Outcome measures

Outcome measures
Measure	Placebo n=20 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=19 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=23 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=24 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Change From Baseline in Dysmenorrhea Component of the CPSSS	-1.03 units on a scale Standard Error 0.17	-1.29 units on a scale Standard Error 0.17	-1.47 units on a scale Standard Error 0.16	-1.75 units on a scale Standard Error 0.15	—	—

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: All randomized participants who received at least 1 dose of study drug and had at least 1 evaluable e-Diary report following randomization (intent-to-treat population). Data collection for this endpoint was added via a protocol amendment; therefore, the analysis only includes the subset of participants affected by the protocol amendment.

The CPSSS consists of 5 components that address dysmenorrhea, dyspareunia, non-menstrual pelvic pain, pelvic tenderness, and pelvic induration. To assess non-menstrual pelvic pain, participants were asked to select the best description of pelvic pain over the past 28 days using the following response categories: * 0 = Absent; No discomfort. * 1 = Mild; Occasional pelvic discomfort that can be treated with NSAIDs. * 2 = Moderate; Noticeable discomfort or pain for most of cycle requiring regular use of NSAID or weak opiate. * 3 = Severe; Pain persisting during the cycle or pain requiring strong analgesics.

Outcome measures

Outcome measures
Measure	Placebo n=20 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=19 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=23 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=24 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Change From Baseline in Non-menstrual Pelvic Pain CPSSS Component	-0.60 units on a scale Standard Error 0.12	-0.58 units on a scale Standard Error 0.12	-0.48 units on a scale Standard Error 0.11	-0.79 units on a scale Standard Error 0.11	—	—

SECONDARY outcome

Timeframe: Weeks 4, 8 and 12

Population: All randomized participants who received at least 1 dose of study drug and had at least 1 evaluable e-Diary report following randomization (intent-to-treat population). The analysis includes participants with non-missing data at each time point.

The Patient Global Impression of Change (PGIC) is a questionnaire-based assessment of the change in endometriosis pain since the initiation of study drug. The participant was asked to select from one of seven response categories: 1. Very Much Improved 2. Much Improved 3. Minimally Improved 4. Not Changed 5. Minimally Worse 6. Much Worse 7. Very Much Worse

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=43 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=44 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=44 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Patient Global Impression of Change at Weeks 4, 8 and 12 Week 4	3.4 units on a scale Standard Error 0.1	3.0 units on a scale Standard Error 0.1	2.9 units on a scale Standard Error 0.2	3.3 units on a scale Standard Error 0.1	—	—
Patient Global Impression of Change at Weeks 4, 8 and 12 Week 8	2.8 units on a scale Standard Error 0.1	2.5 units on a scale Standard Error 0.2	2.2 units on a scale Standard Error 0.1	2.3 units on a scale Standard Error 0.1	—	—
Patient Global Impression of Change at Weeks 4, 8 and 12 Week 12	2.6 units on a scale Standard Error 0.2	2.4 units on a scale Standard Error 0.1	2.2 units on a scale Standard Error 0.2	2.1 units on a scale Standard Error 0.1	—	—

SECONDARY outcome

Timeframe: Weeks 4, 8 and 12

Population: All randomized participants who received at least 1 dose of study drug and had at least 1 evaluable e-Diary report following randomization (intent-to-treat population). The analysis includes participants with non-missing data at each time point.

The PGIC is a questionnaire-based assessment of the change in endometriosis pain since the initiation of study drug. The participant was asked to select from one of seven response categories: 1. Very Much Improved 2. Much Improved 3. Minimally Improved 4. Not Changed 5. Minimally Worse 6. Much Worse 7. Very Much Worse

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=43 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=44 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=44 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Percentage of Participants With a PGIC Response of Minimally Improved, Much Improved, or Very Much Improved Week 12	80.5 percentage of participants Interval 68.4 to 92.6	88.1 percentage of participants Interval 78.3 to 97.9	88.4 percentage of participants Interval 78.8 to 98.0	93.2 percentage of participants Interval 85.7 to 100.0	—	—
Percentage of Participants With a PGIC Response of Minimally Improved, Much Improved, or Very Much Improved Week 4	56.1 percentage of participants Interval 40.9 to 71.3	74.4 percentage of participants Interval 61.4 to 87.5	65.1 percentage of participants Interval 50.9 to 79.4	50.0 percentage of participants Interval 35.2 to 64.8	—	—
Percentage of Participants With a PGIC Response of Minimally Improved, Much Improved, or Very Much Improved Week 8	75.6 percentage of participants Interval 62.5 to 88.8	81.4 percentage of participants Interval 69.8 to 93.0	90.7 percentage of participants Interval 82.0 to 99.4	88.6 percentage of participants Interval 79.3 to 98.0	—	—

SECONDARY outcome

Timeframe: Weeks 4, 8 and 12

Population: All randomized participants who received at least 1 dose of study drug and had at least 1 evaluable e-Diary report following randomization (intent-to-treat population). The analysis includes participants with non-missing data at each time point.

