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

• Sponsor: AbbVie (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02654054
• Collaborator: (none)
• Enrollment: 413
• Locations: 96
• Arms: 3
• Actual Duration (Months): 35.7
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study seeks to evaluate the efficacy, safety and tolerability of elagolix alone and in combination with estradiol/norethindrone acetate for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women.

Condition or Disease	Intervention/Treatment	Phase
Uterine Fibroids; Heavy Menstrual Bleeding	Drug: Elagolix; Drug: Placebo for Estradiol/Norethindrone Acetate; Drug: Estradiol/Norethindrone Acetate; Drug: Placebo for Elagolix	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 413 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Study to Evaluate the Efficacy and Safety of Elagolix in Combination With Estradiol/Norethindrone Acetate for the Management of Heavy Menstrual Bleeding Associated With Uterine Fibroids in Premenopausal Women
• Actual Study Start Date: Dec 22, 2015
• Actual Primary Completion Date: Jan 18, 2018
• Actual Study Completion Date: Dec 12, 2018

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo for both elagolix twice daily (BID) and norethindrone acetate (E2/NETA) once daily (QD)	Drug: Placebo for Estradiol/Norethindrone Acetate; Placebo capsules; Drug: Placebo for Elagolix; Film-coated placebo tablets
Experimental: Elagolix Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Drug: Elagolix; Film-coated tablets; Other Names: ABT-620 elagolix sodium ; Drug: Placebo for Estradiol/Norethindrone Acetate; Placebo capsules
Experimental: Elagolix + E2/NETA Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Drug: Elagolix; Film-coated tablets; Other Names: ABT-620 elagolix sodium ; Drug: Estradiol/Norethindrone Acetate; Commercially-available E2/NETA tablets were over-encapsulated to maintain study blinding.; Other Names: E2/NETA

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Meeting the Criteria for Responder [Final Month (the last 28 days prior to and including the Reference Day), up to Month 6]

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

Secondary Outcome Measures

1. Change From Baseline in MBL Volume to the Final Month [Month 0 (Baseline), Final Month (the last 28 days prior to and including the Reference Day), up to Month 6]

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

2. Percentage of Participants With Suppression of Bleeding at the Final Month [Final Month (the last 28 days prior to and including the Reference Day), up to Month 6]

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

3. Change From Baseline in MBL Volume to Month 6 [Month 0 (Baseline), Month 6]

4. Change From Baseline in MBL Volume to Month 3 [Month 0 (Baseline), Month 3]

5. Percentage of Participants With Baseline Hemoglobin <= 10.5 g/dL Who Have an Increase in Hemoglobin > 2 g/dL at Month 6 [Month 0 (Baseline), Month 6]

6. Change From Baseline in MBL Volume to Month 1 [Month 0 (Baseline), Month 1]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 51 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject is a premenopausal female at the time of Screening.

• Subject has a diagnosis of uterine fibroids documented by a pelvic ultrasound (transabdominal ultrasound/transvaginal ultrasound).

• Subject has heavy menstrual bleeding associated with uterine fibroids as evidenced by menstrual blood loss > 80 mL during each of two screening menses as measured by the alkaline hematin method.

• Subject has negative urine and/or serum pregnancy test in Screening and just prior to first dose.

• Subject has an adequate endometrial biopsy performed during Screening, the results of which show no clinically significant endometrial pathology.

Exclusion Criteria:

• Subject has screening pelvic ultrasound or saline infusion sonohysterography results that show a clinically significant gynecological disorder.

• Subject has history of osteoporosis or other metabolic bone disease.

• Subject has clinically significant abnormalities in clinical chemistry, hematology, or urinalysis.

• Subject has a history of major depression or post-traumatic stress disorder (PTSD) within 2 years of screening, OR a history of other major psychiatric disorder at any time (e.g., schizophrenia, bipolar disorder).

