Clinical trial NCT02925494
Conditions: Uterine Fibroids Heavy Menstrual Bleeding
Keywords: Uterine Fibroids Elagolix Heavy Menstrual Bleeding Elagolix Sodium Elagolix plus Norethindrone Acetate
Sponsor: AbbVie
Start date: 2016-09-14; Completion date: 2019-03-22
Enrollment: 433 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an extension study for women who have already received six months of treatment in the phase III clinical trial M12-815 (NCT02654054) or M12-817 (NCT02691494), and will evaluate the long-term efficacy and safety of elagolix administered alone and in combination with estradiol/norethindrone acetate for an additional six months in the treatment of heavy menstrual bleeding associated with uterine fibroids.

Detailed description:

Arms: arm 1: Elagolix 300 mg twice daily (BID) and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) once daily (QD) arm 2: Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD
Interventions: intervention 1: Estradiol/Norethindrone Acetate intervention 2: Elagolix
Intervention descriptions: intervention 1: capsules intervention 2: film-coated tablets

Protocol documents:
Prot_000.pdf: 
NCT02925494


Elagolix (ABT-620)
M12-816 Protocol Amendment 1
2
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
29 July 2016
Administrative Change 1
08 August 2016
Administrative Change 2
25 August 2016
The purpose of this Amendment is to: 
●
Update Table 1, Visit and Assessment Windows to remove MRI from Post-
Treatment Follow Up Period Month 6
Rationale:  MRI is not required at Post-Treatment Month 6
●
Update Section 5.1 Overall Study Design and Plan, Visit Windows to clarify 
Treatment Period Visit schedule.
Rationale:  Clarify the scheduling of visits in the Treatment Period is based on 
the date of the Day 1 Visit.
●
Update Section 5.3.1.1 Study Procedures, Mammogram to clarify when a 
mammogram is performed at the Premature Discontinuation Visit.
Rationale:  A mammogram is only required at the Premature Discontinuation 
Visit if it has been approximately 12 months since the Screening mammogram 
was performed. 
●
Update Section 5.3.3.2 Secondary Efficacy Variable to remove fibroid and 
uterine volume.
Rationale:  This is included in other efficacy variables.
●
Update Section 5.4 Removal of Subjects from Therapy or Assessment to 
clarify when in the Study, surgical interventions and elevated liver enzymes 
constitute study withdrawal.
Rationale:  Clarify which subjects require withdrawal during treatment and 
post-treatment follow up period.


Elagolix (ABT-620)
M12-816 Protocol Amendment 1
3
●
Update Appendix C Study Activities – Treatment Period and Post-Treatment 
Follow-Up Period footnote for mammogram at the Treatment Period 
Premature Discontinuation Visit
Rationale:  To clarify when a mammogram is performed at the Treatment 
Period Premature Discontinuation Visit. 
●
Update Section 5.3.1.1 Study Procedures, Endometrial Biopsy to remove the 
sixth paragraph
Rationale:  Sixth paragraph is a repeat of the text in the second paragraph 
and is not required
●
Update Section 5.4.1 Discontinuation of Individual Subjects to clarify Post-
Treatment Follow-Up Period Visit schedule for subjects who prematurely 
discontinue
Rationale:  Clarify the scheduling of visits in the Post-Treatment Follow-Up 
Period is based on the date of the last dose of study drug for subjects who 
prematurely discontinue from study drug treatment.
●
Update Section 5.5.5 Blinding of Investigational Product to add time period 
AbbVie will remain blinded.
Rationale:  To clarify the time period AbbVie will remain blinded.
●
Update Section 8.1.2 Data Sets Analyzed to change modified intent to treat 
(mITT) analysis to full analysis and remove requirement for at least one post 
baseline visit.
Rationale: To use consistent analysis set across efficacy analysis.
●
Update Section 8.1.7.1.1 Primary Analysis to change modified intent to treat 
(mITT) analysis to full analysis and remove requirement for at least one post 
baseline visit.
Rationale: To use consistent analysis set across efficacy analysis.
●
Update Section 8.1.7.1.2 Derivation of Primary Efficacy Endpoint to add 
evaluable to AH data reported.
Rationale:  To clarify AH data used for primary endpoint.
●
Update Section 8.1.7.1.3 Multiple Imputation to remove last sentence and add 
method to summarize responders.
Rationale:  To clarify how percentage of responders will be summarized.


Elagolix (ABT-620)
M12-816 Protocol Amendment 1
4
●
Update Section 8.1.7.1.4 Sensitivity Analysis of the Primary Efficacy Variable 
to clarify the analysis data set used.
Rationale:  To be remain consistent with the type of analysis.
●
Update to add Section 8.1.7.3 Other Efficacy Variables.
Rationale:  To differentiate these variables from secondary variables.
●
Update Section 8.1.7.3.1 Reduction in Bleeding to remove the last sentence.
Rationale:  To remain consistent with other efficacy variables.
●
Update Section 8.1.8.4 Bone Mineral Density percentage of subjects 
summarized.
Rationale:  To clarify the percent change in BMD to be summarized for each 
treatment group.
●
Update Section 8.2, Determination of Sample Size to remove the first sentence
Rationale:  This information is already specified in Section 5.2, Selection of 
Study Population.
An itemized list of all changes made to this protocol amendment can be found in 
Appendix M.


Elagolix (ABT-620)
M12-816 Protocol Amendment 1
5
1.2
Synopsis
AbbVie Inc.
Protocol Number:  M12-816
Name of Study Drug:  Elagolix (ABT-620)
Phase of Development:  3
Name of Active Ingredient:  Elagolix sodium
Date of Protocol Synopsis:  18 December 2017
Protocol Title:  Extension Study to Evaluate the Efficacy and Safety of Elagolix in Premenopausal 
Women with Heavy Menstrual Bleeding Associated with Uterine Fibroids
Objective:
The objectives of this study are to evaluate the long-term efficacy and safety of elagolix administered 
alone and in combination with add-back therapy (estradiol/norethindrone acetate or E2/NETA) to reduce 
heavy menstrual bleeding (HMB) associated with uterine fibroids for up to 12 months (initial 6 months if 
on active treatment in the Pivotal Study M12-815 or Study M12-817 and an additional 6 months in this 
Extension Study).
The study will also evaluate the effects of the treatment regimens on hypoestrogenic side effects, 
changes in bone mineral density (BMD) as assessed by Dual Energy X-Ray Absorptiometry (DXA), and 
vasomotor symptoms, such as hot flush.
Investigators:  Multicenter trial.  Investigator information is on file at AbbVie.
Study Sites:  Approximately 250 sites
Study Population:  Subjects who completed the 6-month Treatment Period of their respective Pivotal 
Study, have signed informed consent and meet eligibility criteria will be eligible for participation into 
this Extension Study.
Number of Subjects to be Enrolled:  Approximately 400
Methodology:
This Extension Study is designed to:
!
Obtain 6 months of treatment data in subjects who were randomized to placebo in one of the 
two Pivotal Studies and subsequently randomized to receive 6 months of treatment with 
elagolix 300 mg BID or elagolix 300 mg BID plus E2/NETA (estradiol 1 mg/norethindrone 
acetate 0.5 mg) QD.
!
Obtain 12 months of continuous treatment data in subjects who received elagolix 300 mg BID 
or elagolix 300 mg BID plus E2/NETA (estradiol 1 mg/norethindrone acetate 0.5 mg) QD for
6 months in one of the two Pivotal Studies and will continue to receive an additional 6 months 
of the same treatment in this study.
!
Obtain data on endometrial health (TAU, TVU and endometrial biopsy).
!
Assess bone mineral density, bone health and general safety with long-term treatment and 
recovery during Treatment and Post-Treatment Follow-Up Period (up to 12-Months of 
Treatment and 12-Months of Post-Treatment Follow-Up).


Elagolix (ABT-620)
M12-816 Protocol Amendment 1
6
Methodology (Continued):
Following completion of the 6-Month Treatment Period, all subjects will then enter into a 12-Month 
(48 weeks) Post-Treatment Follow-Up Period.  Approximately 400 subjects will be enrolled in this 
Extension Study.  Among them, those subjects who received elagolix 300 mg BID or elagolix 300 mg 
BID plus E2/NETA QD in the Pivotal Studies will continue to receive the same treatment while subjects 
who received placebo in the Pivotal Studies will be randomized in a 1:1 ratio to one of the following 
two treatment groups:
!
elagolix 300 mg BID 
!
elagolix 300 mg BID plus E2/NETA (estradiol 1 mg/norethindrone acetate 0.5 mg) QD
Study Duration:
The total duration for this Extension Study is approximately 18 months.
The study consists of 2 periods:
1.) 6-Month Treatment Period; and
2.) 12-Month Post-Treatment Follow-Up Period.
Treatment Period:
!
After providing informed consent and meeting eligibility criteria, subjects will enter a 6-Month 
(24 weeks) Treatment Period.
!
Subjects who received placebo during the Pivotal Studies will be randomized in an equal ratio 
to receive either elagolix 300 mg BID or elagolix 300 mg BID plus E2/NETA QD during the 
Treatment Period.
!
Subjects who received elagolix 300 mg BID or elagolix 300 mg BID plus E2/NETA QD during 
their respective Pivotal Studies will remain on the same treatment during the Treatment Period 
of this Extension Study.
During the Treatment Period, subjects will be required to return to the study site monthly.  Study visits 
will occur at Day 1, and then monthly (28-day intervals) at Month 1 through Month 6.  Additional study 
visits may occur either for subjects returning their sanitary products at a Product Collection Visit or for a 
Premature Discontinuation Visit.
At each monthly visit during the Treatment Period, except Treatment Month 6, a 1-Month supply of 
study drug will be dispensed, urine and/or serum pregnancy testing will be performed, and contraception 
counseling will occur.  All subjects will self-administer study drug, elagolix 300 mg twice daily (once in 
the morning and once in the evening approximately 12 hours apart) and E2/NETA or matching Placebo 
once daily (in the morning) orally throughout the 6-Month Treatment Period.


Elagolix (ABT-620)
M12-816 Protocol Amendment 1
7
Treatment Period (Continued):
Treatment Period Assessments:
Sanitary product collection kits will continue to be dispensed at all Treatment Period Visits in this 
Extension Study.  Subjects will be required to collect all sanitary products on days with menstrual 
bleeding or spotting and return them to the Clinical Study Site, either during a scheduled Monthly Visit 
or at a Product Collection Visit. Subjects must be instructed to collect and return all used or worn 
products even if there is no visible blood on the products.  If a subject does not return a sanitary 
product collection keg at any site visit (scheduled Monthly Visit, Product Collection Visit, Unscheduled 
Visit, or Premature Discontinuation Visit), the Site Staff will administer the Uterine Bleeding 
Questionnaire (UBQ) to record if subject had any bleeding or spotting since the last Study Visit.  If the 
subject had bleeding or spotting since the last Study Visit, the Site Staff will record the subjects response 
indicating why she did not collect products or return a sanitary product collection keg.
A pelvic ultrasound will be performed in all subjects at Month 3, Month 6 or Premature Discontinuation 
Visit, if applicable, to assess volume of the largest fibroid, uterine volume, endometrial thickness and 
potential presence of ovarian and uterine pathology.  During the Treatment Period, Magnetic Resonance 
Imaging (MRIs) in a subset of subjects will be conducted at Month 6 or Premature Discontinuation Visit, 
if applicable, to assess fibroid and uterine volume.  An endometrial biopsy will be performed in all 
subjects at the Month 6 or at the Premature Discontinuation Visit (if the subject prematurely 
discontinues after the Month 3 Visit).
Subjects who enter the Extension Study with BMD decrease < 5% in both spine and total hip will require 
a DXA scan at Month 6.  Subjects who enter the Extension Study with BMD decrease ≥ 5% in spine or 
total hip require a DXA scan at Month 3 of this Extension Study.  If the Month 3 DXA scan shows BMD 
decrease < 8% in spine, total hip, and femoral neck, the subject can continue in the Extension Study with 
a DXA scan to be performed at Month 6.  If, however, the Month 3 DXA scan shows BMD decrease 
≥8% in spine, total hip, or femoral neck, the subject must discontinue treatment and enter the Post-
Treatment Follow-Up Period.
Sites will continue to collect concomitant medications and assess for adverse events at every visit.
Subjects will be asked to complete several patient-reported outcome questionnaires, such as the EQ-5D-
5L, Uterine Fibroid Symptom Questionnaire (UFS-QoL), Work Productivity and Activity Impairment 
(WPAI) questionnaire, Health Care Resource Utilization questionnaire (HCRU), C-SSRS – Since Last 
Visit questionnaire and Patient Global Impression of Change (PGIC), based on bleeding and non-
bleeding uterine fibroid symptoms.  Site Staff will administer the Uterine Bleeding Questionnaire 
(UBQ), as applicable and the HCRU. 
Pregnancy (urine and/or serum) tests will be performed at each visit throughout the study.  Subjects will 
continue to be required to participate in contraceptive counseling, and at each visit will be reminded of 
the importance of using appropriate and effective forms of dual non-hormonal contraceptives to promote 
pregnancy prevention.
During the Treatment Period, blood samples will be collected to assay for serum estradiol and 
progesterone, and to measure plasma concentrations of elagolix and NETA, as well as blood samples for 
clinical safety labs, (including lipid panel) will be collected during the study.


Elagolix (ABT-620)
M12-816 Protocol Amendment 1
8
Post-Treatment Follow-Up Period:
For subjects entering the 12-Month Post-Treatment Follow-Up Period, visits will be conducted either by 
phone or on-site from Month 1 through Month 12.
During the Phone Visits, Site Personnel will discuss adverse events, concomitant medications, if 
applicable, obtain the results of the subject's self-administered urine pregnancy test and will remind 
subjects of the importance of consistent use of appropriate and effective dual non-hormonal 
contraception through the Post-Treatment Follow-Up Period.  Subjects may begin taking hormonal 
contraception or Tranexamic Acid (Lysteda, Cyklokapron, Cyclo-f) after completing the Post-Treatment 
Follow-Up Month 2 Visit and return to first full menses in the Post-Treatment Follow-Up Period.
Subjects will be required to collect sanitary products through their first menses with full menstrual flow 
in the Post-Treatment Follow-Up Period.  Subjects will return the sanitary products at a Product 
Collection Visit within approximately 5 days after cessation of bleeding or spotting.
During the On-Site Visits, procedures such as TAU, TVU, MRI (if applicable), DXA, clinical safety labs 
and pregnancy testing will be performed.  At the Post-Treatment Follow-Up Period Month 12 Visit, 
procedures including vital signs, lipid panel, Apolipoprotein A and B and DXA will be performed.
Adverse event and concomitant medication review will be conducted at all visits during the Post-
Treatment Follow-Up Period, including the Phone Visits.
Central Laboratory and Central Imaging Vendors:
DXA, Ultrasound, MRI (if applicable), safety clinical lab samples including Apo A, and Apo B, 
endocrine panels, and alkaline hematin will be analyzed/evaluated using central laboratories or vendors.  
Assays for PK and PD will be analyzed at AbbVie.
Analysis of Menstrual Blood Loss:
This study will utilize the alkaline hematin (AH) method for measuring MBL volume. Alkaline hematin 
is an objective and reliable measurement of total MBL based on the quantitation of menstrual blood 
collected on sanitary products.
Key Criteria for Inclusion/Exclusion:
Key Inclusion Criteria:
1.
Subject has voluntarily signed and dated the informed consent form (ICF), approved by an 
Institutional Review Board/Ethics Committee (IRB/EC), prior to initiation of any study-specific 
procedures.
2.
Subject has completed the 6-Month Treatment Period of their respective Pivotal Study (either 
Study M12-815 or Study M12-817).
3.
Subject has BMD decrease < 8% in the spine, total hip and femoral neck at Month 6 of the 
Treatment Period of their respective Pivotal Study.
4.
Subject's urine and/or serum pregnancy test(s) results were consistently negative during the 
Treatment Period of their respective Pivotal Study and at Day 1 of this Extension Study.


Elagolix (ABT-620)
M12-816 Protocol Amendment 1
9
Key Criteria for Inclusion/Exclusion (Continued):
Key Inclusion Criteria (Continued):
5.
Subject must agree to use two forms of non-hormonal contraception (dual contraception) 
consistently during the Treatment Period and Post-Treatment Follow-Up Periods.  (Subject may 
start hormonal contraception after completion of the Post-Treatment Follow-Up Month 2 Visit and 
return to first full menses).  Acceptable methods of dual contraception include the following 
combinations:
!
Condom with spermicide (foam, gel or polymer film)
!
Diaphragm with spermicide (condom may or may not be used)
!
Cervical cap with spermicide (condom may or may not be used)
Subject is not required to use dual contraception methods if:
!
Sexual partner(s) is vasectomized, at least 6 months prior to Screening.
!
Subject practices total abstinence from sexual intercourse, as the preferred lifestyle of the 
subject; periodic abstinence is not acceptable.
!
Subject had a bilateral tubal occlusion (including ligation and blockage methods such as 
Essure®), at least 4 months prior to Screening.  
!
Subject is not sexually active with men; periodic sexual relationship(s) with men requires the 
use of dual non hormonal contraception as noted above.
6.
Subject's endometrial biopsy from the Month 6 Visit of their respective Pivotal Study shows no 
clinically significant endometrial pathology.
Rationale For Inclusion Criteria:
1
This is standard criterion in accordance with harmonized Good Clinical Practice (GCP)
2, 3
These criteria were selected to ensure an appropriate subject population of premenopausal 
women with HMB associated with uterine fibroids (prognostic and predictive)
4, 5
The impact of elagolix on pregnancies or breastfed infants is unknown and there is a possible 
risk of miscarriage due to changes in hormone levels; therefore, these criteria ensure pregnant 
women are not enrolled into the study and adequate precautions are taken to avoid pregnancy 
during study participation (prognostic and risk)
6
This is standard criteria to ensure general good health and the safety of the subjects (risk)
Key Criteria for Inclusion/Exclusion:
Key Exclusion Criteria:
1.
Subject met criteria for removal from therapy in her respective Pivotal Study.
2.
Subject is planning a pregnancy within the next 18 months.
3.
Subject has current suicidal ideation as evidenced by answering 'yes' to questions 4 or 5 on the 
suicidal ideation portion of the Columbia-Suicide Severity Rating Scale (C-SSRS) completed at 
Treatment Period Month 6 Visit of her respective Pivotal Study.


Elagolix (ABT-620)
M12-816 Protocol Amendment 1
10
Key Criteria for Inclusion/Exclusion (Continued):
Key Exclusion Criteria (Continued):
4.
Subject has a newly diagnosed clinically significant medical condition that requires intervention 
OR an unstable medical condition that makes the subject an unsuitable candidate for the study in 
the opinion of the Investigator (including, but not limited to:  uncontrolled diabetes mellitus, 
uncontrolled hypertension, epilepsy requiring anti-epileptic medication, unstable angina, confirmed 
inflammatory bowel disease, hyperprolactinemia, clinically significant infection or injury or 
symptomatic endometriosis [confirmed by laparoscopy/laparotomy]).
5.
Subject is using any systemic corticosteroids for over 14 days 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.
6.
Subject, who in the judgment of the Investigator, will be unable or unwilling to comply with study-
related assessments and procedures, including collection of sanitary products.
Rationale for Exclusion Criteria:
1, 3, 4, 5
This is standard criteria to ensure general good health and the safety of the subjects (risk)
2
The impact of elagolix on pregnancies or breastfed infants is unknown and there is a 
possible risk of miscarriage due to changes in hormone levels; therefore, these criteria 
ensure adequate precautions are taken to avoid pregnancy or breastfeeding while 
receiving elagolix (risk)
6 
This criterion was added to ensure the population of subjects enrolled will comply with
study-related procedures and subject collection requirements throughout the entire study 
(predictive)
Investigational Products:
Elagolix sodium 300 mg tablets
Estradiol 1 mg/norethindrone acetate 0.5 mg (E2/NETA) capsules
Doses:
Elagolix 300 mg BID plus placebo for E2/NETA
Elagolix 300 mg BID plus estradiol/norethindrone acetate (E2 
1 mg/NETA 0.5 mg) QDElagolix 300 mg BID alone plus placebo for 
estradiol/norethindrone acetate (E2 1 mg/NETA 0.5 mg) QDElagolix 
300 mg BID plus estradiol/norethindrone acetate (E2 1 mg/NETA 
0.5 mg) QD
Note:  This study will evaluate an elagolix total daily dose of 600 mg, 
administered as 300 mg BID
Reference Therapy:
Placebo capsules to match E2/NETA for blinding
Mode of Administration:
Oral
Duration of Treatment:  6-Months
Duration of Post-Treatment Follow-Up:  12-Months


Elagolix (ABT-620)
M12-816 Protocol Amendment 1
11
Criteria for Evaluation:
Efficacy:
Primary Efficacy Endpoint:
The primary endpoint will be the percentage of subjects meeting a composite endpoint consisting of 
these two bleeding assessments:
!
MBL volume < 80 mL during the Final Month (the last 28 days of treatment in the Extension 
Study), AND
!
50% or greater reduction in MBL volume from Baseline to the Final Month (the last 28 days 
of treatment in the Extension Study).
A subject who prematurely discontinues the study drug due to adverse events, "lack of efficacy," or 
"requires surgery or invasive intervention for treatment of uterine fibroids" will be considered as a non-
responder regardless whether she meets the two aforementioned responder criteria or not.
Secondary Efficacy Variables:
!
MBL volume assessed using alkaline hematin methodology and UBQ
!
Suppression of bleeding 
!
Hemoglobin concentration 
Other Efficacy Variables:
!
Amenorrhea
!
Control of bleeding
!
Bleeding days
!
Fibroid and uterine volume
!
UFS-QoL Questionnaire
!
EuroQol (EQ-5D-5L) Questionnaire
!
Health Care Resource Utilization (HCRU) Questionnaire
!
Patient Global Impression of Change (PGIC) Questionnaires
!
Work Productivity and Activity Impairment (WPAI) Questionnaire
Safety:
Safety evaluations include physical examination, vital signs, ECG, BMD changes, endometrial 
assessment (endometrial thickness and biopsy), clinical laboratory tests (hematology, chemistry, 
urinalysis, lipid panel) and adverse event monitoring.
Statistical Methods:
Efficacy:
Separate summaries will be provided for each of the following groups of subjects:
1.
Subjects randomized to elagolix 300 mg BID in the Pivotal Studies and continued to receive 
elagolix 300 mg BID in the Extension Study;
2.
Subjects randomized to elagolix 300 mg BID plus E2/NETA QD in the Pivotal Studies and 
continued to receive elagolix 300 mg BID plus E2/NETA QD in the Extension Study;
3.
Subjects randomized to placebo in the Pivotal Studies, and re-randomized to elagolix 300 mg BID 
in the Extension Study; and


Elagolix (ABT-620)
M12-816 Protocol Amendment 1
12
Statistical Methods (Continued):
Efficacy (Continued):
4.
Subjects randomized to placebo in the Pivotal Studies, and re-randomized to elagolix 300 mg BID 
plus E2/NETA QD in the Extension Study.
Unless otherwise specified, no statistical comparisons will be performed.
Primary Efficacy Analysis:
The primary analysis of the primary endpoint will be performed using the full analysis set, which is 
comprised of all subjects who took at least one dose of the study drug in this Extension Study.
The alkaline hematin method and the UBQ will be used to assess the MBL volume.  The approach of 
handling missing data will be the same as in the Pivotal Studies.
The percentage of subjects with MBL volume < 80 mL at the Final Month and 50% or greater reduction 
in MBL volume from baseline to the Final Month in the Extension Study will be summarized by 
treatment group. 
Analyses for Secondary and Other Efficacy Variables:
The change and percent change from baseline in MBL volume to each month and to the Final Month 
will be summarized for each treatment group.  The percentage of subjects with MBL volume < 80 mL 
and 50% or greater reduction in MBL volume from baseline to each month in the Extension Study will 
be summarized by treatment group.  The percentage of subjects with suppression of bleeding and the 
percentage of subjects with amenorrhea will be summarized by treatment group.
The change and percent change from baseline to the Month 6 in the Extension Study in hemoglobin 
concentration will be summarized by treatment group.
The change and percent change from baseline in primary fibroid volume, total fibroid volume, and 
uterine volume will be summarized for each treatment group.
The change from baseline for Quality of Life assessments (e.g., UFS-QoL, EQ-5D-5L) will be 
summarized for each treatment group.  For the PGIC-MB and PGIC-NBUFS, the number and percentage 
of subjects in each response category will be summarized by treatment group.
Safety:
All subjects who took at least one dose of the study drug in this Extension Study will be included in the 
safety analyses.
Separate summaries will be provided for each of the following groups of subjects:
1.
Subjects randomized to elagolix 300 mg BID in the Pivotal Studies and continued to receive 
elagolix 300 mg BID in the Extension Study;
2.
Subjects randomized to elagolix 300 mg BID plus E2/NETA QD in the Pivotal Studies and 
continued to receive elagolix 300 mg BID plus E2/NETA QD in the Extension Study;
3.
Subjects randomized to placebo in the Pivotal Studies, and re-randomized to elagolix 300 mg BID 
in the Extension Study; and
4.
Subjects randomized to placebo in the Pivotal Studies, and re-randomized to elagolix 300 mg BID 
plus E2/NETA QD in the Extension Study.
Unless otherwise specified, no statistical comparisons will be performed.
The number and percentage of subjects having adverse events will be tabulated by primary System 
Organ Class (SOC) and MedDRA Preferred Term with a breakdown by treatment group.  Hematology, 
chemistry, urinalysis, lipid panel, vital signs and endometrial biopsy variables will be summarized.


Elagolix (ABT-620)
M12-816 Protocol Amendment 1
13
Statistical Methods (Continued):
Safety (Continued):
The within-group percent change from baseline to Month 6 in the Extension Study in BMD will be 
summarized by treatment group.
For subjects who have at least 12 months of total exposure to elagolix, the percent change from Baseline 
to Month 6 in the Extension Study in BMD will be compared between elagolix dose groups (elagolix 
300 mg BID versus elagolix 300 mg BID plus E2/NETA QD) using analysis of covariance (ANCOVA) 
with treatment as the main effect and baseline BMD as a covariate.  A two-sided 95% confidence 
interval will be constructed for the between-group difference in percent change from baseline to Month 6 
in the Extension Study in BMD.
Sample Size:
All subjects who complete either the Pivotal Study M12-815 or Study M12-817, sign an inform consent 
form, and meet the inclusion/exclusion criterion will be eligible to enroll in this Extension Study.  The 
two Pivotal Studies M12-815 and M12-817 have a planned enrollment of a total of 800 subjects.  Based 
on assumptions related to discontinuation in the Pivotal Study and the estimated roll over rate into this 
Extension Study, approximately 400 subjects are expected to be enrolled in this Extension Study.
Pharmacokinetics/Pharmacodynamics:
Plasma concentrations of elagolix and norethindrone will be listed for each subject by visit day and dose 
regimen.  Pharmacokinetic data may be combined with data from other studies in women. 
Serum concentrations of estradiol, progesterone, FSH, and LH will be listed for each subject by visit day 
and dose regimen.
Exposure-response analyses may be conducted as appropriate. 
Study Schematic:


Elagolix (ABT-620)
M12-816 Protocol Amendment 1
14
1.3
List of Abbreviations and Definition of Terms
Abbreviations
Ab
Antibody
ABT
Abbott/AbbVie
AE
Adverse Event
AGC
Atypical Glandular Cells
AH
Alkaline Hematin
APO A
Apolipoprotein A
APO B
Apolipoprotein B
ASC-H
Atypical Squamous Cells cannot exclude High grade squamous intraepithelial 
lesion
ASC-US
Atypical Squamous Cells of Undetermined Significance
AESI
Adverse Event of Special Interest
BID
Twice daily (bis in die)
BI-RADS
Breast Imaging Reporting and Data System
BMD
Bone Mineral Density
BUN
Blood Urea Nitrogen
CIN
Cervical Intraepithelial Neoplasia
CRF
Case Report Form
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP3A
Cytochrome P450 3A
D&C
Dilation and curettage
DXA
Dual energy X-Ray Absorptiometry
E2
Estradiol
ECG
12-Lead Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EQ-5D-5L
EuroQol-5D-5L
FDA
US Food and Drug Administration
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GLP
Good Laboratory Practices
GnRH
Gonadotropin releasing hormone


Elagolix (ABT-620)
M12-816 Protocol Amendment 1
15
HCRU
Health Care Resource Utilization
HCV Ab
Hepatitis C Virus Antibody
Hgb
Hemoglobin
HIFU
High Intensity Focused Ultrasound
HMB
Heavy Menstrual Bleeding
HSIL
High-Grade Squamous Intraepithelial Lesion 
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICL
Imaging Core Lab
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IR
Immediate Release
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intra-Uterine Device
K2EDTA
K2-ethylenediaminetetraacetic acid
LDL
Low-density Lipoprotein
LH
Luteinizing Hormone
LNG-IUS
Levonorgestrel Intrauterine System
LSIL
Low-grade squamous intraepithelial lesion
M
Month (visit)
MAD
Multiple Ascending Dose
MBL
Menstrual Blood Loss
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Cell volume of RBC
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
NETA
Norethindrone acetate
NBI
Neurocrine Biosciences Inc
P
Progesterone
Pap
Papanicolau 
PCV
Product Collection Visit
PD
Premature Discontinuation 


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PGIC-MB
Patient Global Impression of Change – Menstrual Bleeding
PGIC-NBUFS
Patient Global Impression of Change – Non-Bleeding Uterine Fibroid Symptoms
PID
Pelvic Inflammatory Disease
P-gp
P-glycoprotein
PK
Pharmacokinetic
POC
Proof-of-Concept
PRO
Patient Reported Outcome
PTSD
Post-Traumatic Stress Disorder
QD
Once a day (quaque die)
QoL
Quality of Life
RANKL
Receptor activator of nuclear factor-κB ligand
RBC
Red Blood Cell
RR
Respiration Rate
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SGOT/ASAT
Serum glutamic-oxaloacetic transaminase/aspartate aminotransferase
SIS
Saline Infusion Sonohysterography
SGPT/ALAT
Serum glutamic-pyruvic transaminase/alanine aminotransferase
SPRM
Selective Progesterone Receptor Modulator                                                                    
TA MD
Therapeutic Area Medical Director
T-SG
Trial-Specific Guidelines
TAU
Transabdominal Ultrasound
TDD
Total Daily Dose
TBG
Thyroxine-Binding Globulin
TSH
Thyroid Stimulating Hormone
TEAEs
Treatment-emergent adverse events
TVU
Transvaginal Ultrasound
UBQ
Uterine Bleeding Questionnaire
UFS-QoL
Uterine Fibroid Symptom Quality of Life Questionnaire
WBC
White Blood Cells
WHO
World Health Organization
WPAI
Work Productivity and Activity Impairment


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Pharmacokinetic and Statistical Abbreviations
ANOVA
Analysis of variance
ANCOVA
Analysis of covariance
Cmax
Maximum concentration in plasma
PD
Pharmacodynamic
PK
Pharmacokinetic
Tmax
Time to maximum observed plasma concentration
Definition of Terms
Pivotal Study
Studies M12-815/M12-817:  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.
Extension Study
Study M12-816:  Extension Study to Evaluate the Efficacy and Safety of 
Elagolix in Premenopausal Women with Heavy Menstrual Bleeding 
Associated with Uterine Fibroids.
Day 1 or Treatment Period 
Day 1
The day a subject takes her first dose of study drug in this Extension 
Study M12-816.  The Day 1 Visit will occur only after completing 
Treatment Period of the Pivotal Studies M12-815/M12-817.
Monthly Visits:  Treatment 
Period Months 1 through 6 
and Post-Treatment Period 
Months 1 through 12
A month is defined as 28 days.
Product Collection Visits
Visits at which subjects return used sanitary products for assessment of 
alkaline hematin levels (either during Screening or the Treatment Period); 
visits should occur within approximately 5 days after the last sanitary 
product was collected during a bleeding and/or spotting episode.
Home Product Collection 
Visits
Product Collection Visit conducted at home by a Home Health Care Agent 
who will go to the subject's home to draw a venous blood sample and 
retrieve the collection keg to return to the study site.
Heavy Menstrual Bleeding
Menorrhagia or > 80 mL blood loss.
Vasomotor Symptoms
Examples:  hot flush and night sweats.


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2.0
Table of Contents
1.0
Title Page ...............................................................................1
1.1
Protocol Amendment:  Summary of Changes ......................................... 2
1.2
Synopsis................................................................................................. 5
1.3
List of Abbreviations and Definition of Terms...................................... 14
2.0
Table of Contents ................................................................ 18
3.0
Introduction......................................................................... 24
3.1
Uterine Fibroids ................................................................................... 24
3.2
Elagolix................................................................................................ 25
3.2.1
Preclinical Experience .......................................................................... 26
3.2.1.1
Toxicology........................................................................................... 26
3.2.2
Clinical Experience .............................................................................. 27
3.2.2.1
Pregnancy in Elagolix Studies .............................................................. 35
3.3
Estradiol/Norethindrone Acetate........................................................... 40
3.4
Differences Statement .......................................................................... 41
3.5
Benefits and Risks................................................................................ 41
4.0
Study Objective ................................................................... 42
5.0
Investigational Plan.............................................................42
5.1
Overall Study Design and Plan:  Description ........................................ 42
5.2
Selection of Study Population............................................................... 48
5.2.1
Inclusion Criteria.................................................................................. 48
5.2.2
Exclusion Criteria................................................................................. 50
5.2.2.1
Concomitant Therapy........................................................................... 51
5.2.2.2
Iron Supplementation ........................................................................... 52
5.2.2.3
Concomitant Use of Corticosteroids ..................................................... 52
5.2.2.4
Prohibited Therapy............................................................................... 52
5.2.3
Contraception Recommendations and Pregnancy Testing ..................... 55
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, Pharmacogenetic 
and Safety Assessments/Variables ........................................................ 60
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ............... 60
5.3.1.1
Study Procedures.................................................................................. 60
5.3.1.2
Collection and Handling of Pharmacodynamic Variables ..................... 83


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5.3.2
Drug Concentration Measurements....................................................... 83
5.3.2.1
Collection of Samples for Analysis....................................................... 83
5.3.2.2
Measurement Methods ......................................................................... 84
5.3.3
Efficacy Variables................................................................................ 84
5.3.3.1
Primary Efficacy Variable .................................................................... 84
5.3.3.2
Secondary Efficacy Variable ................................................................ 84
5.3.4
PRO and Quality of Life Variables ....................................................... 84
5.3.5
Safety Variables ................................................................................... 85
5.3.6
Pharmacodynamic Variables ................................................................ 85
5.3.7
Pharmacokinetic Variables ................................................................... 85
5.3.8
Independent Data Monitoring Committee............................................. 86
5.4
Removal of Subjects from Therapy or Assessment ............................... 86
5.4.1
Discontinuation of Individual Subjects ................................................. 87
5.4.2
Discontinuation of Entire Study............................................................ 88
5.4.3
Treatment Interruption.......................................................................... 89
5.5
Treatments ........................................................................................... 89
5.5.1
Treatments Administered...................................................................... 89
5.5.2
Identity of Investigational Products ...................................................... 91
5.5.2.1
Packaging and Labeling........................................................................ 91
5.5.2.2
Storage and Disposition of Study Drugs ............................................... 92
5.5.3
Method of Assigning Subjects to Treatment Groups ............................. 92
5.5.4
Selection and Timing of Dose for Each Subject .................................... 93
5.5.5
Blinding of Investigational Product ...................................................... 94
5.5.6
Treatment Compliance ......................................................................... 94
5.5.7
Drug Accountability ............................................................................. 96
5.6
Discussion and Justification of Study Design........................................ 96
5.6.1
Discussion of Study Design and Choice of Control Groups .................. 96
5.6.2
Appropriateness of Measurements........................................................ 97
5.6.3
Suitability of Subject Population .......................................................... 97
5.6.4
Selection of Doses in the Study ............................................................ 97
6.0
Complaints........................................................................... 98
6.1
Medical Complaints ............................................................................. 98
6.1.1
Definitions ........................................................................................... 99


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6.1.1.1
Adverse Event...................................................................................... 99
6.1.1.2
Serious Adverse Events.......................................................................100
6.1.1.3
Adverse Events of Special Interest.......................................................101
6.1.2
Adverse Event Severity .......................................................................101
6.1.3
Relationship to Study Drug..................................................................102
6.1.4
Adverse Event Collection Period.........................................................102
6.1.5
Adverse Event Reporting.....................................................................103
6.1.6
Pregnancy............................................................................................105
6.2
Product Complaint...............................................................................106
6.2.1
Definition............................................................................................106
6.2.2
Reporting ............................................................................................106
7.0
Protocol Deviations ........................................................... 107
8.0
Statistical Methods and Determination of Sample 
Size ..................................................................................... 107
8.1
Statistical and Analytical Plans............................................................107
8.1.1
General Considerations........................................................................107
8.1.2
Data Sets Analyzed .............................................................................108
8.1.3
End-of-Treatment Period Analysis.......................................................109
8.1.4
Independent Data Monitoring Committee............................................109
8.1.5
Demographic, Baseline Characteristics and Concomitant 
Medications.........................................................................................109
8.1.6
Time Points, Time Windows and Time Periods for Analysis ...............110
8.1.7
Efficacy...............................................................................................110
8.1.7.1
Primary Efficacy Variable ...................................................................110
8.1.7.1.1
Primary Analysis.................................................................................110
8.1.7.1.2
Derivation of Primary Efficacy Endpoint.............................................111
8.1.7.1.3
Multiple Imputation.............................................................................113
8.1.7.1.4
Sensitivity Analysis of the Primary Efficacy Variable..........................113
8.1.7.2
Secondary Efficacy Variables..............................................................113
8.1.7.3
Other Efficacy Variables .....................................................................114
8.1.7.3.1
Reduction of Bleeding.........................................................................114
8.1.7.3.2
Hemoglobin Concentration..................................................................115
8.1.7.3.3
Fibroid and Uterine Volume ................................................................115


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8.1.7.3.4
Quality of Life.....................................................................................115
8.1.7.3.5
Patient Global Impression of Change (PGIC) ......................................116
8.1.7.3.6
Work Productivity and Activity Questionnaire (WPAI) .......................116
8.1.7.3.7
Health Care Resource Utilization Questionnaire (HCRU)....................116
8.1.7.3.8
Multiple Comparisons .........................................................................116
8.1.8
Safety..................................................................................................117
8.1.8.1
General Considerations........................................................................117
8.1.8.2
Adverse Events....................................................................................117
8.1.8.3
Analysis of Laboratory Data and Vital Signs .......................................118
8.1.8.4
Bone Mineral Density..........................................................................118
8.1.8.5
Post-Treatment Analysis of Menstruation............................................119
8.1.8.6
Endometrial Biopsy.............................................................................119
8.1.8.7
Pelvic Ultrasound ................................................................................119
8.1.8.8
Columbia Suicide Severity Rating Scale (C-SSRS) .............................120
8.1.9
Pharmacokinetic/Pharmacodynamic Analysis......................................120
8.2
Determination of Sample Size .............................................................120
9.0
Ethics.................................................................................. 120
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ........................................................................................120
9.2
Ethical Conduct of the Study...............................................................121
9.3
Subject Information and Consent.........................................................121
10.0
Source Documents and Case Report Form 
Completion ........................................................................ 122
10.1
Source Documents...............................................................................122
10.2
Case Report Forms..............................................................................122
11.0
Data Quality Assurance .................................................... 124
12.0
Use of Information ............................................................ 125
13.0
Completion of the Study ................................................... 126
14.0
Investigator's Agreement.................................................. 127
15.0
Reference List.................................................................... 128


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List of Tables
Table 1.
Visit and Assessment Windows............................................................ 48
Table 2.
Prohibited Medications......................................................................... 54
Table 3.
Clinical Laboratory Tests ..................................................................... 73
Table 4.
Treatments Administered...................................................................... 90
Table 5.
Identity of Investigational Products ...................................................... 91
List of Figures
Figure 1.
Study Schematic................................................................................... 44
Figure 2.
Management of BMD % Decrease:  Treatment Period and 
Post-Treatment Period.......................................................................... 69
Figure 3.
Management of BMD % Decrease:  Post-Treatment Follow-Up 
Month 12.............................................................................................. 72
Figure 4.
Sanitary Product Dispensation and Collection ...................................... 77
Figure 5.
Adverse Event Collection....................................................................103
Figure 6.
Flow-Chart for Deriving Primary Endpoint..........................................112
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.........................................130
Appendix B.
List of Protocol Signatories .................................................................132
Appendix C.
Study Activities – Treatment Period and Post-Treatment 
Follow-Up Period................................................................................133
Appendix D.
Uterine Bleeding Questionnaire – Treatment Period – SAMPLE .........139
Appendix E.
Uterine Bleeding Questionnaire Post-Treatment Follow-Up Period 
– SAMPLE..........................................................................................140
Appendix F.
UFS-QoL – SAMPLE .........................................................................141
Appendix G.
Patient Global Impression of Change – Menstrual Bleeding 
(PGIC-MB) SAMPLE .........................................................................142
Appendix H.
Patient Global Impression of Change Non-Bleeding Uterine 
Fibroid Symptoms (PGIC-NBUFS) – SAMPLE ..................................143


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Appendix I.
Work Productivity and Activity Impairment Questionnaire:  
Uterine Fibroids V2.0 (WPAI:UF) – SAMPLE....................................145
Appendix J.
EurolQol (EQ-5D-5L) – SAMPLE ......................................................147
Appendix K.
Columbia-Suicide Severity Rating Scale (C-SSRS) – Since Last 
Visit – SAMPLE .................................................................................149
Appendix L.
Health Care Resource Utilization Questionnaire HCRU 
Version 2.0 – SAMPLE.......................................................................152
Appendix M.
Protocol Amendment:  List of Changes ...............................................161


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3.0
Introduction
3.1
Uterine Fibroids
Uterine fibroids (leiomyomata) are the most common benign tumors in women and occur 
in up to 80% of women of reproductive age.1  The incidence increases with age, and 
uterine fibroids are the most common reason for hysterectomy.1,2  Uterine fibroids may 
develop in African-American women on average 10 years earlier than in white women.3  
The overall cost of symptomatic uterine fibroids exceeds $2 billion per year in the United 
States.4
The growth of uterine fibroids is highly dependent on both estrogen and progesterone.5
Although often asymptomatic, fibroids may cause symptoms severe enough to warrant 
therapy in 20% to 50% of women3 and the most common symptom is heavy or prolonged 
menstrual bleeding.  Other symptoms may include anemia, pelvic pressure and pelvic 
organ compression, back pain, and adverse reproductive outcomes.  Heavy menstrual 
bleeding (HMB) (menorrhagia, defined as > 80 mL per menstrual cycle)1 is extremely 
inconvenient, can significantly impact quality of life and may lead to iron-deficiency 
anemia.
The choice of treatment is based on individual symptoms, patient preference, and the 
desire to preserve either fertility or the uterus or both.  Historically, hysterectomy or 
myomectomy were the preferred treatment options for women with symptomatic uterine 
fibroids.2  However, surgery is also associated with risks such as infections, bleeding 
complications, thromboembolic effects, scarring/adhesions, and even increased mortality.6  
As more women delay pregnancy into their 30s and 40s, there is a growing need for 
alternatives to surgical treatments, especially hysterectomy.  To meet this demand, during 
the past 2 decades many new uterus-sparing therapies have been proposed and studied 
including semi-invasive procedures, such as uterine artery embolization and magnetic 
resonance imaging (MRI)-guided high-intensity focused ultrasound ablation therapy as 
well as nonsurgical, medical treatments.  There is no long-term medical treatment for 


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symptomatic uterine fibroids.  Treatment with GnRH agonists such as Lupron® is 
effective but induces full gonadal suppression and menopause-like symptoms that limit 
their use to 3 months of presurgical treatment.  High-dose progestins, oral contraceptives 
and tranexamic acid (Lysteda®-an antifibrinolytic drug) are used for short-term 
management of heavy uterine bleeding only.  Recently, the selective progesterone 
receptor modulator (SPRM), ulipristal acetate, has been approved in the EU as a short-
term preoperative treatment, as well as an extended intermittent treatment of women with 
of symptomatic uterine fibroids.
The ideal medical treatment for symptomatic uterine fibroids, as an alternative to surgical 
interventions, should control HMB, improve non-bleeding symptoms and quality of life, 
and prove safe and tolerable as a chronic therapy.  Unfortunately, currently available 
medical options provide only short-term improvement of symptoms, and as such, are only 
indicated prior to surgery, and/or their side-effects limit their long-term use.  A safe and 
effective chronic medical therapy for the management of HMB associated with uterine 
fibroids, as an alternative to hysterectomy or other surgical intervention, has not yet been 
approved.
3.2
Elagolix
Elagolix is an orally active, non-peptide (GnRH) antagonist that is being developed by 
AbbVie for the management of endometriosis-related pain and the chronic management of 
HMB associated with symptomatic uterine fibroids.  The initial preclinical and clinical 
evaluation of elagolix was conducted by Neurocrine Biosciences Inc. (NBI).  Safety 
results from these studies show that elagolix is generally well tolerated.  Elagolix, unlike 
injectable GnRH analogs, produces a dose dependent suppression of pituitary and ovarian 
hormones in women, i.e., from partial ovarian suppression at lower doses to full 
suppression at higher doses.  A detailed discussion of the preclinical toxicology, 
metabolism, pharmacology and pharmacokinetics of elagolix in humans and a summary 
of clinical studies can be found in the Investigator's Brochure and is also discussed in 
lesser detail in Section 3.2.1 and Section 3.2.2.7


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The initial 3-month, Phase 2a, dose-finding, POC study (Study M12-663) evaluated total 
daily doses (TDDs) of elagolix of 200, 400, and 600 mg in premenopausal women with 
HMB associated with uterine fibroids.  Data from this study indicated that an elagolix 
TDD of 600 mg best met the agreed-upon dose selection criteria for Phase 2b and Phase 3 
(predicated on a dose in Phase 2a that provided the most robust response [responder rates 
of approximately > 80% for the composite bleeding assessment] and an acceptable safety 
and bleeding profile for the majority of women).  It was known that to support long-term 
dosing with elagolix at these higher doses, low dose hormonal add-back therapy would be 
required to mitigate bone loss and minimize other hypoestrogenic adverse events, e.g., hot 
flush.
Subsequently, a 6-month safety and efficacy Phase 2b study (Study M12-813) evaluating 
elagolix TDD of 600 mg (administered as 300 mg BID in Cohort 1 or 600 mg QD in 
Cohort 2) with and without add-back therapy was conducted.  As add-back therapy, the 
study evaluated two doses of E2/NETA (low dose, 0.5 mg/0.1 mg and standard dose, 
1 mg/0.5 mg).  Preliminary results from Cohort 1 demonstrated that treatment with 
elagolix 300 mg BID alone and in combination with E2/NETA provided robust efficacy 
in controlling HMB associated with uterine fibroids and provided an acceptable 
safety/tolerability profile that could potentially support the proposed chronic use 
indication.  While similar efficacy results were noted in Cohort 2 (elagolix 600 mg QD),
review of the totality of data (preclinical, Phase 1 and Phase 2) comparing two dosing 
regimens support selection of the 300 mg BID + standard dose E2/NETA as the regimen 
for Phase 3.
Additional details on rationale for dose selection are included in Section 5.6.4.
3.2.1
Preclinical Experience
3.2.1.1
Toxicology
Elagolix has been well characterized in repeated-dose animal toxicity studies of up to 
15 weeks in mouse, 28 weeks in rat, 39 weeks (9 months) in dog and 13 weeks in 
monkey. 


