Conditions: Endometriosis
Keywords: Elagolix Endometriosis associated pain Dysmenorrhea (DYS) Non-menstrual pelvic pain (NMPP) ORILISSA
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 681
Healthy volunteers: no

Brief summary:
The objective of this study is to evaluate safety and efficacy of elagolix in the management of moderate to severe endometriosis-associated pain in adult premenopausal female participants including the safety and efficacy of elagolix in combination with concomitant hormonal add-back therapy.

Detailed description:

Arms:
arm 1: Placebo for elagolix administered twice daily (BID) plus placebo for estradiol/norethindrone acetate (E2/NETA) administered once daily (QD) for the 12-month placebo-controlled Treatment Period, followed by elagolix 200 mg BID plus E2/NETA 1 mg/0.5 mg QD for the remaining 36 months of the Treatment Period. arm 2: Elagolix 200 mg BID alone for the first 6 months of the 12-month placebo-controlled Treatment Period and elagolix 200 mg BID+E2/NETA 1 mg/0.5 mg QD for the second 6 months, followed by elagolix 200 mg BID+E2/NETA 1 mg/0.5 mg QD for the remaining 36 months of the Treatment Period. arm 3: Elagolix 200 mg BID + E2/NETA 1 mg/0.5 mg QD for the 12-month placebo-controlled Treatment Period, followed by elagolix 200 mg BID plus E2/NETA 1 mg/0.5 mg QD for the remaining 36 months of the Treatment Period.

Interventions: intervention 1: Estradiol/Norethindrone Acetate intervention 2: Placebo for Elagolix intervention 3: Elagolix intervention 4: Placebo for E2/NETA
Intervention descriptions: intervention 1: Tablets intervention 2: Tablet intervention 3: Tablet intervention 4: Tablets

Protocol document:
Prot_002.pdf: 
Elagolix
M14-702 Protocol Amendment 7 
1 
1.0
Title Page
Clinical Study Protocol M14-702
A Phase 3 Study to Evaluate the Safety and Efficacy 
of Elagolix in Combination with 
Estradiol/Norethindrone Acetate in Subjects with 
Moderate to Severe Endometriosis-Associated Pain
Incorporating Administrative Changes 1 and 2 and 
Amendments 1, 2, 3, 4, 5, 6 and 7
AbbVie Investigational
  Product: 
Elagolix (ABT-620) 
Date:
07 April 2022 
Development Phase:
3 
Study Design: 
This study employs a randomized, double-blind, placebo-
controlled design during the first 12 months of the 
Treatment Period.  The remaining 36 months of the 
Treatment Period is open-label, active treatment
Investigators: 
Multicenter Trial:  Investigator information is on file at 
AbbVie
Sponsor: 
AbbVie
Sponsor Contact: 
Pharm D, PhD 
Specialty Development
Women's Health, AbbVie 
1 North Waukegan Road 
North Chicago, IL  60064 
Office:
Mobile
NCT03213457




Elagolix
M14-702 Protocol Amendment 7 
3 
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol
Date
Original
04 February 2016
Amendment 1
02 June 2017
Amendment 2
04 September 2018
Administrative Change 1
09 May 2019
Amendment 3
02 July 2019
Amendment 4
27 March 2020
Amendment 5
22 December 2020
Amendment 6
13 October 2021
Administrative Change 2
02 February 2022
The purpose of this amendment is to: 
●
Update Section 5.3.1.1, Study Procedures, Endometrial Biopsy 
Rationale:  Based on FDA feedback, the endometrial biopsy at Month 36 was 
reinstated and the criteria revised so that the endometrial biopsy is required 
regardless of endometrial thickness. 


Elagolix
M14-702 Protocol Amendment 7 
4 
1.2
Synopsis
AbbVie Inc.
Protocol Number:  M14-702
Name of Study Drug:  Elagolix (ABT-620)
Phase of Development:  3 
Name of Active Ingredient:  Elagolix sodium
Date of Protocol Synopsis:  07 April 2022
Protocol Title:  A Phase 3 Study to Evaluate the Safety and Efficacy of Elagolix in Combination with 
Estradiol/Norethindrone Acetate in Subjects with Moderate to Severe Endometriosis-Associated Pain
Objectives:  The objectives of the study are to 1) assess the safety and efficacy of elagolix 200 mg 
administered twice daily (BID) in combination with estradiol 1 mg/0.5 mg norethindrone acetate 
(E2/NETA 1 mg/0.5 mg) once a day (QD) compared to placebo at 6 and 12 months; 2) to assess the 
effect of elagolix 200 mg BID in combination with E2/NETA (1 mg/0.5 mg) QD, on bone mineral 
density (BMD) compared to elagolix 200 BID alone at 6 months, and compared to placebo at 6 months 
and at 12 months of treatment and 3) to evaluate the continued safety and efficacy of elagolix 200 mg 
BID plus E2/NETA (1 mg/0.5 mg) QD for up to 48 months in the management of premenopausal 
women with moderate to severe endometriosis-associated pain.
Investigators:  Multicenter Trial:  Investigator information is on file at AbbVie
Study Sites:  Approximately 200 sites
Study Population:  Premenopausal female subjects (aged 18 to 49 years, inclusive) with a surgical 
diagnosis of endometriosis within 10 years prior to screening and with moderate to severe 
endometriosis-associated pain.
Number of Subjects to be Enrolled:  Approximately 700
Methodology:
This Phase 3 study includes a 48-month Treatment Period and is designed to evaluate the safety and 
efficacy of elagolix in combination with concomitant hormonal add-back therapy (E2/NETA 
1 mg/0.5 mg) in the management of endometriosis-associated pain in premenopausal women.  The 
first 12 months of the Treatment Period will employ a randomized, double-blind, placebo-controlled 
design (12 months), an elagolix 200 mg BID alone arm (the first 6 months followed by elagolix 200 mg 
BID plus E2/NETA [1 mg/0.5 mg] QD for 6 months), and an elagolix 200 mg BID plus E2/NETA 
(1 mg/0.5 mg) QD arm.  The last 36 months of the Treatment Period will be open-label, such that all 
subjects, will receive active treatment with elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD.  
Protocol specific rescue analgesics will be allowed for all subjects throughout the Screening and 
Treatment Periods.
Approximately 700 subjects will be randomly assigned on Study Day 1 in a 4:1:2 ratio of elagolix 
treatment in combination with E2/NETA or elagolix alone or placebo as follows:
•
elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD (n = 400)
•
elagolix 200 mg BID (n = 100)
•
placebo (n = 200)


Elagolix
M14-702 Protocol Amendment 7 
5 
Methodology (Continued):
Study Duration:
The total duration for a subject's participation in this study is approximately 51 to 74 months consisting 
of 4 study periods:
•
Washout Period – up to 10 months prior to Screening (only applicable if subject is taking 
exclusionary medication at the time of consent; duration of washout depends on the type of 
exclusionary medication being taken).
•
Screening Period – approximately 1.5 to 4 months prior to first dose of study drug.
•
Treatment Period – up to 48-month treatment duration.
•
Follow-Up Period –12 month duration following the last dose of study drug.  Subjects are 
expected to enter Follow-Up after Treatment Month 48, or if a subject prematurely discontinues 
from the Treatment Period at the time of or after Treatment Month 6.
Washout Period:
After signing the informed consent, subjects, who have been taking exclusionary medications prior to 
screening that require protocol specified discontinuation, must enter a Washout Period.  The duration of 
the washout period is based on the excluded medication as described in the protocol.  The following 
study procedures may be performed:  medical, social and gynecological history (including 
documentation of diagnosis of endometriosis via surgical visualization or histologic diagnosis), a 
physical examination with vital signs, and urine pregnancy testing; protocol-related adverse event review 
and documentation of current medications.  Subjects must complete the Washout Period and have had at 
least 1 menstrual period (menses) prior to entering the Screening Period.  Contraceptive counseling will 
be provided, and non-hormonal contraceptives dispensed, as necessary.


Elagolix
M14-702 Protocol Amendment 7 
6 
Methodology (Continued):
Screening Period:
Following informed consent (if Washout was not required), subjects will enter into the approximately 
1.5- to 4-month Screening Period to establish eligibility based on inclusion and exclusion criteria, 
including the following safety baseline assessments:  a dual energy x-ray absorptiometry (DXA) scan; an 
endometrial biopsy and transvaginal ultrasound (TVU); a Papanicolaou (Pap) test; a mammogram in 
subjects 40 years of age or older if one has not been performed within 3 months prior to Screening.  An 
electronic daily diary (e-Diary) will be provided to subjects to begin recording dysmenorrhea (DYS) and 
non-menstrual pelvic pain (NMPP) via the 4 point Endometriosis Daily Pain Impact Diary (no pain, mild 
pain, moderate pain, severe pain coded as 0 – 3); dyspareunia via a 4-point scale, plus a choice of "not 
applicable;" and the presence and intensity of uterine bleeding.  A minimum of 45 days of daily e-Diary 
entries are required to be completed during the Screening Period.  During the last 35 calendar days of the 
Screening Period, subjects must have at least 2 days of moderate or severe DYS and at least 2 days of 
moderate or severe NMPP with an average NMPP score of at least 1.0, or at least 4 days of moderate or 
severe NMPP and an average NMPP score of at least 0.5.  Subjects must have 2 menstrual cycles with 
cycle length of 21 – 38 days, and at least 1 full menstrual cycle (i.e., 2 menses or menstrual periods) 
must be documented in the e-Diary during Screening.  Subjects are required to use dual non-hormonal 
contraception (as applicable).  Contraceptive counseling will be provided and contraceptives dispensed, 
as necessary.  Subjects will be allowed to take protocol defined analgesic rescue medication for 
endometriosis-associated pain.  Protocol allowed analgesic rescue medication for endometriosis-
associated pain will include multiple non-steroidal anti-inflammatory drug (NSAID) choices and 
2 opioid choices:  codeine plus acetaminophen or hydrocodone plus acetaminophen; use of other rescue 
analgesic or prophylactic analgesic medications for endometriosis-associated pain will not be allowed 
during this period.  NSAID and opioid baseline use will be established during the Screening Period 
based on the subject's preference and historical use of analgesics for endometriosis-associated pain and 
Investigator judgment.  Subjects will record use of protocol allowed analgesic rescue medications for 
endometriosis-associated pain in the daily e-Diary.
Treatment Period:
The Treatment Period begins on Day 1, which will occur between Cycle Days 1 to 10 from the first day 
of menses (defined as first day with full menstrual flow) for all subjects who meet eligibility criteria 
during the Screening Period.
Subjects entering the Treatment Period will visit the site monthly (28-day months) through Month 6 of 
the Treatment Period.  After the Month 6 visit and through Month 12, on-site visits will be conducted at 
Treatment Months 8, 10, and 12; phone contacts will be made at other monthly timepoints.  Subsequent 
to the Month 12 visit, on-site visits will be conducted every three months at Treatment Months 15, 18, 
21, 24, 27, 30, 33, 36, 39, 42, 45, and 48; phone contacts will be made at other monthly time points.  
Months 13 – 48 of the Treatment Period will be open-label such that all subjects (including those 
previously randomized to elagolix 200 mg alone or placebo) will receive active treatment with elagolix 
200 mg BID plus E2/NETA (1 mg/0.5 mg) QD.  Study drug kits will be dispensed to subjects at each on-
site visit with the exception of the final visit at Treatment Month 48.


Elagolix
M14-702 Protocol Amendment 7 
7 
Methodology (Continued):
Treatment Period (Continued):
Subjects will use the daily e-Diary to continue recording DYS and NMPP; dyspareunia, if applicable; the 
presence and intensity of uterine bleeding; and the use of protocol specific analgesic rescue medication 
for endometriosis-associated pain through Treatment Period Month 12.  During Months 13 to 48, 
information regarding subjects' use of rescue analgesic medications for endometriosis-associated pain 
will be collected at monthly study visits and recorded in source documents and eCRF.  At the Day 1 visit 
(prior to dosing) and at all monthly visits (on-site and phone contacts), site staff will administer to 
subjects a questionnaire assessing overall endometriosis-associated pain over a 7-day recall period 
(11-point NRS).
Throughout the 48-month Treatment Period, all subjects will continue to be able to take protocol specific 
analgesic rescue medications for endometriosis-associated pain.  Use of non-protocol specific rescue 
analgesic or prophylactic analgesic medications for endometriosis-associated pain will not be allowed 
during the Treatment Period.
All subjects will self-administer study medication or matching placebo (through Treatment Month 12) 
twice daily (once in the morning and once in the evening approximately 12 hours apart), orally without 
regard to food or meals throughout the 48-month Treatment Period.
Subjects will complete various patient-reported outcome (PRO) questionnaires at study visits.
Pregnancy (serum and/or urine) tests will be performed at each visit throughout the Treatment Period.  
Urine pregnancy test kits will be provided to subjects for use at home for the study visits when subjects 
are not required to come into the clinic/site. Subjects will self-administer the tests and report the results 
to the site at the phone contact visits.  A positive urine pregnancy test must be confirmed with a serum 
pregnancy test.  If a serum pregnancy test result is positive at any time during the Treatment Period, 
study drug will be discontinued.
During the Treatment Period, blood samples will be collected for Clinical Safety Labs and vitamin D 
testing.  In addition, blood samples will be collected for assay of serum estradiol, and to measure plasma 
concentrations of elagolix and norethindrone, at designated study visits.  For subjects who consent, a 
DNA and RNA pharmacogenetic (PG) blood sample will be collected on Day 1, Month 6 and Month 12.
Vitals signs assessments will be conducted at designated time points throughout the Treatment Period.  
Additional safety assessments including TVUs, mammograms, Pap tests, endometrial biopsies and 
DXAs are completed as appropriate throughout the Treatment Period.  Adverse event and concomitant 
medication review will be conducted at all visits (on-site and phone contacts) during the Treatment 
Period.
Bone Mineral Density (BMD) Assessment and Study Specific Safety Stopping Criteria for BMD 
During the Treatment Period:
DXA scans of the lumbar spine, total hip, and femoral neck will be obtained at Treatment Months 6, 12, 
18, 24, 30, 36, 42, and 48.  If the results of any post-baseline DXA prior to Month 48, as read by the 
central reader selected for the study, document a Z-score (for subjects < 40 years of age at the time of the 
Screening DXA) or T-score (for subjects ≥ 40 years of age at the time of the Screening DXA) of < –2.5 
or BMD decrease from baseline of > 8% in the lumbar spine, total hip or femoral neck, the subject must 
be discontinued from study drug dosing and will enter the Follow-Up Period.


Elagolix
M14-702 Protocol Amendment 7 
8 
Methodology (Continued):
Follow-Up Period:
Subjects will enter the Follow-Up Period for 12 months to assess bone recovery after up to 48 months of 
treatment.  Subjects who prematurely discontinue from the study at the time of or after the Treatment 
Period Month 6 visit will enter the Follow-Up Period.  DXA scans of the lumbar spine, total hip, and 
femoral neck will be obtained at Follow-Up Months 6 and 12.
Vital signs and pregnancy testing will be performed at designated study visits.  Adverse events and 
concomitant medication use will also be reviewed.
Central Laboratory and Central Imaging Vendors:
DXA, TVU, endometrial biopsy and clinical safety lab samples will be analyzed/evaluated using central 
laboratories or vendors.  Assays for pharmacokinetics, pharmacodynamics and pharmacogenetics will be 
analyzed at AbbVie.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:
•
Subject is a premenopausal female 18 to 49 years of age (inclusive) at the time of Screening.
•
Subject has a documented surgical diagnosis (e.g., laparoscopy or laparotomy) of endometriosis 
established by visualization or histology within 10 years prior to entry into Washout or 
Screening.
•
Subject must agree to use only those rescue analgesics permitted by the protocol during the 
Screening and Treatment Periods for her endometriosis-associated pain.
•
Subject must have the following documented in the e-Diary during the last 35 days prior to 
Study Day 1:
o
At least 2 days of "moderate" or "severe" DYS
AND either
o
At least 2 days of "moderate" or "severe" NMPP and an average NMPP score of at least 
1.0,
OR
o
At least 4 days of "moderate" or "severe" NMPP and an average NMPP score of at least 
0.5.
Main Exclusion:
•
Subject has chronic pelvic pain that is not caused by endometriosis (e.g., interstitial cystitis, 
adenomyosis [as a dominant condition diagnosed by MRI or ultrasound], fibroids, pelvic 
inflammatory disease [PID], non-endometriosis-related pelvic adhesive disease, irritable bowel 
syndrome), that requires chronic analgesic therapy, which would interfere with the assessment 
of endometriosis-related pain.
•
Subject is using any systemic corticosteroids for over 14 days within 3 months prior to 
Screening or is likely to require treatment with systemic corticosteroids during the course of the 
study.  Over-the-counter and prescription topical, inhaled or intranasal corticosteroids are 
allowed.


Elagolix
M14-702 Protocol Amendment 7 
9 
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
•
Subject has any of the following:
o
Major depression or post-traumatic stress disorder (PTSD) episode within 2 years prior to 
the Screening visit
o
Other major psychiatric disorder at any time (e.g., schizophrenia, bipolar disorder) 
•
Subject has a history of suicide attempts or answered "yes" to questions 4 or 5 on the suicidal 
ideation portion of the Columbia-Suicide Severity Rating Scale (C-SSRS) within the last 1 year 
at Screening or prior to randomization on Day 1.
•
Subject has any history of osteoporosis or other metabolic bone disease or any condition that 
would interfere with obtaining adequate DXA measurements (e.g., history of spinal surgery, 
spinal hardware, severe scoliosis or weight) including:
o
Intercurrent bone disease (e.g., osteomalacia, osteogenesis imperfecta)
o
History or presence of an unstable condition that is associated with a decrease in BMD 
(e.g., uncontrolled hyperthyroidism, uncontrolled hyperparathyroidism, anorexia nervosa)
o
History of low-trauma hip or vertebral fractures (e.g., fracture resulting from a fall from a 
standing height or lower)
o
Bilateral hip replacement
o
Clinically significant hypocalcemia, hypo- or hyperphosphatemia, including during 
Screening (lab results)
o
Treatment with medication (excluding calcium and Vitamin D) for bone disease associated 
with a decrease in BMD.
•
Screening DXA results of the lumbar spine (L1-L4), femoral neck or total hip BMD 
corresponding to less than 2.0 or more standard deviations below normal (Z-score < –2.0 for 
subjects < 40 years of age, T-score for subjects ≥ 40 years of age).
•
Subject has either:
o
a newly diagnosed, clinically significant medical condition that requires therapeutic 
intervention (e.g., new onset hypertension), that has not been stabilized 30 days prior to 
randomization on Day 1 OR
o
a clinically significant medical condition that is anticipated to require intervention during 
the course of study participation (e.g., anticipated major elective surgery) OR
o
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).
•
Subject has any conditions contraindicated with use of E2/NETA such as:  
o
Current or history of deep vein thrombosis (DVT) or pulmonary embolism
o
Current or history (within 1 year of screening) of arterial thromboembolic disease 
(e.g., stroke, myocardial infarction).


Elagolix
M14-702 Protocol Amendment 7 
10
Investigational Products:
Elagolix Sodium 200 mg tablets
Overencapsulated Estradiol 1 mg/norethindrone acetate 0.5 mg 
(E2/NETA 1 mg/0.5 mg)
Doses:
Elagolix 200 mg BID 
Elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD
Mode of Administration:
Oral
Reference Therapy:
Placebo to match Elagolix; Placebo to match E2/NETA
Dose:
Placebo to match Elagolix 200 mg BID equivalent 
Placebo to match Elagolix 200 mg BID plus Placebo to match 
E2/NETA 1 mg/0.5 mg QD equivalent
Mode of Administration:
Oral
Duration of Treatment:  Subjects will receive up to 48 months of Treatment
Duration of Follow-Up:  Subjects will receive 12 months of Follow-Up
Criteria for Evaluation:
Efficacy:
Primary Efficacy Variables:
The co-primary efficacy endpoints will be the proportion of responders at Month 6 based upon the 
mutually-exclusive scales for daily assessment of DYS and NMPP measured by the 4-point 
Endometriosis Daily Pain Impact Diary; use of analgesic medication for endometriosis-associated pain 
will be included in the responder definition.
Secondary Efficacy Variables:
•
Change from baseline in Overall Endometriosis-Associated Pain at Month 3, Month 6, and 
Month 12
•
Change from baseline in DYS at Month 3, Month 6, and Month 12
•
Change from baseline in NMPP at Month 3, Month 6, and Month 12
•
Change from baseline in dyspareunia at Month 3, Month 6, and Month 12
•
Change from baseline in PROMIS Fatigue Short Form 6a T-Score at Month 6 and 12
Additional Efficacy Variables:
The following efficacy variables will be collected during the treatment period:
•
Proportion of responders as assessed by change from Baseline in average pain score and 
analgesic use monthly for DYS, NMPP and dyspareunia, respectively.
•
Proportion of responders as assessed by change from Baseline in average pain score alone (i.e., 
not taking into consideration of analgesic use) monthly for DYS, NMPP and dyspareunia, 
respectively.
•
Change from Baseline, in the monthly average pain score (DYS, NMPP, and dyspareunia), as 
assessed using information from the e-Diary.
•
Change from Baseline in analgesic use (average pill counts) to treat endometriosis-related pain, 
as assessed using information from the e-Diary monthly.


Elagolix
M14-702 Protocol Amendment 7 
11
Criteria for Evaluation (Continued):
Efficacy (Continued):
•
Proportion of analgesic use responders monthly (based only on reduction of rescue analgesics 
used).
•
Monthly response in the PGIC and overall endometriosis-associated pain questionnaire.
•
Change from baseline for each of six domains of EHP-30 questionnaire scores.
•
Change from baseline for the EuroQoL-5D (EQ-5D-5L).
•
Change from baseline for the WPAI:SHP.
•
HCRU at each scheduled assessment.
•
Change from baseline for the PROMIS Fatigue short Form 6A T-Score.
Safety Assessments:
Safety assessment will include BMD measurements including Z- and T-scores and percent change from 
baseline as measured by DXA at Months 6, 12, 18, 24, 30, 36, 42, and 48 of the Treatment Period.  
Other safety evaluations will include physical examinations, mammograms, Adverse Events (AEs), 
clinical laboratory tests (including hematology, chemistry, urinalysis, and lipid panel), the C-SSRS, vital 
sign measurements (including electrocardiogram).  Endometrial assessments will include TVU and 
endometrial biopsy.
Statistical Methods:
Efficacy:
All subjects who receive at least 1 dose of study medication will be included in the efficacy analyses.  
For each of the co-primary endpoints, the criterion for defining a subject as a pain responder at Month 6 
of the Treatment Period will be a reduction of 'X' or greater from Baseline in pain as well as no increased 
rescue analgesic use for endometriosis-associated pain.  The threshold X will be determined based on 
ROC analysis at Month 6 using the Month 6 PGIC as an anchor.  The use of protocol specified rescue 
analgesics at Month 6 of the Treatment Period for endometriosis-associated pain will be included in the 
responder definition.  The primary analysis of the co-primary endpoint will be based on a logistic 
regression model including treatment as the main factor and baseline pain scores as a covariate and the 
elagolix 200 mg BID plus E2/NETA dose will be compared to placebo.
Analysis details for Months 1 – 12 and Months 13 – 48 of the treatment period will be specified in the 
statistical analysis plan (SAP).  No statistical tests will be performed following the 12-month placebo-
controlled portion of the 48-month Treatment Period.  Data from subjects randomized to the elagolix 
200 mg BID alone will be summarized separately from subjects randomized to the elagolix 200 mg BID 
plus E2/NETA (1 mg/0.5 mg) QD arm.  Unless otherwise specified, no statistical tests will be performed 
to evaluate potential differences between the two elagolix dose groups.
The mean change from baseline in key secondary endpoints will be analyzed using a mixed-effects 
model with repeated measures.  Key secondary endpoints will be assessed at Month 3, Month 6 or 
Month 12.  Other efficacy endpoints and analyses will be defined in the SAP.
For subjects randomized to placebo in the first 12 months of the treatment period, baseline will be re-set 
to the data collected the month prior to the first dose of elagolix in Months 13 – 48 of the treatment 
period.  For subjects randomized to either one of the elagolix treatment groups, baseline for these 
subjects will refer to the baseline prior to the first dose of elagolix at the time of randomization.


Elagolix
M14-702 Protocol Amendment 7 
12
Statistical Methods (Continued):
BMD Assessments:
The key BMD comparisons are in lumbar spine at Month 6 and Month 12.  Secondary BMD endpoints 
include total hip and femoral neck.  The elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD dose 
will be compared to placebo at Months 6 and 12 and will be compared to elagolix 200 mg BID alone at 
Month 6 based on percent change from baseline.  Percent change in BMD from baseline values, as well 
as Z-scores and T-scores at all time points will also be summarized.  Analysis details will be provided in 
the SAP. 
Safety Assessments:
All subjects who receive at least 1 dose of study medication will be included in the safety analyses.  
Hematology, chemistry (including lipid panel), urinalysis, vital signs, endometrial assessments and 
uterine bleeding variables will be summarized.  Changes from Baseline to each Treatment Period visit 
during the first 12 months of treatment will be analyzed using an ANOVA or ANCOVA model as 
appropriate as specified in the SAP.
Safety analysis for Months 1 – 12 and Months 13 – 48 of the treatment period will be specified in the 
statistical analysis plan.  No statistical tests will be performed to evaluate potential differences between 
dose groups following the 12-month placebo-controlled portion of the 48-month Treatment Period.
Safety data from subjects randomized to the elagolix 200 mg BID alone treatment group will be 
summarized separately from subjects randomized to the elagolix 200 mg BID plus E2/NETA 
(1 mg/0.5 mg) QD arm.
Other safety analyses will be pre-specified in the SAP.
Pharmacokinetic:
Exposures of elagolix and norethindrone will be summarized and elagolix concentrations may be used to 
develop a population pharmacokinetic model.  Additional parameters may be calculated if useful for the 
interpretation of the data.
Pharmacodynamic:
Concentrations of estradiol (E2) will be obtained throughout the Treatment Period.  Additional 
pharmacodynamic parameters may be calculated if useful in the interpretation of the data.


Elagolix
M14-702 Protocol Amendment 7 
13
1.3
List of Abbreviations and Definition of Terms
Abbreviations 
Ab
Antibody
ABT
AbbVie
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BID
Twice daily
BMD
Bone Mineral Density
CIN
Cervical Intraepithelial Neoplasia
COVID-19
Coronavirus Disease - 2019
CR
Controlled release
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP3A
Cytochrome P450 3A
DFP
Direct-from-patient
DNA
Deoxyribonucleic acid
DTP 
Direct-to-patient
DYS
Dysmenorrhea
DXA
Dual Energy X-Ray Absorptiometry
E2
Estradiol
E2/NETA
Estradiol/Norethindrone acetate
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
e-Diary
Electronic Daily Diary
EHP-30
Endometriosis Health Profile-30
ePRO
Electronic Patient Reported Outcome
EQ-5D-5L
EuroQol-5D 5 Level
ER
Extended release
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GnRH
Gonadotropin releasing hormone


Elagolix
M14-702 Protocol Amendment 7 
14
HAV-IgM
Hepatitis A Virus immunoglobulin M
HBsAg
Hepatitis B Surface Antigen
HCV Ab
Hepatitis C Virus Antibody
HCRU
Health Care Resource Utilization
HDL
High-density lipoprotein
HIV
Human Immunodeficiency Virus
HIV Ab
Human Immunodeficiency Virus Antibody
HPV
Human Papillomavirus
HSIL
High-Grade Squamous Intraepithelial Lesion 
ICH
International Conference on Harmonization
ICF
Informed consent form
IEC
Independent Ethics Committee
IR
Immediate release
IRB
Institutional Review Board
IUD
Intrauterine device
IRT
Interactive Response Technology
LDL
Low-density lipoprotein
NMPP
Non-menstrual pelvic pain
NRS
Numeric Rating Scale
NSAID
Non-steroidal anti-inflammatory drug
ORT
Opioid Risk Tool
Pap
Papanicolaou 
PD
Premature Discontinuation 
PG
Pharmacogenetic
PGIC
Patient Global Impression of Change
PK
Pharmacokinetic
POR
Proof of Receipt
PRO
Patient Reported Outcome
QD
Once a day
RBC
Red Blood Cell
RNA
Ribonucleic acid
SAE
Serious adverse event
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2
SIS
Saline infusion sonography


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TA MD
Therapeutic Area Medical Director
TSH
Thyroid Stimulating Hormone
TVU
Transvaginal Ultrasound
WPAI:SHP
Work Productivity and Activity Impairment Questionnaire – Specific 
Health Problem
Pharmacokinetic and Statistical Abbreviations 
ANOVA
Analysis of variance
ANCOVA 
Analysis of covariance
AUC 
Area under the plasma concentration-time curve
LOCF
Last Observation Carried Forward
mITT
Modified intent to treat
MMRM
Mixed-model with repeated measures
ROC
Receiver Operating Characteristics
SAP
Statistical Analysis Plan
Tmax
Time to maximum observed plasma concentration
Definition of Terms
Randomization
Randomization at the end of the Screening Period on Study Day 1.
E2/NETA
1 mg E2/0.5 mg NETA
Month 
A month is defined as 28 days.


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ........................................... 3
1.2
Synopsis ..................................................................................................... 4
1.3
List of Abbreviations and Definition of Terms ........................................ 13
2.0
Table of Contents...................................................................16
3.0
Introduction ...........................................................................21
3.1
Endometriosis .......................................................................................... 21
3.2
Elagolix .................................................................................................... 21
3.2.1
Preclinical Experience.............................................................................. 21
3.2.1.1
Toxicology ............................................................................................... 21
3.2.2
Clinical Experience .................................................................................. 22
3.3
Differences Statement .............................................................................. 22
3.4
Benefits and Risks .................................................................................... 23
4.0
Study Objective......................................................................24
5.0
Investigational Plan...............................................................24
5.1
Overall Study Design and Plan:  Description .......................................... 24
5.2
Selection of Study Population .................................................................. 33
5.2.1
Inclusion Criteria ..................................................................................... 33
5.2.2
Exclusion Criteria .................................................................................... 36
5.2.3
Prior and Concomitant Therapy ............................................................... 41
5.2.3.1
Prior Therapy ........................................................................................... 42
5.2.3.2
Concomitant Therapy ............................................................................... 44
5.2.3.3
Prohibited Therapy ................................................................................... 45
5.2.3.4
Rescue Therapy ........................................................................................ 49
5.2.4
Contraception Recommendations and Pregnancy Testing....................... 51
5.3
Efficacy:  Pharmacokinetic, Pharmacodynamic, Pharmacogenetic 
and Safety Assessments/Variables ........................................................... 56
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................ 56
5.3.1.1
Study Procedures ..................................................................................... 56
5.3.1.2
Collection and Handling of Exploratory Research Samples .................... 82
5.3.1.3
Collection and Handling of Pharmacodynamic Variables ....................... 83


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5.3.2
Drug Concentration Measurements ......................................................... 84
5.3.2.1
Collection of Samples for Analysis ......................................................... 84
5.3.2.2
Measurement Methods ............................................................................. 84
5.3.3
Efficacy Variables .................................................................................... 84
5.3.3.1
Primary Variables .................................................................................... 84
5.3.3.2
Secondary Variables ................................................................................ 85
5.3.3.3
Additional Efficacy Variables .................................................................. 85
5.3.4
Safety Variables ....................................................................................... 86
5.3.5
Pharmacodynamic Variables.................................................................... 86
5.3.6
Pharmacokinetic Variables ...................................................................... 86
5.3.7
Exploratory Research Variables .............................................................. 86
5.4
Removal of Subjects from Therapy or Assessment ................................. 87
5.4.1
Discontinuation of Individual Subjects .................................................... 88
5.4.2
Discontinuation of Entire Study ............................................................... 89
5.5
Treatments ................................................................................................ 90
5.5.1
Treatments Administered ......................................................................... 90
5.5.2
Identity of Investigational Products ......................................................... 94
5.5.2.1
Packaging and Labeling ........................................................................... 95
5.5.2.2
Storage and Disposition of Study Drug ................................................... 95
5.5.3
Method of Assigning Subjects to Treatment Groups ............................... 96
5.5.4
Selection and Timing of Dose for Each Subject ...................................... 97
5.5.4.1
Treatment Interruption ............................................................................. 97
5.5.5
Blinding .................................................................................................... 98
5.5.5.1
Blinding of Investigational Product ......................................................... 98
5.5.6
Treatment Compliance ............................................................................. 98
5.5.7
Drug Accountability ............................................................................... 100
5.6
Discussion and Justification of Study Design ........................................ 101
5.6.1
Discussion of Study Design and Choice of Control Groups .................. 101
5.6.2
Appropriateness of Measurements ......................................................... 101
5.6.3
Suitability of Subject Population ........................................................... 102
5.6.4
Selection of Doses in the Study ............................................................. 102
6.0
Complaints ...........................................................................103
6.1
Medical Complaints ............................................................................... 104


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6.1.1
Definitions .............................................................................................. 104
6.1.1.1
Adverse Event ........................................................................................ 104
6.1.1.2
Serious Adverse Events ......................................................................... 105
6.1.1.3
Adverse Events of Special Interest ........................................................ 106
6.1.2
Adverse Event Severity .......................................................................... 106
6.1.3
Relationship to Study Drug .................................................................... 107
6.1.4
Adverse Event Collection Period ........................................................... 107
6.1.5
Adverse Event Reporting ....................................................................... 108
6.1.6
Pregnancy ............................................................................................... 110
6.2
Product Complaint ................................................................................. 112
6.2.1
Definition ............................................................................................... 112
6.2.2
Reporting ................................................................................................ 112
7.0
Protocol Deviations..............................................................113
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................113
8.1
Statistical and Analytical Plans .............................................................. 113
8.1.1
General Considerations .......................................................................... 114
8.1.2
Data Sets Analyzed ................................................................................ 114
8.1.3
Demographic, Baseline Characteristics and Concomitant 
Medications ............................................................................................ 115
8.1.4
End of Placebo Controlled Treatment Period Analysis ......................... 115
8.1.5
Month 24, Month 36, Month 48 and Other Timepoints Analyses ......... 116
8.1.6
Efficacy .................................................................................................. 116
8.1.6.1
Primary Efficacy Variable ..................................................................... 116
8.1.6.1.1
Primary Analysis .................................................................................... 116
8.1.6.1.2
Sensitivity Analyses of the Primary Efficacy Variable ......................... 119
8.1.6.2
Secondary Efficacy Variables ................................................................ 120
8.1.6.3
Other Efficacy Variables ........................................................................ 121
8.1.6.3.1
Dysmenorrhea and Non-Menstrual Pelvic Pain ..................................... 122
8.1.6.3.2
Dyspareunia ........................................................................................... 123
8.1.6.3.3
Analgesic Use for Endometriosis-Associated Pain ................................ 123
8.1.6.3.4
Patient Global Impression of Change (PGIC)........................................ 124
8.1.6.3.5
Overall Endometriosis-Associated Pain Questionnaire ......................... 124


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8.1.6.4
Multiple Comparisons ............................................................................ 125
8.1.7
Safety ..................................................................................................... 125
8.1.7.1
General Considerations .......................................................................... 125
8.1.7.2
Adverse Events ...................................................................................... 126
8.1.7.3
Analysis of Laboratory Data and Vital Signs ........................................ 126
8.1.7.4
Bone Mineral Density ............................................................................ 127
8.1.7.5
Post-Treatment Analysis of Menstruation ............................................. 127
8.1.7.6
Endometrial Biopsy ............................................................................... 128
8.1.7.7
Transvaginal Ultrasound ........................................................................ 128
8.1.8
Pharmacokinetics/Pharmacodynamics ................................................... 128
8.2
Determination of Sample Size ............................................................... 128
9.0
Ethics .....................................................................................129
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ........................................................................................... 129
9.2
Ethical Conduct of the Study ................................................................. 129
9.3
Subject Information and Consent ........................................................... 130
10.0
Source Documents and Case Report Form 
Completion ...........................................................................131
10.1
Source Documents ................................................................................. 131
10.2
Case Report Forms ................................................................................. 132
11.0
Data Quality Assurance ......................................................135
12.0
Use of Information...............................................................136
13.0
Completion of the Study .....................................................137
14.0
Investigator's Agreement....................................................138
15.0
Reference List ......................................................................139
List of Tables
Table 1.
Washout Intervals for Exclusionary Hormonal/Anti-Hormonal 
Therapy .................................................................................................... 43
Table 2.
Prohibited Medications ............................................................................ 46
Table 3.
Permitted Rescue Therapy for Endometriosis-Associated Pain .............. 50
Table 4.
Clinical Laboratory Tests ......................................................................... 71


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Table 5.
Treatments Administered (Day 1 – Month 6) .......................................... 91
Table 6.
Treatments Administered (Month 7 – Month 12) .................................... 91
Table 7.
Treatments Administered (Month 13 – Month 48) .................................. 92
Table 8.
Identity of Investigational Products ......................................................... 94
List of Figures
Figure 1.
Study Schematic ....................................................................................... 27
Figure 2.
Adverse Event Collection ...................................................................... 108
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator .......................................... 141
Appendix B.
List of Protocol Signatories.................................................................... 143
Appendix C.
Study Activities ...................................................................................... 144
Appendix D.
BI-RADS Classification ......................................................................... 161
Appendix E.
Overall Endometriosis-Associated Pain Questionnaire ......................... 162
Appendix F.
Patient Global Impression of Change (PGIC)........................................ 163
Appendix G.
Dietary Calcium Intake Questionnaire ................................................... 164
Appendix H.
Return to Menses Questionnaire ............................................................ 166
Appendix I.
Analgesic Change During Treatment Period ......................................... 167


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3.0
Introduction
3.1
Endometriosis
Endometriosis is defined as the presence of endometrial-like tissue outside the uterus.1  
Endometriosis primarily affects women of childbearing age, and is a frequently 
debilitating condition that is associated with a range of symptoms, the most common of 
which are dysmenorrhea (DYS) or painful menses, and non-menstrual pelvic pain 
(NMPP), as well as painful sexual intercourse or dyspareunia.  Endometriosis is also a 
common reason cited for infertility.
The treatment of pain in women with endometriosis is remarkable for the number of 
therapeutic classes that are used to manage these symptoms and their use has been 
detailed in key clinical practice guidelines from the American College of Obstetricians 
and Gynecologists (ACOG),2 American Society for Reproductive Medicine (ASRM),3
European Society of Human Reproduction and Embryology (ESHRE),4 the Society of 
Obstetrics and Gynecology Canada (SOGC) and the World Endometriosis Society 
(WES).5  To date, no therapy has an optimal benefit/risk profile, which attests to the 
unmet need for effective therapy for women suffering from endometriosis-associated pain.
3.2
Elagolix
Elagolix is an oral, GnRH antagonist that has been approved for the management of 
moderate to severe pain associated with endometriosis and in combination with E2/NETA 
to treat heavy menstrual bleeding in women with uterine fibroids. 
3.2.1
Preclinical Experience
3.2.1.1
Toxicology
A detailed discussion of the preclinical toxicology in addition to data on absorption, 
metabolism, distribution and elimination can be found in the Investigator Brochure. 


