Conditions: Endometriosis
Keywords: Endometriosis associated pain Elagolix Non-menstrual pelvic pain (NMPP) Dysmenorrhea (DYS)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 11
Healthy volunteers: no

Brief summary:
This is a Phase 3, dose-escalation study designed to evaluate the safety and efficacy of both elagolix alone and elagolix plus estradiol/norethindrone acetate (E2/NETA) over 24 months in the management of endometriosis with associated moderate to severe pain in premenopausal women.

Detailed description:

Arms:
arm 1: Day 1 Through Month 3 (Open-Label): Open-Label elagolix 150 mg QD

Month 4 Through Month 24 (Double-Blind): Efficacy responders to elagolix 150 mg QD at Month 3 and continue treatment through Month 24 arm 2: Day 1 Through Month 3 (Open-Label): Open-Label elagolix 150 mg QD

Month 4 Through Month 24 (Double-Blind): Incomplete efficacy responders to elagolix 150 mg QD at Month 3 and randomized to elagolix 200 mg BID plus E2/NETA 1/0.5 mg QD treatment group and continue treatment through Month 24. arm 3: Day 1 Through Month 3 (Open-Label): Open-Label elagolix 150 mg QD

Month 4 Through Month 6 (Double-Blind): Incomplete efficacy responders to elagolix 150 mg QD at Month 3 and randomized to elagolix 150 mg QD treatment group

Month 7 Through Month 24 (Double-Blind): Incomplete efficacy responders to elagolix 150 mg QD at Month 6 and assigned to elagolix 200 mg BID plus E2/NETA 1/0.5 mg QD treatment group and continue treatment through Month 24. arm 4: Day 1 Through Month 3 (Open-Label): Open-Label elagolix 150 mg QD

Month 4 Through Month 6 (Double-Blind): Incomplete efficacy responders to elagolix 150 mg QD at Month 3 and randomized to elagolix 150 mg QD treatment group

Month 7 Through Month 24 (Double-Blind): Efficacy responders to elagolix 150 mg QD at Month 6 and continue treatment through Month 24.

Interventions: intervention 1: elagolix intervention 2: estradiol/norethindrone acetate (E2/NETA)
Intervention descriptions: intervention 1: Tablets intervention 2: Capsules

Protocol document:
Prot_SAP_000.pdf: 
Elagolix
M16-383 Protocol
1
1.0
Title Page
Clinical Study Protocol M16-383
A Study to Evaluate Safety and Efficacy of Elagolix 
Alone or Elagolix with Hormonal Add-Back in 
Subjects with Endometriosis with Associated 
Moderate to Severe Pain
AbbVie Investigational 
  Product:
Elagolix
Date:
29 September 2017
Development Phase:
3
Study Design:
The study employs an open label 3 month run in period 
with a 21 month randomized, double-blind active treatment 
period.
Investigator(s):
Multicenter Trial:  Investigator information is on file at 
AbbVie
Sponsor:
AbbVie
Sponsor/Emergency 
  Contact:
* The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are 
provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
Application with the Competent Authority.
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
NCT03343067


Elagolix
M16-383 Protocol
2
1.1
Synopsis
AbbVie Inc.
Protocol Number:  M16-383
Name of Study Drug:  Elagolix
Phase of Development:  3
Name of Active Ingredient:  Elagolix sodium
Date of Protocol Synopsis:  29 September 2017
Protocol Title:  A Study to Evaluate Safety and Efficacy of Elagolix Alone or Elagolix with Hormonal 
Add-Back in Subjects with Endometriosis with Associated Moderate to Severe Pain
Objectives:
The objectives of this study are to:
!
Compare the efficacy at Treatment Month 6 of dose escalation to elagolix 200 mg BID + 
estradiol 1 mg/norethindrone acetate 0.5 mg (E2/NETA 1 mg/0.5 mg) QD versus continuing 
elagolix 150 mg QD in subjects who are incomplete efficacy responders to elagolix 150 mg QD 
at Treatment Month 3
!
Assess the effects of elagolix 150 mg QD and elagolix 200 mg BID + E2/NETA (1 mg/0.5 mg) 
QD on BMD after up to 24 months of treatment
!
Evaluate the modifiable and non-modifiable risk factors associated with changes in Bone 
Mineral Density (BMD) over 24 months of treatment
Investigators:
Multi-center; Investigator information is on file at AbbVie.
Study Site(s):  Approximately 200
Study Population:  Premenopausal females (aged 18 – 49 years, inclusive) who have a documented 
surgical diagnosis of endometriosis (e.g., laparoscopy or laparotomy) established by visualization or 
histology within 10 years prior to entry into Washout or Screening and with moderate to severe pain.
Number of Subjects to be Enrolled:  Approximately 890
Methodology:
This is a Phase 3, dose-escalation study designed to evaluate the safety and efficacy of both elagolix 
150 mg QD and elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD over 24 months in the 
management of endometriosis with associated moderate to severe pain in premenopausal women.  After 
establishing eligibility, the study starts with open-label treatment on elagolix 150 mg QD for the 
first 3 months.
Following the Treatment Month 3 visit and continuing through Treatment Month 24, the study is 
conducted in a double-blinded manner with treatment assignment determined based on the efficacy 
responder status assessed at Months 3 and 6.


Elagolix
M16-383 Protocol
3
Methodology (Continued):
At the Treatment Month 3 study visit, the efficacy responder status of each subject will be determined 
based on the responses to the Daily Diary endometriosis-associated pain score via a Numeric Rating 
Scale (NRS) in the electronic diary (e-Diary).  The results of the responder status determination are 
blinded and the details of the responder status calculation are outlined below.  Subjects determined to be 
efficacy responders at the Treatment Month 3 visit will continue to dose with elagolix 150 mg QD in a 
blinded manner throughout the remainder of the 24-month Treatment Period.  Subjects determined to be 
incomplete efficacy responders at the Treatment Month 3 visit will be randomized in a 1:1 ratio to 
receive elagolix 150 mg QD or elagolix 200 mg BID + E2/NETA (1 mg/0.5 mg) QD.  Subjects who 
were randomized to receive elagolix 200 mg BID + E2/NETA (1 mg/0.5 mg) QD will continue with this 
treatment in a blinded manner throughout the remainder of the 24-month Treatment Period.
At the Treatment Month 6 study visit, the efficacy responder status of each subject will be determined in 
the same blinded manner as at the Treatment Month 3 study visit.  Subjects who randomized at 
Treatment Month 3 to receive elagolix 150 mg QD and are subsequently determined to be efficacy 
responders at Treatment Month 6 will continue to receive elagolix 150 mg QD throughout the remainder 
of the 24-month Treatment Period.  Subjects who randomized at Treatment Month 3 to receive elagolix 
150 mg QD and are subsequently determined to be incomplete efficacy responders at Month 6 will 
receive elagolix 200 mg BID + E2/NETA (1 mg/0.5 mg) QD throughout the remainder of the 24-month 
Treatment Period.
The Treatment Groups are described below:
Day 1 Through Month 3 (Open-Label):  
!
Open-Label elagolix 150 mg QD
Month 4 Visit Through Month 6 (Double-Blind): 
!
(A) Efficacy responders to elagolix 150 mg QD at Month 3 
!
(B) Incomplete efficacy responders to elagolix 150 mg QD at Month 3 and randomized to 
elagolix 150 mg QD treatment group 
!
(C) Incomplete efficacy responders to elagolix 150 mg QD at Month 3 and randomized to 
elagolix 200 mg BID plus E2/NETA 1/0.5 mg QD treatment group
Month 7 Through Month 24 (Double-Blind):
!
(A) Efficacy responders to elagolix 150 mg QD at Month 3 and continue treatment through 
Month 24
!
(C) Incomplete efficacy responders to elagolix 150 mg QD at Month 3 and randomized to 
elagolix 200 mg BID plus E2/NETA 1/0.5 mg QD treatment group and continue treatment 
through Month 24.
!
(D) Incomplete efficacy responders to elagolix 150 mg QD at Month 3, randomized to elagolix 
150 mg QD treatment group and remain incomplete efficacy responders at Month 6, dose 
increased to elagolix 200 mg BID plus E2/NETA 1/0.5 mg QD through Month 24
!
(E) Incomplete efficacy responders to elagolix 150 mg QD at Month 3, randomized to elagolix 
150 mg QD treatment group and are efficacy responders at Month 6 continue treatment through 
Month 24