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The safety margin for the 200 mg BID human dose for the endometriosis indication is 
approximately 8.6 (28 week rate study) and 7.5 (9 month dog study).
There were no significant findings from in vitro and in vivo genotoxicity studies.  Also, 
there was no significant increase in tumors in the 2-year mouse carcinogenicity study with 
elagolix sodium.  In the 2-year rat carcinogenicity study increase in thyroid or liver 
tumors was rat specific with no risk anticipated for human.
Elagolix is not teratogenic (no fetal abnormalities in preclinical studies) based on data 
from the rat and rabbit Segment II studies).  However, there were non-teratogenic 
findings, e.g., observations of abortions in rabbit and post-implantation loss in rat at 
higher doses.  These could either be due to maternal toxicity or related to indirect 
pharmacological activity.  
Please refer to the most recent edition of the elagolix Investigator Brochure for complete 
information on toxicology studies for elagolix.
3.2.2
Clinical Experience
Refer to Edition 15 of the elagolix Investigator's Brochure (April 2016 or the most recent 
version) for the complete information on clinical studies, exposure to study drug, and 
safety.
Clinical Program Overview
As of 31 January 2016, a total of 3,417 subjects have received at least 1 dose of elagolix 
in clinical studies conducted by NBI and AbbVie (30 Phase 1 studies, 6 Phase 2 
endometriosis studies, 2 Phase 2 uterine fibroid studies [Studies M12-663 and M12-813], 
and 1 ongoing Phase 3 endometriosis extension study [Study M12-665] and 2 ongoing 
Phase 3 endometriosis extension studies [Studies M12-667 and M12-821]).  More than 
1,000 of these subjects were dosed for ≥ 6 weeks.  Of the 3,417 subjects, 95 were healthy 
men, 795 were healthy women, 1,296 were women with endometriosis, 221 were women 
with uterine fibroids, 16 were women with hepatic impairment, and 9 were women with 


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renal impairment.  In ongoing studies (including 2 extension studies mentioned above and 
excluding Study M12-671), more than 1,625 subjects have received at least 1 dose of 
elagolix.
Twelve Phase 1 clinical studies (7 in healthy men and 5 in healthy women) and 6 Phase 2 
studies (in women with endometriosis) were completed by NBI.  To date, 18 Phase 1 
studies have been completed by AbbVie.  The Phase 3 endometriosis registration program 
consists of 2 replicate 6-month Pivotal Studies, Study M12-665 and Study M12-671 and 
2 extension studies, Study M12-667 and Study M12-821, respectively.  In women with 
HMB associated with uterine fibroids, 2 Phase 2 studies have been completed by AbbVie, 
Study M12-663 and Study M12-813.  The Phase 3 uterine fibroid registration program 
consists of 2 Pivotal Studies, Study M12-815 and Study M12-817, and a single planned 
associated 6-month safety/efficacy extension study, Study M12-816.
Clinical Pharmacokinetic and Pharmacodynamic Summary
Clinical pharmacokinetic (PK) studies indicate that elagolix is rapidly absorbed from the 
gastrointestinal tract (GI) with time to maximum plasma concentration (Tmax) of 
approximately 1 hour for immediate release (IR) tablet formulations.  The following 
points are key findings of elagolix PK:
●
Elagolix exposure (area under the plasma concentration versus time curve 
[AUC] and maximum concentration in plasma [Cmax]) appears to be 
approximately dose-proportional across the daily dose range studied (25 to 
400 mg).  At single daily doses of 600 mg and above, more than dose 
proportional increases in elagolix exposures were observed.
●
Elagolix displays biphasic disposition with a terminal elimination half-life of 
approximately 4 – 6 hours.  Little or no accumulation resulted from BID 
(400 mg BID), or once daily (QD) (400 mg QD) dosing at steady state which 
is not deemed clinically relevant.
●
Food decreases the AUC of the immediate-release tablet formulation by 
approximately 25%.


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●
Elagolix is a substrate of CYP3A and P-gp and may be a weak inducer of 
CYP3A enzymes.
●
Elagolix is primarily excreted in feces as metabolites (64%) and parent 
compound (26%).  Less than 3% is excreted unchanged in the urine.  Plasma 
exposure of elagolix metabolites was low (< 3% of each metabolite) relative to 
the parent.
Pharmacodynamic data from the AbbVie multiple-ascending dose (MAD) study, 
Study M12-790, in premenopausal healthy female subjects showed a dose-dependent 
suppression of E2, reaching maximum suppression at approximately 200 mg BID.  
Anovulatory progesterone levels were observed through Day 21 in all subjects at doses as 
low as 100 mg BID.  In addition, luteinizing hormone (LH) and follicle-stimulating 
hormone (FSH) decline in a dose dependent manner, with maximal suppression and near 
maximal suppression, respectively, at 300 mg BID.  The elagolix 400 mg BID dose does 
not appear to result in substantial additional E2 suppression compared with the 300 mg 
BID dose.
Effects on Ovulation
Elagolix is not a contraceptive and data on ovulation rates from the 3-month 
folliculogenesis study, Study M12-673, showed that the 100 mg BID, 150 mg QD, and 
200 mg QD doses do not appear to differentiate.  The percentage of subjects with at least 
1 ovulation during the 3 months of elagolix treatment was 47.4% to 57.1%, and the 
percentage of subjects with ovulation was 28.1% to 33.3% within each month (28-day 
period).  In contrast, when ovulation rates are counted by subject or by month, the 200 mg 
BID dose appears to decrease ovulation rates to almost half of that observed with the 
150 mg QD dose.  The 300 mg BID dose appeared to have a slightly lower ovulation rate 
than 200 mg BID (27% versus 32%), and when the standard-dose estradiol 
1 mg/norethindrone acetate 0.5 mg (standard-dose E2/NETA) was co-administered with 
elagolix 300 mg BID, the ovulation rate decreased further to approximately 10%. 


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Summary of Safety Findings
Adverse Events Across Elagolix Studies
As of 31 January 2016, the most common adverse events overall in the 3,417 subjects 
who received elagolix across all clinical studies were hot flush (598/3,417; 17.5%), 
headache (546/3,417; 16.0%), and nausea (411/3,417; 12%).  These are also the adverse 
events that most commonly resulted in discontinuation from study:  hot flush in 
33 subjects (1.0%), headache in 15 subjects (0.4%), and nausea in 16 subjects (0.5%).
Adverse Events in Phase 2 Studies in Uterine Fibroids
Study M12-663
Preliminary data from the completed Phase 2a POC study, Study M12-663, show that the 
most commonly reported adverse event in all the elagolix treatment cohorts was hot flush; 
this was reported for approximately 45% to 63% of the subjects in the cohorts in which 
elagolix was administered alone.  The use of both add-back therapies [elagolix 200 mg 
BID + LD (low-dose) E2/NETA QD and elagolix 300 mg BID + cyclical EP] was 
associated with an approximate 30% lower overall incidence of hot flush that was 
approximately 30% lower relative to the corresponding elagolix treatment regimen alone.
Other than hot flushes, the only other adverse events in the elagolix 300 mg BID group 
reported for more than 2 subjects were headache (6 subjects, 20%), and abdominal pain 
and dizziness (3 subjects each, 10%).  At the 600 mg QD dose of elagolix, the presence of 
nausea (9 subjects), headache (9 subjects), dizziness (6 subjects), and back pain 
(5 subjects) was more prevalent than in the remaining elagolix treatment cohorts.
Study M12-813
Preliminary data from the completed Phase 2b study, Study M12-813, show that, overall, 
the percentage of subjects who reported treatment-emergent adverse events was generally 
similar across all treatment groups in both cohorts, ranging from 67.9% to 87.0%, with the 
highest values in the elagolix alone groups (300 mg BID, 80.0%; 600 mg QD, 87.0%).  


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The most common adverse events in both cohorts were hot flush, insomnia, and headache.  
The rates for hot flush in Cohort 1 were 3.1% for placebo and 44.6% for elagolix 300 mg 
BID alone, and the addition of low-dose or standard-dose E2/NETA significantly 
decreased the rates by approximately 20% and 34%, respectively (25.0% for elagolix 
300 mg BID + low-dose E2/NETA and 10.8% for elagolix 300 mg BID + standard-dose 
E2/NETA).  In Cohort 2, the rates of hot flush were 5.1% for placebo and 49.4% for 
elagolix 600 mg QD alone.  Addition of low-dose or standard-dose E2/NETA 
significantly decreased the rates by approximately 31% and 35%, respectively (18.4% for 
elagolix 600 mg QD + low-dose E2/NETA and 14.3% for elagolix 600 mg QD + 
standard-dose E2/NETA). 
Adverse Events of Special Interest
Adverse events of special interest in elagolix clinical studies include mood changing 
disorders (suicidality and depression), cutaneous adverse events, hot flush, ovarian-related 
events, BMD decrease and fractures, uterine bleeding and changes in serum lipids.  In the 
completed Phase 2 studies in uterine fibroids, there was a higher percentage of women 
experiencing cutaneous/hypersensitivity events and hot flush with elagolix treatment 
compared with placebo.  Adverse events of special interest are monitored continuously in 
all clinical studies.
Serious Adverse Events
As of 31 January 2016, 129 serious adverse events have been reported by 92/3,417 (2.7%) 
subjects who received elagolix.  Serious adverse events in all completed studies and in 
ongoing Studies M12-667 and M12-821 through the data cutoff date of 31 January 2016 
are captured in the analysis for this update.  The most common serious adverse event was 
pelvic pain occurring in 8 subjects (0.2%) followed by induced abortion occurring in 
4 subjects (0.2%) and spontaneous abortion and endometriosis, each occurring in 
5 subjects (0.1%), and abdominal pain and uterine leiomyoma, each occurring in 
4 subjects (0.1%).  Among women participating in elagolix clinical trials, one subject 
delivered an infant with congenital pneumonia.  During the Phase 2 clinical development 


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program in endometriosis, there were 2 pregnancy-related serious adverse events 
(congenital malformations, i.e., 1 cleft palate and 1 tracheoesophageal fistula), which 
occurred during treatment and were assessed as unrelated to elagolix.
In the completed Phase 2a study in women with HMB associated with uterine fibroids, 
there were 2 serious adverse events of prolapsed uterine fibroid.
Based on the preliminary results of Cohort 1 of the Phase 2b study in women with HMB 
associated with uterine fibroids, as of 31 January 2016, there were 7 serious adverse 
events that either occurred during the Treatment Period or within 30 days of last dose in 
8 subjects randomized to receive active treatment.  Four events occurred in the elagolix 
300 mg BID alone arm [pulmonary embolism, deep vein thrombosis (both events 
experienced by the same subject), menorrhagia and endometrial adenocarcinoma]; 
2 events occurred in the 300 mg BID plus low-dose activella arm (uterine leiomyoma and 
hypertension), and 1 event occurred in the 300 mg BID plus standard-dose activella arm 
(anemia).
Effects of Elagolix on Bone Mineral Density (BMD)
The effects of elagolix 300 mg BID alone and in combination with low-dose and standard 
dose E2/NETA were evaluated in the 6-month Phase 2b study (Study M12-813).  BMD 
was assessed at the lumbar spine (L1-L4), femoral neck, and total hip via DXA at 
Screening and at Month 6 of the Treatment Period, or Premature Discontinuation.
Preliminary results from the 6-month Phase 2b uterine fibroid study, Study M12-813, 
demonstrate that treatment with elagolix 300 mg BID and 600 mg QD, significantly 
decrease BMD, which is partially mitigated by addition of E2/NETA in a dose-dependent 
manner.  In Cohort 1, the mean percentage change from Baseline to Month 6 in BMD in 
the lumbar spine for the elagolix 300 mg BID alone group was –3.8% at Month 6; 19% of 
subjects had a 3 to ≤ 5% BMD decrease, 25% had > 5% to < 8% BMD decrease, and 8% 
had a ≥ 8% BMD decrease.


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While the addition of low-dose E2/NETA partially prevented BMD loss at the lumbar 
spine at Month 6 of treatment compared to the elagolix alone group (mean change from 
baseline –1.5% versus –3.6%), the E2/NETA (estradiol 1 mg/norethindrone acetate 
0.5 mg) more substantially mitigated BMD loss at the lumbar spine at Month 6 compared 
with the elagolix alone group (mean change from baseline –0.1% versus –3.6%).  In the 
E2/NETA (estradiol 1 mg/norethindrone acetate 0.5 mg) group 8.2% of subjects had a 3 
to ≤ 5% BMD decrease, 1 subject (2%) had a 5% – 8% BMD decrease and no subjects 
(0%) had ≥ 8% BMD decrease at the lumbar spine.
Effects of Elagolix on Clinical Laboratory Parameters
Data from the Phase 2 studies with elagolix in women with uterine fibroids showed dose-
dependent increases in serum lipid parameters, corresponding to the degree of estrogen 
suppression and similar to those seen with other GnRH analogs.  Changes in serum lipids, 
in particular total cholesterol and low-density lipoprotein cholesterol (LDL-C), were 
observed in this study, similar to those observed in postmenopausal women8 and these 
changes, as expected, were somewhat attenuated by E2/NETA in a dose-dependent 
manner.  Mean percentage increases from Baseline in total cholesterol, high-density 
lipoprotein cholesterol (HDL-C), LDL-C, and triglycerides were observed across each of 
the elagolix treatment groups over the 6-month treatment duration.  Ongoing clinical trials 
with elagolix suggest similar findings, again which are consistent with those noted with 
other GnRH analogs.  While the significance of these lipid changes in premenopausal 
women with low-risk baseline lipid values is unknown, further monitoring and evaluation 
is needed.  In all these studies, the increased lipid values usually occur during the first 1 to 
2 months of elagolix use, stabilize or plateau, and return to pretreatment baseline levels 
within 1 to 3 months after elagolix is discontinued.
Uterine Bleeding in Phase 2 Studies in Uterine Fibroids
Studies with elagolix have shown that overall, patients on elagolix experienced fewer days 
of bleeding per month, reduced bleeding intensity, and extended intervals between 
bleeding episodes compared with patients on placebo.  Some subjects experienced periods 


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of oligomenorrhea or amenorrhea with evidence of irregular bleeding as well, in particular 
at lower doses.  The effect of elagolix on bleeding appeared to be dose-dependent.
Study M12-813
Preliminary data from Phase 2b uterine fibroid study demonstrates that subjects reported 
no bleeding during the last 90 days on treatment most frequently in the elagolix 300 mg 
BID alone group and the elagolix 600 mg QD alone group, and reports of no bleeding 
declined in a dose-dependent fashion with the addition of E2/NETA.
Of subjects who received elagolix and were amenorrheic upon entering the Post-treatment 
Follow-Up Period, the majority of subjects (52% in Cohort 1 and 59% in Cohort 2) 
returned to menses at Month, and an additional 42% in Cohort 1 and 38% in Cohort 2 
returned to menses at Month 2.
Endometrial Safety in Phase 2 Studies in Uterine Fibroids
Study M12-813 
Endometrial biopsies were conducted at Baseline and at Month 6 in Study M12-813.  
Preliminary results from Cohort 1 show that, among subjects in elagolix treatment groups, 
39% to 43% had normal quiescent/minimally stimulated endometrium and 14% to 28% 
had normal proliferative endometrium at Month 6.  No clinically significant findings were 
observed.
Preliminary results from Cohort 2 are similar.  Among subjects in elagolix treatment 
groups, 21% to 36% had normal quiescent/minimally stimulated endometrium and 20% to 
32% had normal proliferative endometrium at Month 6.  No clinically significant findings 
were observed.


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3.2.2.1
Pregnancy in Elagolix Studies
Pregnancies Outcomes (Across the Entire Elagolix Clinical Development Program)
The mechanism of action of elagolix, bleeding pattern, and the indirect evidence for 
follicular escapes (high E2 and progesterone values) indicate that elagolix does not 
consistently inhibit ovulation and as discussed in Section 3.2.2, Clinical Pharmacokinetic 
and Pharmacodynamic Summary, elagolix is not contraceptive.
As of 05 February 2016, 172 pregnancies have been reported among women participating 
in elagolix clinical trials, including 104 that occurred off-treatment (58 during Screening 
and 46 during Post-Treatment [had a conception date more than 30 days after the last dose 
of study drug]) and 68 On-Treatment (i.e., had conception date during the Treatment 
Period with study drug or were deemed to have a conception date within 30 days after the 
last dose of study drug).  Among the 68 on-treatment pregnancies, 21 subjects had no 
exposure to elagolix (20 subjects treated with placebo only and 1 subject treated with oral 
contraceptives only).  The remaining 47 on-treatment pregnancies were in elagolix-treated 
subjects, and 21were carried to term, with 18 subjects delivering live infants without 
complications (1 pair of twins).  One subject delivered an infant with meconium 
aspiration pneumonia (MedDRA preferred term = congenital pneumonia).  Two subjects 
who received 150 mg elagolix QD in Phase 2 endometriosis studies delivered infants with 
congenital anomalies:  1 infant with tracheoesophageal fistula with findings of patent 
ductus arteriosus, tricuspid valve incompetence, and pneumothorax and 1 infant with cleft 
soft palate.  Internal and external causality assessment of these malformations supported 
that both congenital malformation cases were unlikely to be related to elagolix.  In 
Phase 3 studies in endometriosis, 14 pregnancies have been reported in Study M12-665 
and 6 have been reported in Study M12-671.  In the aforementioned Phase 2b UF study, 
1 on-treatment pregnancy has been reported.
Extensive counseling on pregnancy prevention along with a requirement for dual non-
hormonal barrier contraception is utilized in all ongoing and planned elagolix clinical 


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trials.  Women are also counseled on the unknown, thus potential, risk to children born to 
mothers exposed to elagolix during pregnancy, including the possibility of malformations.
Pregnancies must be reported immediately and study drug discontinued.  Information on 
the outcome of the pregnancy will be collected.  For live infant births, information on the 
health of the infant will be collected 6 to 12 months after delivery.
Pregnancy outcomes must also be monitored vigilantly across the entire development 
program, including adverse events related to pregnancy outcomes.  Women should also be 
counseled on the unknown, thus potential, risk to children born to mothers exposed to 
elagolix during pregnancy, including the possibility of malformations.
Efficacy in Phase 2 Uterine Fibroid Studies
The main objectives of the uterine fibroids Phase 2 program in premenopausal women 
were as follows:  1) to select the most appropriate dose(s) of elagolix to evaluate in 
Phase 2b and Phase 3 from both an efficacy and safety perspective, and 2) to assess the 
need for, adequacy, and type of add-back therapy to be used in conjunction with elagolix.  
The first objective was accomplished in the 3-month Phase 2a, dose-ranging POC study, 
Study M12-663, and the second objective was accomplished in both Phase 2 studies (need 
for and type of add-back in Phase 2a and adequacy of add-back therapy in Phase 2b 
[6-month safety and efficacy study]).
The Phase 2a dose-finding, POC study evaluated TDDs of elagolix of 200, 400, and 
600 mg in premenopausal women with HMB associated with uterine fibroids.  While it 
was anticipated that some women would likely benefit (reduction in menstrual bleeding), 
even with low doses (TDD of 200 mg) of elagolix, the agreed-upon dose selection criteria 
for Phase 2b was predicated on a dose in Phase 2a that provided the most robust response 
(responder rates of approximately > 80% for the composite bleeding assessment) and an 
acceptable safety and bleeding profile for the majority of women.  It was known that to 
support long-term dosing with elagolix at these higher doses, hormone add-back therapy 
would be required for all of these.


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All elagolix doses resulted in statistically superior reductions in the mean percentage of 
menstrual blood loss (MBL) from baseline measured by the alkaline hematin method 
compared to placebo, with the largest effect noted with the 300 mg BID dosing regimen.  
With regard to the primary endpoint, the add-back therapy with low-dose E2/NETA or 
cyclical EP had marginal effects on the efficacy of elagolix.  Furthermore, co-
administration of low-dose E2/NETA or cyclical EP (progesterone administered from 
Day 17 through Day 28 per treatment cycle) had comparable efficacy on the percentage 
change in MBL or the percentage of subjects who met the composite bleeding endpoint 
(MBL volume of < 80 mL at the Final Month [last 28 days of treatment], and ≥ 50% 
reduction in MBL volume from Baseline to the Final Month [last 28 days of treatment]) 
relative to elagolix administration alone.  When co-administered with elagolix (200 or 
300 mg BID), both add-back therapy regimens were efficacious in reducing the 
percentage of moderate-to-severe bleeding days, with increases in bleeding days being 
primarily due to spotting.
Based on data from the Phase 2a study, a TDD of 600 mg and 2 doses of E2/NETA add-
back therapy (low-dose E2/NETA and standard-dose E2/NETA) were selected for 
Phase 2b.
The Phase 2b study evaluated the safety and efficacy of elagolix TDD of 600 mg 
administered either (QD or BID regimens), alone and in combination with 2 different 
strengths of E2/NETA in premenopausal women age 18 to 51 years with HMB associated 
with uterine fibroids.  The study consisted of a 2.5- to 3.5-month Screening Period, a 
6-month Treatment Period, and a 6-month Post-Treatment Follow-Up Period.  Cohort 1 
utilized elagolix 300 mg BID dosing (with and without add-back therapy) while Cohort 2 
utilized elagolix 600 mg QD dosing (with and without add-back therapy).
The primary efficacy endpoint was the percentage of subjects meeting a composite 
endpoint consisting of 2 bleeding assessments:  MBL volume of < 80 mL at the Final 
Month (last 28 days of treatment), and ≥ 50% reduction in MBL volume from Baseline to 
the Final Month (last 28 days of treatment).  The key secondary efficacy endpoints 
include change in fibroid and uterine volume by ultrasound (and MRI in a subset), other 


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key bleeding assessments, specific non-bleeding assessments based on a Non-Bleeding 
Symptoms Uterine Fibroid Questionnaire (NBUFSQ), and other QOL variables including 
UFS-QOL.  The safety and tolerability objectives include the assessment of standard 
safety parameters, in addition to hypoestrogenic adverse events of interest, including 
BMD loss as assessed by dual energy x-ray absorptiometry (DXA) and vasomotor 
symptoms, such as hot flush.  Endometrial health via transvaginal ultrasound (TVU) and 
endometrial biopsy are also evaluated.
Preliminary results from Cohort 1 demonstrated that treatment with elagolix 300 mg BID 
plus E2/NETA showed the following:
●
Robust efficacy in controlling HMB (composite bleeding endpoint of 91.9%, 
85.5%, and 79% in the elagolix 300 mg BID alone, elagolix 300 mg BID plus 
low-dose E2/NETA, and elagolix 300 mg BID plus standard-dose E2/NETA 
treatment groups, respectively) associated with uterine fibroids
●
Clinically meaningful improvement in quality of life measures and symptom 
severity scores as assessed by UFS-QOL
●
Mitigation of BMD loss at the lumbar spine, with standard-dose E2/NETA
●
Substantial dose-dependent reduction in the incidence of vasomotor 
symptoms, e.g., hot flushes
●
No evidence of endometrial safety concerns
●
Overall safety profile remains unchanged, with no new or unexpected findings 
to date.
Overall, preliminary findings from the Phase 2b study suggest that standard-dose 
E2/NETA as add-back therapy may be effective in preventing BMD loss during treatment 
with elagolix 300 mg BID, with minimal impact on primary efficacy bleeding endpoints 
in premenopausal women with HMB associated with uterine fibroids.  This dosing 
regimen could potentially meet the objective of a long-term therapy for the management 
of symptomatic uterine fibroids in premenopausal women.


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Preliminary results from Study M12-813 show that all treatment arms (both doses of 
elagolix [300 mg BID and 600 mg QD] alone or in combination with either strength of 
E2/NETA) met the primary endpoint, which is the proportion of subjects who achieved an 
MBL volume of < 80 mL at the Final Month and 50% or greater reduction in MBL 
volume from Baseline to the Final Month compared to that of placebo (all P < 0.001), as 
measured by the alkaline hematin method.
AbbVie Ongoing Phase 3 Clinical Studies
Endometriosis
The Phase 3 endometriosis clinical development program is comprised of two 6-month 
replicate, randomized, double-blind, placebo-controlled Pivotal Studies (Studies M12-665 
and M12-667), each with complimentary 6-month safety/efficacy extension studies 
(Studies M12-667 and M12-821).  The extension studies are ongoing.  The primary 
objective of the Pivotal Studies are to evaluate the safety, tolerability, and efficacy, of 
elagolix, administered QD or BID compared to placebo, in the management of moderate 
to severe endometriosis-associated pain while taking into account the use of rescue 
analgesics.  Secondary efficacy objectives include assessments of other endometriosis-
related symptoms, analgesic use, as well as quality of life (QoL) endpoints.  The 6-month 
extension studies assess the long-term safety and efficacy of elagolix for a total treatment 
duration of up to 12 months.
Phase 3 Clinical Development Program for Uterine Fibroids 
The overall objective of the registration clinical development program is to generate 
requisite safety, tolerability, and efficacy data in 2 replicate 6-month Phase 3 Pivotal
Studies, Studies M12-815 and M12-817, and 1 safety and efficacy Extension Study, 
Study M12-816 (to receive up to a total of 12 months of treatment) to support use of 
elagolix 300 mg BID with E2/NETA (estradiol 1 mg/norethindrone acetate 0.5 mg) for 
the intended indication of the chronic management of HMB associated with uterine 
fibroids. 


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Subjects in this Extension Study will have completed the 6-month Treatment Period in 
one of the Pivotal Studies (Studies M12-815 or M12-817).  In this study, they will receive 
6 months of therapy, for a total of up to 12 months of active treatment for those 
randomized in the Pivotal Studies to active treatment and a total of 6 months of treatment 
for those randomized to placebo in the Pivotal Studies.
The primary objective of the Pivotal Studies is to evaluate the efficacy and safety of 
elagolix 300 mg BID in combination with add-back therapy (E2/NETA) as compared to 
placebo to reduce HMB associated with uterine fibroids.  The goal of the Extension Study 
is to generate data that supports long-term use of elagolix 300 mg BID in combination 
with E2/NETA.
Given the difficulties with extending placebo for periods beyond 6 months, the elagolix 
300 mg BID alone arm serves as a reference arm in this Extension Study, which will be 
useful in fully understanding the protective effects of standard dose E2/NETA on BMD 
over a 12-month treatment period, therefore the primary objectives of this Extension 
Study are to:
●
Evaluate the long-term efficacy and safety of elagolix administered alone and 
in combination with E2/NETA
●
Reduce heavy menstrual bleeding (HMB) associated with uterine fibroids for 
up to 12 months (initial 6 months if on active treatment in the Pivotal 
Study M12-815 or Study M12-817 and an additional 6 months in this 
Extension Study), and
●
Further characterize the impact of E2/NETA on the safety and tolerability 
(including bone mineral density and other hypoestrogenic effects and efficacy 
of elagolix. 
3.3
Estradiol/Norethindrone Acetate
E2/NETA (1 mg E2 and 0.5 mg NETA) is a continuous combined oral estrogen/progestin 
regimen.  E2/NETA is approved in the United States as postmenopausal hormone 
replacement therapy for the treatment of moderate to severe vasomotor symptoms 


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associated with menopause and the prevention of postmenopausal osteoporosis.  
E2/NETA is also approved in the United States for the treatment of moderate to severe 
symptoms of vulvar and vaginal atrophy associated with menopause.
3.4
Differences Statement
Phase 2 studies in women with HMB associated with uterine fibroids demonstrated that 
elagolix 300 mg BID provides the most robust efficacy in reducing HMB, and E2/NETA 
is the optimal regimen for managing and limiting BMD loss, such that longer-term dosing 
is feasible.
Continued assessments of this treatment regimen in the pivotal Phase 3 trials will provide 
the requisite data to support registration of elagolix 300 mg BID + E2/NETA as safe and 
efficacious treatment for the chronic management of HMB associated with uterine 
fibroids.
3.5
Benefits and Risks
The most common symptom in premenopausal women with uterine fibroids is heavy 
menstrual bleeding (HMB).  A safe and effective chronic pharmacologic therapy for 
symptomatic uterine fibroids, as an alternative to hysterectomy or other surgical 
intervention, has not yet been approved, which is the objective of the Elagolix Phase 3 
Clinical Development Program.  Results from Phase 2 studies in women with HMB 
associated with uterine fibroids demonstrated that treatment with elagolix 300 mg BID 
alone and in combination with E2/NETA provided robust efficacy in reducing HMB 
associated with uterine fibroids.  Importantly, when co-administered with elagolix 300 mg 
BID, E2/NETA (estradiol 1 mg/norethindrone acetate 0.5 mg) QD mitigated BMD loss 
observed with elagolix 300 mg BID alone and substantially other hypoestrogenic adverse 
events such as hot flushes.  Also co-administration of elagolix and E2/NETA attenuated 
increases in serum lipid parameters observed with elagolix 300 mg BID alone.  
Furthermore, there was no evidence of endometrial safety concerns and the overall safety 
profile remained unchanged, with no new or unexpected findings to date.


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This therapeutic approach, if successful, could provide an alternative to surgical 
interventions, and/or semi-invasive procedures as a chronic pharmacologic treatment for 
HMB associated with uterine fibroids.  Based on the totality of data to date from the 
Phase 2 clinical development program, the overall benefit/risk profile of elagolix 300 mg 
BID with E2/NETA appears to be favorable for the chronic management of HMB 
associated with uterine fibroids, and will be further defined in this Phase 3 trial.
4.0
Study Objective
The primary objective of this study is to evaluate the long-term efficacy and safety of 
elagolix administered alone and in combination with add-back therapy 
(estradiol/norethindrone acetate or E2/NETA) to reduce heavy menstrual bleeding (HMB) 
associated with uterine fibroids for up to 12 months (initial 6 months if on active 
treatment in the Pivotal Study M12-815 or Study M12-817 and an additional 6 months in 
this Extension Study).
The study will also evaluate the effects of the treatment regimens on hypoestrogenic side 
effects, changes in bone mineral density (BMD) as assessed by Dual Energy X-Ray 
Absorptiometry (DXA), and vasomotor symptoms, such as hot flush.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3, double-blind, multicenter, Extension Study designed to:
●
Obtain 6 month treatment data in subjects who were randomized to placebo in 
one of the two Pivotal Studies and subsequently randomized to receive 
6 months of treatment with elagolix 300 mg BID or elagolix 300 mg BID plus 
E2/NETA (estradiol 1 mg/norethindrone acetate 0.5 mg) QD in this study.
●
Obtain 12 months of continuous treatment data in subjects who received 
elagolix 300 mg BID or elagolix 300 mg BID plus E2/NETA (estradiol 
1 mg/norethindrone acetate 0.5 mg) QD for 6 months in one of the two Pivotal 


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Studies and will continue to receive an additional 6 months of the same 
treatment in this study.
●
Obtain data on endometrial health (TAU, TVU and endometrial biopsy).
●
Assess bone mineral density, bone health and general safety with long-term 
treatment and recovery during Treatment and  Post-Treatment Follow-Up 
Period (up to 12 months of Treatment and 12 months Post-Treatment Follow-
Up).
All subjects who completed the 6-Month Treatment Period in their respective Pivotal 
Study, who meet eligibility criteria and provide informed consent, will be eligible to 
enroll in this Extension Study.  This study is designed to enroll approximately 
400 subjects across approximately 250 clinical study sites to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.
The study consists of 2 periods as follows:
1.
6-Month Treatment Period
2.
12-Month Post-Treatment Follow-Up Period
Following the 6-Month Treatment Period, subjects will enter into a 12-Month Post-
Treatment Follow-Up Period.  The Study Periods are illustrated in Figure 1.


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Figure 1.
Study Schematic
Treatment Period
Subjects will perform Day 1 Visit procedures after completing the 6-Month Treatment 
Period of their respective Pivotal Study.  Subjects who do not meet criteria for inclusion 
into or are not willing to participate in the Extension Study will enter the Post-Treatment 
Follow-Up Period in their respective Pivotal Study, Study M12-815 or Study M12-817.
Subjects will continue to be assigned study drug kits via the IRT system for the Extension 
Study, after eligibility is confirmed and consent is obtained.  Subjects who received active 
treatment in the Pivotal Study will continue to receive the same treatment; subjects 
randomized to placebo will be re-randomized in IRT to receive either elagolix 300 mg 
BID) or elagolix 300 mg BID plus E2/NETA QD for 6 months.  Subjects will remain 
blinded to their original treatment received in the Pivotal Studies as well as their treatment 
in this Extension Study.  The first dose of study drug will be administered at the study site 
on Day 1.  Subjects will continue to self-administer study drug twice daily (once in the 
morning and once in the evening approximately 12 hours apart) orally without regard to 
food throughout the 6-Month Treatment Period.  Subjects randomized into the study will 
visit the site during the 6-Month Treatment Period on Day 1, and then monthly (28-day 


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intervals) from Month 1 through Month 6.  Additional study visits may occur, either for 
subjects returning their sanitary products at a Product Collection Visit or for a Premature 
Discontinuation Visit (if applicable).
Pregnancy tests (urine and/or serum) will be performed at each visit throughout the study 
and subjects will be counseled at each visit on appropriate and effective forms of dual 
non-hormonal contraception to promote pregnancy prevention. 
Sanitary product collection kits will continue to be dispensed at all Treatment Period 
Visits.  Subjects will be required to collect all sanitary products on days with menstrual 
bleeding or spotting throughout the Treatment Period.  Subjects will return sanitary 
products to the Clinical Study Site, either during a scheduled monthly visit or at a Product 
Collection Visit.  There may be an option for subjects to have a Product Collection Visit 
conducted at home by a Home Health Care Agent.
As in the Pivotal Studies, when a Subject does not return a sanitary product collection keg 
at any site visit (scheduled monthly visit or at time of Premature Discontinuation, Product 
Collection Visit or Unscheduled Visit) during the Treatment Period, the Uterine Bleeding 
Questionnaire (UBQ) will be administered by the Site Staff to indicate if the subject had 
any bleeding or spotting since the last study visit.  If the subject had bleeding or spotting, 
she will be asked why she did not return a sanitary product collection keg.  The subject's 
responses will be recorded on the UBQ by the Site Staff.
A pelvic ultrasound (TAU and TVU) will be performed during the Treatment Period as 
outlined in Appendix C.
Subjects will continue the use of dual non-hormonal contraception and receive counseling 
on the importance of consistent, appropriate and effective use of birth control.  Subjects 
who prematurely discontinue from the Treatment Period will be asked to complete 
Premature Discontinuation procedures and enter the Post-Treatment Follow-Up Period.  
Premature Discontinuation Procedures will be performed as specified in Appendix C, 
Study Activities.


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Post-Treatment Follow-Up Period
During the 12-Month Post-Treatment Follow-Up Period, visits will occur either by phone 
or on-site from Months 1 through 12.
During the Phone Visits (Post-Treatment Follow-up Visits Month 2, Month 4, Month 5, 
Month 7, Month 8, Month 10 and Month 11), Site Personnel will discuss adverse events, 
concomitant medications, if applicable, obtain the results of the subject's self-administered 
urine pregnancy test and will remind subjects of the importance of consistent use of 
appropriate and effective dual non-hormonal contraception throughout the Post-Treatment 
Follow-Up Period.  Subjects may begin taking hormonal contraceptive preparations only 
after completing the Post-Treatment Follow-Up Month 2 Visit and following the return to 
a full menses (menses with full menstrual flow) in the Post-Treatment Follow-Up Period.  
If the subject's full menses has not returned by the Post-Treatment Follow-Up Month 2 
Visit, an adverse event of amenorrhea should be documented.
Subjects will be required to collect sanitary products for their first menses with full 
menstrual flow in the Post-Treatment Follow-Up Period.  If the subject does not return 
sanitary products for her first full menses, she will be required to collect and return 
sanitary products for her next full menses.  Subjects will return the sanitary products at a 
Product Collection Visit within approximately 5 days after cessation of bleeding or 
spotting.  The Post-Treatment UBQ will be administered by Site Staff at each Phone or 
Site Visit until the subject has returned sanitary products from her first full menses in the 
Post-Treatment Follow-Up Period.  Once a subject returns sanitary products from a full 
menses in the Post-Treatment Follow-Up Period, the Post-Treatment UBQ no longer 
needs to be completed.
All subjects will be required to have DXA scans at Post-Treatment Follow-Up Months 6 
and 12.
Procedures and assessments in the Post-Treatment Follow-Up Period should be performed 
as specified in Appendix C, Study Activities.


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Unscheduled Visit
In the event an Unscheduled Visit is necessary during the Treatment or Post-Treatment 
Follow-Up Period, the site will perform at minimum, the UBQ and an assessment of
adverse events and concomitant medications.  For Unscheduled Visits when study drug is 
dispensed (e.g., to replenish lost or damaged study drug), the subject will also be required 
to have a negative urine pregnancy test result prior to dispensing.  Clinical judgment 
should dictate when other safety assessments (such as vital signs and/or symptom-directed 
physical examination) should be conducted and should also support the reason for the 
Unscheduled Visit.
Visit Windows
Visit windows will be allowed for the monthly visits during the Treatment and Post-
Treatment Follow-Up Periods.  During the Treatment Period, each subsequent monthly 
visit should be scheduled based on the date of the Day 1 Visit.  At the Month 6 Treatment 
Period Visit, a –4 or +6 day visit window will be allowed in order to collect sanitary 
products from the last episode of menstrual bleeding or spotting prior to the Month 6 Visit 
if menstrual bleeding starts immediately prior to or coincides with the scheduled visit.  
The subject will be instructed to continue taking study drug from the extra blister card 
until she returns for the Month 6 Visit.
Specific assessment-related visit windows are allowed.  Please refer to Table 1, Visit and 
Assessment Windows, for assessment-specific visit windows.