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3.2.2
Clinical Experience
The current Investigator Brochure provides details of the pharmacology and 
pharmacokinetics of elagolix in humans, in addition to a summary of elagolix clinical 
studies in Phases 1, 2 and 3.6,7
In two replicate Phase 3 endometriosis studies, elagolix met its primary efficacy endpoints 
of a statistically significant and clinically meaningful decrease in dysmenorrhea (DYS) 
and non-menstrual pelvic pain (NMPP) at 3 months with continued efficacy at 6 months 
for both the 150 mg QD and 200 mg BID dose levels.  The 150 mg QD dose 
demonstrated efficacy in 3 of 7 key ranked secondary outcome measures while the 
200 mg BID dose showed a statistically significant improvement in all 7 key ranked 
secondary outcome measures.  Also consistent with estradiol (E2) suppression and 
previous elagolix studies, there was a dose dependent effect on BMD, such that a longer 
duration of treatment with the higher elagolix dose (200 mg BID) would likely require 
concomitant use of hormonal add back therapy to mitigate BMD loss. 
Elagolix is not contraceptive and can change the menstrual bleeding pattern.  A 
folliculogenesis study with elagolix revealed a dose-dependent suppression of ovulation.  
Although there is no evidence of fetal abnormalities in preclinical studies, there have been 
2 cases of congenital malformations in clinical studies of elagolix to date.  Although not 
thought to be related to elagolix, the true relationship is unknown.  Elagolix should not be 
used in women who are pregnant or trying to become pregnant because, elagolix, like 
most GnRH analogues, affects the reproductive hormonal milieu.  Information regarding 
contraception counseling and pregnancy testing is provided in Section 5.2.4. 
3.3
Differences Statement
This Phase 3 study will evaluate the safety and efficacy of the elagolix 200 mg BID dose 
in combination with hormonal add-back therapy in 18 to 49 year old premenopausal 
women with moderate to severe endometriosis-associated pain over a 4 year period.  The 
objective is to generate safety and efficacy data that would support a longer duration of 


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use of this regimen for the management of endometriosis-associated pain than the Phase 3 
registration program. 
Efficacy data from the ongoing Phase 3 clinical development program supports the ability 
of elagolix to reduce endometriosis-associated pain at both the 150 mg QD and 200 mg 
BID dose levels in a dose-dependent fashion.  Also consistent with E2 suppression and 
previous elagolix studies, there was a dose dependent effect on BMD, such that longer 
duration of treatment with the higher elagolix dose (200 mg BID) would likely require 
concomitant use of hormonal add back therapy to mitigate BMD loss, which is the 
hypothesis being tested in this study.  The current study evaluates the safety and efficacy 
of the elagolix 200 mg BID dose in combination with estrogen/progestin hormonal add-
back therapy for a 48 month treatment period.  All subjects will be followed for 
12 months during the Follow-up Period. 
3.4
Benefits and Risks
Clinical studies with elagolix have demonstrated a statistically significant reduction in 
endometriosis-associated pain in premenopausal women with moderate to severe 
endometriosis-associated pain, including clinically meaningful improvements in DYS, 
NMPP, and in some cases, dyspareunia.  Elagolix has been administered to over 
3,700 subjects to date, and has been generally well tolerated.  The most common adverse 
events associated with its use have included hot flush, headache and nausea.6  A modest 
degree of BMD decrease has been associated with elagolix, also in a dose-dependent 
manner, as expected from its mechanism of action.  Hormonal add-back therapy may help 
to mitigate this effect.  Menstrual cycle changes are also observed in individuals 
administered elagolix, and include lengthening of the cycle, and in some subjects, oligo- 
or amenorrhea and/or irregular bleeding or spotting.  Pregnancies have been observed in 
subjects exposed to elagolix, which is consistent with the dose-dependent effect on 
suppression of ovulation.  To date, the benefit/risk profile of elagolix appears to remain 
favorable for the management of endometriosis-associated pain, and will be further 
defined by data from this Phase 3 trial. 


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Considering the Coronavirus Disease-19 (COVID-19) pandemic, the benefit and risk to 
subjects participating in this study has been re-evaluated.  The use of elagolix plus 
E2/NETA addback provides a viable option to treat the chronic pain of women with 
endometriosis.  Based on the limited information to date, no additional risk to study 
participants is anticipated with the use of elagolix in combination with E2/NETA in 
subjects who may contract COVID-19. 
4.0
Study Objective
The objectives of this study are to: 
●
Assess the safety and efficacy of elagolix 200 mg administered twice daily 
(BID) in combination with estradiol 1 mg/0.5 mg norethindrone acetate 
(E2/NETA 1 mg/0.5 mg) QD compared to placebo at 6 months and 12 months; 
●
Assess the effect of elagolix 200 mg BID in combination with E2/NETA 
(1 mg/0.5 mg) QD on bone mineral density (BMD) compared to elagolix 
200 mg BID alone at 6 months and compared to placebo at 6 months and 
12 months; 
●
Evaluate the continued safety and efficacy of elagolix 200 mg BID plus 
E2/NETA (1 mg/0.5 mg) QD for up to 48 months in premenopausal women 
with moderate to severe endometriosis-associated pain
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
COVID-19 Pandemic-Related Acceptable Protocol Modifications
During the COVID-19 pandemic, it has been necessary to employ mitigation strategies to 
enable the investigator to ensure subject safety and continuity of care.  Acceptable 
mitigation strategies are identified and included throughout the protocol. 


Elagolix
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The investigator should contact the TA MD before discontinuing a subject from the study 
for a reason other than "planned per protocol," (refer to Section 5.4) to ensure all 
acceptable mitigation steps have been explored. 
This Phase 3 study includes a 48-month Treatment Period and is designed to evaluate the 
safety and efficacy of elagolix in combination with concomitant hormonal add-back 
therapy (E2/NETA 1 mg/0.5 mg) in the management of endometriosis-associated pain in 
premenopausal women.  The first 12 months of the Treatment Period will employ a 
randomized, double-blind, placebo-controlled design (12 months), an elagolix 200 mg 
BID alone arm (the first 6 months followed by elagolix 200 mg BID plus E2/NETA 
[1 mg/0.5 mg] QD), and an elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD arm.  
The remaining 36 months of the Treatment Period will be open-label, such that all 
subjects will receive elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD. 
Approximately 700 subjects will be randomly assigned on Study Day 1 in a 4:1:2 ratio as 
follows: 
●
elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD (n = 400) 
●
elagolix 200 mg BID (n = 100) 
●
placebo (n = 200) 
The study was designed to enroll approximately 700 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  Therefore, if the target number of subjects has been enrolled, there 
is a possibility that additional subjects in screening will not be enrolled.  The total 
duration for a subject's participation in this study is approximately 51 to 74 months, 
consisting of the following 4 study periods: 
●
Washout Period – up to 10 months prior to Screening (only applicable if subject 
is taking exclusionary medication at the time of consent; duration of washout 
depends on the type of exclusionary medication being taken) 


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●
Screening Period – approximately 1.5 to 4 months prior to first dose of study 
drug 
●
Treatment Period – up to 48-month treatment duration
●
Follow-Up Period –12 months duration following the last dose of study drug.  
Subjects are expected to enter Follow-Up after completing Treatment Month 
48, or if a subject prematurely discontinues from the Treatment Period at the 
time of or after Treatment Month 6. 
The study schematic is shown below in Figure 1: 


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Figure 1. 
Study Schematic


Elagolix
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Washout Period 
Following informed consent, subjects, who are or were taking exclusionary 
hormonal/anti-hormonal medications prior to screening that require discontinuation 
(washout), must enter a Washout Period.  The duration of the required washout period is 
based on the excluded medication that the subject is or was taking.  Additional details 
about washout intervals for exclusionary medication is provided in Section 5.2.3.1.  Study 
procedures to be performed during the Washout Period are specified in Appendix C, 
Study Activities and described in Section 5.3.1.1.  Subjects must complete the Washout 
Period and have had at least 1 menstrual period (menses) prior to entering the Screening 
Period.  Subjects will also begin the use of non-hormonal dual contraception during the 
Washout Period and receive counseling on the importance of consistent, appropriate and 
effective use of contraception, and contraceptives dispensed, as necessary. 
Screening Period
Subjects who do not require washout will enter directly into the Screening Period 
(approximately 1.5 to 4 months) and will provide written informed consent before any 
study related procedures are performed.  Subjects will undergo screening procedures as 
specified in Appendix C, Study Activities and described in Section 5.3.1.1, to establish 
eligibility based on inclusion and exclusion criteria including the following safety 
assessments:
●
a dual energy x-ray absorptiometry (DXA) scan to document baseline bone 
mineral density (BMD)
●
a transvaginal ultrasound (TVU) to rule out any exclusionary gynecological 
disorders such as ovarian cysts, large fibroids, endometrial polyps 
●
an endometrial biopsy to rule out other endometrial pathology 
●
a Papanicolaou (Pap) test in subjects ≥ 21 years of age, to rule out significant 
cervical/gynecological pathology 
●
a mammogram in subjects 40 years of age or older if one has not been 
performed within 3 months prior to the time of entry into Screening 


Elagolix
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An electronic daily diary (e-Diary) will be provided to subjects at screening to begin 
recording:  
●
endometriosis-associated pain (dysmenorrhea [DYS] or non-menstrual pelvic 
pain [NMPP]) using the 4 point Endometriosis Daily Pain Impact Diary scale 
(no pain, mild pain, moderate pain, severe pain coded as 0 – 3) 
●
dyspareunia via a 4-point scale (no pain, mild pain, moderate pain, severe pain 
coded as 0 – 3, and not applicable) 
●
the presence of uterine bleeding (menstrual period and other uterine bleeding) 
and intensity of bleeding (spotting, light, medium, heavy) 
A minimum of 45 days of daily e-Diary entries are required to be completed during the 
Screening Period.  During the last 35 calendar days of the Screening Period, subjects must 
have at least 2 days of moderate or severe DYS and at least 2 days of moderate or severe 
NMPP with an average NMPP score of at least 1.0, OR at least 4 days of moderate or 
severe NMPP and with an average NMPP score of at least 0.5.  Subjects must have 
2 menstrual cycles with cycle length of 21 – 38 days, and at least 1 full menstrual cycle 
(i.e., 2 menses or menstrual periods) must be documented in the e-Diary during Screening.  
Subjects are required to use appropriate non-hormonal contraception throughout the 
Screening Period.  Contraceptive counseling will be provided and contraceptives 
dispensed, as necessary.  Subjects will be allowed to take protocol allowed analgesic 
rescue medication for endometriosis-associated pain which includes multiple NSAID 
choices and opioid choices.  Use of other rescue analgesic or prophylactic analgesic 
medications for endometriosis-associated pain will not be allowed.  NSAID and opioid 
baseline use will be established during the Screening Period based on the subject's 
preference and historical use of analgesics for endometriosis-associated pain and 
Investigator judgment.  Subjects will record use of protocol allowed analgesic rescue 
medications for endometriosis-associated pain in the daily e-Diary.  Sites will record the 
use of protocol-allowed rescue analgesics in the source documents and eCRF. 
Subjects who have signed informed consent and did not complete the Day 1 visit will be 
considered screen failures.  Subjects who initially screen fail for the study may be 


Elagolix
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permitted to re-screen following re-consent.  Subjects who screen failed due to e-Diary 
pain criteria, Screening DXA results, or C-SSRS criteria cannot be re-screened.  
The subject must meet all inclusion and none of the exclusion criteria during re-screening 
to qualify for the study.  There is no minimum period of time a subject must wait to re-
screen for the study.  Subjects may only re-screen once.
Urine and serum pregnancy tests must be repeated upon re-screen.  The following 
screening procedures do not need to be repeated upon re-screen:
●
Endometrial biopsy, PAP and/or mammogram if completed within 12 months 
for the study, 
●
DXA, TVU, Clinical/Safety Labs, Vitamin D Testing, Hepatitis/HIV Screen, if 
completed within 4 months for the study. 
Treatment Period
The Treatment Period begins on Day 1, which should occur between Cycle Days 1 to 10 
of the subject's menstrual cycle (Cycle Day 1 is defined as the first day with full menstrual 
flow), for all subjects following determination of eligibility during the Screening Period.  
Randomizations beyond Cycle Day 10 of the subject's menstrual cycle must be discussed 
with the AbbVie Therapeutic Area Medical Director (TA MD) prior to randomizing the 
subject and will be evaluated on a case by case basis, including whether additional 
procedures are required.
On Day 1 of the Treatment Period, subjects will be randomly assigned (in a 4:1:2 ratio) to 
receive either elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD (n = 400), elagolix 
200 mg BID alone (n = 100), or placebo (n = 200).  The first dose of study drug will be 
administered at the study site on Day 1.  Thereafter, subjects will self-administer study 
medication or matching placebo twice daily (once in the morning and once in the evening, 
approximately 12 hours apart) orally without regard to food or meals throughout the 
48-month Treatment Period.  Subjects will visit the site monthly (28-day months) through 
Month 6 of the Treatment Period.  After the Month 6 visit and through Month 12, on-site 


Elagolix
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visits will be conducted at Treatment Months 8, 10, and 12; phone contacts will be made 
at Treatment Months 7, 9, and 11. 
Months 13 – 48 of the Treatment Period will be open-label such that all subjects 
(including those previously randomized to elagolix 200 mg BID alone or placebo) will 
receive active treatment with elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD.  
On-site visits will be conducted at Months 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and 
48; phone contacts will be made at Months 13 – 14, 16 – 17, 19 – 20, 22 – 23, 25 – 26, 
28 – 29, 31 – 32, 34 – 35, 37 – 38, 40 – 41, 43 – 44, and 46 – 47. 
Study drug kits will be dispensed to subjects at each on-site visit with the exception of the 
final visit at Treatment Month 48.  Subjects randomized to elagolix plus E2/NETA on 
Day 1 of the Treatment Period will continue with the same dosing regimen (dose and 
frequency) throughout the entire Treatment Period; subjects randomized to elagolix 
200 mg BID alone during the first 6 months will be reassigned to receive elagolix 200 mg 
BID plus E2/NETA (1 mg/0.5 mg) QD for the remainder of the Treatment Period 
(Months 7 – 48); subjects randomized to placebo will be reassigned at Treatment 
Month 12 to receive elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD for the 
remainder of the Treatment Period.  All subjects will know they are receiving elagolix 
200 mg BID plus E2/NETA (1 mg/0.5 mg) QD during Months 13 – 48. 
Through Treatment Month 12, subjects will use the daily e-Diary to continue recording: 
●
endometriosis-associated pain (DYS and NMPP via the 4 point Endometriosis 
Daily Pain Impact Scale) (no pain, mild pain, moderate pain, severe pain coded 
as 0 – 3) 
●
dyspareunia via a 4-point scale (no pain, mild pain, moderate pain, severe pain 
coded as 0 – 3, and not applicable) 
●
the presence of uterine bleeding (menstrual period and other uterine bleeding) 
and intensity of bleeding (spotting, light, medium, heavy) 
●
use of protocol specific analgesic rescue medications for endometriosis-
associated pain


Elagolix
M14-702 Protocol Amendment 7 
32
At the Day 1 visit (prior to dosing) and at all monthly visits during the Treatment Period 
(on-site and phone contacts), site staff will administer to subjects the overall 
endometriosis-associated pain questionnaire, an 11-point numeric rating scale (NRS). 
Information regarding the use of rescue analgesic medications for endometriosis-
associated pain will be collected at monthly study visits and recorded in source documents 
and eCRF.
At select study visits, subjects will be asked to complete various patient-reported outcome 
(PRO) questionnaires, including a Patient Global Impression of Change (PGIC).  Vital 
signs assessments will be conducted at designated time points.  Additional safety 
assessments including mammograms, TVUs, Pap tests, endometrial biopsies, and DXAs 
are completed as appropriate throughout the Treatment Period. 
Blood samples for clinical safety labs and vitamin D testing and will be obtained.  In 
addition, blood samples will be collected for assay of serum estradiol prior to dosing on 
Day 1 and at designated study visits, and to measure plasma concentrations of elagolix 
and norethindrone at designated study visits.  For subjects who consent, 3 separate DNA 
(Deoxyribonucleic acid) and RNA (Ribonucleic acid) pharmacogenetic (PG) blood 
samples and 2 endometrial samples will be collected.  Pregnancy tests will be performed 
at each monthly visit throughout the Treatment Period.  Urine pregnancy test kits will be 
provided to subjects for use at home for the study visits when subjects are not required to 
come into the clinic/site.  Subjects will self-administer the tests and report the results to 
the site at the phone contact visits.  Subjects will be counseled at each visit on consistent, 
appropriate and effective forms of dual non-hormonal contraception to promote 
pregnancy prevention.  A positive urine pregnancy test must be confirmed with a serum 
pregnancy test.  A positive serum pregnancy test at any time will necessitate 
discontinuation from the Treatment Period. 
Additional detail regarding study procedures during the Treatment Period is provided in 
Section 5.3.1.1 and Appendix C, Study Activities. 


Elagolix
M14-702 Protocol Amendment 7 
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Follow-Up Period
Subjects will enter the Follow-Up Period for 12 months to assess bone recovery after up 
to 48 months of treatment.  Subjects who prematurely discontinue from the study at the 
time of or after the Treatment Period Month 6 visit will enter the Follow-Up Period. 
DXA scans will be obtained at designated visits as described in Appendix C.  Additional 
study procedures will be performed at designated study visits as outlined in Appendix C.  
Adverse event collection is detailed in Section 6.1.4 and Appendix C.  Concomitant 
medication use will be reviewed at on-site visits.
Additional detail regarding study procedures during the Follow-Up Period is provided in 
Section 5.3.1.1 and Appendix C, Study Activities. 
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Study visits may be impacted due to the COVID-19 pandemic.  This may include changes 
such as phone or virtual visits, visits at alternative locations, or changes in the visit 
frequency and timing of study procedures, among others.  Additional details are provided 
in the subsequent section.  Every effort should be made to ensure the safety of subjects 
and site staff, while maintaining the integrity of the study.  If visits cannot be conducted 
onsite due to travel restrictions or other pandemic-related reasons, study visits may be 
conducted over the phone where feasible and AbbVie should be notified. 
5.2
Selection of Study Population
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 
washout (if applicable), or initiation of any screening or study-specific procedures.
2.
Subject is a premenopausal female 18 to 49 years of age (inclusive) at the time of 
Screening.


Elagolix
M14-702 Protocol Amendment 7 
34
3.
Subject has a documented surgical diagnosis (e.g., laparoscopy or laparotomy) of 
endometriosis established by visualization or histology within 10 years prior to 
entry into Washout or Screening. 
4.
Subject must agree to use only those rescue analgesics permitted by the protocol 
during the Screening and Treatment Periods for her endometriosis-associated pain.
5.
Subject must have a negative urine and/or serum pregnancy test(s) during the 
Washout (if applicable) and/or Screening Periods, and a negative urine pregnancy 
test just prior to administration of the first dose of study drug. 
6.
Subject must agree to use two forms of non-hormonal contraception (dual 
contraception) consistently during the Washout (if applicable), Screening, 
Treatment and through the end of Month 1 of the Follow-Up Period.  Acceptable 
methods of dual contraception include the following combinations: 
●
Condom with spermicide (e.g., cream, spray, foam, gel, suppository or polymer 
film)
●
Diaphragm with spermicide (condom may or may not be used) 
●
Cervical cap with spermicide (condom may or may not be used) 
●
Vaginal sponge impregnated with spermicide and used with a condom. 
Subject is not required to use dual contraception methods if: 
●
Sexual partner(s) is (are) 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 and requires use of 
dual contraception. 
●
Subject had a bilateral tubal ligation or bilateral tubal occlusion at least 
4 months prior to the start of Screening 
●
Subject is not sexually active with men; however, periodic sexual 
relationship(s) with men require the use of study defined dual non-hormonal 
contraception. 


Elagolix
M14-702 Protocol Amendment 7 
35
7.
Subject ≥ 40 years of age at entry into screening has a normal mammogram during 
Screening or within 3 months prior to the start of Screening (BI-RADS 
Classification 1 to 3 or equivalent). 
8.
Prior to Study Day 1, subject must have two documented menstrual cycles with a 
cycle length of 21 – 38 days.  A minimum of one full menstrual cycle 
(i.e., including 2 menses or periods) must be documented in the e-Diary; however, 
the start of the previous menstrual cycle may be based on the subject's historical 
recall and must be appropriately recorded in the subject's source documents. 
9.
Subject has a minimum of 45 days of e-Diary entries during the Screening Period. 
10.
Subject must have the following documented in the e-Diary during the last 35 days 
prior to Study Day 1: 
●
At least 2 days of "moderate" or "severe" DYS
AND either,
●
At least 2 days of "moderate" or "severe" NMPP and an average NMPP score 
of at least 1.0, 
OR
●
At least 4 days of "moderate" or "severe" NMPP and an average NMPP score 
of at least 0.5. 


Elagolix
M14-702 Protocol Amendment 7 
36
Rationale for Inclusion Criteria
1 
This is standard criterion in accordance with harmonized Good Clinical 
Practice (GCP)
2 – 4, 8 – 10 
These criteria were selected to ensure an appropriate subject population 
of premenopausal women with moderate to severe endometriosis-
associated pain
5, 6 
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 
7 
To ensure general good health and the safety of subjects 
5.2.2
Exclusion Criteria
1.
Subject is pregnant or breastfeeding, or is planning a pregnancy during the duration 
of study participation (potentially up to 74 months; inclusive of the Washout, 
Screening, Treatment and Follow-Up Periods). 
2.
Subject is less than 6 months postpartum or 3 months post-abortion (spontaneous 
or elective), prior to the start of Screening. 
3.
Subject has an intra-uterine device (IUD) or contraceptive sub-dermal implant.  If 
the IUD or sub-dermal implant is removed and subject completes the appropriate 
washout, subject may be screened for the study. 
4.
Subject has a surgical history of: 
●
Hysterectomy (with or without oophorectomy) 
●
Bilateral oophorectomy 
●
Any major surgery (including laparotomy for endometriosis) within 3 months 
OR endometrial ablation within 6 months OR minor surgery (including 
laparoscopy for endometriosis) within 1 month prior to the Screening visit.


Elagolix
M14-702 Protocol Amendment 7 
37
5.
Subject has a history of previous non-response to GnRH agonists, GnRH 
antagonists, depo-medroxyprogesterone acetate (DMPA), or aromatase inhibitors 
as assessed by subject report of no improvement in DYS or NMPP (subject report 
of partial response to or side effects from these agents is not exclusionary).
6.
Subject has any of the following identified on the Screening TVU or endometrial 
biopsy: 
●
A simple ovarian cyst > 5 cm in longest diameter that persists on repeat TVU
●
A complex ovarian cyst > 3.5 cm in diameter (longest diameter) that persists on 
repeat TVU
●
An endometrioma > 3.5 cm in diameter (longest diameter)
●
Large endometrial polyp ≥ 1 cm (confirmed by SIS and/or office hysteroscopy)
●
Single fibroid ≥ 4 cm
●
Multiple fibroids (> 4) that measure ≥ 2 cm
●
Symptomatic submucousal fibroid of any size 
●
Any other clinically significant gynecologic condition or endometrial pathology 
7.
Subject ≥ 21 years of age at Screening (or age at which Pap smears are routinely 
performed according to local guidelines) has a Screening Pap test result showing 
any evidence of malignancy or pre-malignant changes. 
8.
Subject has a current history of undiagnosed abnormal uterine (vaginal or genital) 
bleeding. 
9.
Subject has a hypersensitivity, documented allergy or is unable to tolerate 
norethindrone, norethindrone acetate or estradiol, or these preparations 
(e.g., E2/NETA) are contraindicated for medical reasons.
10.
Subject is unable or unwilling to discontinue use of any prior analgesics on entry 
into the Screening Period or if a subject has a clinically significant sensitivity, 
allergy to, or any other reason that in the Investigators opinion that would prevent 
the subject from using all of the protocol allowed rescue analgesic medications. 


Elagolix
M14-702 Protocol Amendment 7 
38
11.
Subject is unable or unwilling to discontinue use of medical treatments for 
endometriosis on entry into the Washout or Screening Period. 
12.
Subject has chronic pelvic pain that is not caused by endometriosis (e.g., interstitial 
cystitis, adenomyosis [as a dominant condition diagnosed by MRI or ultrasound], 
fibroids, pelvic inflammatory disease [PID], non-endometriosis-related pelvic 
adhesive disease, irritable bowel syndrome), that requires chronic analgesic 
therapy, which would interfere with the assessment of endometriosis-related pain.
13.
Subject has any other chronic pain syndrome (e.g., fibromyalgia, chronic back 
pain, myofascial pain syndrome, chronic headaches) that requires chronic analgesic 
or other chronic therapy, which, in the opinion of the Investigator, would interfere 
with the assessment of endometriosis-related pain.
14.
Subject is using any systemic corticosteroids for over 14 days within 3 months 
prior to Screening or is likely to require treatment with systemic corticosteroids 
during the course of the study.  Over-the-counter and prescription topical, inhaled 
or intranasal corticosteroids are allowed.
15.
Subject has any of the following: 
●
Major depression or a post-traumatic stress disorder (PTSD) episode within 
2 years of the Screening visit 
●
Other major psychiatric disorder at any time (e.g., schizophrenia, bipolar 
disorder) 
16.
Subject has a history of suicide attempts or answered "yes" to questions 4 or 5 on 
the suicidal ideation portion of the Columbia-Suicide Severity Rating Scale 
(C-SSRS) within the last 1 year at Screening or Day 1, prior to randomization. 
17.
Subject has clinically significant abnormalities in clinical chemistry, hematology or 
urinalysis, including aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) or bilirubin (unless known diagnosis of Gilbert's syndrome) ≥ 3.0 times the 
upper limit of the reference range or a serum creatinine > 2.0 mg/dL at Screening.  
Clinically significant laboratory abnormalities may be retested 1 time prior to 


Elagolix
M14-702 Protocol Amendment 7 
39
Day 1; however, the results must meet entry criteria prior to study drug 
administration on Day 1. 
18.
Subject has a reactive or positive Screening test result for Hepatitis A Virus 
Immunoglobulin M (HAV IgM), Hepatitis B Surface Antigen (HBsAg) or 
Hepatitis C Virus Antibody (HCV Ab) or Human Immunodeficiency Virus (HIV) 
or HIV Antibody (HIV Ab). 
19.
Subject used any known moderate or strong inducers of cytochrome P450 3A 
(CYP3A) (e.g., phenobarbital, rifampin, carbamazepine, St. John's Wort) as 
indicated in Table 2 within 1 month prior to Day 1. 
20.
Subject has a clinically significant abnormal electrocardiogram (ECG) at 
Screening.
21.
Subject has any condition that would interfere with obtaining adequate DXA 
measurements (e.g., history of spinal surgery, spinal hardware, severe scoliosis or 
weight) or any history of osteoporosis or other metabolic bone disease or including: 
●
Intercurrent bone disease (e.g., osteomalacia, osteogenesis imperfecta) 
●
History or presence of an unstable condition that is associated with a decrease 
in BMD (e.g., uncontrolled hyperthyroidism, uncontrolled 
hyperparathyroidism, anorexia nervosa) 
●
History of low-trauma hip or vertebral fractures (e.g., fracture resulting from a 
fall from a standing height or lower) 
●
Bilateral hip replacement
●
Clinically significant hypocalcemia, hypo- or hyperphosphatemia, including 
during Screening (lab results) 
●
Treatment with medication (excluding calcium and Vitamin D) for bone 
disease associated with a decrease in BMD.
22.
Screening DXA results of the lumbar spine (L1-L4), femoral neck or total hip 
BMD corresponding to less than 2.0 or more standard deviations below normal 
(Z-score < –2.0 for subjects < 40 years of age, T-score for subjects ≥ 40 years of 
age).


Elagolix
M14-702 Protocol Amendment 7 
40
23.
Subject has a history of or active malignancy (with or without systemic 
chemotherapy), except treated basal cell carcinoma of the skin.
24.
Subject has either:
●
a newly diagnosed, clinically significant medical condition that requires 
therapeutic intervention (e.g., new onset hypertension), that has not been 
stabilized 30 days prior to randomization on Day 1 OR 
●
a clinically significant medical condition that is anticipated to require 
intervention during the course of study participation (e.g., anticipated major 
elective surgery) 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). 
25.
Subject has any conditions contraindicated with use of E2/NETA such as: 
●
Current or history of deep vein thrombosis (DVT) or pulmonary embolism 
●
Current or history (within 1 year of screening) of arterial thromboembolic 
disease (e.g., stroke, myocardial infarction). 
26.
Subject has a history of drug and/or alcohol abuse within 1 year prior to Screening. 
27.
Subject was previously enrolled (randomized) in an elagolix study less than 1 year 
prior to entry into the Screening Period. 
28.
Subject is currently participating in another investigational study (drug or device) 
or has participated in an investigational drug study within 2 months prior to the 
Screening Visit.  If a subject has participated in an investigational trial with 
hormonal treatment, the minimal washout period must be completed prior to 
entering the Screening Period for this study. 
29.
In the judgment of the Investigator, subject is an unsuitable candidate to receive 
elagolix or E2/NETA or will be unable or unwilling to comply with study-related 


Elagolix
M14-702 Protocol Amendment 7 
41
assessments and procedures, including completion of the e-Diary and consistent 
use of non-hormonal dual contraception throughout the required time period. 
30.
Subject scores an 8 or higher on the Opioid Risk Tool at Screening.
Rationale for Exclusion Criteria
4, 5, 12 
These criteria were selected to ensure an adequate subject 
population of premenopausal women with moderate to severe 
endometriosis pain and no significant gynecological disorders 
3, 6 – 9, 14 – 26, 
30 
These are standard criteria selected to ensure general good health 
and the safety of the subjects 
1, 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 pregnant women 
are not enrolled into the study and adequate precautions are taken to 
avoid pregnancy during study participation 
27, 28 
These criteria were selected to avoid bias for the evaluation of 
efficacy and safety by prior participation in an elagolix or similar 
study 
10, 11, 13, 29 
These criteria were selected to ensure that efficacy can be 
adequately assessed
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving at the time of enrollment, 
or receives during the study, must be recorded along with the reason for use, date(s) of 
administration including start and end dates, and dosage information including dose, route 
and frequency. 
The AbbVie TA MD should be contacted if there are any questions regarding concomitant 
or prior therapies. 


Elagolix
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42
5.2.3.1
Prior Therapy
To document historical use, any medication administered to treat endometriosis or 
endometriosis-associated pain prior to Washout or Screening will be recorded in source 
documents and the electronic case report forms (eCRFs).  The date(s) of administration 
(including start and treatment end dates), and reason for use and discontinuation must be 
recorded in source documents and eCRFs. 
Subjects using or who have used hormonal contraception or other 
hormonal/anti-hormonal therapies may be considered for study participation provided 
they complete the required washout (Washout Period) and have had at least 1 menstrual 
period (menses) before entering into the Screening Period.  Subjects currently using 
hormonal/anti-hormonal therapies will sign an ICF before they discontinue these 
medications and begin the washout.  Subjects who discontinued taking hormonal 
contraception or other hormonal/anti-hormonal therapies before they were approached to 
participate in the study must sign the ICF and complete the remainder of the washout and 
have had at least 1 menstrual period (menses) before entering the Screening Period.  
Discontinuation of hormonal contraception should be done according to prescribing 
information (e.g., complete current cycle of birth control pills) and per the investigator's 
discretion. 
The minimum washout intervals for hormonal/anti-hormonal therapies prior to entering 
Screening are described in Table 1.  Subjects may enter the Screening Period after the 
required washout has been completed and documentation of at least 1 menstrual period.  
Subjects who have an IUD or contraceptive sub-dermal implant and agree to have the 
IUD or sub-dermal implant removed must complete the washout period described in 
Table 1 and have had at least 1 menstrual period prior to entering Screening. 
If the type of hormonal product and the length of Washout are not listed in the table 
below, consult your AbbVie TA MD. 


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Table 1. 
Washout Intervals for Exclusionary Hormonal/Anti-Hormonal 
Therapy
Therapy
Minimum Interval for 
Washout* (Prior to 
Initial Screening Visit)
Number of Menses 
Required AFTER 
Completion of Washout 
Period (Prior to Initial 
Screening Visit)
Medroxy progesterone acetate injection (Depo-
Provera®; Sayana®)
10 months from injection
2 menses
GnRH agonist 3 month depot (Lupron Depot®
11.25 mg), goserelin acetate (Zoladex®, 
10.8 mg) 
6 months from injection
1 menses
Synarel® (Nasal Spray), Nafarelin acetate, 
GnRH agonist – 1 month depot (including 
Lupron Depot® 3.75 mg), goserelin acetate 
(Zoladex® 3.6 mg)
4 months
1 menses
GnRH antagonist
3 months
1 menses
Selective Progesterone Receptor Modulators 
(e.g., Ulipristal acetate, Vilaprisan)
Danazol (Cyclomen®) 
Aromatase inhibitors
Oral contraceptives**
1 month
1 menses
Oral, transdermal or intravaginal estrogen 
preparations
Oral, intravaginal or transdermal 
progesterone/progestin preparations***, 
including tibolone
Hormonal and Non-Hormonal IUD, sub-
dermal progestin implant (e.g., Nexplanon®) 
1 month after removal
1 menses
NuvaRing®
* 
This is the minimum washout; however, subjects may not enter Screening until at least 1 menses has occurred 
during the Washout Period.  If less than a full course of therapy is administered, the Investigator should contact 
their Monitor who will discuss with the AbbVie TA MD and confirm the required washout interval. 
**
Subjects must complete the mandatory month of washout from oral contraceptives and subsequently have a 
menses/period.  Bleeding due to withdrawal of the oral contraceptives cannot be considered the required 
menses/period.
*** Exception:  levonorgestrel 1.5 mg or ulipristal acetate 30 mg used for emergency contraception.


Elagolix
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5.2.3.2
Concomitant Therapy
All concomitant medications taken during the duration of study participation (Washout [if 
required], Screening, Treatment, Follow-Up) must be recorded in source documents and 
eCRFs, along with the reason for use, dates of administration, dosages, routes and 
frequency.
The following concomitant medications are allowed during study participation, as these 
medications are not expected to significantly confound the efficacy evaluation, nor are 
there substantial safety concerns with concomitant use: 
●
Inhaled corticosteroids for treatment of asthma or similar airways diseases
●
Over-the-counter and prescription topical, intranasal or local injectable (for 
occasional use) corticosteroids 
●
Vaccines
●
Triptans or ergotamines for the treatment of infrequent migraine headaches
●
Multivitamins
●
Anti-depressants
●
Non-opioid analgesics (e.g., NSAIDs) may be used for conditions other than 
endometriosis-associated pain (e.g., acute conditions such as headache or fever)
●
Levonorgestrel or ulipristal acetate only when used as emergency contraception 
(e.g., Plan B)
Given the ongoing COVID-19 pandemic, selected non-live vaccines (e.g., mRNA, non-
replicating viral vector, protein subunit, etc.) to prevent SARS-CoV-2 infection may be 
administered during the Treatment and Post-Treatment Follow-Up Periods, as long as 
components of the vaccine are not contraindicated. 
The decision to receive a locally available vaccine should be based on local guidance and 
an individual discussion between the treating physician and the subject. 
If a subject requires the use of a concomitant medication from a medication class not 
listed, the AbbVie TA MD should be notified for additional guidance. 