Elagolix
M16-383 Protocol
4
Study Duration:
The total duration for this study is approximately 27 to 50 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 consenting; duration of washout depends on the type of 
excluded medication being taken)
!
Screening Period – approximately 1.5 to 4 months prior to the first dose of study drug.
!
Treatment Period – up to a total of 24-months treatment duration consisting of the following: 
o
Open-Label Run-In Period:  3 month treatment duration from  Day 1 to Treatment Month 3 
study visit
o
Double-Blind Active Treatment Period:  Treatment Month 3 study visit through Treatment 
Month 24 study visit
!
Follow-up Period – up to 12 months following the last dose of study drug
Washout Period:
Following informed consent, subjects who have been taking exclusionary medications prior to screening 
that require discontinuation (washout), must enter the Washout Period.  The duration of the required 
washout period is based on the excluded medication being taken.  Applicable study procedures may be 
performed, such as medical, social and gynecological history (including documentation of diagnosis of 
endometriosis via surgical visualization, histological diagnosis), a brief 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.  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:
Following informed consent (if Washout was not required), subjects will enter into the Screening Period.  
Eligible subjects will have documentation of a surgical confirmation of endometriosis.  In addition to 
medical and gynecological history, specific history will be obtained to help identify potential risk 
factors/predictors related to changes in BMD, including modifiable and non-modifiable risk factors.  The 
following safety assessments will be completed during the Screening Period:  a dual energy x-ray 
absorptiometry (DXA) of the lumbar spine, total hip and femoral neck  to document baseline BMD; a 
transvaginal ultrasound (TVU) to rule out any clinically significant gynecological disorders such as 
ovarian cysts, fibroids or endometrial polyps; a Papanicolau (Pap) test to rule out malignancy or pre-
malignant changes; a mammogram in subjects 39 years of age or older if one has not been performed 
within 3 months prior to start of Screening; baseline ECG; as well as clinical laboratory testing.  


Elagolix
M16-383 Protocol
5
Screening Period (Continued):
An electronic 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; Daily Diary 
endometriosis-associated pain score via NRS; dyspareunia (if applicable) via a 4-point scale and the 
presence and intensity of uterine bleeding.  Subjects will record use of protocol allowed analgesic rescue 
medications for endometriosis-associated pain in the e-Diary.  A minimum of 45 days of daily e-Diary 
entries are required to be completed during the Screening Period.  To be considered eligible for the 
study, during the last 35 calendar days of the Screening Period, subjects must have at least 2 days of 
moderate or severe DYS and one of the following:  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.  Additionally, subjects must have 2 menstrual cycles with cycle lengths 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 the Screening Period.  Subjects will be allowed to take protocol-
specified analgesic rescue medication for endometriosis-associated pain and will record use daily in the 
e-Diary.  Protocol specific analgesic rescue medication for endometriosis-associated pain will include 
four equivalent NSAID choices and two equivalent opioid choices); use of other rescue analgesic or the 
use of prophylactic analgesic medications for endometriosis-associated pain is not allowed.  The subject 
and Investigator will decide on the appropriate rescue analgesic medications for that subject (based on 
the approved options).  
Subjects are also required to use appropriate non-hormonal methods of contraception (as applicable).  
Contraceptive counseling will be provided and contraceptives dispensed, as necessary.
Treatment Period:
The Treatment Period begins with Study Day 1.  Study Day 1 will occur between Cycle Days 1 to 10 of 
a subject's menses (Cycle Day 1 is defined as first day with full menstrual flow) for all subjects who 
meet eligibility criteria during the Screening Period.  On Study Day 1, all subjects will begin open-label 
dosing with elagolix 150 mg QD.  The first dose of study drug will be administered at the study site on 
Day 1 and study drug kits will be dispensed to subjects to continue daily dosing.  Monthly on-site study 
visits will be conducted during the first 6 months of the Treatment Period.  Subjects will be expected to 
come in to the site every other month during Treatment Months 7 – 12 and every third month during 
Treatment Months 13 – 24.  Telephone contacts will be conducted at months without an on-site visit.  
Subjects will be asked to complete various patient-reported outcome (PRO) questionnaires at designated 
study visits.  At the Day 1 visit (prior to dosing) and at all monthly visits (on-site and telephone 
contacts), site staff will administer to subjects the overall endometriosis-associated pain questionnaire, 
an 11-point NRS with a 7-day recall period.  Starting at Treatment Month 1 and at all on-site visits 
thereafter, subjects will complete the Patient Global Impression of Change (PGIC) questionnaire.  
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 telephone contact visits.  A positive urine pregnancy test result must be confirmed with 
a serum pregnancy test.  If a serum pregnancy test result is positive at any time during the Treatment 
Period, study drug will be discontinued.


Elagolix
M16-383 Protocol
6
Treatment Period (Continued):
Subjects will continue to use the daily e-Diary to record DYS, NMPP; dyspareunia; Daily Diary 
endometriosis-associated pain score via NRS; rescue analgesic use for endometriosis-associated pain and 
the presence and intensity of uterine bleeding through Treatment Month 6.  Throughout the 24-month 
Treatment Period, all subjects will be allowed to take protocol specified analgesic medication for 
endometriosis-associated pain.  Use of non-protocol specific analgesic or prophylactic analgesic 
medications for endometriosis-associated pain will not be allowed.  After Treatment Month 6 use of 
protocol specific analgesic rescue medications will be assessed and documented at the study visits.
At designated study visits during the 24-month Treatment Period, blood samples will be collected for 
clinical safety labs, including vitamin D levels.  In addition, blood samples will be collected for assay of 
serum estradiol, plasma concentrations of elagolix and norethindrone.
BMD will be assessed throughout the Treatment Period.  Following baseline, DXA scans will be 
obtained at Treatment Months 6, 12, 18 and 24.  A DXA scan will be required if a subject discontinues 
at the time of or after the Treatment Month 6 visit or if the reason for premature discontinuation is due to 
the occurrence of a fracture or any newly diagnosed bone condition.  
Vital signs assessments will be conducted at all on-site study visits.  Additional safety assessments are 
completed as appropriate at designated study visits throughout the Treatment Period.  Adverse event and 
concomitant medication review will be conducted at all study visits.
Criteria for Assessment of Subject Status Following the Open-Label Run-In Period:
At the Treatment Month 3 study visit, subjects will be assessed as either an 'efficacy responder' or an 
'incomplete efficacy responder' based on responses entered in the e-Diary on the Daily Diary 
endometriosis-associated pain score via NRS.  The status of a subject will be determined (in a blinded 
manner) within the e-Diary system as follows: 
!
Efficacy responder:  ≥ 30% decrease (improvement) from Baseline based on the average of the 
daily Diary endometriosis-associated pain score via NRS over a 35 day window
!
Incomplete efficacy responder:  < 30% decrease (improvement) from Baseline based on the 
average of the Daily Diary endometriosis-associated pain score via NRS over a 35 day window
Following conclusion of the Open-Label Run-In Period, treatment arm assignment for all subjects will 
become and remain blinded for the remainder of the 24-month Treatment Period.
Dose Escalation During the Treatment Period:
Subjects assessed as "efficacy responders" (as defined above) at Treatment Month 3 visit will be 
assigned to continue dosing with elagolix 150 mg QD (Group A) in a blinded manner via Interactive 
Response Technology (IRT).  All other subjects assessed as "incomplete efficacy responders" at 
Treatment Month 3 visit will be assigned randomly (in an equal ratio) via IRT to either elagolix 150 mg 
QD (Group B) or elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD (Group C) for 3 months.  To 
preserve the blind, IRT will be utilized for study drug assignment for all subjects.  The first dose from 
the newly assigned study drug kit at Treatment Month 3 will be administered at the site.  The 
pharmacokinetic and pharmacodynamics samples must be obtained prior to study drug administration at 
the Treatment Month 3 visit.