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Table 1.
Visit and Assessment Windows
Study Visit Windows
Study Visit
Visit Windows
Treatment Period:  Months 1 – 5
±4 days
Treatment Period:  Month 6
–4 or +6 days
Post-Treatment Follow-Up Period:  Months 1 – 12
±7 days
Assessment-Specific Windows for Treatment and Post-Treatment Period
Study Visit/Assessment
Visit Windows
Treatment Period
Month 3:  Ultrasound, DXA Scan (if applicable)
±7 days
Month 6:  Ultrasound, MRI (if participating in MRI subset) DXA Scan and 
Endometrial Biopsy
–15 or + 4 days
Post-Treatment Follow-Up Period
Month 3:  MRI (if participating in MRI subset)
–15 or +4 days
Month 6:  Ultrasound, DXA Scan
–15 or +4 days
Month 12:  DXA Scan
–15 or +4 days
5.2
Selection of Study Population
Subjects who completed the 6-Month Treatment Period of their respective Pivotal Study, 
have signed informed consent and meet eligibility criteria will be eligible for participation 
into this Extension Study.
Each Investigator will employ their clinical judgment in conjunction with protocol 
specified inclusion/exclusion criteria to determine if subject meets eligibility.  Questions 
should be directed to the AbbVie Therapeutic Area Medical Director (TA MD) listed in 
Section 6.1.5 if further clarification is required.
5.2.1
Inclusion Criteria
1.
Subject has voluntarily signed and dated the informed consent form (ICF), 
approved by an Institutional Review Board/Ethics Committee (IRB/EC), prior to 
initiation of any study-specific procedures.


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2.
Subject has completed the 6-Month Treatment Period of their respective Pivotal 
Study (either Study M12-815 or Study M12-817).
3.
Subject has BMD decrease < 8% in the spine, total hip and femoral neck at 
Month 6 of the Treatment Period of their respective Pivotal Study. 
4.
Subject's urine and/or serum pregnancy test(s) results were consistently negative 
during the Treatment Period of their respective Pivotal Study and at Day 1 of this 
Extension Study. 
5.
Subject must agree to use two forms of non-hormonal contraception (dual 
contraception) consistently during the Treatment Period and Post-Treatment 
Follow-Up Period (Subject may start hormonal contraception after completion of 
the Post-Treatment Follow-Up Month 2 Visit and return to first full menses).
Acceptable methods of dual contraception include the following combinations:
●
Condom with spermicide (foam, gel, or polymer film)
●
Diaphragm with spermicide (condom may or may not be used)
●
Cervical cap with spermicide (condom may or may not be used)
Subject is not required to use dual contraception methods if:
●
Sexual partner(s) is vasectomized, at least 6 months prior to Screening.
●
Subject practices total abstinence from sexual intercourse, as the preferred 
lifestyle of the subject; periodic abstinence is not acceptable.
●
Subject had a bilateral tubal occlusion (including ligation and blockage 
methods such as Essure®), at least 4 months prior to Screening.
●
Subject is not sexually active with men; periodic sexual relationship(s) with 
men requires the use of dual non-hormonal contraception as noted above.
6.
Subject's endometrial biopsy from the Month 6 Visit of their respective Pivotal 
Study shows no clinically significant endometrial pathology.


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Rationale for Inclusion Criteria:
1
This is standard criterion in accordance with harmonized Good Clinical 
Practice (GCP)
2, 3
These criteria were selected to ensure an appropriate subject population of 
premenopausal women with HMB associated with uterine fibroids 
(prognostic and predictive)
4, 5
The impact of elagolix on pregnancies or breastfed infants is unknown and 
there is a possible risk of miscarriage due to changes in hormone levels; 
therefore, these criteria ensure pregnant women are not enrolled into the 
study and adequate precautions are taken to avoid pregnancy during study 
participation (prognostic and risk)
6
This is standard criteria to ensure general good health and the safety of the 
subjects (risk)
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if she meets any of the following 
criteria:
1.
Subject met criteria for removal from therapy in her respective Pivotal Study.
2.
Subject is planning a pregnancy within the next 18 months.
3.
Subject has current suicidal ideation as evidenced by answering "yes" to 
questions 4 or 5 on the suicidal ideation portion of the Columbia-Suicide Severity 
Rating Scale (C-SSRS) completed at Treatment Period Month 6 Visit of her 
respective Pivotal Study.
4.
Subject has a newly diagnosed clinically significant medical condition that requires 
intervention OR an unstable medical condition that makes the subject an unsuitable 
candidate for the study in the opinion of the Investigator (including, but not limited 
to, uncontrolled diabetes mellitus, uncontrolled hypertension, epilepsy requiring 
anti-epileptic medication, unstable angina, confirmed inflammatory bowel disease, 


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hyperprolactinemia, clinically significant infection or injury or symptomatic 
endometriosis [confirmed by laparoscopy/laparotomy]).
5.
Subject is using any systemic corticosteroids for over 14 days 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.
6.
Subject, who in the judgment of the Investigator, will be unable or unwilling to 
comply with study-related assessments and procedures, including collection of 
sanitary products. 
Rationale for Exclusion Criteria:
1, 3, 4, 5
This is standard criteria to ensure general good health and the safety of 
the subjects (risk)
2
The impact of elagolix on pregnancies or breastfed infants is unknown 
and there is a possible risk of miscarriage due to changes in hormone 
levels; therefore, these criteria ensure adequate precautions are taken to 
avoid pregnancy or breastfeeding while receiving elagolix (risk)
6
This criterion was added to ensure the population of subjects enrolled 
will comply with study-related procedures and subject collection 
requirements throughout the entire study (predictive)
5.2.2.1
Concomitant Therapy
Any medications and therapies that were administered in the Pivotal Study and are 
continuing to be administered at the time of entry into this study should be reviewed, 
assessed and if applicable, added to the source documents and eCRFs of this Extension 
Study.
Any new medications or vaccines (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject receives during the Treatment and 
Post-Treatment Follow-Up Periods must be recorded in source documents and on the 


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Concomitant Medication eCRFs.  The reason for use, date(s) of administration (including 
start and end dates) and dosage information (including dose and frequency) must be 
recorded.
5.2.2.2
Iron Supplementation
Excessive blood loss from heavy menses may result in iron deficiency anemia.  Iron 
deficiency anemia is defined by the World Health Organization (WHO) as an Hgb 
concentration below 12 g/dL (120 g/L) for non-pregnant women.  Subjects entering the 
study with anemia or who develop anemia during the study,  if not already taking iron 
supplements, should be prescribed iron supplementation by the Investigator, as per 
standard of care.  If the Investigator does not prescribe iron supplements for subjects with 
a Hgb < 12g/dL, the reason should be documented in source documents.
The recommended oral dose of ferrous sulfate is 300 to 325 mg following the diagnosis of 
anemia.  If a subject is unable to tolerate ferrous sulfate then ferrous gluconate, liquid iron 
or intravenous (IV) iron may be prescribed.  If subjects experience constipation from iron 
supplement use, stool softeners may be prescribed.  All iron supplements taken during the 
study must be recorded on the concomitant medications eCRF.
Further instructions on the provision of iron supplementation and stool softeners will be 
provided separately from this protocol.
5.2.2.3
Concomitant Use of Corticosteroids
Chronic use (> 14 days) of systemic corticosteroids is prohibited during the Treatment 
and Post-Treatment Follow-Up Periods; however, inhaled corticosteroids for the treatment 
of asthma are permitted.  Over-the-counter and prescription topical, inhaled, intranasal or 
injectable (for occasional use) corticosteroids are allowed.
5.2.2.4
Prohibited Therapy
All hormonal forms of birth control (except the emergency contraceptive pill, 
levonorgestrel 1.5 mg [such as Plan B®], or ulipristal acetate 30 mg [such as Ella® or 


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EllaOne®]) are prohibited during the Treatment Period and until the Post-Treatment 
Follow-Up Month 2 Visit and return to first full menses.  If subject does not return to 
menses she must continue use of dual non-hormonal contraception.
For subjects who are prescribed/administered the emergency contraceptive pill during the 
study, the AbbVie TA MD must be informed.
Tranexamic acid should not be taken during the Treatment or Post-Treatment Follow-Up 
Period; however, tranexamic acid, if necessary, can be prescribed following completion of 
the Post-Treatment Follow-Up Month 2 Visit and the subject has returned to first full 
menses.
Due to the extensive list of herbal remedies and supplements, please contact the AbbVie 
TA MD for any that may be prohibited.  Generally-speaking, any supplements or herbal 
remedies used to treat premenstrual or gynecological problems, such as black cohosh, are 
excluded.
The following medications should not be taken during the Treatment and Post-Treatment 
Follow-Up Period.


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Table 2.
Prohibited Medications
Prohibited During the Treatment Period and Post-Treatment Follow-Up Periods
Hormonal/Anti-Hormonal 
Medications%, such as:
GnRH agonists leuprolide acetate (Lupron®), nafarelin acetate 
(Synarel®), goserlin acetate (Zoladex®)
GnRH antagonists (other than elagolix)
Danazol (Danocrine®)
Medroxyprogesterone acetate (Depo-Provera®, Provera®)
Oral contraceptives
Estrogen preparations*
Testosterone preparations
Other progestins* (oral, vaginal, transdermal, implantable, IUD, or 
LNG-IUS, except emergency contraception) 
HCG or HCG products
Glucocorticoids, oral or injectable (chronic use only)
Mifepristone
Selective Progesterone Receptor Modulators (e.g., Ulipristal acetate 
(except as emergency contraception, i.e., 30 mg) and
Tamoxifen)
Bromocriptine (Parlodel®)
Cabergoline (Dostinex®)
Raloxifene (Evista®)
Aromatase Inhibitors (e.g., Anastrozole [Arimidex®], Exemestane 
[Aromasin®])
Non-hormonal estrogen 
supplements#
Natural estrogen preparations (e.g., soy-containing supplements, 
black cohosh)
Antifibrinolytics%
Tranexamic acid (Lysteda, Cyklokapron, Cyclo-f)
Moderate or strong CYP3A 
Inducers,9 and Anti-epileptic 
medications, such as:
Strong Inducers:
St. John's Wort
Rifampin
Carbamazepine
Phenytoin
Dexamethasone chronic use
Moderate Inducers:
Bosentan
Efavirenz
Etravirine
Modafinil
Nafcillin


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Table 2.
Prohibited Medications (Continued)
Prohibited During the Treatment Period and Post-Treatment Follow-Up Periods
Bisphosphonates, RANKL 
inhibitors, Anabolic Bone Agents or 
rPTH, such as:
Fosamax®, Fosamax Plus D®, Binosto®, Boniva®, Reclast®, 
Zomata®,  Prolia®  XGEVA, Forteo®, Actonel®, Atelvia®, 
Miacalcin®, Fortical®
Synthetic Prostaglandin E1 (PGE1) 
Analogs, such as:
Misoprostol (Cytotec®, Arthrotec®)
Single use of PGE1 for cervical preparation prior to biopsy is 
allowed; chronic use is prohibited
Oral Retinoids (topical applications 
are permitted), such as:
Accutane® (isotretinoin)
*
E2/NETA will be taken by subjects randomized to the E2/NETA dose group.
#
Due to the extensive list of herbal remedies and supplements, please contact the AbbVie TA MD for any that may 
be prohibited.
%
Subjects may begin the use of hormonal contraceptives or tranexamic following completion of the Post-Treatment 
Follow-Up Month 2 Visit and she has returned to first full menses.  Tranexamic acid, if necessary can be 
prescribed following completion of the Post-Treatment Follow-Up Month 2 Visit and return to first full menses.
If a prohibited medication is necessary to treat an adverse event or a pre-existing 
condition other than uterine fibroids, the AbbVie TA MD noted in Section 6.1.5 should be 
consulted; however, if clinically required and to prevent an immediate hazard to the 
subject being treated, the AbbVie TA MD should be notified as soon as possible after the 
start of use.  Additionally, if a subject takes a prohibited medication during the study, 
except as permitted per protocol (hormonal medication taken after completion of the Post-
Treatment Follow-Up Month 2 Visit and return to first full menses), her continued 
participation in the study will be evaluated by the Investigator and the AbbVie TA MD.  If 
there are any questions regarding prior or concomitant therapy, please contact your Study 
Monitor.
5.2.3
Contraception Recommendations and Pregnancy Testing
Contraception Counseling/Dispense Contraceptives
Subjects (excluding those subjects who have had a bilateral tubal ligation or bilateral tubal 
occlusion) will continue to be counseled at every visit throughout their participation in the 
study on the importance of pregnancy prevention and the use of appropriate and effective 


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methods of birth control during the Treatment and Post-Treatment Follow-Up Periods of 
the Extension Study.
Subjects must agree to use two forms of non-hormonal contraception (dual contraception) 
consistently throughout the Treatment Period and Post-Treatment Follow-Up Periods 
(Subjects may begin the use of hormonal contraception (e.g., oral or IUD) after 
completing the Post-Treatment Follow-Up Month 2 Visit and have returned sanitary 
products for a full menses).
Acceptable methods of dual non-hormonal contraception include the following 
combinations:
●
Condom with spermicide (foam, gel, or polymer film)
●
Diaphragm with spermicide (condom may or may not be used)
●
Cervical cap with spermicide (condom may or may not be used)
Subjects are not required to use dual contraception methods if:
●
Sexual partner(s) is vasectomized at least 6 months prior to Screening
●
Subject practices total abstinence from sexual intercourse, as the preferred 
lifestyle of the subject; periodic abstinence is not acceptable
●
Subject had a bilateral tubal occlusion (including ligation and blockage 
methods such as Essure®) at least 4 months prior to Screening.
●
Subject is not sexually active with men; periodic sexual relationship(s) with 
men requires the use of dual non-hormonal contraception as indicated above.
Subjects may begin the use of hormonal contraception in place of dual non-hormonal 
contraception during the Post-Treatment Follow-Up Period if they meet both of the 
following: 
●
Completed the Post-Treatment Follow-Up Month 2 Visit and
●
Returned sanitary products for a full menses in the Post-Treatment Follow-Up 
Period


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If subject does not return to full menses, she must continue use of dual non-hormonal 
contraception.
The following measures will be taken to help ensure pregnancy prevention during the 
Extension Study.
1.
The informed consent form will include an attestation requiring the subject to 
confirm in writing her full awareness that the potential risks of study drug 
(elagolix) on the unborn child are unknown and therefore she must not get pregnant 
during the entire time of study participation, and that she agrees to consistently use 
dual non-hormonal contraception throughout her study participation (during the 
Treatment and Post-Treatment Follow-Up Period.
2.
The Investigator or designated study staff will counsel the subject that the study 
drug is not contraceptive, that ovulation may occur even though the study drug may 
have altered menstrual cyclicity, and that fetal abnormalities have been observed in 
women who have received elagolix in clinical studies that were not deemed to be 
related to elagolix based on the totality of data; however, it is unknown whether 
these abnormalities were the result of taking elagolix.
3.
The Sponsor will provide training materials to the sites for instructing subjects on 
the types of protocol-allowed contraception methods, their effectiveness and proper 
use.
●
The Sponsor will provide sites with a supply of materials to promote 
pregnancy prevention, including contraceptives (condoms and spermicides), 
and lubricants to provide to subjects at no charge.  Subjects should only use 
the pregnancy prevention materials provided by the Sponsor as these products 
have undergone analytical testing by the analytical lab to confirm there is no or 
limited interference with the alkaline hematin method.
●
Subjects will be allowed to choose a contraception method of their choice from 
the contraceptives provided by the Sponsor and practice the allowable methods 
of dual contraception.  The site will assess the subject's basic understanding of 


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the proper use through discussion and demonstration of proper techniques, 
including proper diaphragm use.
●
The site will dispense contraceptives to subjects throughout Treatment and 
through the Post-Treatment Follow-Up Period, as needed.  Subjects may begin 
the use of hormonal medication after completion of the Post-Treatment 
Follow-Up Month 2 Visit and return to first full menses.
●
The source documents will capture date contraception counseling was 
performed, whether the subject is sexually active with men, the type of 
contraceptive used, a change in contraceptive method, use of a non-study 
supply brand, contraceptives provided to the subject, and the date supplies 
were provided.
●
As appropriate, the subject will be asked to attest by signature at the time of 
consent, and in a stand-alone attestation form at Day 1 and at the Month 6 or 
Premature Discontinuation study visit that allowable methods of contraception, 
as described during the pregnancy prevention counseling, are being practiced.
●
For subjects who have had a bilateral tubal occlusion, attestation is only 
required to be collected once at the time of consent.
4.
Subjects will be reminded to use dual non-hormonal contraception.
5.
The study drug will be dispensed as a monthly supply at the beginning of each 
month during the Treatment Period to promote frequent interaction with site staff 
and opportunities for continued education.
6.
At each visit, subjects will be asked to name the type of contraception used since 
their last visit and will be reminded of the proper use of that type of method to 
prevent ineffective contraception and the risk of unexpected pregnancy due to 
unprotected sexual activity.
Pregnancy Tests and Reporting a Pregnancy
Urine and/or serum pregnancy tests will be performed as specified in Appendix C, Study 
Activities, in all subjects regardless of sexual activity status or method of contraception.  


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The subject must have a confirmed negative urine pregnancy test within 24 hours prior to 
performing endometrial biopsy or SIS (if applicable).
The urine and serum pregnancy tests performed at the Final Treatment Visit (Month 6 or 
Unscheduled Visit just prior to roll-over into the Extension Study) of the Pivotal Study 
will serve to assess subject eligibility for entry into this Extension Study and the urine 
pregnancy test result must be reviewed and determined to be negative prior to registering 
the subject in IRT.  If the Final Treatment Visit in the Pivotal Study (just prior to roll-over 
into this Extension Study) does not occur on the same day as Day 1 of this Extension 
Study, a urine pregnancy test must be performed at Day 1 and a negative urine pregnancy 
test result must be obtained prior to administration of the first dose of study drug in this 
Extension Study.
Urine pregnancy test results must be negative prior to providing subjects with their Day 1 
and subsequent supply of study drug, (including an Unscheduled Visit at which study 
drug is dispensed).
Home pregnancy test kits will be provided to the subject at the Day 1 Visit and Month 6 
or Premature Discontinuation Visit during the Treatment Period when logistically, a urine 
pregnancy test cannot be performed at the study site or other medical facility within 
24 hours prior to an endometrial biopsy or SIS (if applicable).  The subject must self-
administer and report a negative urine pregnancy test result to the site within 24 hours 
prior to undergoing these procedures.
A positive urine pregnancy test result must be confirmed with a quantitative serum 
pregnancy test.  The subject should temporarily discontinue study drug administration 
while waiting for the results of the serum pregnancy test.  If a serum pregnancy test result 
is positive at any time during the Treatment Period, the site will immediately inform the 
subject to discontinue study drug (Section 6.1.6).  If a subject is confirmed as pregnant, 
the subject will be prematurely discontinued from the study.


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An ultrasound examination will be performed during the first trimester of pregnancy to 
assess the gestational age and estimated date of delivery if the subject becomes pregnant 
during the Treatment or Post-Treatment Follow-Up Periods of the study.  Refer to 
Section 6.1.6 for instructions on reporting of a pregnancy to the Sponsor and the required 
follow-up on the subject/fetus and live infant births.
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, 
Pharmacogenetic and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures during the Treatment and Post-Treatment Follow-Up Periods described 
in this protocol are summarized in Appendix C, Study Activities.
5.3.1.1
Study Procedures
Subjects entering into this Extension Study will have completed all Month 6 study 
procedures in their respective pivotal study, Studies M12-815 or M12-817, and following 
availability of all assessment results, the subject will have been determined to be eligible 
for this Extension Study.
Study procedures in this Extension Study begin on Day 1 and should be conducted as per 
Appendix C, Study Activities.  When the Day 1 Visit occurs on the same day as the Final 
Treatment Visit of the respective Pivotal Study, assessments and procedures performed at 
the Final Treatment Visit should not be repeated at the Day 1 Visit of this Extension 
Study, unless deemed necessary by the Principal Investigator. 
The study procedures outlined in Appendix C, Study Activities, are discussed in detail in 
this section, with the exception of the monitoring of study drug accountability 
(Section 5.5.7) and the collection of concomitant medication and adverse event
information (Section 5.2.2.1 and Section 6.1, respectively).  Study data will be recorded 
on eCRFs with the exception of several PRO questionnaires that will be recorded on 
source documents and on eCRFs.


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Study procedures during the Treatment and Post-Treatment Follow-Up Periods may be 
performed within the visit windows specified in Table 1.  Scheduled monthly visits during 
the Treatment and Post-Treatment Follow-Up Period are based on a 28-day month.
This protocol provides recommendations regarding the sequence of procedures to be 
performed during the study.  In no case should these recommendations outweigh clinical 
judgment or standard of care.  If the protocol indicates that the AbbVie TA MD is to be 
contacted prior to performing a procedure, yet the timing of the request would either 
interrupt a procedure or would interfere with standard of care and clinical judgment, then 
clinical judgment should prevail and the AbbVie TA MD should be notified afterwards.
When findings of past medical, surgical, gynecological or uterine fibroid history are 
identified, the relevant eCRF(s) and Source Note(s) of the Pivotal Study 
(Studies M12-815 or M12-817) should be updated, unless otherwise instructed by the 
Monitor.
Informed Consent
The IRB/IEC approved informed consent will be signed by the subject before beginning 
any study-specific procedures.  Details about how informed consent will be obtained and 
documented are provided in Section 9.3.
Gynecological (Pelvic and Breast) Examination
A complete breast, and pelvic examination, including external genitalia will be performed 
during the Month 6 or Premature Discontinuation Visit in the Treatment Period.
Pap Test
A Pap test will be performed at Treatment Period Month 6 or Premature Discontinuation 
Visit.
A Pap test will be collected using the Thin Prep® Pap Test™ provided and analyzed by 
the central laboratory.  If the subject is experiencing menstrual bleeding that precludes the 


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performance of the Pap test, this procedure should be performed as soon as possible after 
the menstrual bleeding has ended.  In the case of an unsatisfactory sample, the Pap test 
should be repeated.  The repeat Pap test should be performed when the subject is not 
experiencing menstrual bleeding.
Subjects who have Pap test results that require additional evaluation should follow local 
guidelines or standard of care.  In addition, the AbbVie TA MD should be notified to 
discuss subject's management plan for any clinically significant pathologic findings 
during the Post-Treatment Follow-Up Period.
All subjects will continue in the Post-Treatment Follow-Up Period.  Subjects who may 
require colposcopy will enter the Post-Treatment Follow-Up Period and should be treated 
per local guidelines or standard of care.
Endometrial Biopsy
Instructions on endometrial biopsy collection and processing procedures for shipping will 
be provided by the central laboratory.  Sites can use the endometrial biopsy instruments 
provided by the Central Lab or any other endometrial biopsy instruments available at the 
study site.  Subjects must have a confirmed negative urine pregnancy test within 24 hours 
prior to undergoing the endometrial biopsy.
Pre-medication for the endometrial biopsy procedure is allowable and should be recorded 
in source documents and on the appropriate eCRF.  Misoprostol for cervical dilatation is 
allowable.  An office hysteroscopy may be performed to obtain the endometrial biopsy 
sample if the endometrial biopsy cannot be performed because of anatomical reasons.
An endometrial biopsy will be performed at the Treatment Period Month 6 Visit or at the 
Premature Discontinuation Visit (if the subject prematurely discontinues after the Month 3 
Visit).


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If the endometrial biopsy is performed on the same day as the Pap smear or pelvic 
ultrasound, the endometrial biopsy should be performed after the Pap smear and pelvic 
ultrasound.
In the event that the Month 6 or Premature Discontinuation Visit endometrial biopsy 
cannot be performed (e.g., due to a stenotic cervix or location of fibroids), or an 
insufficient biopsy sample is obtained and the concurrent TVU indicates a thickness of 
> 4 mm, a repeat biopsy must be performed.  If upon repeat, a sample cannot be obtained 
or remains insufficient, the AbbVie TA MD should be consulted.
Subjects with abnormal endometrial pathology results at Treatment Month 6 will enter the 
Post-Treatment Follow-Up Period and should be managed according to standard of care.  
The subject's management plan for any of these significant pathologic findings should be 
reviewed with the AbbVie TA MD, and the subject outcome documented in the eCRF.
Physical Examination
During the Treatment Period and Post-Treatment Follow-Up Periods, a complete physical 
examination will be performed at Treatment Period Month 6 and Post-Treatment Follow-
Up Month 6 or Premature Discontinuation Visits.  The complete physical examination 
will include weight measurements.  Symptom-directed physical examinations will be 
performed as specified in Appendix C, Study Activities.
Any clinically significant physical examination findings will be recorded in the source 
documents and in the eCRFs as adverse events.
Vital Signs
Vital sign determination of heart rate, blood pressure, respiratory rate and body 
temperature will be obtained at all visits during the study as indicated in Appendix C, 
Study Activities.  The blood pressure and heart rate measurements should be taken prior 
to scheduled blood collections.  Body temperature measurements should be assessed using 


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the same modality consistently throughout the study, e.g., oral, aural, axillary, etc., and 
the modality will be reported in the source documents and eCRF.
12-Lead Electrocardiogram (ECG)
During the Treatment Period, a resting 12-lead ECG will be conducted at the Month 6 
Visit or Premature Discontinuation Visit (if applicable) as indicated in Appendix C, Study 
Activities.
The Investigator or qualified designee at the study site will determine if any findings 
outside the normal physiological variation are clinically significant (in consultation with a 
cardiologist if necessary), and document this on the ECG tracing/report with signature and 
date.  The original ECG tracing or a certified copy of the original tracing with the 
physician's assessment will be retained in the subject's records at the study site.  For ECG 
with QT interval corrected for heart rate (QTc) > 450 msec, the correction formula used 
(i.e., Bazett's or Fridericia's) and the corrected result should be recorded in source 
documents and eCRF.  The study site should use the same correction formula used in the 
respective pivotal study and continue to consistently use throughout this study.
Mammogram
All subjects who had a mammogram performed to determine eligibility into their 
respective Pivotal Study, will have a mammogram performed at Treatment Period 
Month 6 or at the Premature Discontinuation Visit if it has been approximately 12 months 
since the screening mammogram was performed.
Central Imaging Procedures
Fibroid and uterine assessments will be obtained using pelvic ultrasound (TAU and TVU) 
throughout the study.  In addition to the TAU and TVU, an MRI will continue to be 
performed in the subset of subjects who consented and participated in the MRI Subset 
during their respective pivotal study.  The MRI subset will continue to evaluate uterine 
fibroid size and volume and uterine volume using another technique in addition to 
ultrasound.


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All ultrasound and MRI images will be sent to the Central Imaging Core Lab (ICL) for 
review to monitor safety during the Treatment and Post-Treatment Follow-Up Periods.
The pelvic ultrasound (TAU, TVU) and/or SIS and MRI (if applicable) will be performed 
by the Investigative Sites' or affiliated Radiology Department.  The Ultrasonographer at 
each Investigative Site will be required to acquire the ultrasound and MRI (if applicable) 
images according to the Imaging Acquisition Guidelines provided by the ICL.  Images 
should be sent/transmitted to the ICL for subject evaluation during the course of the study.  
Refer to the Image Acquisition Guidelines for instructions on submitting images to the 
ICL.
The pelvic ultrasound (TAU, TVU), and/or SIS and MRI (if applicable) will be assessed 
both locally and by the ICL.  If images are unevaluable, the ICL will inform the 
Investigative Site and additional images will need to be resubmitted.  If there is a 
discrepancy between the local assessment and the central reader's assessment, this should 
be brought to AbbVie's attention and AbbVie will discuss the findings with the local site 
and central reader on a case-by-case basis.  The Investigator or designee should consult 
the local ultrasound and SIS reports and/or images in order to make any safety-related 
judgments concerning the subject.  The interpretation of the local report and/or images 
will be filed or recorded in the subject's source documents.  Data and/or local 
interpretation from the local ultrasound and SIS images will not be recorded in the eCRF 
unless associated with a significant finding or adverse event.
During the Treatment and Post-Treatment Periods, the ICL may issue a report if any 
significant changes are observed that may affect subject safety during the study.  In these 
cases, the Investigator should review the local ultrasound and/or MRI images and treat as 
per standard of care.
The pelvic ultrasound, and MRI (if applicable) will be performed as specified in 
Appendix C, Study Activities.


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Pelvic Ultrasound:  TAU and TVU
Pelvic ultrasounds (TAU and TVU) will be performed at Treatment Period Month 3 and 
Month 6 and at Post-Treatment Follow-Up Period at Month 3 and Month 6 or at the time 
of premature discontinuation (if not performed within the past 2 months).  Assessments 
for the pelvic ultrasound include, but are not limited to the following:
●
Endometrial thickness 
●
Presence of abnormal endometrial appearance or endometrial pathology
●
Presence of uterine fibroids
○
Number of uterine fibroids
○
Volume and location of the 3 largest fibroids
●
Uterine volume in cubic centimeters
●
Presence of ovarian cysts 
○
Number
○
Size (cm)
○
Location (right or left ovary)
○
Simple versus complex
●
Endometrioma > 3.5 cm longest diameter
●
Solid ovarian lesions > 1.5 cm longest diameter
Magnetic Resonance Imaging (MRI) Subset:
Subjects who participated in the MRI subset in the Pivotal Studies will continue to be 
included in the MRI subset in this study.
An MRI will be performed at the Month 6 or Premature Discontinuation Visit during the 
Treatment Period and at the Post-Treatment Follow-Up Month 3 Visit.  Subjects who had 
an MRI performed in the past 3 months prior to prematurely discontinuing are not 
required to repeat the MRI at the time of Premature Discontinuation during the Treatment 
or Post-Treatment Follow-Up Period.


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Assessments for the MRI include, but are not limited to the following:
●
Fibroid volume in cubic centimeters (of 3 largest fibroids) 
●
Fibroid location
●
Uterine volume in cubic centimeters
●
Presence of adenomyosis (diffuse adenomyosis as the dominant condition 
versus focal) 
●
Presence of any concerning findings
Depending on the size of the uterus, MRI images of the abdominal cavity may need to be 
submitted to measure uterine volume and to assess for safety.  It is recommended to 
follow standard of care when determining which anatomical sections are to be included in 
order to prevent incomplete views, thus leading to repeat procedures.  Please refer to the 
Image Acquisition Guidelines for further details. 
Intracavitary Uterine Findings
An SIS may be performed during the Treatment or Post-Treatment Follow-Up Periods 
when the pelvic ultrasound (TAU and TVU) or MRI (if applicable) results suggest an 
intracavitary lesion such as a polyp.  The finding of a polyp during the Treatment or Post-
Treatment Follow-Up Periods should be documented as an adverse event if the 
Investigator considers it to be clinically significant.
The AbbVie TA MD should be notified of the subject's management plan for any 
clinically significant pathologic findings during the Treatment and Post-Treatment 
Follow-Up Periods.
Ovarian Findings:
During Treatment or Post-Treatment Follow-Up Periods, if the pelvic ultrasound shows a 
simple ovarian cyst > 5 cm or a complex ovarian cyst (including endometriomas) 
> 3.5 cm in longest diameter the findings should be documented as an adverse event if the 
Investigator considers them to be clinically significant.


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Bone Mineral Density (DXA Scan)
DXA scans of the spine, femoral neck and total hip will continue to be performed by 
qualified technologist/radiologists utilizing GE Lunar or Hologic equipment and sent to 
an ICL for review and analysis.  The same instructions on calibration and standardization 
of instruments as used in the pivotal studies and as specified in the manual provided to all 
study sites should be used.
DXA Scans Performed in the Treatment Period
DXA scans are required to be performed during the Treatment Period as follows:
●
Month 3:  Only for those subjects with BMD decrease ≥ 5% in the spine or
total hip at Month 6 of their respective pivotal study (Studies M12-815 or 
M12-817) as determined by the central reader
●
Month 6: All subjects


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Figure 2.
Management of BMD % Decrease:  Treatment Period and Post-
Treatment Period
Management of BMD % Decrease on DXA scan obtained at Treatment Month 3:
●
Subjects with BMD decrease ≥ 8% in the spine, femoral neck or total hip will 
discontinue study drug treatment and enter the Post-Treatment Follow-Up 
Period to have the required BMD evaluation at Follow-Up Months 6 and 12.
●
Subjects with BMD decrease ≥ 5% and < 8% in the spine or total hip will 
continue in treatment and will require a DXA scan at Treatment Month 6.
DXA Scans Performed in the Follow-Up Period
DXA scans will be performed in the Follow-Up Period as follows:


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●
Follow-Up Month 6 
●
Follow-Up Month 12
●
Follow-Up Premature Discontinuation visit unless the subject prematurely 
discontinued from Follow-Up and had a study DXA scan within approximately 
1 month prior to the Follow-Up Premature Discontinuation Visit.
Management of BMD % Decrease from Baseline for Subjects Who Prematurely 
Discontinue in the Follow-Up Period
Subjects who prematurely discontinue at the time of or after the Month 3 study visit will 
and have a Follow-Up Premature Discontinuation DXA scan performed will be referred to 
a bone specialist for further evaluation utilizing the criteria listed below for referral at the 
end of the 12 Month Follow-Up Period.
Management of BMD % Decrease at Post-Treatment Follow-Up Month 12
Management of subjects with BMD % decrease at Post-Treatment Follow-Up Month 12 is 
outlined below and illustrated in Figure 3.
Subjects with Post-Treatment Month 12 BMD % decrease of < 3% in the spine, femoral 
neck and total hip and no decrease in any region from Post-Treatment Follow-Up Month 6 
to Month 12 will not require a referral to a bone specialist.
Subjects will be referred to a Bone Specialist at Post-Treatment Follow-Up Month 12, 
even if the overall BMD decrease from baseline is < 3%, if they meet the following 
criteria:
●
Subject had Post-Treatment Month 6 BMD decrease compared to baseline (of 
the Pivotal Study) in any region and demonstrates further BMD decrease at 
Month 12 in the same region (between Post-Treatment Month 6 and Month 12) 
and, subject meets one of the following:
○
Subject was ≥ 45 years of age at the time of last dose of study drug in the 
Treatment Period
OR


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○
Subject has not had a menses in the past 12 months
●
Subjects with Post-Treatment Month 12 BMD % decrease of ≥ 3% in the 
spine, femoral neck or total hip and a T-score < –1.0 OR T-score < –1.5 will 
be referred to a bone specialist for further management, and will be followed 
on an individual basis.
The management plan for subjects referred to a Bone Specialist (e.g., Endocrinologist, 
Rheumatologist, International Society for Clinical Densitometry (ISCD) certified 
physician) will be reviewed with the AbbVie TA MD; this includes, follow-up 
information on the subject evaluation, treatment, and outcome.  Follow-up information 
from the initial evaluation will be recorded in the eCRF.  It is recommended that the bone 
specialist should be someone other than the Principal Investigator or Sub-Investigator.
Subjects who do not meet any of the above criteria will not require additional BMD 
follow-up.


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Figure 3.
Management of BMD % Decrease:  Post-Treatment Follow-Up 
Month 12
Note:
If criteria is not met, no referral to bone specialist is required.
The baseline DXA is the Screening DXA performed in the respective Pivotal 
Study M12-815 or Study M12-817.  In the event that there is a change in DXA machine 
for a subject between baseline and a subsequent time-point, the AbbVie TA MD must be 
consulted.
A BMD decrease at any anatomic location (spine, total hip or femoral neck) during the 
Treatment or Post-Treatment Follow-Up Period that leads to premature discontinuation 
from study or a BMD decrease at any anatomic location with a T-score < –1.5 should be 
reported as an adverse event.


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Clinical Laboratory Tests
Samples will be obtained for the laboratory tests listed in Table 3, at the time points 
indicated in Appendix C, Study Activities.
Table 3.
Clinical Laboratory Tests
Hematology
Clinical Chemistry (After 
Minimum 8-Hour Fast)
Urinalysis
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands (if indicated)
Lymphocytes
Monocytes
Basophils (if indicated)
Eosinophils (if indicated)
Platelet count (estimate not 
acceptable)
Mean Cell Volume of RBC 
(MCV)
Mean Corpuscular Hemoglobin 
(MCH)
Mean Corpuscular Hemoglobin 
Concentration (MCHC)
Sodium
Potassium
Chloride
Bicarbonate
Serum creatinine
Glucose
Calcium
Inorganic phosphorus
Magnesium
Total protein
Albumin
Total bilirubin
Serum glutamic-pyruvic 
transaminase (SGPT/ALAT)
Serum glutamic-oxaloacetic 
transaminase (SGOT/ASAT)
Alkaline phosphatase
Uric acid
Lactate dehydrogenase
Creatinine Phosphokinsae
Serum iron
Serum ferritin
Total iron binding capacity (TIBC)
Specific gravity
Ketones
Protein
Blood
Glucose
pH
Microscopic Exam
Urine%
Gonorrhea
Chlamydia
Lipid Panel (After 
Minimum 8-Hour Fast)
LDL cholesterol
HDL cholesterol
Triglycerides
Total cholesterol
Lipid Profile
Apolipoprotein A and B
Pregnancy Test
Serum pregnancy
Endocrine Panel
PK and PD Assay
Follicle-stimulating hormone (FSH)
Luteinizing Hormone (LH)
Reflexive Thyroid Stimulating 
Hormone (TSH)
Thyroxine Binding Globulin (TBG)
Elagolix and NETA*
E2 and P*
*
Samples will be shipped to the Central Laboratory by the Study Site and then shipped by the Central Laboratory to 
AbbVie for analysis.
%
Optional – ordered at Investigator's discretion.


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All laboratory samples (hematology, chemistry, urinalysis, endocrine panel, lipid panel) 
will be assessed using a certified central laboratory and these data will be used for data 
analysis.  The central laboratory will provide instructions regarding the collection 
(including any fasting requirements), processing and shipping of samples.  Blood draws 
should be performed after vital signs and ECG recordings are conducted at a visit.  All
clinical laboratory samples will be shipped to the central laboratory, with the exception of 
the venous blood sample for alkaline hematin analysis which will be sent to the alkaline 
hematin laboratory.  Residual serum samples remaining after chemistry testing has been 
performed will be stored frozen at the central laboratory for possible repeat testing or 
further analysis upon AbbVie's request.
The laboratory results (except Apo A and Apo B) will be provided by the central 
laboratory to the Investigative Site where they will be reviewed, signed and dated by the 
Investigator.  For any value outside of the reference range, the Investigator will indicate 
on the report if the result is clinically significant (CS) or not clinically significant (NCS).  
The Investigator will assess clinically significant laboratory values per standard of care 
which may include repeating the test to verify the out-of-range value.  Clinically 
significant laboratory abnormalities may be documented as adverse events, depending on 
the interpretation of the Investigator (Section 6.1).
The Investigator will receive Sponsor defined alerts from the central laboratory.  The 
Investigator will review the lab alerts and assess clinical significance for potential events.
Blood samples for Pharmacokinetic (PK) and Pharmacodynamic (PD) analysis will be 
collected and processed as indicated in Section 5.3.1.2 (PD) and Section 5.3.2 (PK).
Safety Laboratory Tests
Clinical safety laboratory tests consist of hematology, clinical chemistry, including lipid 
panel and urinalysis samples.  The clinical chemistry and lipid panel samples should be 
obtained in the morning following an overnight fast (minimum of 8 hours); however, 
there may be circumstances when a sample was not under fasting conditions.  If a sample 


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was obtained with less than 8 hours of fasting, the Source Documents and the lab 
requisition should be marked to indicate that the sample was obtained under non-fasting 
conditions.
Lipid Panel
If, during the Treatment or through Post-Treatment Follow-Up Period Month 12 Visit the 
lipid panel results for LDL cholesterol, Triglycerides, Total cholesterol are more than 3 × 
the upper limit of normal range and the sample was not obtained under fasting conditions 
(minimum 8 hour fast), the subject will return to the office as soon as possible to have the 
panel repeated under fasting conditions. 
Apolipoprotein A and B, (Apo A and Apo B)
Blood samples for Apo A and Apo B will be collected as part of the Chemistry Panel.  
The Apo A and Apo B data are exploratory and results will not be provided to the 
Investigative Site.
Urine Test for Gonorrhea and Chlamydia (Optional) 
Gonorrhea and chlamydia testing can be ordered at the Investigator's discretion to test for 
active gonorrhea or chlamydia.  Any treatment provided will occur outside of the 
protocol.
Endocrine Panel
The endocrine panel consists of the following analytes:  FSH, LH, reflexive TSH and 
thyroxine-binding globulin (TBG).
Sanitary Product Collection for Alkaline Hematin Assay
Quantitative measurement of the volume of MBL will be performed using the alkaline 
hematin method.  Menstrual blood loss will be assessed in all subjects using validated 
sanitary products, also referred to as "validated" products.  Validated products have 
undergone analytical testing by the analytical lab to confirm adequate precision and 


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accuracy of blood recovery as well as no or limited interference with the alkaline hematin 
method.
Subjects will continue to collect their sanitary products throughout the 6-Month 
Treatment Period and up through their first menses with full menstrual flow in the Post-
Treatment Follow-Up Period to assess return to menses.  Subjects will be dispensed 
sanitary collection kits that consist of validated sanitary products, product collection bags, 
bar-coded labels and a keg with screw-on lid for storage as provided by the vendor.  It is 
important that only the sanitary products provided for use during the study are used.  
Validated sanitary products may include:
●
Tampax tampons (Regular, Super or Super-Plus absorbency)
●
Stayfree Maxi Pads (Regular, Super Long or Overnight absorbency)
●
Carefree Original Long Unscented pantiliners
Subjects will be required to collect and retain all sanitary products on days with menstrual 
bleeding or spotting (subjects must be instructed to collect and return all used or 
worn products even if there is no visible blood on the products or if non-validated 
products were used) as described in the Alkaline Hematin Laboratory Manual.
The dispensation and collection requirements in the Treatment and Post-Treatment 
Follow-Up Periods are outlined in Figure 4.