Elagolix
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5.2.3.3
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 
EllaOne®]) are prohibited during Washout, Screening, Treatment and until the Follow-Up 
Month 1 visit.  Subjects may start hormonal contraception after completion of Follow-Up 
Month 1, provided that the subject has a documented menstrual period (menses) after the 
Treatment Period and prior to that visit.  For subjects who are prescribed/administered the 
emergency contraceptive pill during the study, the information should be captured in the 
source documents and eCRF. 
To protect subject safety and to minimize confounding the study results, the following 
concomitant medications are prohibited during the study as specified below: 


Elagolix
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Table 2. 
Prohibited Medications
Prohibited During the Washout, Screening, Treatment, and Follow-Up Periods 
GnRH agonist
Leuprolide acetate (Lupron®) 
Prohibited During the Washout, Screening and Treatment Periods and thru Follow-Up Month 1 
Hormonal Medications and Non-hormonal 
Estrogen Supplements, such as:
GnRH agonist:  nafarelin acetate (Synarel®), goserelin 
acetate (Zoladex®) 
Danazol (Danocrine®, Cyclomen®) 
Medroxyprogesterone Acetate (Depo-Provera®, Provera®) 
Oral contraceptives
Other progestins (oral, vaginal, IUDs, implantable)
Levonorgestrel (except emergency contraception, 
i.e., levonorgestrel 1.5 mg)
Spironolactone
Mifepristone
Ulipristal acetate (except emergency contraception, 
i.e., ulipristal acetate 30 mg)
Testosterone preparations
Tamoxifen
Bromocriptine (Parlodel®) 
Cabergoline (Dostinex®) 
Raloxifene (Evista®, Optruma, or generics)
Bazedoxifene (Conbriza)
Aromatase Inhibitors (e.g., Anastrozole [Arimidex®], 
Exemestane [Aromasin®])
Natural Estrogen preparations or herbal 
remedies/supplements to treat premenstrual or 
gynecological problems (e.g., soy-containing supplements, 
black cohosh)


Elagolix
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Table 2. 
Prohibited Medications (Continued)
Prohibited During the Screening and Treatment Periods
Immediate Release (IR) Opioid 
Analgesics, such as:
Oxymorphone
Hydromorphone
Morphine
Buprenorphine
Except for short-term use as noted below.
Long-acting, Controlled Release (CR), 
Extended Release (ER) or Transdermal 
Opioid Analgesics, such as:
CR/ER Morphine
CR/ER Hydromorphone
CR/ER Oxymorphone
CR/ER Oxycodone
ER Tapentadol
ER Tramadol
Fentanyl
Methadone
Levorphanol 
Buprenorphine
Intravenous Analgesics, such as:
Fentanyl
Morphine
Buprenorphine
Synthetic Prostaglandin E1 Analogs, such 
as:
Misoprostol (Cytotec®, Arthrotec®) 
These medications may influence bleeding and should not 
be taken during the time noted above.  However, use for 
the endometrial biopsy procedure is permitted, if needed.
Prohibited 1 Month Prior to Day 1 and During the Treatment Period
Moderate or strong CYP3A8 Inducers, 
such as:
Moderate Inducers:
Bosentan
Efavirenz
Etravirine
Modafinil
Strong Inducers:
St. John's Wort
Rifampin
Carbamazepine
Phenytoin
Mitotane
Dexamethasone (chronic use)


Elagolix
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Table 2. 
Prohibited Medications (Continued)
Prohibited During the Screening, Treatment, and Follow-Up Periods
Osteoporosis Medications 
(Bisphosphonates, RANKL Inhibitors, 
Anabolic Bone Agents or rPTH), such as:
denosumab, teriparatide Fosamax®, Boniva®, Reclast®, 
XGEVA®, Forteo®
Glucocorticoids/Corticosteroids, systemic 
administration (oral, IM or IV)
Except for short-term use as noted below.
Cannabinoids (including marijuana use)
Other Teratogens, such as:
Topiramate, Accutane® and other oral retinoids
GnRH antagonists (including 
investigational ones), such as:
Orilissa®, relugolix
Any analgesic medications used to specifically treat endometriosis-associated pain, with 
the exception of the protocol-specified allowable rescue medications outlined in 
Section 5.2.3.4, are not permitted during the study (Screening and Treatment Periods).  
Prophylactic use (i.e., on a standing basis or for prevention of pain) of any analgesics for 
endometriosis-associated pain (including protocol specified rescue analgesics) is likewise
prohibited. 
Short-term use (no longer than 2 weeks per occurrence) of immediate-release 
opioids/opioid-containing products or systemic glucocorticoids/corticosteroids to manage 
acute conditions not related to endometriosis-associated pain, is allowed during the 
Treatment Period.  A maximum of 6 weeks (total of 42 days) over the 48 month 
Treatment Period is allowed during a subject's participation.  If the subject requires more 
than 2 weeks duration per occurrence or more than 6 weeks (total of 42 days) over the 
48 month Treatment Period, their continued participation in the study must be reviewed 
with the AbbVie TA MD.
If a prohibited medication is necessary to treat an adverse event or a pre-existing
condition other than endometriosis, it should be documented in the subject's source and 
eCRF.  If a subject's use of prohibited medication continues during the study, her 
continued participation will be evaluated by the Investigator and the AbbVie TA MD.  If 


Elagolix
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there are any questions regarding prior or concomitant therapy, please contact the AbbVie 
TA MD.
5.2.3.4
Rescue Therapy
The protocol-allowed analgesic rescue therapies for endometriosis-associated pain are 
presented in Table 3.  Investigators must prescribe a specific analgesic rescue medication 
from each medication class for subjects at the time of entry into the Screening Period.  
The choice of which protocol-allowed rescue NSAID and opioid prescribed per protocol 
should take into consideration the subject's preference and/or historical use of analgesics. 
Investigators are not to suggest or advise subjects on any modifications to their rescue 
medication regimen.  Subjects will be instructed to contact the site if a change in their 
analgesic medication is needed, such that appropriate adjustments can be considered.  
Investigators may then prescribe a different analgesic rescue medication (from each 
medication class if necessary) for the subject.  Investigators should not prescribe more 
than one analgesic rescue medication from the same medication class at one time.  The 
dosage form outlined in Table 3 must be utilized.
During the Screening and Treatment Periods, the use of protocol-specific rescue analgesic 
medications by the subject will be elicited by site staff at study visits and recorded in the 
source documents and eCRF.  Site staff will be expected to review use of protocol-
specific rescue analgesic medications taken by the subject for endometriosis-associated 
pain throughout the Screening and Treatment Periods.  If an abuse pattern is detected, the 
subject's continued participation in the study should be evaluated by the Investigator. 
Subjects will record use of the protocol-specific rescue analgesic medications taken for 
endometriosis-associated pain daily in the e-Diary during Screening and the 
first 12 months of the Treatment Period.  This will include specific information for the 
allowable rescue analgesics, including total number of pills/tablets taken for each category 
of rescue analgesic medication within a 24-hour period. 


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Prophylactic use of protocol-specific rescue analgesic medications or other analgesic 
medications for endometriosis-associated pain is not allowed.  Also, use of any other 
analgesic for treatment of endometriosis-associated pain is prohibited during the study 
(from the start of the Screening Period through the 48-month Treatment Period).  
However, if other analgesic medication for treatment of endometriosis-associated pain is 
used or if protocol specified rescue analgesics are used for other acute conditions/reasons 
(e.g., headache, fever, joint pain), such usage will be recorded in the source and eCRF, not 
in the e-Diary.
If a subject continues to take analgesic(s) other than the protocol-specified rescue 
analgesics for endometriosis-associated pain, her continued participation in the study will 
be evaluated by the Investigator and the AbbVie TA MD.  If there are any questions 
regarding rescue therapy, please contact your Monitor. 
Table 3. 
Permitted Rescue Therapy for Endometriosis-Associated Pain 
Medication Class
Medication Name
Dosing Strength*
Country
NSAIDS
Naproxen**
200 mg
All
NSAIDS
Ibuprofen
200 mg
All
NSAIDS
Diclofenac
25 mg
All
NSAIDS
Celecoxib
50 mg
All
Opioid Analgesics
Hydrocodone + 
acetaminophen
5 mg Hydrocodone + 300 or 
325 mg acetaminophen
US and PR
Opioid Analgesics
Codeine phosphate + 
acetaminophen***
30 mg codeine + 300 mg 
acetaminophen***
All
* 
Total daily dose of these rescue analgesic medications should be according to appropriate clinical practice 
standards and Investigator's clinical judgment.
**
Naproxen 200 mg is equivalent to naproxen sodium 220 mg.
*** Combination with or without caffeine is permitted.


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5.2.4
Contraception Recommendations and Pregnancy Testing
Contraception Counseling/Dispensing Contraceptives
Investigators and study staff will be trained by the Sponsor on the importance of 
contraception in this clinical trial.  Subjects (excluding those subjects who have had a 
bilateral tubal ligation or bilateral tubal occlusion) will be counseled by the Investigator or 
designated study staff at every visit throughout study participation on the importance of 
pregnancy prevention and the use of appropriate and effective methods of contraception. 
Subjects must agree to use two forms of non-hormonal contraception (dual contraception) 
consistently throughout the Washout (if applicable), Screening and Treatment Periods, 
and the first month of the Follow-Up Period.  Subjects may begin the use of hormonal 
contraception (e.g., oral or IUD) after completion of the Follow-Up Month 1 visit 
provided that the subject has a documented menstrual period after the Treatment Period 
and prior to that visit. 
Acceptable methods of dual non-hormonal contraception include the following 
combinations: 
●
Condom with spermicide (e.g., cream, spray, foam, gel, suppository or polymer 
film)
●
Diaphragm with spermicide (condom may or may not be used) 
●
Cervical cap with spermicide (condom may or may not be used) 
●
Vaginal sponge impregnated with spermicide; used with a condom 
Subjects are not required to use dual contraception methods if: 
●
Sexual partner(s) is vasectomized at least 6 months prior to Screening.
●
Subject had a bilateral tubal ligation or bilateral tubal occlusion at least 
4 months prior to the start of Screening. 


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●
Subject is not sexually active with men; however, periodic sexual 
relationship(s) with men requires the use of dual non-hormonal contraception 
as indicated above.
●
Subject practices total abstinence from sexual intercourse as the preferred 
lifestyle of the subject; periodic abstinence is not acceptable and requires use of 
dual contraception. 
●
Subject has begun the use of hormonal contraception after the Follow-Up 
Month 1 visit.
Subjects may begin the use of hormonal contraception after the Follow-Up Month 1 visit, 
provided she has a negative urine pregnancy test 1 month off study drug and has returned 
to menses.  If the Subject has not returned to menses by Follow-Up Month 1, the 
investigator would use acceptable medical practice to reinitiate hormonal contraceptive 
(e.g., pregnancy test, serum FSH, induction of withdrawal bleed). 
The following measures will be taken to help promote pregnancy prevention during the 
study. 
1.
The informed consent form will include an attestation requiring the subject to 
confirm in writing (via signature) her full awareness that the potential risks of study 
drug 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 
protocol required non-hormonal contraception throughout her study participation. 
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 cycle patterns, and that fetal abnormalities have been 
reported in pregnant women who have received elagolix in clinical studies; 
however, it is unknown whether these abnormalities were the result of taking 
elagolix. 


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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 all investigative sites with a supply of materials to 
promote pregnancy prevention, including contraceptives (e.g., condoms and 
spermicides) to provide to subjects at no charge.   
●
Subjects will be allowed to choose an acceptable contraception method of their 
choice from the contraceptive options provided by the Sponsor and will be 
expected to consistently practice the allowable methods of contraception.  The 
site will assess the subject's basic understanding of proper contraceptive use 
through discussion and demonstration of proper techniques, if needed, 
including proper diaphragm use. 
●
The site will provide contraceptives and other supplies (e.g., lubricants) to 
subjects throughout the Washout (if applicable), Screening, and Treatment
Periods, as needed.  If necessary, the subject may obtain protocol-allowed 
contraceptives apart from the study site.  In this situation, the study site still 
must document the form/type of contraceptives obtained, and subjects' 
attestation of consistent use of these non-hormonal contraceptives throughout 
study participation. 
●
The source documents will capture the date initial contraception counseling 
was performed, whether the subject meets protocol criteria for not requiring use 
of dual contraception, and the type of contraceptive provided to the subject (as 
applicable).  At subsequent study visits, the source documents will capture if 
there was a change in contraceptive method and whether additional 
contraceptives were provided to the subject. 
●
The subject will be asked to attest by signature at the time of consent, and 
subsequently in a stand-alone attestation form at all on-site study visits that 
allowable methods of contraception, as described during the pregnancy 
prevention counseling, are being practiced.
●
For subjects who have had a bilateral tubal ligation or bilateral tubal occlusion 
(including Essure®), attestation is only required to be collected once during the 
study prior to randomization, ideally at the time of consent.  Additionally, these 


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subjects do not require contraception counseling at any study visit or the 
associated documentation of that counseling. 
4.
The e-Diary will be designed to include a daily reminder to use non-hormonal 
contraception. 
5.
Monthly study contacts are used to promote frequent interaction with site staff and 
opportunities for continued education. 
6.
At each Treatment Period visit (on-site and phone contacts), the proper use of 
contraception will be reinforced to address possible ineffective use and the risk of 
unexpected pregnancy due to unprotected sexual activity. 
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to come on-site, contraception 
counseling should be conducted during phone visits (as applicable).  The site should ship 
a reasonable quantity of contraceptive supplies to the subject for use until the next on-site 
visit.  The type and quantity of contraceptives shipped to the subject must be documented 
in source along with the shipping and tracking number.  When the subject can return to 
the site, the site should make sure that adequate contraceptives are dispensed to the 
subject.
Pregnancy Testing
Urine and serum pregnancy tests will be performed as specified in Appendix C in all 
subjects regardless of sexual activity status or method of contraception, including subjects 
who are surgically sterilized.
The urine pregnancy test result on Day 1 must be reviewed and confirmed to be negative 
prior to randomization.  Prior to performing an endometrial biopsy, the subject must have 
a confirmed negative urine pregnancy test.  In addition, during the Treatment Period, the 
urine pregnancy test must be negative prior to providing subjects with their next supply of 
study drug. 


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Home urine pregnancy test kits will be provided to subjects during the Treatment and 
Follow-Up Periods for use at home when subjects are not required to come into the 
clinic/site (e.g., phone contact visits and prior to certain study procedures).  Subjects will 
self-administer the tests and report the results to the site during phone contacts.  Subject 
reported test results will be entered into the source and eCRF. 
A positive urine pregnancy test result (including a home urine pregnancy test) 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 
dosing (Section 6.1.6).  If a subject is confirmed as pregnant, the subject will be 
prematurely discontinued from the study. 
If the subject becomes pregnant at any time after randomization up through 30 days post 
last dose of study drug, an ultrasound examination will be performed during the 
first trimester of pregnancy to assess the gestational age and estimated date of delivery.  
Refer to Section 6.1.6 for instructions on reporting a pregnancy to the Sponsor and the 
required follow-up on the subject's fetus, pregnancy outcome and infant. 
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If a subject or study personnel cannot come to the site for a study visit requiring a urine 
pregnancy test because of the COVID-19 pandemic, the site may dispense home urine 
pregnancy test kits to the subject to self-administer at home and report results to the study 
site over the phone.  The site should document the result of the pregnancy test in the 
source.  If a urine pregnancy test cannot be completed, the site must consult the AbbVie 
TA MD for additional guidance and to determine if study drug should be discontinued. 


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5.3
Efficacy:  Pharmacokinetic, Pharmacodynamic, 
Pharmacogenetic and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Appendix C. 
5.3.1.1
Study Procedures
The study procedures outlined in Appendix C are discussed in detail in this section, with 
the exception of study drug dispensing/compliance/accountability (Section 5.5.7), 
contraception counseling/contraceptive dispensing (Section 5.2.4), the collection of 
concomitant medication (Section 5.2.3) and adverse event information (Section 6.0).  All 
study data will be recorded on the eCRF with the exception of the e-Diary, select PRO 
data and data from central lab/imaging vendor. 
The Screening Period will occur within approximately 1.5 to 4 months prior to 
administration of the first dose of study drug on Day 1 (randomization).  For procedures 
repeated during the Screening Period (as allowed per protocol or at the discretion of the 
AbbVie TA MD), the procedure performed closest to dosing will serve as a baseline for 
clinical assessment.
Study procedures during the Treatment and Follow-Up Periods may be performed within 
the visit windows specified in the applicable sections of the protocol.  Scheduled monthly 
visits during the Treatment and Follow-Up Periods are based on a 28-day month.  All 
scheduled study visits during the Treatment and Follow-Up Periods should occur within 
± 5 days of the projected date.  However, the TVU, DXA scan, PAP test and endometrial 
biopsy may be performed within approximately ± 15 days around the scheduled 
Treatment Month visit.
This protocol provides recommendations regarding the sequence of procedures to be 
performed during the study.  In no case should these recommendations outweigh clinical 


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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. 
Informed Consent
The IRB/IEC approved informed consent will be signed by the subject before 
discontinuing any hormonal contraception/therapies or other prohibited medications or 
performing any study-specific procedures.  Pharmacogenetic (PG) testing is optional and 
a subject must be provided a separate informed consent form for this blood and 
endometrial biopsy sample collection.  Details about how informed consent will be 
obtained and documented are provided in Section 9.3. 
Subjects who have signed informed consent and did not randomize on Day 1 because they 
either did not complete the Washout Period (if applicable), did not complete the 
study-specific procedures during the Screening Period or did not meet all entry criteria 
will be considered Screen Failures.  The reason(s) for screen failure will be recorded in 
the source documents and will be captured in the eCRF.  Subjects who re-screen will be 
required to sign a new informed consent form. 
Medical/Social History
A complete medical history, including documentation of any clinically significant medical 
conditions and medications, and history of tobacco and alcohol use, and licit/illicit drug 
abuse will be collected during the Washout Period (if applicable) or during the Screening 
Period for those subjects who do not require washout.  The medical history will be 
reviewed and should be updated if significant clinical findings are noted on Day 1 prior to 
dosing and will serve as the baseline for clinical assessment.


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Gynecological and Endometriosis History 
A gynecological and endometriosis history will be collected either during the Washout 
Period (if applicable) or during the Screening Period for those who do not require 
washout. 
The gynecological and endometriosis history will be reviewed and should be updated if 
needed prior to dosing on Day 1 and will serve as the baseline for clinical assessment. 
Physical Examination 
A complete physical examination will include height (at Screening only) and weight 
measurements (the subject should wear lightweight clothing and not wear shoes) and will 
serve as the baseline for clinical assessment.
A brief, symptom-directed physical examination will be performed at Washout (if 
applicable).
Visits requiring either the complete physical examination (including weight) or a brief, 
symptom-directed physical examination are outlined in the Study Activities Table in 
Appendix C. 
Clinically significant physical examination findings prior to randomization will be 
recorded as medical history.  Any clinically significant physical examination findings 
after initiation of dosing will be recorded in the source documents and in the eCRFs as 
adverse events.  The complete physical examination performed during Screening will 
serve as the baseline for clinical assessment.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to go on site for the physical 
exam, it can be delayed up to one month from its scheduled time.  Should the delay be 
longer, AbbVie should be notified for further guidance. 


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Gynecological (External Genitalia, Pelvic and Breast) Examination 
A complete breast and pelvic examination, including external genitalia, will be performed 
during the Screening and Treatment periods as listed in Appendix C.  Timing of brief 
symptom-directed gynecologic examinations are outlined in Appendix C, but may also be 
performed at any time throughout the study as deemed clinically necessary.  The complete 
breast and pelvic examination completed during Screening will serve as the baseline for 
clinical assessment.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to go on site for the 
gynecological exam, it can be delayed up to one month from its scheduled time.  Should 
the delay be longer, AbbVie should be notified for further guidance. 
12-Lead Electrocardiogram (ECG)
A resting 12-lead ECG will be conducted during the Screening Period.  The ECG should 
be obtained prior to any blood collection. 
For any abnormal screening test results, the ECG may be repeated one time prior to/on 
Day 1, however the subject may not be enrolled if any clinically significant findings are 
noted on the repeat ECG.  Final results (i.e., results used to determine eligibility) will be 
entered into the eCRF.
The Investigator or qualified designee at the study site will determine if any findings are 
clinically significant (in consultation with a cardiologist, if necessary), and document this 
on the ECG tracing/report, sign and date it.  The original ECG tracing or a certified copy 
of the original tracing with the physician's assessment will be retained in the subject's 
source records at the study site. 


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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.  
The blood pressure, heart rate, and respiratory rate measurements should be taken prior to 
scheduled blood collections (if applicable).  Measurements should be assessed 
consistently throughout the study and will be recorded in the source documents and eCRF.
The vital signs measurements obtained prior to dosing on Day 1 will serve as the baseline 
measurements for clinical assessment.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to go on site to complete vital 
signs, it can be delayed up to one month from its scheduled time.  Should the delay be 
longer, AbbVie should be notified for further guidance. 
Mammogram 
Mammograms at Screening will only be required for subjects who are 40 years of age or 
older and have not had one performed within 3 months prior to the time of entry into 
Screening.  If a subject's mammogram results are incomplete (BI-RADS 0) and need to be 
repeated, the AbbVie TA MD does not need to be contacted for approval prior to 
conducting the repeat mammogram or other mode of imaging (e.g., ultrasound, spot 
compression).  If these results meet entry requirements, subject would be allowed to 
continue in Screening. 
If the repeat mammogram or other breast imaging results indicate further testing is 
required (e.g., breast biopsy) to rule out any potential exclusionary findings, the subject is 
not eligible for the study.  Any further imaging or testing will be performed outside of the 
protocol and should follow standard of care. 


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Mammograms will be read locally and the local radiologist's interpretation will be used to 
determine if a subject meets eligibility criteria.  Subjects with normal or benign findings 
or BI-RADS Classifications 1, 2 or 3 (via mammogram or other mode of imaging) as 
outlined in Appendix D will be eligible for randomization on Day 1.  Subjects with an 
abnormal mammogram or BI-RADS Classifications 4, 5, or 6 will not be eligible for the 
study.  Subjects not eligible for the study should continue with recommended 
mammography testing outside of the protocol per local guidelines and standard of care 
during the study. 
During the Treatment Period, mammograms will also be performed for subjects who are 
40 years of age or older at the time of the scheduled study visit at Month 12, Month 24, 
Month 36, and Month 48 or the Premature Discontinuation (PD) visit (for subjects who 
prematurely discontinue at the time of or after their Treatment Month 6 visit, unless the 
subject had a study mammogram within approximately 6 months prior to the PD visit).  
Mammograms may be performed within approximately ± 15 days of the scheduled 
corresponding visit.  All mammograms will be read locally.  If a subject has a clinically 
significant mammogram finding in the opinion of the investigator, or BI-RADS 
Classifications 4, 5, or 6, or there is a recommendation for additional testing, the AbbVie 
TA MD should be notified for additional guidance and approval. 
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to complete the mammogram at 
its scheduled time, the mammogram can be delayed up to one month.  Should the delay be 
longer, AbbVie should be notified for further guidance. 
TVU
The TVU will be performed by the site, affiliated Radiology Department or ultrasound 
facility per the acquisition guidelines provide by the Central Imaging Core Lab (central 
reader).  The ultrasonographer or designee for each investigative site should submit 
electronically the subject's TVU imaging data to the central reader within 3 business days 


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following collection in order to determine eligibility for participation in this study and for 
subject evaluation during the course of the study. 
TVUs will be assessed both locally and by a central reader.  The TVU performed during 
the Screening Period will assess subject eligibility and establish baseline findings.  The 
Central Imaging vendor will issue a qualification form documenting the presence or 
absence of protocol-defined exclusionary pathology during Screening.  Subject eligibility 
will be based on the central reader's or AbbVie TA MD's assessment, which will override 
the local radiologist's assessment.  If a repeat TVU is performed per protocol, data 
reported from both procedures may be taken into the consideration by the AbbVie TA 
MD when assessing eligibility.  The TVU data from the central imaging vendor will be 
used for analysis and for subject management. 
The Investigator should consult the local ultrasound report (or images if the report is not 
available) in order to make any safety related judgments concerning the subject.  In this 
case, the local ultrasound reports will be maintained in the subject's source documents and 
copies may be collected upon request by the Sponsor.  Data from the local ultrasound 
report will not be reported in the eCRF unless associated with an adverse event. 
The Screening TVU should ideally be performed during the subject's early proliferative 
phase of the menstrual cycle (approximately Days 4 – 8 of the cycle).  The Screening 
TVU may be repeated per protocol (e.g., ovarian cyst criteria) or as clinically appropriate.
During the Treatment Period, a TVU will also be performed at Month 12, Month 24, 
Month 36, and Month 48 or the Premature Discontinuation (PD) visit (for subjects who 
prematurely discontinue at the time of or after their Treatment Month 6 visit, unless the 
subject had a study TVU within approximately 6 months prior to the PD visit).  Sites will 
receive reports from the central reader detailing the results of the TVU performed for 
these visits.
The TVU for the Month 12, Month 24, Month 36, and Month 48 visit may be performed 
within approximately ± 15 days of the scheduled corresponding visit to allow for the 


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evaluation of results.  Per Investigator review of the report from the central reader, 
subjects with clinically significant ovarian, endometrial or other abnormal findings in the 
opinion of the Investigator will require a repeat TVU, saline infusion sonography (SIS) or 
office hysteroscopy.  The repeat TVU will be submitted to the central reader; the SIS or 
office hysteroscopy will be read locally, with results recorded in the source and eCRF.  If 
in the Investigator's clinical judgment, the clinically significant findings persist on the 
repeat procedure and would preclude the subject from continuing in the Treatment Period 
due to safety reasons, the subject will be discontinued from the Treatment Period 
(Section 5.4).  If a repeat TVU is performed per protocol, data reported from both 
procedures may be taken into the consideration by the Investigator/AbbVie TA MD when 
assessing.
Assessments to be completed by the central imaging vendor include, but are not limited 
to: 
●
endometrial thickness (double layer, mm) 
●
other clinically relevant endometrial findings
●
presence/size/location of uterine fibroids 
●
presence/size/appearance (simple versus complex) of ovarian cysts 
●
presence/size/appearance of endometriomas.
An unscheduled (elective) TVU (with a local read) may also be performed as clinically 
indicated for subject evaluation during the course of the study.  Information regarding this 
procedure should be recorded in the source documents and eCRF. 
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to complete the TVU at its 
scheduled time, it can be delayed up to 1 month.  Should the delay be longer, AbbVie 
should be notified for further guidance. 


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Bone Mineral Density (DXA Scan)
DXA scans of the lumbar spine, femoral neck and total hip will be performed throughout 
the study as indicated in Appendix C, by qualified technologists/radiologists at the site or 
affiliated imaging facility utilizing GE Lunar or Hologic equipment and per the 
acquisition guidelines provided by the Central Imaging Core Lab (central reader).  The 
DXA technologist/radiologist or designee for each investigative site should electronically 
submit the subject's DXA images to the central reader for review and analysis within 
3 business days following acquisition.  Subject eligibility and treatment management will 
be made based on the central reader review.  Sites will receive reports from the central 
reader detailing the results (including Z-scores for subjects < 40 years of age or T-scores 
for subjects ≥ 40 years of age, BMD measurements and % change from baseline, as 
applicable measurements) of the DXA scans performed.  Instructions on calibration and 
standardization of instruments and any additional required information will be specified in 
a manual from the central reader that will be provided to all study sites.  Site training and 
qualifications, including assessment of instruments, will be evaluated/approved by the 
central reader, ideally prior to screening the first subject.
DXA Scan Performed in the Screening Period
The DXA scan performed during the Screening Period will be used to determine 
eligibility and will serve as the baseline scan for subject management.  Subjects with a 
Z-score or T-score of < –2.0 at the lumbar spine, total hip or femoral neck on the 
screening DXA scan will not be eligible for randomization into the study. 
DXA Scans Performed in the Treatment Period
DXA scans are required to be performed for all subjects during the Treatment Period at 
Months 6, 12, 18, 24, 30, 36, 42, and 48 and will be submitted to the central reader for 
review and analysis.  The central reader will be blinded to the subjects' treatment 
assignment, but not to the corresponding time point. 


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The window for performing DXA scans at Treatment Months 6, 12, 18, 24, 30, 36, 42, 
and 48 is ± 15 days around the respective study visit. 
If the results of any post-baseline DXA prior to Month 48, as read by the central reader 
selected for the study, document either of the following results, the subject must be 
discontinued from study drug dosing and will enter the Follow-Up Period: 
●
a Z-score (for subjects < 40 years of age at the time of the Screening DXA) or 
T-score (for subjects ≥ 40 years of age at the time of the Screening DXA) of
< –2.5 in the lumbar spine, total hip or femoral neck OR
●
a BMD decrease from baseline of > 8% in the lumbar spine, total hip or 
femoral neck
If the BMD percent change from baseline of any post-baseline DXA prior to Month 48 
cannot be provided by the central reader (i.e., due to scanner changes), then the TA MD 
must be consulted to confirm if the subject can continue study drug dosing.  A BMD 
decrease at any anatomic region (lumbar spine, total hip or femoral neck) that results in 
discontinuation from the study should be reported as an adverse event (Section 6.1.1).
DXA Scans Performed for Subjects who Prematurely Discontinue in the Treatment Period 
DXA scans are required to be performed as part of the Premature Discontinuation visit as 
follows: 
●
Subjects who discontinue prior to the Treatment Month 6 visit only if the 
reason for premature discontinuation is due to the occurrence of a fracture or 
any newly diagnosed bone condition 
●
Subjects who discontinue any time at the time of or after the Treatment 
Month 6 visit, or if one was not performed within approximately 6 months of 
the PD visit.
However, if a subject is being discontinued from the study due to a Z-score or T-score of 
< –2.5 in any region, BMD decrease from baseline of > 8% in any region, or TA MD 


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assessment, additional DXA scans do not need to be performed as a part of the Premature 
Discontinuation visit procedures.  In these circumstances, the subject would enter the 
Follow-Up Period and continue with required BMD evaluations. 
DXA Scans Performed in the Follow-Up Period 
DXA scans of the lumbar spine, total hip, and femoral neck will be obtained at Follow-Up 
Months 6 and 12. 
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to complete the DXA at its 
scheduled time, it can be delayed up to one month.  Should the delay be longer, AbbVie 
should be notified for further guidance. 
Endometrial Biopsy
Endometrial biopsies will be performed during the Screening and Treatment Periods, as 
indicated in Appendix C.  Instructions on endometrial biopsy collection, processing and 
shipping procedures will be provided by the central laboratory selected for this study.  All 
central laboratory pathologists will be blinded to the subjects' treatment group 
assignments.  Endometrial biopsies will be independently read by two qualified central 
laboratory pathologists.  If the results are discrepant, the biopsy will be read by a third 
central laboratory pathologist to facilitate resolution and the worst case reading (of all 
three reads) will be taken as the final diagnosis.  A final pathology report containing the 
final diagnosis from the central laboratory will be issued to the Investigator in all cases. 
Prior to performing the endometrial biopsy, a negative urine pregnancy result must be 
obtained on the day of the procedure.  Pre-medication for the endometrial biopsy 
procedure is allowable, e.g., at the investigator's discretion, misoprostol for cervical 
dilation is allowable.  In addition, lidocaine may be used as local anesthesia on the cervix.  
Any medications used for the procedure should be recorded in source documents and on 
the appropriate eCRF.  The Investigator should write a brief procedure note in the source 


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documentation noting the depth of placement of the Pipelle during the procedure.  If an 
endometrial biopsy cannot be performed because of anatomical reasons, the AbbVie TA 
MD should be consulted for further guidance. 
If the endometrial biopsy is performed on the same day as the Pap test or transvaginal 
ultrasound, the endometrial biopsy should be performed after the Pap test and transvaginal 
ultrasound. 
Biopsy results from the central laboratory must be obtained and reviewed by the 
Investigator to ensure eligibility criteria are met before the subject can be randomized on 
Day 1.  In case of an insufficient sample the biopsy should be repeated.  Subjects must 
have an adequate endometrial biopsy with results documenting no significant endometrial 
pathology in order to be eligible for randomization on Day 1.  However, if the repeat 
sample is deemed insufficient by the central laboratory, the AbbVie TA MD should be 
consulted regarding eligibility. 
If an endometrial biopsy has been performed within a year prior to entry into Screening 
and is not abnormal (hyperplasia or worse) then endometrial biopsy does not need to be 
repeated prior to randomization.  Biopsy results must be obtained and reviewed by the 
Investigator to ensure eligibility criteria are met before the subject can be randomized on 
Day 1.  Results from the historical biopsy (i.e., results used to determine eligibility) will 
be entered into the eCRF.
On the Screening endometrial biopsy, if a clinically significant abnormal finding such as 
endometrial hyperplasia (with or without atypia) or endometrial cancer is reported, 
subjects will not be eligible for randomization into the study.  If the Investigator 
determines that an abnormal finding (e.g., endometritis) can be treated outside of the 
protocol, a repeat biopsy can be performed after treatment at the Investigator's discretion.  
The results of the repeat biopsy will determine if the subject may remain in Screening.  
The repeat biopsy must meet eligibility criteria prior to randomization.


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The endometrial biopsies required during the Treatment period may be performed within 
approximately ± 15 days around the scheduled study visit.  At Treatment Month 12, 24, or 
36, subjects with significant endometrial pathology (e.g., acute or chronic endometritis, 
endometrial hyperplasia, endometrial cancer) will not be allowed to continue in the 
Treatment Period and will be prematurely discontinued.  Additional endometrial biopsy 
should be performed if clinically indicated for breakthrough bleeding, taking into account 
the subject's previous biopsy results, TVU findings, subject compliance with study drugs 
and recognizing subjects are receiving a daily dose of progestin.  Treatment of subjects 
with endometrial pathology should be managed according to the Investigator's clinical 
judgment and local standard of care and should be documented appropriately in source 
documents and eCRFs.  Clinically significant changes from baseline should be 
documented as an adverse event. 
An endometrial biopsy is not required during the Treatment Period if the TVU findings at 
Treatment Month 12 or 24, indicate an endometrial thickness < 4 mm.  If the ultrasound 
findings during the Treatment Period Months 12 or 24 indicate an endometrial thickness 
≥ 4 mm, then the subject must have an endometrial biopsy performed at these time points.   
For this amendment (Amendment 7) as all subjects are past Month 36 and based upon 
FDA feedback, endometrial biopsy at Month 36 and 48 is required regardless of the TVU 
findings at the corresponding visit.   
If a subject is prematurely discontinued during Treatment prior to Month 36, an 
endometrial biopsy is not required if the TVU findings at the PD visit indicate an 
endometrial thickness < 4 mm.  If the TVU findings indicate an endometrial thickness ≥ 4 
mm then the subject must have an endometrial biopsy performed.   
If a subject is prematurely discontinued after Month 36, the endometrial biopsy (if needed 
at the PD visit) will be performed regardless of the TVU findings at the corresponding 
visit.  An endometrial biopsy is also not required at Premature Discontinuation if one was 
performed within approximately six months of the subject discontinuing from the study.   


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If the TVU findings at any visit time point during the Treatment Period indicate an 
endometrial thickness ≥ 4 mm (Month 12 or 24), then the subject must have a repeat 
endometrial biopsy performed and the AbbVie TA MD must be notified to assess the 
subject's continued eligibility.  Data from both procedures may be taken into 
consideration by the AbbVie TA MD when assessing the subject's continued eligibility. 
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to complete the endometrial 
biopsy at its scheduled time, it can be delayed up to one month.  Should the delay be 
longer, AbbVie should be notified for further guidance. 
Pap Test
Pap test will be performed on subjects 21 years of age or older at the visits listed in 
Appendix C.  Pap Tests will be performed using the Thin Prep® Pap Test™ provided and 
analyzed by the central laboratory.  If the subject is experiencing uterine bleeding that 
precludes the performance of the Pap test, this procedure should be performed as soon as 
possible after the uterine bleeding has ended.  In the case of an unsatisfactory sample, the 
Pap test can be repeated.  However, in order to be enrolled in the study, the Screening Pap 
test must contain adequate endocervical cells and show no evidence of malignancy or pre-
malignant changes prior to randomization on Day 1.
Subjects with following finding will be eligible for randomization into the study: 
●
ASC-US (atypical squamous cells of undetermined significance) who are 
negative for high risk human papillomavirus (HPV) 
Subjects ≥ 25 years of age (at the time the Pap Test is performed) with the following 
diagnoses will need to undergo additional evaluation with colposcopy and cervical biopsy: 
●
ASC-US with high risk HPV 


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●
low-grade squamous intraepithelial lesion (LSIL) (unless a colposcopy with 
cervical biopsy has been performed within the prior year and results are 
available for review).
Those subjects with a histology finding of CIN 1 or less (from the colposcopy and 
cervical biopsy) are eligible for the study. 
Subjects ≤ 24 years of age (at the time the Pap test is performed) with the above diagnoses 
do not require additional evaluation with colposcopy and cervical biopsy and are eligible 
for the study. 
Subjects with the following cytology screening/colposcopy results are not eligible for 
randomization into the study: 
●
atypical squamous cells cannot exclude HSIL (ASC-H),
●
high-grade intraepithelial lesion (HSIL),
●
atypical glandular cells (AGC) or epithelial cell abnormality,
●
cervical intraepithelial neoplasia grade 2 (CIN 2) (on cervical biopsy), 
●
cervical intraepithelial neoplasia grade 3 (CIN 3) (on cervical biopsy). 
For any atypical finding that can be treated, please contact the AbbVie TA MD to 
determine if the subject may remain in screening and can be eligible for randomization. 
During the Treatment Period, if the Pap Test performed at Month 24 and/or Month 48 
indicates a clinically significant finding in the opinion of the investigator and requires 
additional testing (e.g., colposcopy or biopsy) as follow-up, the AbbVie TA MD should 
be notified for additional guidance and approval.  A Pap Test is not required at PD if one 
was performed within approximately six months prior to the PD visit. 