Elagolix
M16-383 Protocol
7
Dose Escalation During the Treatment Period (Continued):
At the Treatment Month 6 study visit, in a blinded manner via IRT, all subjects who were incomplete 
efficacy responders and randomly assigned at Treatment Month 3 to elagolix 150 mg QD will again be 
assessed for efficacy response in the same manner as was done at the Treatment Month 3 visit.  All 
subjects in this group (Group B) who become efficacy responders will continue dosing with elagolix 
150 mg QD in a blinded manner (Group E).  All other subjects in this group who are assessed as 
incomplete efficacy responders at Treatment Month 6 will escalate dosing to elagolix 200 mg BID plus 
E2/NETA 
(1 mg/0.5 mg) QD (Group D).  To preserve the blind, IRT will be utilized for treatment assignment of all 
subjects; however, only subjects randomly assigned at Treatment Month 3 to the elagolix 150 mg QD 
(Group B) will have a chance for dose modification.  The first dose from the newly assigned study drug 
kit at Treatment Month 6 will be administered at the site.  The pharmacokinetic and pharmacodynamics 
samples must be obtained prior to study drug administration at the Treatment Month 6 visit.
The treatment assignments following the Treatment Month 6 study visit will continue for all subjects for 
the duration of the 24-month Treatment Period in a blinded manner.  There will not be further dose 
adjustments following the Treatment Month 6 visit for any subject.
BMD Assessment and Subject 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 and 24.  If the results of any post-baseline DXA prior to the Treatment Month 24 timepoint, as read 
by the central imaging vendor selected for the study, document a Z-score (for subjects < 40 years of age 
at the time of the Screening DXA) or a 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 > 8% decrease in BMD 
from baseline the subject must be discontinued from study drug dosing and will enter the Follow-Up 
Period.
Follow-Up Period:
Subjects will enter the Follow-Up Period for up to 12 months to assess bone recovery after up to 
24 months of treatment with the study drug.  Subjects who prematurely discontinue (PD) from the study 
at the time of or after the Treatment Month 6 visit or if the reason for PD is related to bone fracture will 
enter the Follow-Up Period.  
DXA scans of the lumbar spine, total hip and femoral neck will be obtained.  Any ongoing adverse 
events or adverse events of bone fracture, clinically significant BMD decrease or a newly diagnosed 
medically-related bone condition will be collected during the Follow-Up Period.  Concomitant 
medication use will be reviewed at on-site visits.
The Follow-Up Period for the study should conclude for all subjects approximately 30 days after the last 
completed Treatment Month 24 visit.  
Central Laboratory and Central Imaging Vendors:
DXA, TVU, safety clinical lab samples will be analyzed/evaluated using central laboratories or imaging 
vendors.  Assays for pharmacokinetics and pharmacodynamics will be analyzed at AbbVie.


Elagolix
M16-383 Protocol
8
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 [IBS]), that requires chronic analgesic therapy, which would interfere with the 
assessment of endometriosis-associated 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.
!
Subject has a history of any of the following:
o
Major depression or post-traumatic stress disorder (PTSD) 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) at Screening or prior 
to study drug dosing on Day 1.


Elagolix
M16-383 Protocol
9
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
!
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:
o
Intercurrent bone disease (e.g., ostemalacia, 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 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 
enrollment on Day 1 OR 
o
a clinically significant medical condition that is anticipated to required 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).
Investigational Product(s):
Elagolix 150 mg and 200 mg
Estradiol 1 mg/norethindrone acetate 0.5 mg (E2/NETA)
Dose(s):
Elagolix 150 mg QD
Elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD 
Reference Therapy:
Placebo to match elagolix; placebo to match E2/NETA
Mode of Administration:
Oral
Duration of Treatment:  Up to 24 months of treatment
Duration of Follow-Up:  Up to 12 months


Elagolix
M16-383 Protocol
10
Criteria for Evaluation:
Efficacy:
Primary Efficacy Variables:
The co-primary efficacy endpoints will be the proportion of responders (treatment Group B versus 
treatment Group C) 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 collected in the daily e-Diary will also be 
included in the responder definition.
Other Efficacy Endpoints:
The following efficacy variables will be collected in the daily e-Diary through Treatment Month 6 and 
will be summarized:
!
DYS
!
NMPP
!
Dyspareunia
!
Daily Diary endometriosis-associated  pain score via Numeric Rating Scale (NRS)
!
Rescue analgesic medication use
In addition, the following efficacy variables will be collected and summarized:
!
PGIC
!
Overall endometriosis-associated pain via NRS (7-day recall)
!
Patient reported outcome (PRO) and Outcomes Rating Scales questionnaires
Safety:
BMD Assessments:
BMD assessments will be summarized.  Modifiable and non-modifiable risk factors will be assessed as 
they relate to baseline BMD and changes in BMD over time, including:  smoking and alcohol use, 
previous use of calcium and vitamin D, prior medications, race, age, height and weight (BMI), physical 
activity (collected via the International Physical Activity Questionnaire [August 2002] Short Last 7 days 
Self-Administered format) family history of fracture and family history of osteoporosis.
Other Safety Assessments:
Safety evaluations will include physical examinations, AEs and concomitant medications, clinical 
laboratory tests and vital sign measurements.  Endometrial health will be assessed via TVU and biopsy.
Statistical Methods:
Efficacy:  
The primary efficacy comparisons will be at Treatment Month 6 between the elagolix 200 mg BID plus 
E2/NETA treatment group (Group C) and elagolix 150 mg QD group (treatment Group B) in patients 
who are incomplete efficacy responders to elagolix 150 mg QD treatment at Month 3.  Change and 
percent change from baseline in pain parameters collected via the e-Diary, proportion of responders for 
each pain parameter, change and percent change from baseline in protocol-specified rescue analgesic 
use, and other PROs will be summarized by month.  


Elagolix
M16-383 Protocol
11
Statistical Methods (Continued):
Pharmacokinetic:  
Plasma concentrations of elagolix and norethindrone will be listed for each subject by visit.  Elagolix 
and norethindrone exposures will be summarized.  Elagolix pharmacokinetic data may be combined with 
data from other studies to conduct population pharmacokinetic analysis and may be used in exposure-
response analysis.
Pharmacodynamic:
Concentrations of estradiol will be obtained at designated visits throughout the study.  Additional 
pharmacodynamic parameters may be calculated if useful in the interpretation of the data.  Estradiol data 
may be combined with data from other studies and may be used for exposure-response analysis.
Safety:  
All enrolled subjects who took at least one dose of the study drug will be included in the safety analyses. 
Data collected during the 3 month Open-Label Period will be summarized for all subjects combined.
Baseline for all subjects will refer to the data obtained prior to dosing on Day 1 of the Open-label Run-in 
Period.  In general, for continuous variables, descriptive statistics (mean, standard deviation, median, 
minimum and maximum) will be summarized by treatment group.  Categorical data will be summarized 
with frequencies and percentages by treatment group.  Unless otherwise specified, no statistical tests will 
be performed.
Analysis details will be specified in the SAP.