• Subject is using any systemic corticosteroids for over 14 days within 3 months prior to Screening or is likely to require treatment with systemic corticosteroids during the course of the study. Over the counter and prescription topical, inhaled, intranasal or injectable (for occasional use) corticosteroids are allowed.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Summers, Birmingham, AL /ID# 139684	Birmingham	Alabama	United States	35235
2	University of South Alabama /ID# 148763	Mobile	Alabama	United States	36604-3302
3	WCCT Global, LLC /ID# 145666	Costa Mesa	California	United States	92626
4	American Clinical Trials /ID# 147374	Hawaiian Gardens	California	United States	90716
5	Grossmont Ctr Clin Research /ID# 144011	La Mesa	California	United States	91942
6	Long Beach Clinical Trial Serv /ID# 152424	Long Beach	California	United States	90806
7	National Research Institute /ID# 151629	Los Angeles	California	United States	90057
8	University of California, Los Angeles /ID# 144107	Los Angeles	California	United States	90095
9	Beach OBGYN Medical Group /ID# 151414	Newport Beach	California	United States	92663-3657
10	Advanced RX Clinical Research /ID# 149168	Westminster	California	United States	92683-4567
11	Bluebird Clinical Trials, LLC /ID# 144843	Colorado Springs	Colorado	United States	80923
12	Advanced Women's Health Institution /ID# 144108	Greenwood Village	Colorado	United States	80111
13	Medstar Health Research Institute /ID# 145933	Washington	District of Columbia	United States	20010
14	James A. Simon, MD, PC /ID# 139675	Washington	District of Columbia	United States	20036
15	Helix Biomedics, LLC /ID# 147114	Boynton Beach	Florida	United States	33436-6634
16	Brandon Premier Health Care, PA /ID# 153130	Brandon	Florida	United States	33510-3107
17	Florida Clin Res Group /ID# 139811	Ckearwater	Florida	United States	33759
18	Universal Clinical Research A /ID# 139742	Doral	Florida	United States	33166
19	Clinical Physiology Associates /ID# 139736	Fort Myers	Florida	United States	33912
20	Meridien Research /ID# 139663	Kenneth City	Florida	United States	33709-3113
21	Altus Research, Inc /ID# 139662	Lake Worth	Florida	United States	33461
22	South Florida Wellness & Clinic /ID# 143558	Margate	Florida	United States	33063
23	LCC Medical Research Institute /ID# 143551	Miami	Florida	United States	33126
24	Healthcare Clinical Data, Inc /ID# 139650	Miami	Florida	United States	33161
25	Ocean Blue Med Research Ctr /ID# 139826	Miami	Florida	United States	33166
26	Salom Tangir, LLC /ID# 151732	Miramar	Florida	United States	33027
27	Advanced Research Institute /ID# 143554	New Port Richey	Florida	United States	34653
28	Clinical Associates of Orlando /ID# 148123	Orlando	Florida	United States	32806
29	Omega Research Consultants /ID# 139648	Orlando	Florida	United States	32810
30	Unified Womens Clin Research /ID# 145169	Panama City	Florida	United States	32045
31	Comprehensive Clinical Trials /ID# 139644	West Palm Beach	Florida	United States	33409
32	Atlanta Medical Research Insti /ID# 147117	Alpharetta	Georgia	United States	30005-4419
33	Paramount Research Solutions /ID# 139645	Alpharetta	Georgia	United States	30005
34	Agile Clinical Research Trials /ID# 143563	Atlanta	Georgia	United States	30328
35	Perimeter Inst Clinical Resear /ID# 148298	Atlanta	Georgia	United States	30338
36	Masters of Clinical Research, Inc. /ID# 139658	Augusta	Georgia	United States	30909
37	Fellows Research Alliance, Inc /ID# 139655	Savannah	Georgia	United States	31406
38	Boise Family Medical Center /ID# 139844	Boise	Idaho	United States	83709
39	Women's Health Practice, LLC /ID# 143569	Champaign	Illinois	United States	61820
40	Great Lakes Clinical Trials /ID# 148135	Chicago	Illinois	United States	60640
41	Affinity Clinical Research /ID# 150980	Oak Brook	Illinois	United States	60523
42	American Health Network of IN /ID# 139822	Avon	Indiana	United States	46123
43	GTC Research /ID# 141854	Kansas City	Kansas	United States	66218
44	Cypress Medical Research Ctr /ID# 147116	Wichita	Kansas	United States	67226
45	Research Integrity, LLC /ID# 139727	Owensboro	Kentucky	United States	42303-1089
46	Clinical Trials Management, LLC - Covington /ID# 139651	Covington	Louisiana	United States	70433