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COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to complete the Pap Test at its 
scheduled time, it can be delayed up to one month.  Should the delay be longer, AbbVie 
should be notified for further guidance. 
Clinical Laboratory Tests 
Samples will be obtained for the laboratory tests listed in Table 4, at the time points 
indicated in Appendix C. 
Table 4. 
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
Blood Urea Nitrogen (BUN)
Serum creatinine
Glucose
Calcium
Total protein
Albumin
Total bilirubin 
Serum glutamic-pyruvic 
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic 
transaminase (SGOT/AST)
Alkaline phosphatase
Vitamin D
Specific gravity
Ketones 
Protein
Blood
Glucose
pH
Lipid Panel (After 
Minimum 8-Hour Fast)
Low-density Lipoprotein 
(LDL) cholesterol
High-density Lipoprotein 
(HDL) cholesterol
Total cholesterol
Triglycerides
Endocrine Panel
Follicle-stimulating hormone 
(FSH)
Reflexive Thyroid 
Stimulating Hormone 
(TSH)
Pregnancy Test
Serum pregnancy
Laboratory samples indicated in Table 4 will be assessed using a certified central 
laboratory selected for the study and these data will be used for data analysis.  The central 


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laboratory will provide instructions regarding the collection (including any fasting 
requirements), processing and shipping of samples.  Blood draws should be performed 
after efficacy assessments, vital signs and ECG recordings are conducted at a visit.  
Clinical chemistry panel samples should be obtained in the morning following an 
overnight fast (minimum of 8 hours); however, there may be circumstances when a 
sample is obtained later in the day and/or not under fasting conditions.  If a sample was 
obtained after 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.  
All clinical laboratory samples will be shipped to the central laboratory.
The laboratory results 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 review and indicate on the report if the result 
is clinically significant or not clinically significant.  The Investigator will evaluate 
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 
post-randomization 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 (Section 6.0).
All screening laboratory results must be reviewed prior to randomization, including any 
repeated test results.  Screening laboratory tests may be repeated one time prior to Day 1, 
however, results must satisfy entry criteria prior to randomization.  Subjects will not be 
randomized on Day 1 if Screening laboratory results do not meet entry criteria or are 
assessed as clinically significant by the Investigator.  The laboratory test results obtained 
from the Day 1 pre-dose samples will serve as the baseline for clinical assessment.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic prevent the subject from having blood drawn for laboratory testing at the study 
site, the subject can be rescheduled to return within 28 days to have blood drawn.  If the 


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subject cannot return to the site within 28 days (1 month), the AbbVie TA MD should be 
contacted for additional guidance. 
Study drug administration may be continued provided the investigator has reviewed all 
prior laboratory results and confirms and discusses with the subject that there are no 
safety concerns for the subject to continue use of the study drug in the absence of current 
labs.  If the Investigator has questions about the subject's historical lab results and/or the 
subject's continued eligibility, the AbbVie TA MD should be consulted. 
Lipid Panel 
Serum lipids consist of LDL cholesterol, HDL cholesterol, triglycerides and total 
cholesterol; non-HDL cholesterol and lipid ratios will also be calculated, but will not be 
reported to the investigative site. 
The 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 is obtained 
later in the day and/or not under fasting conditions.  If a sample was obtained after 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. 
Endocrine Panel 
The endocrine panel consists of the following analytes:  serum FSH and reflexive TSH.  
Reflexive TSH will be obtained at Screening only. 
Optional Testing for Gonorrhea and Chlamydia 
Gonorrhea and chlamydia testing can be ordered at the Investigator's discretion during the 
Screening and Treatment Periods, to test for active gonorrhea or chlamydia prior to 
performing the endometrial biopsy.  These samples will be sent to the central laboratory 
for analysis.  If the Investigator determines that an abnormal test result can be treated, 
treatment will be outside of the protocol.  Follow-up chlamydia/gonorrhea testing (per 


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instructions from the central lab) can be performed after treatment at the Investigator's 
discretion. 
Serology Screening for Hepatitis and HIV 
Samples will be tested for HAV-IgM, HBsAg, HCV Ab, HIV Ag/anti-HIV Ab by the 
central laboratory for all subjects during the Screening Period.  If any of these tests are 
positive or reactive, the subject is excluded from study participation.  Borderline hepatitis 
test results should be repeated.
The results of the HIV Ag/anti-HIV Ab testing will be retained confidentially by the study 
site.
Electronic Daily Diary (e-Diary) 
An electronic patient-recorded outcomes device (e-Diary) will be provided to all subjects 
during Screening, and subjects will record daily entries through Treatment Month 12.  The 
e-Diary contains training information for the subject and/or site staff will provide training 
on the required entries in the e-Diary.  Subjects will also be instructed to complete the 
diary at approximately the same time(s) every day throughout the Screening Period 
through Month 12 of the Treatment Period, including prior to study visits as applicable.  
The e-Diary will also remind subjects about consistent use of acceptable forms of non-
hormonal contraception. 
Site staff should review subject e-Diary data periodically beginning at Screening through 
Treatment Month 12, as well as at every study visit, to ensure subject comprehension and 
completion.  Subjects who are screen failures will be instructed to return the e-Diary 
device to the site.  All subjects will be instructed to return the e-Diary device to the site at 
the Treatment Month 12 study visit or at the Premature Discontinuation visit (if prior to 
Treatment Month 12). 
Subjects will use the e-Diary to record assessments of DYS, NMPP, dyspareunia and 
uterine bleeding, as well as the use of protocol-allowed rescue analgesic medications for 


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endometriosis-associated pain.  Scores from these daily assessments collected during 
Screening will be used to evaluate subject eligibility for the study prior to randomization 
on Day 1.  These assessments will continue to be completed daily through Month 12 of 
the Treatment Period or until a subject prematurely discontinues from the Treatment 
Period (if they discontinue prior to Treatment Month 12). 
Based on the subject's response to the question "Did you have your period in the last 
24 hours?" in the daily e-Diary, the subject will be asked to assess either their 
dysmenorrhea or non-menstrual pelvic pain as follows: 
Dysmenorrhea (DYS) 
Subjects will be asked to assess their DYS and its impact on their daily activities.  
Subjects will be prompted to "Choose the item that best describes your pain during the 
last 24 hours when you had your period." 
None
No discomfort.
Mild
Mild discomfort but I was easily able to do the things I usually do.
Moderate
Moderate discomfort or pain.  I had some difficulty doing the things I usually do.
Severe
Severe pain.  I had great difficulty doing the things I usually do.
Non-Menstrual Pelvic Pain (NMPP)
Subjects will be asked to assess their NMPP and its impact on their daily activities.  
Subjects will be prompted to "Choose the item that best describes your pain during the 
last 24 hours without your period." 
None
No discomfort.
Mild
Mild discomfort but I was easily able to do the things I usually do.
Moderate
Moderate discomfort or pain.  I had some difficulty doing the things I usually do.
Severe
Severe pain.  I had great difficulty doing the things I usually do.


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Dyspareunia 
Subjects will be asked to assess their dyspareunia (described as 'pain during sexual 
intercourse').  Subjects will be prompted to "Choose the item that best describes your pain 
during sexual intercourse during the last 24 hours." 
Not applicable
I was not sexually active for reasons other than my endometriosis or did not have 
sexual intercourse.
None
No discomfort during sexual intercourse.
Mild
I was able to tolerate the discomfort during sexual intercourse.
Moderate
Intercourse was interrupted due to pain.
Severe
I avoided sexual intercourse because of pain.
Uterine Bleeding
Subjects will be prompted to indicate if they had "Did you have any uterine bleeding in 
the last 24 hours?"  For subjects who answer yes, the subject will then document the 
intensity of the bleeding as follows: 
Spotting
A light amount of bleeding noted, no protection or panty shield only.
Light
1 to 2 regular tampons or pads required in 24 hours.
Medium
3 to 4 regular tampons or pads required in 24 hours.
Heavy
More than 4 tampons or pads required in 24 hours.
Rescue Analgesic Use for Endometriosis-Associated Pain
Subjects will record the use of protocol-allowed rescue analgesic medications 
(Section 5.2.3.4) taken for endometriosis-associated pain on a daily basis using the 
e-Diary during the Screening Period and through Treatment Month 12.  Subjects will 
report whether they have taken pain medication documenting the total number of pills 
taken within each class (NSAIDs or opioids) of protocol-allowed rescue analgesic during 
the last 24-hour period. 


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The use of protocol-allowed rescue analgesic medications taken during the Screening and 
Treatment Periods will be recorded by site staff in the subjects' source documents and 
eCRF.
Patient Reported Outcomes (PRO) and Outcomes Rating Scales
Prior to the start of the study, detailed instructions and training for study site staff 
administering these rating scales will be provided by AbbVie and/or its designee.  The 
objective of this training is to establish uniformity across sites in administration of these 
rating instruments.  The following questionnaires will be completed by the subjects and/or 
the Investigator or site staff, as appropriate at the time points indicated in Appendix C and 
should be administered prior to any other study procedures being performed at that visit.  
Subjects and site staff will be asked to record their responses either electronically and/or 
directly onto paper questionnaires (which will then be entered into the eCRF), as 
applicable.
Overall Endometriosis-Associated Pain
Beginning at Day 1 of the Treatment Period and at all monthly visits during the Treatment 
Period (on-site and phone contacts), site staff will administer the overall endometriosis-
associated pain questionnaire (Appendix E) (11-point NRS) assessing overall 
endometriosis-associated pain over a 7-day recall period.  Site staff will ask subjects to 
assess their endometriosis-associated pain on a scale of 0 – 10, with 0 = no pain and 
10 = worst pain ever.  Site staff will record the subject's response electronically via a 
tablet device at the time of the visit.
Endometriosis Health Profile-30 (EHP-30)9
The EHP-30 is a disease-specific self-administered questionnaire used to measure health 
related quality of life in women with endometriosis.  The EHP-30 is composed of two 
parts:  a core questionnaire containing 5 scales that are applicable to all women with 
endometriosis and a modular part containing 6 scales which do not necessarily apply to all 
women with endometriosis.  This study will employ the Core EHP-30 and modular 


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Section C-Sexual Relationships (Part 2).  Subjects will complete the EHP-30 
electronically via a tablet device.
EuroQol-5D 5 level (EQ-5D-5L™)10,11
The self-administered EQ-5D-5L 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 analogue scale that provides 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.  Subjects will complete the EQ-5D-5L electronically via a tablet device.
Work Productivity and Activity Impairment Questionnaire:  Specific Health Problem 
(WPAI:SHP)12
The WPAI:SHP questionnaire is a standardized, self-administered questionnaire about 
work and activity impairment due to health problems.  The WPAI-SHP will be adapted to 
inquire about work and activity impairment due to endometriosis-associated pain.  
Subjects will complete this questionnaire on an electronic tablet device.
PROMIS Fatigue Short Form 6a13
The PROMIS Fatigue Short Form 6a is self-administered and composed of 6 questions to 
evaluate fatigue.  Subjects will complete this questionnaire on an electronic tablet device.
Patient Global Impression of Change (PGIC) 
The Patient Global Impression of Change (Appendix F) questionnaire evaluates the 
change in the subject's endometriosis-related pain since initiation of study drug.  The 
subject selects one of seven responses:  very much improved, much improved, minimally 
improved, not changed, minimally worse, much worse or very much worse.  Subjects will 
complete this questionnaire on an electronic tablet device.


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Additional Questionnaires
BMD Risk Factor Assessment Questionnaire (Appendix G) 
Information will be obtained to help identify risk factors potentially associated with 
changes in bone mineral density (BMD) at study visits as outlined in Appendix C.  
Subjects will be asked about modifiable and non-modifiable risk factors, e.g., smoking 
and alcohol use, exercise habits, and dietary intake of calcium.  Information about 
exercise habits will be collected via the IPAQ.14  As applicable, site staff will elicit subject 
responses and record appropriately or subjects will be asked to enter their responses via an 
electronic tablet device.
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.  The Screening-Baseline C-SSRS questionnaire will be 
administered by site staff at Screening and on Day 1 (prior to randomization).  The 
C-SSRS, Since Last Visit questionnaire should be administered by site staff during the 
Treatment Period as indicated in Appendix C. 
During Screening or at the Day 1 visit, prior to randomization, any subject noted to have 
suicidal ideation within the last year, either via answering "yes" to question 4 and/or 
question 5 to the suicidal ideation portion of the C-SSRS, or via clinical interview, is not 
eligible for randomization.  Following randomization, if the subject expresses suicidal 
ideation on the C-SSRS or via clinical interview at any time during the study, the 
Investigator should immediately 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 administered at the Day 1 visit will serve 
as the baseline for clinical assessment.


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Opioid Risk Tool (ORT)15
The Opioid Risk Tool (ORT) is a self-report screening tool designed to assess risk for 
opioid abuse among individuals prescribed opioids for treatment of chronic pain.  The 
ORT will be administered to subjects and scored by site staff at the Screening visit.  
Subjects with a score of 8 or higher are not eligible for randomization. 
Health Care Resource Utilization (HCRU)
The Health Care Resource Utilization tool captures subject visits to non-study Health 
Care Practitioners prior to randomization and during the Treatment Period.  On Day 1, 
subjects will be asked to provide information on any visits to non-study Health Care 
Practitioners for non-study health visits over the last 4 weeks.  At subsequent Treatment 
Period study visits (on-site and phone call), subjects will be asked to provide information 
on any visits to non-study Health Care Practitioners for non-study health visits since their 
last scheduled monthly study visit (Treatment Month 1 to Treatment Month 24) or in the 
last six months (Treatment Month 25 to Treatment Month 48).  The subject's responses 
will be recorded on the HCRU worksheet by the site staff. 
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If a subject or study personnel cannot come to the site because of the COVID-19 
pandemic, subject visits may be conducted via phone or video conference.  The PRO 
questionnaires and other scales (i.e., Overall Endometriosis Associated Pain C-SSRS, 
EHP-30, EQ-5D-5L™ [version for interviewer administration must be used], WPAI:SHP, 
PROMIS Fatigue Short Form 6a, PGIC, and HCRU) may be administered by site staff 
over the phone or via video conference. 
In this situation, sites will read the PRO (or other questionnaire) questions and response 
options to the subject, record the subject's responses in the source, and transcribe into the 
electronic device provided to the site, as applicable.  The subject's ability to view the PRO 
to understand the questions and response options should be preserved.  Sites may share 
the questionnaire by video conference or send the questionnaires (email or hard copy) to 


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the subject to allow them to read/understand the questions and responses when the subject 
is providing responses over the phone.  The date and time of PRO data collection should 
be recorded in the source along with who collected the information. 
Post-Treatment Assessment of Menstruation
Subjects will be asked about post-treatment to menses using the Return to Menses 
Questionnaire (Appendix H) in the Follow-Up Period, as outlined in Appendix C.  Site 
staff will ask subjects if they have had a menstrual period since discontinuation of study 
drug and record subjects' responses directly onto the paper questionnaire (which will then 
be entered into the eCRF).  If the subject indicates she has not returned to menses, site 
staff will continue to assess return to menstruation and repeat the questionnaire at 
subsequent follow-up visits, as applicable.  The date when menses returned will be 
documented in the source documents and eCRFs. 
Assignment of Subject Numbers
The site will contact the Interactive Response Technology (IRT) during the Washout or 
Screening Period to obtain a subject (Screening) number after the subject has signed the 
informed consent.  Consecutive and unique subject numbers within each site will be 
assigned.  The same subject number will be used to identify the subject throughout the 
study (Screening, Treatment and Follow-Up Periods).  If the subject is not randomized 
into the study on Day 1, the reason for screen failure will be documented in the eCRF and 
the site will register the subject as a screen failure in IRT.
Randomization/Study Drug Kit Assignment
Subjects are to be randomized between Cycle Days 1 – 10 of her menstrual cycle (Cycle 
Day 1 is defined as the first day with full menstrual flow); however, randomizations 
beyond Day 10 of the subject's menstrual cycle must be discussed with the AbbVie TA 
MD prior to randomizing the subject and will be evaluated on a case by case basis, 
including whether additional procedures are required. 


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At the Day 1 visit, eligible subjects will be randomly assigned to 1 of 3 treatment groups 
by using IRT and entering the same subject number received during Screening or 
Washout.  During the IRT randomization contact session, a unique randomization number 
and study drug kit number will be assigned by the IRT according to a randomization 
schedule generated by the Statistics department at AbbVie.  However, the randomization 
number will not be provided to the site and is strictly used within the system for treatment 
assignment.  In order to maintain the blind through Treatment Month 12 for all subjects, 
at Month 6 subjects randomized to elagolix 200 mg BID alone on Day 1 will be re-
assigned (in a blinded manner) to the elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) 
QD treatment group via IRT and continue with this dosing regimen throughout the 
remainder of the Treatment Period (Months 7 – 48). 
During the Treatment Period, sites will register each on-site monthly visit in IRT in order 
to obtain the appropriate amount of scheduled re-supply of study drug to dispense to each 
subject.  (For example, the site will register the Treatment Month 8 visit in IRT in order to 
have 2 months' worth of study drug dispensed until the next on-site study visit at 
Treatment Month 10). 
5.3.1.2
Collection and Handling of Exploratory Research Samples
Exploratory Research Samples
Subjects will have the option to provide samples for exploratory research.  Subjects may 
still participate in the main study even if they decide not to participate in this optional 
exploratory research. 
AbbVie (or people or companies working with AbbVie) will store the exploratory 
research samples in a secure storage space with adequate measures to protect 
confidentiality.  The samples will be retained while research on elagolix (or drugs of this 
class) or this disease and related conditions continues, but for no longer than 20 years 
after study completion.  The procedure for obtaining and documenting informed consent 


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(via a separate consent document) for exploratory research samples is discussed in 
Section 9.3. 
Samples for Pharmacogenetic Exploratory Research
Two optional whole blood samples, one for DNA and a second for RNA will be collected 
on Day 1, Month 6, Month 12 and Premature Discontinuation Visit (if applicable) from 
each subject who consents to provide samples for exploratory research.  An endometrial 
sample for pharmacogenetic testing will be collected during Screening and at Month 12 
for each subject who consents to provide samples for exploratory research. 
Samples will be shipped frozen to AbbVie or a designated laboratory for DNA and RNA 
extraction and long-term storage.  Instructions for the preparation and shipment of the 
pharmacogenetic exploratory research samples will be provided in a study-specific 
laboratory manual. 
5.3.1.3
Collection and Handling of Pharmacodynamic Variables
A single blood sample will be collected at each timepoint as indicated in Appendix C to 
be used for the analysis of estradiol and potentially for additional testing (e.g., re-testing 
of hormone levels with an alternative methodology or for testing and potential validation 
of exploratory biomarkers for endometriosis).  The blood samples for assay of estradiol 
will be collected by venipuncture in one 7 mL evacuated collection tube without 
anticoagulant (red cap, no gel separators to be used).  Sufficient blood volume will be 
collected to provide approximately 3 mL serum from each sample.  Refer to the study 
specific laboratory manual for detailed instructions on sample collection, processing and 
shipment. 
The date and time of collection will be recorded in the source documentation.  The Day 1 
sample will be obtained pre-dose; samples collected at all other visits can be drawn at any 
time during the visit.


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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 (PK samples) will be collected by 
venipuncture into 4 mL evacuated K2-ethylenediaminetetraacetic acid 
(K2EDTA)-containing collection tubes at the times indicated in Appendix C.  Sufficient 
blood will be collected to provide approximately 2 mL plasma from each sample.  Refer 
to the study specific laboratory manual for detailed instructions on sample collection, 
processing and shipment. 
Samples will be collected regardless of the time of last dose.  The date and time of 
collection will be recorded in the lab requisition form.
5.3.2.2
Measurement Methods
Plasma concentrations of elagolix and norethindrone and serum concentrations of 
estradiol will be determined using validated methods by the Bioanalysis 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 Variables
The co-primary efficacy endpoints will be the proportion of responders at Month 6 based 
upon the mutually-exclusive scales for daily assessment of DYS and NMPP measured by 
the 4-point Endometriosis Daily Pain Impact Diary.  Use of protocol specific analgesic 
medication for endometriosis-associated pain will also be included in the responder 
definition.  The comparison is between the elagolix plus E2/NETA group and placebo 
group. 


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5.3.3.2
Secondary Variables
The key secondary measures of the Treatment Period that will be tested will include the 
following: 
●
Change from baseline in Overall Endometriosis-Associated Pain at Month 3, 
Month 6, and Month 12 
●
Change from baseline in DYS at Month 3, Month 6, and Month 12 
●
Change from baseline in NMPP at Month 3, Month 6, and Month 12 
●
Change from baseline in dyspareunia at Month 3, Month 6, and Month 12 
●
Change from baseline in PROMIS Fatigue Short Form 6a T-Score at Month 6 
and 12 
5.3.3.3
Additional Efficacy Variables
The following efficacy variables will be collected during the treatment period: 
●
Proportion of responders as assessed by change from Baseline in average pain 
score and analgesic use monthly for DYS, NMPP and dyspareunia, 
respectively.
●
Proportion of responders as assessed by change from Baseline in average pain 
score alone (i.e., not taking into consideration of analgesic use) monthly for 
DYS, NMPP and dyspareunia, respectively. 
●
Change from Baseline, in the monthly average pain score (DYS, NMPP, and 
dyspareunia), as assessed using information from the e-Diary.
●
Change from Baseline in analgesic use (average pill counts) to treat 
endometriosis-related pain, as assessed using information from the e-Diary 
monthly. 
●
Proportion of analgesic use responders monthly (based only on reduction of 
rescue analgesics used).
●
Monthly response in the PGIC and overall endometriosis-associated pain 
questionnaire. 
●
Change from baseline for each of six domains of EHP-30 questionnaire scores. 


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●
Change from baseline for the EuroQoL-5D (EQ-5D-5L).
●
Change from baseline for the WPAI:SHP. 
●
HCRU at each scheduled assessment.
●
Change from baseline for the PROMIS Fatigue short Form 6A T-Score.
5.3.4
Safety Variables
●
Bone mineral density and percentage change from baseline measured by DXA 
●
Summary of hypoestrogenic adverse events  
●
Proportion of subjects reporting adverse events 
●
Time to the first post-treatment menses
●
Uterine bleeding measured by e-Diary
●
Clinical laboratory parameters
●
Vital signs and body weight 
●
Endometrial biopsy and TVU findings 
5.3.5
Pharmacodynamic Variables
Concentrations of estradiol will be obtained throughout the Treatment Period.  Additional 
pharmacodynamic parameters may be calculated if useful in the interpretation of the data.
5.3.6
Pharmacokinetic Variables
Exposures of elagolix and norethindrone will be summarized and elagolix concentrations 
may be used to develop a population pharmacokinetic model.  Additional parameters may 
be calculated if useful in the interpretation of the data.
5.3.7
Exploratory Research Variables
Exploratory Research Variables
Optional samples may be collected to conduct exploratory investigations into known and 
novel biomarkers.  The types of biomarkers to be analyzed may include, but are not 


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limited to, nucleic acids, proteins, lipids, metabolites or hormone concentrations 
(estradiol).  The samples may be analyzed as part of a multi-study assessment of factors 
influencing the subjects' response to the study drug (or drugs of the same or similar class) 
or the development and progression of the subjects' disease or related conditions.  The 
samples may also be used to develop new diagnostic tests, therapies, research methods or 
technologies.  The results from these analyses are exploratory in nature and may not be 
included with the study report. 
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 unless it is mutually agreed upon, in writing, by the Investigator and AbbVie.  
Subjects will be withdrawn from study drug treatment and/or 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 becomes pregnant or subject has a positive serum pregnancy test 
●
The subject has ALT or AST elevation > 5 times the upper limit of normal, 
confirmed upon repeat testing 
●
The subject develops clinically significant gynecological findings or condition 
on either the TVU (confirmed by repeat TVU and/or SIS and/or office 
hysteroscopy) or endometrial biopsy that in the opinion of the Investigator or 
AbbVie TA MD would preclude the subject from continuing in the Treatment 
Period due to safety reasons 
●
The results of any post-baseline DXA prior to Month 48 document a Z-score 
(for subjects < 40 years of age) or T-score (for subjects ≥ 40 years of age) of 


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< –2.5, a BMD decrease from baseline of > 8% in the lumbar spine, total hip or 
femoral neck, or due to TA MD assessment when the BMD percent change 
from baseline cannot be provided by the central reader 
●
The subject will require ongoing use of prohibited medications to manage or 
treat her endometriosis or endometriosis-associated pain in the opinion of the 
Investigator or AbbVie TA MD 
●
The subject requires use of prohibited medications to manage or treat bone 
mineral density changes during the Treatment Period as described in 
Section 5.2.3.3.  Subject continuation in the Follow-Up Period is at the 
discretion of the AbbVie TA MD. 
●
The subject requires surgical intervention for treatment of endometriosis or 
uterine bleeding (e.g., laparoscopy, hysterectomy, ovarian cystectomy) 
●
The Investigator and AbbVie TA MD deems it appropriate to protect the 
subject because the subject expresses suicidal ideation on the C-SSRS or via 
clinical interview at any time during the study.
●
In the Investigator's opinion, the subject is unable or unwilling to comply with 
study-related assessments and procedures, including completion of the e-Diary
●
Any other medical reason that AbbVie or the 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 Premature Discontinuation Visit as soon as 
possible (preferably within 2 – 7 days after last dose of study drug, if possible) and 
undergo study procedures as outlined in Appendix C.  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 Treatment Period will be recorded.  Subjects who 
prematurely discontinue at the time of or after the Month 6 visit during the Treatment 
Period are expected to enter the Follow-Up Period for 12 months unless discontinuing due 
to pregnancy. 


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If a subject becomes pregnant during the Treatment Period or within 30 days of the last 
dose of study drug, no additional study procedures, except an ultrasound will be 
conducted.  Refer to Section 6.1.4 for instructions on reporting of a pregnancy to the 
Sponsor and the required follow-up on the subject and fetus/infant. 
If a subject requires surgery (e.g., laparoscopy, hysterectomy, ovarian cystectomy) for the 
management of their endometriosis during the Treatment Period, study drug should be 
discontinued and the Premature Discontinuation visit should be completed prior to 
surgery, if possible. 
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. 
If a subject is being discontinued from the study prior to the completion of Treatment 
Month 6 time point, a mammogram (only for subjects ≥ 40 years of age), DXA, TVU, Pap 
test, or endometrial biopsy does not need to be performed. 
In addition, if a subject is being discontinued from the study due to a documented Z-score 
or T-score result of < –2.5, BMD decrease from baseline of > 8%, or TA MD assessment, 
an additional DXA scan does not need to be performed as a part of the Premature 
Discontinuation visit procedures. 
Upon discontinuation from the Treatment Period, all used and unused study drug 
containers should be returned to the study site. 
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.  


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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 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. 
5.5
Treatments
5.5.1
Treatments Administered
Subjects will be randomly assigned by IRT to receive one of the following treatment 
groups on randomization into the Treatment Period: 
●
elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD (n = 400) 
●
elagolix 200 mg BID (n = 100) 
●
placebo (n = 200) 
The treatment administration for Treatment Period Day 1 through Month 6 is presented in 
Table 5. 


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Table 5. 
Treatments Administered (Day 1 – Month 6) 
Investigational Product
Treatment Group
Dosing 
Time
Elagolix 
200 mg 
Tablets
Elagolix 
Placebo 
Tablets
E2/NETA 
Capsules 
Matching 
E2/NETA 
Placebo 
Capsules
Elagolix 200 mg BID plus 
E2/NETA (1 mg/0.5 mg) QD 
AM
1 
0 
1 
0 
PM
1 
0 
0 
0 
Elagolix 200 mg BID 
AM
1 
0 
0 
1 
PM
1 
0 
0 
0 
Placebo
AM
0 
1 
0 
1 
PM
0 
1 
0 
0 
Treatment assignment will remain blinded through Treatment Month 12 for all subjects 
and subjects previously randomized to elagolix 200 mg BID alone will be re-assigned at 
Month 6 (in a blinded manner) to the elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) 
QD treatment group and continue with this dosing regimen throughout the remainder of 
the Treatment Period (Months 7 – 48). 
The treatment administration for Treatment Months 7 through 12 is presented in Table 6. 
Table 6. 
Treatments Administered (Month 7 – Month 12) 
Investigational Product
Treatment Group
Dosing 
Time
Elagolix 
200 mg 
Tablets
Elagolix 
Placebo 
Tablets
E2/NETA 
Capsules
Matching 
E2/NETA 
Placebo 
Capsules
Elagolix 200 mg BID plus 
E2/NETA (1 mg/0.5 mg) QD
AM
1 
0 
1 
0 
PM
1 
0 
0 
0 
Placebo
AM
0 
1 
0 
1 
PM
0 
1 
0 
0 
Study drug treatment after Treatment Month 12 will be open-label such that all subjects 
will receive elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD. 


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The treatment administration for Treatment Months 13 through 48 is presented in Table 7. 
Table 7. 
Treatments Administered (Month 13 – Month 48) 
Investigational Product
Treatment Group
Dosing 
Time
Elagolix 
200 mg 
Tablets
Elagolix 
Placebo 
Tablets
E2/NETA 
Capsules
Matching 
E2/NETA 
Placebo 
Capsules
Elagolix 200 mg BID plus 
E2/NETA (1 mg/0.5 mg) QD
AM
1 
0 
1 
0 
PM
1 
0 
0 
0 
The elagolix study drug, consisting of elagolix or matching placebo (Treatment 
Months 1 – 12 only), will be supplied in a carton.  The E2/NETA study drug, consisting 
of E2/NETA or matching placebo, will be supplied in a separate carton.  The subject will 
take the first elagolix/placebo dose (morning dose) and first E2/NETA/placebo dose of 
study drug at the study site on Day 1 (randomization).  Subjects will be instructed to 
thereafter self-administer their study drug throughout the Treatment Period. 
A 1-month (28-day) supply of each study drug (plus 1 week additional supply) will be 
dispensed at the Day 1 visit and at each subsequent monthly study visit up to Month 5 of 
the Treatment Period.  For Treatment Month Visits 6 – 10, a 2 month supply 
(two 28-day kits, plus 2 weeks additional supply) will be dispensed at each on-site 
monthly visit (i.e., Months 6, 8, and 10) to last until the next scheduled study visit.  
Likewise, for Treatment Months 13 – 48, study drug kits will be dispensed at each on-site 
visit (Months 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, and 45), with enough to supply 
subjects until the next scheduled on-site visit.  Study drug will be taken orally twice daily 
during the 48-month Treatment Period.  A morning dose of 1 tablet (elagolix or placebo 
[Treatment Months 1 – 12 only]) and 1 capsule (E2/NETA or placebo) and an evening 
dose of 1 tablet (elagolix or placebo [Treatment Months 1 – 12 only]) 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. 


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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 next morning dose. 
On days when the subject visits the study site for the scheduled visits, she should 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.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If allowed by local regulations and the relevant ethics committee, study drug may be 
shipped directly to the study subject's home upon request from AbbVie.  AbbVie should 
be notified prior to direct-to-patient (DTP) or direct-from-patient (DFP) shipments of 
study drug before shipping. 
Sites can utilize Marken and/or another local courier for drug shipment in such 
circumstances.  Shipments may also include other study supplies (e.g., pregnancy tests, 
contraceptive supplies).  AbbVie has an agreement with Marken (third-party vendor) for 
sites to use when necessary to ship study drug to subjects (and from as applicable).  
Shipments of study drug from the study site to a subject's home will be appropriately 
temperature-controlled (qualified shipper or temperature monitoring) within the labeled 
storage conditions.  Signature is required upon delivery; due to COVID-19 related social 
distancing, this may be provided by the courier after delivery.  Documentation of the 
shipment is to be retained by the clinical site.
The study site is responsible for meeting IRB/IEC reporting requirements related to DTP 
shipments of study drug, as applicable. 
Prior to shipping study drug or supplies, the investigator or designee must complete the 
DTP/DFP process with the subject: 


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●
Obtain consent to provide delivery information to Marken and/or local courier 
and document this consent in source documents 
●
Obtain results of required safety procedures (i.e., urine pregnancy test) before 
registering subject dispensation of study drug in IRT. 
●
Confirm that the subject will be available to accept delivery of shipment.
●
Follow-up with the subject to confirm receipt of shipment. 
●
Instruct the subject to maintain all drug containers, as well as any unused drug 
for return to the site. 
Sites will be required to retain documentation of the shipment for IP accountability and 
monitoring.  AbbVie will not receive subject identifying information related to these 
shipments, as the site will work directly with the courier.
5.5.2
Identity of Investigational Products
Information about the drug formulations to be used in this study is presented in Table 8. 
Table 8. 
Identity of Investigational Products 
Study Drug
Formulation
Route of 
Administration
Trademark
Manufacturer
Elagolix 
(ABT-620)
200 mg film coated tablets 
Oral
N/A
AbbVie
Matching 
Elagolix Placebo
Placebo tablets 
Oral
N/A
AbbVie
E2/NETA*
Estradiol 1 mg/Norethindrone 
acetate 0.5 mg capsules*
Oral
N/A
Novo Nordisk, 
A/S 
Or
Amneal 
Pharmaceuticals
Matching 
E2/NETA 
Placebo
Placebo capsules
Oral
N/A
AbbVie
* 
Commercially-available standard dose E2/NETA tablets are over-encapsulated.


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5.5.2.1
Packaging and Labeling
AbbVie will supply blinded and open label study drug in monthly kits (i.e., cartons).  Kits 
will consist of either:
●
Elagolix or matching placebo, and 
●
E2/NETA capsules or matching placebo
Each kit contains 5 blister cards, with each blister card containing 7 days of study 
medication.  There are 5 weekly blister cards in each kit (carton) to supply enough study 
drug for 4 weeks (28 days) of dosing, plus 1 week of additional study drug supply. 
Each individual elagolix or matching placebo blister card contains 14 tablets for a 7-day 
(1 week) supply of study medication.  Also, each E2/NETA or matching placebo blister 
card contains 7 capsules for a 7-day (1 week) supply of study medication. 
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.  Each kit will contain a unique 
kit number. 
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 Drug
Elagolix, E2/NETA, and respective matching placebo study medication must be stored at 
controlled room temperature 15° to 25°C (59° to 77°F). 
Temperature excursion(s) must be entered into AbbVie Temperature Excursion 
Management System (ATEMS) immediately by the site staff and study drug should not be 
dispensed until ATEMS or AbbVie deems the drug as acceptable. 


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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 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
All subjects will be centrally randomized using an IRT.  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.
As subjects enter into either the Washout Period or the Screening Period, a unique subject 
number will be assigned to each subject by IRT.  This unique subject number will be used 
for each subject throughout the study. 
After confirming that the subject has met randomization criteria and prior to the Day 1 
(randomization) dose, a unique randomization number will be provided via IRT. 
Subjects will be randomly assigned by IRT to one of the treatment groups as outlined in 
Section 5.5.1 upon entry into the Treatment Period. 
For the second 6 months of the Treatment Period (Months 7 – 12), subjects previously 
randomized to elagolix 200 mg BID alone will be re-assigned by IRT to the elagolix 
200 mg BID plus E2/NETA (1 mg/0.5 mg) QD treatment group as outlined in 
Section 5.5.1.  At Treatment Month 12, all subjects will be re-assigned by IRT to receive 
open label elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD, including subjects 
previously randomized to placebo.  Subjects re-assigned by IRT will not be assigned new 
subject numbers.
In the event a study drug kit becomes lost or damaged, the site can contact IRT to obtain 
an unscheduled study drug kit re-supply to dispense to the subject.  Sites will register 
subjects as "Completed" or "Discontinued" (if the subject prematurely discontinues) at the 


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end of the Treatment Period and will also indicate whether the subject will enter the 
Follow-Up Period. 
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 will be 
randomized into treatment groups as described in Section 5.5.1. 
Study drug will be administered at the study site on Day 1 (randomization).  Subjects will 
be instructed to thereafter 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 (cartons and blister cards, used or 
unused) at the subsequent on-site study visit.
5.5.4.1
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 study drug or prevents a subject from taking study drug 
●
Due to malfunction of protocol-specified methods of contraception or 
unprotected intercourse 
●
After a positive urine pregnancy test, while waiting for results of the serum test
●
Clinical laboratory findings that require repeating or confirmation of a 
clinically significant value (e.g., may necessitate discontinuation from the 
study). 
These examples are not all-inclusive; if the Investigator has any questions, these should be 
directed to the AbbVie TA MD. 


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5.5.5
Blinding
5.5.5.1
Blinding of Investigational Product
The active elagolix dose will be identical in appearance to its matched placebo; 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 
after the blind being broken.  The date and reason that the blind was broken must be 
recorded in the source documents and eCRF, as applicable.
5.5.6
Treatment Compliance
The Investigator or his/her designated and qualified representatives will 
administer/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 that described in the 
protocol. 
Subjects will be instructed to return all study drug kits (even if empty, unused or 
damaged) to the study site personnel at study visits throughout the Treatment Period, or 
Premature Discontinuation visit (if applicable).  The study site personnel will assess 
compliance at on-site visits.
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. 


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Through month 12 of the Treatment Period, which is blinded, daily recordings of study 
drug dosing will be obtained using a compliance packaging blister card for all subjects 
(for both elagolix/matching placebo and E2/NETA/matching placebo).  Study site 
personnel will assess study drug compliance after review of the study drug blister cards 
returned by the subjects at on-site visits.
Through the Open Label Treatment Period, compliance packaging blister cards will not be 
used and blister cards without compliance packaging will be used instead.  Study site 
personnel will assess study drug compliance after review of the study drug blister cards 
returned by the subjects at on-site visits.  The subject will be asked at each study visit (on-
site and phone) to provide the dates and approximate times of the last 4 doses taken prior 
to the study visit which will be recorded in source and in the eCRF.
Sites will be provided scanning technology for direct access to the dosing and compliance 
data; sites are expected to scan all returned compliance packaging blister cards to obtain 
the dosing information at each of the on-site treatment Period visits when study drug is 
returned to the site by the subject.  Any unused/unopened compliance packaging 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 the importance of treatment 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 
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 doses prior to the study visit.  In this case, 
the subject reported data will be recorded in source and in the eCRF.  Sites will document 
when any blister cards are not returned or when compliance packaging blister cards 
cannot be scanned. 
Sites should instruct subjects not to remove extra or multiple tablets/capsules from the 
blister cards all at once (e.g., transferring multiple doses into a separate pill organizer) 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 tablets/capsules, sites 


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should re-train the subjects on the importance of only removing study medication when it 
is time to take the dose and record re-training in the source documents. 
Discrepancies in the number of tablets/capsules dispensed minus the number of 
tablets/capsules to be taken versus the number of tablets/capsules returned will be 
clarified with the subject during the study visit.  Appropriate information, including 
retraining if provided, should be recorded in the source documents. 
It is at the discretion of the Investigator to discontinue subjects from the study who fail to 
take and/or return the appropriate amount of study drug. 
Compliance packaging data and subject reported dosages will be used for exposure 
response analysis.
5.5.7
Drug Accountability
The study Investigator or designee will verify via direct recording in IRT or by signature 
and date that study drug supplies are received intact and in the correct amounts indicated 
on the shipping document Clinical Site Shipment Request (CSSR) or similar shipping 
document.  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 
completes or 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 may also 
include the lot number, kit number, CSSR number, the number of pills/capsules dispensed 
and the date study drug was dispensed for each subject.  In addition to using IRT 
inventory, an accurate inventory of study drug may 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 original containers will be 
returned to AbbVie according to instructions from AbbVie. 


