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

• Sponsor: AbbVie (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02691494
• Collaborator: (none)
• Enrollment: 378
• Locations: 105
• Arms: 3
• Actual Duration (Months): 35.6
• Patients Per Site: 3.6
• 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: 378 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: Feb 3, 2016
• Actual Primary Completion Date: Feb 14, 2018
• Actual Study Completion Date: Jan 23, 2019

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 [Baseline and 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]

   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.

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

   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.

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]

   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.

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	Alabama Clinical Therapeutics, LLC /ID# 152258	Birmingham	Alabama	United States	35235-3430
2	Choice Research, LLC /ID# 150988	Dothan	Alabama	United States	36303
3	Brown, Pearson, Guepet Gynecology /ID# 151020	Fairhope	Alabama	United States	36532
4	Mobile, Ob-Gyn, P.C. /ID# 144294	Mobile	Alabama	United States	36608
5	Mesa Obstetricians and Gynecol /ID# 149139	Mesa	Arizona	United States	85209
6	Visions Clinical Research-Tucs /ID# 151017	Tucson	Arizona	United States	85712
7	Core Healthcare Group /ID# 151016	Cerritos	California	United States	90703
8	Diagnamics Inc. /ID# 152469	Encinitas	California	United States	92024
9	HCP Clinical Research LLC /ID# 154434	Huntington Beach	California	United States	92646
10	Alliance Research Centers /ID# 149752	Laguna Hills	California	United States	92653-3621
11	University of California, Los Angeles /ID# 149760	Los Angeles	California	United States	90095
12	Futura Research, Inc. /ID# 149759	Norwalk	California	United States	90650
13	Farid Yasharpour MD Medical Co /ID# 149770	San Fernando	California	United States	91340
14	Clinical Trial Investigators /ID# 152470	Tustin	California	United States	92780
15	Bayview Research Group LLC /ID# 153799	Valley Village	California	United States	91607
16	Emerson Clinical Research Inst /ID# 152348	Washington	District of Columbia	United States	20011
17	Ideal Clinical Research Inc. /ID# 149757	Aventura	Florida	United States	33180
18	Seffner Premier Health Care, P /ID# 167480	Brandon	Florida	United States	33510
19	Olympian Clinical Research /ID# 149756	Clearwater	Florida	United States	33756
20	KO Clinical Research, LLC /ID# 144299	Fort Lauderdale	Florida	United States	33316
21	University of Florida /ID# 149751	Gainesville	Florida	United States	32610
22	Solutions Through Adv Rch /ID# 151021	Jacksonville	Florida	United States	32256
23	Meridien Research /ID# 167100	Kenneth City	Florida	United States	33709-3113
24	Precision Research Org, LLC /ID# 144335	Miami Lakes	Florida	United States	33016-1501
25	Invictus Clinical Research Group,LLC /ID# 141859	Miami	Florida	United States	33144
26	Suncoast Clinical Research /ID# 149765	New Port Richey	Florida	United States	34652
27	All Wmns HC of West Broward /ID# 144298	Plantation	Florida	United States	33324
28	Oncova Clinical Research, Inc. /ID# 149764	Saint Cloud	Florida	United States	34769
29	Physician Care Clin. Res., LLC /ID# 149766	Sarasota	Florida	United States	34239
30	Qps-Mra, Llc /Id# 144325	South Miami	Florida	United States	33143
31	Martin Health System Center /ID# 152263	Stuart	Florida	United States	34994
32	University of South Florida /ID# 149754	Tampa	Florida	United States	33612
33	Axcess Medical Research /ID# 149769	Wellington	Florida	United States	33414
34	Virtus Research Consultant,LLC /ID# 144296	Wellington	Florida	United States	33414
35	Paramount Research Solutions /ID# 149291	Alpharetta	Georgia	United States	30005
36	Agile Clinical Research Trials /ID# 167074	Atlanta	Georgia	United States	30328
37	Mount Vernon Clinical Res, LLC /ID# 144297	Atlanta	Georgia	United States	30328
38	Atlanta Women's Research Inst /ID# 144303	Atlanta	Georgia	United States	30342
39	Masters of Clinical Research, Inc. /ID# 167400	Augusta	Georgia	United States	30909
40	Georgia Regents University /ID# 144295	Augusta	Georgia	United States	30912
41	Meridian Clinical Research, LLC /ID# 149144	Savannah	Georgia	United States	31406-2675
42	Gyn-Care, Inc. /ID# 149341	Smyrna	Georgia	United States	30080
43	Atlanta Gynecology Research Institute /ID# 151014	Suwanee	Georgia	United States	30024-7159
44	Womens Healthcare Assoc, DBA /ID# 149762	Idaho Falls	Idaho	United States	83404
45	Advanced Clinical Research /ID# 149767	Meridian	Idaho	United States	83642
46	University of Chicago /ID# 152257	Chicago	Illinois	United States	60637-1443
47	Affinity Clinical Research /ID# 167119	Oak Brook	Illinois	United States	60523