47	Ochsner Baptist Medical Center /ID# 139740	New Orleans	Louisiana	United States	70115
48	Omni Fertility and Laser Insti /ID# 139836	Shreveport	Louisiana	United States	71118
49	Capital Women's Care /ID# 144109	Frederick	Maryland	United States	21708
50	Genesis Clinical Research - Fall River /ID# 148449	Fall River	Massachusetts	United States	02723
51	Great Lakes Research Group,Inc /ID# 139659	Bay City	Michigan	United States	48706
52	Grand Rapids Womens Health /ID# 139705	Grand Rapids	Michigan	United States	49503
53	Wayne State University Physician Group - Southfield /ID# 139802	Southfield	Michigan	United States	48034
54	Office of Edmond E. Pack, MD /ID# 139792	Las Vegas	Nevada	United States	89113
55	Mabey, Las Vegas, NV /ID# 148138	Las Vegas	Nevada	United States	89128
56	Lawrence OB/GYN /ID# 143567	Lawrenceville	New Jersey	United States	08648
57	Bosque Women's Care /ID# 145934	Albuquerque	New Mexico	United States	87109
58	Manhattan Medical Research /ID# 144471	New York	New York	United States	10016-6023
59	Cwrwc /Id# 139664	Durham	North Carolina	United States	27713
60	Unified Women's Clinical Research-Greensboro /ID# 139829	Greensboro	North Carolina	United States	27408
61	Unified Women's Clinical Resea /ID# 139774	Raleigh	North Carolina	United States	27607
62	PMG Research of Wilmington LLC /ID# 152563	Wilmington	North Carolina	United States	28401
63	Unified Women's Clinical Resea /ID# 144721	Winston-Salem	North Carolina	United States	27103
64	University of Cincinnati /ID# 139820	Cincinnati	Ohio	United States	45267-0585
65	Univ Hosp Cleveland /ID# 139741	Cleveland	Ohio	United States	44106
66	Complete Healthcare for Women /ID# 139673	Columbus	Ohio	United States	43231
67	Miami Valley Hospital /ID# 144430	Dayton	Ohio	United States	45409
68	University of Toledo /ID# 139787	Toledo	Ohio	United States	43614
69	Legacy Medical Group-Portland /ID# 148807	Portland	Oregon	United States	97210
70	Main Line Fertility Center /ID# 150295	Bryn Mawr	Pennsylvania	United States	19010
71	Penn State University and Milton S. Hershey Medical Center /ID# 139733	Hershey	Pennsylvania	United States	17033
72	Thomas Jefferson University /ID# 139812	Philadelphia	Pennsylvania	United States	19107-4414
73	Temple University Hospital /ID# 151429	Philadelphia	Pennsylvania	United States	19140
74	Clinical Trials Research Svcs /ID# 139707	Pittsburgh	Pennsylvania	United States	15206
75	Medical University of South Carolina /ID# 148754	Charleston	South Carolina	United States	29425
76	Vista Clinical Research /ID# 139797	Columbia	South Carolina	United States	29201
77	WR-ClinSearch /ID# 143538	Chattanooga	Tennessee	United States	37421-1605
78	Research Memphis Associates, LLC /ID# 139674	Memphis	Tennessee	United States	38119-3895
79	Access Clinical Trials, Inc. /ID# 139730	Nashville	Tennessee	United States	37203
80	UT Southwestern Medical Center /ID# 143537	Dallas	Texas	United States	75390-7208
81	Advances in Health, Inc. /ID# 139672	Houston	Texas	United States	77030
82	Victorium Clinical Research /ID# 149630	San Antonio	Texas	United States	78230
83	Discovery Clinical Trials-San Antonio /ID# 139776	San Antonio	Texas	United States	78258
84	Houston Ctr for Clin Research /ID# 149149	Sugar Land	Texas	United States	77479
85	Center of Reproductive Medicin /ID# 139813	Webster	Texas	United States	77598
86	Eastern Virginia Med School /ID# 139647	Norfolk	Virginia	United States	23507-1627
87	Clinical Research Partners, LL /ID# 143999	North Chesterfield	Virginia	United States	23235-4722
88	Clinical Trials Virginia, Inc. /ID# 139801	Richmond	Virginia	United States	23225
89	Emerson Clinical Research /ID# 147373	Vienna	Virginia	United States	22182
90	Seattle Women's Health, Research, Gynecology /ID# 139768	Seattle	Washington	United States	98105
91	Premier Clinical Research /ID# 148145	Spokane	Washington	United States	99202
92	Froedtert and Medical College /ID# 143566	Milwaukee	Wisconsin	United States	53226-3522
93	IWK Health Center /ID# 149066	Halifax	Nova Scotia	Canada	B3K 6R8
94	The Ottawa Hospital /ID# 148695	Ottawa	Ontario	Canada	K1H 8L6
95	Rodriguez-Ginorio, San Juan /ID# 139847	San Juan		Puerto Rico	00917
96	School of Medicine University of Puerto Rico-Medical Sciences Campus /ID# 139848	San Juan		Puerto Rico	00935