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Figure 4.
Sanitary Product Dispensation and Collection
Sanitary Product Collection During the Treatment Period
During the Treatment Period, Subjects will collect sanitary products on all days with 
menstrual bleeding or spotting.
Sanitary products collected during the Treatment Period will be returned by the Subject 
within approximately 5 days after cessation of menstrual bleeding or spotting and a 
venous sample will be obtained at either a scheduled monthly visit or at a Product 
Collection Visit, as appropriate.
Treatment Period Product Collection Visits
Product Collection Visits are only necessary if a monthly visit is not scheduled to occur 
within approximately 5 days after cessation of menstrual bleeding or spotting.  During the 
Product Collection Visits, subjects will have a venous blood sample, urine pregnancy test, 
vital signs, contraception counseling, as well as adverse event and concomitant 
medication assessment.  Product Collection Visits Period should be numbered in 


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sequential order (e.g., Product Collection Visit 1, Product Collection Visit 2, etc.) and 
entered into the eCRF.
Subjects who do not return a sanitary product collection keg at a site visit (scheduled 
monthly visit, PCV or Unscheduled Visit) will be administered the UBQ by the Site Staff.  
The Site Staff will ask the subject if she had any bleeding or spotting since the previous 
visit.  If the subject did have bleeding or spotting since the previous visit, the site staff 
will ask why the subject did not return sanitary products.  Responses to these questions 
will be documented on the UBQ by the Site Staff.
Sanitary Product Collection During the Post-Treatment Follow-Up Period
Subjects will be required to collect sanitary products on days with menstrual bleeding or 
spotting up through and including their first menses with full menstrual flow in the Post-
Treatment Follow-Up Period.  Once a subject has submitted sanitary products from her 
first full menses in the Post-Treatment Follow-Up Period she will no longer be required to 
collect sanitary products during her subsequent menses.
Subjects who have not returned to their first full menses and have not returned a sanitary 
product collection keg in the Post-Treatment Follow-Up Period will be administered the 
UBQ by the Site Staff.  The Site Staff will ask the subject if she had any bleeding or 
spotting since the previous visit.  If the subject did have bleeding or spotting since the 
previous visit, the site staff will ask why the subject has not returned for a Post-Treatment 
Product Collection Visit to return her sanitary products.  Responses to these questions will 
be documented on the UBQ by the Site Staff.  Once a subject returns sanitary products 
from a full menses in the Post-Treatment Follow-Up Period, the Post-Treatment UBQ no 
longer needs to be completed.
Return of Sanitary Products to Alkaline Hematin Vendor
The site will submit sanitary products and venous blood sample collected at the scheduled 
monthly visits or Product Collection Visits to the Alkaline Hematin Lab for analysis as 
outlined in the Alkaline Hematin Laboratory Manual.


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Home Visits
There may be an option for subjects to have a Product Collection Visit conducted at home 
by a Home Health Care Agent who will go to the Subject's home to draw a venous blood 
sample and retrieve the collection keg to return to the site.
Use of Non-Validated Products
All subjects are to only use validated products, however, in cases when a subject used 
non-validated (a product not provided for use in the study), the subject should be 
instructed to collect and submit the non-validated products to the Study Site.
Patient Reported Outcomes (PRO) Rating Scales
As in the Pivotal Studies, Site Personnel will be trained on all rating scales used in this 
study.  The objective of this training is to establish uniformity across sites in 
administration of these rating instruments.  The following questionnaires will continue to 
be completed by the Subjects and/or the Investigator or Site Staff, as appropriate at the 
time points indicated in Appendix C, Study Activities.  Subjects and Site Staff will be 
asked to record their responses directly onto paper questionnaires and enter into the eCRF.
Uterine Bleeding Questionnaire (Treatment-UBQ)
Subjects who did not return a Sanitary Product Collection Keg (for alkaline hematin 
analysis) at a site visit (scheduled monthly visit, PCV or Unscheduled Visit) during the 
Treatment Period, will be asked to indicate whether they had any uterine bleeding or 
spotting since their last study visit.  If the subject did not have uterine bleeding or spotting 
the site staff will indicate "No" on the UBQ.  If the subject did have bleeding or spotting, 
the subject will be asked the reason they did not return sanitary product collection keg.  
This response will be recorded on the UBQ (Appendix D) by the Site Staff.
Post-Treatment Uterine Bleeding Questionnaire (Post-Treatment-UBQ)
Subjects who have not collected and returned sanitary products for their first menses with 
full menstrual flow in the Post-Treatment Follow-Up Period, will be asked at each visit 


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before sanitary products are returned if they had any bleeding or spotting since their last 
visit.  If the subject did not have uterine bleeding or spotting the site staff will indicate 
"No" on the UBQ.  If the subject did have bleeding or spotting, the subject will be asked 
the reason she did not return the sanitary product collection keg.  This response will be 
recorded on the UBQ (Appendix E) by the Site Staff.
Uterine Fibroid Symptoms Quality of Life (UFS-QoL) (4-Week Recall)
The UFS-QoL (Appendix F) is a disease-specific self-administered questionnaire used to 
measure health-related quality of life in women with symptomatic uterine fibroids.  Each 
subject will be asked to complete a modified (4-week recall) UFS-QoL Questionnaire10 to 
report fibroid-related symptoms experienced during the previous 4 weeks.
Patient Global Impression of Change – Menstrual Bleeding (PGIC-MB)
Subjects will use the PGIC-MB (Appendix G) to assess the change in their severity of 
menstrual bleeding (from very much improved to very much worse) since initiation of 
study drug in their respective pivotal study by choosing one of seven responses.
Patient Global Impression of Change – Non-Bleeding Uterine Fibroids Symptoms 
(PGIC-NBUFS)
Subjects will complete the PGIC-NBUFS (Appendix H) to document the presence of and 
to assess the change in the overall severity of non-bleeding uterine fibroid symptoms and 
the severity of specific non-bleeding uterine fibroid symptoms (from very much improved 
to very much worse) since initiation of study drug in their respective Pivotal Study.
Work Productivity and Activity Impairment Questionnaire (WPAI)
The WPAI questionnaire (Appendix I) will consist of questions measuring the impact of 
uterine fibroid symptoms on work productivity and daily activities during the previous 
7 days.  The questionnaire will be completed by Study Subjects.


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EuroQol-5D 5 level (EQ-5D-5L™)11
The EQ-5D-5L (Appendix J) is a standardized measure comprised of 5 questions, 
measuring 5 dimensions of health status (mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression).  Subjects will be asked to select a response to 
each category that best describes their current health.  The EQ-5D-5L also contains a 
visual analogues scale that collects the quantitative measure of health as judged by the 
individual respondents.  Subjects will also be asked to rate their current health on a scale 
of 0 – 100.
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is a systematically administered instrument developed to track suicidal 
adverse events across a treatment study.  The instrument is designed to assess suicidal 
behavior and ideation, track and assess all suicidal events, as well as the lethality of 
attempts.  Additional features assessed include frequency, duration, controllability, reason 
for ideation, and deterrents.  During the Treatment Period, the C-SSRS, Since Last Visit 
(Appendix K) questionnaire will be administered as specified in Appendix C, Study 
Activities. 
If the subject expresses suicidal ideation on the C-SSRS or via clinical interview at any 
time during the study, the Investigator should take appropriate action and notify the 
AbbVie TA MD.  Appropriate steps will be taken to protect the subject (including 
possible discontinuation from the study and referral for appropriate psychiatric care).  The 
C-SSRS will be administered at the times outlined in Appendix C, Study Activities.
Health Care Resource Utilization (HCRU)
The Health Care Resource Utilization questionnaire (Appendix L) will be used to capture 
routine/general health care visits (that are not associated with an adverse event) to non-
study Health Care Providers during the Treatment Period.  Subjects will be asked to 
provide information on any visits to non-study Health Care Practitioners in the past 
4 weeks for routine/general health visits including any diagnostic or therapeutic 


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procedures that were performed.  The responses will be recorded on the HCRU by the Site 
Staff.  Health care resource use related to an Adverse Event or Serious Adverse Event will 
be captured as part of the Adverse Event, independent of the HCRU, and recorded in the 
eCRF.
Phone Contact During Follow-Up Period
During the Follow-Up Period at Follow-Up Months 2, 4, 5, 7, 8, 10, and 11, Site Staff will 
telephone subjects to assess ongoing adverse events, concomitant medications, provide 
contraception counseling and obtain the result of the subject-administered urine 
pregnancy test.  Site staff will also assess return to full menses and administration of the 
Post-Treatment UBQ as applicable.  The phone call and pregnancy test result will be 
documented in source documents and eCRF.
Randomization and Assignment of Subject Numbers
The site will contact IRT to assign the subject to the Extension Study once the subject has 
signed the informed consent and meets all eligibility criteria for the Extension Study.  
Only subjects randomized to placebo in the Pivotal Study will be randomized at Day 1 by 
IRT to receive either elagolix 300 mg BID or elagolix 300 mg BID plus E2/NETA QD.
The same subject number assigned in the Pivotal Study will be used to identify the subject 
throughout the Extension Study.  The site will register the Day 1 Visit in IRT to dispense 
the first study drug kit for the Extension Study.
During the Treatment Period, sites will register each monthly visit in IRT in order to 
obtain a scheduled re-supply of study drug to dispense to each subject.  In the event study 
drug becomes lost or damaged, the site can contact IRT to obtain an unscheduled re-
supply of study drug kit numbers to dispense.  Sites will register subjects as "Completed" 
or "Discontinued" (if the subject prematurely discontinues) at the end of the Treatment 
Period and will also register Post-Treatment Follow-Up Month 6 and Month 12 Visits or 
Premature Discontinuation from Post-Treatment, if applicable.


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5.3.1.2
Collection and Handling of Pharmacodynamic Variables
Blood Samples for Estradiol (E2) and Progesterone (P) Assay 
A single blood sample will be collected at each timepoint indicated in Appendix C, Study 
Activities, to be used for the pharmacodynamic analysis of estradiol and progesterone.  
The blood samples for assay of estradiol and progesterone will be collected in one 9 mL 
evacuated collection tube without anticoagulant (red cap, no gel separators to be used).  
Sufficient blood volume will be collected to provide approximately 4 mL serum from 
each sample.  Refer to the study specific laboratory manual for detailed instructions on 
sample collection, processing, and shipment.
Estradiol and progesterone samples will be collected at all visits indicated in Appendix C, 
Study Activities, and drawn at any time during the visit.  The date and time of collection 
will be recorded on the central laboratory requisition form.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood Samples for Elagolix and Norethindrone Assay
Blood samples for assay of elagolix and norethindrone, also known as PK samples, will 
be collected by venipuncture into 3 mL evacuated K2-ethylenediaminetetraacetic acid 
(K2EDTA)-containing collection tubes at the time points indicated in Appendix C, Study 
Activities.  Sufficient blood will be collected to provide approximately 1 mL plasma from 
each sample.
Refer to the study specific laboratory manual for detailed instructions on sample 
collection, processing and shipment.  Elagolix and norethindrone samples will be 
collected at all visits indicated in Appendix C, Study Activities, and drawn at any time 
during the visit.  The date and time of collection will be recorded on the central laboratory 
requisition form.


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5.3.2.2
Measurement Methods
Plasma concentrations of elagolix and norethindrone and serum concentrations of 
estradiol and progesterone will be determined using validated methods by the Drug 
Analysis Department at AbbVie.  Plasma or serum concentrations of other possible 
metabolites may be determined with validated or non-validated methods.
5.3.3
Efficacy Variables
5.3.3.1
Primary Efficacy Variable
The primary endpoint will be the percentage of subjects meeting a composite endpoint 
consisting of these two bleeding assessments:
●
MBL volume of < 80 mL during the Final Month (the last 28 days of treatment 
in the Extension Study), AND
●
50% or greater reduction in MBL volume from baseline to the Final Month 
(the last 28 days of treatment in the Extension Study)
A subject who prematurely discontinues the study drug due to adverse events, "lack of 
efficacy" or "requires surgery or invasive intervention for treatment of uterine fibroids" 
will be considered as a non-responder regardless whether she meets the 
two aforementioned responder criteria or not.
5.3.3.2
Secondary Efficacy Variable
The following will be considered secondary variables:
●
MBL volume assessed using AH methodology and UBQ
●
Suppression of bleeding
●
Hemoglobin concentration
5.3.4
PRO and Quality of Life Variables
●
UFS-QoL Questionnaire


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●
EuroQol (EQ-5D-5L) Questionnaire
●
Health Care Resource Utilization (HCRU) Questionnaire
●
Patient Global Impression of Change (PGIC) Questionnaires
●
Work Productivity and Activity Impairment (WPAI) Questionnaire
5.3.5
Safety Variables
●
Change from baseline to Month 6 in bone mineral density measured by DXA
●
Number and percentage of subjects reporting treatment-emergent adverse 
events (TEAEs)
●
Number and percentage of subjects reporting adverse events of special interest 
(AESI) (e.g., hypoestrogenic adverse events)
●
Time to the first Post-Treatment menses
●
Change from baseline in clinical laboratory parameters
●
Change from baseline in vital signs
●
Endometrial biopsy and pelvic ultrasound findings
●
Columbia Suicide Severity Rating Scale (C-SSRS)
5.3.6
Pharmacodynamic Variables
Concentrations of E2, P, LH and FSH will be obtained throughout the Treatment Period.  
Additional pharmacodynamic parameters may be calculated if useful in the interpretation 
of the data.
5.3.7
Pharmacokinetic Variables
Exposures of elagolix and norethindrone, may be determined using a population PK 
approach.  Additional parameters may be calculated if useful in the interpretation of the 
data.


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5.3.8
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) will be employed for this Phase 3 
study and will have the usual responsibilities for safeguarding the interests of study 
participants and monitoring the overall study conduct.  The IDMC will provide 
recommendations about continuing, modifying, or stopping the trial for safety reasons.  
The IDMC membership and responsibilities will be documented in its charter.  After each 
IDMC meeting, the IDMC will communicate its recommendations to the sponsor, as 
described in the IDMC charter.
5.4
Removal of Subjects from Therapy or Assessment
Each subject has the right to withdraw from the study at any time.  In addition, the 
Investigator may discontinue a subject from the study at any time if the Investigator 
considers it necessary for any reason, including the occurrence of an adverse event or 
noncompliance with the protocol.  Subjects who withdraw from the study will not be 
replaced.  Each subject will be withdrawn from the study if any of the following occur:
●
The subject decides to withdraw consent for any reason.
●
The investigator believes it is in the best interest of the subject.
●
Clinically significant deterioration of the subject's medical status as 
determined by the investigator.
●
The subject requires surgical intervention for treatment of uterine fibroids and 
menstrual bleeding or other procedures including hysterectomy, myomectomy, 
uterine artery embolization, high intensity focused ultrasound (HIFU), 
endometrial ablation, dilation and curettage (D&C), etc. during the Treatment 
Period.  In the post treatment period these procedures do not warrant 
withdrawal if performed during the Post-Treatment Period unless a 
hysterectomy with bilateral salpingo-oophorectomy (BSO) is performed and 
the Subject does not plan to use Hormone Replacement Therapy within 
1 month of the surgery date.
●
The subject becomes pregnant.


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●
The subject has ALT or AST elevation > 5 times the upper limit of normal 
confirmed upon repeat during the Treatment Period.
●
The subject's legally acceptable representative decides to withdraw consent for 
any reason (when applicable).
●
Heavy menstrual bleeding during the Treatment Period that requires a blood 
transfusion at any time after having taken 28 days of study drug.  If a subject 
has a blood transfusion during the Post-Treatment Period, the AbbVie TA MD 
should be contacted to determine if the subject can remain in the study.
●
Any other medical reason that AbbVie or the study investigator deems 
appropriate.
5.4.1
Discontinuation of Individual Subjects
In the event that a subject withdraws or is prematurely discontinued from study drug 
treatment, the subject should complete the Treatment Period Premature Discontinuation 
Visit as soon as possible (preferably within 2 days of last dose of study drug, if possible) 
and undergo study procedures as outlined in Appendix C, Study Activities.  Subjects who 
prematurely discontinue during the Treatment Period are expected to enter the 12-Month 
Post-Treatment Follow-Up Period, unless discontinuing due to pregnancy.  Each 
subsequent monthly Post-Treatment Follow-Up Period Visit should be scheduled based 
on the date of the last dose of study drug.
In the event that a subject withdraws or is prematurely discontinued during the Post-
Treatment Follow-Up Period, the subject should complete the Post-Treatment Premature 
Discontinuation Visit as soon as possible and undergo study procedures as outlined in 
Appendix C, Study Activities.  These procedures should not interfere with the initiation of 
any new treatments or therapeutic modalities the Investigator determines are necessary to 
treat the subject's condition.  The reason(s) for the discontinuation from the study will be 
recorded in the eCRFs.
All used and unused study drug containers will be returned to the study site.


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If a subject becomes pregnant during the Treatment or Post-Treatment Follow-Up 
Periods, no additional study procedures, except an ultrasound will be conducted.  Refer to 
Section 6.1.6 for instructions on reporting of a pregnancy to the Sponsor and the required 
follow-up on the subject/fetus and live births.
If a subject is discontinued from the study with an ongoing adverse event or an unresolved 
laboratory result that is clinically significant (as determined by the Investigator), the 
Investigator will attempt to provide follow-up until a satisfactory clinical resolution of the 
laboratory result or adverse event is achieved.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The Investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
The following procedures for study discontinuation will be followed:
●
If the Sponsor has decided to prematurely discontinue the study, the Sponsor 
will promptly notify in writing the Investigator as well as regulatory 
authorities of the decision and give detailed reasons for the discontinuation.
●
The Investigator must promptly notify the IRB/IEC and give detailed reasons 
for the discontinuation.
●
The Investigator must promptly notify the enrolled subjects of the premature 
discontinuation and administer appropriate treatments such as replacement of 
the treatment regimen, if applicable, by other appropriate regimens.


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5.4.3
Treatment Interruption
AbbVie or the Investigator may request that a subject temporarily discontinue study drug 
administration, which will be referred to as "treatment interruption."  The following are 
examples for reasons when the AbbVie TA MD must be notified in order to assess 
whether a subject should undergo temporary treatment interruption:
●
Adverse event, that based on clinical judgment, requires temporary suspension 
of treatment or prevents a subject from taking study drug
●
Due to malfunction of barrier contraception or unprotected intercourse
Additionally, there may be times when a subject has had treatment interruption due to 
having forgotten to take study drug, lost study drug, etc.  If the subject has missed 7 or 
more consecutive days of dosing (with either ABT-620 or elagolix plus E2/NETA), the 
AbbVie TA MD must be consulted to determine whether the subject may resume study 
drug administration or continue in the Treatment Period.  
These examples are not all-inclusive; if the Investigator has any questions, these should be 
directed to the AbbVie TA MD.
5.5
Treatments
5.5.1
Treatments Administered
Subjects on active treatment in the Pivotal Studies will be assigned by IRT to receive the 
same treatment, either elagolix 300 mg BID or elagolix 300 mg BID plus E2/NETA 
(estradiol 1 mg/norethindrone acetate 0.5 mg) QD, for an additional 6 months in the 
Extension Study.  Subjects on placebo in the Pivotal Studies will be randomly assigned by 
IRT to receive elagolix 300 mg BID or elagolix 300 mg BID plus E2/NETA (estradiol 
1 mg/norethindrone acetate 0.5 mg) QD in a 1:1 ratio for a total of 6 months of treatment.  
The treatment administration is presented in Table 4 below.


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Table 4.
Treatments Administered
Investigational Product
Treatment Group
Dosing Time
Elagolix 300 mg 
Tablets
E2/NETA 
Capsules
Matching E2/NETA 
Placebo Capsules
Elagolix 300 mg BID
AM
1
0
1
PM
1
0
0
Elagolix 300 mg BID plus 
E2/NETA 
AM
1
1
0
PM
1
0
0
Study drug consisting of elagolix and E2/NETA or placebo will each be supplied in a 
carton.  The subject will be instructed to self-administer the first dose of study drug 
approximately 12 hours after their last dose taken as part of the Pivotal Study.  In 
addition, Subject will be instructed to self-administer their study drug throughout the 
6-Month Treatment Period.
A 1-month supply of each study drug (plus 1 week extra) will be dispensed at Day 1 and 
at the Month 1, 2, 3, 4 and 5 Visits.
Study drug will be taken orally twice daily for the entire 6-Month Treatment Period.  A 
morning dose of 1 tablet of elagolix and 1 capsule of (E2/NETA) or matching placebo and 
an evening dose of 1 tablet of (elagolix) should be taken each day approximately 12 hours 
apart.  Study drug should be taken with approximately 8 oz. (240 mL) of water without 
regard to food.  Study drug should be taken at approximately the same time each morning 
and evening in order to promote compliance.
If the subject forgets to take the morning dose, she should be instructed to take the 
morning dose as soon as possible and take the evening dose as scheduled.  If the subject 
forgets to take the evening dose, she should be instructed to take the evening dose as soon 
as possible; if the subject misses the evening dose completely (until the next morning), the 
subject should only take the morning dose.


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On days when the subject visits the study site for the scheduled visits, she will take her 
morning dose at home, prior to the visit.  The evening dose will be taken from the newly 
dispensed supply of study drug.  Subjects must return all study drug containers at each 
monthly visit.
When during the Treatment Period, a monthly visit occurs > 28 days since the last visit, 
the subject will be instructed to continue taking study drug from the extra blister card 
(1 week supply) until she returns for the next month's visit.
5.5.2
Identity of Investigational Products
Information about the drug formulations to be used in this study is presented in Table 5.
Table 5.
Identity of Investigational Products
Study Drug
Formulation
Route of 
Administration
Trademark
Manufacturer
Elagolix
Film-coated 300 mg tablets
Oral
N/A
AbbVie
E2/NETA*
Estradiol 1 mg/ 
Norethindrone acetate 0.5 mg 
capsules*
Oral
N/A
Commercial Tablets:  
Pharmaceutics 
International, Inc
Matching E2/NETA 
Placebo 
Placebo capsules
Oral
N/A
AbbVie
*
Commercially-available E2/NETA tablets are over-encapsulated to maintain study blinding.
5.5.2.1
Packaging and Labeling
AbbVie will supply study drug in monthly kits (i.e., cartons).  Two kits of study drug will 
be provided at each dispensing visit.  One kit consists of elagolix and the other kit consists 
of E2/NETA capsules or matching placebo capsules.  Each kit contains 5 blister cards, 
with each blister card containing 7 days of study drug.  There are 4 weekly blister cards 
and 1 extra medication blister card in each kit to supply enough medication for 4 weeks 
(28 days) plus an extra week of dosing.


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Each individual elagolix blister card contains 14 tablets for a 7-day (weekly) supply of 
study drug.  Also, each E2/NETA or matching placebo blister card contains 7 capsules for 
a 7-day (weekly) supply of study drug.  Each kit will contain a unique kit number.
The kits will be assigned to a subject via IRT and will encode the appropriate study drug 
to be dispensed at the subject's corresponding study visit.
The kits and blister cards are labeled as per country requirements.  All blank spaces on the 
label will be completed by the site staff prior to dispensing to the subject.  Labels must 
remain affixed to the study drug containers.  Adequate supplies of study drug will be 
provided to each study site automatically via IRT.
5.5.2.2
Storage and Disposition of Study Drugs
Elagolix and E2/NETA or matching placebo study drug must be stored at controlled room 
temperature 15° to 25°C (59° to 77°F).  Additionally, E2/NETA or matching placebo 
study drug must be protected from light.
The investigational products are for investigational use only and are to be used only 
within the context of this study.  The study drug supplied for this study must be 
maintained under adequate security and stored under the conditions specified on the label 
until dispensed for subject's use or returned to AbbVie.  Returned study drug should not
be re-dispensed to the subject.
5.5.3
Method of Assigning Subjects to Treatment Groups
Before the study is initiated, contact information and user guidelines for IRT will be 
provided to each site.  Study drug will be dispensed at the study visits outlined in 
Appendix C, Study Activities.
Subjects will retain the unique subject number assigned to each subject by the IRT during 
the Pivotal Study M12-815 or Study M12-817.  This unique subject number will be used 
for each subject throughout this study.


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Subjects who received placebo in the Pivotal Study M12-815 or Study M12-817 will be 
randomly assigned to receive elagolix alone or elagolix plus E2/NETA via assignment of 
a unique randomization number in IRT.  The Site Personnel, Investigator, and the Sponsor 
do not see this information while the study is ongoing.  Hence, there is no unblinding 
concern related to the assignment of the unique randomization number in this Extension 
Study.  Subjects who received elagolix alone or elagolix plus E2/NETA in the Pivotal 
Study M12-815 or Study M12-817 will continue to receive the same dose of active drug 
in this study.
The randomization schedule will be computer-generated by the Statistics Department at 
AbbVie, North Chicago, IL prior to the start of the study.  A copy of all of the 
randomization schedules will be kept by the Statistics Department at AbbVie and a copy 
will be forwarded to the IRT provider.
Study drug must not be dispensed without contacting IRT and may only be dispensed to 
subjects enrolled in the study according to kit numbers provided by IRT.
5.5.4
Selection and Timing of Dose for Each Subject
Selection of the doses used for this study is discussed in Section 5.6.4.  Subjects who 
received placebo in their respective Pivotal Study will be randomized into one of the 
two treatment groups as described in Section 5.5.1.  Subjects who received active 
treatment in their respective Pivotal Study will continue to be assigned to receive the same 
treatment they received during the pivotal study.
Study drug will be initiated at the study site on Day 1.  Subjects will be instructed to self-
administer study drug twice a day (once in the morning and once in the evening 
approximately 12 hours apart) with approximately 8 oz (240 mL) of water.  Subjects must 
return all study drug containers (used or unused) at the subsequent visit.


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5.5.5
Blinding of Investigational Product
The elagolix dose will be provided open label and each active E2/NETA dose will be 
identical in appearance to its matched placebo.  The study site personnel and subject will 
remain blinded to each subject's treatment throughout the course of the study.  The IRT 
will provide access to blinded subject treatment information during the study.
AbbVie must be notified before the blind is broken, unless identification of the study drug 
is required for medical emergency; i.e., situation in which the knowledge of the specific 
blinded treatment will affect the immediate management of the subject/patient's 
conditions (e.g., antidote is available).  AbbVie must then be notified within 24 hours of 
the blind being broken.  The date and reason that the blind was broken must be recorded 
in the source documents and eCRF, as applicable.  AbbVie will remain blinded until the 
database of the 6-month Treatment Period is locked.
5.5.6
Treatment Compliance
Subjects will be instructed to return all study drug kits (used or unused) to the study site 
personnel at the Month 1, Month 2, Month 3, Month 4, Month 5 and Month 6 or 
Premature Discontinuation Visits during the Treatment Period.  The study site personnel 
will document compliance in the IRT system.
The Investigator or his/her designated and qualified representatives will dispense study 
drug only to subjects enrolled in the study in accordance with the protocol.  The study 
drug must not be used for reasons other than those described in the protocol.
Subjects should be advised of the importance of treatment compliance.  Study drug should 
be taken consistently at approximately the same time in the morning and evening each 
day.  Daily recordings of study drug dosing will be obtained using a compliance 
packaging blister card for all subjects (for both elagolix and E2/NETA/matching placebo).  
AbbVie will provide training and study drug compliance materials to sites for instructing 
subjects on study drug compliance.


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Sites will be provided scanning technology for direct access to the dosing compliance 
data; sites are expected to scan all returned blister cards (used/unused/unopened) to obtain 
the dosing information at each of the Treatment Period Visits when study drug is returned 
to the site by the subject.  Any unused/unopened blister cards should be documented as 
such in the scanning technology source documentation.  Sites are expected to use the 
compliance data to guide them in discussions with the subject regarding compliance.  
Upon reviewing the dosing data, if the date(s) and time(s) for any of the last 4 doses of 
study drug (elagolix or E2/NETA or matching placebo) prior to the monthly Treatment 
Period Visit or Premature Discontinuation Visit are missing, the subject will be asked to 
confirm whether doses were taken and to provide the dates and approximate times of the 
last 4 scheduled doses prior to the study visit.  The subject reported data will be recorded 
in source and in the eCRF.  Sites will document when the blister cards are not returned or 
when blister cards cannot be scanned.
Sites should instruct subjects not to remove extra or multiple medications from the blister 
cards all at once and should only remove the study drug from the blister when it is the 
time to take the dose.  If the compliance data shows incidence of removing a number of 
extra medications, sites should re-train the subjects on the importance of only removing 
study drug when it is time to take the dose and record re-training in the source documents.
During review of the study drug compliance with the study subject, if the number of 
tablets/capsules to be taken and the number of tablets/capsules returned do not add up to 
the number of tablets/capsules dispensed, an explanation should be provided by the 
subject and recorded in the source documents.
If a subject missed more than 7 consecutive days of taking study drug, the AbbVie TA 
MD should be notified to determine whether the subject may continue.
Compliance packaging data will be used for exposure response analysis.


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5.5.7
Drug Accountability
The study Investigator or designee will verify by signature and date that study drug 
supplies are received intact and in the correct amounts indicated on the shipping document 
Proof of Receipt or similar shipping document or via direct recording in IRT.  The 
shipment receipt must be acknowledged in IRT in order to become available for 
dispensation to subjects.  The IRT must also be contacted when any subject discontinues 
study drug.
The IRT will maintain a current and accurate inventory of all clinical drug supplies, 
accountability, reconciliation, returns and destruction for each site.  The IRT will also 
include the lot number, kit number, Proof of Receipt number, the number of blister 
cards/cartons dispensed, initials of person who dispensed the drug, and the date study 
drug was dispensed for each subject.  In addition to using IRT inventory, an accurate 
inventory of study drug can also be kept by the site.
An overall accountability of the study drug will be performed and verified by the site 
monitor via IRT throughout the study and at the Study Site Closeout Visit.  Throughout 
the study and upon completion or termination of the study, all used and unused containers 
will be returned to AbbVie according to instructions from AbbVie.
The study Investigator or his/her designated representative agrees not to supply study drug 
to any persons not enrolled in the study or not named as a Sub-Investigator.
Study drug will be dispensed at the study visits summarized in Appendix C, Study 
Activities.  Returned study drug should not be re-dispensed to the subject.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This Phase 3 extension study will be conducted as a double-blind, multi-center, study in 
premenopausal women with HMB associated with uterine fibroids.  This study will 
continue to evaluate the safety and efficacy of elagolix 300 mg BID alone and elagolix 


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300 mg BID in combination with E2/NETA QD (1 mg/0.5 mg).  The elagolix alone arm 
in this extension study is being used as a reference arm in order to better understand the 
effects of add-back therapy on safety and efficacy parameters.  This allows a benchmark 
for efficacy, as well as safety in regards to BMD and hypoestrogenic effects.  In addition, 
for a long term treatment, this will allow a better understanding of elagolix alone, as well 
as activella.
5.6.2
Appropriateness of Measurements
The safety assessments used in this study are standard, widely used and generally 
recognized as reliable, accurate and relevant within the context of this study design.
Heavy menstrual bleeding is the most common symptom of women with uterine fibroids.  
The quantitation of menstrual blood loss using the alkaline hematin method on sanitary 
products has been validated by the analytical testing laboratory.  Pelvic ultrasound is a 
standard method for assessing uterine fibroid size, and fibroid and uterine volume.  
Endometrial biopsy is a standard method for assessing endometrial safety.  DXA is the 
established gold standard method to assess changes in BMD.
5.6.3
Suitability of Subject Population
Premenopausal women with HMB (> 80 mL per menstrual cycle) and uterine fibroids 
were selected for this study because that is the population who suffer from HMB 
associated with uterine fibroids.  No studies in males or in females outside of the 
reproductive years are necessary for this proposed indication.
5.6.4
Selection of Doses in the Study
This is an extension study to the pivotal studies, Studies M12-815 and M12-817, therefore 
the doses used in this extension study are the same as those used in the pivotal Studies 
with the exception that subjects randomized to placebo in their respective pivotal study 
will be re-randomized to active treatment, either elagolix 300 mg BID alone or elagolix 
300 mg BID in combination with E2/NETA QD in a 1:1 ratio, therefore all subjects in this 


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extension study will receive active treatment.  The maximum elagolix dose administered 
in this study will not exceed a total daily dose of 600 mg.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Section 6.1
through Section 6.1.5.  For product complaints, please refer to Section 6.2.
All adverse events will be followed to a satisfactory conclusion.
6.1
Medical Complaints
The Investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The Investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
Investigator will provide an Other cause of the event.  For adverse events to be considered 
intermittent, the events must be of similar nature and severity.  Adverse events, whether in 
response to a query, observed by site personnel, or reported spontaneously by the subject 
will be recorded.


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6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities, and vital signs are considered to be adverse events only 
if they result in discontinuation from the study, necessitate therapeutic medical 
intervention and/or if the investigator considers them to be adverse events.
An adverse event of amenorrhea will be reported for subjects who do not return to menses 
by the Post-Treatment Follow-Up Month 2 Phone Visit and the adverse event will be 
followed until resolution.  The onset date of the adverse event will be the date of the 
Follow-Up Month 2 Visit.
A BMD decrease at any anatomic location (spine, total hip or femoral neck) during the 
Treatment or Post-Treatment Follow-Up Period that leads to discontinuation from study 
or a BMD decrease at any anatomic location with a T-score < –1.5 should be reported as 
an adverse event.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre planned prior to study entry.  However, if the pre-
existing condition deteriorates unexpectedly during the study (e.g., surgery performed 


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earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study subject.  
Disability is not intended to include experiences of relatively 
minor medical significance such as headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).


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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, life-
threatening, hospitalization, prolongation of hospitalization, 
congenital anomaly, or persistent or significant 
disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.1.1.3
Adverse Events of Special Interest
Some adverse events, such as adverse events of special interest (AESI), such as 
rash/hypersensitivity, fracture, neuro-psychiatric (depression, mood swings, etc.), 
vasomotor symptoms (hot flush, night sweats) or serious adverse events.  AbbVie may 
require additional information, including family history, to be collected and recorded in 
the eCRF.
6.1.2
Adverse Event Severity
The Investigator will use the following definitions to rate the severity of each adverse 
event:
Mild
The adverse event is transient and easily tolerated by the subject.
Moderate
The adverse event causes the subject discomfort and interrupts the 
subject's usual activities.
Severe
The adverse event causes considerable interference with the subject's 
usual activities and may be incapacitating or life-threatening.


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6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an "Other" cause of event must be provided by the investigator for the serious 
adverse event.
6.1.4
Adverse Event Collection Period
All adverse events reported from the time of study drug administration through Month 12 
in the Post-Treatment Follow-Up Period, (if applicable) will be collected, whether 
solicited or spontaneously reported by the subject.  In addition, serious adverse events and 
protocol-related nonserious adverse events will be collected from the time the subject 
signed the study-specific informed consent.
If a subject prematurely discontinues from the study, i.e., either prematurely discontinues 
from Treatment Period and does not enter the Post-Treatment Follow-Up Period or 
prematurely discontinues from the Post-Treatment Follow-Up Period, adverse events and 
serious adverse events will be collected up to 30 days after the last dose of study drug.
Adverse event information will be collected as shown in Figure 5.


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Figure 5.
Adverse Event Collection
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
electronic data capture (EDC) system.  Serious adverse events that occur prior to the site 
having access to the RAVE® system, or if RAVE is not operable, should be documented 
on the SAE Non-CRF forms and emailed (preferred route) or faxed to Clinical 
Pharmacovigilance within 24 hours of the site being made aware of the serious adverse 
event.
Email:  
FAX to:  




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6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Subjects who become pregnant during the Treatment 
or Post-Treatment Follow-Up Periods of the study must be discontinued (Section 5.4 and 
Section 5.4.1).  A positive urine pregnancy test result must be confirmed with a serum 
pregnancy test.  If a serum pregnancy test result is positive at any time during the 
Treatment Period of the study, the site will immediately inform the subject to discontinue 
study drug.  Information regarding a pregnancy occurrence in a study subject and the 
outcome of the pregnancy will be collected for any study subject with a positive serum 
pregnancy test from the signing of the informed consent through the Post-Treatment 
Follow-Up Period.  The site will report a positive pregnancy test to the Sponsor, will 
follow the course of the subject's pregnancy, and report to the Sponsor on the health of the 
subject and fetus at each trimester and at the first post-delivery pediatrician visit.
If the subject becomes pregnant during the Treatment or Post-Treatment Follow-Up 
Periods of the study, an ultrasound examination will be performed as early as possible 
during the first trimester of pregnancy to assess the conception date and document an 
intrauterine pregnancy.  The following information on the outcome of the pregnancy that 
occurred after signing of the informed consent, regardless of when the subject became 
pregnant (i.e., either during the Treatment or Post-Treatment Follow-Up Periods) should 
be collected: fetal outcome (e.g., spontaneous or elective abortion, live infant or still 
birth), date of delivery, birth weight, birth length, gender, birth defects, congenital 
anomaly and medically significant complications during pregnancy or labor or delivery.  
For live infant births, information on the health of the infant will be collected 6 to 
12 months after delivery.
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the 
site becoming aware of the event.


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6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (e.g., printing illegible), missing 
components/product, or packaging issues.
Any information available to help in the determination of causality by the product to the 
events outlined directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and recorded in source documents as required by the Sponsor.  
Product Complaints associated with adverse events will be reported in the study summary.  
All other complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition (investigational product).  In instances where a return is requested, every effort 
should be made by the investigator to return the product within 30 days.  If returns cannot 
be accommodated within 30 days, the site will need to provide justification and an 
estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.




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performed will be two-sided and a significance level of 0.05 will be used.  A test will be 
deemed statistically significant if the P value rounded to three decimal places is less than 
or equal to 0.05 unless otherwise specified.
Separate summaries will be provided for each of the following groups of subjects.
1.
Subjects randomized to elagolix 300 mg BID in the Pivotal Studies M12-815 or 
M12-817 and continued to receive elagolix 300 mg BID in the Extension Study;
2.
Subjects randomized to elagolix 300 mg BID plus E2/NETA QD in the Pivotal 
Studies M12-815 or M12-817 and continued to receive elagolix 300 mg BID plus 
E2/NETA QD in the Extension Study;
3.
Subjects randomized to placebo in the Pivotal Studies M12-815 or M12-817, and 
re-randomized to elagolix 300 mg BID in the Extension Study;
4.
Subjects randomized to placebo in the Pivotal Studies M12-815 or M12-817, and 
re-randomized to elagolix 300 mg BID plus E2/NETA QD in the Extension Study.
8.1.2
Data Sets Analyzed
Full Analysis Set
The full analysis set is comprised of all subjects who took at least one dose of the study 
drug in this Extension Study.  The full analysis set will be used for all efficacy analyses 
unless otherwise specified in the Statistical Analysis Plan (SAP).
Safety Analysis Set
The safety analysis set includes all subjects who took at least one dose of the study drug 
in the Extension Study M12-816.  All safety analyses will be performed based on the 
safety analysis set unless otherwise specified in the SAP.


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8.1.3
End-of-Treatment Period Analysis
An end-of-treatment period analysis of efficacy, demographic and safety variables will be 
performed after all subjects enrolled in this study completes the 6-Month Treatment 
Period of this Extension Study M12-816.  This end-of-treatment period analysis will 
include all Treatment Period data from all subjects enrolled into the Extension Study.  The 
data base will be versioned and any discrepant data will be clarified before the lock.  The 
analyses will be completed by the Clinical Statistics Department at AbbVie.
8.1.4
Independent Data Monitoring Committee
The IDMC will receive an analysis summary by treatment group, which will include data 
on enrollment, baseline characteristics, and safety.
8.1.5
Demographic, Baseline Characteristics and Concomitant 
Medications
Subjects initially randomized to placebo in the Pivotal Studies M12-815 or M12-817 will 
have their baseline (except for the MBL volume) re-set to the last non-missing 
assessments collected prior to the first dose of elagolix 300 mg BID or elagolix 300 mg 
BID plus E2/NETA QD in this Extension Study, unless otherwise specified.  Subjects 
initially randomized to elagolix 300 mg BID or elagolix 300 mg BID plus E2/NETA QD 
in the Pivotal Studies M12-815 or M12-817 will have their baseline refer to the baseline 
from the respective Pivotal Studies M12-815 or M12-817, unless otherwise specified.  
Exceptions will be specified in the SAP.
For the MBL volume, the baseline for all subjects will refer to the baseline from Pivotal 
Studies M12-815 or M12-817.
Baseline characteristics will be summarized for each treatment group.
Demographic characteristics will be summarized by treatment group.
The duration of study drug will be summarized by treatment group.


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Protocol deviations and reasons for discontinuation will be summarized.
Concomitant medications will be coded using the World Health Organization (WHO) 
dictionary and summarized with frequencies and percentages.
8.1.6
Time Points, Time Windows and Time Periods for Analysis
As appropriate, time windows for various safety and efficacy analyses will be defined in 
the SAP.
For subjects who received at least one dose of the study drug in this Extension Study, the 
Study Day is defined as the number of days since (positive values) or prior (negative 
values) to the first study drug dose in this Extension Study.  The day of the first study 
drug dose is defined as Study Day 1, while the last day prior to the first study drug dose is 
defined as Study Day –1.  There is no Study Day 0.
8.1.7
Efficacy
Data will be summarized separately for each of the treatment groups of subjects described 
in Section 8.1.1.
8.1.7.1
Primary Efficacy Variable
8.1.7.1.1
Primary Analysis
The primary endpoint will be the percentage of subjects meeting a composite endpoint 
consisting of two bleeding assessments:
●
Menstrual blood loss (MBL) volume < 80 mL during the Final Month (the last 
28 days of treatment in the Extension Study), and
●
50% or greater reduction in MBL volume from baseline to the Final Month 
(the last 28 days of treatment in the Extension Study).