48	Center for Women's Research, Inc /ID# 144300	Palos Heights	Illinois	United States	60463-1440
49	Women's Health Advantage /ID# 144301	Fort Wayne	Indiana	United States	46825
50	The Iowa Clinic /ID# 150105	West Des Moines	Iowa	United States	50266
51	PRN Professional Research Network of Kansas, LLC /ID# 152265	Wichita	Kansas	United States	67205
52	Bluegrass Clinical Research /ID# 150103	Louisville	Kentucky	United States	40291
53	Clinical Trials Management, LLC - Covington /ID# 144314	Covington	Louisiana	United States	70433
54	Women Under Study, LLC /ID# 144312	New Orleans	Louisiana	United States	70125-1923
55	Baltimore Suburban Health /ID# 154638	Baltimore	Maryland	United States	21208
56	Womens Health Center /ID# 154209	Glen Burnie	Maryland	United States	21063
57	Maryland Ctr for Sexual Health /ID# 149778	Lutherville	Maryland	United States	21093
58	NECCR Fall River LLC /ID# 149584	Fall River	Massachusetts	United States	02720-2972
59	Saginaw Valley Med Res Group /ID# 149768	Saginaw	Michigan	United States	48604
60	Accent Clinical Trials /ID# 149753	Las Vegas	Nevada	United States	89106-4017
61	Jersey Shore University Medical Center /ID# 149779	Neptune	New Jersey	United States	07753-4859
62	Rowan University SOM /ID# 152697	Stratford	New Jersey	United States	08084
63	Montefiore Medical Center /ID# 149582	Bronx	New York	United States	10461
64	SUNY Downstate Medical Center /ID# 144311	Brooklyn	New York	United States	11203
65	Manhattan Medical Research /ID# 167077	New York	New York	United States	10016-6023
66	Weill Cornell Medicine /ID# 149585	New York	New York	United States	10032-3725
67	Duplicate_Unified Women's Clinical Research-Fayetteville /ID# 149587	Fayetteville	North Carolina	United States	28304
68	Unified Women's Clinical Research-Greensboro /ID# 149588	Greensboro	North Carolina	United States	27408
69	Pinewest Ob-Gyn, Inc. /ID# 145671	High Point	North Carolina	United States	27262
70	Eastern Carolina Women's Centr /ID# 144309	New Bern	North Carolina	United States	28562
71	Wake Research Associates, LLC /ID# 144307	Raleigh	North Carolina	United States	27612
72	Clinical Inquest Center Ltd /ID# 148728	Beavercreek	Ohio	United States	45432
73	CTI Clinical Research Center /ID# 149761	Cincinnati	Ohio	United States	45212
74	The Christ Hospital /ID# 150104	Cincinnati	Ohio	United States	45219
75	Alpha Research Associates LLC /ID# 152471	Dayton	Ohio	United States	45417
76	Comprehensive Womens Care /ID# 144306	Westerville	Ohio	United States	43081
77	Family Medical Associates /ID# 145668	Levittown	Pennsylvania	United States	19056
78	University of Pennsylvania /ID# 149586	Philadelphia	Pennsylvania	United States	19104-5502
79	Clinical Research of Philadelphia, LLC /ID# 151015	Philadelphia	Pennsylvania	United States	19114
80	Reading Hosp Clncl Trials Ofc /ID# 149583	West Reading	Pennsylvania	United States	19611
81	Holston Medical Group /ID# 149763	Bristol	Tennessee	United States	37620-7346
82	Chattanooga Medical Research /ID# 145667	Chattanooga	Tennessee	United States	37404
83	Chattanooga Women for Women /ID# 167051	Hixson	Tennessee	United States	37343-3992
84	The Jackson Clinic, PA /ID# 145670	Jackson	Tennessee	United States	38305
85	The Womens Physician Group /ID# 144317	Memphis	Tennessee	United States	38104
86	Access Clinical Trials, Inc. /ID# 167333	Nashville	Tennessee	United States	37203
87	Lotus Gynecology /ID# 149140	Austin	Texas	United States	78703-1448
88	Inquest Clinical Research /ID# 149755	Baytown	Texas	United States	77521-2415
89	Texas Health Presbyterian Hosp /ID# 149142	Dallas	Texas	United States	75231
90	Baylor College of Medicine /ID# 149141	Houston	Texas	United States	77030-3411
91	The Woman's Hospital of Texas /ID# 144319	Houston	Texas	United States	77054
92	Centex Studies, Inc. - Houston /ID# 150106	Houston	Texas	United States	77058
93	BI Research Center /ID# 149143	Houston	Texas	United States	77084
94	FMC Science /ID# 151802	Lampasas	Texas	United States	76550
95	Willowbend Health and Wellness /ID# 144318	Plano	Texas	United States	75035
96	Clinical Trials of Texas,Inc. /ID# 144322	San Antonio	Texas	United States	78229
97	Center of Reproductive Medicin /ID# 167235	Webster	Texas	United States	77598
98	Southampton Women's Health /ID# 152325	Franklin	Virginia	United States	23851
99	Tidewater Physicians for Women /ID# 144321	Norfolk	Virginia	United States	23502
100	Clinical Research Partners, LLC /ID# 144310	Richmond	Virginia	United States	23220-4459
101	Alliance Womens Health /ID# 152468	Richmond	Virginia	United States	23226-1930
102	Zain Research /ID# 151018	Richland	Washington	United States	99352
103	Virginia Mason Medical Center /ID# 149758	Seattle	Washington	United States	98101
104	Medicor Research Inc. /ID# 153406	Sudbury	Ontario	Canada	P3A 1W8
105	Victory Reproductive Care /ID# 150247	Windsor	Ontario	Canada	N8W 5R7