Sponsors and Collaborators

• AbbVie

Investigators

• Study Director: AbbVie Inc., AbbVie

Study Documents (Full-Text)

• Study Protocol - Sep 25, 2017
• Statistical Analysis Plan - Feb 2, 2018

More Information

Publications

None provided.

• Responsible Party: AbbVie
• ClinicalTrials.gov Identifier: NCT02654054
• Other Study ID Numbers: M12-815
• First Posted: Jan 13, 2016
• Last Update Posted: Jun 29, 2020
• Last Verified: Jun 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by AbbVie: Elagolix; Elagolix Sodium; Heavy Uterine Bleeding; Heavy Menstrual Bleeding; Leiomyomata; Menorrhagia; ABT-620; Elagolix + E2/NETA; Elagolix + Norethindrone Acetate; HMB
• Additional relevant MeSH terms: Leiomyoma; Myofibroma; Menorrhagia; Hemorrhage; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Norethindrone; Norethindrone Acetate; Estradiol; Polyestradiol phosphate

Study Results

Participant Flow

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

Arm/Group Title	Placebo	Elagolix	Elagolix + E2/NETA
Arm/Group Description	Placebo for both elagolix BID and E2/NETA QD	Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
Period Title: Treatment Period
STARTED	102	104	207
Randomized and Treated	102	104	206
COMPLETED	83	81	164
NOT COMPLETED	19	23	43
Period Title: Treatment Period
STARTED	25	32	59
COMPLETED	17	24	29
NOT COMPLETED	8	8	30

Baseline Characteristics

Arm/Group Title	Placebo	Elagolix	Elagolix + E2/NETA	Total
Arm/Group Description	Placebo for both elagolix BID and E2/NETA QD	Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Total of all reporting groups
Overall Participants	102	104	206	412
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.6 (5.68)	42.6 (5.16)	42.6 (5.30)	42.3 (5.37)
Sex: Female, Male (Count of Participants)
Female	102 100%	104 100%	206 100%	412 100%
Male	0 0%	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	19 18.6%	4 3.8%	34 16.5%	57 13.8%
Not Hispanic or Latino	83 81.4%	100 96.2%	172 83.5%	355 86.2%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	2 1%	2 0.5%
Asian	1 1%	2 1.9%	3 1.5%	6 1.5%
Native Hawaiian or Other Pacific Islander	0 0%	1 1%	0 0%	1 0.2%
Black or African American	70 68.6%	69 66.3%	141 68.4%	280 68%
White	30 29.4%	27 26%	59 28.6%	116 28.2%
More than one race	1 1%	4 3.8%	1 0.5%	6 1.5%
Unknown or Not Reported	0 0%	1 1%	0 0%	1 0.2%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Meeting the Criteria for Responder
Description	Percentage of responders, defined as participants who met the following conditions: Menstrual blood loss (MBL) volume < 80 mL during the Final Month (the last 28 days prior to and including the Reference Day, which is defined as the last visit date during the Treatment Period [last treatment visit date] or the last dose date if there are evaluable alkaline hematin data after the last treatment visit date and prior to or on the last dose date), and ≥ 50% reduction in MBL volume from Baseline to the Final Month. Participants who prematurely discontinued study drug due to "lack of efficacy," "requires surgery or invasive intervention for treatment of uterine fibroids," or "adverse events" were considered non-responders regardless of whether she meets the two aforementioned responder criteria or not.
Time Frame	Final Month (the last 28 days prior to and including the Reference Day), up to Month 6

Outcome Measure Data

Analysis Population Description

All randomized and treated participants.