Elagolix
M16-383 Protocol
12
1.2
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
CR
Controlled release
CYP3A
Cytochrome P450 3A
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
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


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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
IPAQ
International Physical Activity Questionnaire
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
Pap
Papanicolau 
PD
Premature Discontinuation 
PGIC
Patient Global Impression of Change
PK
Pharmacokinetic
PRO
Patient Reported Outcome
QD
Once a day
RBC
Red Blood Cell
SAE
Serious adverse event
SIS
Saline infusion sonography
TA MD
Therapeutic Area Medical Director
TSH
Thyroid Stimulating Hormone
TVU
Transvaginal Ultrasound
WPAI:SHP
Work Productivity and Activity Impairment Questionnaire – Specific Health 
Problem


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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
MMRM
Mixed-model with repeated measures
ROC
Receiver Operating Characteristics
SAP
Statistical Analysis Plan
Tmax
Time to maximum observed plasma concentration
Definition of Terms
Open Label Period
Portion of the Treatment Period (from Day 1 through Treatment Period 
Month 3) wherein all subjects will dose with unblinded active study drug 
(150 mg Elagolix QD).  
Randomization
Blinded treatment arm assignment at the Treatment Period Month 3 visit based 
on responder status determination.
Re-assignment
Re-assignment at Treatment Period Month 6 of the incomplete efficacy 
responding subjects previously randomized to 150 mg elagolix alone.
E2/NETA
Estradiol (E2) 1 mg/norethindrone acetate (NETA) 0.5 mg 
Month
A month is defined as 28 days.
Efficacy Responder 
≥ 30% decrease (improvement) from baseline in the average score on the Daily 
Diary endometriosis-associated pain score via NRS for endometriosis-
associated pain based on a 35 day window
Efficacy Incomplete 
Responder
< 30% decrease (improvement) from baseline in the average score on the Daily 
Diary endometriosis-associated pain score via NRS for endometriosis-
associated pain based on a 35 day window


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2.0
Table of Contents
1.0
Title Page ...............................................................................1
1.1
Synopsis................................................................................................. 2
1.2
List of Abbreviations and Definition of Terms...................................... 12
2.0
Table of Contents ................................................................ 15
3.0
Introduction......................................................................... 20
3.1
Endometriosis....................................................................................... 20
3.2
Elagolix................................................................................................ 20
3.2.1
Preclinical Experience .......................................................................... 20
3.2.1.1
Toxicology........................................................................................... 20
3.2.2
Clinical Experience .............................................................................. 21
3.3
Differences Statement .......................................................................... 21
3.4
Benefits and Risks................................................................................ 22
4.0
Study Objective ................................................................... 22
5.0
Investigational Plan.............................................................23
5.1
Overall Study Design and Plan:  Description ........................................ 23
5.2
Selection of Study Population............................................................... 33
5.2.1
Inclusion Criteria.................................................................................. 33
5.2.2
Exclusion Criteria................................................................................. 35
5.2.3
Prior and Concomitant Therapy............................................................ 40
5.2.3.1
Prior Therapy ....................................................................................... 41
5.2.3.2
Concomitant Therapy........................................................................... 43
5.2.3.3
Prohibited Therapy............................................................................... 43
5.2.3.4
Rescue Therapy.................................................................................... 47
5.2.4
Contraception Recommendations and Pregnancy Testing ..................... 48
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic and Safety 
Assessments/Variables ......................................................................... 52
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ............... 52
5.3.1.1
Procedures............................................................................................ 53
5.3.1.2
Collection and Handling of Pharmacodynamic Variables ..................... 74
5.3.2
Drug Concentration Measurements....................................................... 74
5.3.2.1
Collection of Samples for Analysis....................................................... 74


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5.3.2.2
Measurement Methods ......................................................................... 75
5.3.3
Efficacy Variables................................................................................ 75
5.3.3.1
Primary Variables................................................................................. 75
5.3.3.2
Secondary Variables............................................................................. 75
5.3.4
Safety Variables ................................................................................... 76
5.3.5
Pharmacodynamic Variables ................................................................ 76
5.3.6
Pharmacokinetic Variables ................................................................... 77
5.4
Removal of Subjects from Therapy or Assessment ............................... 77
5.4.1
Discontinuation of Individual Subjects ................................................. 78
5.4.2
Discontinuation of Entire Study............................................................ 79
5.5
Treatments ........................................................................................... 80
5.5.1
Treatments Administered...................................................................... 80
5.5.2
Identity of Investigational Products ...................................................... 83
5.5.2.1
Packaging and Labeling........................................................................ 84
5.5.2.2
Storage and Disposition of Study Drug................................................. 85
5.5.3
Method of Assigning Subjects to Treatment Groups ............................. 85
5.5.4
Selection and Timing of Dose for Each Subject .................................... 87
5.5.4.1
Treatment Interruption.......................................................................... 87
5.5.5
Blinding ............................................................................................... 88
5.5.5.1
Blinding of Investigational Product ...................................................... 88
5.5.6
Treatment Compliance ......................................................................... 89
5.5.7
Drug Accountability ............................................................................. 89
5.6
Discussion and Justification of Study Design........................................ 90
5.6.1
Discussion of Study Design and Choice of Control Groups .................. 90
5.6.2
Appropriateness of Measurements........................................................ 90
5.6.3
Suitability of Subject Population .......................................................... 91
5.6.4
Selection of Doses in the Study ............................................................ 91
6.0
Complaints........................................................................... 92
6.1
Medical Complaints ............................................................................. 92
6.1.1
Definitions ........................................................................................... 93
6.1.1.1
Adverse Event...................................................................................... 93
6.1.1.2
Serious Adverse Events........................................................................ 94
6.1.1.3
Adverse Events of Special Interest........................................................ 95


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6.1.2
Adverse Event Severity ........................................................................ 95
6.1.3
Relationship to Study Drug................................................................... 96
6.1.4
Adverse Event Collection Period.......................................................... 96
6.1.5
Adverse Event Reporting...................................................................... 97
6.1.6
Pregnancy............................................................................................. 99
6.2
Product Complaint...............................................................................100
6.2.1
Definition............................................................................................100
6.2.2
Reporting ............................................................................................100
7.0
Protocol Deviations ........................................................... 101
8.0
Statistical Methods and Determination of Sample 
Size ..................................................................................... 102
8.1
Statistical and Analysis Plans ..............................................................102
8.1.1
General Considerations........................................................................102
8.1.2
Data Sets Analyzed .............................................................................102
8.1.3
Demographic, Baseline Characteristics and Concomitant 
Medications.........................................................................................102
8.1.4
Efficacy...............................................................................................103
8.1.4.1
General Considerations........................................................................103
8.1.4.2
Primary Efficacy Variable ...................................................................104
8.1.4.2.1
Primary Analysis.................................................................................104
8.1.4.3
Secondary Efficacy Variables..............................................................106
8.1.4.3.1
Dysmenorrhea and Non-Menstrual Pelvic Pain....................................108
8.1.4.3.2
Dyspareunia ........................................................................................108
8.1.4.3.3
Rescue Analgesic Use for Endometriosis-Associated Pain...................108
8.1.4.3.4
Daily Diary Endometriosis-Associated Pain Score via NRS.................109
8.1.4.3.5
Additional Endpoints...........................................................................109
8.1.5
Safety..................................................................................................109
8.1.5.1
General Considerations........................................................................109
8.1.5.2
Adverse Events....................................................................................111
8.1.5.3
Analysis of Laboratory Data and Vital Signs .......................................111
8.1.5.4
Bone Mineral Density..........................................................................111
8.1.5.5
Uterine Bleeding .................................................................................112
8.1.5.6
Endometrial Variables .........................................................................112


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8.2
Pharmacokinetics/Pharmacodynamics .................................................112
8.3
Determination of Sample Size .............................................................112
9.0
Ethics.................................................................................. 113
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ........................................................................................113
9.2
Ethical Conduct of the Study...............................................................114
9.3
Subject Information and Consent.........................................................114
10.0
Source Documents and Case Report Form 
Completion ........................................................................ 115
10.1
Source Documents...............................................................................115
10.2
Case Report Forms..............................................................................116
11.0
Data Quality Assurance .................................................... 118
12.0
Use of Information ............................................................ 119
13.0
Completion of the Study ................................................... 121
14.0
Investigator's Agreement.................................................. 122
15.0
Reference List.................................................................... 123
List of Tables
Table 1.
Washout Intervals for Exclusionary Hormonal/Anti-Hormonal 
Therapy................................................................................................ 42
Table 2.
Prohibited Medications......................................................................... 44
Table 3.
Permitted Rescue Therapy for Endometriosis-Associated Pain ............. 48
Table 4.
Clinical Laboratory Tests ..................................................................... 65
Table 5.
Treatments Administered (Day 1 – Month 3)........................................ 80
Table 6.
Treatments Administered (Month 4 – Month 24).................................. 82
Table 7.
Identity of Investigational Products ...................................................... 84
List of Figures
Figure 1.
Study Schematic................................................................................... 24
Figure 2.
Adverse Event Collection..................................................................... 97