The PGIC is a questionnaire-based assessment of the change in endometriosis pain since the initiation of study drug. The participant was asked to select from one of seven response categories: 1. Very Much Improved 2. Much Improved 3. Minimally Improved 4. Not Changed 5. Minimally Worse 6. Much Worse 7. Very Much Worse

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=43 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=44 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=44 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Percentage of Participants With a PGIC Response of Much Improved or Very Much Improved Week 12	53.7 percentage of participants Interval 38.4 to 68.9	54.8 percentage of participants Interval 39.7 to 69.8	67.4 percentage of participants Interval 53.4 to 81.4	70.5 percentage of participants Interval 57.0 to 83.9	—	—
Percentage of Participants With a PGIC Response of Much Improved or Very Much Improved Week 4	7.3 percentage of participants Interval 0.0 to 15.3	25.6 percentage of participants Interval 12.5 to 38.6	32.6 percentage of participants Interval 18.6 to 46.6	27.3 percentage of participants Interval 14.1 to 40.4	—	—
Percentage of Participants With a PGIC Response of Much Improved or Very Much Improved Week 8	36.6 percentage of participants Interval 21.8 to 51.3	53.5 percentage of participants Interval 38.6 to 68.4	72.1 percentage of participants Interval 58.7 to 85.5	54.5 percentage of participants Interval 39.8 to 69.3	—	—

SECONDARY outcome

Timeframe: Baseline and week 12

Population: All randomized participants who received at least 1 dose of study drug and had at least 1 evaluable e-Diary report following randomization (intent-to-treat population). The analysis includes participants with non-missing data for each dimension at baseline and week 12.

The EHP-5 is an instrument to measure health-related quality of life in women with endometriosis. The EHP-5 consists of two parts: * A core questionnaire consisting of five questions that measure the areas of pain, control and powerlessness, emotional well-being, social support, and self-image with five response categories for each item (Never, Rarely, Sometimes, Often, Always) * A supplemental questionnaire consisting of six additional questions which assess the areas of work, relationship with children, sexual intercourse, feelings about the medical profession, treatment, and infertility with the same five response categories plus an additional response category of Not Relevant which was not scored. The scores associated with each possible outcome category are as follows: never (0), rarely (25), sometimes (50), often (75), and always (100). A negative change from baseline score indicates improvement in quality of life.

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=43 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=44 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=44 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Change From Baseline in Endometriosis Health Profile-5 (EHP-5) at Week 12 Pain	-14.0 units on a scale Standard Error 4.8	-19.0 units on a scale Standard Error 4.1	-25.0 units on a scale Standard Error 4.7	-31.8 units on a scale Standard Error 3.9	—	—
Change From Baseline in Endometriosis Health Profile-5 (EHP-5) at Week 12 Control and Powerlessness	-18.3 units on a scale Standard Error 4.4	-17.9 units on a scale Standard Error 3.9	-20.9 units on a scale Standard Error 5.1	-23.9 units on a scale Standard Error 4.9	—	—
Change From Baseline in Endometriosis Health Profile-5 (EHP-5) at Week 12 Emotional Wellbeing	-14.6 units on a scale Standard Error 4.2	-10.7 units on a scale Standard Error 4.1	-12.8 units on a scale Standard Error 4.4	-13.6 units on a scale Standard Error 4.4	—	—
Change From Baseline in Endometriosis Health Profile-5 (EHP-5) at Week 12 Social Support	-22.0 units on a scale Standard Error 4.4	-16.1 units on a scale Standard Error 4.4	-18.6 units on a scale Standard Error 5.6	-15.3 units on a scale Standard Error 5.1	—	—
Change From Baseline in Endometriosis Health Profile-5 (EHP-5) at Week 12 Self-image	-12.2 units on a scale Standard Error 6.5	-7.7 units on a scale Standard Error 4.5	-5.8 units on a scale Standard Error 5.0	-8.5 units on a scale Standard Error 4.1	—	—
Change From Baseline in Endometriosis Health Profile-5 (EHP-5) at Week 12 Work	-23.7 units on a scale Standard Error 3.9	-21.5 units on a scale Standard Error 4.5	-29.9 units on a scale Standard Error 5.1	-38.6 units on a scale Standard Error 4.3	—	—
Change From Baseline in Endometriosis Health Profile-5 (EHP-5) at Week 12 Relationship with Children	-11.5 units on a scale Standard Error 6.7	-15.3 units on a scale Standard Error 5.4	-25.0 units on a scale Standard Error 7.6	-22.9 units on a scale Standard Error 9.5	—	—
Change From Baseline in Endometriosis Health Profile-5 (EHP-5) at Week 12 Sexual Intercourse	-32.2 units on a scale Standard Error 5.7	-21.2 units on a scale Standard Error 6.2	-30.6 units on a scale Standard Error 5.3	-28.9 units on a scale Standard Error 5.7	—	—
Change From Baseline in Endometriosis Health Profile-5 (EHP-5) at Week 12 Medical Profession	-5.3 units on a scale Standard Error 4.5	-5.5 units on a scale Standard Error 4.0	-7.6 units on a scale Standard Error 3.0	-6.3 units on a scale Standard Error 4.2	—	—
Change From Baseline in Endometriosis Health Profile-5 (EHP-5) at Week 12 Frustration with Treatment	-11.4 units on a scale Standard Error 6.1	-10.9 units on a scale Standard Error 6.3	-7.6 units on a scale Standard Error 6.9	-12.5 units on a scale Standard Error 6.9	—	—
Change From Baseline in Endometriosis Health Profile-5 (EHP-5) at Week 12 Concerns with Infertility	-19.7 units on a scale Standard Error 5.0	-24.0 units on a scale Standard Error 7.0	-13.8 units on a scale Standard Error 5.2	-13.3 units on a scale Standard Error 4.8	—	—