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The primary analysis of the primary endpoint will be performed using the full analysis set 
which is comprised of all subjects who took at least one dose of the study drug in this 
Extension Study.
A subject who prematurely discontinues the study drug due to adverse events, "lack of 
efficacy," or "requires surgery or invasive intervention for treatment of uterine fibroids" 
will be considered as a non-responder regardless whether she meets the 
two aforementioned responder criteria or not.
The baseline MBL volume is described in Section 8.1.5.  The Final Month is defined as 
the last 28 days of treatment prior to and including the last dose date in this Extension 
Study.
The MBL volume used for the primary and sensitivity analyses is defined as the total 
combined volume of blood ascertained via the AH method from all used (validated and 
non-validated) sanitary products that a subject returns.  In case a subject does not return 
any used sanitary products and indicates on the UBQ that she experienced bleeding during 
the Final Month, the MBL volume will be imputed per the procedure described in 
Section 8.1.7.1.2.
The percentage of subjects with MBL volume < 80 mL at the Final Month and 50% or 
greater reduction in MBL volume from baseline to the Final Month in the Extension 
Study will be summarized by treatment group.
8.1.7.1.2
Derivation of Primary Efficacy Endpoint
The Final Month MBL volume will be derived as follows:
●
If a subject has any evaluable AH data reported during the Final Month 
(i.e., she has at least 1 day of AH data during the last 28 days of treatment), 
then her primary endpoint will be based on AH data during the Final Month.  
The subject's Final Month MBL volume will be the total MBL volume which 
is the sum of the observed MBL volume over the last 28 days of treatment.


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●
If a subject is missing the Final Month AH data and the Uterine Bleeding 
Questionnaire is completed, then:
○
A value of 0 will be assigned to the Final Month MBL volume if no 
bleeding or spotting, "Subject only had spotting that did not require the use 
of sanitary products" or "There was no visible blood on the sanitary 
products" is indicated on the Uterine Bleeding Questionnaire 
(Appendix D).
●
Otherwise, the primary endpoint will be imputed using multiple imputation as 
described in Section 8.1.7.1.3.
A flow-chart showing how the primary endpoint will be derived is presented in Figure 6.
Figure 6.
Flow-Chart for Deriving Primary Endpoint


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8.1.7.1.3
Multiple Imputation
The imputation model will include but is not limited to the following variables:  baseline 
MBL volume, treatment group, and 28-day MBL volume at each post-baseline treatment 
cycle.  The final imputation model will be specified in the SAP.
First, M "semi-complete" datasets will be imputed to produce monotone missing data via 
MCMC using SAS PROC MI.  Then, M "complete" datasets for the Final Month MBL 
volume will be generated based on each "semi-complete" dataset via linear regression 
using SAS PROC MI.  M represents the number of imputed datasets and its value will be 
specified in the SAP.
Each subject's responder status will be derived based on the imputed Final Month MBL 
volume from the M imputed datasets.  The percentage of responders will be summarized 
by treatment group.
8.1.7.1.4
Sensitivity Analysis of the Primary Efficacy Variable
The sensitivity analyses for the primary endpoint will use different approaches for 
handling prematurely discontinued subjects and different approaches for dealing with 
missing Final Month MBL volume.  The details of the sensitivity analyses will be 
specified in the SAP.
Unless otherwise specified, the analysis dataset used for sensitivity analysis is the full 
analysis set.
8.1.7.2
Secondary Efficacy Variables
The secondary efficacy measures during the Treatment Period of the Extension Study 
include the following:
●
Change and percent change from baseline in MBL volume to each month and 
to the Final Month;
●
Percentage of subjects with suppression of bleeding (no bleeding allowed, 
spotting allowed) at the Final Month;


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●
Percentage of subjects with baseline hemoglobin ≤ 10.5 g/dL who have an 
increase in hemoglobin > 2 g/dL at Month 6.
8.1.7.3
Other Efficacy Variables
●
Percentage of subjects with MBL volume < 80 mL and 50% or greater 
reduction in MBL volume from baseline during 28-day intervals throughout 
the Treatment Period;
●
Percentage of subjects with amenorrhea;
●
Percentage of subjects with control of bleeding;
●
The bleeding days;
●
Change and percent change from baseline in hemoglobin concentration;
●
PGIC for Menstrual Bleeding and Non-Bleeding Uterine Fibroid Symptoms;
●
Change and percent change from baseline in fibroid and uterine volume;
●
Change from baseline for the UFS-QoL; 
●
Change from baseline for the EuroQoL-5D (EQ-5D-5L);
●
The HCRU;
●
Change from baseline for the WPAI.
Analysis details will be specified in the SAP.
8.1.7.3.1
Reduction of Bleeding
The percentage of subjects with MBL volume < 80 mL and 50% or greater reduction in 
MBL volume from baseline during the Treatment Period in this Extension Study will be 
summarized for each treatment group.  Also, the individual component (the percentage of 
subjects with MBL volume of < 80 mL as well as the percentage of subjects with ≥ 50% 
in MBL volume reduction from baseline) will be summarized. 
The change and percent change from baseline in MBL volume to each month and to the 
Final Month, will be summarized for each treatment group.  The percentage of subjects 
with suppression of bleeding and the percentage of subjects with amenorrhea will be 


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summarized by monthly intervals throughout the Treatment Period.  For each subject, 
suppression of bleeding will be defined as having no days of bleeding (spotting is 
allowed) during a 28-day interval.  Amenorrhea is defined as having no days of bleeding 
or spotting during a 28-day interval.  In addition, the cumulative percentage of subjects 
with suppression of bleeding and the cumulative percentage of subjects with amenorrhea 
will be summarized by treatment group.
The change and percent change from baseline to monthly intervals in number of bleeding 
days will be summarized by treatment group.  
8.1.7.3.2
Hemoglobin Concentration
The change and percent change from baseline in hemoglobin concentration will be 
summarized monthly for each treatment group.  Shift tables from baseline to values over 
time will be summarized by anemia status.
8.1.7.3.3
Fibroid and Uterine Volume
The change and percent change from baseline in primary fibroid volume, total fibroid 
volume and uterine volume will be summarized for each treatment group.
The percentage of subjects with ≥ 25% reduction in total and primary fibroid volume and 
uterine volume will be summarized for each treatment group.
8.1.7.3.4
Quality of Life
UFS-QoL
Improvement in quality of life will be assessed on the UFS-QoL Questionnaire (4-week 
recall).  The change from baseline will be calculated and summarized for each of the 
UFS-QoL subscales (symptom severity, concern, activities, energy/mood, control, self-
conscious and sexual function) and the UFS-QoL total.


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EQ-5D-5L
The number and percentage of subjects with answers in each level for Mobility, Self-care, 
Usual activities, Pain/Discomfort, Anxiety/Depression will be summarized by treatment 
group.
The change from baseline in subject health status will be summarized for each treatment 
group.
8.1.7.3.5
Patient Global Impression of Change (PGIC)
PGIC for Menstrual Bleeding (PGIC-MB):
PGIC-MB is to assess the change in subjects' severity of menstrual bleeding.  The number 
and percentage of subjects in each response category based on PGIC-MB will be 
summarized by treatment group.
PGIC for Non-Bleeding Uterine Fibroid Symptoms (PGIC-NBUFS):
PGIC-NBUFS is to assess the severity of overall non-bleeding symptoms and the severity 
of specific non-bleeding uterine fibroid symptoms.  The number and percentage of 
subjects in each response category of each question based on PGIC-NBUFS will be 
summarized by treatment group.
8.1.7.3.6
Work Productivity and Activity Questionnaire (WPAI)
The change from baseline for the WPAI will be summarized for each treatment group.
8.1.7.3.7
Health Care Resource Utilization Questionnaire (HCRU)
HCRU will be summarized for each treatment group.
8.1.7.3.8
Multiple Comparisons
No statistical tests will be performed to test the differences between the active treatment 
arms.  Therefore no multiplicity adjustment is required.


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8.1.8
Safety
All subjects who took at least one dose of the study drug in the Extension Study will be 
included in the safety analyses.
8.1.8.1
General Considerations
Unless otherwise specified, missing safety data will not be imputed.
Data will be summarized separately for each of the treatment groups of subjects described 
in Section 8.1.1.
8.1.8.2
Adverse Events
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary.  Treatment-emergent adverse events (TEAEs) will be 
summarized for each treatment group.  TEAEs are defined as AEs with a start date on or 
after the first dose of the study drug and within 30 days of the last dose of the study drug 
in the Extension Study.  AEs starting more than 30 days following discontinuation of the 
study drug will not be included in the summaries of TEAEs.  AEs starting more than 
30 days following discontinuation of the study drug will be summarized separately as 
Post-Treatment AEs.
When summarizing TEAEs by relationship or severity, if a subject has an event with 
unknown severity or relationship, then the subject will be counted in the 
severity/relationship category of "unknown," even if the subject has a second occurrence 
of the same event with a severity/relationship present.  The only exception is if the subject 
has a second occurrence of the same event with the most extreme severity (i.e., "severe") 
or a relationship category of "reasonable possibility."  In this case, the subject will be 
counted under these most extreme severity/relationship categories.
The frequencies and percentages of subjects with TEAEs will be calculated for each 
treatment group as follows:


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●
Any event
●
By system organ class, and preferred term
●
By system organ class, preferred term and maximum relationship
●
By system organ class, preferred term and maximum severity
●
Any event and by system organ class and preferred term for events resulting in 
study drug discontinuation
●
Any event and by system organ class and preferred term for serious events
●
Any event and preferred term for AESI's (e.g., hypoestrogenic adverse events)
The Post-Treatment AEs will be summarized in a similar manner as the TEAEs described 
above.
8.1.8.3
Analysis of Laboratory Data and Vital Signs
Changes from the baseline to each visit in continuous laboratory and vital sign parameters 
will be summarized by treatment group.
Laboratory values will be categorized as low, normal or high based on normal ranges of 
the central laboratory used in this study.  Low or high laboratory values will be flagged in 
the data listings.
Analysis details will be specified in the SAP.
8.1.8.4
Bone Mineral Density
The within-group percent change from baseline to Month 6 in the Extension Study in 
BMD will be summarized for each treatment group with mean, standard deviation, 
median and two-sided 95% confidence interval.
For subjects randomized to placebo in the Pivotal Studies M12-815 and M12-817, their 
BMD baseline will be re-set to the last data collected prior to the first dose of either 
elagolix 300 mg BID or elagolix 300 mg BID plus E2/NETA QD in this Extension Study.  
For subjects randomized to either elagolix 300 mg BID or elagolix 300 mg BID plus 


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E2/NETA QD in the Pivotal Studies M12-815 and M12-817, the BMD data from the 
Pivotal Studies will be included in the analysis, and baseline for these subjects will refer 
to the baseline from the Pivotal Studies M12-815 or M12-817.
For subjects who have at least 12 months of total exposure to elagolix, the percent change 
from baseline to Month 6 in the Extension Study in BMD will be compared between 
elagolix dose groups (elagolix 300 mg BID versus elagolix 300 mg BID plus E2/NETA 
QD) using analysis of covariance (ANCOVA) with treatment as the main effect and 
baseline BMD as a covariate.  A two-sided 95% confidence interval will be constructed 
for the between-group difference in percent change from baseline to Month 6 in the 
Extension Study in BMD.  Additionally, the mixed model repeated measures (MMRM) 
method for analyzing percent change in BMD will be conducted as appropriate.
The number and percentage of subjects with categorized percent change from baseline to 
Month 6 in the Extension Study in BMD (≤ 0%, > 0% – ≤ 1.5%, > 1.5% – ≤ 3%, > 3% –
≤ 5%, > 5% – < 8%, or ≥8%) will be summarized for each treatment group.  Analysis 
details will be specified in the SAP.
8.1.8.5
Post-Treatment Analysis of Menstruation
The time of the first post-treatment full menses onset in days relative to the date of the last 
dose of the study drug in the Extension Study will be calculated.
8.1.8.6
Endometrial Biopsy
The number and percentage of subjects in each category of endometrial biopsy results will 
be summarized.
8.1.8.7
Pelvic Ultrasound
The number and percentage of subjects with complex ovarian cysts > 3.5 cm, as well as 
the number and percentage of subjects with simple ovarian cysts > 5 cm will be 
summarized for each treatment group at each time point.  The change from baseline to 


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Month 6 in the Extension Study in endometrial thickness will be summarized for each 
treatment group.
8.1.8.8
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS will be summarized by treatment group according to published scoring 
guidelines.
8.1.9
Pharmacokinetic/Pharmacodynamic Analysis
Plasma concentrations of elagolix and norethindrone and serum concentrations of 
estradiol, progesterone, luteinizing hormone and follicle stimulating hormone will be 
listed for each subject by visit day and dose regimen, as applicable.  Pharmacokinetic data 
may be combined with data from other studies in women.  Exposure-response analyses 
may be conducted as appropriate.  For example, if pharmacokinetic exposures are 
estimated, analyses may be conducted to assess the relationship of pharmacokinetic 
parameters and estradiol and progesterone concentrations, versus efficacy and safety.  
Additional analyses will be performed if useful and appropriate.
8.2
Determination of Sample Size
The two Pivotal Studies M12-815 and M12-817 have a planned enrollment of a total of 
800 subjects.  Based on assumptions related to discontinuation in the Pivotal Studies and 
the estimated roll over rate into this Extension Study, approximately 400 subjects are 
expected to be enrolled in this Extension Study.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 


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ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to ICH GCP.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the Clinical Investigator are specified in Appendix A.
9.3
Subject Information and Consent
The Investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
procedures being performed on the subject, the informed consent statement will be 
reviewed and signed and dated by the subject, the person who administered the informed 
consent, and any other signatories according to local requirements.  A copy of the 
informed consent form will be given to the subject and the original will be placed in the 
subject's medical record.  An entry must also be made in the subject's dated source 


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documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.
For all adverse events, the onset date and event description will be captured in source 
documents.  Other adverse event data points required for eCRF completion can be entered 
directly in the eCRF and may serve as the source document and should be printed and 
signed and dated by the Investigator/designated physician.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject enrolled in this study.  These 
forms will be used to transmit information collected during the study to AbbVie and 
regulatory authorities, as applicable.  The CRF data for this study are being collected with 
an electronic data capture (EDC) system called Rave® provided by the technology vendor 
Medidata Solutions Incorporated, NY, USA.  The EDC system and the study-specific 


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electronic case report forms (eCRFs) will comply with Title 21 CFR Part 11.  The 
documentation related to the validation of the EDC system is available through the 
vendor, Medidata, while the validation of the study-specific eCRFs will be conducted by 
AbbVie and will be maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by Investigative Site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
Patient reported data must be completed for each subject screened/enrolled in this study 
and entered into the eCRFs.


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11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates. Any necessary corrections will be made to the eCRF.
Prior to enrolling any subject in the study, a Site Initiation Visit will be held with AbbVie 
personnel (and/or their representatives), the investigators, and the appropriate site 
personnel.  This meeting will include a detailed discussion and review of the protocol and 
essential documents, performance of study procedures, eCRF completion, and specimen 
collection methods.  The personnel at the study site will be trained on the study 
procedures, when applicable, by an AbbVie monitor or designee.
The AbbVie monitor or designee will monitor the study site throughout the study.  A 
source document review will be performed against entries on the eCRFs and a quality 
assurance check will be performed to ensure that the investigator is complying with the 
protocol and regulations.  In addition, ongoing review of the data will be conducted by a 
physician or representative at AbbVie.
Data entered into eCRFs will be electronically transferred to AbbVie and imported into
the database using validated software throughout the study.  Computer logic checks will 
be run to identify such items as inconsistent study dates.  Any necessary corrections will 
be made to the eCRF.
Routine hematology, serum chemistry, lipid and endocrine panels, urinalysis, Pap smears 
and endometrial biopsies will be analyzed using a central laboratory.  The data from these 
analyses will be electronically transferred from the central laboratory to the study 
database.
A review of all laboratory results will be conducted by a physician and clinical review 
team at AbbVie, the AbbVie monitors (or their representatives), the investigator and other 
appropriate personnel from AbbVie.


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Alkaline hematin analysis will be performed by Alkaline Hematin laboratory.  The data 
from these analyses will be electronically transferred from the Alkaline Hematin 
laboratory to the study database.
PK and PD samples will be analyzed by the Drug Analysis Department at AbbVie and 
data will be loaded into the study database.
Pelvic ultrasound, SIS and MRI scans will be read by the Central Imaging Vendor.  The 
results of these scans will be electronically transferred from the Central Imaging Vendor 
to the study database.
DXA scans will be read by a Central DXA Reader.  The results of these scans will be 
electronically transferred from the Central DXA Reader to the study database.
12.0
Use of Information
All information concerning elagolix and AbbVie operations, such as AbbVie patent 
applications, formulas, manufacturing processes, basic scientific data, or formulation 
information, supplied by AbbVie and not previously published is considered confidential 
information.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of elagolix.  
This information may be disclosed as deemed necessary by AbbVie to other clinical 
investigators, other pharmaceutical companies, and to governmental agencies.  To allow 
for the use of the information derived from this clinical study and to ensure complete and 
thorough analysis, the investigator is obligated to provide AbbVie with complete test 
results and all data developed in this study and to provide direct access to source 
data/documents for study-related monitoring, audits, IEC/IRB review, and regulatory 
inspection.


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This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie, and shall not be used except in 
the performance of this study.
The investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study, including each subject's name, subject number, address, phone 
number and emergency contact information.  This list will be maintained at the study site 
with other study records under adequate security and restricted access, and will not be 
retrieved by AbbVie.
13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The investigator must retain any records related to the study according to local 
requirements.  If the investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report.  The 
end-of-study is defined as the date of the last subject's last visit.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for elagolix (ABT-620).
2.
I have read this protocol and agree that the study is ethical.
3.
I have read the Package Insert/Product Label for E2/NETA.
4.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
5.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
6.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
Extension Study to Evaluate the Efficacy and Safety of Elagolix in 
Premenopausal Women with Heavy Menstrual Bleeding Associated 
with Uterine Fibroids
Protocol Date:
18 December 2017
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
Baird DD, Dunson DB, Hill MC, et al.  High cumulative incidence of uterine 
leiomyoma in black and white women:  ultrasound evidence.  Am J Obstet 
Gynecol.  2003;188(1):100-7.
2.
Stewart EA.  Uterine fibroids.  Lancet.  2001;357(9252):293-8.
3.
Laughlin SK, Schroeder JC, Baird DD.  New directions in the epidemiology of 
uterine fibroids.  Semin Reprod Med.  2010;28(3):204-17.
4.
Rein MS, Barbieri RL, Friedman AJ.  Progesterone:  a critical role in the 
pathogenesis of uterine myomas.  Am J Obstet Gynecol.  1995;172 (1 Pt 1):14-8.
5.
Buttram VC Jr, Reiter RC.  Uterine leiomyomata:  etiology, symptomatology, and 
management.  Fertil Steril.  1981;36(4):433-45.
6.
Maresh MJ, Metcalfe MA, McPherson K, et al.  The VALUE national 
hysterectomy study:  description of the patients and their surgery.  BJOG.  
2002;109(3):302-12.
7.
AbbVie.  ABT-620 (Elagolix) Investigator's Brochure Edition 15.  07 April 2016.
8.
Derby CA, Crawford SL, Pasternak RC, et al.  Lipid changes during the menopause 
transition in relation to age and weight:  the study of women's health across the 
nation.  Am J Epidemiol.  2009;169(11):1352-61.
9.
US Department of Health and Human Services Food and Drug Administration 
Center for Drug Evaluation and Research (CDER).  Guidance for Industry Drug 
Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and 
Labeling Recommendations.  February 2012.  Available from:  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
default.htm.
10.
Spies JB, Coyne K, Guaou Guaou N, et al.  The UFS-QoL, a new disease-specific 
symptom and health-related quality of life questionnaire for leiomyomata.  Obstet 
and Gynecol.  2002;99(2):290-6.


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11.
Herdman M, Gudex C, Lloyd A, et al.  Development and preliminary testing of the 
new five-level version of EQ-5D (EQ-5D-5L).  Qual Life Res.  
2011;20(10):1727-36.


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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.


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9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Clinical Development
Global Drug Supply Management
Clinical Operations
Clinical Pharmacokinetics
Bioanalysis
Clinical Development
Data and Statistical Sciences


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Appendix C.
Study Activities – Treatment Period and Post-Treatment Follow-Up Period
Treatment Period
Treatment Perioda
Procedure
Day 1b
Month 
1
Month 
2
Month 
3
Month 
4
Month 
5
Month 
6
PCVc
Unsch 
Visit
PD (if 
appl)
Informed Consent
Xd
Gynecological (External Genitalia, Pelvic and Breast) 
Examination
X
X
Pap Test
X
X
Endometrial Biopsy
Xe
Xe,f
Complete Physical Examination Including Weight
X
X
Symptom-Directed Physical Examination
X
X
X
X
X
Vital Signs (Temp, BP, Pulse, RR)
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram (ECG)
X
X
Mammogram
Xg
Xg
Pelvic Ultrasound:  TAU, TVU
Xh
Xh
Xh,i
MRI (Subset of Subjects)
Xh
Xh,j
DXA Scan
Xk
X
Xi
Dispense Sanitary Products and Collection Kit (Keg, 
Collection Bags, etc.) as Needed
X
X
X
X
X
X
X
X
X
Collect and Return Sanitary Products and Draw Venous 
Blood Sample
Xl
Xl
Xl
Xl
Xl
Xl
X
X


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Treatment Perioda
Procedure
Day 1b
Month 
1
Month 
2
Month 
3
Month 
4
Month 
5
Month 
6
PCVc
Unsch 
Visit
PD (if 
appl)
UBQ
Xm
Xm
Xm
Xm
Xm
Xm
Xm
Xm
Xm
Clinical Safety Labs:  Chemistry, Lipid Panel and 
Hematology
X
X
X
X
X
X
X
Clinical Safety Labs:  Chemistry Creatinine 
Phosphokinase  
X
X
Clinical Safety Labs:  Urinalysis
X
X
X
Apolipoprotein A and B
X
X
X
Endocrine:  FSH and LH
X
X
X
X
X
X
X
Endocrine:  Reflexive TSH and Thyroxine-Binding 
Globulin (TBG)
X
Xn
Xn
Pharmacodynamic Sample:  Serum Estradiol (E2) and 
Progesterone (P)
X
X
X
X
X
X
X
Pharmacokinetic Sample (PK):  Elagolix and NETA 
Plasma Concentration
X
X
X
X
X
X
X
Urine Pregnancy Tests
Xo
Xp,q
Xp,q
Xp,q
Xp,q
Xp,q 
Xq
X
X
Serum Pregnancy Tests
X
X
Contraception Counseling/Dispense Contraceptives as 
Necessary
Xr
X
X
X
X
X
X
X
X
Birth Control Attestation
X
X
X


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Treatment Perioda
Procedure
Day 1b
Month 
1
Month 
2
Month 
3
Month 
4
Month 
5
Month 
6
PCVc
Unsch 
Visit
PD (if 
appl)
PRO 
Questionnaires
EQ-5D-5L
X
X
UFS-QoL
X
X
X
Work Productivity and Activity 
Questionnaire (WPAI)
X
X
PGIC-MB
X
X
X
X
PGIC-NBUFS
X
X
X
X
Health Care Resource Utilization 
(HCRU)
X
X
X
X
X
X
X
C-SSRS – (Since Last Visit)
Xr
X
X
X
X
X
X
X
Interactive Response Technology (IRT)p
X
X
X
X
X
X
X
X
Study Drug Dispense
X
X
X
X
X
X
Drug Accountability
X
X
X
X
X
X
X
Adverse Event Monitoring
Xr
X
X
X
X
X
X
X
X
X
Concomitant Medication Review and Update
Xp,r
X
X
X
X
X
X
X
X
X
a.
Refer to Table 1, Visit and Assessment Windows, for allowable visit and assessment-specific windows during the Treatment Period.
b.
Day 1 will be performed only after all study procedures are completed and results available from the Final Treatment Visit of the Pivotal Study M12-815 or Study M12-817.
c.
Product Collection Visit (PCV) is to occur approximately 5 days after cessation of bleeding or spotting and is only necessary if a monthly visit is not scheduled to occur 
within approximately 5 days after cessation of bleeding or spotting.
d.
Protocol-specific informed consent must be obtained prior to the initiation of any Extension Study procedures. 
e.
Subject must have a confirmed negative urine pregnancy test within 24 hours prior to the endometrial biopsy or SIS (if applicable).
f.
Subjects who had an endometrial biopsy performed in the 3 months prior to prematurely discontinuation are not required to have an endometrial biopsy performed at the 
Premature Discontinuation Visit.


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g.
All subjects who had a Mammogram in the Pivotal Study will have a mammogram performed at Month 6 or at the Premature Discontinuation Visit if it has been 
approximately 12 months since the screening mammogram was performed.
h.
An SIS may be performed if any new finding on the pelvic ultrasound (TAU and TVU) or MRI results suggest an intracavitary lesion such as a polyp.  Refer to 
Section 5.3.1.1, Study Procedures, for further instruction.
i.
Procedure does not need to be performed at the Premature Discontinuation Visit if performed within the past 1 month.
j.
Subjects participating in the MRI subset:  An MRI does not need to be performed at the Premature Discontinuation Visit if performed within the past 3 months.
k.
DXA scan to be performed as outlined per Figure 2, Management of BMD % Decrease:  Treatment Period.
l.
If menstrual bleeding or spotting stops within approximately 5 days of a scheduled monthly visit, subject will return sanitary products at the scheduled monthly visit and a 
venous blood sample will be obtained.  The venous blood sample will be sent with collected products to the Alkaline Hematin laboratory.
m.
The UBQ is to be completed by Site Staff at a scheduled monthly visit, PCV or Unscheduled Visit only if the subject did not return a sanitary product collection keg at the 
visit.
n.
TBG only.
o.
Day 1 urine pregnancy test:  Sample must be collected and a negative test result must be available prior to administration of study drug, unless a urine pregnancy test (with a 
negative tests result) was performed at the Final Treatment Visit (Month 6 or Unscheduled Visit) of the Pivotal Study and the Final Treatment Visit occurs on the same day as 
Day 1.
p.
To either be performed or collected prior to study drug administration.
q.
Study drug must not be dispensed if the subject has a positive urine pregnancy test result at a visit during the Treatment Period.  A positive urine pregnancy test result must be 
confirmed with a quantitative serum pregnancy test.  For any subject who has a positive serum pregnancy test result, a TVU must be conducted as early as possible in the 
first trimester in order to assess the gestational age and estimated due date.  The subject will be discontinued from the study at the point the pregnancy was confirmed.
r.
Sample or procedure or assessment does not need to be collected or performed when the Final Treatment Visit of the Pivotal Study occurs on the same day as the Day 1 Visit 
of this Extension Study; the test results and documentation that the procedure was performed must be captured in Source and in the Extension Study eCRFs. 


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Study Activities – Post-Treatment Follow-Up Period
12-Month Post-Treatment Follow-Up Perioda
Month 
1
Month 
2
Month 
3
Month 
4
Month 
5
Month 
6
Month 
7
Month 
8
Month 
9
Month 
10
Month 
11
Month 
12
PCV
PD
Phone Contact/Phone Visit
X
X
X
X
X
X
X
Pelvic Ultrasound@:  TVU, TAU
X
X
X
MRI (Subset of Subjects)@
X
Xb
Complete Physical Examination, 
Including Weight
X
X
Symptom Directed Physical 
Examination
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
DXA Scan
Xc
Xc
Xc,d
Clinical Safety Labs:  Chemistry, 
Hematology, Lipid Panel and 
Urinalysis
X
X
X
X
Xe
X
Apolipoprotein A and B
X
X
X
X
X
X
Urine Pregnancy Test
Xf
Xf,g
Xf
Xf,g
Xf,g
Xf
Xf,g
Xf,g
Xf
Xf,g
Xf,g
Xf
Xf
Xf
Serum Pregnancy Test
X
X
Return Sanitary Products for the 
First Menses in Post-Treatment
Xh
UBQ (as applicable)i
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contraception Counseling/Dispense 
Contraceptivesj
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Monitoring
X
Xk
X
X
X
X
X
X
X
X
X
X
X
X


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12-Month Post-Treatment Follow-Up Perioda
Month 
1
Month 
2
Month 
3
Month 
4
Month 
5
Month 
6
Month 
7
Month 
8
Month 
9
Month 
10
Month 
11
Month 
12
PCV
PD
Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
@
Subjects with a finding of polyp on pelvic ultrasound or MRI at during the Post-Treatment Follow-Up Period will undergo evaluation per standard of care which may include 
an SIS.
a.
Refer to Table 1, Visit and Assessment Windows, for allowable visit and assessment-specific windows during the Post-Treatment Follow-Up Period.
b.
Subjects who had an MRI performed in the past 3 months prior to prematurely discontinuing are not required to have an MRI performed at the Premature Discontinuation 
Visit.
c.
DXA Scan to be performed as outlined in Figure 3 for Management of BMD % Decrease during the Post-Treatment Follow-Up Month 12.
d.
Procedure does not need to be performed at the Premature Discontinuation Visit if performed within the past 1 month.
e.
Safety labs at Post-Treatment Follow-Up Month 12:  Lipid Panel only.
f.
A positive urine pregnancy test result must be confirmed with a quantitative serum pregnancy test.  For any subject who has a positive serum pregnancy test result, a TVU 
must be performed during the first trimester of pregnancy to assess the gestational age and estimated date of delivery.
g.
Home pregnancy test kit will be self-administered at home by the subject.
h.
Subject should return sanitary products within approximately 5 days after cessation of bleeding or spotting from the first menses with full menstrual flow in the Post-
Treatment Follow-Up Period at a Product Collection Visit or a scheduled site visit.  The venous blood sample will be sent with collected products to the Alkaline Hematin 
laboratory.
i.
Post-Treatment UBQ will only be completed when a Subject has not returned sanitary products for a full menses in the Post-Treatment Follow-Up Period.
j.
Subjects are required to continue the use of two forms of non-hormonal birth control.  Subjects may begin the use of hormonal contraception in place of non-hormonal birth 
control after completing the Month 2 Visit in the Post-Treatment Follow-Up Period and the subject has returned products for one full menses.
k.
An adverse event of amenorrhea will be reported for subjects who do not return to menses by the Post-Treatment Follow-Up Month 2 Phone Visit and the adverse event will 
be followed until resolution.


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Appendix D.
Uterine Bleeding Questionnaire – Treatment Period – SAMPLE
(To be Completed by Site Staff)
Version 2.0
During site visits in the Treatment Period, subjects who did not return a Sanitary Product 
Collection Keg (for menstrual blood loss analysis) will be asked whether they had any 
uterine bleeding or spotting since their last study visit.  Did the subject have any 
bleeding or spotting since her last study visit.
☐No    ☐Yes
If yes, why were sanitary products not collected/returned?  (Please select one 
response)
☐  Subject only had spotting that did not require the use of sanitary products*
☐  There was no visible blood on sanitary products*
☐  Subject forgot to/did not collect*
☐  Subject/Site discarded the sanitary products*
☐  Subject is still bleeding/spotting; will return when bleeding/spotting 
complete
☐  Subject collected sanitary products and did not bring them to this visit; will 
return sanitary products at a later date
☐  Other
* If this response is checked, remind subject to collect and return all used or worn sanitary 
products with or without visible blood.


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Appendix E.
Uterine Bleeding Questionnaire Post-Treatment Follow-Up Period 
– SAMPLE
(To be Completed by Site Staff)
Version 2.0
Subjects who have not returned sanitary products for their first full menses in the Post-
Treatment Period, will be asked at the Post-Treatment Phone and Site Visits whether they 
had any bleeding or spotting since their last site or phone visit.  Once a subject returns 
sanitary products for a full menses in the Post-Treatment Follow-up Period, this 
questionnaire no longer needs to be completed.
1.
Did the subject have any bleeding or spotting since her last study visit (Site 
visit or phone visit)?
☐No    ☐Yes
If yes, why were sanitary products not collected/returned?  (Please select 
one response)
☐  Subject only had spotting that did not require the use of sanitary products* 
☐  There was no visible blood on sanitary products* 
☐  Subject forgot to/did not collect* 
☐  Subject/Site discarded the sanitary products* 
☐  Subject is still bleeding/spotting; will return when bleeding/spotting 
complete
☐  Subject collected sanitary products and did not bring them in yet; will 
return sanitary products at a later date
☐  Other
*
Subject will be required to collect sanitary products for her next full menses.


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Appendix F.
UFS-QoL – SAMPLE


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Appendix G.
Patient Global Impression of Change – Menstrual Bleeding (PGIC-
MB) SAMPLE
Please answer the following question regarding your menstrual bleeding:
Since I started taking study medication, my menstrual bleeding has:
☐Very much improved
☐Much improved
☐Minimally improved
☐Not changed
☐Minimally worse
☐Much worse
☐Very much worse


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Appendix H.
Patient Global Impression of Change Non-Bleeding Uterine Fibroid 
Symptoms (PGIC-NBUFS) – SAMPLE
Thinking about your condition, please answer the following questions regarding your 
non-bleeding uterine fibroid symptoms, that is, any symptom(s) that is present, whether 
or not you are having your period:
1.
Since I started taking study medication, my abdominal or pelvic pain has/is
☐Very much improved
☐Much improved
☐Minimally improved
☐Not changed
☐Minimally worse
☐Much worse
☐Very much worse
2.
Since I started taking study medication, my abdominal or pelvic pressure has/is
☐Very much improved
☐Much improved
☐Minimally improved
☐Not changed
☐Minimally worse
☐Much worse
☐Very much worse
3.
Since I started taking study medication, my abdominal or pelvic cramping has/is
☐Very much improved
☐Much improved
☐Minimally improved
☐Not changed
☐Minimally worse


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☐Much worse
☐Very much worse
4.
Since I started taking study medication, my back pain has/is
☐Very much improved
☐Much improved
☐Minimally improved
☐Not changed
☐Minimally worse
☐Much worse
☐Very much worse
5.
Since I started taking study medication, my abdominal bloating has/is
☐Very much improved
☐Much improved
☐Minimally improved
☐Not changed
☐Minimally worse
☐Much worse
☐Very much worse
6.
Overall since I started taking study medication, my non-bleeding symptoms
have/are
☐Very much improved
☐Much improved
☐Minimally improved
☐Not changed
☐Minimally worse
☐Much worse
☐Very much worse


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Appendix I.
Work Productivity and Activity Impairment Questionnaire:  
Uterine Fibroids V2.0 (WPAI:UF) – SAMPLE
The following questions ask about the effect of uterine fibroid symptoms on your ability 
to work and perform regular activities.  Please fill in the blanks or circle a number, as 
indicated.
1.
Are you currently employed (working for pay)? _____ NO ___ YES
If NO, check "NO" and skip to Question 6.
The next questions are about the past seven days, not including today.
2.
During the past seven days, how many hours did you miss from work because of 
problems associated with your uterine fibroid symptoms?  Include hours you 
missed on sick days, times you went in late, left early, etc., because of your uterine 
fibroid symptoms.  Do not include time you missed to participate in this study.
_____ HOURS
3.
During the past seven days, how many hours did you miss from work because of 
any other reason, such as vacation, holidays, time off to participate in this study?
_____HOURS
4.
During the past seven days, how many hours did you actually work?
_____ HOURS  (If "0," skip to question 6.)
5.
During the past seven days, how much did your uterine fibroid symptoms affect 
your productivity while you were working?  
Think about days you were limited in the amount or kind of work you could do, 
days you accomplished less than you would like, or days you could not do your 
work as carefully as usual.  If uterine fibroid symptoms affected your work only a 
little, choose a low number.  Choose a high number if uterine fibroid symptoms 
affected your work a great deal.


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Consider only how much uterine fibroids affected productivity while you were working.
Uterine fibroid 
symptoms had no 
effect on my work
Uterine fibroid 
symptoms completely 
prevented me from 
working
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER
6.
During the past seven days, how much did your uterine fibroid symptoms affect 
your ability to do your regular daily activities, other than work at a job?  
By regular activities, we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc.  Think about times you were 
limited in the amount or kind of activities you could do and times you accomplished 
less than you would like.  If uterine fibroid symptoms affected your activities only a 
little, choose a low number.  Choose a high number if uterine fibroid symptoms 
affected your activities a great deal.
Consider only how much uterine fibroid symptoms affected your ability to do your 
regular daily activities, other than work at a job.
Uterine fibroid 
symptoms had no 
effect on my daily 
activities
Uterine fibroid 
symptoms completely 
prevented me from 
doing my daily activities
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER
WPAI:SHP V2.0 (US English)


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Appendix J.
EurolQol (EQ-5D-5L) – SAMPLE


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Appendix K.
Columbia-Suicide Severity Rating Scale (C-SSRS) – Since Last 
Visit – SAMPLE


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Appendix L.
Health Care Resource Utilization Questionnaire HCRU Version 2.0 
– SAMPLE
(To be completed by Site Staff)
Non-Study Visits for Routine/General Health Care
Version 2.0
Complete Version 2.0 for Subject's who randomize under Amendment 2
Instructions to Site Staff:  At each scheduled monthly visit (Month 1 through Month 6) in 
the Treatment Period, please ask if the subject saw a Non-Study Health Care Practitioner 
(HCP) since her last scheduled monthly visit for a routine/general health care visit that is 
not associated with an adverse event.  
Only record routine/general health care visits with Non-Study HCPs below.
Record Non-Study HCP Visits associated with an adverse event on the Adverse Event 
form only.  Do not record below.
1.
Since the Subject's last scheduled monthly study visit, has she seen a non-study 
Health Care Practitioner (e.g., Physician, Nurse Practitioner, Physician Assistant, 
Dentist, Physical Therapist) for a routine/general health care visit that is not 
associated with an adverse event?  ☐No  ☐  Yes
If Yes, please complete the questions below.


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Health Care Resource Utilization Questionnaire HCRU – SAMPLE
Record Non-Adverse Event Related Visits Below
Any Visits Associated with Adverse Events should be Recorded on the Adverse Event eCRF only
2.
What type of facility was 
the subject seen at?
3.
How many times was the 
subject seen by each 
facility?
4.
What type(s) of Non-Study Health 
Care Practitioner was the Subject 
seen by?  (Check all that apply)
5.
How many times was the subject 
seen by each Non-Study Health 
Care Practitioner?
☐Office
☐AUDIOLOGIST
☐ALLERGIST
☐CARDIOLOGIST
☐DENTIST
☐DERMATOLOGIST
☐ENDOCRINOLOGIST
☐ENT
☐FAMILY PHYSICIAN
☐GASTROENTEROLOGIST
☐GYNECOLOGIST
☐HEMATOLOGIST
☐HEPATOLOGIST
☐IMMUNOLOGIST
☐INFECTIOUS DISEASE SPECIALIST
☐INTERNAL MEDICINE SPECIALIST
☐INTERNIST
☐MEDICAL GENETICIST


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Record Non-Adverse Event Related Visits Below
Any Visits Associated with Adverse Events should be Recorded on the Adverse Event eCRF only
2.
What type of facility was 
the subject seen at?
3.
How many times was the 
subject seen by each 
facility?
4.
What type(s) of Non-Study Health 
Care Practitioner was the Subject 
seen by?  (Check all that apply)
5.
How many times was the subject 
seen by each Non-Study Health 
Care Practitioner?
☐NEPHROLOGIST
☐NEUROSURGEON
☐NURSE
☐NURSE PRACTITIONER
☐OCCUPATIONAL THERAPIST
☐OPHTHALMOLOGIST
☐ORTHOPEDIC SURGEON
☐OPTOMETRIST
☐PHYSIATRIST
☐PHYSICAL THERAPIST
☐PLASTIC SURGEON
☐PODIATRIST
☐PSYCHOLOGIST
☐PULMONOLOGIST
☐RADIOLOGIST 
☐REPRODUCTIVE 
ENDOCRINOLOGIST 
☐RHEUMATOLOGIST


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Record Non-Adverse Event Related Visits Below
Any Visits Associated with Adverse Events should be Recorded on the Adverse Event eCRF only
2.
What type of facility was 
the subject seen at?
3.
How many times was the 
subject seen by each 
facility?
4.
What type(s) of Non-Study Health 
Care Practitioner was the Subject 
seen by?  (Check all that apply)
5.
How many times was the subject 
seen by each Non-Study Health 
Care Practitioner?
☐SURGEON
☐UROLOGIST
☐UNKNOWN
☐OTHER HEALTH CARE 
PRACTITIONER (specify type):
☐Urgent Care
☐AUDIOLOGIST
☐ALLERGIST
☐CARDIOLOGIST
☐DENTIST
☐DERMATOLOGIST
☐ENDOCRINOLOGIST
☐ENT
☐FAMILY PHYSICIAN
☐GASTROENTEROLOGIST
☐GYNECOLOGIST
☐HEMATOLOGIST
☐HEPATOLOGIST
☐IMMUNOLOGIST


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Record Non-Adverse Event Related Visits Below
Any Visits Associated with Adverse Events should be Recorded on the Adverse Event eCRF only
2.
What type of facility was 
the subject seen at?
3.
How many times was the 
subject seen by each 
facility?
4.
What type(s) of Non-Study Health 
Care Practitioner was the Subject 
seen by?  (Check all that apply)
5.
How many times was the subject 
seen by each Non-Study Health 
Care Practitioner?
☐INFECTIOUS DISEASE SPECIALIST
☐INTERNAL MEDICINE SPECIALIST
☐INTERNIST
☐MEDICAL GENETICIST
☐NEPHROLOGIST
☐NEUROSURGEON
☐NURSE
☐NURSE PRACTITIONER
☐OCCUPATIONAL THERAPIST
☐OPHTHALMOLOGIST
☐ORTHOPEDIC SURGEON
☐OPTOMETRIST
☐PHYSIATRIST
☐PHYSICAL THERAPIST
☐PLASTIC SURGEON
☐PODIATRIST
☐PSYCHOLOGIST
☐PULMONOLOGIST


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Record Non-Adverse Event Related Visits Below
Any Visits Associated with Adverse Events should be Recorded on the Adverse Event eCRF only
2.
What type of facility was 
the subject seen at?
3.
How many times was the 
subject seen by each 
facility?
4.
What type(s) of Non-Study Health 
Care Practitioner was the Subject 
seen by?  (Check all that apply)
5.
How many times was the subject 
seen by each Non-Study Health 
Care Practitioner?
☐RADIOLOGIST 
☐REPRODUCTIVE 
ENDOCRINOLOGIST 
☐RHEUMATOLOGIST
☐SURGEON
☐UROLOGIST
☐UNKNOWN
☐OTHER HEALTH CARE 
PRACTITIONER (specify type):  
☐Emergency Room
☐AUDIOLOGIST
☐ALLERGIST
☐CARDIOLOGIST
☐DENTIST
☐DERMATOLOGIST
☐ENDOCRINOLOGIST
☐ENT
☐FAMILY PHYSICIAN
☐GASTROENTEROLOGIST
☐GYNECOLOGIST


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Record Non-Adverse Event Related Visits Below
Any Visits Associated with Adverse Events should be Recorded on the Adverse Event eCRF only
2.
What type of facility was 
the subject seen at?
3.
How many times was the 
subject seen by each 
facility?
4.
What type(s) of Non-Study Health 
Care Practitioner was the Subject 
seen by?  (Check all that apply)
5.
How many times was the subject 
seen by each Non-Study Health 
Care Practitioner?
☐HEMATOLOGIST
☐HEPATOLOGIST
☐IMMUNOLOGIST
☐INFECTIOUS DISEASE SPECIALIST
☐INTERNAL MEDICINE SPECIALIST
☐INTERNIST
☐MEDICAL GENETICIST
☐NEPHROLOGIST
☐NEUROSURGEON
☐NURSE
☐NURSE PRACTITIONER
☐OCCUPATIONAL THERAPIST
☐OPHTHALMOLOGIST
☐ORTHOPEDIC SURGEON
☐OPTOMETRIST
☐PHYSIATRIST
☐PHYSICAL THERAPIST
☐PLASTIC SURGEON




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Record Non-Adverse Event Related Visits Below
Any Visits Associated with Adverse Events should be Recorded on the Adverse Event eCRF only
7.
Diagnostic/Therapeutic Procedure (Check 
all that apply)
8.
How many times was the procedure performed?
Ultrasound Scan
☐
Physical Examination
☐
Vital Signs
☐
MRI
☐
CT Scan
☐
X-Ray
☐
Biopsy and Histologic Examination
☐
Pelvic Exam
☐
Urine Test
☐
Blood Test
☐
Other (specify):___________________
☐


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Appendix M.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Global Protocol Change
"Estradiol 1.0 mg" has been changed to read "Estradiol 1 mg" throughout the protocol.
Specific Protocol Changes
Section 1.2  Synopsis
Subsection Criteria for Evaluation:
Heading "Efficacy:"
Sub-heading "Secondary Efficacy Variables:" previously read:
Secondary Efficacy Variables:
!
MBL volume assessed using alkaline hematin methodology and UBQ
!
Suppression of bleeding 
!
Hemoglobin concentration 
!
Fibroid and uterine volume
!
UFS-QoL Questionnaire
!
EuroQol (EQ-5D-5L) Questionnaire
!
Health Care Resource Utilization (HCRU) Questionnaire
!
Patient Global Impression of Change (PGIC) Questionnaires
!
Work Productivity and Activity Impairment (WPAI) Questionnaire
Has been changed to read:
Secondary Efficacy Variables:
!
MBL volume assessed using alkaline hematin methodology and UBQ
!
Suppression of bleeding 
!
Hemoglobin concentration
Other Efficacy Variables:
!
Amenorrhea
!
Control of bleeding
!
Bleeding days 
!
Fibroid and uterine volume
!
UFS-QoL Questionnaire
!
EuroQol (EQ-5D-5L) Questionnaire
!
Health Care Resource Utilization (HCRU) Questionnaire


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!
Patient Global Impression of Change (PGIC) Questionnaires
!
Work Productivity and Activity Impairment (WPAI) Questionnaire
Section 1.2  Synopsis
Subsection Statistical Methods:
Heading "Primary Efficacy Analysis:"
First paragraph previously read:
The primary analysis of the primary endpoint will be performed using the modified intent-
to-treat (mITT) analysis set, which is comprised of all subjects who took at least one dose 
of the study drug and have at least one post-baseline visit in this Extension Study.
Has been changed to read:
The primary analysis of the primary endpoint will be performed using the full analysis set, 
which is comprised of all subjects who took at least one dose of the study drug in this 
Extension Study.
Section 1.2  Synopsis
Subsection Statistical Methods:
Heading "Analyses for Secondary Efficacy Variables:"
Heading previously read:
Analyses for Secondary Efficacy Variables:
Has been changed to read:
Analyses for Secondary and Other Efficacy Variables:
Section 5.1  Overall Study Design and Plan:  Description
Subsection Visit Window
First paragraph, second sentence previously read:
Each subsequent monthly visit should be scheduled based on the date of the Day 1 Visit.