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List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.........................................125
Appendix B.
List of Protocol Signatories .................................................................127
Appendix C.
Study Activities...................................................................................128
Appendix D.
BI-RADS Classification ......................................................................139
Appendix E.
Overall Endometriosis-Associated Pain Questionnaire.........................140
Appendix F.
Patient Global Impression of Change (PGIC) ......................................141
Appendix G.
BMD Risk Factor Assessment Questionnaire.......................................142
Appendix H.
Analgesic Change During Treatment Period........................................144


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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 sodium (hereinafter "elagolix") is a novel, oral, short-acting, nonpeptide 
competitive gonadotropin releasing hormone (GnRH) antagonist that is being developed 
by AbbVie for the management of endometriosis with associated pain and heavy 
menstrual bleeding associated 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.6


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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
In two replicate Phase 3 studies in women with endometriosis-associated pain, both 
elagolix treatment groups (elagolix 150 mg QD and 200 mg BID) met the coprimary 
efficacy endpoints showing a statistically significant higher proportion of responders for 
dysmenorrhea (DYS) and non-menstrual pelvic pain (NMPP) than those who received 
placebo at Month 3.7  Persistence of efficacy was observed through Month 6.  The 150 mg 
QD dose demonstrated efficacy in 3 of 7 key ranked secondary outcome measures 
including significant reductions from baseline with the Daily Diary endometriosis-
associated pain score via NRS (at Month 3), DYS (at Month 6) and NMPP (at Month 6).  
The 200 mg BID dose showed additional statistically significant improvement in all 
7 key ranked secondary outcome measures, including reductions in any rescue analgesic 
agent (NSAIDS or opioids), and dyspareunia scores.
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) may 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.  
Elagolix should not be used in women who are pregnant or trying to become pregnant.  
Information regarding contraception counseling and pregnancy testing is provided in 
Section 5.2.4.
3.3
Differences Statement
This Phase 3b study will evaluate the safety and efficacy of elagolix 150 mg QD and 
elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD in 18 to 49 year old 


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premenopausal women with endometriosis with moderate to severe pain.  This study is 
intended to provide additional dosing guidance for elagolix 150 mg daily over a 2 year 
treatment period, and dose escalation to 200 mg BID with E2/NETA in incomplete 
responders.  In addition, this study will investigate known modifiable risk factors for 
BMD decrease to further educate practitioners as to which patients may be at higher risks 
for BMD decrease.  Such information would equip prescribers to safely prescribe elagolix 
for longer periods of time.  
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.
4.0
Study Objective
The objectives of this study are to:


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●
Compare the efficacy at Treatment Month 6 of dose escalation to elagolix 
200 mg BID + E2/NETA (1 mg/0.5 mg) QD versus continuing elagolix 
150 mg QD in subjects who are incomplete efficacy responders to elagolix 
150 mg QD at Treatment Month 3
●
Assess the effects of elagolix 150 mg QD and elagolix 200 mg 
BID + E2/NETA (1 mg/0.5 mg) QD on BMD after up to 24 months of 
treatment
●
Evaluate the modifiable and non-modifiable risk factors associated with 
changes in BMD over 24 months of treatment
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3, dose-escalation study designed to evaluate the safety and efficacy of 
both elagolix 150 mg QD and elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD 
over 24 months in the management of premenopausal women with endometriosis with 
moderate to severe pain.  After establishing eligibility, the study starts with open-label 
treatment for the first 3 months.  Following the Treatment Month 3 visit and continuing 
through Month 24, the study is conducted in a double-blinded manner with treatment 
assignment determined based on the efficacy responder status assessed at Treatment 
Months 3 and 6.   
At the Treatment Month 3 study visit, the efficacy responder status of each subject will be 
determined based on the responses to the Daily Diary endometriosis-associated pain score 
via NRS collected in the electronic diary (e-Diary).  The results of the responder status 
determination are blinded and the details of the responder status calculation are outlined in 
Section 5.5.3.  Subjects determined to be efficacy responders at the Treatment Month 3 
visit will continue to dose with elagolix 150 mg QD in a blinded manner throughout the 
remainder of the 24-month Treatment Period.  Subjects determined to be incomplete 
efficacy responders at the Treatment Month 3 visit will be randomized in a blinded 
manner in a 1:1 ratio to receive elagolix 150 mg QD or elagolix 200 mg BID + E2/NETA 


Elagolix
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(1 mg/0.5 mg) QD.  Subjects who were randomized to receive elagolix 200 mg BID + 
E2/NETA (1 mg/0.5 mg) QD will continue with this treatment in a blinded manner 
throughout the remainder of the 24-month Treatment Period.
At the Treatment Month 6 study visit, the efficacy responder status of each subject will be 
determined in the same blinded manner as at the Month 3 study visit.  Subjects who 
randomized at Treatment Month 3 to receive elagolix 150 mg QD and are subsequently 
determined to be efficacy responders at Month 6 will continue to receive elagolix 150 mg 
QD throughout the remainder of the 24-month Treatment Period.  Subjects who 
randomized at Month 3 to receive elagolix 150 mg QD and are subsequently determined 
to be incomplete efficacy responders at Month 6 will receive elagolix 200 mg BID + 
E2/NETA (1 mg/0.5 mg) QD throughout the remainder of the 24-month Treatment 
Period.
The study schematic is shown below in Figure 1.
Figure 1.
Study Schematic


Elagolix
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25
The Treatment Groups are outlined below:
Day 1 through Month 3 (Open-Label):  
●
Open-Label elagolix 150 mg QD
Month 4 through Month 6 (Double-Blind): 
●
(A) Efficacy responders to elagolix 150 mg QD at Month 3 
●
(B) Incomplete efficacy responders to elagolix 150 mg QD at Month 3 and 
randomized to elagolix 150 mg QD treatment group 
●
(C) Incomplete efficacy responders to elagolix 150 mg QD at Month 3 and 
randomized to elagolix 200 mg BID plus E2/NETA 1 mg/0.5 mg QD 
treatment group 
Months 7 through Month 24 (Double-Blind):
●
(A) Efficacy responders to elagolix 150 mg QD at Month 3 and continue 
treatment through Month 24
●
(C) Incomplete efficacy responders to elagolix 150 mg QD at Month 3,
randomized to elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD 
treatment group and continue the same treatment through Month 24.
●
(D) Incomplete efficacy responders to elagolix 150 mg QD at Month 3, 
randomized to elagolix 150 mg QD treatment group and are incomplete 
efficacy responders at Month 6, and dose increased to elagolix 200 mg BID 
plus E2/NETA (1 mg/0.5 mg) QD through Month 24
●
(E) Incomplete efficacy responders to elagolix 150 mg QD at Month 3, 
randomized to elagolix 150 mg QD treatment group and are efficacy 
responders at Month 6 continue the same treatment through Month 24 
The total duration for this study is approximately 27 to 50 months, consisting of 
4 study periods.  One month is defined as 28 days.


Elagolix
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●
Washout Period – up to 10 months prior to Screening (only applicable if 
subject is taking exclusionary medication at the time of consenting; duration of 
washout depends on the type of excluded medication being taken)
●
Screening Period – approximately 1.5 to 4 months prior to the first dose of 
study drug.
●
Treatment Period – up to a total of 24 month treatment duration consisting of 
the following: 
○
Open-Label Run-In Period:  3 months treatment duration from Day 1 
through Treatment Month 3 study visit
○
Double-Blind Active Treatment Period:  Treatment Month 3 study visit 
through Treatment Month 24 study visit
●
Follow-up Period – up to 12 months following the last dose of study drug
Details for each Study Period are described below.
Washout Period:
Following informed consent, subjects who have been taking exclusionary medications 
prior to screening that require discontinuation (washout), must enter the Washout Period.  
The duration of the required washout period is presented in Table 1.  Applicable study 
procedures may be performed, such as medical, social and gynecological history 
(including documentation of diagnosis of endometriosis via surgical visualization or 
histological diagnosis), a brief 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.  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.