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 8 and 12

Population: Randomized participants who received at least one dose of randomized, double-blind study drug with at least one eDiary value following randomization, excluding participants who had less than 80% oral study drug dosing compliance during Weeks 1-12 (per protocol population). The analysis includes participants with non-missing data at each time point.

The concentration of serum estradiol (E2) was quantified using liquid chromatography with tandem mass spectrophotometry (LC/MS/MS). Serum estradiol concentrations below the limit of quantification (BLQ) were set equal to the lower limit of quantification (2.5 pg/mL).

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=41 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=43 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=44 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Concentration of Serum Estradiol Baseline	39.10 pg/mL Interval 12.0 to 168.0	43.40 pg/mL Interval 2.5 to 199.0	47.50 pg/mL Interval 12.4 to 497.0	46.20 pg/mL Interval 19.6 to 154.0	—	—
Concentration of Serum Estradiol Week 4	49.50 pg/mL Interval 14.6 to 436.0	36.40 pg/mL Interval 4.5 to 247.0	22.00 pg/mL Interval 6.2 to 127.0	3.63 pg/mL Interval 2.5 to 87.5	—	—
Concentration of Serum Estradiol Week 8	61.00 pg/mL Interval 12.7 to 440.0	36.90 pg/mL Interval 6.8 to 182.0	23.65 pg/mL Interval 2.5 to 213.0	4.36 pg/mL Interval 2.5 to 44.9	—	—
Concentration of Serum Estradiol Week 12	87.90 pg/mL Interval 2.5 to 338.0	36.70 pg/mL Interval 2.5 to 521.0	26.20 pg/mL Interval 2.5 to 235.0	6.38 pg/mL Interval 2.5 to 421.0	—	—

SECONDARY outcome

Timeframe: Baseline and week 12

Population: Participants who received at least one dose of randomized, double-blind study drug (safety analysis set) and with available BMD data at baseline and week 12.

Bone mineral density (BMD) of the femur (total hip) was measured by dual-energy X-ray absorptiometry (DXA).

Outcome measures

Outcome measures
Measure	Placebo n=40 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=41 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=42 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=43 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Percent Change From Baseline in Bone Mineral Density of the Femur at Week 12	-0.90 percent change Standard Deviation 1.316	-0.342 percent change Standard Deviation 1.583	-0.5623 percent change Standard Deviation 1.367	-1.122 percent change Standard Deviation 1.634	—	—

SECONDARY outcome

Timeframe: Baseline and week 12

Population: Participants who received at least one dose of randomized, double-blind study drug (safety analysis set) and with available BMD data at baseline and week 12.

Bone mineral density (BMD) of the spine was measured by dual-energy X-ray absorptiometry (DXA).