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The study Investigator or his/her designated representative agrees not to supply study 
medication 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. 
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event a subject cannot visit the site because of the COVID-19 pandemic, the site 
may contact IRT for kit assignment after confirming the subject's continued eligibility to 
continue study drug dosing and that a home urine pregnancy test was performed with a 
negative result.  Study drug dispensing can then be undertaken as outlined in 
Section 5.5.1. 
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This Phase 3 study in premenopausal women 18 to 49 years of age with moderate to 
severe endometriosis-associated pain employs a randomized design during the Treatment 
Period, the first 12 months of which is double-blind, placebo-controlled.  The remaining 
36 months is open-label, active treatment.  The randomized, double-blind, 
placebo-controlled study design is the standard for unbiased assessments of treatment 
group differences.  The randomized double-blind study design will allow for an unbiased 
evaluation of safety and efficacy. 
5.6.2
Appropriateness of Measurements
The co-primary efficacy endpoints for this trial will be based upon the mutually-exclusive 
validated scales for daily assessment of DYS and NMPP measured by the 4-point 
Endometriosis Daily Pain Impact Diary.  Use of protocol allowed analgesic medication 
for endometriosis-associated pain will be included in the responder definition of the 
primary endpoints.  Additional efficacy measures of DYS and NMPP, dyspareunia, 
uterine bleeding scale, the PGIC, and overall endometriosis-associated pain (NRS) are 


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widely used in endometriosis as assessment tools.  In addition to assessment of pain 
reduction, the effects of treatment of endometriosis can be assessed using evidence of 
impact on subjects' functioning and overall well-being as well as subjects' utilization of 
health resources and loss of time from work.  Thus, PRO endpoints will also be utilized in 
the study. 
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. 
For measurement of endometrial health, TVU has been selected as a reliable and 
established clinical assessment tool.  TVU will also be utilized for evaluation of subjects 
for evidence of exclusionary gynecologic findings.  Endometrial biopsy will provide a 
direct measure of any effect of elagolix on the endometrium. 
DXA is a standard accepted measure of bone mineral density, and will be utilized to 
assess the effect of elagolix following therapy.  Given the known relationship between 
estradiol levels and bone loss, serum E2 measurements will also be utilized to assess 
potential bone effects of elagolix. 
Subjects will be counseled at every visit on the importance of pregnancy prevention and 
use of appropriate and effective methods of contraception throughout the study as outlined 
in Section 5.2.4. 
5.6.3
Suitability of Subject Population
Premenopausal women 18 to 49 years of age with moderate to severe endometriosis-
associated pain were selected for this study because this is the demographic that suffers 
from endometriosis-related pain, including dyspareunia.  No studies in males or females 
outside of their reproductive years are necessary for this indication. 
5.6.4
Selection of Doses in the Study
Elagolix has a dose-dependent effect on BMD loss that is mediated through suppression 
of estradiol levels.  Preliminary efficacy data from the completed Phase 3 clinical 


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development program supports the ability of elagolix to reduce endometriosis-associated 
pain at both the 150 mg QD and 200 mg BID dose levels in a dose-dependent fashion 
(higher responder rate for 200 mg BID than for 150 mg QD).  Also consistent with E2 
suppression and findings from previous elagolix studies, there was a dose dependent 
effect on BMD, such that longer duration of treatment with the higher elagolix dose 
(200 mg BID) would likely require concomitant use of hormonal add back therapy to 
mitigate BMD loss.  Furthermore, data from the Phase 2b study of elagolix in subjects 
with heavy menstrual bleeding due to uterine fibroids demonstrated the effect of 
E2/NETA on mitigating the BMD decrease associated with elagolix 300 mg BID.  
E2/NETA is approved for the prevention of osteoporosis in postmenopausal 
(estrogen-deficient) women.
As such, the elagolix 200 mg BID dose, in combination with E2/NETA add-back therapy 
was selected for this Phase 3 study, which will evaluate the safety and efficacy of this 
regimen in premenopausal women with moderate to severe endometriosis-associated pain.  
The objective is to generate data that would support a longer duration of use of this 
regimen for the proposed indication of management of endometriosis-associated pain, 
similar to the ongoing Phase 3 registration program. 
The maximum elagolix dose administered in this study will not exceed a total daily dose 
of 400 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 6.1.6.  For product complaints, please refer to Section 6.2. 


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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.  All adverse events should be followed to a 
satisfactory conclusion. 
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.  Any 
worsening of a subject's endometriosis-associated pain during the course of the study will 
not be captured as an adverse event unless it meets the criteria for a serious adverse event 
(Section 6.1.1.2), at which point, it will be reported as such.  Worsening in severity of a 
reported adverse event should be reported as a new adverse event.  Laboratory 
abnormalities, changes in BMD (during the Treatment Period) and changes in vital signs 


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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 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 
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 SAEs and adverse events of special interest (AESI), may 
require additional information to be collected, including family history.  AESIs include, 
but are not limited to rash/hypersensitivity, fracture, neuro-psychiatric (depression, mood 
swings, etc.) and vasomotor symptoms (hot flush, night sweats). 
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
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information) to suggest a 
causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is insufficient evidence (information) to suggest a 
causal relationship.
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 serious adverse 
events.
6.1.4
Adverse Event Collection Period
All adverse events reported from the time of study drug administration until 30 days 
following discontinuation of study drug administration have elapsed will be collected, 
whether solicited or spontaneously reported by the subject.  All nonserious adverse events 
of bone fracture, clinically significant BMD loss, or newly diagnosed medically-related 
bone condition will be collected during the Follow-Up Period, until the subject 
discontinues from study participation.  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. 


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Adverse event information will be collected as shown in Figure 2. 
Figure 2. 
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:  PPDINDPharmacovigilance@abbvie.com
FAX to:  +1 (847) 938-0660




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Reference Safety Information (RSI).  The RSI in effect at the start of a DSUR reporting 
period serves as the RSI during the reporting period.  For follow-up reports, the RSI in 
place at the time of occurrence of the 'suspected' Serious Adverse Reaction will be used to 
assess expectedness.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Supplemental study case report forms should be completed in the event of COVID-19 
related missed/virtual visits, study drug interruptions or discontinuations, or adverse 
events (including capture of specific signs/symptoms of infection and testing results). 
COVID-19 infections should be captured as adverse events.  If the event meets the criteria 
for a serious adverse event (SAE), then follow the SAE reporting directions per the 
protocol and above.  The following COVID-19 related supplemental eCRFs should be 
completed:
●
COVID-19 Supplemental Signs/Symptoms 
●
COVID-19 Status Form 
If a subject has a confirmed or suspected COVID-19 infection and study drug 
was interrupted, the Investigator should contact the Sponsor emergency 
medical contact listed above before reintroducing study drug. 
6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 24 hours of the site 
becoming aware of the pregnancy.  Subjects who become pregnant during the Treatment 
or 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.  
While waiting for the results of the serum pregnancy test, study drug should be 
temporarily discontinued pending results of the 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.  However, an 


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ultrasound examination will be performed as early as possible during the first trimester of 
pregnancy to assess the gestational age and document an intrauterine pregnancy.  
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 (i.e., washout [if applicable] or screening) 
through the completion of the Follow-Up Month 1 study visit.  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, the 
newborn at the first post-delivery pediatrician visit and the infant 6 – 12 months post-
delivery. 
If the subject has a positive serum pregnancy test during the Treatment or Follow-Up 
Periods of the study, no additional study procedures, including protocol required DXA 
scans, will be conducted.  The following information on the outcome of a pregnancy that 
occurs after signing of the informed consent, regardless of when the subject became 
pregnant (i.e., either during the Washout, Screening, Treatment Period or through Follow-
Up Month 1) should be collected:  fetal outcome (e.g., spontaneous or elective abortion, 
live infant or still birth), date and mode of delivery, birth weight, birth length, gender, 
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 
from the first post-delivery pediatrician visit and at 6 to 12 months after delivery. 
For each subject with a confirmed pregnancy, the Investigator will provide information 
about the option to participate in an elagolix pregnancy registry study (P18-954) for 
pregnancy outcomes.  The contact information for the Bloom Pregnancy Registry is in the 
Oriahnn/Orilissa label (pregnancy registry telephone number:  1-833-782-7241). 
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome for mother or infant, meeting any serious criteria including 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 (example:  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 1 business day 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 documented in source 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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8.1.1
General Considerations
The SAS system will be used to perform the statistical analyses.  All statistical tests will 
be two-sided and a significance level of 0.05 will be used unless otherwise specified.  A 
test will be deemed statistically significant if the P value rounded to three decimal places 
is less than or equal to 0.050 unless otherwise specified.  The primary safety and efficacy 
comparisons will be between the elagolix plus E2/NETA treatment group and the placebo 
group.  Data from subjects randomized to elagolix 200 mg BID alone will be summarized 
separately from subjects randomized to the elagolix 200 mg BID plus E2/NETA 
(1 mg/0.5 mg) QD arm.  Unless otherwise specified, no statistical tests will be performed 
to evaluate potential differences between the two elagolix dose groups. 
Data collected during the treatment period will be summarized by randomized treatment 
assignment on study Day 1. 
●
Subjects randomized to elagolix plus E2/NETA in the first 12 months of 
treatment.
●
Subjects randomized to elagolix alone in the first 6 months of treatment 
●
Subjects randomized to placebo in the first 12 months of treatment
Analysis details will be specified in the statistical analysis plan.  No statistical tests will be 
performed to evaluate potential differences between dose groups following the 12 month 
placebo-controlled portion of the 48-month Treatment Period. 
8.1.2
Data Sets Analyzed
Full Analysis Set and Safety Analysis Sets 
The full analysis set is comprised of all randomized subjects who took at least one dose of 
the study drug and subjects will be analyzed in the treatment group to which she was 
randomized.  The full analysis set will be used for all efficacy and demographic analyses 
unless otherwise specified in the Statistical Analysis Plan (SAP).  The safety analysis set 
is comprised of all randomized subjects who took at least one dose of study drug and 


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subjects will be analyzed as the treatment actually received no matter what treatment 
group was assigned at the time of randomization.  If a subject takes more than one 
treatment, the subject will be analyzed in the safety analysis set as taking the treatment to 
which she is randomized.  All safety analyses will be performed based on safety analysis 
set.
8.1.3
Demographic, Baseline Characteristics and Concomitant 
Medications
Demographic and baseline characteristics will be summarized by treatment group.
Medical 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.  The duration of the study drug exposure will be summarized by 
treatment group. 
Protocol deviations and reasons for premature discontinuation will be summarized. 
Concomitant medications will be coded using the World Health Organization (WHO) 
dictionary and summarized with frequencies and percentages. 
Unless noted otherwise, the baseline values will be defined as the last value obtained prior 
to the initiation of elagolix, either in the first 12 months placebo controlled treatment 
period, (i.e., if the subject was randomized to active treatment on study Day 1) or 
Months 13 – 48 of the treatment period (i.e., if the subject was randomized to placebo on 
study Day 1). 
8.1.4
End of Placebo Controlled Treatment Period Analysis
An end-of-placebo-controlled treatment period analysis of the primary, secondary and 
other efficacy variables along with demographic and safety variables will be performed 
after the last subject completes the 12-Month placebo-controlled Treatment Period.  These 
analyses will include data collected during the Treatment Period (placebo-controlled and 
open label) and Follow-Up Period.  The database will be versioned for an interim lock and 


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any discrepant data will be clarified before the versioning.  Analyses will be performed by 
AbbVie.
Since this end-of-placebo-controlled treatment period analysis is the only and final 
analysis of the primary and key secondary endpoints, no additional adjustment of alpha-
level is necessary.
8.1.5
Month 24, Month 36, Month 48 and Other Timepoints 
Analyses
At the end of Treatment Month 24, Month 36, Month 48 or other timepoints during the 
open-label period, analysis of the efficacy and safety variables may be performed after the 
last subject completes the Treatment Month 24, Month 36, Month 48 visit, or other 
timepoints during the open-label period, respectively.  For subjects who prematurely 
discontinued during the treatment period, their data collected during the Follow-up Period 
will be included in the analysis, as appropriate.  The database will be versioned for an 
interim lock and any discrepant data will be clarified before the versioning.  Analyses will 
be performed by AbbVie. 
8.1.6
Efficacy
Analysis details for the efficacy variables will be specified in the statistical analysis plan.  
Unless otherwise specified, no statistical tests will be performed following the 12 month 
placebo-controlled portion of the 48-month Treatment Period. 
8.1.6.1
Primary Efficacy Variable
8.1.6.1.1
Primary Analysis
The primary analysis of the co-primary endpoints will be performed using the full analysis 
set.
The co-primary efficacy endpoints will be the proportion of responders at Month 6 of the 
placebo-controlled Treatment Period based upon the mutually-exclusive scales for daily 
assessment of DYS and NMPP measured by the 4 point Endometriosis Daily Pain Impact 


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Diary using the daily e-Diary.  The elagolix plus E2/NETA dose group will need to 
demonstrate a statistically significantly greater proportion of responders for both co-
primary endpoints (DYS and NMPP) in order for the elagolix plus E2/NETA dose group 
to be considered more efficacious than placebo for the co-primary endpoints.   
For each of the co-primary endpoints, the criterion for defining a subject as a responder at 
Month 6 of the Treatment Period will include a reduction of X or greater from baseline in 
pain as well as no increased analgesic rescue use for endometriosis-associated pain.
The specific drugs allowed for rescue analgesic use will be the following:
●
NSAIDs (Naproxen 200 mg, ibuprofen 200 mg, diclofenac 25 mg, celecoxib 
50 mg) 
●
opioid combination medication (5 mg Hydrocodone + 300 or 325 mg 
acetaminophen, 30 mg codeine + 300 mg acetaminophen) 
The subjects will record use of these rescue analgesic medications on a daily basis in the 
e-Diary.
The definition of increased analgesic use is as follows: 
●
The average pill count of rescue analgesics within each class during the 
screening period will be summarized over the last 35 days prior to and 
including the first dose of study medication. 
●
For the primary endpoints of DYS and NMPP, subjects will be considered 
nonresponders if they have a 15% or greater increase in average pill count of 
rescue analgesics and analgesic change as further specified in Appendix I. 
The rescue analgesic use for any defined period will be based on the average pill count for 
each class of rescue analgesics (endometriosis-associated):  NSAID and opioids and any 
(NSAID or opioids).  The total pill count for each class of rescue analgesic is the sum of 
the pill count of the corresponding class of rescue analgesic, as reported in the e-Diary 
during the time period of interest.  For the purposes of the rescue analgesic analysis, the 


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number of pills within each class of rescue analgesic (NSAID or opioid) will be 
considered equivalent for the primary analysis, regardless of specific pill choice, e.g., 
average NSAID pill count will consider all types of NSAIDs specified in Table 3 and will 
not be conducted separately by NSAID type. 
The pain threshold X will be determined at the end of the placebo-controlled treatment 
period prior to any unblinded analysis.  The calculation of the threshold will be based on a 
receiver operating characteristics (ROC) analysis described below.
For both DYS and NMPP, responses of "None," "Mild," "Moderate," and "Severe" will be 
assigned a score of 0, 1, 2, and 3, respectively. 
The average pain score for DYS or NMPP for Month 6 will be based on the 35 calendar 
days immediately prior to and including the Month 6 reference study day.  If a subject's 
mean score for dysmenorrhea is undefined numerically for a time point because her daily 
e-Diary reports indicate she did not experience her period on any days during the 
35 calendar day time period, then mean score for DYS for that time point will be set equal 
to zero (which reflects the absence of any dysmenorrhea during that reporting time 
period). 
For each of the co-primary endpoints, the criterion for defining a subject as a pain 
responder at Month 6 will be a reduction of X or greater from baseline.  The threshold for 
response in the responder analysis (i.e., the value of X) will be chosen to represent a 
clinically meaningful reduction in pain.  The threshold will be determined based on a 
ROC analysis using the PGIC at Month 6 as an anchor and change from baseline at 
Month 6.  The PGIC is a 7-point response scale:  "Since I started taking the study 
medication, my endometriosis related pain has:  very much improved (1), much improved 
(2), minimally improved (3), no change (4), minimally worse (5), much worse (6), very 
much worse (7)." 
The responses of "much improved" and "very much improved" on PGIC will be used to 
define responders, and the threshold for response (the value of X) will be chosen to 


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balance sensitivity and specificity.  That is, it will be the value that corresponds to the 
point on the ROC curve that is closest to the upper left corner when plotting 1-specificity 
versus sensitivity, i.e., closest to 100% sensitivity and 100% specificity.  No other 
covariates will be included in the ROC analysis.  All available subjects will be included in 
the ROC analysis.  For subjects who prematurely discontinue before Month 6, the last 
available observation prior to discontinuation (Last Observation Carried Forward) will be 
used in the ROC analysis. 
The ROC analysis may identify different response thresholds for DYS and NMPP.  The 
results of the ROC analysis, containing the determined threshold, will be included in the 
final Statistical Analysis Plan prior to blind break.
The primary analysis of the co-primary endpoint will be based on a logistic regression 
model including treatment as the main factor and baseline pain score as a covariate to 
compare the elagolix plus E2/NETA dose group to placebo.  For subjects who 
prematurely discontinue before or at Month 6 of the placebo-controlled Period, last 
observation carried forward (LOCF) will be used in the primary responder analysis. 
8.1.6.1.2
Sensitivity Analyses of the Primary Efficacy Variable
The following sensitivity analyses for each of the co-primary endpoints of the proportion 
of responders at Month 6 in pain scores will be conducted: 
1.
The difference between the elagolix plus E2/NETA and placebo in response rates 
will be analyzed using a chi-square test with a corresponding 95% CI for the 
difference in response rate based on normal approximation to the binomial 
distribution. 
2.
All subjects who prematurely discontinue the study drug at or before Month 6 will 
be considered as non-responders and the primary analysis will be repeated.  
Subjects who discontinue after Month 6 will be categorized as 
responders/non-responders in the same manner as done in the primary analysis. 


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3.
The primary analysis will be repeated using mixed-imputation.  In particular, 
subjects who discontinue prior to or at Month 6 due to an adverse event (AE) or 
lack of efficacy will be considered non-responders, while subjects who discontinue 
prior to or at Month 6 due to other reasons will have their monthly pain score 
carried forward following the LOCF rules previously described.  Subjects who do 
not discontinue before Month 6 will be categorized as responders/non-responders 
in the same manner as done in the primary analysis.
4.
All subjects who switched NSAIDs use at Baseline or Month 6 will be considered 
as non-responders and the primary analysis will be repeated.
5.
All subjects who switched NSAIDs use at Baseline or Month 6 will be excluded 
from the primary analysis.
6.
The following rules will be used to standardize different NSAIDs use and opioid 
use.  The standardized rescue analgesic use will be re-evaluated based on Table 1
and the primary analysis will be repeated.
●
NSAID:  1 pill Naproxen = 1 pill Ibuprofen = 1 pill Diclofenac = 4 pills 
Celecoxib = 1 pill of NSAIDs use 
●
Opioid:  1 pill hydrocodone + acetaminophen = 1 pills codeine phosphate + 
acetaminophen = 1 pill of opioid use 
8.1.6.2
Secondary Efficacy Variables
A pre-specified multiple testing approach will be applied to maintain the family-wise 
type I error rate for the co-primary and key secondary endpoints.  In order to test the key 
secondary endpoints, the null hypothesis for the co-primary endpoints for elagolix 
200 BID plus E2/NETA versus placebo must be rejected.  Subsequently, the key 
secondary endpoints may be tested following the multiple-testing procedure defined in the 
statistical analysis plan.
The key secondary measures of the Treatment Period that will be tested will include the 
following: 


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●
Change from baseline in Overall Endometriosis-Associated Pain at Month 3, 
Month 6, and Month 12 
●
Change from baseline in DYS at Month 3, Month 6, and Month 12 
●
Change from baseline in NMPP at Month 3, Month 6, and Month 12 
●
Change from baseline in dyspareunia at Month 3, Month 6, and Month 12 
●
Change from baseline in PROMIS Fatigue Short Form 6a T-Score at Month 6 
and 12 
8.1.6.3
Other Efficacy Variables
Other efficacy endpoints during the treatment period will include the following (in no 
particular order).
●
Proportion of responders as assessed by change from Baseline in average pain 
score and analgesic use monthly for DYS, NMPP and dyspareunia, 
respectively.
●
Proportion of responders as assessed by change from Baseline in average pain 
score alone (i.e., not taking into consideration of analgesic use) monthly for 
DYS, NMPP and dyspareunia, respectively. 
●
Change from Baseline, in the monthly average pain score (DYS, NMPP, and 
dyspareunia), as assessed using information from the e-Diary.
●
Change from Baseline in analgesic use (average pill counts) to treat 
endometriosis-related pain, as assessed using information from the e-Diary 
monthly. 
●
Proportion of analgesic use responders monthly (based only on reduction of 
rescue analgesics used).
●
Monthly response in the PGIC and overall endometriosis-associated pain 
questionnaire. 
●
Change from baseline for each of six domains of EHP-30 questionnaire scores. 
●
Change from baseline for the EuroQoL-5D (EQ-5D-5L).
●
Change from baseline for the WPAI:SHP. 
●
HCRU at each scheduled assessment.


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●
Change from baseline for the PROMIS Fatigue short Form 6A T-Score.
The analyses for those other efficacy endpoints will be conducted at an alpha level of 0.05 
without multiplicity adjustment.  95% CIs will be constructed as needed.  Analysis details 
will be specified in the SAP.
Statistical Analyses for Secondary and Other Efficacy Variables
Generally, for continuous variables, including change from baseline analyses, treatment 
group differences will be analyzed as appropriate using analysis of covariance 
(ANCOVA) models with treatment group as the main effect and baseline score as a 
covariate.  The mixed model with repeated measures (MMRM) method for change from 
baseline to each post-baseline assessment during the placebo controlled Treatment Period 
will be conducted as appropriate. 
Categorical data will be analyzed using CMH test, chi-square, Fisher's exact test or 
logistic regression as appropriate. 
During Months 13 – 48, visit values and change from baseline to each visit will be 
summarized by each group described in Section 8.1.1.  No statistical tests of data from 
Months 13 – 48 will be performed. 
Analysis details will be specified in the SAP.
8.1.6.3.1
Dysmenorrhea and Non-Menstrual Pelvic Pain
The mean change from baseline to each visit during the first 12 months of the placebo 
controlled treatment period in DYS and NMPP will be analyzed for each monthly visit.  
Monthly mean scores will be the average of the daily values reported during the 
35 calendar days prior to and including the reference study day as defined in the SAP for 
the specific time point.


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The proportion of responders in DYS and NMPP at Months 1 – 12 will be compared 
between the elagolix plus E2/NETA dosing group and the placebo group, based on the 
threshold for response determined for the primary analysis. 
8.1.6.3.2
Dyspareunia
For dyspareunia, responses of "None," "Mild," "Moderate," and "Severe" will be assigned 
a score of 0, 1, 2, and 3, respectively.  The dyspareunia monthly mean scores will be 
calculated as described above for DYS and NMPP.  Responses of "Not applicable" will be 
excluded from the calculation.  If a subject's mean score is not defined because all reports 
in that month are "Not applicable," then that mean score will be treated as a missing value 
and will not be included in analyses. 
The proportion of responders at each post-baseline Months 1 – 12 visit will be compared 
between the elagolix plus E2/NETA dosing group and the placebo group.  The threshold 
for defining responders will be determined using the same ROC method described for 
DYS and NMPP.
The mean change from baseline to each visit during the first 12 months of the Treatment 
Period in dyspareunia will be summarized similar to the method for DYS and NMPP.  
Monthly mean scores will be the average of the daily values reported during the 
35 calendar days prior to and including the reference study day as defined in the SAP for 
the specific time point.
8.1.6.3.3
Analgesic Use for Endometriosis-Associated Pain
The use of rescue analgesics for endometriosis-associated pain will be reported by study 
subjects in the e-Diary during the first 12 months of the Treatment Period. 
The percentage of days a rescue analgesic for endometriosis-associated pain is taken by 
the subject will be calculated for the following analgesic categories:  (a) NSAID or opioid 
endometriosis analgesics, and (b) opioid endometriosis analgesics.  The percentage of 


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days a subject takes an analgesic during each month will be calculated for each analgesic 
category using the 35 calendar day interval as noted previously. 
The mean change from baseline to each visit during the first 12 months of the treatment 
period in percentage of days as well as monthly average dose of endometriosis analgesic 
use for each analgesic category will be compared between the elagolix plus E2/NETA 
dosing group and the placebo group.  Baseline will be calculated as percentage of days of 
endometriosis analgesic use for each analgesic category during the last 35 calendar days 
prior to and including Day 1 during the Screening Period. 
The average pill count for each class of rescue analgesic for each visit during the 
first 12 months of the placebo controlled treatment period will be calculated by adding the 
daily pill count of the corresponding class of rescue analgesic in the 35 calendar day 
period immediately prior to and including the day of the reference study day, except for 
Month 1, and dividing over the length of the window, generally equal to 35.  For Month 1, 
average values will be based on data collected between Study Day 1 and the Month 1 
reference study day. 
8.1.6.3.4
Patient Global Impression of Change (PGIC)
The number and percentage of subjects in each PGIC response category will be 
summarized monthly for the first 12 months of the placebo controlled treatment period for 
each treatment group and compared between the elagolix plus E2/NETA treatment group 
and the placebo group. 
The percentage of subjects with response of "Much Improved" or "Very Much Improved" 
will be summarized.
8.1.6.3.5
Overall Endometriosis-Associated Pain Questionnaire
For the first 12 months of the placebo controlled treatment period, the mean change from 
baseline to each visit average NRS scores will be summarized for each treatment group 
and compared between the elagolix plus E2/NETA treatment group and the placebo 


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group.  The change in overall endometriosis-associated pain questionnaire NRS during 
Months 13 – 48 will be summarized.
8.1.6.4
Multiple Comparisons
The co-primary endpoint for the elagolix 200 BID plus E2/NETA group will be tested 
versus placebo and an α = 0.050 level.
The key secondary endpoints will be tested following a pre-specified multiple testing 
procedure to control the Type I error rate and will be described in the Statistical Analysis 
Plan.
8.1.7
Safety
8.1.7.1
General Considerations
All randomized subjects who took at least one dose of the study drug will be included in 
the safety analyses.
During the placebo-controlled treatment period (Months 1 – 12), baseline for all subjects 
will refer to the data obtained prior to Day 1.  During the non-placebo controlled 
treatment period (Months 13 – 48), baselines will be defined as follows.  For subjects 
randomized to elagolix or elagolix plus E2/NETA on Study Day 1, baseline for these 
subjects will refer to the baseline prior to the first dose of elagolix at the time of 
randomization.  For subjects randomized to placebo in the first 12 months of the treatment 
period, their baseline will be reset to the data collected prior to reassignment at Month 13. 
In general, for continuous variables, descriptive statistics (mean, standard deviation, 
median, minimum and maximum) will be summarized by treatment group.  The treatment 
group differences in change and percent change from baseline will be analyzed using a 
one-way ANOVA with treatment as the main effect, or in some cases, one-way ANCOVA 
with treatment as the main effect, and baseline as a covariate.  This will be detailed in the 
Statistical Analysis Plan.


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Categorical data will be summarized with frequencies and percentages by treatment 
group.  Fisher's exact test (or its generalization to r × c tables) will be used to analyze 
treatment group differences for qualitative categorical variables.
Unless specified otherwise, missing safety data will not be imputed. 
Analysis details will be specified in the SAP.
8.1.7.2
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.  
AEs starting more than 30 days following discontinuation of the study drug will not be 
included in the summaries of TEAEs. 
Frequencies and percentages of subjects with TEAEs will be calculated for each treatment 
group as follows: 
●
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) 
8.1.7.3
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.  Treatment group differences for changes from 


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baseline during the first 12 months of the treatment period will be analyzed using a 
one-way ANOVA with treatment as the main effect.
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.
The number of subjects reaching potentially clinically significant levels will be 
summarized by treatment group.  Criteria will be summarized by treatment group. 
8.1.7.4
Bone Mineral Density
The key BMD assessment comparisons are at the lumbar spine at Month 6 and Month 12.  
Secondary BMD endpoints include total hip and femoral neck.  The elagolix 200 mg BID 
plus E2/NETA (1 mg/0.5 mg) QD dose will be compared to placebo at Months 6 and 12 
and will be compared to Elagolix 200 BID alone at Month 6 based on percent change 
from baseline.
Percent change from baseline in BMD during Months 13 through 48, as well as Z-score 
and T-score values will also be summarized.
Full analysis details will be provided in the SAP.
Post-treatment bone mineral density scans will be summarized similarly, as appropriate.  
Percentage change from baseline in the post-treatment period will be compared with the 
percentage change from baseline at the end of the treatment period.  There will be no 
statistical testing in the Follow-Up period. 
Additional analysis details will be specified in the SAP.
8.1.7.5
Post-Treatment Analysis of Menstruation
The time of the first post-treatment menses onset relative to the date of the last dose of the 
study drug will be summarized. 


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8.1.7.6
Endometrial Biopsy
The number and percentage of subjects in each category of endometrial biopsy result will 
be summarized.
8.1.7.7
Transvaginal Ultrasound
Ultrasound assessments, listed below, will be summarized for each treatment group at 
each time point as appropriate.
●
endometrial thickness 
●
uterine fibroids 
●
ovarian cysts 
8.1.8
Pharmacokinetics/Pharmacodynamics
Plasma concentrations of elagolix and norethindrone and serum concentrations of 
estradiol 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 concentrations, versus efficacy 
and safety.  Additional analyses will be performed if useful and appropriate. 
8.2
Determination of Sample Size
Approximately 700 subjects will be randomized in a 4:1:2 ratio to elagolix 200 mg BID 
plus E2/NETA (N = 400), elagolix 200 mg BID alone (N = 100) or placebo (N = 200).  
Assuming NMPP responder rates of 54% for the elagolix with E2/NETA therapy dose 
group and 35% for placebo, and DYS responder rates of 59% for the elagolix with 
E2/NETA therapy dose group and 23% for placebo, these sample sizes provide greater 
than 90% power to detect a difference in response rate between elagolix with E2/NETA 
and placebo, based on a 2-sided test at the significance level of α = 0.05.  The above 
sample size was calculated using nQuery advisor 7.0. 


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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 
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.  During the COVID-19 pandemic, virtual/remote monitoring of data may be 
employed if allowed by the local regulatory authority, IRB/IEC, and the 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. 


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COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event of a state of emergency due to the COVID-19 pandemic leading to difficulties 
in performing protocol-specified procedures, AbbVie will engage with study site 
personnel in efforts to ensure the safety of subjects, maintain protocol compliance, and 
minimize risks to the integrity of the study while trying to best manage subject continuity 
of care.  This may include alternative methods for assessments (e.g., phone contacts or 
virtual site visits), and shipping investigational product and/or supplies direct to subjects 
to ensure continuity of treatment where allowed.  Refer to the Study Procedures sections 
for additional details.  In all cases, these alternative measures must be allowed by local 
regulations and permitted by IRB/IEC.  Investigators should notify AbbVie if any urgent 
safety measures are taken to protect the subjects against any immediate hazard.
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 washout 
(if applicable) or screening 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 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. 
An additional informed consent, approved by an IRB/IEC, must be voluntarily signed and 
dated before samples are collected for optional exploratory research.  The nature of the 
testing should be explained and the subject given an opportunity to ask questions.  The 


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informed consent must be signed before the samples are collected and any testing is 
performed.  If the subject does not consent to provide samples for the optional exploratory 
research, it will not impact their participation in the study.
In the event a subject withdraws consent to participate from the study, exploratory 
research samples will continue to be used for research and analysis.  In the event that a 
subject would like to withdraw consent for research using these samples, the subject may 
request for their samples to be withdrawn.  Once AbbVie receives the request, remaining 
exploratory research samples will be destroyed.  If the subject changes his/her consent, 
and the samples have already been tested, those results will still remain as part of the 
overall research data.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, it is possible that additional protocol modifications not 
outlined in this protocol may become necessary.  If this situation arises, in addition to the 
study informed consent, additional verbal consent must be obtained prior to these 
adaptations or substantial changes in study conduct in accordance with local regulations. 
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.  The Investigator Awareness Date (SAE CRF) may serve 
as the source for this data point.  This adverse event data point required for eCRF 
completion can be entered directly in the eCRF. 


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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. 
COVID-19 Pandemic-Related Acceptable Protocol Modifications
The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported.  All source documents should be attributable, legible, 
contemporaneous, original, accurate, and complete to ensure accurate interpretation of 
data.  Clinical site monitoring is conducted to ensure that the rights and well-being of 
human subjects are protected, that the reported trial data are accurate, complete, and 
verifiable, and that the conduct of the trial is in compliance with the currently approved 
protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).  During the COVID-19 pandemic, remote monitoring of data may be 
employed if allowed by the local regulatory authority, IRB/IEC, and the study site.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/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 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. 


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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, 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. 
Electronic Patient Reported Outcomes (ePRO)
Patient reported data must be completed for each subject screened/enrolled in this study.  
Some of these data are being collected with an Electronic Patient Reported Outcome 
(ePRO) tool called TrialMax®, provided by the technology vendor CRF Health of 
Plymouth Meeting, PA, USA.  The ePRO system is in compliance with Title 21 CFR 
Part 11.  The documentation related to the system validation of the ePRO tool is available 
through the vendor, CRF Health, while the user acceptance testing of the study-specific 
PRO design will be conducted and maintained at AbbVie. 
The subject will enter the data on an electronic device; these data will be uploaded to a 
server.  The data on the server will be considered source, and maintained and managed by 
CRF Health.


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Internet access to the ePRO data will be provided by CRF Health for the duration of the 
trial.  This access will be available for the duration of the trial to the site investigator, as 
well as delegated personnel.  Such access will be removed from investigator sites 
following the receipt of the study archive.  Data from the ePRO tool 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 ePRO data.  It will be possible for the Investigator to make 
paper print-outs from that media.
The ePRO data will be collected electronically via a handheld device into which the 
subject will record the required pieces of information on a daily basis.  The electronic 
device will be programmed to allow data entry for diary data being collected outside the 
clinic.  Data entered on the device will be immediately stored to the device itself and 
automatically uploaded to a central server administrated by CRF Health.  The Investigator 
and delegated site staff will be able to access all uploaded subject-entered data via a 
password protected website, up until the generation, receipt and confirmation of the study 
archive.
The EHP-30, EQ-5D-5L, WPAI:SHP, PROMIS Fatigue Short Form 6a, the PGIC 
questionnaires and information regarding some modifiable and non-modifiable risk 
factors possibly related to BMD (e.g., IPAQ, dietary calcium intake questions) will be 
collected electronically via a tablet device into which the subject will directly enter the 
required pieces of information.  The electronic device will be programmed to allow data 
entry for only the visits specified in the protocol and will not allow for subjects to 
complete more than one of the same assessments at any one visit.  The subject's response 
to the overall endometriosis-associated pain questionnaire will be entered electronically 
via a tablet device by site staff.  All data entered on the device will be immediately stored 
to the device itself and automatically uploaded to a central server administrated by CRF 
Health.  The Investigator and delegated site staff will be able to access all uploaded 
subject entered data via a password protected website, up until the generation, receipt and 
confirmation of the study archive. 


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11.0
Data Quality Assurance
Prior to enrolling any subject in the study, a Site Training 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. 
Source document verification will be performed.  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, vitamin D, serum lipid and endocrine panels, 
serum pregnancy tests, urinalysis, Pap tests (colposcopy plus biopsy, if applicable) 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. 
Pharmacokinetic and pharmacodynamic samples will be analyzed by the Drug Analysis 
Department at AbbVie and data will be loaded into the study database. 


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Transvaginal ultrasounds 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 Imaging Vendor.  The results of these scans will be 
electronically transferred from the Central Imaging Vendor 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. 
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. 


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Any research that may be done using optional exploratory research samples from this 
study will be experimental in nature and the results will not be suitable for clinical 
decision making or patient management.  Hence, the subject will not be informed of 
individual results, should analyses be performed, nor will anyone not directly involved in 
this research.  Correspondingly, researchers will have no access to subject identifiers.  
Individual results will not be reported to anyone not directly involved in this research 
other than for regulatory purposes.  Aggregate data from optional exploratory research 
may be provided to Investigators and used in scientific publications or presented at 
medical conventions.  Optional exploratory research information will be published or 
presented only in a way that does not identify any individual subject. 
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 ICH GCP and 
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 in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports. 
The end-of-study is defined as the date of the last subject's last visit/last procedure.


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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: 
A Phase 3 Study to Evaluate the Safety and Efficacy of Elagolix in 
Combination with Estradiol/Norethindrone Acetate in Subjects 
with Moderate to Severe Endometriosis-Associated Pain
Protocol Date:
07 April 2022 
Signature of Principal Investigator 
Date
Name of Principal Investigator (printed or typed) 


Elagolix
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15.0
Reference List
1.
Kennedy SH, Moore SJ.  The investigation and management of endometriosis.  
Royal College of Obstetricians and Gynecologists Guideline Number 24, 2nd ed.  
October 2006.  p.  1-14. 
2.
American Congress of Obstetricians and Gynecologists (ACOG).  ACOG practice 
bulletin 114:  management of endometriosis.  Obstet Gynecol.  
2010;116(1):223-36. 
3.
The Practice Committee of ASRM.  Treatment of pelvic pain associated with 
endometriosis:  a committee opinion.  Fertil Steril.  2014;101(4):927-35. 
4.
Dunselman GA, Vermeulen N, Becker C, et al.  European Society of Human and 
Embryology.  ESHRE guideline:  management of women with endometriosis.  
Hum Reprod.  2014;29(3):400-12. 
5.
Johnson NP, Hummelshoj L.  World Endometriosis Society Montpellier 
Consortium.  Consensus on current management of endometriosis.  Hum Reprod.  
2013;28(6):1552-68. 
6.
AbbVie.  ABT-620 (Elagolix) Investigator's Brochure Edition 20.  
04 October 2020. 
7.
AbbVie.  Elagolix + E2/NETA Investigator's Brochure Edition 1.  
05 October 2020. 
8.
US Department of Health and Human Services Food and Drug Administration.  
Drug Development and Drug Interactions:  Table of Substrates, Inhibitors and 
Inducers.  November 2017.  Available from:  
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/
DrugInteractionsLabeling/ucm093664.htm#table3-3. 
9.
Jones G, Kennedy S, Barnard A, et al.  Development of an endometriosis 
quality-of-life instrument.  The Endometriosis Health Profile-30.  Obstet Gynecol.  
2001;98(2):258-64. 