Elagolix
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Screening Period
Following informed consent (if Washout was not required), subjects will enter into the 
Screening Period.  Eligible subjects will have documentation of a surgical confirmation of 
endometriosis.  In addition to medical and gynecological history, specific history will be 
obtained to help identify potential risk factors/predictors related to changes in BMD, 
including modifiable and non-modifiable risk factors.  The following safety assessments 
will be completed during the Screening Period:  
●
dual energy x-ray absorptiometry (DXA) of the lumbar spine total hip and 
femoral neck to document baseline BMD
●
transvaginal ultrasound (TVU) to rule out any clinically significant 
gynecological disorders such as ovarian cysts, fibroids or endometrial polyps; 
●
Papanicolau (Pap) test to rule out malignancy or pre-malignant changes;
●
endometrial biopsy to rule out endometrial pathology;
●
mammogram in subjects 39 years of age or older if one has not been 
performed within 3 months prior to start of Screening;
●
baseline ECG;
●
clinical laboratory testing.
An electronic diary (e-Diary) will be provided to subjects to begin recording:
●
DYS and NMPP via the 4-point Endometriosis Daily Pain Impact Diary;
●
Daily Diary endometriosis-associated pain score via NRS;
●
dyspareunia (if applicable) via a 4-point scale 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.  To be considered eligible for the study, during the last 35 calendar days 
of the Screening Period, subjects must have:
●
at least 2 days of moderate or severe DYS AND


Elagolix
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28
●
one of the following:
○
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.
Additionally, 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 the Screening Period.
Subjects will be allowed to take protocol-specified analgesic rescue medication for 
endometriosis-associated pain and will record use daily in the e-Diary.  Protocol specific 
analgesic rescue medication for endometriosis-associated pain will include four equivalent 
NSAID choices and two equivalent opioid choices.
Use of other rescue analgesic or the use of prophylactic analgesic medications for 
endometriosis-associated pain is not allowed.  The subject and Investigator will decide on 
the appropriate rescue analgesic medications for that subject (based on the approved 
options).  Subjects are also required to use appropriate non-hormonal methods of 
contraception. 
Subjects who have signed the 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 
permitted to re-screen following re-consent.  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.  
Treatment Period:
The Treatment Period begins with Study Day 1.  Study Day 1 will occur between Cycle 
Days 1 to 10 of a subject's menses (Cycle Day 1 is defined as first day with full menstrual 
flow) for all subjects who meet eligibility criteria during the Screening Period.  On Study 
Day 1, all subjects will begin open-label dosing with elagolix 150 mg QD.  The first dose 


Elagolix
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of study drug will be administered at the study site on Day 1 and study drug kits will be 
dispensed to subjects to continue daily dosing.  Monthly on-site study visits will be 
conducted during the first 6 months of the Treatment Period.  Subjects will be expected to 
come in to the site every other month during Treatment Months 7 – 12 and every 
third month during Treatment Months 13 – 24.  Telephone contacts will be conducted at 
months without an on-site visit.  Subjects will be asked to complete various patient-
reported outcome (PRO) questionnaires at designated study visits.  At the Day 1 visit 
(prior to dosing) and at all monthly visits (on-site and telephone contacts), site staff will 
administer to subjects the overall endometriosis-associated pain questionnaire, an 
11-point NRS with a 7-day recall period.  Starting at Treatment Month 1 and at all on-site 
study visits thereafter, subjects will complete the Patient Global Impression of Change 
(PGIC) questionnaire.  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 telephone contact visits.  A positive urine pregnancy test result (including those from 
home pregnancy testing) 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.
Subjects will continue to use the daily e-Diary to record DYS, NMPP; dyspareunia; Daily 
Diary endometriosis-associated pain score via NRS; rescue analgesic use for 
endometriosis-associated pain and the presence and intensity of uterine bleeding through 
Treatment Month 6.  Throughout the 24-month Treatment Period, all subjects will 
continue to be allowed to take protocol specified rescue analgesic medication for 
endometriosis-associated pain.  Use of non-protocol specific analgesic or prophylactic 
analgesic medications for endometriosis-associated pain will not be allowed.  Subjects 
will record the use of protocol specific analgesic rescue medications for endometriosis-
associated pain in the daily e-Diary until Treatment Month 6; thereafter, use of protocol 
specific analgesic rescue medications will be assessed and documented at the study visits.


Elagolix
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30
At designated study visits during the 24-month Treatment Period, blood samples will be 
collected for clinical safety labs, including vitamin D levels.  In addition, blood samples 
will be collected for assay of serum estradiol, plasma concentrations of elagolix and 
norethindrone.
BMD will be assessed throughout the Treatment Period.  Following baseline, DXA scans 
will be obtained at Treatment Months 6, 12, 18 and 24.  A DXA scan will be required if a 
subject discontinues at the time of or after the Treatment Month 6 visit or if the reason for 
premature discontinuation is due to the occurrence of a fracture or any newly diagnosed 
bone condition.
Vital signs assessments will be conducted at all on-site study visits.  Additional safety 
assessments are completed as appropriate at designated study visits throughout the 
Treatment Period.  Adverse event and concomitant medication review will be conducted 
at all Treatment Period study visits.
Criteria for Assessment of Subject Status Following the Open-Label Run-In Period:
At the Treatment Month 3 study visit, subjects will be assessed as either an 'efficacy 
responder' or an 'incomplete efficacy responder' based on responses entered in the e-Diary 
on the Daily Diary endometriosis-associated pain score via NRS.  The status of a subject 
will be determined within the e-Diary system as follows: 
●
Efficacy responder:  ≥ 30% decrease (improvement) from Baseline based on 
the average of the Daily Diary for endometriosis-associated pain score via 
NRS over a 35 day window
●
Incomplete efficacy responder:  < 30% decrease (improvement) from Baseline 
based on the average of the Daily Diary for endometriosis-associated pain 
score via NRS over a 35 day window
●
Following conclusion of the Open-Label Run-In Period, treatment arm 
assignment for all subjects will become and remain blinded for the remainder 
of the 24-month Treatment Period.  The assessment of responder status is also 
blinded.


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31
At the Treatment Month 3 study visit, any subjects that have zero entries for the Daily 
Diary for endometriosis-associated pain score via NRS during the 35 day window prior to 
the study visit will continue dosing with 150 mg QD for the remainder of the treatment 
period (will be assigned to Group A).
Dose Escalation During the Treatment Period:
Subjects assessed as "efficacy responders" (as defined above) will be assigned to continue 
dosing with elagolix 150 mg QD (Group A) in a blinded manner via Interactive Response 
Technology (IRT).  All other subjects assessed as "incomplete efficacy responders" will
be assigned randomly (in an equal ratio) via IRT to either elagolix 150 mg QD (Group B) 
or elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD (Group C) for 3 months.  To 
preserve the blind, IRT will be utilized for study drug assignment for all subjects.  The 
first dose from the newly assigned study drug kit at Treatment Month 3 will be 
administered at the site.  The pharmacokinetic and pharmacodynamics samples must be 
obtained prior to study drug administration at the Treatment Month 3 visit.
At the Treatment Month 6 study visit, in a blinded manner via IRT, all subjects who were 
incomplete efficacy responders and randomly assigned at Treatment Month 3 to elagolix 
150 mg QD will again be assessed for efficacy response in the same manner as was done 
at the Treatment Month 3 visit.  All subjects in this group (Group B) who become efficacy 
responders will continue dosing with elagolix 150 mg QD in a blinded manner (Group E).  
All other subjects in this group who are assessed as incomplete efficacy responders at
Month 6 will escalate dosing to elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD 
(Group D).  To preserve the blind, IRT will be utilized for treatment assignment of all 
subjects; however, only subjects randomly assigned at Treatment Month 3 to the elagolix 
150 mg QD (Group B) will have a chance for dose modification.  The first dose from the 
newly assigned study drug kit at Treatment Month 6 will be administered at the site.  The 
pharmacokinetic and pharmacodynamics samples must be obtained prior to study drug 
administration at the Month 6 visit.