Arm/Group Title	Placebo	Elagolix	Elagolix + E2/NETA
Arm/Group Description	Placebo for both elagolix BID and E2/NETA QD	Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
Measure Participants	102	104	206
Number [percentage of participants]	8.7 8.5%	84.1 80.9%	68.5 33.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Elagolix
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	The P value for test of difference is by pooling the results from a logistic regression model including treatment as the main effect and baseline MBL volume as a covariate in each data set from multiple imputation.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	56.79
	Confidence Interval	(2-Sided) 95%; 23.002 to 140.227
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Elagolix + E2/NETA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	The P value for test of difference is by pooling the results from a logistic regression model including treatment as the main effect and baseline MBL volume as a covariate in each data set from multiple imputation.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	22.98
	Confidence Interval	(2-Sided) 95%; 10.466 to 50.451
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in MBL Volume to the Final Month
Description	Baseline MBL volume was defined as the mean of total MBL volume from all the qualified menstrual cycles during the Screening Period, in which the total MBL volume is from all validated and non-validated sanitary products and the MBL volume of validated sanitary products only (excluding non-validated sanitary products) was greater than 80 mL. The Reference Day is defined as the last visit date during the Treatment Period (last treatment visit date) or the last dose date if there are evaluable alkaline hematin data after the last treatment visit date and prior to or on the last dose date.
Time Frame	Month 0 (Baseline), Final Month (the last 28 days prior to and including the Reference Day), up to Month 6

Outcome Measure Data

Analysis Population Description

All randomized and treated participants.

Arm/Group Title	Placebo	Elagolix	Elagolix + E2/NETA
Arm/Group Description	Placebo for both elagolix BID and E2/NETA QD	Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
Measure Participants	102	104	206
Least Squares Mean (Standard Error) [mL]	0.8 (14.86)	-221.5 (14.49)	-176.7 (10.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Elagolix
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	The P value for test of difference between each elagolix treatment group and placebo is by pooling the results from an ANCOVA model with treatment as the main effect and baseline MBL volume as a covariate in each dataset from multiple imputation.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean of Difference
	Estimated Value	-222.3
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 20.77
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Elagolix + E2/NETA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	The P value for test of difference between each elagolix treatment group and placebo is by pooling the results from an ANCOVA model with treatment as the main effect and baseline MBL volume as a covariate in each dataset from multiple imputation.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean of Difference
	Estimated Value	-177.5
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.24
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants With Suppression of Bleeding at the Final Month
Description	Suppression of bleeding is defined as having 0 days of bleeding (spotting is allowed) during the Final Month with the interval starting from Study Day 11. The Reference Day is defined as the last visit date during the Treatment Period (last treatment visit date) or the last dose date if there are evaluable alkaline hematin data after the last treatment visit date and prior to or on the last dose date.
Time Frame	Final Month (the last 28 days prior to and including the Reference Day), up to Month 6

Outcome Measure Data

Analysis Population Description

All randomized and treated participants with an assessment

Arm/Group Title	Placebo	Elagolix	Elagolix + E2/NETA
Arm/Group Description	Placebo for both elagolix BID and E2/NETA QD	Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
Measure Participants	91	94	183
Number [percentage of participants]	4.4 4.3%	84.0 80.8%	56.8 27.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Elagolix
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	The P value is calculated based on chi-square test (or Fisher's exact test if ≥ 20% of the cells have expected cell count < 5).
	Method	Chi-square or Fisher's exact test
	Comments
Method of Estimation	Estimation Parameter	Between-Group Difference (%)
	Estimated Value	79.6
	Confidence Interval	(2-Sided) 95%; 71.13 to 88.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Elagolix + E2/NETA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	The P value is calculated based on chi-square test (or Fisher's exact test if ≥ 20% of the cells have expected cell count < 5).
	Method	Chi-square or Fisher's exact test
	Comments
Method of Estimation	Estimation Parameter	Between-Group Difference (%)
	Estimated Value	52.4
	Confidence Interval	(2-Sided) 95%; 44.11 to 60.76
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in MBL Volume to Month 6
Time Frame	Month 0 (Baseline), Month 6