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M14-702 Protocol Amendment 7 
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10.
EuroQol Group.  EuroQol--a new facility for the measurement of health-related 
quality of life.  Health Policy 1990;16(3):199-208. 
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. 
12.
Reilly MC, Zbrozek AS, Dukes EM.  The validity and reproducibility of a work 
productivity and activity impairment measure.  Pharmacoeconomics.  
1993;4(5):353-65. 
13.
Reeve B, Hays RD, Bjorner J, et al.  the PROMIS cooperative group.  
Psychometric evaluation and calibration of health-related quality of life item banks:  
plans for the Patient-Reported Outcome Measurement Information System 
(PROMIS).  Medical Care.  2007;45(5), S22-31. 
14.
Booth, M.  Assessment of physical activity:  an international perspective.  Res Q 
Exerc Sport.  2000;71 (2 Suppl):s114-20. 
15.
Webster LR, Webster R.  Predicting aberrant behaviors in Opioid-treated patients:  
preliminary validation of the Opioid risk too.  Pain Med.  2005;6(6):432. 
16.
National Institutes of Health.  Calcium:  fact sheet for health professionals.  
Updated on:  17 November 2016.  Available from:  
https://ods.od.nih.gov/factsheets/Calcium-HealthProfessional/#h2. 
17.
Bandolier.  The Oxford League Table of Analgesic Efficacy.  2007 [cited 2019 
Oct 14].  Available from:  
http://www.bandolier.org.uk/booth/painpag/Acutrev/Analgesics/lftab.html. 


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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
Specialty Development, 
Women's Health
Specialty Development, 
Women's Health
Specialty Development, 
Women's Health
Clinical Study Leadership
Medical Writing
Clinical Pharmacology and 
Pharmacometrics
Data and Statistical Sciences
Data and Statistical Sciences


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Appendix C.
Study Activities
Study Activities – Washout, Screening and Treatment Periods
Activity 
Washoutb
Screening
Treatment Perioda
Day 1c
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Informed Consent
X 
Xd
Medical Historye
X 
Xf
Xf
Smoking/Alcohol Assessment
X 
X 
Physical Exam
Xg
Xh
Xg
Gynecological (External Genitalia, Pelvic and Breast) Exam
X 
12-lead ECG
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Mammogrami
X 
TVUj
X 
DXA
X 
X 
PAP smear
X 
Pregnancy Testsj,k,l Urine (u) serum (s)
X (u)
X (u, s)
X (u, s)
X (u)
X (u)
X (u, s)
X (u)
X (u)
X (u, s)
Endometrial Biopsym
X 
Clinical/Safety Labs:  Chemistry, Hematology, Lipid Panel 
& Urinalysis
X 
X 
X 
Vitamin D Testing
X 
X 
X 
Subset of Chemistry Labs:  ALT, AST & Alkaline 
Phosphatase
X 
Hepatitis/HIV Screen
X 


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Study Activities – Washout, Screening and Treatment Periods (Continued)
Activity 
Washoutb
Screening
Treatment Perioda
Day 1c
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Reflexive Thyroid Stimulating Hormone
X 
Urine Test for Gonorrhea and Chlamydia (optional)n
X 
Pharmacogenetic DNA/RNA blood sample (optional)
X 
X 
Pharmacogenetic endometrial sample (optional)
X 
Pharmacokinetic Sample (elagolix and norethindrone 
concentration) 
X 
X 
Pharmacodynamic Sample (E2)
Xo
X 
X 
X 
X 
X 
X 
Begin e-Diary Daily Entry 
Endometriosis Daily Pain Impact Diary, Dyspareunia, 
Uterine Bleeding, Rescue Analgesic Use for Endometriosis-
Associated Pain
X 
Endometriosis Health Profile-30 (EHP-30)
X 
X 
X 
EuroQol-5D 5 level (EQ-5D-5L)
X 
X 
X 
•
PROMIS Fatigue Short Form 6a,
•
Work Productivity and Activity Impairment 
Questionnaire:  Specific Health Problem (WPAI:SHP)
X 
X 
IPAQ and Dietary Calcium Intake Questionnaire
X 
X 
Columbia-Suicide Severity Rating Scale (C-SSRS) – 
Baseline/Screening
X 
X 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Since 
Last Visit
X 
X 
Opioid Risk Tool (ORT)
X 


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Study Activities – Washout, Screening and Treatment Periods (Continued)
Activity 
Washoutb
Screening
Treatment Perioda
Day 1c
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Health Care Resource Utilization (HCRU)
X 
X 
X 
X 
X 
X 
X 
Overall endometriosis-associated pain via NRSp
X 
X 
X 
X 
X 
X 
X 
PGIC
X 
X 
X 
X 
X 
X 
Review Adverse Events & Analgesic Rescue/Concomitant 
Medication
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contraceptive Counseling/Contraceptive Dispensing (prn) & 
Birth Control Attestation
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization
X 
Dispense Study Drug
X 
X 
X 
X 
X 
X 
X 


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Study Activities – Treatment Period (Continued)
Activity 
Treatment Perioda
Month 7
Month 8
Month 9
Month 10
Month 11
Month 12
Phone Contact
X 
X 
X 
Physical Exam
Xh
Gynecological (External Genitalia, Pelvic and Breast) Exam
Xh
Vital Signs
X 
X 
X 
TVUj
X 
Mammogrami
X 
DXA
X 
Pregnancy Test:j,k,l Urine (u) serum (s)
X (u)
X (u, s)
X (u)
X (u)
X (u)
X (u, s)
Endometrial Biopsym
X 
Clinical/Safety Labs:  Chemistry, Hematology, Lipid Panel & Urinalysis
X 
Vitamin D Testing
X 
Subset of Chemistry Labs:  ALT, AST, Alkaline Phosphatase
X 
Urine Test for Gonorrhea and Chlamydia (Optional)n
X 
Pharmacogenetic DNA/RNA blood sample (optional)
X 
Pharmacogenetic endometrial sample (optional)
X 
Pharmacokinetic Sample (elagolix and norethindrone concentration) 
X 
X 


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Study Activities – Treatment Period (Continued)
Activity 
Treatment Perioda
Month 7
Month 8
Month 9
Month 10
Month 11
Month 12
Pharmacodynamic Sample (E2)
X 
X 
X 
End e-Diary Daily Entry Endometriosis Daily Pain Impact Diary, Dyspareunia, Uterine 
Bleeding, Rescue Analgesic Use for Endometriosis-Associated Pain
X 
Smoking/Alcohol Assessment
X 
•
Endometriosis Health Profile-30 (EHP-30)
•
EuroQol-5D 5 level (EQ-5D-5L)
•
PROMIS Fatigue Short Form 6a
•
Work Productivity and Activity Impairment Questionnaire:  Specific Health Problem 
(WPAI:SHP)
X 
IPAQ and Dietary Calcium Intake Questionnaire
X 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Since Last Visit
X 
X 
X 
Health Care Resource Utilization (HCRU)
X 
X 
X 
X 
X 
X 
Overall endometriosis-associated pain via NRSp
X 
X 
X 
X 
X 
X 
PGIC
X 
X 
X 
Review Adverse Events & Analgesic Rescue/Concomitant Medication
X 
X 
X 
X 
X 
X 
Contraceptive Counseling/Contraceptive Dispensing (prn) 
X 
X 
X 
X 
X 
X 
Birth Control Attestation
X 
X 
X 
Dispense Study Drug
X 
X 
X 


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Study Activities – Treatment Period (Continued)
Activity 
Treatment Perioda
Month 13
Month 14
Month 15
Month 16
Month 17
Month 18
Phone Contact
X 
X 
X 
X 
Vital Signs
X 
X 
DXA
X 
Pregnancy Tests:j,k,l urine (u) serum (s)
X (u)
X (u)
X (u, s)
X (u)
X (u)
X (u, s)
Clinical/Safety Labs:  Chemistry, Hematology, Lipid Panel & Urinalysis
X 
Vitamin D testing
X 
Subset of Chemistry Labs:  ALT, AST & Alkaline Phosphatase
X 
Pharmacokinetic Sample (elagolix and norethindrone concentration) 
X 
Pharmacodynamic Sample (E2)
X 
X 
Smoking/Alcohol Assessment
X 
•
Endometriosis Health Profile-30 (EHP-30)
•
EuroQol-5D 5 level (EQ-5D-5L)
•
PROMIS Fatigue Short Form 6a
•
Work Productivity and Activity Impairment Questionnaire:  Specific Health 
Problem (WPAI:SHP)
X 
IPAQ and Dietary Calcium Intake Questionnaire
X 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Since Last Visit
X 
X 
Health Care Resource Utilization (HCRU)
X 
X 
X 
X 
X 
X 
Overall endometriosis-associated pain via NRSp
X 
X 
X 
X 
X 
X 
PGIC
X 
X 
Review Adverse Events & Analgesic Rescue/Concomitant Medication
X 
X 
X 
X 
X 
X 


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Study Activities – Treatment Period (Continued)
Activity 
Treatment Perioda
Month 13
Month 14
Month 15
Month 16
Month 17
Month 18
Contraceptive Counseling/Contraceptive Dispensing (prn)
X 
X 
X 
X 
X 
X 
Birth Control Attestation
X 
X 
Dispense Study Drug
X 
X 


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Study Activities – Treatment Period (Continued)
Activity 
Treatment Perioda
Month 19
Month 20
Month 21
Month 22
Month 23
Month 24
Phone Contact
X 
X 
X 
X 
Physical Exam
Xh
Gynecological (External Genitalia, Pelvic and Breast) Exam
Xh
Vital Signs
X 
X 
TVUj
X 
Mammogrami
X 
DXAl
X 
Pap smear
X 
Pregnancy Tests:j,k,l urine (u) serum (s)
X (u)
X (u)
X (u, s)
X (u)
X (u)
X (u, s)
Endometrial Biopsym
X 
Clinical/Safety Labs:  Chemistry, Hematology, Lipid Panel & Urinalysis
X 
Vitamin D testing
X 
Subset of Chemistry Labs:  ALT, AST & Alkaline Phosphatase
X 
Urine Test for Gonorrhea and Chlamydia (Optional)n
X 
Pharmacokinetic Sample (elagolix and norethindrone concentration) 
X 
Pharmacodynamic Sample (E2)
X 
X 
Health Care Resource Utilization (HCRU)
X 
X 
X 
X 
X 
X 
Smoking/Alcohol Assessment
X 


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Study Activities – Treatment Period (Continued)
Activity 
Treatment Perioda
Month 19
Month 20
Month 21
Month 22
Month 23
Month 24
•
Endometriosis Health Profile-30 (EHP-30)
•
EuroQol-5D 5 level (EQ-5D-5L)
•
PROMIS Fatigue Short Form 6a
•
Work Productivity and Activity Impairment Questionnaire:  Specific Health 
Problem (WPAI:SHP)
X 
IPAQ and Dietary Calcium Intake Questionnaire
X 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Since Last Visit
X 
X 
Overall endometriosis-associated pain via NRSp
X 
X 
X 
X 
X 
X 
PGIC
X 
X 
Review Adverse Events & Analgesic Rescue/Concomitant Medication
X 
X 
X 
X 
X 
X 
Contraceptive Counseling/Contraceptive Dispensing (prn)
X 
X 
X 
X 
X 
X 
Birth Control Attestation
X 
X 
Dispense Study Drug
X 
X 


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Study Activities – Treatment Period (Continued)
Activity 
Treatment Perioda
Month 25
Month 26
Month 27
Month 28
Month 29
Month 30
Phone Contact
X 
X 
X 
X 
Vital Signs
X 
X 
DXA
X 
Pregnancy Tests:j,k,l urine (u) serum (s)
X (u)
X (u)
X (u)
X (u)
X (u)
X (u)
Lipids and Subset of Chemistry Labs:  ALT, AST & Alkaline Phosphatase
X 
X 
Pharmacokinetic Sample (elagolix and norethindrone concentration)
X 
Pharmacodynamic Sample (E2)
X 
•
Endometriosis Health Profile-30 (EHP-30)
•
PROMIS Fatigue Short Form 6a
•
Work Productivity and Activity Impairment Questionnaire: Specific Health Problem 
(WPAI:SHP)
X 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Since Last Visit
X 
X 
Health Care Resource Utilization (HCRU)
X 
Overall endometriosis-associated pain via NRSp  
X 
X 
X 
X 
X 
X 
Smoking/Alcohol Assessment
X 
Review Adverse Events & Analgesic Rescue/Concomitant Medication
X 
X 
X 
X 
X 
X 
Contraceptive Counseling/Contraceptive Dispensing (prn)
X 
X 
X 
X 
X 
X 
Birth Control Attestation
X 
X 
Dispense Study Drug
X 
X 


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Study Activities – Treatment Period (Continued)
Activity 
Treatment Perioda
Month 31
Month 32
Month 33
Month 34
Month 35
Month 36
Phone Contact
X 
X 
X 
X 
Physical Exam
Xh
Gynecological (External Genitalia, Pelvic and Breast) Exam
Xh
Vital Signs
X 
X 
TVUj  
X 
Mammogrami
X 
DXAl  
X 
Pregnancy Tests:j,k,l urine (u) serum (s)
X (u)
X (u)
X (u)
X (u)
X (u)
X (u)
Endometrial Biopsym  
X 
Lipids and Subset of Chemistry Labs:  ALT, AST & Alkaline Phosphatase
X 
Clinical/Safety Labs:  Chemistry, Hematology, Lipid Panel & Urinalysis
X 
Urine Test for Gonorrhea and Chlamydia (Optional)n  
X 
Pharmacokinetic Sample (elagolix and norethindrone concentration)
X 
Pharmacodynamic Sample (E2)
X 
•
Endometriosis Health Profile-30 (EHP-30)
•
PROMIS Fatigue Short Form 6a
•
Work Productivity and Activity Impairment Questionnaire: Specific Health Problem 
(WPAI:SHP)
X 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Since Last Visit
X 
X 
Smoking/Alcohol Assessment
X 


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Study Activities – Treatment Period (Continued)
Activity 
Treatment Perioda
Month 31
Month 32
Month 33
Month 34
Month 35
Month 36
Health Care Resource Utilization (HCRU)
X 
Overall endometriosis-associated pain via NRSp  
X 
X 
X 
X 
X 
X 
Review Adverse Events & Analgesic Rescue/Concomitant Medication
X 
X 
X 
X 
X 
X 
Contraceptive Counseling/Contraceptive Dispensing (prn)
X 
X 
X 
X 
X 
X 
Birth Control Attestation
X 
X 
Dispense Study Drug
X 
X 


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Study Activities – Treatment Period (Continued)
Activity 
Treatment Period
Month 37
Month 38
Month 39
Month 40
Month 41
Month 42
Phone Contact
X 
X 
X 
X 
Vital Signs
X 
X 
DXAl  
X 
Pregnancy Tests:j,k,l urine (u) serum (s)
X (u)
X (u)
X (u)
X (u)
X (u)
X (u)
Lipids and Subset of Chemistry Labs:  ALT, AST & Alkaline Phosphatase
X 
X 
Urine Test for Gonorrhea and Chlamydia (Optional)n 
X 
Pharmacokinetic Sample (elagolix and norethindrone concentration)
X 
Pharmacodynamic Sample (E2)
X 
Health Care Resource Utilization (HCRU)
X 
•
Endometriosis Health Profile-30 (EHP-30)
•
PROMIS Fatigue Short Form 6a
•
Work Productivity and Activity Impairment Questionnaire:  Specific Health Problem 
(WPAI:SHP)
X 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Since Last Visit
X 
X 
Smoking/Alcohol Assessment
X 
Overall endometriosis-associated pain via NRSp
X 
X 
X 
X 
X 
X 
Review Adverse Events & Analgesic Rescue/Concomitant Medication
X 
X 
X 
X 
X 
X 
Contraceptive Counseling/Contraceptive Dispensing (prn)
X 
X 
X 
X 
X 
X 
Birth Control Attestation
X 
X 
Dispense Study Drug
X 
X 


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Study Activities – Treatment Period (Continued)
Activity 
Treatment Perioda
PDq
Month 43
Month 44
Month 45
Month 46
Month 47
Month 48
Phone Contact
X 
X 
X 
X 
Physical Exam
Xh
Xh
Gynecological (External Genitalia, Pelvic and Breast) Exam
Xh
Xg
Vital Signs
X 
X 
Xh
Pap smear
X 
Xq
TVUj
X 
Xq
Mammogrami
X 
Xq
DXA
X 
Xq
Pregnancy Tests:j,k,l urine (u) serum (s)
X (u)
X (u)
X (u)
X (u)
X (u)
X (u)
X (u)
Endometrial Biopsym
X 
Xq
Lipids and Subset of Chemistry Labs:  ALT, AST & Alkaline Phosphatase
X 
Clinical/Safety Labs:  Chemistry, Hematology, Lipid Panel & Urinalysis
X 
X 
Urine Test for Gonorrhea and Chlamydia (Optional)n
X 
X 
Pharmacokinetic Sample (elagolix and norethindrone concentration)
X 
X 
Pharmacodynamic Sample (E2)
X 
X 
Pharmacogenetic endometrial sample (optional)
X 
•
Endometriosis Health Profile-30 (EHP-30)
•
PROMIS Fatigue Short Form 6a
•
Work Productivity and Activity Impairment Questionnaire:  Specific Health 
Problem (WPAI:SHP)
X 
X 


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Study Activities – Treatment Period (Continued)
Activity 
Treatment Perioda
PDq
Month 43
Month 44
Month 45
Month 46
Month 47
Month 48
Smoking/Alcohol Assessment
X 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Since Last Visit
X 
X 
Health Care Resource Utilization (HCRU)
X 
X 
Overall endometriosis-associated pain via NRSp  
X 
X 
X 
X 
X 
X 
X 
Review Adverse Events & Analgesic Rescue/Concomitant Medication
X 
X 
X 
X 
X 
X 
X 
Contraceptive Counseling/Contraceptive Dispensing (prn)
X 
X 
X 
X 
X 
X 
Xr
Birth Control Attestation
X 
X 
Dispense Study Drug
X 
a.
The window for visits during the Treatment Period is ± 5 days of the scheduled date.  Site will record the dates and approximate times of the last 4 doses of study drug taken 
prior to each on-site and phone study visit after Month 12 in source and in the eCRF.
b.
Subjects using exclusionary hormonal or analgesic therapy for endometriosis or hormonal contraceptives must discontinue these therapies during the Washout Period.  
Informed consent must be obtained prior to entering a subject in washout or performing any study specific procedures.
c.
Day 1 should occur between Days 1 to 10 of the onset (first day with full menstrual flow) of menses.  All activities should be completed prior to dosing.
d.
For subjects who completed the Washout Period, it is not required to repeat the informed consent.
e.
Includes Gynecological/Endometriosis History.
f. 
Update prior to dosing as needed.
g.
Brief, symptom-directed examination.
h.
Complete physical examination, including weight.  The subject should wear lightweight clothing and no shoes during weighing.
i.
For subjects who are ≥ 40 years of age at the time of entry into Screening, if no mammogram has been performed within 3 months.  During the Treatment Period, 
mammograms will also be performed for subjects who are 40 years of age or older at the time of the scheduled study visit.  A mammogram is not required at Premature 
Discontinuation if a study mammogram was performed within approximately 6 months prior to the PD visit.  Mammograms will be read locally.  


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Study Activities – Treatment Period (Continued)
j.
For any subject who has a positive serum pregnancy test result during the Treatment Period up through 30 days post last dose of study drug, a TVU must be conducted as 
early as possible in the first trimester in order to assess the conception date.  The subject will be discontinued from the study at the point the serum pregnancy test is confirmed 
positive.
k.
A positive urine pregnancy test result must be confirmed with a serum pregnancy test.
l.
Urine pregnancy tests will be self-administered at home by the study subject at Treatment Months 7, 9, 11, 13 – 14, 16 – 17, 19 – 20 and 22 – 23, 25 – 26, 28 – 29, 31 – 32, 34 
– 35, 37 – 38, 40 – 41, 43 – 44, and 46 – 47.  Subjects will self-administer the at home urine pregnancy tests (kits provided by the central laboratory) and report the results to 
the site at the phone contact visits.  A positive urine pregnancy test result must be confirmed with a serum pregnancy test.
m.
A negative urine pregnancy result should be obtained on the day of the endometrial biopsy, prior to performing the procedure.  Prior to Month 36 an endometrial biopsy is not 
required if the TVU findings at the PD visit indicate an endometrial thickness <4 mm.  If the TVU findings indicate an endometrial thickness ≥ 4 mm, then the subject must 
have an endometrial biopsy performed.  Endometrial biopsy at Month 36 or 48 (or PD after Month 36 if needed) will be performed regardless of TVU finding at the 
corresponding visit.  
n.
Optional urine test for gonorrhea/chlamydia should be performed prior to undergoing the endometrial biopsy.  Positive test results will be treated outside of the protocol.
o.
On Day 1, the Pharmacodynamic sample should be collected with the safety labs prior to dosing.  
p.
Overall endometriosis-associated pain will be assessed via an 11-point numeric rating scale (NRS [0 – 10]) that will be administered to the subject by site staff.
q.
Premature Discontinuation prior to the time of the Treatment Month 6 visit or within six months of a mammogram, DXA, TVU, Pap test, or endometrial biopsy does not 
require a mammogram, DXA, TVU, Pap test, or endometrial biopsy.
r. 
If the subject prematurely discontinues, the site should counsel the subject on the continued use of non-hormonal contraceptive use for at least 30 days after the last dose of 
study drug.


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Study Activities – Follow-Up Period
Follow-Up Perioda
Activity
Month 1
Month 6
Month 12
DXA
Xb
Xb
Physical Examc
X 
Estradiol (E2) sample 
X 
X 
X 
FSH sample
X 
Pregnancy Test
Xd (u, s)
Xe (u)
Xe (u)
Review Adverse Events 
Xf
Xg 
Xg 
Concomitant Medication
Xe
X 
X 
Return to Menses Questionnaireh
Xi
a.
All subjects will complete a 12 month Follow-Up Period after the last Treatment Month 48 Visit. 
b.
DXA scans of the lumbar spine, total hip, and femoral neck will be obtained at Follow-Up Months 6 and 12.  DXA scans in Follow-Up may be performed ± 15 days around 
the respective study visit.
c. 
Brief, symptom-directed examination to assess any ongoing AEs for resolution.
d.
A positive urine pregnancy test result must be confirmed with a serum pregnancy test.  For any subject who has a positive serum pregnancy test result during the Follow-Up 
Period, a TVU must be conducted as early as possible in the first trimester in order to assess the conception date.  The subject will be discontinued from the Follow-Up Period 
at the point the pregnancy is confirmed.
e.
A negative urine pregnancy test must be obtained on the date of (or within 2 days prior) the DXA, prior to performing the procedure.  A positive urine pregnancy test result 
must be confirmed with a serum pregnancy test.  For any subject who has a positive serum pregnancy test result, the DXA should not be performed.  The subject will be 
discontinued from the Follow-Up Period at the point the pregnancy is confirmed.
f. 
Any ongoing AEs and concomitant medications at the end of the Treatment Period will be reviewed for resolution during this visit.
g.
AESIs of bone fracture, clinically significant BMD loss, or newly diagnosed medically-related bone condition will be collected during the Follow-Up Period.
h.
If the subject has a documented menstrual period after the last dose of study drug, the subject may begin the use of hormonal contraception (e.g., oral or IUD) in place of non-
hormonal birth control.
i.
If subject has not returned to menses by Follow-Up Month 1, continue to follow.


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Appendix D.
BI-RADS Classification
The BI-RADS assessment categories are:
●
0 – Incomplete
●
1 – Negative
●
2 – Benign findings 
●
3 – Probably benign 
●
4 – Suspicious abnormality 
●
5 – Highly suspicious of malignancy 
●
6 – Known biopsy with proven malignancy 


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Appendix E.
Overall Endometriosis-Associated Pain Questionnaire 
Within the past 7 days on a scale of 0 – 10, 0 being no pain and 10 being worst pain ever, 
how do you rate your endometriosis pain? 


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Appendix F.
Patient Global Impression of Change (PGIC) 
Since I started taking the study medication, my endometriosis related pain has: 
☐ Very much improved 
☐ Much improved 
☐Minimally improved
☐ Not changed 
☐Minimally worse
☐ Much Worse 
☐ Very much worse 




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Food Type
Standard Serving Size
Number of Servings on Average
Other
Ready to eat cereal (calcium-fortified) 
1 cup
Bread (white)
1 slice
Bread (whole-wheat)
1 slice
Tortilla (corn, ready to bake/fry)
one
6" diameter
Tortilla (flour, ready to bake/fry)
one
6" diameter
Chocolate Pudding (refrigerated ready to eat)
4 ounces
Note:
National Institutes of Health 2016.16


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Appendix H.
Return to Menses Questionnaire


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Appendix I.
Analgesic Change During Treatment Period
Use of No Analgesics at Baseline
Analgesic used during Screening
Analgesic dose status at end of study
Responder?*
None
None
Responder
Opioid analgesic and/or NSAID is 
started
Nonresponder
Use of Only NSAID at Baseline
Analgesic used at Baseline
Analgesic dose status at end of study
Responder?*
NSAID
Dose stopped, decreases, or is stable**
Responder
Dose increases by 15% or more
Nonresponder
Opioid analgesic is substituted or added
Nonresponder
Use of Only Opioid Analgesic at Baseline
Analgesic used at Baseline
Analgesic dose status at end of study
Responder?*
Opioid analgesic
Dose stopped, decreases, or is stable**
Responder
Dose stopped and NSAID substituted 
(any dose)
Responder
Dose decreases and NSAID added (any 
dose)
Responder
Dose stable** and NSAID added (any 
dose)
Nonresponder
Dose increases by 15% or more
Nonresponder
Use of NSAID and Opioid Analgesic at Baseline
Analgesics used at Baseline
Analgesic dose status at end of study
Responder?*
NSAID + opioid analgesic
NSAID dose stops + opioid analgesic 
use stops, decreases, or is stable**
Responder
NSAID use stops + opioid analgesic 
dose increases by more than 15%
Nonresponder
NSAID dose decreases + opioid 
analgesic use stops, decreases, or is 
stable**
Responder
NSAID dose decreases + opioid 
analgesic dose increases by more than 
15%
Nonresponder
NSAID dose stable** + opioid analgesic 
use stops, decreases, or is stable**
Responder
NSAID dose stable** + opioid analgesic 
dose increases by more than 15%
Nonresponder


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Use of No Analgesics at Baseline
Analgesic used during Screening
Analgesic dose status at end of study
Responder?*
NSAID dose increases by more than 
15% + opioid analgesic use stops
Responder
NSAID dose increases by more than 
15% + opioid analgesic dose decreases
Responder
NSAID dose increases by more than 
15% + opioid analgesic dose is stable**
Nonresponder
NSAID dose increases by more than 
15% + opioid analgesic dose increases 
by 15% or more
Nonresponder
* 
Analgesic Responder = Defined as a subject who meets the criteria for no increase in analgesic use.
**
Stable = Dose is the same as the baseline dose or increases by less than 15% of the baseline dose.

SAP_001.pdf: 
Elagolix
M14-702 – Statistical Analysis Plan
Version 2.0 – 08 May 2020
1
Statistical Analysis Plan for Study M14-702
A Phase 3 Study to Evaluate the Safety and Efficacy 
of Elagolix in Combination with 
Estradiol/Norethindrone Acetate in Subjects with 
Moderate to Severe Endometriosis-Associated Pain
Date:  08 May 2020
Version 2.0
NCT03213457


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M14-702 – Statistical Analysis Plan
Version 2.0 – 08 May 2020
2
Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design, Objectives and Procedures.............................5
2.1
Objectives ..................................................................................................5
2.2
Study Design Overview .............................................................................6
2.3
Treatment Assignment and Blinding .........................................................7
2.4
Sample Size Determination........................................................................7
2.5
End of 12-Month Placebo-Controlled Treatment Period Analysis............8
2.6
Treatment Month 24 and Month 36 Analyses ...........................................8
3.0
Endpoints..................................................................................9
3.1
Primary Endpoint(s)...................................................................................9
3.2
Secondary Endpoint(s)...............................................................................9
3.3
Other Efficacy Endpoint(s)......................................................................10
3.4
Safety Endpoint(s) ...................................................................................11
4.0
Analysis Populations .............................................................11
5.0
Subject Disposition................................................................12
6.0
Study Drug Duration.............................................................13
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................15
7.1
Demographics and Baseline Characteristics............................................15
7.2
Medical History .......................................................................................15
7.3
Prior, Concomitant, and Post-Treatment Medications.............................16
8.0
Efficacy Analyses...................................................................17
8.1
General Considerations............................................................................17
8.2
Handling of Missing Data........................................................................18
8.3
Primary Efficacy Endpoint(s) and Analyses............................................19
8.3.1
Primary Efficacy Endpoint(s) ..................................................................19
8.3.2
Handling of Missing Data for the Primary Efficacy Endpoints...............22
8.3.3
Primary Efficacy Analysis .......................................................................23
8.3.4
Additional Analyses of the Primary Efficacy Endpoint(s) ......................23
8.4
Secondary Efficacy Analyses...................................................................24
8.4.1
Key Secondary Efficacy Analyses...........................................................24


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8.4.1.1
Change from Baseline in DYS, NMPP, Dyspareunia, and Overall 
Endometriosis-Associated Pain ...............................................................24
8.4.1.2
Change from Baseline in PROMIS Fatigue Short Form 6a T-
Score ........................................................................................................25
8.5
Additional Efficacy Analyses ..................................................................25
8.5.1
Endpoints related to DYS, NMPP, Dyspareunia and Overall 
endometriosis-associated pain..................................................................25
8.5.2
Rescue Analgesic Use for Endometriosis-Associated Pain.....................27
8.5.3
Patient Global Impression of Change (PGIC)..........................................29
8.5.4
Endometriosis Health Profile Questionnaire (EHP-30)...........................29
8.5.5
EuroQol-5D 5 Level (EQ-5D-5L)............................................................30
8.5.6
Work Productivity and Activity Impairment Questionnaire:  
Specific Health Problem (WPAI:SHP)....................................................31
8.5.7
PROMIS Fatigue Short Form 6a..............................................................31
8.5.8
Health Care Resource Utilization Questionnaire (HCRU) ......................32
8.5.9
Hospitalization .........................................................................................32
8.6
Efficacy Subgroup Analyses....................................................................33
9.0
Safety Analyses ......................................................................33
9.1
General Considerations............................................................................33
9.2
Adverse Events ........................................................................................34
9.2.1
Treatment-Emergent Adverse Events ......................................................34
9.2.2
Adverse Event Overview .........................................................................36
9.2.3
Treatment-Emergent Adverse Events by SOC and PT............................36
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure ..................................................................................................37
9.2.5
Serious Adverse Events (Including Deaths) and Adverse Events 
Leading to Study Drug Discontinuation ..................................................37
9.2.6
Adverse Events of Special Interest ..........................................................38
9.2.7
Hot Flushes and Night Sweats .................................................................38
9.2.8
Post-Treatment Adverse Events...............................................................38
9.3
Analysis of Laboratory Data....................................................................39
9.4
Analysis of Vital Signs and Weights .......................................................42
9.5
Other Safety Analyses..............................................................................43
9.5.1
Columbia Suicide Severity Rating Scale (C-SSRS) ................................43


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9.5.2
Bone Mineral Density..............................................................................44
9.5.2.1
Bone Mineral Density during the Treatment Period................................44
9.5.2.2
Bone Mineral Density during the Follow-up Period................................46
9.5.3
Uterine Bleeding ......................................................................................49
9.5.4
Amenorrhea..............................................................................................50
9.5.5
Post-treatment Assessment of Menstruation............................................52
9.5.6
Transvaginal Ultrasound..........................................................................52
9.5.6.1
Ovarian Cysts...........................................................................................52
9.5.6.2
Endometrial Thickness.............................................................................52
9.5.6.3
Uterine Fibroids .......................................................................................53
9.5.7
Endometrial Biopsy .................................................................................53
9.5.8
Pregnancy Results....................................................................................53
10.0
Overall Type-I Error Control ..............................................56
11.0
Version History......................................................................56
12.0
References...............................................................................56
List of Tables
Table 1.
Analgesic Change During the Placebo-Controlled Treatment 
Period .......................................................................................................20
Table 2.
Monthly Summary of Amenorrhea – 56 days..........................................51
Table 3.
SAP Version History Summary...............................................................56
List of Figures
Figure 1.
Study Schematic.........................................................................................7
List of Appendices
Appendix A.
Receiver Operating Characteristics (ROC) Analysis for 
Determination of Thresholds for Reduction in Pain................................57
Appendix B.
Definition of Adverse Events of Special Interest (AESI)........................59
Appendix C.
Receiver Operating Characteristics (ROC) Thresholds for 
Reduction in Pain.....................................................................................60


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for Study M14-702 
"A Phase 3 Study to Evaluate the Safety and Efficacy of Elagolix in Combination with 
Estradiol/Norethindrone Acetate in Subjects with Moderate to Severe Endometriosis-
Associated Pain."
Study M14-702 examines the efficacy and safety of elagolix 200 mg administered twice 
daily (BID) in combination with estradiol 1 mg/0.5 mg norethindrone acetate (E2/NETA 
1 mg/0.5 mg) in subjects with moderate to severe endometriosis associated pain.
The analyses of pharmacokinetic endpoints, pharmacodynamic biomarker endpoints and 
exploratory research endpoints will not be covered in this SAP.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC  27513) or later under the UNIX operating system.
2.0
Study Design, Objectives and Procedures
2.1
Objectives
The objectives of this study are to:
●
Assess the safety and efficacy of elagolix 200 mg administered twice daily 
(BID) in combination with estradiol 1 mg/0.5 mg norethindrone acetate 
(E2/NETA 1 mg/0.5 mg) QD compared to placebo at 6 months and 12 months; 
●
Assess the effect of elagolix 200 mg BID in combination with E2/NETA 
(1 mg/0.5 mg) QD on bone mineral density (BMD) compared to elagolix 
200 mg BID alone at 6 months and compared to placebo at 6 months and 
12 months;


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●
Evaluate the continued safety and efficacy of elagolix 200 mg BID plus 
E2/NETA (1 mg/0.5 mg) QD for up to 48 months in premenopausal women 
with moderate to severe endometriosis-associated pain.
2.2
Study Design Overview
This Phase 3 study includes a 48-month Treatment Period and is designed to evaluate the 
safety and efficacy of elagolix in combination with concomitant hormonal add-back 
therapy (E2/NETA 1 mg/0.5 mg) in the management of endometriosis-associated pain in 
premenopausal women.  The first 12 months of the Treatment Period will employ a 
randomized, double-blind, placebo-controlled design (12 months), with an elagolix 
200 mg BID alone arm (the first 6 months followed by elagolix 200 mg BID plus 
E2/NETA [1 mg/0.5 mg] QD), and an elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) 
QD arm.  The last 36 months of the Treatment Period will be open-label, such that all 
subjects will receive elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD.  
The total duration for a subject's participation in this study is approximately 51 to 
74 months, consisting of the following 4 study periods:
●
Washout Period – up to 10 months prior to Screening (only applicable if 
subject is taking exclusionary medication at the time of consent; duration of 
washout depends on the type of exclusionary medication being taken).
●
Screening Period – approximately 1.5 to 4 months prior to first dose of study 
drug.
●
Treatment Period – up to 48-month treatment duration.
●
Follow-Up Period – up to 12 months duration following the last dose of study 
drug.  Subjects are expected to enter Follow-Up after completing Treatment 
Month 48, or if a subject prematurely discontinues from the Treatment Period 
at the time of or after Treatment Month 6.
The schematic of the study is shown in Figure 1.