Elagolix
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32
At the Treatment Month 6 study visit, any subjects that have zero entries for the Daily 
Diary for endometriosis-associated pain score via NRS during the 35 day window prior to 
the study visit will continue dosing on the current dose assignment for the remainder of 
the treatment period.
The treatment assignments following the Treatment Month 6 study visit will continue for 
all subjects for the duration of the 24-month Treatment Period in a blinded manner.  There 
will not be further dose adjustments following the Treatment Month 6 visit for any 
subject.
BMD Assessment and Subject 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 and 24.  If the results of any post-baseline DXA prior to the Treatment 
Month 24 timepoint, as read by the central imaging vendor selected for the study, 
document a Z-score (for subjects < 40 years of age at the time of the Screening DXA) or a 
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 bseline 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.
Follow-Up Period:
Subjects will enter the Follow-Up Period for up to 12 months to assess bone recovery 
after up to 24 months of treatment with the study drug.  Subjects who prematurely 
discontinue (PD) from the study at the time of or after the Treatment Period Month 6 visit, 
or who PD due to occurance of a fracture or newly diagnosed bone condition 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.  


Elagolix
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33
Adverse event collection is detailed in Section 6.1.4 and Appendix C.  Concomitant 
medication use will be reviewed at all study visits.
The Follow-Up Period for the study should conclude for all subjects approximately 
30 days after the last completed Treatment Month 24 visit.
Additional detail regarding study procedures during the Follow-Up Period is provided in 
Appendix C, Study Activities.
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.
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 has 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:


Elagolix
M16-383 Protocol
34
●
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; however, periodic abstinence requires use of dual 
contraception.
●
Subject had a bilateral tubal ligation, bilateral tubal occlusion or bilateral 
salpingectomy 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.
7.
Subject ≥ 39 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 2 or equivalent).
8.
Prior to Study Day 1, subject has 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 has 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 one of the following:


Elagolix
M16-383 Protocol
35
●
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.
Rationale for Inclusion Criteria
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 50 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)


Elagolix
M16-383 Protocol
36
●
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. 
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 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.
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, 


Elagolix
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37
allergy to, or any other reason that in the Investigators opinion that would prevent 
the subject from using any of the protocol allowed rescue analgesic medications.  
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 a history of any of the following:
●
Major depression or post-traumatic stress disorder (PTSD) 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) at Screening or prior to enrollment on Day 1.
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


Elagolix
M16-383 Protocol
38
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 
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 


Elagolix
M16-383 Protocol
39
(Z-score < –2.0 for subjects < 40 years of age, T-score for subjects ≥ 40 years of 
age).
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 enrollment 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.  
A history of legal recreational or medicinal cannabinoid/marijuana use is not 
exclusionary.
27.
Subject was previously enrolled (randomized) in either an elagolix study or a study 
involving another investigational GnRH antagonist, 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 


Elagolix
M16-383 Protocol
40
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 
assessments and procedures, including completion of the e-Diary and consistent 
use of non-hormonal dual contraception throughout the required time period.
Rationale for Exclusion Criteria
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 consent, 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.


Elagolix
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41
If there are any questions regarding concomitant or prior therapies the AbbVie 
Therapeutic Area Scientific Director should be contacted who will then discuss with the 
AbbVie Therapeutic Area Medical Director (TA MD) and provide a recommendation.
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 clinical 
judgement.
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 contraception 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.


Elagolix
M16-383 Protocol
42
If the type of hormonal product and the length of Washout are not listed in the table 
below, consult AbbVie Therapeutic Area Scientific Director who will discuss with the 
AbbVie TA MD and provide a recommendation.
Table 1.
Washout Intervals for Exclusionary Hormonal/Anti-Hormonal 
Therapy
Therapy
Minimum Interval for Washout* 
(Prior to Initial Screening Visit)
Medroxy progesterone acetate injection (Depo-Provera®; Sayana®)
10 months from injection
GnRH agonist 3 month depot (Lupron Depot® 11.25 mg), 
goserelin acetate (Zoladex®)
6 months from injection
Synarel® (Nasal Spray)
4 months
GnRH antagonist (parenteral)
3 months
Selective Progesterone Receptor Modulators (e.g., Ulipristal 
acetate, Vilaprisan)
Nafarelin acetate
Danazol (Cyclomen®)
Aromatase inhibitors
Oral contraceptives**
1 month
Oral, transdermal or intravaginal estrogen preparations
Oral, intravaginal or transdermal progesterone/progestin 
preparations***, including tibolone
GnRH agonist – 1 month depot (including Lupron Depot®
3.75 mg)
Hormonal and Non-Hormonal IUD, sub-dermal progestin implant
(e.g., Nexplanon®)
1 month after removal
NuvaRing®
*
This is the minimum washout; however, subjects may not enter Screening until at least 1 menstrual cycle 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 Scientific Director/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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43
5.2.3.2
Concomitant Therapy
All concomitant medications taken (except protocol specific rescue analgesic medications 
[Section 5.2.3.4] taken for endometriosis- associated pain, which are recorded in the 
e-Diary during Screening and the first 6 months of Treatment) 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 meaningfully 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®)
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 


Elagolix
M16-383 Protocol
44
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:
Table 2.
Prohibited Medications
Prohibited During the Washout, Screening, Treatment, and Follow-Up Periods 
GnRH analogues
Leuprolide acetate (Lupron®)
GnRH agonist:  nafarelin acetate (Synarel®), goserelin 
acetate (Zoladex®)
GnRH antagonists (other than elagolix)
Medroxyprogesterone Acetate (Depo-Provera®, Provera®)
Prohibited During the Washout, Screening and Treatment Periods and thru Follow-Up Month 1
Hormonal Medications and Non-hormonal 
Estrogen Supplements, such as:
Danazol (Danocrine®, Cyclomen®)
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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45
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 and protocol 
specified rescue opioid analgesics
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.
Cannabinoids 
Including any marijuana use
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
Nafcillin
Strong Inducers:
St. John's Wort
Rifampin
Carbamazepine
Phenytoin
Dexamethasone (chronic use)


Elagolix
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46
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.
Other Teratogens, such as:
Topiramate, Accutane® and other oral retinoids
Legal recreational or medicinal use of cannabinoids/marijuana prior to Washout or prior 
to Screening is not prohibited; however any use of cannabinoids/marijuana during study 
participation is prohibited.
Analgesic medications used to specifically treat endometriosis-associated pain, other than 
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 (total of 14 days) 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 24 month 
Treatment Period is allowed during a subject's participation.  If the subject requires 
> than 2 weeks duration per occurrence or > 6 weeks (total of 42 days) over the 24 month 
Treatment Period, their continued participation in the study must be reviewed with the 
AbbVie TA Scientific Director/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 


Elagolix
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Scientific Director/MD.  If there are any questions regarding prior or concomitant therapy, 
please contact AbbVie TA Scientific Director.
5.2.3.4
Rescue Therapy
The protocol-allowed analgesic rescue therapies for endometriosis-associated pain are 
presented in Table 3.  Investigators will prescribe a specific analgesic rescue medication 
from each medication class for subjects at the time of entry into the Screening Period, 
taking into consideration the subject's preference and/or historical use of analgesics and 
the Investigator's clinical judgement. 
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 
rescue 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, but all prescribed use of 
rescue analgesic medication should be according to appropriate clinical practice standards 
and the Investigator's clinical judgment. 
Subjects will record use of the protocol-specific rescue analgesic medications taken for 
endometriosis-associated pain daily in the e-Diary during Screening through the 
first 6 months of the Treatment Period.  This will include the total number of pills/tablets 
taken for each category of rescue analgesic medication within a 24-hour period.  During 
Treatment Period Months 7 – 24, when the e-Diary is not in use, 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.