Sponsors and Collaborators

• AbbVie

Investigators

• Study Director: AbbVie Inc., AbbVie

Study Documents (Full-Text)

• Study Protocol - Oct 6, 2017
• Statistical Analysis Plan - Feb 2, 2018

More Information

Publications

None provided.

• Responsible Party: AbbVie
• ClinicalTrials.gov Identifier: NCT02691494
• Other Study ID Numbers: M12-817
• First Posted: Feb 25, 2016
• Last Update Posted: Jul 13, 2021
• Last Verified: Jul 1, 2021

• 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 (HMB); Leiomyomata; Menorrhagia; ABT-620; Elagolix + E2/NETA (Elagolix + Norethindrone acetate)
• 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	94	95	189
COMPLETED	72	69	148
NOT COMPLETED	22	26	41
Period Title: Treatment Period
STARTED	14	25	59
COMPLETED	9	18	42
NOT COMPLETED	5	7	17

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	94	95	189	378
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.5 (5.43)	42.2 (5.41)	42.5 (5.33)	42.4 (5.36)
Sex: Female, Male (Count of Participants)
Female	94 100%	95 100%	189 100%	378 100%
Male	0 0%	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	11 11.7%	17 17.9%	31 16.4%	59 15.6%
Not Hispanic or Latino	83 88.3%	78 82.1%	158 83.6%	319 84.4%
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%	0 0%	0 0%
Asian	1 1.1%	2 2.1%	0 0%	3 0.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	2 1.1%	2 0.5%
Black or African American	63 67%	66 69.5%	124 65.6%	253 66.9%
White	30 31.9%	27 28.4%	59 31.2%	116 30.7%
More than one race	0 0%	0 0%	3 1.6%	3 0.8%
Unknown or Not Reported	0 0%	0 0%	1 0.5%	1 0.3%

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	94	95	189
Number [percentage of participants]	10.5 11.2%	76.9 80.9%	76.5 40.5%

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	28.73
	Confidence Interval	(2-Sided) 95%; 12.248 to 67.387
	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	28.31
	Confidence Interval	(2-Sided) 95%; 13.042 to 61.431
	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	Baseline and 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	94	95	189
Least Squares Mean (Standard Error) [mL]	-4.3 (15.44)	-198.8 (15.44)	-168.8 (10.72)

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	-194.5
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 21.70
	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	-164.6
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.87
	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	85	81	172
Number [percentage of participants]	4.7 5%	88.9 93.6%	61.0 32.3%

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 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	84.2
	Confidence Interval	(2-Sided) 95%; 75.99 to 92.37
	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	56.3
	Confidence Interval	(2-Sided) 95%; 47.77 to 64.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in MBL Volume to Month 6
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.
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	64	53	124
Least Squares Mean (Standard Error) [mL]	28.5 (16.68)	-223.7 (17.98)	-198.1 (11.89)

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	-252.3
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 24.53
	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	-226.6
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 20.50
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in MBL Volume to Month 3
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.
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	78	72	157
Least Squares Mean (Standard Error) [mL]	-14.2 (11.57)	-211.1 (11.96)	-200.3 (8.17)