Outcome measures

Outcome measures
Measure	Placebo n=40 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=41 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=42 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=44 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Percent Change From Baseline in Bone Mineral Density of the Spine at Week 12	0.106 percent change Standard Deviation 1.893	-1.053 percent change Standard Deviation 1.985	-0.799 percent change Standard Deviation 2.352	-1.633 percent change Standard Deviation 2.113	—	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Participants who received at least one dose of randomized, double-blind study drug (safety analysis set) and with available BMD data at baseline and week 24.

Bone mineral density (BMD) of the femur (total hip) was measured by dual-energy X-ray absorptiometry (DXA).

Outcome measures

Outcome measures
Measure	Placebo n=36 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=38 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=17 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=20 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg n=18 Participants Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg n=21 Participants Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Percent Change From Baseline in Bone Mineral Density of the Femur at Week 24	-0.549 percent change Standard Deviation 1.827	-0.699 percent change Standard Deviation 1.574	-0.126 percent change Standard Deviation 1.732	-0.573 percent change Standard Deviation 1.328	-1.784 percent change Standard Deviation 1.571	-1.783 percent change Standard Deviation 2.096

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Participants who received at least one dose of randomized, double-blind study drug (safety analysis set) and with available BMD data at baseline and week 24.

Bone mineral density (BMD) of the spine was measured by dual-energy X-ray absorptiometry (DXA).

Outcome measures

Outcome measures
Measure	Placebo n=35 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=39 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=17 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=20 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg n=18 Participants Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg n=21 Participants Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Percent Change From Baseline in Bone Mineral Density of the Spine at Week 24	-1.288 percent change Standard Deviation 2.681	-1.855 percent change Standard Deviation 2.670	-0.990 percent change Standard Deviation 2.636	-0.648 percent change Standard Deviation 2.377	-2.899 percent change Standard Deviation 2.733	-4.378 percent change Standard Deviation 2.099

SECONDARY outcome

Timeframe: Baseline and week 12

Population: Participants who received at least one dose of randomized, double-blind study drug (safety analysis set) and with available data at baseline and week 12.

Blood samples to determine N-telopeptide concentrations were analyzed by a central laboratory using an enzyme-linked immunosorbent assay (ELISA).

Outcome measures

Outcome measures
Measure	Placebo n=39 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=43 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=41 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=40 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Change From Baseline in Serum N-telopeptide Concentration at Week 12	0.62 nM bone collagen equivalents (BCE) Standard Error 0.78	0.77 nM bone collagen equivalents (BCE) Standard Error 0.69	2.04 nM bone collagen equivalents (BCE) Standard Error 0.66	3.18 nM bone collagen equivalents (BCE) Standard Error 0.72	—	—

SECONDARY outcome

Timeframe: Screening (8 weeks prior to day 1), Treatment phase (weeks 1 to 12 for participants in the placebo and leuprorelin treatment groups and weeks 1 to 24 for participants in the elagolix treatment groups)

Population: Participants who received at least one dose of randomized, double-blind study drug (safety analysis set).

Hot flashes, if any, were reported daily by participants during the study using the e-Diary. The average number of hot flashes per day was calculated for each participant as the total number of hot flashes divided by total days in the phase.

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=43 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=44 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=44 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Average Number of Hot Flashes Per Day Screening	0.00 hot flashes per day Interval 0.0 to 4.8	0.00 hot flashes per day Interval 0.0 to 4.6	0.00 hot flashes per day Interval 0.0 to 2.6	0.00 hot flashes per day Interval 0.0 to 3.7	—	—
Average Number of Hot Flashes Per Day Treatment Phase	0.11 hot flashes per day Interval 0.0 to 3.0	0.22 hot flashes per day Interval 0.0 to 7.5	1.10 hot flashes per day Interval 0.0 to 11.4	1.73 hot flashes per day Interval 0.0 to 9.4	—	—

SECONDARY outcome

Timeframe: Screening (8 weeks prior to day 1), Treatment phase (weeks 1 to 12 for participants in the placebo and leuprorelin treatment groups and weeks 1 to 24 for participants in the elagolix treatment groups)

Population: Participants who received at least one dose of randomized, double-blind study drug (safety analysis set).

Uterine bleeding was reported daily by participants during the study using the e-Diary. The percentage of days a participant reported any bleeding was calculated as the total number of days the participant reported any bleeding ( light, moderate, or heavy) divided by the total number of days the participant had a non-missing eDiary report of vaginal bleeding in the phase.