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Figure 1.
Study Schematic
2.3
Treatment Assignment and Blinding
Approximately 700 subjects will be randomly assigned on Study Day 1 in a 4:1:2 ratio as 
follows:
●
Elagolix plus E2/NETA group:  elagolix 200 mg BID plus E2/NETA 
(1 mg/0.5 mg) QD (n = 400)
●
Elagolix alone group:  elagolix 200 mg BID (n = 100)
●
Placebo group:  placebo (n = 200)
Unless otherwise specified, data will be summarized by group as listed above.
2.4
Sample Size Determination
This study plans to enroll approximately 700 subjects, with 400 subjects in the elagolix 
200 mg BID plus E2/NETA (1 mg/0.5 mg) QD, 100 subjects in the elagolix 200 mg BID, 
and 200 subjects in placebo, representing a randomization ratio of 4:1:2.  These sample 
sizes were chosen to ensure a sufficient number of subjects completing 12 months of total 
treatment with elagolix during the placebo-controlled treatment period for the evaluation 
of safety assessment.  Assuming Non-Menstrual Pelvic Pain (NMPP) responder rates of 
54% for the elagolix with E2/NETA therapy dose group and 35% for placebo, and 


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Dysmenorrhea (DYS) responder rates of 59% for the elagolix with E2/NETA therapy 
dose group and 23% for placebo, these sample sizes provide greater than 90% power to 
detect a difference in response rate between elagolix with E2/NETA and placebo for both 
DYS and NMPP, based on a 2-sided test at the significance level of α = 0.05.
2.5
End of 12-Month Placebo-Controlled Treatment Period 
Analysis
An end-of-placebo-controlled treatment period analysis of the primary, secondary and 
other efficacy variables along with demographic and safety variables will be performed 
after the last subject completes the 12-Month placebo-controlled Treatment Period.  These 
analyses will include data collected during the Treatment Period (placebo-controlled and 
open-label Treatment Periods) and the Follow-Up Period up to the data cut-off for the 
interim lock.  The database will be versioned for an interim soft lock and any discrepant 
data will be clarified before the versioning.  Analyses will be performed by AbbVie.
Since this end-of-placebo-controlled treatment period analysis is the only and final 
analysis of the primary and key secondary endpoints, no additional adjustment of alpha-
level is necessary.
2.6
Treatment Month 24 and Month 36 Analyses
At the end of Treatment Month 24 and Month 36, analysis of the efficacy and safety 
variables may be performed after the last subject completes the Treatment Month 24 and 
Month 36 visit, respectively.  For subjects who prematurely discontinued during the 
treatment period, their data collected during the Follow-up Period will be included in the 
analysis, as appropriate.  The database will be versioned for an interim lock and any 
discrepant data will be clarified before the versioning.  Analyses will be performed by 
AbbVie.  


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3.0
Endpoints
3.1
Primary Endpoint(s)
The co-primary efficacy endpoints (elagolix plus E2/NETA versus placebo) will be the 
proportion of responders (defined in Section 3.3.1) at Month 6 based upon the mutually-
exclusive scales for daily assessment of Dysmenorrhea (DYS) and Non-Menstrual Pelvic 
Pain (NMPP) measured by the 4-point Endometriosis Daily Pain Impact Diary.  Use of 
protocol specific rescue analgesic medication for endometriosis-associated pain will also 
be included in the responder definition.
3.2
Secondary Endpoint(s)
The ranked secondary efficacy endpoints (elagolix plus E2/NETA versus placebo) will be 
tested in the following order:
1.
Change from Baseline to Month 12 in DYS
2.
Change from Baseline to Month 6 in DYS
3.
Change from Baseline to Month 3 in DYS
4.
Change from Baseline to Month 12 in NMPP
5.
Change from Baseline to Month 6 in NMPP
6.
Change from Baseline to Month 3 in NMPP
7.
Change from Baseline to Month 6 in PROMIS Fatigue Short Form 6a T-Score
8.
Change from Baseline to Month 12 in dyspareunia
9.
Change from Baseline to Month 6 in dyspareunia
10.
Change from Baseline to Month 3 in dyspareunia
11.
Change from Baseline to Month 12 in PROMIS Fatigue Short Form 6a T-Score
12.
Change from Baseline to Month 12 in Overall Endometriosis-Associated Pain
13.
Change from Baseline to Month 6 in Overall Endometriosis-Associated Pain


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14.
Change from Baseline to Month 3 in Overall Endometriosis-Associated Pain
3.3
Other Efficacy Endpoint(s)
The primary and secondary efficacy endpoints are listed in Section 3.1 and Section 3.2, 
respectively.  The additional efficacy endpoints (elagolix plus E2/NETA versus placebo) 
are:
●
Proportion of responders as assessed by change from Baseline in average pain 
score and rescue analgesic use monthly during the 12-month Placebo-
Controlled Treatment Period for DYS, NMPP and dyspareunia, respectively.
●
Proportion of responders as assessed by change from Baseline in average pain 
score alone (i.e., not taking into consideration of rescue analgesic use) monthly 
during the 12-month Placebo-Controlled Treatment Period for DYS, NMPP 
and dyspareunia, respectively.
●
Change from Baseline in the monthly average pain score (DYS, NMPP, and 
dyspareunia), as assessed using information from the e-Diary during the 
12-month Placebo-Controlled Treatment Period.
●
Change from Baseline in rescue analgesic use (average pill counts) to treat 
endometriosis-related pain, as assessed using information from the e-Diary 
monthly during the first 12 months of the Treatment Period.
●
Proportion of rescue analgesic use responders monthly (based only on 
reduction of rescue analgesics used) during the first 12 months of the 
Treatment Period.
●
Monthly response in the PGIC and overall endometriosis-associated pain 
questionnaire during the first 12 months of the Treatment Period.
●
Change from baseline for each of six domains of EHP-30 questionnaire scores
at each scheduled assessment during the Treatment Period.
●
Change from baseline for each category of the EuroQoL-5D (EQ-5D-5L) and 
index values at each scheduled assessment during the Treatment Period.
●
Change from baseline for each measure of the WPAI:SHP at each scheduled 
assessment during the Treatment Period.


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●
HCRU at each scheduled assessment during the Treatment Period.
●
Change from baseline for the PROMIS Fatigue short Form 6A T-Score at each 
scheduled assessment during the Treatment Period.
3.4
Safety Endpoint(s)
The safety endpoints will be based on the following evaluations:
●
Adverse events Monitoring
●
Clinical laboratory tests
●
Dual energy X-ray absorptiometry (DXA) scan
●
Vital signs
●
Endometrial biopsy
●
Pelvic ultrasound (transabdominal ultrasound [TAU]/transvaginal ultrasound 
[TVU])
●
Columbia Suicide Severity Rating Scale (C-SSRS)
●
Pregnancy
●
Uterine bleeding measured by e-Diary
4.0
Analysis Populations
The Full Analysis Set (FAS) is composed of all randomized subjects who have received at 
least 1 dose of study drug in this study.  The data from the FAS will be presented by the 
treatment group assigned at the time of randomization, even if a subject does not receive 
the correct treatment or does not follow the protocol until completion.  The FAS will be 
used for all efficacy and baseline analyses unless otherwise specified in the SAP.  
Subjects who do not continue into the open-label Treatment Period will be excluded from 
the analyses in the open-label Treatment Period.


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The following populations will be used for safety analyses:
●
The Safety Analysis Set includes all randomized subjects who received at least 
1 dose of study drug.  The data from the Safety Analysis Set will be analyzed 
based on the actual treatment received at the time of randomization (elagolix 
plus E2/NETA, elagolix alone or placebo).  Subjects who do not continue into 
the open-label Treatment Period will be excluded from the analyses in the 
open-label Treatment Period.
●
The All Elagolix plus E2/NETA Analysis Set is defined as subjects who 
received at least 1 dose of elagolix plus E2/NETA in the study (either in the 
placebo-controlled or open-label Treatment Periods).  Subjects will be 
summarized based on the actual treatment received at the time of 
randomization (elagolix plus E2/NETA, elagolix alone or placebo).
5.0
Subject Disposition
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized for all randomized subjectsby 
treatment group and overall:
●
Subjects randomized in the study.
●
Subjects who took at least one dose of study drug.
●
Subjects who completed the placebo-controlled Treatment Period.
●
Subjects who prematurely discontinued during the placebo-controlled 
Treatment Period.
●
Subjects who entered into the open-label Treatment Period.
●
Subjects who prematurely discontinued during the open-label Treatment 
Period.
●
Subjects who completed protocol-specified treatment.
●
Subjects who prematurely discontinued study drug (all reasons and primary 
reason).
●
Subjects who entered into the Follow-up Period.


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●
Subjects who Completed the Follow-up Period.
The number and percentage of subjects who discontinued study drug will be summarized 
by treatment group and overall as follows based on the Full Analysis Set:
●
By any reason for discontinuation
●
By primary reason for discontinuation
In addition, the number and percentage of subjects who discontinued study will be 
summarized for the FAS by treatment group and overall as follows:
●
By any reason for discontinuation
●
By primary reason for discontinuation
6.0
Study Drug Duration
Duration (days) of treatment will be summarized for the Safety Analysis Set using the 
number of subjects treated, mean, standard deviation, median, minimum and maximum.  
Study drug duration will be summarized as follows:
Placebo-controlled Treatment Period (Safety Analysis Set):
Duration of treatment during the placebo-controlled Treatment Period is defined as 
follow:
●
For subjects who did not continue into the open-label Treatment Period:
○
Last dose date during the placebo-controlled Treatment Period – First dose 
date during the placebo-controlled Treatment Period + 1
●
For subjects who continued into the open-label Treatment Period:
Minimum of
○
Last dose date during the placebo-controlled Treatment Period – First dose 
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○
First dose date during the open-label Treatment Period – First dose date 
during the placebo-controlled Treatment Period.
In addition, the number and percentage of subjects in each treatment duration interval (1 –
28 days, > 28 – 56 days, > 56 – 84 days, > 84 – 112 days, > 112 – 140 days, > 140 –
168 days, > 168 days) will be summarized.
Open-label Treatment Period (Safety Analysis Set):
Duration of treatment during the open-label Treatment Period is defined as last dose date 
during the open-label Treatment Period minus first dose date during the open-label 
Treatment Period plus 1 day.
In addition, the number and percentage of subjects in each treatment duration interval 
(1 – 84 days, > 84 – 168 days, > 168 – 252 days, > 252 – 336 days, > 336 – 420 days, 
> 420 – 504 days, > 504 – 588 days, > 588 – 672 days, > 672 – 756 days, >756 –
840 days, > 840 – 924 days, > 924 – 1008 days, > 1008 days) will be summarized.
All Elagolix plus E2/NETA Analysis Set:
For subjects who received at least 1 dose of elagolix plus E2/NETA (either in the placebo-
controlled or open-label Treatment Periods), the duration of treatment is defined as the 
last dose date of receiving elagolix plus E2/NETA minus the first dose date of receiving 
elagolix plus E2/NETA plus 1 day.
In addition, the number and percentage of subjects in each treatment duration interval 
(1 – 84 days, > 84 – 168 days, > 168 – 252 days, > 252 – 336 days, > 336 – 420 days, 
> 420 – 504 days, > 504 – 588 days, > 588 – 672 days, > 672 – 756 days, > 756 –
840 days, > 840 – 924 days, > 924 – 1008 days, > 1008 – 1092 days, > 1092 – 1176 days, 
> 1176 – 1260 days, > 1260 – 1344 days, > 1344 days) will be summarized.


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7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline characteristics, medical history, prior medication, concomitant 
medication, and post-treatment medication will be summarized by treatment group and 
overall using the Full Analysis Set.  Categorical variables will be summarized with the 
number and percentage of subjects; percentages will be calculated based on the number of 
non-missing observations.  Continuous variables will be summarized with descriptive 
statistics (number of non-missing observations, mean and standard deviation, median, 
minimum and maximum).
7.1
Demographics and Baseline Characteristics
Continuous demographic variables include age, weight, height, and body mass index 
(BMI).  Categorical demographic variables include sex, ethnicity, race, age (18 – 19, 20 –
24, 25 – 29, 30 – 34, 35 – 39, 40 – 44, 45 – 49, ≥50 years), BMI (≤ 18.5, > 18.5 – < 25, 
≥25 – < 30, ≥30 – < 35, ≥35 – < 40, ≥ 40 kg/m2), tobacco use (current, former, never, 
unknown), and alcohol use (current, former, never, unknown).
For endometriosis history, the stage of endometriosis at diagnosis as reported by subjects 
at screening based on their gynecological history will be summarized as the number and 
percentage of subjects in each category (Stage 1, 2, 3, 4, or unknown) for each treatment 
group and overall.  The number of months between the first study drug dose date and the 
subject's surgical diagnosis of endometriosis will be summarized for each treatment group 
and overall.
7.2
Medical History
Medical history and gynecological medical/surgical history data will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  The actual version of the 
MedDRA coding dictionary will be noted in the statistical tables and clinical study report.  
The number and percentage of subjects in each medical history category (by MedDRA 
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for the FAS.  The system organ class (SOC) will be presented in alphabetical order, and 
the preferred terms will be presented in alphabetical order within each SOC.  Subjects 
reporting more than one condition/diagnosis will be counted only once in each row (SOC 
or preferred term).
7.3
Prior, Concomitant, and Post-Treatment Medications
Prior, concomitant, and post-treatment medications will be summarized by generic name
for the FAS.
Prior medications are those medications with a start date prior to the first study drug 
administration date.  Prior medications will be summarized separately for prior 
endometriosis medications and other medications.  
Concomitant medications are those medications, other than study drug and protocol 
specified analgesic medications taken for endometriosis-associated pain which will be 
recorded in e-Diary during Screening and the first 12 months of Treatment, taken during 
the Treatment Period with an end date after the first dose of study drug or ongoing at the 
end of the study, and a start date prior to 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 not missing and the end date is missing; (3) both the start date and the 
end date are missing.  Concomitant medications will be summarized separately for 
analgesic medications taken for endometriosis-associated pain recorded in eCRF during 
the Open-Label Treatment Period and other medications.
Post-treatment medications are those medications with an end date after the last dose of 
study drug or ongoing at the end of study.  Post-treatment medications will be 
summarized separately for analgesic medications taken for endometriosis-associated pain 
recorded in eCRF during the Follow-up Period and other medications.
Prior, concomitant, and post-treatment medications will be summarized by ATC 
Classification and preferred terms from the World Health Organization (WHO) Drug 


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Dictionary with number and percentage by treatment group and overall.  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.
8.0
Efficacy Analyses
8.1
General Considerations
All efficacy analyses will be conducted in the FAS Population.  
Unless otherwise specified, during the 12-month placebo-controlled Treatment Period, the 
analyses of efficacy endpoints will only include data from the placebo group and elagolix 
plus E2/NETA group; elagolix plus E2/NETA group will be compared against placebo.  
Statistical tests will be conducted at an alpha level of 0.05 (two-sided).  A test will be 
deemed significant if the P value rounded to three decimal places is less than or equal to 
0.05 unless otherwise specified.  
In addition, efficacy endpoints collected during each of the placebo-controlled and open-
label Treatment Periods will also be summarized as observed cases (by treatment group); 
no comparisons or statistical tests will be performed.
The primary and secondary analyses will be performed after all ongoing subjects have 
completed the 12-month placebo-controlled Treatment Period and the database has been 
locked.  This will be the only and final analysis for the co-primary and key secondary 
efficacy endpoints as well as all other efficacy endpoints collected in the 12-Month 
Placebo-Controlled Treatment Period.
Unless otherwise specified, categorical data will be summarized by frequencies and 
percentages; continuous data will be summarized by the mean, standard deviation, 
median, minimum, and maximum.  For the analyses of change from baseline, the within-
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and 95% confidence intervals (CIs); between-group differences will be summarized with 
the mean, standard error, P value (as appropriate), and the 95% CIs.
For efficacy variables collected using the daily e-Diary, the baseline will be based on the 
average of the last 35 calendar days during the Screening Period prior to and including 
Study Day 1.  For other efficacy variables, the baseline during the 12-month placebo-
controlled Treatment period (Months 1 – 12) will be the last non-missing value obtained 
prior to or on Study Day 1.  The baseline during the open-label Treatment Period 
(Months 13 – 48) will be the last non-missing value obtained prior to or on the initiation 
day of elagolix (either elagolix alone or elagolix pus E2/NETA).  
8.2
Handling of Missing Data
Missing data will be imputed using the following methods for the efficacy analyses:
●
Last Observation Carried Forward (LOCF):  The LOCF analyses will use the 
completed evaluation from the previous post-baseline evaluation to impute 
missing data at the current evaluations.  Values will only be carried forward if 
a subject prematurely discontinues and if the analysis month is equal to or after 
the month in which the subject prematurely discontinued.  For Month 1 
analysis, only observed cases will be used.
●
Mixed-Effect Model Repeat Measurement (MMRM):  The repeated measures 
analysis will be conducted using a mixed model including observed 
measurements at all visits.  The mixed model includes the categorical fixed 
effects of treatment, visit and treatment-by-visit interaction, and the continuous 
fixed covariate of baseline measurement.  An unstructured variance covariance 
matrix will be used.  Parameter estimation is based on the assumption of data 
being missing at random and using the method of restrictive maximum 
likelihood (REML).
●
Observed Cases (OC):  The OC analysis will not impute values for missing 
evaluations, and thus a subject who does not have an evaluation on a scheduled 
visit will be excluded from the OC analysis for that visit.  OC will exclude 
values after a subject prematurely discontinues from study drug.


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8.3
Primary Efficacy Endpoint(s) and Analyses
8.3.1
Primary Efficacy Endpoint(s)
The co-primary efficacy endpoints will be the proportion of responders at Month 6 based 
upon the mutually-exclusive scales for daily assessment of Dysmenorrhea (DYS) and 
Non-Menstrual Pelvic Pain (NMPP) measured by the 4-point Endometriosis Daily Pain 
Impact Diary.  Use of protocol specific rescue analgesic medication for endometriosis-
associated pain as collected in the daily e-Diary will also be included in the responder 
definition.  
For each of the co-primary endpoints, a subject is considered as a responder at Month 6 if 
(1) she has an absolute reduction of X or greater from baseline in average pain scores 
(DYS or NMPP) at Month 6; and (2) she has stable or decreased rescue analgesic use as 
defined in Table 1 at Month 6.  The pain threshold (i.e., the value of X) will be 
determined based on a Receiver Operating Characteristics (ROC) analysis using the PGIC 
assessment at Month 6 as an anchor and change from baseline in average pain score (DYS 
or NMPP) at Month 6 as the independent variable.  All ROC analyses will be conducted 
prior to blind break and will contain all randomized subjects who receive at least 1 dose of 
study drug.  Thresholds obtained for Month 6 will be used for all monthly visits during 
the 12-month placebo-controlled Treatment Period, i.e., the threshold obtained for DYS at 
Month 6 will be used for DYS at Months 1 – 12.  The details of the ROC analysis are 
presented in Appendix A and the pain threshold values (X) are presented in Appendix C.


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Table 1.
Analgesic Change During the Placebo-Controlled Treatment Period
Use of No Analgesics at Baseline
Analgesic used at Baseline
Analgesic dose status at End of Time 
Window
Responder?*
None
None
Responder
Opioid analgesic and/or NSAID is 
started
Nonresponder
Use of Only NSAID at Baseline
Analgesic used at Baseline
Analgesic dose status at End of Time 
Window
Responder?*
NSAID
Dose stopped, decreases, or is stable**
Responder
Dose increases by 15% or more
Nonresponder
Opioid analgesic is substituted or added
Nonresponder
Use of Only Opioid Analgesic at Baseline
Analgesic used at Baseline
Analgesic dose status at End of Time 
Window
Responder?*
Opioid analgesic
Dose stopped, decreases, or is stable**
Responder
Dose stopped and NSAID substituted 
(any dose)
Responder
Dose decreases and NSAID added (any 
dose)
Responder
Dose stable** and NSAID added (any 
dose)
Nonresponder
Dose increases by 15% or more
Nonresponder
Use of NSAID and Opioid Analgesic at Baseline
Analgesics used at Baseline
Analgesic dose status at End of Time 
Window
Responder?*
NSAID + opioid analgesic
NSAID dose stops + opioid analgesic 
use stops, decreases, or is stable**
Responder
NSAID use stops + opioid analgesic 
dose increases by more than 15%
Nonresponder
NSAID dose decreases + opioid 
analgesic use stops, decreases, or is 
stable**
Responder


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Table 1.
Analgesic Change During the Placebo-Controlled Treatment Period
(Continued)
Use of NSAID and Opioid Analgesic at Baseline
Analgesics used at Baseline
Analgesic dose status at End of Time 
Window
Responder?*
NSAID dose decreases + opioid 
analgesic dose increases by more than 
15%
Nonresponder
NSAID dose stable** + opioid analgesic 
use stops, decreases, or is stable**
Responder
NSAID dose stable** + opioid analgesic 
dose increases by more than 15%
Nonresponder
NSAID dose increases by more than 
15% + opioid analgesic use stops
Responder
NSAID dose increases by more than 
15% + opioid analgesic dose decreases
Responder
NSAID dose increases by more than 
15% + opioid analgesic dose is stable**
Nonresponder
NSAID dose increases by more than 
15% + opioid analgesic dose increases 
by 15% or more
Nonresponder
*
Responder = Defined as a subject who meets the protocol-specified pain score criteria for no increase in analgesic 
use.
**
Stable = Dose is the same as the screening dose or increases by less than 15% of the screening dose.
Dysmenorrhea (DYS) and Non-Menstrual Pelvic Pain (NMPP)
Daily instances when subjects respond "Yes" to the question "Did you have your period in 
the last 24 hours" is counted as a day with reported DYS.  Pain reported daily in response 
to the e-Diary question "On the next screen, choose the item that best describes your pain 
during the last 24 hours when you had your period" is referred in this document as DYS 
related pain.  Daily instances when subjects respond "No" to the question "Did you have 
your period in the last 24 hours" is counted as a day with reported NMPP.  Pain reported 
daily in response to the e-Diary question "On the next screen, choose the item that best 
describes your pain during the last 24 hours without your period" is referred in this 
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For both DYS and NMPP, responses of "None," "Mild," "Moderate," and "Severe" will be 
assigned a score of 0, 1, 2, and 3, respectively.
The monthly average pain score for DYS will be based on averaging the daily pain socre 
over the number of days when the subject reported DYS related pain within each 
respective time window.  The monthly average pain score for NMPP will be based on 
averaging the daily pain scores over the number of days when the subject reported NMPP 
related pain within each respective time window.  If the subject's monthly average pain 
score (DYS or NMPP) is missing because the subject reported only the other kind of pain 
(mutually exclusive daily pain impact scale) in the corresponding time frame of interest 
(e.g., Month 6 DYS score is missing because the subject only reported NMPP during 
Month 6 analysis window), then the monthly average pain score for the relevant 
parameter (DYS or NMPP) will be set to 0 (zero).
Rescue Analgesic Use
For each class of rescue analgesics (NSAIDs and Opioids), analgesic use for each defined 
monthly period during the 12-month placebo-controlled Treatment Period will be based 
on the average pill count as collected in the daily e-Diary.  The monthly average pill count 
for each class of rescue analgesics will be calculated by dividing the total pill count for 
the corresponding class of rescue analgesic by the length of the analysis window.  For 
each class of rescue analgesic, if no analgesic use is reported for a period of interest, but 
e-Diary information is available for the corresponding time period, then the average pill 
count for the corresponding class of rescue analgesic use will be set to 0 (zero).  
8.3.2
Handling of Missing Data for the Primary Efficacy Endpoints
For the co-primary endpoints, subjects who prematurely discontinue at or prior to 
Month 6 will have their average pain scores (DYS and NMPP) and rescue analgesic use 
carried forward (LOCF) from the last month in which both monthly average pain score 
(DYS and NMPP) and analgesic use are observed.


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8.3.3
Primary Efficacy Analysis
The primary null hypothesis for this study is that there is no difference in the proportion 
of responders for each co-primary efficacy endpoint at Month 6 between elagolix plus 
E2/NETA and placebo.  The null hypothesis will be tested against the alternate hypothesis 
that there is a difference between elagolix plus E2/NETA and placebo in the proportion of 
responders for each co-primary efficacy endpoint at Month 6.
Elagolix plus E2/NETA will be considered statistically more efficacious than placebo for 
the co-primary endpoint if and only if the two-sided P value for the comparison of the 
proportion of responders for both DYS and NMPP is less than or equal to 0.05 and in 
favor of elagolix plus E2/NETA.
The primary analysis of each of the co-primary endpoints will be based on a logistic 
regression model with the responder/non-responder categorization as the dependent 
variable, treatment as the main effect, and baseline pain score (DYS or NMPP) as the 
covariate.  Elagolix plus E2/NETA will be compared to placebo for each of the 
co-primary endpoints.  The proportion of responders, difference in proportions between 
each elagolix group and placebo, and odds ratio with corresponding 95% confidence 
intervals (CIs) and P values will be presented.  
8.3.4
Additional Analyses of the Primary Efficacy Endpoint(s)
The following sensitivity analyses for each of the co-primary endpoints of the proportion 
of responders at Month 6 in pain scores will be conducted:
1.
The difference between the elagolix plus E2/NETA and placebo in response rates 
will be analyzed using a chi-square test with a corresponding 95% CI for the 
difference in response rate based on normal approximation to the binomial 
distribution.
2.
All subjects who prematurely discontinue the study drug at or before Month 6 will 
be considered as non-responders and the primary analysis will be repeated.


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3.
The primary analysis will be repeated using mixed-imputation.  In particular, 
subjects who discontinue prior to or at Month 6 due to an adverse event (AE) or 
lack of efficacy will be considered non-responders, while subjects who discontinue 
prior to or at Month 6 due to other reasons will have their monthly pain score 
carried forward following the LOCF rule.
4.
All subjects who switched NSAIDs use at Baseline, Month 6, or from Baseline to 
Month 6 will be considered as non-responders and the primary analysis will be 
repeated.
5.
All subjects who switched NSAIDs use at Baseline, Month 6, or from Baseline to 
Month 6 will be excluded from the primary analysis.
6.
The following rules will be used to standardize different NSAIDs use and opioid 
use.  The standardized rescue analgesic use will be re-evaluated based on Table 1
and the primary analysis will be repeated.
●
NSAID:  1 pill Naproxen = 1 pill Ibuprofen = 1 pill Diclofenac = 4 pills 
Celecoxib = 1 pill of NSAIDs use
●
Opioid:  1 pill hydrocodone + acetaminophen = 1 pills codeine phosphate + 
acetaminophen = 1 pill of opioid use
8.4
Secondary Efficacy Analyses
8.4.1
Key Secondary Efficacy Analyses
8.4.1.1
Change from Baseline in DYS, NMPP, Dyspareunia, and 
Overall Endometriosis-Associated Pain
The change from baseline in DYS, NMPP, dyspareunia, and Overall endometriosis-
associated pain at Months 3, 6, and 12 will be evaluated with mixed-effects model 
repeated measures (MMRM) analysis.  The MMRM analysis will include the fixed 
categorical effects of treatment, visit, and treatment-by-visit interaction, and continuous 
fixed covariate of baseline score.  A random subject effect term is included to account for 
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following covariance structures will be used to estimate the within subject errors in 
preliminary analyses for the changes from baseline to each scheduled visit:  Spatial 
Power, Compound Symmetry, and Unstructured.  For each efficacy parameter, the 
covariance structure converging to the best fit, as determined by the smallest value for the 
Akaike Information Criterion (AIC), will be used as the covariance structure in the 
MMRM analysis for that efficacy parameter.  The LS mean and standard error will be 
reported for each treatment group; the LS mean of treatment difference and associated 
95% CI and P value will be reported comparing elagolix plus E2/NETA group against 
placebo group.
8.4.1.2
Change from Baseline in PROMIS Fatigue Short Form 6a T-
Score
The PROMIS Fatigue Short Form 6a will be summarized as observed.  Missing data will 
not be imputed.  The change from baseline in PROMIS Fatigue Short Form 6a T-score at 
Month 6 and 12 will be evaluated using ANCOVA with treatment as the main effect and 
baseline score as a covariate.  The LS mean and standard error will be reported for each 
treatment group; the LS mean of treatment difference and associated 95% CI and P value 
will be reported comparing elagolix plus E2/NTEA group against placebo group.  
8.5
Additional Efficacy Analyses
8.5.1
Endpoints related to DYS, NMPP, Dyspareunia and Overall 
endometriosis-associated pain 
The proportion of responders at Months 1 – 12 based on change from baseline in average 
pain scores (DYS, NMPP, or dyspareunia) and analgesic use criteria (as defined in 
Table 1) will be analyzed using a logistic regression model with the responder/non-
responder categorization as the dependent variable, treatment as the main effect, and 
baseline pain score (DYS, NMPP or dyspareunia) as a covariate.  The proportion of 
responders, difference in proportions between elagolix plus E2/NETA group and placebo 
group, and odds ratio with corresponding 95% CI and P values will be presented.  The 
pain threshold for defining responders will be determined using the same ROC analysis 


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described for the co-primary endpoints.  Details of the ROC analysis are presented in 
Appendix A and the pain threshold values (X) are presented in Appendix C.  The same 
analyses will be repeated for the proportion of responders at Months 1 – 12 based only on 
change from baseline in average pain scores (DYS, NMPP, or dyspareunia).  The 
responder analysis will be using the LOCF approach.  
In addition, the proportion of responders at Months 1 – 12 based on change from baseline 
in average pain scores (DYS, NMPP, or dyspareunia) and analgesic use criteria and 
proportion of responders based on change from baseline in average pain scores (DYS, 
NMPP, or dyspareunia) only will also be summarized by treatment group using observed 
cases.  
The change from baseline to each month in DYS, NMPP, Dyspareunia, and overall 
endometriosis-associated pain during the 12-month placebo-controlled Treatment Period 
will be evaluated using MMRM analysis.  The MMRM analysis will include the fixed 
categorical effects of treatment, visit, and treatment-by-visit interaction, and the 
continuous fixed covariate of baseline pain score.  A random subject effect term is 
included to account for the correlation among the repeated measurements in the changes 
from baseline.  The selection and use of the covariance structure used in this analysis will 
follow the same process as described previously for the ranked secondary endpoints in 
Section 8.4.1.1.  The LS mean and standard error will be reported for each treatment 
group; the LS mean of treatment difference and associated 95% CI and P value will be 
reported comparing elagolix plus E2/NETA group against placebo group.
In addition, the change from baseline to each month in DYS, NMPP, dyspareunia, and 
overall endometriosis-associated pain during the 12-month placebo-controlled Treatment 
Period will be summarized by treatment group using observed cases.  The change from 
baseline to each monthly visit in overall endometriosis-associated pain during the open-
label Treatment Period will also be summarized by treatment group using observed cases.
In addition, the following plots will be provided using observed cases:


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●
Cumulative distribution function for reduction from baseline in DYS, NMPP, 
and dyspareunia to Months 1 – 12.
8.5.2
Rescue Analgesic Use for Endometriosis-Associated Pain 
The monthly average rescue medication pill counts as collected in the e-diary will be 
summarized using observed cases only with descriptive statistics by treatment group for 
the categories of analgesic use – NSAIDs, opioids, any class of analgesic medications 
(NSAIDs or opioids), and both classes of analgesic medications (NSAIDs and opioids) 
during the 12-month placebo-controlled Treatment Period.
For the following categories of analgesic use – NSAIDs, opioids, any class of analgesic 
medications (NSAIDs or opioids), and both classes of analgesic mediations (NSAIDs and 
opioids), the change from baseline to each month during the 12-month placebo-controlled 
Treatment Period will be evaluated using an MMRM analysis.  The MMRM analysis will 
include the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, 
and the continuous fixed covariate of baseline analgesic use.  A random subject effect 
term is included to account for the correlation among the repeated measurements in the 
dependent variable.  The selection and use of the covariance structure used in this analysis 
will follow the same process as described previously for the ranked secondary endpoints 
in Section 8.4.1.1.  The LS mean and standard error will be reported for each treatment 
group; the LS mean of treatment difference and associated 95% CI and P value will be 
reported comparing elagolix plus E2/NETA group against placebo group.  In addition, the 
change from baseline to each monthly visit during the 12-month placebo-controlled 
Treatment Period will be summarized by treatment group using observed cases.  
Proportion of responders based solely on the change from baseline in analgesic use will be 
summarized by treatment group at each visit during the 12-month placebo-controlled 
Treatment Period using the observed cases.  Definition of analgesic use responder will be 
based on Table 1.  In addition, the proportion of responders will be analyzed using a chi-
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E2/NETA group and placebo group, and odds ratio with corresponding 95% CI and 
P values will be presented.  
The proportion of responders for each category in Table 1 during the 12-month placebo-
controlled Treatment Period will be summarized using LOCF for elagolix plus E2/NETA 
group and placebo group.  In addition, the proportion of responders for each category in 
Table 1 during the 12-month placebo-controlled Treatment Period will be summarized by 
treatment group using observed cases.
For both NSAIDs and opioids, the monthly average rescue medication pill counts as 
collected in the e-diary will be summarized by medication name and treatment group 
using observed cases during the 12-month placebo-controlled Treatment Period.  In 
addition, number of subjects who switch NSAID and opioid medication at baseline, 
Month 6, and any time from Baseline to Month 6 during the placebo-controlled Treatment 
Period will be summarized.  
In addition, the standardized monthly average rescue medication pill counts as collected in 
the e-diary for both NSAIDs and opioids will be summarized by treatment group using 
observed cases during the 12-month placebo-controlled Treatment Period.  The following 
rule will be used to standardize NSAIDs and opioid:  
●
NSAIDs:  1 pill Naproxen = 1 pill Ibuprofen = 1 pill Diclofenac = 4 pills 
Celecoxib = 1 pill of NSAID use;
●
Opioids:  1 pill hydrocodone + acetaminophen = 1 pills codeine phosphate + 
acetaminophen = 1 pill of opioid use.
The monthly total rescue medication pill counts as collected in the e-diary will be 
summarized using observed cases only with descriptive statistics by treatment group for 
the NSAIDs and opioids use during the placebo-controlled Treatment Period.
For subjects with at least 1 pill use of NSAIDs at baseline, the number and percentage of 
subjects who are off NSAIDs use at each month will be summarized using observed cases.  
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subjects who take at least 1 pill count of NSAIDs at each month will be summarized using 
observed cases.  Same analyses will be repeated for opioids.  
8.5.3
Patient Global Impression of Change (PGIC)
During the 12-month placebo-controlled Treatment Period and open-label Treatment 
period, PGIC will be summarized by treatment group using the observed cases.  In 
addition, PGIC will be summarized for elagolix plus E2/NETA group and placebo group 
during the 12-month placebo-controlled Treatment Period using LOCF approach.  
Categorical summary of the PGIC results during the Treatment Period will be presented as 
follows.  
●
The number and percentage of subjects in each PGIC response category 
(7-point scale) will be summarized.  No statistical tests will be performed.
●
The response categories of "Very Much Improved" and "Much Improved" will 
be combined and labeled as "Much Improved or Better."  The remaining 
five categories of the PGIC scale will be combined and labeled "Otherwise."  
The number and percentage of subjects with response of a) "Much Improved 
or Better" and b) "Otherwise" will be summarized.  Elagolix plus E2/NETA 
group will be compared with placebo using a chi-square test at each of 
Months 1 – 12.  No statistical tests will be performed at Months 13 – 48.
8.5.4
Endometriosis Health Profile Questionnaire (EHP-30)
EHP-30 data will be summarized and analyzed using observed cases.  Missing data will 
not be imputed.
EHP-30 data will be summarized for the five dimensions of the core questionnaires (Pain, 
Control and Powerlessness, Emotional well-being, Social Support, Self-Image) and the 
dimension of sexual intercourse of the modular questionnaire during the Treatment 
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During the 12-month placebo-controlled Treatment Period, the change from baseline to 
each scheduled assessment for each dimension of the EHP-30 will be evaluated using an 
ANCOVA model with treatment as the main effect and baseline as a covariate.  The LS 
mean and standard error will be reported for each treatment group; the LS mean of 
treatment difference and associated 95% CI and P value will be reported comparing 
elagolix plus E2/NETA group with placebo.
In addition, the change from baseline to each scheduled assessment for each dimension 
will be summarized with descriptive statistics during the Treatment Period.  No 
comparisons or statistical tests will be performed.
8.5.5
EuroQol-5D 5 Level (EQ-5D-5L)
EQ-5D-5L data will be summarized and analyzed using observed cases.  Missing data will 
not be imputed.
The number and percentage of subjects with answers in each level of the EQ-5D-5L 
dimensions (Mobility, Self-care, Usual activities, Pain/Discomfort, and 
Anxiety/Depression) will be summarized with descriptive statistics during the Treatment 
Period.  No comparisons or statistical tests will be performed.
Subject's responses to the EQ-5D-5L will be combined into a unique health state, which 
consists of a 5-digit code with 1 digit from each of the 5 dimensions at each scheduled 
assessment during the Treatment Period.  The EQ-5D-5L states will be converted into a 
single preference-weighted health utility index score by application of country-specific 
weights (if available) or US weights if country-specific weights are unavailable.
During the 12-month placebo-controlled Treatment Period, the change from baseline to 
each scheduled assessment for health utility index score and EQ VAS will be analyzed 
using ANCOVA with treatment as the main effect and baseline as a covariate.  The LS 
mean and standard error will be reported for each treatment group; the LS mean of 
treatment difference and associated 95% CI and P value will be reported comparing 
elagolix plus E2/NETA group with placebo.


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In addition, the change from baseline to each scheduled assessment for health utility index 
score and EQ VAS will be summarized with descriptive statistics during the Treatment 
Period.  No comparisons or statistical tests will be performed.
8.5.6
Work Productivity and Activity Impairment Questionnaire:  
Specific Health Problem (WPAI:SHP)
Each of the 4 measures of the WPAI:SHP data (work time missed, impairment while 
working, overall work impairment, and activity impairment) will be summarized and 
analyzed using observed cases.  Missing data will not be imputed.
During the 12-month placebo-controlled Treatment Period, the change from baseline to 
each scheduled assessment for each of the measures as presented in the scoring guide will 
be analyzed using ANCOVA with treatment as the main effect and baseline as a covariate.  
The LS mean and standard error will be reported for each treatment group; the LS mean 
of treatment difference and associated 95% CI and P value will be reported comparing 
elagolix plus E2/NETA group with placebo.
In addition, the change from baseline to each scheduled assessment for each of the 
measures as presented in the scoring guide will be summarized with descriptive statistics 
during the Treatment Period.  No comparisons or statistical tests will be performed.
8.5.7
PROMIS Fatigue Short Form 6a
The PROMIS Fatigue Short Form 6a will be summarized and analyzed using observed 
cases.  Missing data will not be imputed.
During the 12-month placebo-controlled Treatment Period, the change from baseline to 
each scheduled assessment for PROMIS Fatigue Short Form 6a T-score will be analyzed 
using ANCOVA with treatment as the main effect and baseline as a covariate.  The LS 
mean and standard error will be reported for each treatment group; the LS mean of 
treatment difference and associated 95% CI and P value will be reported comparing 
elagolix plus E2/NETA group with placebo.