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Has been changed to read:
During the Treatment Period, each subsequent monthly visit should be scheduled based 
on the date of the Day 1 Visit.
Table 1.  Visit and Assessment Windows
"Post-Treatment Follow-Up Period," second row previously read:
Month 6:  MRI (if participating in MRI subset),Ultrasound, DXA Scan –15 or 
+4 days
Has been changed to read:
Month 6:  Ultrasound, DXA Scan 
–15 or +4 days
Section 5.3.1.1  Study Procedures
Subsection Pap Test
First paragraph previously read:
A Pap test will be performed at Treatment Period Month 6 or Premature Discontinuation 
Visit (only performed if subject discontinues at or after the Post-Treatment Follow-Up 
Period Month Visit).
Has been changed to read:
A Pap test will be performed at Treatment Period Month 6 or Premature Discontinuation 
Visit.
Section 5.3.1.1  Study Procedures
Subsection Endometrial Biopsy
Delete:  sixth paragraph
In the event the Month 6 biopsy cannot be performed at Month 6 or the Premature 
Discontinuation Visit (e.g., due to a stenotic cervix or location of fibroids), or an 
insufficient biopsy sample is obtained and the concurrent TVU indicates a thickness of 
> 4 mm, a repeat biopsy must be performed.  If upon repeat, a sample cannot be obtained 
or remains insufficient, the AbbVie TA MD should be consulted.


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Section 5.3.1.1  Study Procedures
Subsection Mammogram
Previously read:
All subjects who had a mammogram performed to determine eligibility into their 
respective Pivotal Study will have a mammogram performed at Treatment Period 
Month 6.
Has been changed to read:
All subjects who had a mammogram performed to determine eligibility into their 
respective Pivotal Study, will have a mammogram performed at Treatment Period 
Month 6 or at the Premature Discontinuation Visit if it has been approximately 12 months 
since the screening mammogram was performed.
Table 3.  Clinical Laboratory Tests
Delete:  column "Serology Testing"
Serology Testing
HAV-IgM
HbsAg
HCV Ab
HIV Ab
Section 5.3.3.2  Secondary Efficacy Variable
Delete:  last bullet
Fibroid and uterine volume
Section 5.4  Removal of Subjects from Therapy or Assessment
Fourth bullet previously read:
The subject requires surgical intervention for treatment of uterine fibroids and menstrual 
bleeding or other procedures including hysterectomy, myomectomy, uterine artery 
embolization, high intensity focused ultrasound (HIFU), endometrial ablation, dilation 
and curettage (D&C), etc.


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Has been changed to read:
The subject requires surgical intervention for treatment of uterine fibroids and menstrual 
bleeding or other procedures including hysterectomy, myomectomy, uterine artery 
embolization, high intensity focused ultrasound (HIFU), endometrial ablation, dilation 
and curettage (D&C), etc. during the Treatment Period.  In the post treatment period these 
procedures do not warrant withdrawal if performed during the Post-Treatment Period 
unless a hysterectomy with bilateral salpingo-oophorectomy (BSO) is performed and the 
Subject does not plan to use Hormone Replacement Therapy within 1 month of the 
surgery date.
Section 5.4  Removal of Subjects from Therapy or Assessment
Sixth bullet previously read:
The subject has ALT or AST elevation > 5 times the upper limit of normal confirmed 
upon repeat.
Has been changed to read:
The subject has ALT or AST elevation > 5 times the upper limit of normal confirmed 
upon repeat during the Treatment Period.
Section 5.4.1  Discontinuation of Individual Subjects
First paragraph
Add:  new last sentence
Each subsequent monthly Post-Treatment Follow-Up Period Visit should be scheduled 
based on the date of the last dose of study drug.
Section 5.5.5  Blinding of Investigational Product
Last paragraph
Add:  new last sentence
AbbVie will remain blinded until the database of the 6-month Treatment Period is locked.


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Section 8.1.2  Data Sets Analyzed
Subsection Modified Intent-to-Treat (mITT) Analysis Set
Subsection title and text previously read:
Modified Intent-to-Treat (mITT) Analysis Set
The modified intent-to-treat (mITT) analysis set is comprised of all subjects who took at 
least one dose of the study drug and have at least one post-baseline visit in this Extension 
Study.  The mITT analysis set will be used for all efficacy analyses unless otherwise 
specified in the Statistical Analysis Plan (SAP).
Has been changed to read:
Full Analysis Set
The full analysis set is comprised of all subjects who took at least one dose of the study 
drug in this Extension Study.  The full analysis set will be used for all efficacy analyses 
unless otherwise specified in the Statistical Analysis Plan (SAP).
Section 8.1.7.1.1  Primary Analysis
Second paragraph previously read:
The primary analysis of the primary endpoint will be performed using the modified intent-
to-treat (mITT) analysis set which is comprised of all subjects who took at least one dose 
of the study drug and have at least one post-baseline visit in this Extension Study.
Has been changed to read:
The primary analysis of the primary endpoint will be performed using the full analysis set 
which is comprised of all subjects who took at least one dose of the study drug in this 
Extension Study.


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Section 8.1.7.1.2  Derivation of Primary Efficacy Endpoint
First bullet, first sentence previously read:
If a subject has any AH data reported during the Final Month (i.e., she has at least 1 day 
of AH data during the last 28 days of treatment), then her primary endpoint will be based 
on AH data during the Final Month.  
Has been changed to read:
If a subject has any evaluable AH data reported during the Final Month (i.e., she has at 
least 1 day of AH data during the last 28 days of treatment), then her primary endpoint 
will be based on AH data during the Final Month.  
Section 8.1.7.1.3  Multiple Imputation
Last paragraph, last sentence previously read:
And the percentages of responders are analyzed using a logistic regression model 
including treatment as the main effect and baseline MBL volume as a covariate. 
Has been changed to read:
The percentage of responders will be summarized by treatment group.
Section 8.1.7.1.4  Sensitivity Analysis of the Primary Efficacy Variable
Last paragraph previously read:
Unless otherwise specified, the analysis dataset used for sensitivity analysis is the mITT 
analysis set.
Has been changed to read:
Unless otherwise specified, the analysis dataset used for sensitivity analysis is the full 
analysis set.


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Section 8.1.7.2  Secondary Efficacy Variables
Previously read:
The secondary efficacy measures during the Treatment Period of the Extension Study 
include the following:
●
Change and percent change from baseline in MBL volume to each month and 
to the Final Month;
●
Percentage of subjects with suppression of bleeding (no bleeding allowed, 
spotting allowed) at the Final Month;
●
Percentage of subjects with baseline hemoglobin ≤ 10.5 g/dL who have an 
increase in hemoglobin > 2 g/dL at Month 6;
●
Percentage of subjects with MBL volume < 80 mL and 50% or greater 
reduction in MBL volume from baseline during 28-day intervals throughout 
the Treatment Period;
●
Change from baseline in total number of sanitary products used;
●
Change and percent change from baseline in hemoglobin concentration;
●
PGIC for Menstrual Bleeding and Non-Bleeding Uterine Fibroid Symptoms;
●
Change and percent change from baseline in fibroid and uterine volume;
●
Change from baseline for the UFS-QoL; 
●
Change from baseline for the EuroQoL-5D (EQ-5D-5L);
●
The HCRU;
●
Change from baseline for the WPAI.
Analysis details will be specified in the SAP.
Has been changed to read:
The secondary efficacy measures during the Treatment Period of the Extension Study 
include the following:
●
Change and percent change from baseline in MBL volume to each month and 
to the Final Month;


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●
Percentage of subjects with suppression of bleeding (no bleeding allowed, 
spotting allowed) at the Final Month;
●
Percentage of subjects with baseline hemoglobin ≤ 10.5 g/dL who have an 
increase in hemoglobin > 2 g/dL at Month 6.
8.1.7.3
Other Efficacy Variables
●
Percentage of subjects with MBL volume < 80 mL and 50% or greater 
reduction in MBL volume from baseline during 28-day intervals throughout 
the Treatment Period;
●
Percentage of subjects with amenorrhea;
●
Percentage of subjects with control of bleeding;
●
The bleeding days;
●
Change and percent change from baseline in hemoglobin concentration;
●
PGIC for Menstrual Bleeding and Non-Bleeding Uterine Fibroid Symptoms;
●
Change and percent change from baseline in fibroid and uterine volume;
●
Change from baseline for the UFS-QoL; 
●
Change from baseline for the EuroQoL-5D (EQ-5D-5L);
●
The HCRU;
●
Change from baseline for the WPAI.
Analysis details will be specified in the SAP.
Section 8.1.7.2.1  Reduction of Bleeding
Last paragraph
Delete:  last sentence
In addition, the change from baseline in total number of sanitary products will be 
summarized by treatment group.


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Section 8.1.8.4  Bone Mineral Density
Last paragraph previously read:
The number and percentage of subjects with categorized percent change from baseline to 
Month 6 in the Extension Study in BMD (e.g., ≤ –3%, ≤ –5%, or ≤ –8%) will be 
summarized for each treatment group.  Analysis details will be specified in the SAP.
Has been changed to read:
The number and percentage of subjects with categorized percent change from baseline to 
Month 6 in the Extension Study in BMD (≤ 0%, > 0% – ≤ 1.5%, > 1.5% – ≤ 3%, > 3% –
≤ 5%, > 5% – < 8%, or ≥8%) will be summarized for each treatment group.  Analysis 
details will be specified in the SAP.
Section 8.2  Determination of Sample Size
Delete:  first sentence
All subjects who complete either Pivotal Study M12-815 or Study M12-817, sign an 
inform consent form, and meet eligibility will be eligible to enroll in this Extension Study.  
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical Development
Global Drug Supply Management
Clinical Operations
Clinical Pharmacokinetics
Bioanalysis
Clinical Development
Statistics


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Has been changed to read:
Name
Title
Functional Area
Clinical Development
Global Drug Supply Management
Clinical Operations
Clinical Pharmacokinetics
Bioanalysis
Clinical Development
Data and Statistical Sciences


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Appendix C. Study Activities – Treatment Period and Post-Treatment Follow-Up Period
Subsection Treatment Period
Procedure "Clinical Safety Labs:  Chemistry, Lipid Panel and Hematology," "Urine Pregnancy Tests," and "Contraception 
Counseling/Dispense Contraceptives as Necessary" previously read:
Treatment Perioda
Procedure
Day 1b
Month 
1
Month 
2
Month 
3
Month 
4
Month 
5
Month 
6
PCVc
Unsch 
Visit
PD (if 
appl)
Clinical Safety Labs:  Chemistry, Lipid Panel and 
Hematology
X
X
X
X
X
X
X
X
Urine Pregnancy Tests
Xo
Xp,q
Xp,q
Xp,q
Xp,q
Xp,q 
Xq
X
X
Contraception Counseling/Dispense Contraceptives as 
Necessary
Xr
X
X
X
X
X
X
X
Has been changed to read:
Treatment Perioda
Procedure
Day 1b
Month 
1
Month 
2
Month 
3
Month 
4
Month 
5
Month 
6
PCVc
Unsch 
Visit
PD (if 
appl)
Clinical Safety Labs:  Chemistry, Lipid Panel and 
Hematology
X
X
X
X
X
X
X
Urine Pregnancy Tests
Xo
Xp,q
Xp,q
Xp,q
Xp,q
Xp,q 
Xq
X
X
Contraception Counseling/Dispense Contraceptives as 
Necessary
Xr
X
X
X
X
X
X
X
X


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173
Appendix C. Study Activities – Treatment Period and Post-Treatment Follow-Up 
Period
Subsection Treatment Period
Table note "g." previously read:
All subjects who had a Mammogram in the Pivotal Study will have a mammogram 
performed at the Month 6 or Premature Discontinuation Visit of this Extension Study.
Has been changed to read:
All subjects who had a Mammogram in the Pivotal Study will have a mammogram 
performed at Month 6 or at the Premature Discontinuation Visit if it has been 
approximately 12 months since the screening mammogram was performed.

SAP_001.pdf: 
Elagolix (ABT-620)
M12-816 – Statistical Analysis Plan
Version 2.0 – 24 May 2018
1
1.0
Title Page
Statistical Analysis Plan
Study M12-816
Extension Study to Evaluate the Efficacy and Safety 
of Elagolix in Premenopausal Women with Heavy 
Menstrual Bleeding Associated with Uterine Fibroids
Date:  24 May 2018
Version 2.0
NCT02925494


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M12-816 – Statistical Analysis Plan
Version 2.0 – 24 May 2018
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2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................7
4.0
Study Objectives, Design and Procedures............................7
4.1
Objectives .............................................................................................. 7
4.2
Study Design.......................................................................................... 7
4.3
Sample Size............................................................................................ 9
4.4
End-of-Treatment Period Analysis.......................................................... 9
5.0
Analysis Populations ........................................................... 10
5.1
Definition for Analysis Populations ...................................................... 10
5.2
Variables for Stratification of Randomization....................................... 10
5.3
Analysis Groups................................................................................... 10
6.0
Protocol Deviation............................................................... 11
7.0
Analysis Conventions .......................................................... 11
7.1
Definition of Baseline........................................................................... 11
7.2
Definitions of Final Month and Final Visit ........................................... 13
7.3
Definition of Study Days (Days Relative to the First Dose of 
Study Drug) and Study End Days (Days Relative to the Last Dose 
of Study Drug) ..................................................................................... 13
7.4
Definition of Analysis Window ............................................................ 14
7.4.1
Treatment Period.................................................................................. 14
7.4.2
Post-Treatment Follow-Up Period ........................................................ 14
7.4.3
Details Regarding Visit Windows......................................................... 15
7.4.4
Handling of Multiple Assessments in a Specific Time Window............ 18
7.5
Dealing with Multiple Values on the Same Day.................................... 18
7.6
Definitions and Conventions of MBL Volume and Bleeding Days ....... 19
7.6.1
MBL Volume ....................................................................................... 19
7.6.1.1
Observed MBL Volume Over a Window.............................................. 19
7.6.2
Bleeding Days ...................................................................................... 20
8.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ...................21


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8.1
Demographic and Baseline Characteristics ........................................... 21
8.1.1
Demographics ...................................................................................... 21
8.1.2
Baseline Characteristics........................................................................ 22
8.2
Medical History.................................................................................... 22
8.3
Prior, Concomitant, and Post-Treatment Medications ........................... 23
9.0
Subject Disposition..............................................................24
10.0
Study Drug Exposure..........................................................25
11.0
Efficacy Analysis .................................................................26
11.1
General Considerations......................................................................... 26
11.2
Primary Efficacy Analysis.................................................................... 26
11.2.1
Primary Efficacy Endpoint ................................................................... 26
11.2.2
Primary Analysis of Primary Efficacy Endpoint ................................... 27
11.2.3
Sensitivity Analyses of the Primary Efficacy Endpoint ......................... 27
11.2.4
Adenomyosis Subset ............................................................................ 28
11.3
Secondary and Other Efficacy Analyses ............................................... 28
11.3.1
Reduction of Bleeding.......................................................................... 29
11.3.2
Amenorrhea, Suppression and Control of Bleeding............................... 30
11.3.2.1
Amenorrhea.......................................................................................... 30
11.3.2.2
Suppression of Bleeding....................................................................... 32
11.3.2.3
Control of Bleeding.............................................................................. 33
11.3.3
Bleeding Days ...................................................................................... 34
11.3.4
Hemoglobin Concentration................................................................... 35
11.3.5
Fibroid and Uterine Volume, FIGO Classification, Adenomyosis, 
and Post-Treatment Menses.................................................................. 36
11.3.5.1
Fibroid and Uterine Volume ................................................................. 36
11.3.5.2
FIGO Classification.............................................................................. 36
11.3.5.3
Adenomyosis........................................................................................ 37
11.3.5.4
Post-Treatment Menses ........................................................................ 37
11.3.6
Quality of Life Questionnaire ............................................................... 39
11.3.6.1
Uterine Fibroid Symptoms Quality of Life (UFS-QoL)......................... 39
11.3.6.2
EQ-5D-5L............................................................................................ 39
11.3.6.3
Patient Global Impression of Change (PGIC) ....................................... 40
11.3.6.3.1
PGIC on Menstrual Bleeding Questionnaire ......................................... 40


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11.3.6.3.2
PGIC on Non-Bleeding Uterine Fibroid Symptoms Questionnaire........ 40
11.3.6.4
Work Productivity and Activity Questionnaire:  Uterine Fibroids 
(WPAI:UF) .......................................................................................... 41
11.3.6.5
Health Care Resource Utilization Questionnaire (HCRU)..................... 41
11.3.6.6
Number of Days in Hospital ................................................................. 41
11.4
Handling of Multiplicity....................................................................... 42
12.0
Safety Analysis.....................................................................42
12.1
General Considerations......................................................................... 42
12.2
Adverse Events..................................................................................... 43
12.2.1
Analysis of Adverse Events in the Extension Study.............................. 43
12.3
Laboratory Variables............................................................................ 45
12.3.1
Analysis of Laboratory Variables ......................................................... 46
12.3.2
Assessment of Hepatotoxicity............................................................... 49
12.4
Bone Mineral Density........................................................................... 50
12.4.1
BMD in the Treatment Period............................................................... 50
12.4.2
BMD in the Post-Treatment Follow-Up Period..................................... 53
12.5
Vital Signs and Body Weight ............................................................... 54
12.6
Endometrial Biopsy.............................................................................. 56
12.7
Pelvic Ultrasound and MRI .................................................................. 56
12.7.1
Ovarian Cysts....................................................................................... 56
12.7.2
Endometrial Thickness ......................................................................... 57
12.8
Columbia Suicide Severity Rating Scale (C-SSRS) .............................. 57
12.9
Pregnancy Results ................................................................................ 58
13.0
Summary of Changes from SAP Version 1.0..................... 58
14.0
References............................................................................58
List of Tables
Table 1.
Analysis Time Windows for Non-Bleeding Measurements 
Collected Monthly................................................................................ 15
Table 2.
Analysis Time Windows for Non-Bleeding Measurements 
Collected Every 3 Months in the Treatment Period............................... 16


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Table 3.
Analysis Time Windows for Non-Bleeding Measurements 
Collected Every 6 Months in the Treatment Period............................... 16
Table 4.
Analysis Time Windows for Non-Bleeding Measurements 
Collected at Post-Treatment Month 1, 3, 6, 9, 12 .................................. 17
Table 5.
Analysis Time Windows for Non-Bleeding Measurements 
Collected at Post-Treatment Month 3 and 6.......................................... 17
Table 6.
Analysis Time Windows for Non-Bleeding Measurements 
Collected at Post-Treatment Month 3.................................................... 17
Table 7.
Analysis Time Windows for Non-Bleeding Measurements 
Collected at Post-Treatment Month 6 and 12 ........................................ 17
Table 8.
Monthly Analysis of Bleeding for Amenorrhea .................................... 31
Table 9.
Categorical Summary of Incidence and Cumulative Incidence of 
Amenorrhea by Last Bleeding/Spotting Day......................................... 32
List of Figures
Figure 1.
Study Schematic..................................................................................... 9
List of Appendices
Appendix A.
UFS-QoL ............................................................................................. 60
Appendix B.
UFS-QoL Scoring Manual.................................................................... 63
Appendix C.
Patient Global Impression of Change (PGIC-MB) – SAMPLE ............. 65
Appendix D.
Patient Global Impression of Change, Non-Bleeding Uterine 
Fibroids Symptoms (PGIC-NBUFS) – SAMPLE.................................. 66
Appendix E.
EurolQol (EQ-5D-5L) – SAMPLE ....................................................... 69
Appendix F.
Uterine Bleeding Questionnaire (UBQ) – Treatment Period –
SAMPLE.............................................................................................. 71
Appendix G.
Uterine Bleeding Questionnaire (UBQ) – Post-Treatment 
Follow-Up Period – SAMPLE.............................................................. 72
Appendix H.
Work Productivity and Activity Impairment Questionnaire:  
Uterine Fibroids V2.0 (WPAI:UF) – SAMPLE..................................... 73
Appendix I.
WPAI:UF Scoring Rules ...................................................................... 75
Appendix J.
Columbia-Suicide Severity Rating Scale (C-SSRS) – Since Last 
Visit – SAMPLE .................................................................................. 77


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Appendix K.
C-SSRS Scoring Rules ......................................................................... 80
Appendix L.
Health Care Resource Utilization Questionnaire (HCRU) 
Version 2.0 – SAMPLE........................................................................ 83
Appendix M.
Adverse Events of Special Interest........................................................ 89
Appendix N.
Exceptions to Standard CTCAE Lab Grading Criteria for Elagolix 
Studies ................................................................................................. 90


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3.0
Introduction
This statistical analysis plan (SAP) describes the planned statistical analyses for elagolix 
(ABT-620) Study M12-816 titled "Extension Study to Evaluate the Efficacy and Safety of 
Elagolix in Premenopausal Women with Heavy Menstrual Bleeding Associated with 
Uterine Fibroids."  The analysis plan was created based on the Study Protocol M12-816 
Amendment 1 dated 18 December 2017.
This analysis plan describes both the efficacy and safety analyses.  The pharmacokinetic 
data will be analyzed separately and is not addressed in this SAP.
The SAS System 9.2 or above will be used to perform the statistical analyses.  No 
statistical tests will be performed unless otherwise specified. 
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objective of this study is to evaluate the long-term efficacy and safety of 
elagolix administered alone and in combination with add-back therapy 
(estradiol/norethindrone acetate or E2/NETA) to reduce heavy menstrual bleeding (HMB) 
associated with uterine fibroids for up to 12 months (initial 6 months if on active 
treatment in the pivotal Study M12-815 or Study M12-817 and an additional 6 months in 
this extension study).
The study will also evaluate the effects of the treatment regimens on hypoestrogenic side 
effects, changes in bone mineral density (BMD) as assessed by Dual Energy X-Ray 
Absorptiometry (DXA), and vasomotor symptoms, such as hot flush.
4.2
Study Design
This is a Phase 3, double-blind, multicenter, extension study designed to:


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●
Obtain 6 month treatment data in subjects who were randomized to placebo in 
one of the two pivotal studies and subsequently randomized to receive 
6 months of treatment with elagolix 300 mg BID or elagolix 300 mg BID plus 
E2/NETA (estradiol 1 mg/norethindrone acetate 0.5 mg) QD in this study.
●
Obtain 12 months of continuous treatment data in subjects who received 
elagolix 300 mg BID or elagolix 300 mg BID plus E2/NETA (estradiol 
1 mg/norethindrone acetate 0.5 mg) QD for 6 months in one of the two pivotal 
studies and will continue to receive an additional 6 months of the same 
treatment in this study.
●
Obtain data on endometrial health (TAU, TVU and endometrial biopsy).
●
Assess bone mineral density, bone health and general safety with long-term 
treatment and recovery during Treatment and Post-Treatment Follow-Up 
Period (up to 12 months of Treatment and 12 months Post-Treatment Follow-
Up).
All subjects who completed the 6-Month Treatment Period in their respective pivotal 
study, who meet eligibility criteria and provide informed consent, will be eligible to enroll 
in this extension study.  This study is designed to enroll approximately 400 subjects 
across approximately 250 clinical study sites to meet scientific and regulatory objectives 
without enrolling an undue number of subjects in alignment with ethical considerations.
The study consists of 2 periods as follows:
1.
6-Month Treatment Period
2.
12-Month Post-Treatment Follow-Up Period
Following the 6-Month Treatment Period, subjects will enter into a 12-Month Post-
Treatment Follow-Up Period.  The Study Periods are illustrated in Figure 1.


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Figure 1.
Study Schematic
4.3
Sample Size
The two pivotal Studies M12-815 and M12-817 have a planned enrollment of a total of 
800 subjects.  Based on assumptions related to discontinuation in the pivotal studies and 
the estimated roll over rate into this extension study, approximately 400 subjects are 
expected to be enrolled in this extension study.
4.4
End-of-Treatment Period Analysis
An end-of-treatment period analysis of efficacy, demographic and safety variables will be 
performed after all subjects enrolled in this study complete the 6-Month Treatment Period 
of this extension Study M12-816.  This end-of-treatment period analysis will include all 
Treatment Period data from all subjects enrolled into the extension study.  The database 
will be versioned and any discrepant data will be clarified before the lock.  The analyses 
will be completed by the Clinical Statistics Department at AbbVie.


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5.0
Analysis Populations
5.1
Definition for Analysis Populations
Full Analysis Set
The full analysis set is comprised of all randomized subjects who have received at least 
one dose of study drug in this study.  The data from the full analysis set will be presented 
by the treatment group assigned at the time of randomization, even if the subject does not 
receive the correct treatment or does not follow the protocol until completion.  The full 
analysis set will be used for all Baseline and efficacy analyses.
Safety Analysis Set
The Safety Analysis Set will include all randomized subjects who received at least 
one dose of study drug.  The data from the safety analysis set will be presented by the 
treatment group as treated, independent of treatment group assignment at the time of 
randomization.  If a subject receives more than one treatment, she will be analyzed in the 
treatment group to which she was randomized.  The safety analysis set will be used for all 
safety analyses.
5.2
Variables for Stratification of Randomization
There is no variable used for stratification of randomization.
5.3
Analysis Groups
Data will primarily be summarized by group for each of the following four main groups of 
subjects listed here based on time of exposure to elagolix. 
●
Subjects randomized to elagolix 300 mg BID plus E2/NETA in the pivotal 
studies and continue on the same treatment in the extension study.
●
Subjects randomized to elagolix 300 mg BID alone in the pivotal studies and 
continue on the same treatment in the extension study.


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●
Subjects randomized to placebo in the pivotal studies and randomized to 
elagolix 300 mg BID plus E2/NETA in the extension study.
●
Subjects randomized to placebo in the pivotal studies and randomized to 
elagolix 300 mg BID alone in the extension study.
Where it is noted that the summaries for six analysis groups will be reported, this refers to 
the four groups above as well as the summaries combining the elagolix treatment groups 
based on exposure groups, seen below.
●
Subjects randomized to placebo in the pivotal studies
●
Subjects randomized to active treatment in the pivotal studies.
6.0
Protocol Deviation
Protocol deviations will be summarized and listed for the six analysis groups.
7.0
Analysis Conventions
7.1
Definition of Baseline
Subjects initially randomized to placebo in the pivotal Study M12-815 or Study M12-817 
will have their baseline (except for the MBL volume, bleeding days, and some 
demographics) re-set to the last non-missing assessment collected prior to the first dose of 
elagolix 300 mg BID or elagolix 300 mg BID plus E2/NETA QD in the extension study, 
unless otherwise specified.  If multiple measurements are recorded on the same day, the 
average of these measurements will be considered as the baseline value.  This same 
baseline value will be used for the Treatment and Post-Treatment Follow Up Periods.  
Subjects initially randomized to elagolix 300 mg BID or elagolix 300 mg BID plus 
E2/NETA QD in the pivotal Study M12-815 or Study M12-817 will have their baseline 
referring to the baseline from the respective pivotal Study M12-815 or Study M12-817, 
unless otherwise specified.


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MBL Volume and Bleeding Days Baseline
For the MBL volume and bleeding days, the baseline for all subjects will refer to the 
baseline from pivotal Study M12-815 or Study M12-817.
Fibroid and Uterine Volume Baseline
For subjects initially randomized to placebo in the pivotal Study M12-815 or 
Study M12-817, baseline for uterine volume, volume of the largest fibroid, total fibroid 
volume (3 largest fibroids), and endometrial thickness measured by ultrasound 
(transvaginal [TVU] or transabdominal [TAU]) or Magnetic Resonance Imaging (MRI) 
will be based on the last non-missing measurement collected on or prior to Study Day 1 in 
the extension study.  If there is no measurement collected on or prior to Study Day 1 in 
the extension study, the first measurement collected prior to Study Day 8 (Study Day 8 is 
not included) in the extension study will be used as Baseline.
Adenomyosis Baseline
For subjects initially randomized to placebo in the pivotal Study M12-815 or 
Study M12-817, baseline for adenomyosis measured by TVU/TAU or MRI will be based 
on the last non-missing measurement collected on or prior to Study Day 1 in the extension 
study.  If there is no measurement collected on or prior to Study Day 1 in the extension 
study, the first measurement collected prior to Study Day 15 (Study Day 15 is not 
included) in the extension study will be used as Baseline.
Quality of Life Questionnaires Baseline
For subjects initially randomized to placebo in the pivotal Study M12-815 or 
Study M12-817, baseline for quality of life questionnaires including Uterine Fibroid 
Symptom Questionnaire (UFS-QoL), EuroQoL-5D (EQ-5D-5L) questionnaire, Work 
Productivity and Activity Impairment (WPAI) questionnaire and Health Care Resource 
Utilization (HCRU) questionnaire will be based on the measurement collected on or 
before Study Day 1 in the extension study.  For UFS-QoL and EQ-5D-5L, if there is no 
measurement collected on or before Study Day 1 in the extension study, the 


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first measurement collected prior to Study Day 8 (Study Day 8 is not included) in the 
extension study will be used as Baseline.
Demographics
All subjects in the extension study will have their baseline demographics including height, 
weight, BMI, race, sex, ethinicity, age, alcohol and tobacco use referring to the baseline 
from the pivotal studies.
When weight is analyzed as a vital sign parameter, subjects initially randomized to 
placebo in the pivotal studies will have their baseline weight re-set to the last non-missing 
assessment collected prior to the first dose of elagolix 300 mg BID or elagolix 300 mg 
BID plus E2/NETA QD in the extension study.
7.2
Definitions of Final Month and Final Visit
Final Month is defined as the last 28 days prior to and including the last dose date in the 
extension study.
Final Visit is defined as the last non-missing assessment during the Treatment Period in 
the extension study. 
Post-Treatment Final Visit is defined as the last non-missing assessment during the 
Post-Treatment Follow-up Period in the extension study.
7.3
Definition of Study Days (Days Relative to the First Dose of 
Study Drug) and Study End Days (Days Relative to the Last 
Dose of Study Drug)
For randomized subjects who received at least one dose of study drug in the extension 
study, the study day is defined as the number of days since (positive values) or prior to 
(negative values) the first study drug dose in the extension study.  The day of the 
first study drug dose in the extension study is defined as Study Day 1 while the last day 
prior to the first dose of study drug is defined as Study Day –1.  There is no Study Day 0.  
Study end days are calculated based on the number of days relative to the last dose of 


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study drug in the extension study.  The first day following the last dose of study drug in 
the extension study is defined as Study End Day 1. 
7.4
Definition of Analysis Window
7.4.1
Treatment Period
Data obtained more than 3 days after the subject's last dose of study drug in the extension 
study will be excluded for assessments in the Treatment Period with the following 
exceptions:
1.
For BMD, TVU/TAU, MRI, and endometrial biopsy assessments, data obtained 
more than 28 days after the last dose of study drug in the extension study will be 
excluded from summaries/analyses in the Treatment Period.
2.
For Alkaline Hematin (AH) data, data obtained after the last dose of study drug in 
the extension study will be excluded from the summaries/analyses in the Treatment 
Period.
7.4.2
Post-Treatment Follow-Up Period
Summaries for the Post-Treatment Follow-up Period will include data obtained more than 
3 days after the subject's last dose of study drug with the following exceptions:
●
For BMD, TVU/TAU, and MRI assessments, data obtained more than 28 days 
after the last dose of study drug in the extension study will be included in the 
summaries during the Post-Treatment Follow-up Period.
●
For AH data, data obtained after the last dose of study drug in the extension 
study will be included in the summaries during the Post-Treatment Follow-up 
Period.


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7.4.3
Details Regarding Visit Windows
For analyses in the Treatment Period in the extension study, time points and 
corresponding time windows are defined based on the time of exposure to study drug 
starting from Study Day 1 in the extension study.
The time windows described in this section will not be applied to bleeding assessments 
including AH data and Uterine Bleeding Questionnaire (UBQ).  Rules described in 
Section 7.4.1 and Section 7.4.2 will be applied prior to defining time windows.  Data 
considered as in the Treatment Period are not considered in the Post-Treatment Follow-up 
Period as described in Section 7.4.1 and Section 7.4.2.  Any data considered as Baseline 
(see Section 7.1) will not be included in any post-baseline windows. 
Table 1 will be used for analyses of endpoints collected monthly in the Treatment Period 
of the extension study.
Table 1.
Analysis Time Windows for Non-Bleeding Measurements Collected 
Monthly
Visit
Nominal Day
(Study Day)
Time Window
(Study Days)
Month 1
28
> 1 – ≤ 42
Month 2
56
> 42 – ≤ 70
Month 3
84
> 70 – ≤ 98
Month 4
112
> 98 – ≤ 126
Month 5
140
> 126 – ≤ 154
Month 6
168
> 154 – ≤ 196
Table 2 will be used for analyses of endpoints collected every 3 months in the Treatment 
Period of the extension study.  If there is a scheduled Month 1 visit for the endpoint 
(e.g., PGIC-MB and PGIC-NBUFS), the first subtable will be used.  If there is no 
scheduled Month 1 visit for the endpoint (e.g., TAU/TVU, BMD, urinalysis, 
apolipoprotein A and B, reflexive TSH, thyroxine-binding globulin (TBG), UFS-QoL), 
the second subtable will be used.


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Table 2.
Analysis Time Windows for Non-Bleeding Measurements Collected 
Every 3 Months in the Treatment Period
Visit
Nominal Day
(Study Day)
Time Window
(Study Days)
Month 1
28
> 1 – ≤ 56
Month 3
84
> 56 – ≤ 140
Month 6
168
> 140 – ≤ 196
Visit
Nominal Day
(Study Day)
Time Window
(Study Days)
Prior to Month 3
28
> 1 – ≤ 56
Month 3
84
> 56 – ≤ 140
Month 6
168
> 140 – ≤ 196
Table 3 will be used for analyses of endpoints collected at Month 6 (biopsy, MRI, 
creatinine phosphokinase, EQ-5D-5L, WPAI) in the Treatment Period of the extension 
study.
Table 3.
Analysis Time Windows for Non-Bleeding Measurements Collected 
Every 6 Months in the Treatment Period 
Visit
Nominal Day 
(Study Day)
Time Window
(Study Days)
Prior to Month 6
70
> 1 – ≤ 140
Month 6
168
> 140 – ≤ 196
Table 4 will be used for analyses of endpoints collected at Post-Treatment Month 1, 3, 6, 
9, and 12 of the extension study (e.g., vital signs, clinical safety labs including chemistry, 
hematology, lipid panel and urinalysis, apolipoprotein A and B).  Table 5 will be used for 
analysis of endpoints collected at Post-Treatment Month 3 and 6 of the extension study 
(e.g., TAU/TVU).  Table 6 will be used for analysis of endpoints collected at Post-
Treatment Month 3 of the extension study (e.g., MRI).  Table 7 will be used for analysis 
of endpoints collected at Post-Treatment Month 6 and 12 of the extension study 
(e.g., BMD).


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Table 4.
Analysis Time Windows for Non-Bleeding Measurements Collected 
at Post-Treatment Month 1, 3, 6, 9, 12
Nominal Day
(Study End Day)
Time Window
(Study End Days)
Post-Treatment Month 1
28
> 3 – ≤ 42
Post-Treatment Month 3
84
> 42 – ≤ 126
Post-Treatment Month 6
168
> 126 – ≤ 210
Post-Treatment Month 9
252
> 210 – ≤ 294
Post-Treatment Month 12
336
> 294
Table 5.
Analysis Time Windows for Non-Bleeding Measurements Collected 
at Post-Treatment Month 3 and 6
Nominal Day
(Study End Day)
Time Window
(Study End Days)
Post-Treatment Month 3
84
> 28 – ≤ 126
Post-Treatment Month 6
168
> 126 – ≤ 210
Post-Treatment Months 7 – 12
266
> 210
Table 6.
Analysis Time Windows for Non-Bleeding Measurements Collected 
at Post-Treatment Month 3
Nominal Day
(Study End Day)
Time Window
(Study End Days)
Post-Treatment Month 3
84
> 28 – ≤ 126
Post-Treatment Months 4 – 12
224
> 126
Table 7.
Analysis Time Windows for Non-Bleeding Measurements Collected 
at Post-Treatment Month 6 and 12
Nominal Day 
(Study End Day)
Time Window
(Study End Days)
Prior to Post-Treatment Month 6
84
> 28 – ≤ 140
Post-Treatment Month 6
168
> 140 – ≤ 196
Post-Treatment Months 7 – 11
252
> 196 – ≤ 308
Post-Treatment Month 12
336
> 308


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7.4.4
Handling of Multiple Assessments in a Specific Time 
Window
For all parameters except MBL volume, multiple assessments in a specific time window 
will be handled as follows:
●
For parameters other than BMD and WPAI data (or otherwise specified), if 
more than one assessment is included in a time window, then the assessment 
performed closest to the scheduled study day (i.e., the nominal day) will be 
used in the analyses.  If more than 1 day is of equal proximity to the nominal 
day, then the data collected after the nominal day will be used in the analyses.
●
For BMD data, if multiple assessments exist in a specific time window, 
analyses of data will be based on the most conservative (worst) assessment.
●
For WPAI data, if multiple assessments exist in a specific time window in the 
treatment period, analyses of data will be based on the last assessment during 
the treatment period. 
7.5
Dealing with Multiple Values on the Same Day
If multiple measurements are made on the same day for a laboratory parameter or a vital 
signs parameter, the average of the values will be used in analyses.  For summaries of 
shifts from Baseline and potentially significant values, multiple values on the same day 
will not be averaged; all values will be considered for these analyses.
If multiple measurements for a particular parameter other than a laboratory parameter and 
a vital signs parameter are made on the same day for the same subject, the most 
conservative (worst) measurement will be used in analyses.