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Elagolix	Elagolix + E2/NETA
Arm/Group Description	Placebo for both elagolix BID and E2/NETA QD	Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
Measure Participants	71	67	132
Least Squares Mean (Standard Error) [mL]	-2.3 (13.53)	-236.2 (13.74)	-194.7 (9.77)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Elagolix
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	The P value is from mixed models repeated measures (MMRM) with treatment, month, and an interaction between treatment and month as fixed effect factors, and baseline MBL volume as a covariate comparing each elagolix treatment group with placebo.
	Method	mixed model repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean of Difference
	Estimated Value	-234.0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 19.27
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Elagolix + E2/NETA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	The P value is from mixed models repeated measures (MMRM) with treatment, month, and an interaction between treatment and month as fixed effect factors, and baseline MBL volume as a covariate comparing each elagolix treatment group with placebo.
	Method	mixed model repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean of Difference
	Estimated Value	-192.5
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.70
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in MBL Volume to Month 3
Time Frame	Month 0 (Baseline), Month 3

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Elagolix	Elagolix + E2/NETA
Arm/Group Description	Placebo for both elagolix BID and E2/NETA QD	Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
Measure Participants	85	83	172
Least Squares Mean (Standard Error) [mL]	6.1 (15.32)	-234.7 (15.38)	-192.2 (10.81)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Elagolix
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	The P value is from MMRM with treatment, month, and an interaction between treatment and month as fixed effect factors, and baseline MBL volume as a covariate comparing each elagolix treatment group with placebo.
	Method	mixed model repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean of Difference
	Estimated Value	-240.8
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 21.69
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Elagolix + E2/NETA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	The P value is from MMRM with treatment, month, and an interaction between treatment and month as fixed effect factors, and baseline MBL volume as a covariate comparing each elagolix treatment group with placebo.
	Method	mixed model repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean of Difference
	Estimated Value	-198.2
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.76
	Estimation Comments

6. Secondary Outcome

Title	Percentage of Participants With Baseline Hemoglobin <= 10.5 g/dL Who Have an Increase in Hemoglobin > 2 g/dL at Month 6
Time Frame	Month 0 (Baseline), Month 6

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Elagolix	Elagolix + E2/NETA
Arm/Group Description	Placebo for both elagolix BID and E2/NETA QD	Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
Measure Participants	31	41	52
Number [percentage of participants]	16.1 15.8%	65.9 63.4%	61.5 29.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Elagolix
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	The P value is calculated based on chi-square test (or Fisher's exact test if ≥ 20% of the cells have expected cell count < 5).
	Method	chi-square or Fisher's exact test
	Comments
Method of Estimation	Estimation Parameter	Between-Group Difference (%)
	Estimated Value	49.7
	Confidence Interval	(2-Sided) 95%; 30.27 to 69.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Elagolix + E2/NETA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	The P value is calculated based on chi-square test (or Fisher's exact test if ≥ 20% of the cells have expected cell count < 5).
	Method	chi-square or Fisher's exact test
	Comments
Method of Estimation	Estimation Parameter	Between-Group Difference (%)
	Estimated Value	45.4
	Confidence Interval	(2-Sided) 95%; 26.90 to 63.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in MBL Volume to Month 1
Time Frame	Month 0 (Baseline), Month 1

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Elagolix	Elagolix + Estradiol/Norethindrone Acetate
Arm/Group Description	Placebo for both elagolix BID and E2/NETA QD	Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD	Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
Measure Participants	95	97	187
Least Squares Mean (Standard Error) [mL]	-19.0 (16.05)	-209.0 (15.91)	-135.2 (11.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Elagolix
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	The P value is from MMRM with treatment, month, and an interaction between treatment and month as fixed effect factors, and baseline MBL volume as a covariate comparing each elagolix treatment group with placebo.
	Method	mixed model repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean of Difference
	Estimated Value	-190.0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 22.59
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Elagolix + E2/NETA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	The P value is from MMRM with treatment, month, and an interaction between treatment and month as fixed effect factors, and baseline MBL volume as a covariate comparing each elagolix treatment group with placebo.
	Method	mixed model repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean of Difference
	Estimated Value	-116.2
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 19.70
	Estimation Comments