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In addition, the change from baseline to each scheduled assessment for PROMIS Fatigue 
Short Form 6a T-score will be summarized with descriptive statistics during the 
Treatment Period.  No comparisons or statistical tests will be performed.
8.5.8
Health Care Resource Utilization Questionnaire (HCRU)
HCRU data will be summarized using observed cases.  Missing data will not be imputed.  
HCRU data will be summarized with descriptive statistics by Visit during the Treatment 
Period.  The total number and percentage of Non-Study Health Care Practitioner visits 
and endometriosis-related Non-Study Health Care Practitioner visits overall and by the 
type of facility will be summarized.  In addition, the number and percentage of subjects 
with Non-Study Health Care Practitioner visits and endometriosis-related Non-Study 
Health Care Practitioner visits overall and by the type of facility will be summarized.
The number and percentage of subjects seen at office will be presented by the type of 
Non-Study Health Care Practitioner and endometriosis-related Non-Study Health Care 
Practitioner who administered care to the subject.  In addition, number of Non-Study 
Health Care Practitioner visits and endometriosis-related Non-Study Health Care 
Practitioner visits by practitioner will be summarized.
The number and percentage of subjects will be presented by the type of diagnostic or 
therapeutic procedures and endometriosis-related diagnostic or therapeutic procedures by 
visit during the Treatment Period.  No statistical tests will be performed.  
8.5.9
Hospitalization
Hospitalization related data will be summarized using observed cases.  Missing data will 
not be imputed.  Hospitalization data will be summarized with descriptive statistics during 
the Treatment Period based on the Adverse Events eCRF.  No statistical tests will be 
performed.
The number and percentage of subjects who were hospitalized or had prolonged 
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had prolonged hospitalization multiple times during the Treatment Period, she will be 
counted only once.  
The number of hospitalizations will be summarized by treatment group.  In addition, the 
number of days in hospital (i.e., discharge date – admission date + 1) will be summarized 
by treatment group.  Only hospitalizations with 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) will be 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.
8.6
Efficacy Subgroup Analyses
For each co-primary endpoint, the following subgroups will be explored to assess 
potential differences in treatment effect across subgroup levels.  The subgroup analyses 
will be performed at Month 6, which represents the study visit for statistical evaluation of 
the co-primary efficacy endpoints.
●
Baseline BMI:  < median, ≥median
●
Baseline BMI category:  Normal (< 25 kg/m2), Overweight (25 – < 30 kg/m2), 
Obese (≥30 kg/m2)
●
Race:  Black or African American, Not Black or African American
●
Baseline Age:  < 25 years old, 25 – ≤ 35 years old, > 35 years old.
The subgroup analysis will consist of a logistic regression with overall responder as the 
response variable, baseline value as a covariate, subgroup and treatment as main effects, 
and a treatment by subgroup interaction term.
9.0
Safety Analyses
9.1
General Considerations
Safety summaries will be provided separately using the Safety Analysis Set during the 
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Period, and All Elagolix plus E2/NETA Analysis Set as defined in Section 4.0.  Unless 
otherwise specified, no statistical comparisons or tests will be performed on Safety 
Analysis Set during the open-label Treatment Period or the All Elagolix plus E2/NETA 
Analysis Set.
Unless otherwise specified, the baseline for the 12-month placebo-controlled Treatment 
Period will be the last non-missing value obtained prior to or on Study Day 1.  The 
baseline during the open-label Treatment Period will be the last non-missing value 
obtained prior to or on the initiation day of elagolix (either elagolix alone or elagolix plus 
E2/NETA).  The baseline for All Elagolix plus E2/NETA Analysis Set will be the last 
non-missing value obtained prior to or on the initiation day of elagolix plus E2/NETA.
All safety analyses will be based on observed data.  Unless otherwise specified, missing 
data will not be imputed.
9.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock.  The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
study report.  Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise.  In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported.
9.2.1
Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) for each safety population are defined as 
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TEAEs during the 12-month placebo-controlled Treatment Period on Safety 
Analysis Set during the placebo-controlled Treatment Period
TEAEs during the 12-month placebo-controlled Treatment Period are defined as any AEs 
with the onset that is on or after the first dose of study drug during the 12-month placebo-
controlled Treatment Period and no more than 30 days after the last dose of study drug for 
subjects who premature discontinue during the 12-month double-blind Treatment Period 
or until the first dose of study drug in the open-label Treatment Period for subjects who 
enter the open-label Treatment Period.  AEs starting more than 30 days following 
discontinuation of study drug will not be included in summaries of treatment-emergent 
AEs but will be summarized separately.
TEAEs during the open-label Treatment Period on the Safety Analysis Set during 
the open-label Treatment Period 
TEAEs during the open-label Treatment Period are defined as any AEs with the onset that 
is on or after the first dose of study drug during the open-label Treatment Period and no 
more than 30 days after the last dose of study drug in the study.  AEs starting more than 
30 days following discontinuation of study drug will not be included in summaries of 
treatment-emergent AEs but will be summarized separately.
TEAEs for All Elagolix plus E2/NETA Analysis Set 
TEAEs for All Elagolix plus E2/NETA Analysis Set are defined as any AEs with the 
onset that is on or after the first dose of elagolix plus E2/NETA (either in the placebo-
controlled Treatment Period or open-label Treatment Period) and no more than 30 days 
after last dose of elagolix plus E2/NETA.  AEs starting more than 30 days following 
discontinuation of study drug will not be included in summaries of treatment-emergent 
AEs but will be summarized separately.
The number and percentage of subjects experiencing treatment-emergent AEs will be 
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The SOCs will be presented in alphabetical order, and the PTs will be presented in 
alphabetical order within each SOC.
9.2.2
Adverse Event Overview
An overview of treatment-emergent AEs will be presented consisting of the number and 
percentage of subjects experiencing at least one event for each of the following AE 
categories:
●
Any treatment-emergent AE
●
Any treatment-emergent AE related to study drug according to the investigator
●
Any severe treatment-emergent AE
●
Any serious treatment-emergent AE
●
Any treatment-emergent AE leading to discontinuation of study drug
●
Any treatment-emergent AE leading to death
●
Any treatment-emergent AE of special interest as specified in Appendix B
●
All deaths
In addition, for subjects who received elagolix 200 mg BID alone at Study Day 1, an 
overview of AEs during the placebo-controlled Treatment Period will be summarized 
separately for the first 6-month and second 6-month.  
9.2.3
Treatment-Emergent Adverse Events by SOC and PT
Treatment-emergent adverse events will be summarized by SOC and PT; by maximum 
relationship to study drug as assessed by the investigator (e.g., reasonable possibility or no 
reasonable possibility) and SOC and PT; by maximum severity and SOC and PT; and by 
subject number and SOC and PT.  Specific adverse events will be counted once for each 
subject for calculating percentages, unless stated otherwise.  In addition, if the same 
adverse event occurs multiple times within a subject, the highest severity and level of 
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In addition, treatment-emergent adverse events will be summarized by PT and sorted by 
decreasing frequency for the elagolix plus E2/NETA group.
In addition, for subjects who received elagolix 200 mg BID alone at Study Day 1, TEAEs 
during the placebo-controlled Treatment Period will be summarized separately for the 
first 6-month and second 6-month by SOC and PT.
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
An overview of AEs for All Elagolix plus E2/NETA Analysis Set will be presented per 
100 patient-years.  In addition, TEAEs for All Elagolix plus E2/NETA Analysis Set will 
be presented per 100 patient-years by SOC and PT.  AEs per 100 patient-years of 
exposure are defined as the number of AEs divided by the total exposure in 100 patient-
years.  Note that one event per preferred term per day per subject will be counted in the 
calculation of the number of AEs (i.e., a preferred term will not be counted twice on the 
same day for the same subject).  
where total patient years are defined as the sum of the study drug exposure (defined as 
date of last dose of elagolix plus E2/NETA – date of first dose of elagolix plus E2/NETA 
+ 30 days) of all subjects normalized by 365.25, and rounded to one decimal place.
9.2.5
Serious Adverse Events (Including Deaths) and Adverse 
Events Leading to Study Drug Discontinuation
The number and percentage of subjects experiencing the following categories will be 
tabulated according to the primary MedDRA SOC and PT.  In addition, listing of subjects 
experiencing the following categories will be generated.
●
Treatment-emergent SAEs


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Treatment-emergent AEs leading to discontinuation of study drug
●
Treatment-emergent AEs leading to death
9.2.6
Adverse Events of Special Interest
Adverse events of special interest will be summarized by SOC and PT and will be based 
on standardized or company MedDRA queries (SMQs or CMQs), or based on 
adjudication results.  
Detailed information about the search criteria are provided in Appendix B.
9.2.7
Hot Flushes and Night Sweats
Summary of total number of hot flushes and night sweats in the last 24 hours by subject-
reported severity categories and summary of total number of hot flushes, night sweats, and 
hot flushes or night sweats in the last 24 hours by maximum subject-reported severity will 
be provided by treatment group at each time point during the Treatment Period and 
Follow-up Period.  Listings of subject IDs associated with hot flush and night sweats in 
the last 24 hours by subject-reported severity categories and by maximum subject-
reported severity categories will be provided separately.
In addition, summary of time to first onset of treatment-emergent AE of hot flush, night 
sweats, hot flush and/or night sweats will be provided separately.
9.2.8
Post-Treatment Adverse Events
Post-Treatment Adverse Events are defined as AEs starting more than 30 days following 
discontinuation of study drug in the Treatment Period.  The Post-Treatment AEs will be 
summarized as follows:
●
Overview of Post-Treatment AEs 
●
Post-Treatment AEs by SOC and PT
●
Post-Treatment SAEs by SOC and PT


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In addition, listing of subjects with Post-Treatment AEs by SOC and PT and Post-
Treatment SAEs by SOC and PT will be provided.
9.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for Baseline where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded.  The 
clinical laboratory tests defined in the protocol operations manual (i.e., hematology and 
clinical chemistry) will be summarized.
Each laboratory variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum.  Mean change from baseline to each applicable post-baseline 
visit will be summarized for selected laboratory variables, with the number of 
observations, baseline mean, and visit mean.  The change from baseline mean, standard 
error, and 95% confidence interval will be presented for the mean change from baseline 
within each treatment group and difference between each elagolix group and placebo.  
Selected laboratory variables are lipid variables, liver variables (alkaline phosphatase, 
ALT, AST, bilirubin), hemoglobin, hematocrit, platelet count, and red blood cell (RBC) 
count.  For lipid variables, in addition to low-density lipoprotein cholesterol (LDL-C), 
high-density lipoprotein cholesterol (HDL-C), total cholesterol, triglycerides (TG)m 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.
Changes in selected laboratory parameters will be tabulated using shift tables by NCI 
CTC criteria and categorized as low, normal, or high based on the normal ranges of the 
laboratory used for each sample.  A shift table from baseline either to the worse value 
(based on NCI CTC criteria) during treatment or to minimum and maximum value (based 
on normal range), will be created.  A similar shift table will be provided to summarize 
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Laboratory abnormalities meeting CTC criteria grade 3 or 4 will be summarized.
The number and percentage of subjects meeting the following sponsor-defined potentially 
clinically significant lipid values will be summarized at baseline and each relevant visit by 
treatment group in the appropriate 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 
appropriateTreatment Period will be summarized by treatment group.  Listings will be 
provided to summarize subject-level laboratory data for subjects meeting PCS criteria.
●
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
The following plots will be provided by treatment group for HDL-C, LDL-C, and 
triglycerides during the appropriate Treatment Period:
●
Final post-baseline lab values vs.  Baseline lab values
●
Final post-baseline lab values vs.  Baseline lab values for subjects with NCI 
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Worst post-baseline lab values vs.  Baseline lab values
●
Worst post-baseline lab values vs.  Baseline lab values for subjects with NCI 
CTC Grade 3 or 4
●
Mean percent change from baseline in lipid parameters over time
In addition, plots of mean lab values over time during the Treatment Period will be 
provided for hemoglobin, total cholesterol, HDL-C, LDL-C, triglycerides, LDL-C/HDL-C 
ratio, ALT, AST, bilirubin, apolipoprotein A and apolipoprotein B.  
The number and percentage of subjects in each treatment group with maximum 
on-treatment laboratory values meeting the following criteria compared to the upper limit 
of normal (ULN) during the appropriate Treatment Period will be summarized 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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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 meets any of the criteria defined above.
The following plots will be generated:  peak AST vs.  peak bilirubin; peak ALT vs.  peak 
bilirubin.
9.4
Analysis of Vital Signs and Weights
Vital sign measurements of pulse rate, sitting systolic blood pressure, and sitting diastolic 
blood pressure will be summarized.
Each vital sign variable and weight will be summarized for all time points (starting with 
Baseline) with the number of non-missing observations, mean and standard deviation, 
median, minimum and maximum.  Mean change from baseline to each applicable post-
baseline visit will be summarized for each vital sign variable, with the number of 
observations, baseline mean, and visit mean.  The change from baseline mean, standard 
error, and 95% confidence interval will be presented for the mean change from baseline 
within each treatment group and difference between each elagolix group and placebo.
The number and percentage of subjects who have potentially clinically significant (PCS) 
vital sign and weight values meeting the following criteria will be summarized by 
treatment group.  All increase/decrease is calculated from Baseline to a post-baseline visit 
in the Treatment Period.  
●
Diastolic blood pressure
○
≤ 50 mmHg and ≥ 15 mmHg decrease
○
> 90 mmHg and ≥ 15 mmHg increase
○
≥ 100 mmHg
●
Systolic blood pressure
○
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○
≥ 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
○
≥ 7% increase.
Listings will be provided to summarize subject-level vital sign and weight data for 
subjects meeting PCS criteria.
The number and percentage of subjects who had a sustained PCS vital sign and weight 
values will be summarized by treatment group and a listing of these subjects will be 
provided.  A sustained PCS value is defined as 3 consecutive PCS values.
9.5
Other Safety Analyses
9.5.1
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS data will be summarized as observed by treatment group.
The C-SSRS – Baseline/Screening measured at Day 1 will be considered as Baseline 
C-SSRS.  Baseline C-SSRS will be summarized.  Other analysis of C-SSRS will only 
include subjects who have at least 1 post-baseline C-SSRS measurement, regardless of 
whether they had a baseline C-SSRS measurement.  The number of subjects with suicidal 
ideation, suicidal behavior, and self-injurious behavior without suicidal intent at each 
scheduled assessment during the appropriate Treatment Period will be summarized.  In 
addition, this table will be repeated for providing a summary of lifetime outcomes and 
past year outcomes at screening and Day 1.  No statistical test will be performed.


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The number of subjects with suicide-related treatment-emergent events based on the 
C-SSRS during the appropriate Treatment Period will be summarized.  No statistical tests 
will be performed.  
A listing of subjects with suicidal ideation, suicidal behavior, or self-injurious behavior 
without suicidal intent based on the C-SSRS during treatment period will be provided.
9.5.2
Bone Mineral Density
All analyses and summaries of bone mineral density (BMD) will be performed for each 
anatomic location, 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 will be included in the analysis with the data for the left femoral neck 
and left total hip, respectively (available for the majority of subjects).  If more than 
one scan is reported for an anatomic location within an analysis window, the worse (the 
lower value) of the multiple measurements will be used for analysis for each anatomic 
location.  Unless otherwise specified, the analysis of BMD will exclude subjects who 
switch machine manufacturer type (Lunar or Hologic).  
9.5.2.1
Bone Mineral Density during the Treatment Period
BMD
A summary of continuous BMD at each scheduled assessment will be provided during the 
appropriate Treatment Period.  This summary will include the sample size, mean, SD, 
median, minimum, and maximum.  This analysis will be repeated including subjects who 
switch machine manufacturer type (Lunar or Hologic), for subjects with scans only on 
Lunar machines, and for subjects with scans only on Hologic machines.
The analysis of percent change in BMD from baseline to each relevant visit during the 
Treatment Period will be based on an ANCOVA model with treatment as the main effect 
and baseline value of corresponding parameter as a covariate.  Elagolix plus E2/NETA 
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elagolix alone group at Month 6 during the placebo-controlled Treatment Period.  In 
addition, elagolix alone group will be compared to placebo at Months 6 and 12 during the 
placebo-controlled Treatment Period.  This analysis will be repeated including subjects 
who switch machine manufacturer type (Lunar or Hologic), for subjects with scans only 
on Lunar machines, and for subjects with scans only on Hologic machines.  
The number and percentage of subjects with percent change from Baseline to each 
scheduled assessment during the Treatment Period in mutually exclusive categories of 
BMD decrease:  ≤ 0%, > 0% – ≤ 1.5%, > 1.5% – ≤ 3%, > 3% – ≤ 4%, > 4% – ≤ 5%, > 5% 
– < 8%, and ≥ 8% will be summarized by treatment group.  Elagolix plus E2/NETA group 
will be compared to placebo at Months 6 and 12 and will be compared to elagolix alone 
group at Month 6 during the placebo-controlled Treatment Period using chi-square tests.  
In addition, elagolix alone group will be compared to placebo at Months 6 and 12 during 
the placebo-controlled Treatment Period.
The analysis of percent change in BMD from Month 6 to Month 12 during the Treatment 
Period will be based on an ANCOVA model with treatment as the main effect and 
Month 6 BMD values of corresponding parameter as a covariate for subjects who have 
both Month 6 and Month 12 BMD values.  Same analyses will be provided for percent 
change in BMD from Month 6 to Month 18 and Month 24.  Each elagolix group will be 
compared to placebo.
Cross-tabulation of the DXA scans performed versus Treatment Period completion will be 
provided after all subjects complete the Treatment Period or premature discontinue from 
the Treatment Period.
Listings of subjects meeting the following criteria during the Treatment Period will be 
provided:
●
Listing of subjects with BMD decrease ≥ 8%
In addition, the following plot will be provided as needed:


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Percent change from Baseline to each scheduled assessment (Months 6, 12, 18, 
24, 30, 36, 42, 48) during the Treatment Period in BMD vs.  Baseline BMD 
values for subjects with greater than 8% BMD decrease at any location during 
the Treatment Period.
●
Cumulative distribution function of percent change from baseline in BMD at 
each scheduled assessment (Months 6, 12, 18, 24, 30, 36, 42, 48) during the 
Treatment Period.
●
Percent change from Baseline to each scheduled assessment (Months 6, 12, 18, 
24, 30, 36, 42, 48) in BMD during the Treatment period.
Z-Score and T-Score
A continuous summary of the Z-score and T-score at each scheduled assessment will be 
provided by treatment group during the Treatment Period.  This summary will include the 
sample size, mean, SD, median, minimum, and maximum.
A categorical summary of Z-score will be provided at each scheduled assessment during 
the Treatment Period for the following categories:  ≤ –2.0, > –2.0 to ≤ –1.5, > –1.5 to
≤ –1.0, and > –1.0.  A categorical summary of T-score will be provided at each scheduled 
assessment during the Treatment Period for the following categories:  ≤ –2.5, > –2.5 to
< –1.0, and ≥ –1.0.  In addition, a categorical summary of the worst Z-score and T-score 
during the Treatment Period for the above categories will be provided.
9.5.2.2
Bone Mineral Density during the Follow-up Period
BMD
A summary of continuous BMD at each scheduled assessment will be provided by 
treatment group during the Follow-up Period.  This summary will include the sample size, 
mean, SD, median, minimum, and maximum.  This analysis will be repeated including
subjects who switch machine manufacturer type (Lunar or Hologic).
The analysis of percent change in BMD from baseline to each relevant visit during the 
Follow-up Period will be based on an ANCOVA model with treatment as the main effect 


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and baseline value of corresponding parameter as a covariate.  No comparison will be 
performed during the Follow-up Period.  This analysis will be repeated including subjects 
who switch machine manufacturer type (Lunar or Hologic).
The analysis of percent change in BMD from baseline will be repeated for the following 
subset of subjects:
●
subjects who have a Treatment Month X (e.g., Month 12) scan and a Follow-
up Month Y (e.g., Follow-up Month 6) scan and premature discontinue prior to 
next scheduled assessments.
The number and percentage of subjects with percent change from Baseline to each 
scheduled assessment during the Follow-up Period in mutually exclusive categories of 
BMD decrease:  ≤ 0%, > 0% – ≤ 1.5%, > 1.5% – ≤ 3%, > 3% – ≤ 4%, > 4% – ≤ 5%, > 5% 
– < 8%, and ≥ 8% will be summarized by treatment group.
In addition, the number and percentage of subjects with percent change from final on-
treatment to each scheduled assessment during the Follow-up Period in mutually 
exclusive categories of BMD decrease:  ≤ 0%, > 0% – ≤ 1.5%, > 1.5% – ≤ 3%, > 3% –
≤4%, > 4% – ≤ 5%, > 5% – < 8%, and ≥ 8% will be summarized by treatment group.
For the purpose of assessing post-treatment BMD recovery, the following summaries will 
be provided.  The "recovery" statistic was defined as
Recovery at Follow-up Month X = 100 × ((% change from baseline to final) – (% change 
from baseline to Follow-up Month X))/(% change from baseline to final) 
The "recovery" statistic is the proportion of BMD decrease at the final treatment scan 
recovered at Follow-up Month X.  For example, a subject who has a change of –2% at the 
end of treatment and has a change of –1% at Follow-up Month 6 has a recovery value of 
50% at Follow-up Month 6.  This statistic will only be defined for subjects who 
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A continuous summary of recovery at each relevant visit during the Follow-up Period will 
be provided including mean, standard deviation, median, and a within-group 95% 
confidence interval for the following subset of subjects:
●
All subjects who experienced a decrease from baseline at final treatment;
●
Subjects who premature discontinue after Month 6 and on or prior to 
Month 12;
●
Subjects who premature discontinue after Month 12 and on or prior to 
Month 18;
●
Subjects who premature discontinue after Month 18 and on or prior to 
Month 24;
●
Subjects who premature discontinue after Month 24 and on or prior to 
Month 30;
●
Subjects who premature discontinue after Month 30 and on or prior to 
Month 36;
●
Subjects who premature discontinue after Month 36 and on or prior to 
Month 42;
●
Subjects who premature discontinue after Month 42 or completed the 
Treatment Period.
Additionally, the number and percentage of subjects in each of the following categories 
will be provided for the subset of subjects listed above:  < 0%, 0 – 25%, > 25 – 50%, > 50 
– 75%, > 75 – 100%, > 100%.
Bone loss will be defined as > 3% at the spine, > 4% at the total hip, or > 5% at the 
femoral neck.  The following listings will be provided:
●
Listing of subjects with bone loss from baseline to final on-treatment visit and 
have continued bone loss from final on-treatment to Follow-up visits will be 
provided.  Subjects subsequently with an increase from Follow-up Month 6 to 
a subsequent Follow-up assessment will be excluded from this listing.
In addition, the following plots will be provided:


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●
Cumulative distribution function of recovery at Follow-up Month 6 and 
Follow-up Month 12.
●
Percent change from baseline to treatment and follow-up months of interest.
9.5.3
Uterine Bleeding
The following analyses will be conducted based on 28-day windows during the placebo-
controlled Treatment Period:  –28 – –1, 1 – 28, 29 – 56, 57 – 84, 85 – 112, 113 – 140, 
141 – 168, 169 – 196, 197 – 224, 225 – 252, 253 – 280, 281 – 308, 309 – 336.  For each 
window, only subjects who were on study drug for the entire window will be included in 
the analysis.
●
Continuous summary (mean, standard deviation, median, minimum, 
maximum) of the bleeding intensity.  This is calculated for any 
bleeding/spotting days only for subjects who experienced bleeding/spotting.  
Bleeding categories are represented numerically as follows:  Spotting = 1, 
Light = 2, Medium = 3, Heavy = 4.  
●
Continuous summary (mean, standard deviation, median, minimum, 
maximum) of the number of bleeding or spotting days.  This is calculated for 
any subjects who experienced bleeding and/or spotting.
●
Continuous summary (mean, standard deviation, median, minimum, 
maximum) of the number of bleeding only (no spotting) days.  This is 
calculated for any subject who experienced bleeding, excluding those who 
experienced spotting only with no bleeding days.
●
Continuous summary (mean, standard deviation, median, minimum, 
maximum) of the number of spotting days.  This is calculated for any subject 
who experienced only spotting or no bleeding (i.e., subjects with at least 1 day
of spotting and no days of light, medium, or heavy bleeding) in the given 
28-day interval.
●
Average number of uterine bleeding days by intensity.  For each time window, 
the number of days when subjects report uterine bleeding will be summarized 
for each bleeding category, i.e., missing, no bleeding, spotting, light, medium 


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or heavy bleeding, spotting to heavy bleeding combined, and light to heavy 
bleeding combined.
9.5.4
Amenorrhea
Determination of amenorrhea depends on a subject indicating both no menstrual period 
and no uterine bleeding as collected in the daily e-Diary.  Missing responses for uterine 
bleeding question will be treated as "No Bleeding."  Missing responses for the menstrual 
period question will be treatment as a response of "No" to the menstrual period question.  
The determination of amenorrhea also requires data indicating "No Bleeding" and the 
absence of a menstrual period for a minimum number of 56 days.  
The number and percentage of subjects with amenorrhea by month based on a 56-day 
window (Table 2) will be summarized by treatment group.  the numerator is the number 
of subjects on treatment who did not bleed during the specified time window and the 
denominator is the number of subjects on drug for the full window.  To be considered 
amenorrheic, a subject must have answered "No Bleeding" at least once during each 
28-day period of interest.  


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Table 2.
Monthly Summary of Amenorrhea – 56 days
Basis
Time Interval
Amenorrheic Status
Amenorrheic at 
least 56 days prior 
to last dose date 
Month 2
(Days 2 – 56)
Subjects did not bleed during Study Days 2 – 56 and 
subjects answered the e-Diary at least once during 
Days 2 – 28 and Days 29 – 56 (Truncated, 55 day 
window)
Month 3
(Days 29 – 84)
Subjects did not bleed during Study Days 29 – 84 and 
subjects answered the e-Diary at least once during 
Days 29 – 56 and Days 57 – 84
Month 4
(Days 57 – 112)
Subjects did not bleed during Study Days 57 – 112 and 
subjects answered the e-Diary at least once during 
Days 57 – 84 and Days 85 – 112
Month 5
(Days 85 – 140)
Subjects did not bleed during Study Days 85 – 140 and 
subjects answered the e-Diary at least once during 
Days 85 – 112 and Days 113 – 140
Month 6
(Days 113 – 168)
Subjects did not bleed during Study Days 113 – 168 and 
subjects answered the e-Diary at least once during Study 
Days 113 – 140 and Days 141 – 168
Month 7
(Days 141 – 196)
Subjects did not bleed during Study Days 141 – 196 and 
subjects answered the e-Diary at least once during 
Days 141 – 168 and Days 169 – 196
Month 8
(Days 169 – 224)
Subjects did not bleed during Study Days 169 – 224 and 
subjects answered the e-Diary at least once during 
Days 169 – 196 and Days 197 – 224
Month 9
(Days 197 – 252)
Subjects did not bleed during Study Days 197 – 252 and 
subjects answered the e-Diary at least once during 
Days 197 – 224 and Days 225 – 252
Month 10
(Days 225 – 280)
Subjects did not bleed during Study Days 225 – 280 and 
subjects answered the e-Diary at least once during Study 
Days 225 – 252 and Days 253 – 280
Month 11
(Days 253 – 308)
Subjects did not bleed during Study Days 253 – 308 and 
subjects answered the e-Diary at least once during Study 
Days 253 – 280 and Days 281 – 308
Month 12
(Days 281 – 336)
Subjects did not bleed during Study Days 281 – 336 and 
subjects answered the e-Diary at least once during 
Days 281 – 308 and Days 309 – 336
Final
(last 56 days including 
last dose day)
Subject did not bleed during the last 56 days on 
treatment and answered the e-Diary at least once during 
the periods [last dose date – 55, last dose date – 28] and 
[last dose date – 27, last dose date]


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9.5.5
Post-treatment Assessment of Menstruation
Time to first post-treatment menses will be summarized based on 28-day windows during 
the Follow-up Period:  Study End Days 1 – 28, 29 – 56, 57 – 84, 85 – 112, 113 – 140, 
141 – 168, and ≥ 169.  The number and percentage of subjects by who answered "Yes" to
the question "Has the subject had a menstrual period since stopping study drug" with an 
onset date fall into the above time interval will be summarized by treatment group.  The 
denominator is the number of subjects who answered the follow-up assessment of
menstruation eCRF at each time interval.  
9.5.6
Transvaginal Ultrasound
9.5.6.1
Ovarian Cysts
The presence of ovarian cysts will be noted at Baseline and each relevant post-baseline 
visit during the placebo-controlled and open-label Treatment Periods.  Significant ovarian 
findings included complex ovarian cyst > 3.5 cm, simple ovarian cyst > 5 cm or 
endometriomas > 3 cm.  The number and percentage of subjects with the pre-defined 
complex ovarian cysts and simple ovarian cysts will be summarized by treatment group at 
each relevant visit during the Treatment Period.
For each TAU/TVU 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).  The subject with multiple cyst findings was counted once in the 
numerator and denominator when reporting the number and percentage of subjects in the 
relevant category of significant ovarian findings.  A listing included all results across 
multiple cysts findings from multiple assessments (where available) from subjects who 
had significant ovarian findings.
9.5.6.2
Endometrial Thickness
The endometrial thickness at each relevant visit during the Treatment Period will be 
summarized with descriptive statistics.  Additionally, analysis of change in endometrial 
thickness from Baseline to each relevant visit during the Treatment Period will be 


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performed.  The mean change from Baseline each relevant visit during the 12-month 
placebo-controlled Treatment Period will be compared between each elagolix treatment 
group and placebo using one-way ANOVA with treatment as the main effect; no 
comparison will be conducted during the open-label Treatment period.  
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 will be summarized by 
treatment group at each relevant visit during the Treatment Period.  Each elagolix group 
will be compared to placebo using Fisher's exact test during the 12-month placebo-
controlled Treatment Period; no comparison will be conducted during the open-label 
Treatment Period.
9.5.6.3
Uterine Fibroids
The number and percentage of subjects with uterine fibroids present indicated by TVU 
will be summarized by treatment group at each relevant visit during the placebo-
controlled and open-label Treatment Periods.  The categories into which the number of 
fibroids are as follows:  0, 1, 2, 3, 4, 5, > 5, diffuse, and not evaluable.  Subjects with 
multiple uterine fibroids present will be counted once in the numerator and denominator 
when reporting the number and percentage of subjects with uterine fibroids.  
Listing of subjects with uterine fibroids will be presented.  
9.5.7
Endometrial Biopsy
The number and percentage of subjects in each category of endometrial biopsy results will 
be summarized by treatment group at each relevant visit during the placebo-controlled and 
open-label Treatment Periods.  If multiple assessments existed in a specific time window, 
all assessments will be displayed.
9.5.8
Pregnancy Results
Pregnancies and outcomes will be summarized by treatment group for the Treatment 
Period (placebo-controlled and open-label) and Follow-up Period.  Subjects with 


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conception date by sponsor more than 30 days after the last dose of study drug will be 
included in the summaries for the Follow-up Period.  
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.  
Positive pregnancy test results (serum, urine, and both) and a listing of all positive 
pregnancy test results will be provided.
Pregnancy outcome will be summarized by treatment group.  Additionally, a listing of 
pregnancy information will be provided.  Pregnancy outcome includes:
●
Number of pregnancies
●
Live births
○
Pre-term (extremely pre-term:  < 28 weeks; very pre-term:  28 –
< 32 weeks; moderate to late preterm:  32 – < 37 weeks)
○
Term (37 – < 42 weeks)
○
Post-term (≥42 weeks)
●
Spontaneous abortion (< 6, 6 – 13, > 13 weeks gestation)
●
Termination of pregnancy
●
Ectopic pregnancy
●
Still birth
●
Congenital anomaly
●
Lost to follow-up
●
Subjects refused to provide information
●
Other
●
Ongoing (pregnancy ongoing at end of study)
●
Maternal exposure to Elagolix/Study drug (0, > 0 – 4, > 4 – 6, > 6 – 12, > 12 –
23, > 23 weeks)
●
Embryo/Fetal exposure to Elagolix/Study drug assessed by the sponsor 
(0, > 0 – 4, > 4 – 6, > 6 – 12, > 12 weeks)


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Annualized pregnancy rate during treatment will be reported by treatment group.  The 
annualized pregnancy rate will be calculated as
Annualized pregnancy rate = (number of pregnancies/days of exposure to treatment) 
× 365
In addition, listings of fetal/newborn, infant post-delivery assessments, and infant during 
6 – 12 month follow-up assessment will be provided.
The above information will be summarized primarily based on data collected on the 
pregnancy case report form.  Information not directly obtained from the case report form 
will use the following definitions.
Gestation day 
Gestation Day 0 was calculated by subtracting the gestational age provided according to 
the first trimester ultrasound date from the first trimester ultrasound date.  If no gestational 
age was provided, it will be imputed by subtracting 14 days from the midpoint between 
the subject's last negative pregnancy test date and the date of the positive pregnancy test.
Gestational age 
Gestational age at delivery was calculated from gestation Day 0 to the date of delivery.  
Gestational age at abortion was calculated from gestation Day 0 to the date of abortion.
Conception date 
Conception date by sponsor was calculated from the gestational age provided from the 
first trimester ultrasound, by adding 14 days to gestation Day 0.  If no gestational age was 
provided, the conception date by sponsor was imputed as the midpoint between the 
subject's last negative pregnancy test date and the date of the positive pregnancy test.


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Maternal exposure
Maternal exposure to study drug was calculated as the last dose date of study drug – the 
first dose date of study drug + 1.
Embryo/fetal exposure 
Embryo/fetal exposure to study drug by sponsor was calculated from the conception date 
by site/sponsor to the date of maternal last dose of study drug.  
10.0
Overall Type-I Error Control
The primary comparison for the co-primary will be made between elagolix plus E2/NETA 
and placebo.  The elagolix alone arm will be served as a reference arm.  Therefore, no 
adjustment of the type I error rate (alpha) for the primary endpoint is needed.  Ranked 
secondary endpoints will be tested following a fixed-sequence testing procedure.  
Specifically, testing will begin with testing each of the co-primary endpoints using alpha 
of 0.05 (2-sided) for elagolix plus E2/NETA compared to placebo.  If both co-primary 
endpoints achieve statistical significance with elagolix W2/NETA as compared to 
placebo, continued testing will be performed for the ranked secondary endpoints 
following a fixed-sequence testing procedure.
11.0
Version History
Table 3.
SAP Version History Summary
Version
Date
Summary
1.0
29 April 2020
Original version
12.0
References


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Appendix A.
Receiver Operating Characteristics (ROC) Analysis for 
Determination of Thresholds for Reduction in Pain
The ROC analysis will be conducted prior to blind break and will contain all randomized 
subjects who received at least one dose of study drug.  Subjects who prematurely 
discontinue at or before Month 6 will have their pain scores and PGIC response carried 
forward (LOCF) – from the previous time point when both PGIC and pain score data are 
observed.  Subjects who a) prematurely discontinue at or before Month 6 and have no 
month with both a PGIC and e-Diary data (DYS, NMPP, or dyspareunia) to carry 
forward, or b) either prematurely discontinue after Month 6 or complete the Treatment 
Period but are missing Month 6 PGIC will be assigned a PGIC response of "No Change."  
Subjects who a) prematurely discontinue at or before Month 6 and have no month with 
both a PGIC and e-Diary data (DYS, NMPP, or dyspareunia) to carry forward, or b) either 
prematurely discontinue after Month 6 or complete the Treatment Period but are missing 
Month 6 pain scores will be assigned a change from baseline in pain score equal to 0.
The threshold for reduction in pain will be determined based on a ROC analysis using the 
PGIC assessment at Month 6 as an anchor and change from baseline in pain score (DYS, 
NMPP, or dyspareunia) at Month 6 as the independent variable.  The PGIC is a 7-point 
response scale "Since I started taking the study medication, my endometriosis related pain 
has:  very much improved (1), much improved (2), minimally improved (3), no change 
(4), minimally worse (5), much worse (6), very much worse (7)."  The responses of "much 
improved" and "very much improved" on PGIC will used to define responders, and the 
threshold for response (the value of X) will be chosen to balance sensitivity and 
specificity.  That is, it is the value that corresponds to the point on the ROC curve that is 
closest to the upper left corner, i.e., closest to 100% sensitivity and 100% specificity.  No 
other covariates will be included in the ROC analysis.  
The ROC analyses for DYS, NMPP, and dyspareunia will be conducted separately.  The 
threshold obtained from the ROC analysis using PGIC at Month 6 and change from 
baseline to Month 6 in DYS will be fixed and used for all responder analyses at all time 


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points during the 12-month placebo-controlled Treatment Period.  Same applies to NMPP 
and dyspareunia.
The results of the ROC analyses can be found in Appendix C.


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Appendix B.
Definition of Adverse Events of Special Interest (AESI)
Adverse Events of Special Interest (AESI) will be identified using the following search 
criteria:
Item of Safety Interest
Method of Surveillance
Hot flashes
Non-bone related hypoestrogenic effects CMQ
Bone mineral density loss
Osteoporosis/Osteopenia SMQ
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
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
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
Elevated hepatic transaminases
Drug related hepatic disorders – comprehensive search SMQ
Enhanced pharmacovigilance hepatic terms (elagolix product 
specific) PMQ


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Appendix C.
Receiver Operating Characteristics (ROC) Thresholds for 
Reduction in Pain
Receiver Operating Characteristics (ROC) Thresholds
Pain Variable
Measure
ROC Threshold
Dysmenorrhea
Change from Baseline
-0.92
Non-Menstrual Pelvic Pain
Change from Baseline
-0.55
Dyspareunia
Change from Baseline
-0.30
Receiver Operating Characteristic Curves (ROC Curves)
Dysmenorrhea – Change from Baseline to Month 6


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Non-Menstrual Pelvic Pain – Change from Baseline to Month 6
Dyspareunia – Change from Baseline to Month 6