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7.6
Definitions and Conventions of MBL Volume and Bleeding 
Days
7.6.1
MBL Volume
The MBL volume is based on validated and non-validated sanitary products unless 
otherwise specified (for some sensitivity analysis, the MBL volume will be based on 
validated sanitary products only).
7.6.1.1
Observed MBL Volume Over a Window
If there were observed AH data between two study visits (Product Collection Visit or site 
visit with UBQ completed), then the MBL volume on the days with observed AH data 
will be the observed AH data and the MBL volume for the rest of days between the 
two study visits will be imputed as 0 by AH data.
UBQ responses indicate if a subject has any bleeding or spotting since the last study visit 
(Product Collection Visit or site visit with UBQ completed).  If observed evaluable AH 
data is available over a window, then the UBQ will not be considered. 
If the AH data is reported as "NVB" (no visible blood, discarded without assay), "NO 
BLEED" (no collection due to no bleeding as indicated by subject or clinical site on assay 
requisition form), or "TL BQL" (total below low limit of quantitation), the numeric value 
for the AH data will be imputed as 0.  If the AH data is reported as other character value 
("NULL," "IN ERROR," "NO DATA," and etc.), the corresponding numeric value for the
AH data will be set as missing.
The observed MBL volume over a window (such as the Final Month, Month 1 [Study 
Days 1 – 28], Month 2 [Day 29 – Day 56], Month 3 [Day 57 – Day 84], Month 4 
[Day 85 – Day 112], Month 5 [Day 113 – Day 140], and Month 6 [Study Days 141 –
168]) is defined as follows:


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●
If a subject has any evaluable AH data reported in the window, then the 
subject's MBL volume in this window will be the total combined observed AH 
data of validated and non-validated sanitary products over this window.
●
If a subject is missing AH data or all AH data are unevaluable in the window 
and the UBQ is completed and indicates no bleeding or spotting, "Subject only 
had spotting that did not require the use of sanitary products" or "There was no 
visible blood on the sanitary products" and covers this window, then:
○
A value of 0 will be assigned to the MBL volume over this window.
●
If a subject is missing AH data or all AH data are unevaluable in the window 
and the UBQ is completed with no bleeding or spotting or "Subject only had 
spotting that did not require the use of sanitary products" or "There was no 
visible blood on the sanitary products" indicated but UBQ does not cover the 
full window, then:
○
A value of 0 will be assigned to the MBL volume over this window if the 
days not covered by UBQ response as described above have AH imputed 
MBL volume (see first paragraph in Section 7.6.1.1) being 0 for those 
days.
If there is still no value assigned after the imputation procedure described above, the 
observed MBL volume over the window is considered missing.
7.6.2
Bleeding Days 
A bleeding/spotting day is defined as a day having daily MBL volume of > 0 mL.
A spotting day is defined as a day having daily MBL volume of > 0 – 2 mL.
A bleeding day is defined as a day having daily MBL volume of > 2 mL.
Bleeding intensity categories are
●
Daily MBL volume of > 2 – 10 mL.
●
Daily MBL volume of > 10 – 40 mL.
●
Daily MBL volume of > 40 – 80 mL.


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●
Daily MBL volume of > 80 mL.
Please note that only observed AH data will be used for daily MBL volume categroies 
above.
8.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
8.1
Demographic and Baseline Characteristics
Demographics and Baseline characteristics will be summarized for all randomized 
subjects who received at least one dose of study drug by the six analysis groups listed in 
Section 5.3.  The number of missing values will also be summarized.
No statistical tests will be performed.
8.1.1
Demographics
Continuous variables such as age, height, weight, and BMI will be summarized with the 
mean, standard deviation (SD), median, minimum, and maximum by analysis group.  
Number and percentage will be computed by analysis group for the following 
demographic parameters:  age group (18 – < 20 years old, 20 – < 25 years old, 25 –
< 30 years old, 30 – < 35 years old, 35 – < 40 years old, 40 – < 45 years old, 45 –
< 50 years old, ≥ 50 years old), BMI (≤ 18.5 kg/m2, > 18.5 kg/m2 – < 25 kg/m2, 
25 kg/m2 – < 30 kg/m2, 30 kg/m2 – < 35 kg/m2, 35 kg/m2 – < 40 kg/m2, ≥ 40 kg/m2), sex, 
race, ethnicity, tobacco use (current, former, never, and unknown), and alcohol use 
(current, former, never, and unknown).
The number and percentage of subjects with Baseline presence of adenomyosis (as 
defined in Section 11.3.5.3) will be summarized.


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8.1.2
Baseline Characteristics
Menstrual Blood Loss (MBL)
Baseline MBL measured by AH method as defined in Section 7.1 will be summarized 
with mean, SD, median, minimum, and maximum values.
Bleeding Days
Baseline for bleeding days will be based on the observed daily AH data as defined in 
Section 7.1 and Section 7.6.  The numbers of bleeding days by intensity categories at 
Baseline will be summarized with mean, SD, median, minimum, and maximum.
Hemoglobin Concentration
Baseline hemoglobin concentration will be summarized with mean, SD, median, 
minimum, and maximum values.  The number and percentage of subjects with Baseline 
hemoglobin concentration in the following categories will be summarized:  ≤ 10.5 g/dL, 
> 10.5 – ≤ 12 g/dL, and > 12 g/dL.
Fibroid and Uterine Volume
Baseline uterine volume, Baseline volume of the largest fibroid, and Baseline total fibroid 
volume (3 largest fibroids) will be summarized with mean, SD, median, minimum, and 
maximum.
8.2
Medical History
Medical/surgical, gynecological, menstrual and obstetrical history will be summarized and 
presented using system organ classes (SOCs) and preferred terms (PTs) from the Medical 
Dictionary for Regulatory Activities (MedDRA) Version 19.0 or higher for each of the six 
analysis groups listed in Section 5.3.  Subjects reporting more than one medical history 
within a SOC will be counted only once for that SOC.  Subjects reporting more than one 
medical history for a PT will be counted only once for that PT.


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8.3
Prior, Concomitant, and Post-Treatment Medications
Prior, concomitant, and post-treatment medications will be summarized for the full 
analysis set for subjects who enrolled in the extension study by the six analysis groups 
listed in Section 5.3.
Prior medications based on data collected prior to the pivotal studies were summarized.
For prior medications administered to treat uterine fibroid symptoms, the following data 
are collected:  dates of administration (including start and stop dates), dose, route, and 
reason for discontinuation.  Prior medications will be summarized for all randomized 
subjects who received at least one dose of study drug with number and percentage for 
each analysis group using ATC Classification and preferred terms from the World Health 
Organization (WHO) Drug Dictionary.
Concomitant medications are those medications, other than study drugs, taken during the 
treatment period of the extension study with an end date on or after the first dose of study 
drug or ongoing at the end of study, and a start date prior to or on the last dose of study 
drug.  A medication will be considered a concomitant medication where one of the 
following three cases occur (1) the start date is missing and the end date is either after or 
on the first study drug dose date; (2) the start date is prior to or on the last dose of study 
drug and the end date is missing; (3) both the start date and the end date are missing.
Concomitant medications for all randomized subjects who received at least one dose of 
study drug will be summarized using ATC Classification and preferred terms from the 
World Health Organization (WHO) Drug Dictionary with number and percentage for each 
analysis group.
Other medications taken during the Post-Treatment Follow-up Period of this extenstion 
study, which includes all medications with an end date after the last dose of study drug or 
ongoing at the end of study, will be summarized by ATC Classification and WHO 
preferred term with number and percentage for each analysis group.


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A subject who reports two or more uses of the same medication will be counted only once 
within each WHO preferred term.  A subject with medications with more than one generic 
name will be counted only once in the overall total.  Prior medications, concomitant 
medications, and other medications during the Post-Treatment Follow-up Period will be 
summarized separately.
9.0
Subject Disposition
The number of subjects for each of the following categories will be summarized by the 
six analysis groups listed in Section 5.3:
●
All randomized subjects
●
Subjects who took at least one dose of study drug
●
Subjects who completed the Treatment Period
●
Subjects who discontinued from the Treatment Period
●
Subjects who completed the Post-Treatment Follow-Up Period
●
Subjects who prematurely discontinued from the Post-Treatment Follow-Up 
Period
Premature discontinuation of the study drug by primary reason and by any reason will be 
summarized for each of the six analysis groups, with number and percentage and by 
reason for discontinuation for all subjects who received at least one dose of study drug.  
Subjects may have multiple reasons for prematurely discontinuing study drug, but will be 
counted no more than once for the total of "Any Reason."
Premature discontinuation of the study by primary reason and by any reason will be 
summarized for each of the six analysis groups, with number and percentage and by 
reason for discontinuation.  Subjects may have multiple reasons for prematurely 
discontinuing during the Post-Treatment Follow-up Period, but will be counted no more 
than once for the total of "Any Reason."


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10.0
Study Drug Exposure
For all subjects who enrolled into the extension study, the duration of study drug exposure 
in the extension study is defined as the difference between the dates of the first and last 
doses of the treatment in the extension study plus 1 day.  For subjects randomized to 
active treatment in the pivotal Study M12-815 or Study M12-817, cumulative exposure to 
study drug in the pivotal studies and the extension study will be the treatment duration of 
pivotal studies and extension study by taking the sum of the exposure during pivotal 
studies and the exposure during the extension study.  If a subject has a study drug end date 
in the pivotal study that is after the study drug start day in the extension study, the 
overlapping days will be only counted once.
Treatment exposure will be summaried for the extension study alone, for the pivotal 
studies and the extension study, and for the pivotal studies alone, separately.  In each 
summary, the duration (days) of treatment will be summarized with the mean, standard 
deviation, median, minimum, and maximum for each of the four main analysis groups 
listed in Section 5.3 and overall.  Additionally, the number and percentage of subjects 
exposed to study drug will be summarized by duration intervals.
In the cumulative summary of the pivotal and extension studies, for subjects randomized 
to placebo in the pivotal Study M12-815 or Study M12-817, exposure will be summarized 
only for the treatment duration of extension study.  In the summary of exposure in the 
pivotal studies, for placebo subjects in the pivotal studies, the time on placebo will be 
summarized.
The duration intervals for the cumulative summary are:  1 – 28 days, > 28 – 56 days, 
> 56 – 84 days, > 84 – 112 days, > 112 – 140 days, > 140 – 168 days, > 168 – 196 days, 
> 196 – 224 days, > 224 – 252 days, > 252 – 280 days, > 280 – 308 days, > 308 –
336 days, and > 336 days.  The duration intervals for the privotal Studies M12-815 and 
M12-817 alone, and for the extension Study M12-816 alone are:  1 – 28 days, > 28 –
56 days, > 56 – 84 days, > 84 – 112 days, > 112 – 140 days, > 140 – 168 days, > 168 –
196 days, > 196 – 224 days, > 224 – 252 days.


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11.0
Efficacy Analysis
11.1
General Considerations
No statistical tests will be performed.
Unless otherwise specified, categorical data will be summarized by frequency and 
percentage; descriptive summaries of continuous data will display the mean, SD, median, 
minimum, and maximum.
For continuous variables, when the analyses of change and/or percent change from 
Baseline to post-baseline visit(s) are performed, the within-group change from Baseline to 
each relevant visit will be summarized with the mean, SD, and 95% Confidence Intervals 
(CIs).  At each post-baseline visit, the Baseline mean and post-baseline visit mean will be 
calculated for all subjects with baseline and post-baseline value at that visit.
Unless otherwise specified, summaries in efficacy analysis will be provided by the 
four main groups as in Section 5.3.
Information regarding corresponding statistical methods for analyses and any additional 
statistical measures required for a specific variable/endpoint are provided in the relevant 
sections.
11.2
Primary Efficacy Analysis
11.2.1
Primary Efficacy Endpoint
The primary endpoint will be the percentage of responders, defined as subjects meeting 
the following two conditions:
●
MBL volume < 80 mL at the Final Month (the last 28 days of treatment), and
●
50% or greater reduction in MBL volume from Baseline to the Final Month 
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Subjects who prematurely discontinue study drug due to "lack of efficacy," "requires 
surgery or invasive intervention for treatment of uterine fibroids," or adverse events will 
be considered as non-responders, regardless if the two conditions above are met or not.  
Only primary discontinuation reason is considered.
Baseline MBL volume is defined in Section 7.1.
Final Month is defined as in Section 7.2.  If a subject has less than or equal to 28 days of 
treatment, then the Final Month will be the interval between Day 1 to the last dose date.
11.2.2
Primary Analysis of Primary Efficacy Endpoint
The primary analysis of the primary endpoint will be performed using the full analysis set 
(Section 5.1) in the extension study.
The responder status (yes/no) will be derived from the observed Final Month MBL 
volume (as in Section 7.6.1.1), using the criteria as described in Section 11.2.1. 
For the primary efficacy analysis, the number and proportion of responders meeting the 
criteria for the primary efficacy endpoint will be summaried by analysis group as 
observed.  The 95% CI using the normal approximation to the binomial distribution will 
also be provided for the proportion of responders in each analysis group.
11.2.3
Sensitivity Analyses of the Primary Efficacy Endpoint
The following sensitivity analyses for the primary endpoint will be performed using the
full analysis set: 
●
The primary analysis will be repeated with all subjects categorized as 
responders/non-responders based on observed MBL volume data only (without 
taking into account their reasons for premature discontinuation of study drug).
●
The primary analysis will be repeated using the total MBL volume collected 
from validated products only.  All subjects will be categorized as 
responders/non-responders in the same manner as done in the primary analysis 
(i.e., subjects who prematurely discontinue study drug due to "lack of 


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efficacy," "requires surgery or invasive intervention for treatment of uterine 
fibroids," or adverse events will be considered as non-responders) with 
exception that all AH data are based on the total MBL volume collected from 
validated products only.
11.2.4
Adenomyosis Subset
The proportion of responders will be summarized by analysis group for subjects with 
Baseline adenomyosis present, and repeated for the subjects with adenomyosis at any time 
during the Baseline or Treatment Period (see definition in Section 11.3.5.3).
11.3
Secondary and Other Efficacy Analyses
Secondary efficacy endpoints during the Treatment Period include the following:
●
Change and percent change from Baseline in MBL volume to each month and 
to the Final Month;
●
Percentage of subjects with suppression of bleeding (no bleeding allowed, 
spotting allowed) at the Final Month;
●
Percentage of subjects with Baseline hemoglobin ≤ 10.5 g/dL who have an 
increase in hemoglobin > 2 g/dL at Month 6.
Other efficacy endpoints during the Treatment Period include the following:
●
Percentage of subjects with MBL volume < 80 mL and 50% or greater 
reduction in MBL volume from Baseline during 28-day intervals throughout 
the Treatment Period;
●
Percentage of subjects with amenorrhea;
●
Percentage of subjects with control of bleeding;
●
The number of bleeding days;
●
Change and percent change from Baseline in hemoglobin concentration;
●
Patient Global Impression of Change (PGIC) questionnaire for Menstrual 
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●
Change and percent change from baseline in fibroid and uterine volume;
●
Change from baseline for the UFS-QoL; 
●
Change from baseline for the EuroQoL-5D (EQ-5D-5L);
●
The Health Care Resource Utilization (HCRU) questionnaire;
●
Change from baseline for the WPAI.
11.3.1
Reduction of Bleeding
The change and percent change from Baseline to the observed Final Month in MBL 
volume will be summarized by analysis group.  
The change and percent change from Baseline to each 28-day window starting at Study 
Day 1 up to Study Day 168 in observed MBL volume in the Treatment Period 
(i.e., Month 1 (Study Days 1 – 28), Month 2 (Study Days 29 – 56), Month 3 (Study 
Days 57 – 84), Month 4 (Study Days 85 – 112), Month 5 (Study Days 113 – 140), and 
Month 6 (Study Days 141 – 168)) will be summarized by analysis group.  For observed 
MBL volume in each 28-day interval, only subjects who did not prematurely discontinue 
in or before this 28-day interval will be included.  For example, for Study Days 29 – 56, it 
includes subjects who were on treatment for at least 56 days.
Each of the two response criteria that are components of the primary endpoint, 
i.e., (1) MBL volume of < 80 mL at the Final Month; and (2) 50% or greater reduction in 
MBL volume from Baseline to the Final Month will be summarized separately in the 
same way as for the primary analysis.  The number and percentage of subjects meeting 
each criterion at the Final Month will be summarized by analysis group.  
The number and percentage of subjects meeting each criterion at the Final Month will also 
be analyzed in the same way as in each sensitivity analysis for the primary endpoint, and 
in the analysis for subjects identified in the adenomyosis subset of interest.


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The number and percentage of subjects satisfying either (1) MBL volume < 80 mL, or 
(2) 50% or greater reduction in MBL volume from Baseline, or both will be summarized 
for every 28-day interval by analysis group based on observed MBL volume. 
Plots will be provided by analysis group using the observed MBL volume data: 
●
Cumulative distribution function for MBL volume at Final Month; 
●
Cumulative distribution function for percent change from Baseline to Final 
Month in MBL volume; 
●
Proportion of responders at Final Month; 
●
Cumulative distribution function for change from baseline to Final Month in 
MBL volume. 
●
Cumulative distribution function for change from baseline in MBL volume to 
each month; 
●
Mean change in MBL volume over time. 
11.3.2
Amenorrhea, Suppression and Control of Bleeding
11.3.2.1
Amenorrhea
The number and percentage of subjects who achieved amenorrhea will be calculated for 
each analysis group.  Amenorrhea analysis will include subjects on study drug for at least 
38 days in this extension study.  For each subject, amenorrhea is defined as having 0 days 
of bleeding or spotting during the last 28 days of treatment with the interval starting from 
Study Day 11.  If a subject did not have evaluable AH data during the last 28 days and no 
bleeding or spotting or "There was no visible blood on the sanitary products" was 
indicated on UBQ, then she is considered amenorrheic.
For subjects initially randomized to placebo in the pivotal Study M12-815 or 
Study M12-817, time to amenorrhea is defined as the number of days from the first study 
drug dose date to the day a subject achieving cumulative amenorrhea (i.e., the day a 
subject achieving amenorrhea – the first study drug dose date + 1).  For a subject who 
achieved amenorrhea, the day she achieved amenorrhea is defined as the next day of the 


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last bleeding/spotting day during the Treatment Period.  The median, Q1, and Q3 of time 
to amenorrhea will be calculated using Kaplan-Meier method.
In the monthly analysis of bleeding for amenorrhea, the numerator is the number of 
subjects on treatment who did not bleed during the specified time window (but may have 
begun bleeding thereafter) and the denominator includes subjects on drug for the full 
window.  For the final visit, the denominator includes subjects with at least 38 days on 
study drug. 
Table 8.
Monthly Analysis of Bleeding for Amenorrhea
Time Interval
Amenorrheic Status
Month 1
(Days 1 – 28)
Subject did not bleed during Study Days 1 – 28
Month 2
(Days 29 – 56)
Subject did not bleed during Study Days 29 – 56
Month 3
(Days 57 – 84)
Subject did not bleed during Study Days 57 – 84
Month 4
(Days 85 – 112)
Subject did not bleed during Study Days 85 – 112
Month 5
(Days 113 – 140)
Subject did not bleed during Study Days 113 – 140
Month 6
(Days 141 – 168)
Subject did not bleed during Study Days 141 – 168
Final Month
(last 28 days of treatment)
Subject did not bleed during the last 28 days of treatment
Incidence and cumulative incidence of amenorrhea by last bleeding/spotting day at each 
month will be reported using the categories specified in in Table 9.  
The summary will be provided in the following 2 ways:  (1) including only subjects who 
have at least 168 days on study drug in the extension study.  The denominator includes 
subjects who have at least 168 days on study drug in the extension study for all windows.  
(2) LOCF:  including all subjects who have at least 38 days on study drug in the extension 
study.  If a subject meets the criteria for amenorrhea but discontinues, this subject's 


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amenorrheic status was carried forward to the time points after the subject has 
discontinued study drug.  The denominator includes subjects who have at least 38 days on 
study drug in the extension study.
Plots will be provided by analysis group for percentage of subjects with incidence and 
cumulative incidence of amenorrhea during the Treatment Period, respectively. 
Table 9.
Categorical Summary of Incidence and Cumulative Incidence of 
Amenorrhea by Last Bleeding/Spotting Day
Analysis
Time Interval
Numerator Calculation
Incidence
Month 2
(≤ Study Day 56)
Last bleeding/spotting day occurred during Study 
Days 1 – 28
Month 3
(Study Day 57 – 84)
Last bleeding/spotting day occurred during Study 
Days 29 – 56
Month 4
(Study Day 85 – 112)
Last bleeding/spotting day occurred during Study 
Days 57 – 84
Month 5
(Study Day 113 – 140)
Last bleeding/spotting day occurred during Study 
Days 85 – 112 
Month 6
(Study Day 141 – 168)
Last bleeding/spotting day occurred during Study 
Days 113 – 140 
Cumulative
Month 2
(≤ Study Day 56)
Last bleeding/spotting day occurred before Study Day 29
Month 3
(Study Day 57 – 84)
Last bleeding/spotting day occurred before Study Day 57
Month 4
(Study Day 85 – 112)
Last bleeding/spotting day occurred before Study Day 85 
Month 5
(Study Day 113 – 140)
Last bleeding/spotting day occurred before Study 
Day 113
Month 6
(Study Day 141 – 168)
Last bleeding/spotting day occurred before Study 
Day 141
11.3.2.2
Suppression of Bleeding
Suppression of bleeding is defined similarly to amenorrhea as in Section 11.3.2 except 
that spotting is allowed.  For each subject, achieving suppression of bleeding is defined as 
having 0 days of bleeding during the last 28 days of treatment with the interval starting 


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from Study Day 11.  The suppression of bleeding analysis will include subjects with at 
least 38 days on study drug in the extension study.  If a subject did not have evaluable AH 
data during the last 28 days and no bleeding was indicated on UBQ ("Subject only has 
spotting that did not require the use of sanitary products" or "There was no visible blood 
on the sanitary products" was allowed), then the subject is considered having achieved 
suppression of bleeding.  The number and percentage of subjects achieving suppression of 
bleeding will be summarized by analysis group. 
For subjects initially randomized to placebo in the pivotal Study M12-815 or 
Study M12-817, time to suppression of bleeding is defined as the number of days from the 
first study drug dose date to the day a subject achieving suppression of bleeding (i.e., the 
day a subject achieving suppression of bleeding – the first study drug dose date + 1).  For 
a subject who achieved suppression of bleeding, the day she achieved suppression of 
bleeding is defined as the next day of the last bleeding day during the Treatment Period.  
The median, Q1, and Q3 of time to suppression of bleeding will be calculated using 
Kaplan-Meier method.
Monthly analysis of bleeding for suppression of bleeding, incidence and cumulative 
incidence of suppression of bleeding by last bleeding day will be provided in the same 
way as was done for amenorrhea in Table 8 and Table 9.  Plots will be provided by 
analysis group for percentage of subjects with incidence and cumulative incidence of 
suppression of bleeding during the Treatment Period, respectively. 
11.3.2.3
Control of Bleeding
For each subject, achieving control of bleeding is defined as having 0 days of bleeding 
and up to 1 day of spotting during the last 28 days of treatment with the interval starting 
from Study Day 11.  The control of bleeding analysis will include subjects with at least 
38 days on study drug in the extension study.  If a subject did not have evaluable AH data 
during the last 28 days and no bleeding or spotting or "There was no visible blood on the 
sanitary products" was indicated on UBQ, then the subject is considered having achieved 


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control of bleeding.  If the subject indicates bleeding or spotting on the UBQ, the subject 
does not meet the criteria for control of bleeding.
The number and percentage of subjects achieving control of bleeding will be summarized 
by analysis group.
11.3.3
Bleeding Days
The numbers of bleeding days by intensity categories (Section 7.6.2) will be calculated for 
each 28-day interval starting at Study Day 1 up to Study Day 168 in the Treatment Period 
(i.e., Study Days 1 – 28, Study Days 29 – 56, Study Days 57 – 84, Study Days 85 – 112,
Study Days 113 – 140, and Study Days 141 – 168) and the first 28-day interval in the 
Post-Treatment Follow-up Period (i.e., Study End Days 1 – 28) for each analysis group.  
For each 28-day interval, each analysis includes subjects who did not premature 
discontinue in or before this 28-day interval.  For example, for Study Days 29 – 56, it 
includes subjects who were on treatment for at least 56 days in the extension study.  For 
Final Month analysis, it includes subjects who were on treatment for at least 38 days in 
the extension study.  The summary of average number of bleeding days in a 28 day 
window during the Treatment Period will be provided for each analysis group by intensity 
categories.  
If a subject did not have evaluable AH data during an interval and no bleeding was 
indicated on UBQ ("Subject only has spotting that did not require the use of sanitary 
products" or "There was no visible blood on the sanitary products" was allowed), then the 
number of bleeding days over the interval is 0.  The number and percentage for each 
analysis group and overall will be provided for subjects who did not have evaluable AH 
data during an interval and bleeding was indicated on UBQ.
The change and percent change from Baseline in the numbers of bleeding/spotting days 
and bleeding days to each 28-day interval and Final Month in the Treatment Period and 
the first 28-day interval in the Post-Treatment Follow-up Period will be summarized for 
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11.3.4
Hemoglobin Concentration
Hemoglobin (Hgb) concentration data will be summarized as observed. 
The change and percent change from Baseline in Hgb concentration to Months 1 – 6 
during the Treatment Period will be summarized by analysis group.
The number and percentage of subjects with changes in Hgb concentration from Baseline 
to Months 1 – 6 during the Treatment Period in each of the following categories will be 
summarized by analysis group.
●
Change from Baseline in Hgb ≤ –1.0 g/dL
●
–1.0 g/dL < Change from Baseline in Hgb ≤ –0.5 g/dL
●
–0.5 g/dL < Change from Baseline in Hgb < 0.5 g/dL
●
0.5 g/dL ≤ Change from Baseline in Hgb < 1.0 g/dL 
●
1.0 g/dL ≤ Change from Baseline in Hgb < 1.5 g/dL
●
1.5 g/dL ≤ Change from Baseline in Hgb < 2.0 g/dL
●
Change from Baseline in Hgb ≥ 2.0 g/dL
Also, shift tables from Baseline to Month 3 and Month 6 will be summarized by the 
following categories.
●
Hgb ≤ 10.5 g/dL
●
10.5 g/dL < Hgb ≤ 12 g/dL
●
Hgb > 12 g/dL
The number and percentage of subjects who had Hgb Baseline ≤ 10.5 g/dL and have an 
increase in Hgb concentration > 2 g/dL from Baseline will be summarized for each month 
by analysis group.
The number and percentage of subjects who had Hgb Baseline ≤ 10.5 g/dL and have an 
increase in Hgb concentration > 1 g/dL from Baseline will be summarized for each month 
by analysis group. 


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In addition, the number and percentage of subjects who have an increase in Hgb 
concentration > 1 g/dL from Baseline will be summarized for each month by analysis 
group and Baseline Hgb concentration categories as follows.  Same summary will be 
provided for increase in Hgb concentration > 2 g/dL from Baseline to each month.
●
Hgb ≤ 10.5 g/dL
●
10.5 g/dL < Hgb ≤ 12 g/dL
●
Hgb > 12 g/dL
11.3.5
Fibroid and Uterine Volume, FIGO Classification, 
Adenomyosis, and Post-Treatment Menses
11.3.5.1
Fibroid and Uterine Volume
Fibroid and uterine volume data will be summarized as observed.  Analyses will be 
conducted separately for results obtained from TAU/TVU and MRI.
The change and percent change in the volume of the largest (primary) fibroid, the total 
fibroid volume (3 largest fibroids), and the uterine volume from Baseline to Month 3 (if 
applicable) and Month 6 during the Treatment Period will be summarized for each 
analysis group.  The change and percent change at Post-Treatment Month 3 and Post-
Treatment Month 6 (if applicable) during the Post-Treatment Follow-up Period will also 
be summarized for each analysis group.
The number and percentage of subjects with ≥ 25% reduction from Baseline in total 
fibroid volume at Month 3 (if applicable) and Month 6 each during the Treatment Period 
will be summarized for each analysis group.  The same summary will be provided for 
largest (primary) fibroid volume and uterine volume, respectively.
11.3.5.2
FIGO Classification
The number and percentage of subjects with fibroids at each location (e.g., intramural, 
subserosal, submucosal non-pedunculated, and subserosal pedunculated) according to the 
FIGO classification3 will be summarized for each analysis group at Baseline, Month 3 (if 


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applicable) and Month 6 during the Treatment Period and Post-Treatment Month 3 and 
Post-Treatment Month 6 (if applicable) during the Post-Treatment Follow-up Period.
11.3.5.3
Adenomyosis
The number and percentage of subjects with presence of adenomyosis will be summarized 
for each analysis group at Baseline and each relevant post-baseline visit in the Treatment 
and Post-Treatment Follow-up Periods.  Analyses above will be conducted separately for 
results obtained from TAU/TVU and MRI.
For subjects initially randomized to placebo in the pivotal studies, baseline presence of 
adenomyosis is defined by considering available TAU/TVU or MRI results at Baseline of 
this extension study (prior to or on Study Day 14).  If a subject has adenomyosis results 
only from either TAU/TVU or an MRI at Baseline, then the Baseline adenomyosis is 
determined by that result; if a subject has adenomyosis results from both TAU/TVU and 
MRI at Baseline and they differ, then the MRI adenomyosis result is used.  If a subject 
has multiple assessments of the same type (TAU/TVU, MRI), the results closest and prior 
to Study Day 1 will be used.
Additionally, the subset of subjects with adenomyosis identified at any point during the 
Baseline or Treatment Period in the pivotal studies and extension study will be defined as 
follows.  If a subject has adenomyosis identified via TAU/TVU or MRI at any time during 
the Baseline or Treatment Period in the pivotal studies and extension study, the subject 
will be included in this set.  This will include subjects who have differing results during 
the Treatment Period.  Post-Treatment results will not be considered in the definition of 
this subset.
11.3.5.4
Post-Treatment Menses
The time to first post-treatment menses is defined as the number of days between the last 
dose date of study drug and the first day of a subject's first post-treatment menses in the 
Post-Treatment Follow-up Period of the extension study.  Menses are defined as having at 
least 1 day when uterine bleeding categories of bleeding and/or spotting were reported.  


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Truncated on-treatment menses at the last dose date, i.e., menses that are ongoing at the 
last dose date will be excluded, and the next occurrence of menses in the Post-Treatment 
Follow-up Period will be considered as the first post-treatment menses and will be used 
for reporting the time to first post-treatment menses.  If the gap between two consecutive 
post-treatment menstrual cycles (or between truncated on-treatment menstrual cycle and 
the next post-treatment menstrual cycle) is 1 day apart or less (i.e., out of the 
two consecutive cycles, the start date of the second cycle – the end date of the first cycle 
≤2), these two menstrual cycles will be combined as one menstrual cycle in determining 
the first post-treatment menses.
AH data will be used for post-treatment menses.  If post-treatment menses could not be 
identified from available AH data, UBQ will be used.  For the first UBQ that indicates 
bleeding ("Subject only has spotting that did not require the use of sanitary products" or 
"There was no visible blood on the sanitary products" not allowed) after the last dose date, 
the date of that UBQ will be considered as the first day of the subject's first post-treatment
menses.
Volume of bleeding in a subject's first post-treatment menses will be calculated and 
summarized.  Only AH data will be used for volume of bleeding in first post-treatment 
menses.  Time to first post-treatment menses and volume of bleeding in first post-
treatment menses will be summarized and analyzed separately for the following groups of 
subjects:
●
All subjects who entered the Post-Treatment Follow-up Period of extension 
study.
●
Subjects who entered the Post-Treatment Follow-up Period and were 
amenorrhiec at the Final Month in the Treatment Period of extension study.  
Amenorrhea is defined as in Section 11.3.2.
●
Subjects who entered the Post-Treatment Follow-up Period and achieved 
suppression of bleeding at the Final Month in the Treatment Period of 
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Based on the time to first post-treatment menses during the Post-Treatment Follow-up 
Period, each subject will be categorized into one of the following non-overlapping 
categories:  Study End Days 1 – 28, Study End Days 29 – 56, Study End Days 57 – 84, 
Study End Days 85 – 112, Study End Days 113 – 140, Study End Days 141 – 168, and 
Study End Days ≥168.  Summary tables will present the number and percentage of 
subjects in the specified categories.
11.3.6
Quality of Life Questionnaire
11.3.6.1
Uterine Fibroid Symptoms Quality of Life (UFS-QoL) 
Improvement in quality of life will be assessed on the UFS-QoL Questionnaire (4-week 
recall).  The change from Baseline to Month 3, Month 6, and Final Visit during the 
Treatment Period will be calculated and summarized by analysis group for each of the 
UFS-QoL subscales (symptom severity, concern, activities, energy/mood, control, self-
conscious, and sexual function) and the HRQL total.  Missing scores will be dealt with 
using the methods recommended by the UFS-QoL Scoring Manual.  The UFS-QoL 
questionnaire is presented in Appendix A, and the relevant UFS-QoL Scoring Manual is 
presented in Appendix B.
11.3.6.2
EQ-5D-5L
The EQ-5D-5L questions and relevant scoring rules are presented in Appendix E.
The number and percentage of subjects with answers in each category of the EQ-5D-5L 
(Mobility, Self-care, Usual activities, Pain/Discomfort, and Anxiety/Depression) domains 
will be summarized at Baseline, each planned assessment, and Final Visit during the 
Treatment Period by analysis group. 
Subject's responses to the EQ-5D-5L will be combined into a unique health state using a 
5-digit code with 1 digit from each of the 5 dimensions at Baseline, each planned 
assessment, and Final Visit during the Treatment Period.  The EQ-5D-5L states will be 
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country-specific weights if available or US weights if country-specific weights are 
unavailable.6,7
The EQ VAS scale is numbered from 0 – 100, with 100 indicating the best health that a 
subject can imagine, and 0 indicating the worst health that a subject can imagine.
11.3.6.3
Patient Global Impression of Change (PGIC)
11.3.6.3.1
PGIC on Menstrual Bleeding Questionnaire
For PGIC on menstrual bleeding (PGIC – MB, Appendix C), the number and percentage 
of subjects in each response category will be summarized at Month 1, Month 3, Month 6, 
and Final Visit by analysis group.
For PGIC – MB, the response categories of "Very Much Improved" and "Much 
Improved" will be combined together.  The remaining five categories of the PGIC scale 
will be combined and labeled "Otherwise."  The number and percentage of subjects with 
response of (a) "Very Much Improved" or "Much Improved," and (b) "Otherwise" will be 
summarized at Month 1, Month 3, Month 6, and Final Visit by analysis group.
11.3.6.3.2
PGIC on Non-Bleeding Uterine Fibroid Symptoms 
Questionnaire
For each of the PGIC questions on non-bleeding uterine fibroids symptoms (PGIC –
NBUFS, Appendix D), the number and percentage of subjects in each response category 
will be summarized at Month 1, Month 3, Month 6, and Final Visit by analysis group.
For each of the PGIC – NBUFS questions, the response categories of "Very Much 
Improved" and "Much Improved" will be combined together.  The remaining 
five categories of the PGIC scale will be combined and labeled "Otherwise."  The number 
and percentage of subjects with response of (a) "Very Much Improved" or "Much 
Improved," and (b) "Otherwise" will be summarized at Month 1, Month 3, Month 6, and 
Final Visit by analysis group.


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11.3.6.4
Work Productivity and Activity Questionnaire:  Uterine 
Fibroids (WPAI:UF)
For each of the measures as presented in the scoring guide Appendix I based on the data 
collected via the WPAI:UF, the change from Baseline to Month 6 and Final Visit during 
the Treatment Period will be summarized by analysis group.  The WPAI:UF is presented 
in Appendix H, and the WPAI:UF scoring guide is presented in Appendix I.
11.3.6.5
Health Care Resource Utilization Questionnaire (HCRU)
HCRU data will be summarized as observed; missing data will not be imputed.  HCRU 
data will be summarized by analysis group at Months 1 – 6 and Final Visit.  Descriptive 
statistics will be presented for the total number of Non-Study Health Care Practitioner 
Visits, overall and by the type of facility subjects were seen at.  The number and 
percentage of subjects will also be presented by the type of Non-Study Health Care 
Practitioner who administered care to the subject.
The number and percentage of subjects will be presented by the type of diagnostic or 
therapeutic procedures performed based on HCRU at Months 1 – 6 and Final Visit during 
the Treatment Period.
11.3.6.6
Number of Days in Hospital
Hospitalization related data will be summarized as observed; missing data will not be 
imputed.  Hospitalization data will be summarized by analysis group in the Treatment 
Period based on the Adverse Events eCRF.
The number and percentage of subjects who were hospitalized or had prolonged 
hospitalization will be summarized by analysis group.  If a subject was hospitalized or had 
prolonged hospitalization multiple times during the Treatment Period, she will be counted 
only once. 
The number of hospitalizations will be summarized by analysis group.  The number of 
days in hospital (i.e., discharge date – admission date + 1) will be summarized by analysis 


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group.  Only hospitalizations with an admission date on or after the first dose date and 
within 30 days following the last dose date (i.e., first dose date ≤ admission date ≤ last 
dose date + 30) are included in the analysis of the number of days in hospital.  If 
discharge date or admission date is missing, then the hospitalization will be excluded from 
the analysis of the number of days in hospital.
11.4
Handling of Multiplicity
No multiplicity adjustment is needed since only summary statistics will be provided for 
the efficacy analysis. 
12.0
Safety Analysis
12.1
General Considerations
Safety analyses will be carried out using the Safety Analysis Set, which includes all 
subjects who received at least one dose of study drug.  Safety data will be summarized by 
actual treatment received.  If a subject receives more than one type of study drug, safety 
data will be analyzed in the treatment group to which she was randomized to.  All safety 
analyses will be based on observed data.  For analyses of safety endpoints, subjects who 
are missing an evaluation will not be included in the analysis of that particular 
parameter/visit, unless otherwise specified.
For continuous variables, when the analyses of change and/or percent change from 
Baseline to post-baseline visit(s) are performed, the within-group change from Baseline to 
each relevant visit will be summarized by analysis group with the mean, SD (or SE), and 
95% CIs.  The between-group differences of the two elagoix dose groups with at least 
12 month of total exposure to elagolix in the Treatment Period will be summarized with 
the mean, SE, 95% CIs, and P value when applicable.  At each post-baseline visit, the 
Baseline mean and post-baseline visit mean will be calculated for all subjects with 
baseline and post-baseline value at that visit by analysis group.  


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For qualitative categorical variables, Fisher's exact test will be used to analyze between-
group differences when applicable.  Categorical data will be summarized by number and 
percentage of subjects by analysis group.  
Pregnancies and outcomes will also be summarized by analysis group.
Statistical comparisons will be performed for BMD between the two elagoix dose groups 
with at least 12 month of total exposure to elagolix in the Treatment Period, as specified 
in Section 12.4.1.  There will be no testing for other safety endpoints in the Treatment 
Period.  There will be no testing for safety endpoints in the Post-Treatment Follow-up 
Period.
Information regarding corresponding statistical methods for analyses and any additional 
statistical measures required for a specific variable/endpoint will be specified in the 
relevant sections.
12.2
Adverse Events
12.2.1
Analysis of Adverse Events in the Extension Study
Adverse events (AEs) in the extenstion study will be summarized using system organ 
classes (SOCs) and preferred terms (PTs) from the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 19.0 or higher by the six analysis groups as described in 
Section 5.3.
For each AE summary, the number and percentage of subjects experiencing at least 
one AE will be presented.  Subjects reporting more than one AE within a SOC will be 
counted only once for that SOC.  Subjects reporting more than one AE for a PT will be 
counted only once for that PT.
Treatment-emergent AEs are defined as AEs with a start date on or after the first dose of 
study drug in the extension study.  AEs starting more than 30 days following 
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AEs.  Post-Treatment AEs are defined as AEs starting more than 30 days following 
discontinuation of study drug in the Treatment Period of this study.  
When summarizing AEs by relationship or severity, if a subject has an event with 
unknown severity or relationship then the subject will be counted in the 
severity/relationship category of "unknown" even if the subject has a second occurrence 
of the same event with a severity/relationship present.  The only exception is if the subject 
has a second occurrence of the same event with the most extreme severity (i.e., "severe") 
or the most extreme relationship category (i.e., "reasonable possibility").  In this case, the 
subject will be counted under these most extreme severity/relationship categories.
Treatment Period
The number and percentage of subjects with treatment-emergent AEs will be calculated 
by analysis group as follows:
●
Any AEs
●
Any AEs by primary MedDRA system organ class (SOC) and preferred term 
(PT)
●
Any AEs occurring in ≥ 5% of subjects by primary MedDRA system organ 
class (SOC) and preferred term (PT)
●
Any AEs by PT in descending frequency of 12 month elagolix 300 mg BID 
plus E2/NETA treatment group 
●
Any AEs by maximum severity (by primary MedDRA SOC and PT)
●
Any AEs by maximum relationship (by primary MedDRA SOC and PT)
●
Any AEs reasonably possibly related to study drug (by primary MedDRA 
SOC and PT, by PT)
●
Any AEs leading to study drug discontinuation (by primary MedDRA SOC 
and PT)
●
Any serious AEs (SAEs) (by primary MedDRA SOC and PT, by PT)
●
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●
Any SAEs reasonably possibly related to study drug (by primary MedDRA 
SOC and PT, by PT)
●
Any SAEs leading to study drug discontinuation (by primary MedDRA SOC 
and PT)
●
Any AEs of special interest as specified in Appendix M
●
Any AEs leading to death (by primary MedDRA SOC and PT)
A listing by the four main analysis group as in Section 5.3 of treatment-emergent AEs 
with subject IDs will be generated.  Listings of all treatment-emergent SAEs, AEs leading 
to death, and AEs leading to study drug discontinuation will be generated.
Summary of total number of hot flush and night sweat by subject-reported severity 
categories, summary of total number of hot flush and night sweat by maximum subject-
reported severity, and summary of time to first onset of hot flush and night sweat will be 
provided.  Listings of subjects associated with hot flush and night sweat will also be 
provided.
Post-Treatment Follow-Up Period
The Post-Treatment AEs will be summarized as follows:
●
Any AEs by primary MedDRA SOC and PT
●
Any SAEs by primary MedDRA SOC and PT.
12.3
Laboratory Variables
Hematology, clinical chemistry, urinalysis, and endocrine panel variables collected in this 
study are specified in the protocol.  An overall summary will be provided for all 
laboratory variables.  For all other analysis, analysis will be performed for the following 
laboratory variables:  lipid variables, liver variables (alkaline phosphatase, ALT, AST, 
bilirubin), glucose, hemoglobin, hematocrit, platelet count, and Red Blood Cell (RBC) 
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For lipid variables, in addition to low-density lipoprotein cholesterol (LDL-C), high-
density lipoprotein cholesterol (HDL-C), total cholesterol, triglycerides (TG), and 
apolipoprotein A and B, the following ratios will be included:  the ratio of total 
cholesterol to HDL-C, the ratio of LDL-C to HDL-C, the ratio of TG to HDL-C, and the 
ratio of non-HDL-C (calculated as total cholesterol minus HDL-C) to HDL-C.
12.3.1
Analysis of Laboratory Variables
Treatment Period
All laboratory variables will be summarized with mean, median, standard deviation, 
minimum, and maximum by the four main analysis groups as in Section 5.3.
For continuous laboratory variables, the analyses of change (for all laboratory variables of 
interest) and percent change (only for lipid variables) from Baseline to each relevant visit 
in the Treatment Period will be summarized by the four main analysis groups as in 
Section 5.3.
In the Treatment Period, the laboratory data will be categorized as low, normal, or high 
based on the normal ranges of the laboratory used in this study.  The low or high 
laboratory values will be flagged in the data listings.
In the Treatment Period, shift tables for change from Baseline according to the normal 
range will be provided for laboratory parameters of interest mentioned above by the 
six analysis groups as in Section 5.3.  The shift tables will tabulate the number and 
percentage of subjects with baseline values of high or normal to post-baseline low, 
baseline values of low or normal to post-baseline high, baseline values of high or normal 
to final post-baseline low, baseline values of low or normal to final post-baseline high.  
The final value in the Treatment Period refers to the last non-missing value collected 
within 3 days following the last dose of study drug.
In the Treatment Period, shift tables for change from Baseline to the minimum, maximum, 
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Adverse Events (CTCAE) v 4.0 grades5 for the laboratory tests.  For those analytes that 
are not reflected in the CTCAE, Exceptions to Standard CTCAE Lab Grading Criteria for 
Elagolix Studies will be used as specified in Appendix N.  The final value in the 
Treatment Period is as defined above.  The number and percentage of subjects meeting the 
CTCAE will be summarized by the four main analysis groups as in Section 5.3 in the 
Treatment Period. 
The number and percentage of subjects meeting the following criteria will be summarized 
at Baseline and each relevant visit by the six analysis groups as in Section 5.3 in the 
Treatment Period:
●
Total cholesterol:  ≤ 300, > 300 – ≤ 400, > 400 – ≤ 500, and > 500 mg/dL
●
HDL-C:  < 40 and ≥ 40 mg/dL
●
LDL-C:  < 130, ≥ 130 – < 160, ≥ 160 – < 190, and ≥ 190 mg/dL
●
TG:  ≤ 150, > 150 – ≤ 300, > 300 – ≤ 500, > 500 – ≤ 1000, and > 1000 mg/dL
●
LDL-C/HDL-C ratio:  ≤ 3, and > 3
●
Total cholesterol/HDL-C ratio:  ≤ 4.5, and > 4.5.
In addition, the number and percentage of subjects who have potentially clinically 
significant (PCS) lipid values meeting the following criteria any time during the 
Treatment Period will be summarized by the six analysis groups as in Section 5.3:
●
Total cholesterol > 200 mg/dL
●
LDL-C > 130 mg/dL
●
LDL-C > 160 mg/dL
●
HDL-C < 40 mg/dL
●
TG > 150 mg/dL
●
TG/HDL-C ratio > 3.5
●
LDL-C/HDL-C ratio > 4.