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=43 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=44 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=44 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Percentage of Days With Uterine Bleeding Screening	21.10 percentage of days Standard Error 1.78	18.32 percentage of days Standard Error 1.14	22.32 percentage of days Standard Error 1.68	21.05 percentage of days Standard Error 1.87	—	—
Percentage of Days With Uterine Bleeding Treatment Phase	21.46 percentage of days Standard Error 1.39	10.78 percentage of days Standard Error 1.14	9.54 percentage of days Standard Error 1.35	11.04 percentage of days Standard Error 1.30	—	—

SECONDARY outcome

Timeframe: From last day of study drug up to 6 weeks after the last dose.

Population: Participants who received at least one dose of randomized, double-blind study drug (safety analysis set) with non-missing post-treatment data.

Defined as the number of days from the last dose of study drug until the start date of the first post-treatment menses.

Outcome measures

Outcome measures
Measure	Placebo n=38 Participants Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Elagolix 150 mg n=39 Participants Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks.	Elagolix 250 mg n=19 Participants Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	Leuprorelin n=20 Participants Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks.	Leuprorelin / Elagolix 150 mg n=20 Participants Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Leuprorelin / Elagolix 250 mg n=21 Participants Participants initially randomized to leuprorelin acetate were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.
Number of Days to First Posttreatment Menses	22.5 days Interval 3.0 to 56.0	26.0 days Interval 10.0 to 103.0	26.0 days Interval 5.0 to 42.0	27.0 days Interval 2.0 to 34.0	29.0 days Interval 5.0 to 62.0	28.0 days Interval 8.0 to 36.0

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Elagolix 150 mg

Serious events: 1 serious events

Other events: 25 other events

Deaths: 0 deaths

Elagolix 250 mg

Serious events: 2 serious events

Other events: 21 other events

Deaths: 0 deaths

Leuprorelin Acetate

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=43 participants at risk Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks.	Elagolix 150 mg n=85 participants at risk Participants initially randomized to elagolix 150 mg received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks. Participants initially randomized to placebo or leuprorelin were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Elagolix 250 mg n=87 participants at risk Participants initially randomized to elagolix 250 mg received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks. Participants initially randomized to placebo or leuprorelin were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.	Leuprorelin Acetate n=44 participants at risk Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks.
Infections and infestations APPENDICITIS	0.00% 0/43 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	0.00% 0/85 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	1.1% 1/87 • Number of events 1 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	0.00% 0/44 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.
Metabolism and nutrition disorders DIABETES MELLITUS NON-INSULIN-DEPENDENT	0.00% 0/43 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	1.2% 1/85 • Number of events 1 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	0.00% 0/87 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	0.00% 0/44 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) PARANASAL SINUS BENIGN NEOPLASM	0.00% 0/43 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	0.00% 0/85 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	1.1% 1/87 • Number of events 1 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	0.00% 0/44 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.

Other adverse events

Other adverse events
Measure	Placebo n=43 participants at risk Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks.	Elagolix 150 mg n=85 participants at risk Participants initially randomized to elagolix 150 mg received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks. Participants initially randomized to placebo or leuprorelin were re-randomized at week 12 to receive elagolix 150 mg for 12 weeks.	Elagolix 250 mg n=87 participants at risk Participants initially randomized to elagolix 250 mg received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks. Participants initially randomized to placebo or leuprorelin were re-randomized at week 12 to receive elagolix 250 mg for 12 weeks.	Leuprorelin Acetate n=44 participants at risk Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks.
Ear and labyrinth disorders VERTIGO	2.3% 1/43 • Number of events 1 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	7.1% 6/85 • Number of events 6 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	2.3% 2/87 • Number of events 2 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	0.00% 0/44 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.
Gastrointestinal disorders NAUSEA	2.3% 1/43 • Number of events 1 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	7.1% 6/85 • Number of events 6 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	5.7% 5/87 • Number of events 5 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	0.00% 0/44 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.
Investigations BONE DENSITY DECREASED	0.00% 0/43 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	8.2% 7/85 • Number of events 7 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	6.9% 6/87 • Number of events 6 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	0.00% 0/44 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.
Nervous system disorders HEADACHE	4.7% 2/43 • Number of events 2 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	12.9% 11/85 • Number of events 21 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	11.5% 10/87 • Number of events 12 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.	13.6% 6/44 • Number of events 6 • From the first dose of any study drug through week 30. The Placebo and Leuprorelin treatment groups include data for the initial 12-week treatment phase. The Elagolix treatment groups include data for the 24 week treatment period plus 6 weeks follow-up for participants initially randomized to elagolix, and 12 week treatment period plus 6-week follow-up for participants initially randomized to placebo or leuprorelin and were re-randomized at week 12.

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