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	-196.9
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.66
	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	-186.1
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.18
	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	24	25	48
Number [percentage of participants]	20.8 22.1%	40.0 42.1%	50.0 26.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Elagolix
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.146
	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	19.2
	Confidence Interval	(2-Sided) 95%; -5.99 to 44.32
	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	0.017
	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	29.2
	Confidence Interval	(2-Sided) 95%; 7.62 to 50.71
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in MBL Volume to Month 1
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.
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 + 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	88	83	175
Least Squares Mean (Standard Error) [mL]	-2.1 (14.31)	-196.6 (14.74)	-127.0 (10.14)

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	-194.5
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 20.56
	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	-125.0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.55
	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 160.3 (51.75), 155.2 (65.19), and 158.7 (54.68) days for the Placebo, Elagolix, and Elagolix and E2-NETA arms, respectively
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	0/94 (0%)		0/95 (0%)		0/189 (0%)
Serious Adverse Events
	Placebo		Elagolix		Elagolix + E2-NETA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/94 (1.1%)		4/95 (4.2%)		7/189 (3.7%)
Blood and lymphatic system disorders
ANAEMIA	0/94 (0%)	0	0/95 (0%)	0	1/189 (0.5%)	1
Endocrine disorders
HYPERTHYROIDISM	0/94 (0%)	0	0/95 (0%)	0	1/189 (0.5%)	1
Gastrointestinal disorders
SMALL INTESTINAL OBSTRUCTION	0/94 (0%)	0	1/95 (1.1%)	1	0/189 (0%)	0
Hepatobiliary disorders
CHOLELITHIASIS	0/94 (0%)	0	1/95 (1.1%)	1	1/189 (0.5%)	1
Infections and infestations
APPENDICITIS	0/94 (0%)	0	1/95 (1.1%)	1	0/189 (0%)	0
CELLULITIS	0/94 (0%)	0	0/95 (0%)	0	1/189 (0.5%)	1
Metabolism and nutrition disorders
OBESITY	0/94 (0%)	0	0/95 (0%)	0	1/189 (0.5%)	1
Pregnancy, puerperium and perinatal conditions
ABORTION COMPLETE	1/94 (1.1%)	1	0/95 (0%)	0	0/189 (0%)	0
Psychiatric disorders
ANXIETY	0/94 (0%)	0	0/95 (0%)	0	1/189 (0.5%)	1
Reproductive system and breast disorders
DYSFUNCTIONAL UTERINE BLEEDING	0/94 (0%)	0	0/95 (0%)	0	1/189 (0.5%)	1
DYSMENORRHOEA	0/94 (0%)	0	0/95 (0%)	0	1/189 (0.5%)	1
MENORRHAGIA	0/94 (0%)	0	0/95 (0%)	0	1/189 (0.5%)	1
PELVIC PAIN	0/94 (0%)	0	1/95 (1.1%)	1	0/189 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Elagolix		Elagolix + E2-NETA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/94 (36.2%)		58/95 (61.1%)		80/189 (42.3%)
Gastrointestinal disorders
NAUSEA	9/94 (9.6%)	11	4/95 (4.2%)	4	14/189 (7.4%)	15
General disorders
FATIGUE	5/94 (5.3%)	5	3/95 (3.2%)	3	10/189 (5.3%)	10
Infections and infestations
NASOPHARYNGITIS	8/94 (8.5%)	9	4/95 (4.2%)	4	10/189 (5.3%)	11
URINARY TRACT INFECTION	5/94 (5.3%)	6	2/95 (2.1%)	2	12/189 (6.3%)	12
Musculoskeletal and connective tissue disorders
ARTHRALGIA	2/94 (2.1%)	2	5/95 (5.3%)	5	9/189 (4.8%)	10
Nervous system disorders
HEADACHE	5/94 (5.3%)	6	13/95 (13.7%)	14	20/189 (10.6%)	21
Psychiatric disorders
LIBIDO DECREASED	2/94 (2.1%)	2	3/95 (3.2%)	3	10/189 (5.3%)	10
MOOD SWINGS	2/94 (2.1%)	2	6/95 (6.3%)	6	6/189 (3.2%)	8
Reproductive system and breast disorders
DYSMENORRHOEA	6/94 (6.4%)	6	0/95 (0%)	0	6/189 (3.2%)	6
Skin and subcutaneous tissue disorders
NIGHT SWEATS	5/94 (5.3%)	6	24/95 (25.3%)	24	20/189 (10.6%)	21
Vascular disorders
HOT FLUSH	4/94 (4.3%)	4	41/95 (43.2%)	41	37/189 (19.6%)	37

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.