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Plots will be provided by the four main analysis groups as in Section 5.3 for HDL-C, 
LDL-C, triglycerides, and hemoglobin during the Treatment Period: 
●
Final post-baseline lab values vs. Baseline lab values; 
●
Final post-baseline lab values vs. Baseline lab values for subjects with 
NCI CTCAE Grade 3 or 4; 
●
Maximum post-baseline lab values vs. Baseline lab values;
●
Maximum post-baseline lab values vs. Baseline lab values for subjects with 
NCI CTCAE Grade 3 or 4. 
Plots will be provided by the four main analysis groups as in Section 5.3 for HDL-C, 
LDL-C, and triglycerides during the Treatment Period: 
●
Mean percent change from Baseline in lipid over month.
Post-Treatment Follow-Up Period
All laboratory variables will be summarized with mean, median, standard deviation, 
minimum, and maximum by the four main analysis groups as in Section 5.3.
Laboratory data collected more than 3 days after the last dose of study drug in the 
Treatment Period will be included in the summary of data from the Post-Treatment 
Follow-up Period.  Baseline for summaries/analyses in the Post-Treatment Follow-up 
Period is the same as Baseline for summaries/analyses in the Treatment Period.
In the Post-Treatment Follow-up Period, the following summaries will be presented:
●
During the Post-Treatment Follow-up Period, shift tables for change from 
Baseline to relevant Post-Treatment Follow-up visit(s) according to the normal 
ranges will be provided for LDL-C, HDL-C, TG, and total cholesterol by the 
six analysis groups as in Section 5.3.  
●
During the Post-Treatment Follow-up Period, shift tables for change from 
Baseline to relevant Post-Treatment Follow-up visit(s) will also be presented 


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based on the CTCAE grades for LDL-C, HDL-C, TG, and total cholesterol by 
the four main analysis groups as in Section 5.3.
●
Change in liver enzymes (SGPT/ALT, SGOT/AST, total bilirubin, and 
alkaline phosphatase) and lipid parameters (LDL-C, HDL-C, TG, and total 
cholesterol) from Baseline to relevant Post-Treatment Follow-up visit(s) will 
be summarized by the four main analysis groups as in Section 5.3 with 
descriptive statistics.
12.3.2
Assessment of Hepatotoxicity 
The number and percentage of subjects in each analysis group with maximum 
on-treatment laboratory values meeting the following criteria compared to the upper limit 
of normal (ULN) will be summarized by the six analysis groups as in Section 5.3 to assess 
potential hepatotoxicity.
●
ALT ≥ 3 × ULN and total bilirubin ≥ 2 × ULN
●
AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN
●
ALT and AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN
●
ALT ≥ 3 × ULN and total bilirubin < 2 × ULN
●
AST ≥ 3 × ULN and total bilirubin < 2 × ULN
●
ALT and AST ≥ 3 × ULN and total bilirubin < 2 × ULN
●
ALT ≥ 3 × ULN and total bilirubin ≥ 1.5 × ULN
●
AST ≥ 3 × ULN and total bilirubin ≥ 1.5 × ULN
●
ALT and AST ≥ 3 × ULN and total bilirubin ≥ 1.5 × ULN
●
ALT ≥ 3 × ULN, ≥ 5 × ULN, ≥ 10 × ULN, ≥ 20 × ULN
●
AST ≥ 3 × ULN, ≥ 5 × ULN, ≥ 10 × ULN, ≥ 20 × ULN
●
Total bilirubin ≥ 1.5 × ULN, ≥ 2.0 × ULN.
The maximum ratio relative to the ULN is used to determine if subjects met the criteria 
listed above.  The ALT, AST, and total bilirubin values do not need to be concurrent in 
order to meet the defined criteria.  For ALT, AST, and total bilirubin, a subject is counted 


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if the post-baseline laboratory value during the Treatment Period meets the above criteria 
regardless of Baseline laboratory value (i.e., the post-baseline laboratory value does not 
need to be worse than Baseline laboratory value).
A listing of all ALT, AST, total bilirubin, and alkaline phosphatase values will be 
provided for each subject who met any of the criteria defined above.
The following eDISH plots will be generated:  peak ASL vs. peak bilirubin; peak ALT vs. 
peak bilirubin.
12.4
Bone Mineral Density
All analyses and summaries of bone mineral density (BMD) will be performed for each 
segment, i.e., femoral neck, lumbar spine, and total hip.  For subjects who had a right-side 
scan performed (rare instances), their data for right femoral neck and right femoral total 
hip were included in the analysis with the data for the left femoral neck and left total hip, 
respectively (available for the majority of subjects), and an additional analysis was 
performed using the left side only.  If more than one scan is reported for an anatomical 
segment within an analysis window, the worse (the lower value) of the multiple 
measurements were used for analysis for each anatomical segment.
Unless otherwise specified, summaries will be provided by the six analysis groups as in 
Section 5.3. 
12.4.1
BMD in the Treatment Period
BMD
A continuous summary of BMD at Baseline, Between Month 3 and Month 6, Month 6, 
and Final Visit will be provided by analysis group.  This summary will include the mean, 
SD, median, minimum, maximum, and first and third quartiles.  This analysis will be 
repeated excluding subjects who switched machine manufacturer type (Lunar or Hologic), 
subjects with scans only on Lunar machines, and subjects with scans only on Hologic 
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The analysis of percent change in BMD from Baseline to each relevant visit in the 
Treatment Period will be performed.  The mean percent change in BMD from baseline to 
Month 6 and Final Visit during the Treatment Period will be compared between the 
two elagoix dose groups with at least 12 month of total exposure to elagolix, using 
ANCOVA with treatment as the main effect and Baseline value of corresponding 
parameter as a covariate.  This analysis will be repeated excluding subjects who switched 
machine manufacturer type (Lunar or Hologic), subjects with scans only on Lunar 
machines, and subjects with scans only on Hologic machines.  Statistical tests will be 
two-sided and a significance level of 0.05 will be used. 
The number and percentage of subjects with percent change from Baseline to Between 
Month 3 and Month 6, Month 6, and Final Visit in the Treatment Period in mutually 
exclusive categories of BMD decrease:  ≤ 0%, > 0% – ≤ 1.5%, > 1.5% – ≤ 3%, > 3% –
≤5%, > 5% – < 8%, and ≥ 8% will be summarized by analysis group and comparison 
between the two elagoix dose groups with at least 12 month of total exposure to elagolix 
will be made using Fisher's exact test.
Z-Score and T-Score 
A continuous summary of the Z-score at Baseline, Between Month 3 and Month 6, 
Month 6, and Final Visit in the extension study will be provided by analysis group.  This 
summary will include the mean, SD, median, minimum, maximum, and first and 
third quartiles.  A categorical summary of Z-score will be summarized at Baseline, 
Between Month 3 and Month 6, Month 6, and Final Visit for the following categories:  
≤–2.0, > –2.0 to ≤ –1.5, > –1.5 to ≤ –1.0, and > –1.0 for all subjects, subjects with BMD 
decrease ≥ 3% at Month 6, and subjects with BMD decrease < 3% at Month 6, 
respectively.  The categorical summary of worst Z-score at any time in the Treatment 
Period will be produced by analysis group for each anatomical region.
A continuous summary of the T-score at Baseline, Between Month 3 and Month 6, 
Month 6, and Final Visit will be provided by analysis group.  A categorical summary of 
T-score will be summarized at Baseline, Between Month 3 and Month 6, Month 6, and 


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Final Visit for the following categories:  ≤ –2.5, > –2.5 to < –1.0, and ≥ –1.0 for all 
subjects, subjects with BMD decrease ≥ 3% at Month 6, and subjects with BMD decrease 
< 3% at Month 6, respectively.  The categorical summary of worst T-score at any time in 
the Treatment Period will be produced by analysis group for each anatomical region.
Plots will be provided by the four main analysis groups as in Section 5.3 for:
●
Percent change from Baseline to Month 6 in BMD vs. Baseline BMD values;
●
Percent change from Baseline to Month 6 in BMD vs. Baseline BMD values 
for subjects with greater than 3% BMD decrease;
●
Percent change from Baseline in BMD at Month 6 vs. Baseline Z-score;
●
Maximum percent change from Baseline to Post-Baseline in BMD vs. 
Baseline Z-score;
●
Categorical summary of lumbar spine BMD percent change from Baseline to 
Month 6. 
A plot by the four main analysis groups as in Section 5.3 of the cumulative distribution 
function of percent change from baseline in BMD at Month 6 and the Z-scores at Month 6 
will be provided.  Additionally, the boxplots of Z-scores at baseline, Month 6, Post-
Treatment Month 6, and Post-treatment Month 12 will be provided by the four main 
analysis groups as in Section 5.3.  This will be repeated for T-scores.
Listings of subjects meeting the following thresholds during the Treatment Period in the 
extension study will be provided:
●
Listing of subjects with bone decrease ≥ 8%
●
Listing of subjects with Z-score ≤ –1.5
●
Listing of subjects with T-score ≤ –1.5
●
Listing of subjects with Z-score ≤ –1.5 and bone decrease ≥ 8% in the same 
region
●
Listing of subjects with T-score ≤ –1.5 and bone decrease ≥ 8% in the same 
region.


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12.4.2
BMD in the Post-Treatment Follow-Up Period
Percent change from Baseline to Post-Treatment Follow-up Month 6, Post-Treatment 
Follow-up Months 7 – 11, and Post-Treatment Follow-up Month 12 will be summarized 
for each analysis group with descriptive statistics.  There will be no statistical testing of 
Post-Treatment Follow-up BMD values.
The analysis of percent change in BMD will be repeated to include only the subset of 
subjects who had a Treatment Month 6 and a Post-Treatment Follow-up Month 6 scan.  
Similarly, this analysis will be repeated to include only the subset of subjects who had a 
Treatment Month 6 and a Post-Treatment Follow-up Month 12 scan.
Percent change from Baseline in BMD to each of the Post-Treatment visits will be 
summarized for each analysis group with frequencies and percentage for categories of 
BMD decrease:  ≤ 0%, > 0% – ≤ 1.5%, > 1.5% – ≤ 3%, > 3% – ≤ 5%, > 5% – < 8%, and 
≥8%.  
Cross-tabulations of the number and percentage of subjects in each of the previously 
noted categories of percent change from Baseline for the following:
●
Treatment Month 6 to Post-Treatment Follow-up Month 6
●
Treatment Month 6 to Post-Treatment Follow-up Month 12
●
Final Treatment to Post-Treatment Follow-up Month 6
●
Final Treatment to Post-Treatment Follow-up Month 12
●
Post-Treatment Follow-up Month 6 to Post-Treatment Follow-up Month 12.
The subjects included in these analyses will be limited to those who had values at these 
time points.
As described above for the Treatment Period, continuous and categorical summaries of 
the Z-score and T-score at each time point during the Post-Treatment Follow-up Period 
will be provided.


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Listings of subjects meeting the following thresholds during the Post-Treatment Follow-
up period will be provided:
●
Listing of subjects with bone decrease ≥ 3% and T-score < –1.0 in the same 
region
●
Listing of subjects with T-score ≤ –1.5.
For the purposes of assessing post-treatment BMD recovery, the following summaries 
will be provided.  The "recovery" statistic will be defined as 
Recovery at post-treatment month X = 100 × ((% change from baseline to final) –
(% change from baseline to post-treatment month X))/(% change from baseline to final) 
i.e., it is the proportion of BMD decrease at the final treatment scan recovered at Post-
Treatment Month X.  For example, a subject who has a change of –2% at the end of 
treatment and has a change of –1% at Post-Treatment Month 6 will have a recovery value 
of 50% at Post-Treatment Month 6.  This statistic is only defined for subjects who 
experience a decrease from baseline at final treatment.
A continuous summary of recovery at each post-treatment visit will be provided including 
mean, standard deviation, median and a within-group 95% confidence interval.  
Additionally, the number and percentage of subjects in each of the following categories 
will be provided:  < 0%, 0 – 25%, > 25 – 50%, > 50 – 75%, > 75 – 100%, > 100%.
A plot of the cumulative distribution function of recovery at Post-Treatment Month 6 and 
Post-Treatment Month 12 will be provided.
12.5
Vital Signs and Body Weight
Vital sign variables include pulse rate, sitting systolic blood pressure, sitting diastolic 
blood pressure, and oral body temperature.
Vital sign variables will be summarized with mean, median, standard deviation, 
minimum, and maximum by the four main groups as in Section 5.3.


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Analyses of mean change from Baseline to each relevant visit during the Treatment Period 
in vital sign variables and weight will be performed by the four main groups as in 
Section 5.3.
The number and percentage of subjects who have PCS vital sign and weight values 
meeting the following criteria will be summarized by the six analysis groups as in 
Section 5.3.  All increase/decrease is calculated from Baseline to a post-baseline visit in 
the Treatment Period.
The number and percentage of subjects who have a sustained PCS vital sign value and a 
listing of these subjects will be provided.  A sustained PCS value is defined as 
3 consecutive PCS values in the Treatment Period.
●
Diastolic blood pressure
○
≤ 50 mmHg and ≥ 15 mmHg decrease
○
> 90 mmHg and ≥ 15 mmHg increase
○
≥ 100 mmHg
●
Systolic blood pressure
○
≤ 90 mmHg and ≥ 20 mmHg decrease
○
≥ 140 mmHg and ≥ 20 mmHg increase
○
≥ 160 mmHg
●
Pulse rate
○
≤ 45 bpm and ≥ 15 bpm decrease
○
> 100 bpm and ≥ 15 bpm increase
○
≥ 120 bpm
●
Weight
○
≥ 5% decrease
○
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Change in vital signs from Baseline to relevant Post-Treatment Follow-up visit(s) (Post-
Treatment Month 1, Month 3, Month 6, Month 9, Month 12, and Final Visit) will be 
summarized by the four main groups as in Section 5.3 with descriptive statistics.
12.6
Endometrial Biopsy
The number and percentage of subjects in each category of endometrial biopsy results will 
be summarized at Baseline, Prior to Month 6, and Month 6 for each of the six analysis 
groups as in Section 5.3.  If multiple assessments exist in a specific time window, all 
assessments will be displayed.
12.7
Pelvic Ultrasound and MRI
Analyses will be conducted separately for results obtained from TAU/TVU and MRI.  
The actual values and the change from Baseline to Month 3 (TAU/TVU only), Month 6, 
Follow-up Month 3 (TAU/TVU only), and Follow-up Month 6 will be summarized by the 
six analysis groups as in Section 5.3 with descriptive statistics.
12.7.1
Ovarian Cysts
The presence of ovarian cysts will be noted at Baseline and each relevant post-baseline 
visit in the Treatment Period and Post-Treatment Follow-up Period.  Significant ovarian 
findings include complex ovarian cyst > 3.5 cm or simple ovarian cyst > 5 cm.  The 
number and percentage of subjects with the pre-defined complex ovarian cysts and simple 
ovarian cysts will be summarized for each analysis group at each relevant visit in the 
Treatment Period.
For each TVU/TAU or MRI assessment, information for significant ovarian findings from 
the cysts assessment may be available for more than one cyst at more than one ovary 
location (left and/or right).  For such assessments, the worst assessment based on the 
greatest of the three dimensions across the multiple cysts at the left and/or right ovary 
location within the same cyst type (i.e., simple or complex) will be included in the 
analyses/summary.  Additionally, the subject with multiple cyst findings will be counted 
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subjects in the relevant category of significant ovarian findings.  A listing will include all 
results across multiple cysts findings from multiple assessments (where available) from 
subjects who have significant ovarian findings.
12.7.2
Endometrial Thickness 
Analysis of change in endometrial thickness from Baseline to Month 3 and Month 6 in the 
Treatment Period will be performed.
In addition, the number and percentage of subjects with endometrial thickness of < 8 mm, 
≥ 8 mm and ≤ 12 mm, > 12 mm and ≤18 mm, and > 18 mm in the Treatment and Post-
Treatment Follow-up Periods will be summarized by analysis group at each relevant visit 
in the Treatment Period.
Change in endometrial thickness from Baseline to relevant Post-Treatment Follow-up 
visit(s) will be summarized by analysis group with descriptive statistics.
12.8
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS data will be summarized as observed by the six analysis groups as in 
Section 5.3.  The C-SSRS – Since Last Visit questionnaires and corresponding scoring 
rules are presented in Appendix J and Appendix K.
The number of subjects with suicidal ideation, suicidal behavior, and self-injurious 
behavior without suicidal intent at each scheduled assessment during the Treatment Period 
(including Day 1) will be summarized.  
The number of subjects with suicide-related treatment-emergent events based on the 
C-SSRS during the Treatment Period (including Day 1) will be summarized.  
A listing of subjects with suicidal ideation, suicidal behavior, or self-injurious behavior 
without suicidal intent based on the C-SSRS during the Treatment Period (including 
Day 1) will be provided.


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12.9
Pregnancy Results
Pregnancies and outcomes will be summarized by the four main groups as in Section 5.3.  
Listings will be prepared of all pregnancy test results for any subject who ever had a 
positive pregnancy test at any time point during the study.
13.0
Summary of Changes from SAP Version 1.0
1.
The analysis windows for parameters collected every 3 months in the Treatment 
Period (Table 2) was updated; normial days were added in Table 5, Table 6, and 
Table 7;
2.
The analysis conventions to handle multiple assessments in a specific time window 
were updated;
3.
The analysis set for prior, concomitant, and post-treatment medications was 
updated to be full analysis set;
4.
The change and percent change from Baseline to each month in the number of 
bleeding days was added;
5.
The general considerations for mean (percent) change in safety analysis were 
updated to include SE for within-group change;
6.
Typo was fixed in one hepatotoxicity criteria;
7.
Added one clarification for the analysis of endometrial biopsy.
14.0
References
1.
Schumacher U, Schumacher J, Mellinger U, et al.  Estimation of menstrual blood 
loss volume based on menstrual diary and laboratory data.  BMC Womens Health.  
2012;12:24.
2.
Heinze G, Schemper M.  A solution to the problem of separation in logistic 
regression.  Stat Med.  2002;21(16):2409-19.


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3.
Munro MG, Critchley HO, Broder MS, et al; FIGO Working Group on Menstrual 
Disorders.  FIGO classification system (PALM-COEIN) for causes of abnormal 
uterine bleeding in nongravid women of reproductive age.  Int J Gynaecol Obstet.  
2011;113(1):3-13.
4.
Belsey EM, Machin D, d'Arcangues C.  The analysis of vaginal bleeding patterns 
induced by fertility regulating methods.  World Health Organization Special 
Programme of Research, Development and Research Training in Human 
Reproduction.  Contraception.  1986;34(3):253-60.
5.
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.  
Published:  May 28, 2009 (v4.03:  June 14, 2010).  US Department of Health and 
Human Services, National Institutes of Health, National Cancer Institute.
6.
Szende A, Williams A, editors.  Measuring self-reported population health:  an 
international perspective based on EQ-5D-5L.  EuroQol Group Monographs 
Volume 1.  SpringMed.  2004.
7.
Rabin R, Oemar M, Oppe M, et al.  EQ-5D-5L user guide:  basic information on 
how to use the EQ-5D-5L instrument Version 1.0.  April 2011.


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Appendix A.
UFS-QoL


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Appendix B.
UFS-QoL Scoring Manual
To calculate a symptom score for symptom severity, create a summed score from the 
items listed below and then use the formula below the table to transform the value.  This 
will provide symptom scores where higher score values are indicative of greater symptom 
severity or bother and lower scores will indicate minimal symptom severity (high 
scores = bad).
Scale
Sum Item Values
Lowest and Highest 
Possible Raw Scores 
(Assuming All Related 
Scale Items are Answered)
Possible Raw Score 
Range (Assuming All 
Related Scale Items are 
Answered)
Symptom Severity
Sum 1 – 8
8, 40
32
Transformation for Symptom Severity Raw Score ONLY:
Transformed Score = (Actual raw score – lowest possible raw score)/possible raw score 
range × 100
For the UFS-QoL subscale (concern, activities, energy/mood, control, self-conscious, and 
sexual function), create summed scores of the items listed below for each individual 
subscale.  To calculate the HRQL total score, sum the value of each individual subscale 
(do not sum individual items).  Use the formula below to transform all values.  Higher 
scores will be indicative of better UFS-QoL (high = good).


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Scale
Sum Item Values
Lowest and Highest 
Possible Raw Scores 
(Assuming All 
Related Scale Items 
are Answered)
Possible Raw Score 
Range (Assuming 
All Related Scale 
Items are 
Answered)
Concern
9 + 15 + 22 + 28 + 32
5, 25
20
Activities
10 + 11 + 13 + 19 + 20 + 27 + 29
7, 35
28
Energy/Mood
12 + 17 + 23 + 24 + 25 + 31 + 35
7, 35
28
Control
14 + 16 + 26 + 30 + 34
5, 25
20
Self-conscious
18 + 21 + 33
3, 15
12
Sexual Function
36 + 37
2, 10
8
HRQL Total
Sum of 6 Subscale Scores
29, 145
116
Formula for transformation of UFS-QoL raw scores ONLY:
Transformed Score = (Highest possible score – Actual raw score)/Possible raw score 
range × 100
HRQL total = Sum of 6 Subscale Scores.
Missing Items:
●
For each subscale listed in the tables above, including the scale of Symptom 
Severity, if some of the answers for related scale items are missing (not to 
exceed 50% of the scale items, details refer to Missing Items rule 2 below), 
then the lowest possible raw score = 1 × (total number of related scale items 
answered) and the highest possible raw score = 5 × (total number of related 
scale items answered).  And the possible raw score range = the highest 
possible raw score – the lowest possible raw score.
●
For the subscale analyses, if < 50% of the scale items are missing, the scale 
should be retained with the mean scale score of the items present used to 
impute a score for the missing items.  If ≥ 50% of the items are missing, no 
scale score should be calculated, the subscale score should be considered 
missing.  If a subscale score is missing, the HRQL total cannot be calculated.


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Appendix C.
Patient Global Impression of Change (PGIC-MB) – SAMPLE
Subjects will complete the PGIC-MB to assess the change in the severity of their 
menstrual bleeding (from very much improved to very much worse) since initiation of 
study drug by choosing one of seven responses at each scheduled monthly visit, starting 
with the Month 1 Visit in the Treatment Period or the Premature Discontinuation Visit, if 
applicable.
Visits to be completed:  Treatment Period Month 1, Month 2, Month 3, Month 4, 
Month 5, Month 6/PD
Question:
Please answer the following question regarding your menstrual bleeding:
Since I started taking study medication, my menstrual bleeding has:
☐
Very much improved
☐
Much improved
☐
Minimally improved
☐
Not changed
☐
Minimally worse
☐
Much worse
☐
Very much worse


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Appendix D.
Patient Global Impression of Change, Non-Bleeding Uterine 
Fibroids Symptoms (PGIC-NBUFS) – SAMPLE
Subjects will complete the PGIC-NBUFS to document the presence of and to assess the 
change in the overall severity of non-bleeding symptoms and the severity of specific 
non-bleeding uterine fibroid symptoms (from very much improved to very much worse, 
or the subject will indicate whether she did not have a particular symptom or cannot 
remember if she had a particular symptom) at Treatment Period Month 1, Month 3 and 
Month 6, or the Premature Discontinuation Visit, if applicable.
Visits to be completed:  Treatment Period Month 1, Month 3, Month 6/PD.
Questions:
Please answer the following questions regarding your non-bleeding uterine fibroid 
symptoms, that is, any symptom(s) that is present, whether or not you are having your 
period:
●
Since I started taking study medication, my abdominal or pelvic pain has/is
☐
Very much improved
☐
Much improved
☐
Minimally improved
☐
Not changed
☐
Minimally worse
☐
Much worse
☐
Very much worse
●
Since I started taking study medication, my abdominal or pelvic pressure has/is
☐
Very much improved
☐
Much improved
☐
Minimally improved
☐
Not changed
☐
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☐
Much worse
☐
Very much worse
●
Since I started taking study medication, my abdominal or pelvic cramping has/is
☐
Very much improved
☐
Much improved
☐
Minimally improved
☐
Not changed
☐
Minimally worse
☐
Much worse
☐
Very much worse
●
Since I started taking study medication, my back pain has/is
☐
Very much improved
☐
Much improved
☐
Minimally improved
☐
Not changed
☐
Minimally worse
☐
Much worse
☐
Very much worse
●
Since I started taking study medication, my abdominal bloating has/is
☐
Very much improved
☐
Much improved
☐
Minimally improved
☐
Not changed
☐
Minimally worse
☐
Much worse
☐
Very much worse


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●
Since I started taking study medication, my urinary problems (urinating too 
frequently or feeling a sudden need to urinate) has/is
☐
Very much improved
☐
Much improved
☐
Minimally improved
☐
Not changed
☐
Minimally worse
☐
Much worse
☐
Very much worse
●
Overall since I started taking study medication, my non-bleeding symptoms
have/are
☐
Very much improved
☐
Much improved
☐
Minimally improved
☐
Not changed
☐
Minimally worse
☐
Much worse
☐
Very much worse


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Appendix E.
EurolQol (EQ-5D-5L) – SAMPLE


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Appendix F.
Uterine Bleeding Questionnaire (UBQ) – Treatment Period –
SAMPLE
Version 2.0
During site visits in the Treatment Period, subjects who did not return a Sanitary Product 
Collection Keg (for menstrual blood loss analysis) will be asked whether they had any 
uterine bleeding or spotting since their last study visit.
●
Did the subject have any bleeding or spotting since her last study visit?
☐No    ☐Yes
If yes, why were sanitary products not collected/returned?  (Please select 
one response)
☐
Subject only had spotting that did not require the use of sanitary products*
☐
There was no visible blood on sanitary products*
☐
Subject forgot to/did not collect*
☐
Subject/Site discarded the sanitary products*
☐
Subject is still bleeding/spotting; will return when bleeding/spotting complete
☐
Subject collected sanitary products and did not bring them to this visit; will
return sanitary products at a later date
☐
Other
*
If this response is checked, remind subject to collect and return all used or worn 
sanitary products with or without visible blood.


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Appendix G.
Uterine Bleeding Questionnaire (UBQ) – Post-Treatment
Follow-Up Period – SAMPLE
Version 2.0
Subjects who have not returned sanitary products for their first full menses in the Post-
Treatment Follow-up Period, will be asked at the Post-Treatment Phone and Site Visits 
whether they had any bleeding or spotting since their last site or phone visit.  Once a 
subject returns sanitary products for a full menses in the Post-Treatment Follow-up 
Period, this questionnaire no longer needs to be completed.
●
Did the subject have any bleeding or spotting since her last study visit (Site 
visit or phone visit)?
☐No    ☐Yes
If yes, why were sanitary products not collected/returned?  (Please select 
one response)
☐
Subject only had spotting that did not require the use of sanitary products* 
☐
There was no visible blood on sanitary products* 
☐
Subject forgot to/did not collect* 
☐
Subject/Site discarded the sanitary products* 
☐
Subject is still bleeding/spotting; will return when bleeding/spotting complete
☐
Subject collected sanitary products and did not bring them in yet; will return
sanitary products at a later date
☐
Other
*
Subject will be required to collect sanitary products for her next full menses.


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Appendix H.
Work Productivity and Activity Impairment Questionnaire:  
Uterine Fibroids V2.0 (WPAI:UF) – SAMPLE
The following questions ask about the effect of uterine fibroid symptoms on your ability 
to work and perform regular activities.  Please fill in the blanks or circle a number, as 
indicated.
●
Are you currently employed (working for pay)? _____ NO ___ YES
If NO, check "NO" and skip to Question 6.
The next questions are about the past seven days, not including today.
●
During the past seven days, how many hours did you miss from work because of 
problems associated with your uterine fibroid symptoms?  Include hours you 
missed on sick days, times you went in late, left early, etc., because of your uterine 
fibroid symptoms.  Do not include time you missed to participate in this study.
_____ HOURS
●
During the past seven days, how many hours did you miss from work because of 
any other reason, such as vacation, holidays, time off to participate in this study?
_____ HOURS
●
During the past seven days, how many hours did you actually work?
_____ HOURS  (If "0," skip to question 6.)
●
During the past seven days, how much did your uterine fibroid symptoms affect 
your productivity while you were working?  
Think about days you were limited in the amount or kind of work you could do, 
days you accomplished less than you would like, or days you could not do your 
work as carefully as usual.  If uterine fibroid symptoms affected your work only a 
little, choose a low number.  Choose a high number if uterine fibroid symptoms 
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Consider only how much uterine fibroids symptoms affected productivity while you were 
working.
Uterine fibroid 
symptoms had no 
effect on my work
Uterine fibroid 
symptoms completely 
prevented me from 
working
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER
●
During the past seven days, how much did your uterine fibroid symptoms affect 
your ability to do your regular daily activities, other than work at a job?  
By regular activities, we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc.  Think about times you were 
limited in the amount or kind of activities you could do and times you accomplished 
less than you would like.  If uterine fibroid symptoms affected your activities only a 
little, choose a low number.  Choose a high number if uterine fibroid symptoms 
affected your activities a great deal.  
Consider only how much uterine fibroid symptoms affected your ability to do your 
regular daily activities, other than work at a job.
Uterine fibroid 
symptoms had no 
effect on my daily 
activities
Uterine fibroid 
symptoms 
completely 
prevented me from 
doing my daily 
activities
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER
WPAI:UF V2.0 (US English)


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Appendix I.
WPAI:UF Scoring Rules
The WPAI yields four types of scores:  
●
Absenteeism (work time missed)
●
Presenteesism (impairment at work/reduced on-the-job effectiveness)
●
Work productivity loss (overall work impairment/absenteeism plus 
presenteeism)
●
Activity Impairment
WPAI:UF
WPAI outcomes are expressed as impairment percentages, with higher numbers indicating 
greater impairment and less productivity, i.e., worse outcomes, as follows:
Questions:
1 = currently employed
2 = hours missed due to specified problem
3 = hours missed other reasons
4 = hours actually worked
5 = degree problem affected productivity while working
6 = degree problem affected regular activities
Scores:
Multiply scores by 100 to express in percentages.
Percent work time missed due to problem:  Q2/(Q2 + Q4)
Percent impairment while working due to problem:  Q5/10


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Percent overall work impairment due to problem:
Q2/(Q2 + Q4) + [(1-(Q2/(Q2 + Q4))) × (Q5/10)]
Percent activity impairment due to problem:  Q6/10
http://www.reillyassociates.net/WPAI_Scoring.html


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Appendix J.
Columbia-Suicide Severity Rating Scale (C-SSRS) – Since Last 
Visit – SAMPLE


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Appendix K.
C-SSRS Scoring Rules
The following outcomes are C-SSRS categories and have binary responses (yes/no).  The 
categories have been re-ordered from the actual scale to facilitate the definitions of the 
composite and comparative endpoints, and to enable clarity in the presentation of the 
results.
Category 1 – Wish to be Dead
Category 2 – Non-specific Active Suicidal Thoughts
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Category 5 – Active Suicidal Ideation with Specific Plan and Intent
Category 6 – Preparatory Acts or Behavior
Category 7 – Aborted Attempt
Category 8 – Interrupted Attempt
Category 9 – Actual Attempt (non-fatal)
Category 10 – Completed Suicide
Self-injurious behavior without suicidal intent is also a C-SSRS outcome (although not 
suicide-related) and has a binary response (yes/no).
The following outcome is a numerical score derived from the C-SSRS categories. 
●
Suicidal Ideation Score:  The maximum suicidal ideation category (1 – 5 on 
the C-SSRS) present at the assessment.  Assign a score of 0 if no ideation is 
present.


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Composite endpoints based on the above categories are defined below.
●
Suicidal ideation:  A "yes" answer at any time during treatment to any one of 
the five suicidal ideation questions (Categories 1 – 5) on the C-SSRS.
●
Suicidal behavior:  A "yes" answer at any time during treatment to any one of 
the five suicidal behavior questions (Categories 6 – 10) on the C-SSRS.
●
Suicidal behavior ideation or behavior:  A "yes" answer at any time during 
treatment to any one of the ten suicidal ideation and behavior questions 
(Categories 1 – 10) on the C-SSRS.
Comparative endpoints of interest are defined below.  "Treatment emergence" is used for 
outcomes that include events that first emerge or worsen.  "Emergence" is used for 
outcomes that include events that first emerge.
●
Treatment-emergent suicidal ideation compared to recent history:  An increase 
in the maximum suicidal ideation score during treatment from the maximum 
suicidal ideation category during a specified pre-treatment period (C-SSRS 
scales taken during the specified pre-treatment period; excludes "lifetime" 
scores from the Baseline C-SSRS scale or Baseline/Screening C-SSRS scale).
●
Treatment-emergent serious suicidal ideation compared to recent history:  An 
increase in the maximum suicidal ideation score to 4 or 5 on the C-SSRS 
during treatment from not having serious suicidal ideation (scores of 0 – 3) 
during a specified pre-treatment period (C-SSRS scales taken during the 
specified pretreatment period; excludes "lifetime" scores from the Baseline 
C-SSRS scale or Baseline/Screening C-SSRS scale).
●
Emergence of serious suicidal ideation compared to recent history:  An 
increase in the maximum suicidal ideation score to 4 or 5 on the C-SSRS 
during treatment from no suicidal ideation (scores of 0) during a specified pre-
treatment period (CSSRS scales taken during the specified pre-treatment 
period; excludes "lifetime" scores from the Baseline C-SSRS scale or 
Baseline/Screening C-SSRS scale).
●
Emergence of suicidal behavior compared to all prior history:  The occurrence 
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suicidal behavior (Categories 6 – 10) prior to treatment (includes "lifetime" 
and/or "screening" scores from the Baseline C-SSRS scale, Screening C-SSRS 
scale, or Baseline/Screening C-SSRS scale, and any "Since Last Visit" from 
the Since Last Visit C-SSRS scales taken prior to treatment)
●
Improvement in suicidal ideation at a time point of interest compared to 
baseline:  An improvement in this endpoint can be considered as a decrease in 
suicidal ideation score at the time point of interest (e.g., the last measurement 
during treatment) from the baseline measurement (e.g., the measurement taken 
just prior to treatment.  This analysis should only be performed for studies in 
which a baseline C-SSRS can be defined (i.e., having improvement from the 
worse event over a lifetime is not clinically meaningful).


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Appendix L.
Health Care Resource Utilization Questionnaire (HCRU)
Version 2.0 – SAMPLE
(To be completed by Site Staff)
Non-Study Visits for Routine/General Health Care
Version 2.0
Instructions to Site Staff:  At each scheduled monthly visit (Month 1 through Month 6) in 
the Treatment Period, please ask if the subject saw a Non-Study Health Care Practitioner 
(HCP) since her last scheduled monthly visit for a routine/general health care visit that is 
not associated with an adverse event.  
Only record routine/general health care visits with Non-Study HCPs below.
Record Non-Study HCP Visits associated with an adverse event on the Adverse Event 
form only.  Do not record below.  
●
Since the Subject's last scheduled monthly study visit, has she seen a non-
study Health Care Practitioner (e.g., Physician, Nurse Practitioner, Physician 
Assistant, Dentist, Physical Therapist) for a routine/general health care visit 
that is not associated with an adverse event?  ☐No  ☐Yes
If Yes, please complete the questions below.


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Appendix M.
Adverse Events of Special Interest
Item of Safety Interest
Method of Surveillance
Hot flashes
Non-bone related hypoestrogenic effects CMQ
Bone mineral density loss
Osteoporosis/Osteopenia SMQ
DXA results from clinical trials
Anemia
Cases are identified through the Non-Hemolytic and Non-
Aplastic Anemias CMQ
Haematopoietic erythropenia SMQ
Bone Fractures
Osteoporosis/Osteopenia SMQ
Rash and hypersensitivity reactions
Anaphylactic reaction SMQ 
Severe cutaneous adverse reactions SMQ 
Drug induced rash CMQ
Lipid abnormalities
Dyslipidemia SMQ
Uterine bleeding change
Female reproductive bleeds CMQ
Endometrial safety
Uterine and fallopian tube neoplasms, malignant and 
unspecified SMQ
Reproductive Premalignant Disorders SMQ
Endometrial biopsy results
Hypoestrogenic AEs (excluding hot 
flashes, BMD loss, and fractures)
Non-bone related hypoestrogenic effects CMQ
Spontaneous abortion
Termination of pregnancy and risk of abortion SMQ
Teratogenicity
Review of pregnancy outcomes
All pregnancies will be followed up to 6 to 12 months post-
delivery and reviewed at least quarterly and as they occur
Obstetrical complications (maternal 
and infant)
Pregnancy, labor, and delivery complications and risk factors 
(excluding abortions and stillbirths) SMQ
Psychiatric events
Depression and suicide/self-injury SMQ
Cardiovascular events
Cardiac arrhythmias SMQ, Cardiomyopathy SMQ, 
and Ischemic heart disease SMQ
Thromboembolic events
Embolic and thrombotic events SMQ


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Appendix N.
Exceptions to Standard CTCAE Lab Grading Criteria for Elagolix Studies
ANALYTE
GRADE 1 TOXICITY
GRADE 2 TOXICITY
GRADE 3 TOXICITY
GRADE 4 TOXICITY
HEMATOLOGY
EOSINOPHIL COUNT 
INCREASED*
650 – 1500 cells/mm3
1501 – 5000 cells/mm3
> 5000 cells/mm3
No Grade 4
HEMATOCRIT DECREASED**
Decrease in > 0% – 5% 
below LLN or below BL if 
BL below LLN
Decrease in > 5% – 10% 
below LLN or below BL if 
BL below LLN
Decrease in > 10% below 
LLN or below BL if BL 
below LLN
No Grade 4
WHITE BLOOD CELL COUNT 
INCREASED*
10,800 – 15,000 cells/mm3
> 15,000 – 20,000 cells/mm3
> 20,000 – 25,000 cells/mm3
> 25,000 cells/mm3
CHEMISTRIES
BUN**
1.25 – 2.5 × ULN
> 2.5 – 5.0 × ULN
> 5 – 10.0 × ULN
> 10 × ULN
LDL CHOLESTEROL HIGH***
130 – 159 mg/dL
≥ 160 – 189 mg/dL
≥ 190 mg/dL
No Grade 4
HDL CHOLESTEROL LOW***
Low abnormal:  < 40 mg/dL***
PROTEIN, SERUM, LOW*
5.5 – 6.0 g/dL
5.0 – < 5.5 g/dL
< 5.0 g/dL
No Grade 4
*
US Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research.  September 27.  Guidance for Industry Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials.
**
Elagolix program criteria based on patient population, the disease states under study, and previous clinical trial experience.
*** National Institutes of Health National Cholesterol Education Program; Detection Evaluation and Treatment of High Blood Cholesterol in Adults (Adult treatment Panel III) 
Final Report NIH Publication No. 02-5215 September 2002.
National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) is applied to all hematology and chemistry analytes across the elagolix program where 
quantitative criteria are available.  In the CTCAE where similar quantitative values are assigned to multiple grades and a qualitative criterion distinguishes between the grades, the 
more conservative quantitative grade is applied. 
The table above includes those instances where CTAE criteria are not provided for applicable lab parameters and alternative references are applied.