Adverse Events

Time Frame	From first dose of study drug through 6 months of treatment with a 30-day follow-up period for participants who did not enroll in the extension study (Study M12-816). Mean (SD) treatment exposure was 158.6 (50.10), 161.2 (51.45), and 159.9 (53.48) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively.
Adverse Event Reporting Description	Treatment-emergent adverse events are presented.
Arm/Group Title	Placebo		Elagolix		Elagolix + E2-NETA
Arm/Group Description	Placebo for both elagolix BID and E2/NETA QD		Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD		Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
All Cause Mortality
	Placebo		Elagolix		Elagolix + E2-NETA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/102 (0%)		0/104 (0%)		0/206 (0%)
Serious Adverse Events
	Placebo		Elagolix		Elagolix + E2-NETA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/102 (4.9%)		3/104 (2.9%)		3/206 (1.5%)
Blood and lymphatic system disorders
ANAEMIA	2/102 (2%)	2	0/104 (0%)	0	0/206 (0%)	0
General disorders
PROLAPSE	0/102 (0%)	0	1/104 (1%)	1	0/206 (0%)	0
Investigations
OXYGEN SATURATION DECREASED	1/102 (1%)	1	0/104 (0%)	0	0/206 (0%)	0
Musculoskeletal and connective tissue disorders
EXOSTOSIS	0/102 (0%)	0	0/104 (0%)	0	1/206 (0.5%)	1
INTERVERTEBRAL DISC PROTRUSION	0/102 (0%)	0	0/104 (0%)	0	1/206 (0.5%)	1
OSTEOARTHRITIS	1/102 (1%)	1	0/104 (0%)	0	0/206 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
UTERINE LEIOMYOMA	0/102 (0%)	0	2/104 (1.9%)	2	0/206 (0%)	0
Pregnancy, puerperium and perinatal conditions
ABORTION SPONTANEOUS	0/102 (0%)	0	1/104 (1%)	1	0/206 (0%)	0
ECTOPIC PREGNANCY	0/102 (0%)	0	1/104 (1%)	1	0/206 (0%)	0
Psychiatric disorders
SUICIDAL IDEATION	1/102 (1%)	1	0/104 (0%)	0	0/206 (0%)	0
Reproductive system and breast disorders
MENORRHAGIA	1/102 (1%)	1	1/104 (1%)	1	0/206 (0%)	0
Respiratory, thoracic and mediastinal disorders
DYSPNOEA EXERTIONAL	1/102 (1%)	1	0/104 (0%)	0	0/206 (0%)	0
Skin and subcutaneous tissue disorders
DERMATITIS	0/102 (0%)	0	0/104 (0%)	0	1/206 (0.5%)	1
PALMOPLANTAR KERATODERMA	0/102 (0%)	0	0/104 (0%)	0	1/206 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Placebo		Elagolix		Elagolix + E2-NETA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/102 (28.4%)		81/104 (77.9%)		96/206 (46.6%)
Gastrointestinal disorders
NAUSEA	10/102 (9.8%)	10	7/104 (6.7%)	7	23/206 (11.2%)	26
General disorders
FATIGUE	2/102 (2%)	2	1/104 (1%)	1	14/206 (6.8%)	14
Infections and infestations
NASOPHARYNGITIS	4/102 (3.9%)	5	6/104 (5.8%)	6	10/206 (4.9%)	12
Nervous system disorders
HEADACHE	9/102 (8.8%)	11	17/104 (16.3%)	20	17/206 (8.3%)	18
Psychiatric disorders
INSOMNIA	6/102 (5.9%)	6	7/104 (6.7%)	7	5/206 (2.4%)	5
MOOD SWINGS	2/102 (2%)	2	7/104 (6.7%)	7	8/206 (3.9%)	8
Reproductive system and breast disorders
DYSMENORRHOEA	4/102 (3.9%)	4	1/104 (1%)	1	13/206 (6.3%)	13
METRORRHAGIA	0/102 (0%)	0	1/104 (1%)	1	13/206 (6.3%)	13
Skin and subcutaneous tissue disorders
NIGHT SWEATS	3/102 (2.9%)	3	28/104 (26.9%)	31	14/206 (6.8%)	15
Vascular disorders
HOT FLUSH	9/102 (8.8%)	10	67/104 (64.4%)	72	42/206 (20.4%)	44

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

AbbVie requests that any investigator or institution that plans on presenting/publishing results disclosure, provide written notification of their request 60 days prior to their presentation/publication. AbbVie requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if AbbVie needs to secure patent or proprietary protection.