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Prophylactic use of protocol-specific rescue analgesic medications is not allowed.  Use of 
any other analgesic medications for endometriosis-associated pain, including 
prophylactically, is not allowed from the start of the Screening Period through the 
24-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 Scientific Director.  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
*
Use 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.
^
Diclofencac Immediate-Release product is preferred.
$
Combination with or without caffeine is permitted.
5.2.4
Contraception Recommendations and Pregnancy Testing
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, bilateral tubal occlusion or bilateral salpingectomy) will be 


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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, except as noted below.
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, bilateral tubal occlusion or bilateral 
salpingectomy at least 4 months prior to the start of Screening.
●
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 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 of study drug and has 
returned to menses.  If the Subject has not returned to menses by Follow-Up Month 1, the 


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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.
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 (as needed).
●
The site will provide contraceptives and other supplies (e.g., lubricants) to 
subjects throughout the Washout (if applicable), Screening, and Treatment 
Periods through Follow-Up Month 1 as needed.  


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●
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 in a stand-alone attestation 
form at all on-site study visits (except as noted below) 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®) or bilateral salpingectomy attestation is only required to be 
collected once during the study prior to enrollment, ideally at the time of 
consent.  Additionally, these 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 during screening and up to Treatment period Month 6
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 telephone 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.
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 study drug dosing.  Prior to performing an endometrial biopsy, the subject must 
have a confirmed negative urine pregnancy test.  In addition, at onsite visits during the 


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Treatment Period, the urine pregnancy test must be negative prior to providing subjects 
with their next supply of study drug.
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., telephone contact visits and prior to certain study procedures).  Subjects 
will self-administer the tests and report the results to the site during telephone 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 5.4.1).  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 baseline 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.
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic 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.


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5.3.1.1
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), randomization (Section 5.5.3) and adverse event 
information (Section 6.0).  All study data will be recorded on the eCRFs 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.  For procedures repeated during 
the Screening Period (as allowed per protocol or at the discretion of the AbbVie TA 
Scientific Director/MD), the procedure performed closest prior to dosing will serve as a 
baseline for clinical assessment. 
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 scheduled date.  However, the TVU, DXA scan, Pap 
test and endometrial biopsy may be performed within approximately ± 15 days around the 
associated 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 
judgment or standard of care.  If the protocol indicates that the AbbVie TA Scientific 
Director 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 Scientific Director 
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 


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performing any study-specific procedures.  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 enroll 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.
Medical/Social History
A complete medical history, including documentation of any clinically significant medical
conditions, procedures and applicable medications (Section 5.2.3.1), history of tobacco 
and alcohol use 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.
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). 
A brief, symptom-directed physical examination will be performed at Washout (if 
applicable). 


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Visits requiring either the complete physical examination (including weight) or a brief, 
symptom-directed physical examinations are outlined in the Study Activities Table in 
Appendix C.
Clinically significant physical examination findings prior to study drug dosing on Day 1 
will be recorded as medical or gynecological 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.
Gynecological 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, pelvic and external genitalia examination completed during Screening will serve as 
the baseline for clinical assessment.
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 


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of the original tracing with the physician's assessment will be retained in the subject's 
source records at the study site.
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.
Mammogram
Mammograms at Screening will only be required for subjects who are 39 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 Scientific Director 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.
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 or 2 (via mammogram or other mode of imaging) as 
outlined in Appendix D will be eligible for study drug dosing on Day 1.  Subjects with an 


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abnormal mammogram or BI-RADS 3, 4, 5, or 6 will not be eligible for the study.  
Subjects should continue with recommended mammography testing outside of the 
protocol per local guidelines and standard of care during the study.
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 
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 Scientific Director/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 Scientific Director/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 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.


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During the Treatment Period, a TVU will also be performed at Month 12 and Month 24 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 1 month 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 and Month 24 visit may be performed within approximately 
± 15 days of the scheduled corresponding visit to allow for the 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 Scientific Director/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.  


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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.  
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 vendor selected for the study.  The 
DXA technologist/radiologist or designee for each investigative site should electronically 
submit the subject's DXA images to the central imaging vendor for review and analysis 
within 3 business days following acquisition.  Subject eligibility and treatment 
management will be made based on results issued by the central imaging vendor.  Sites 
will receive reports from the central imaging vendor detailing the results (including BMD 
measurements and Z- and T-scores 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 imaging vendor that will be provided to all 
study sites.  Site training and qualifications, including assessment of instruments, will be 
evaluated/approved by the central imaging vendor, 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 enrollment 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, and 24 and will be submitted to the central imaging vendor for review 


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and analysis.  The central imaging vendor will be blinded to the subjects' treatment 
assignment, but not to the corresponding time point.
The window for performing DXA scans at Treatment Months 6, 12, 18, and 24 is 
± 15 days around the respective study visit. 
If the results of any post-baseline DXA prior to and including Month 24, as read by the 
central imaging vendor 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, the subject OR
●
a BMD decrease from baseline of > 8% in the lumbar spine, total hip or 
femoral neck.
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 at the time of or after the Treatment Month 6 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, or BMD decrease from baseline of > 8% in any region, additional 


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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/or 12 for those subjects whose follow-up period visits occur prior to the 
study conclusion (i.e., approximately 30 days after the last completed Treatment Period 
visit).
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.  The Investigator should write a brief procedure 
note in the source documentation noting the depth of placement of the Pipelle during the 
procedure.  Pre-medication for the endometrial biopsy procedure is allowable.  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.  If an 
endometrial biopsy cannot be performed because of anatomical reasons, the AbbVie TA 


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Scientific Director should be contacted who will consult with AbbVie TA MD for further 
guidance.
If the endometrial biopsy is performed on the same day as the Pap test or TVU, the 
endometrial biopsy should be performed after the Pap test and TVU.
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 study enrollment on Day 1.  However, if the repeat 
sample is deemed insufficient by the central laboratory, the AbbVie Scientific Director 
should be contacted who will consult with AbbVie TA MD and provide recommendation 
regarding eligibility.
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 enrollment 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 study enrollment.
The endometrial biopsies required during the Treatment period may be performed within 
approximately ± 15 days around the scheduled study visit.  At Treatment Month 12, 
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.  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.


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For subjects with an insufficient endometrial biopsy at either Treatment Period Month 12 
or Month 24 whose concurrent TVU indicates an endometrial thickness > 4 mm, a repeat 
biopsy must be performed.  If upon repeat, a sample cannot be obtained or remains 
insufficient, the AbbVie Scientific Director should be contacted who will consult with 
AbbVie TA MD.
Pap Test
Pap test will be performed on all subjects 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 selected for the study.  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 study drug dosing on Day 1.  
Subjects with following finding will be eligible for enrollment 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 
●
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.


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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 
enrollment 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 Scientific 
Director who will consult with AbbVie TA MD to determine if the subject may remain in 
screening and can be eligible for enrollment.  
Clinical Laboratory Tests
Samples will be obtained for the laboratory tests listed in Table 4, at the time points 
indicated in Appendix C.


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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
Pregnancy Test
Endocrine
Serum pregnancy
Follicle-stimulating 
hormone (FSH)
Reflexive Thyroid
Stimulating Hormone 
(TSH)
Laboratory samples indicated in Table 4 will be assessed using the certified central 
laboratory selected for the study and these data will be used for data analysis.  The central 
laboratory will provide instructions regarding the collection (including any fasting 
requirements), processing and shipping of samples.  Blood draws should be performed 
after 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 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.  


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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 study drug dosing 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 6.1.1).
All screening laboratory results must be reviewed prior to enrollment, 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 enrollment.  Subjects will not be 
enrolled 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.
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 lab requisition should be marked to indicate that the sample 
was obtained under non-fasting conditions.
Endocrine Testing
The endocrine testing for the study consists of the following analytes:  serum FSH and 
reflexive TSH.  Reflexive TSH will be obtained at Screening only.


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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 or Pap test.  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 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 6.  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 from Screening through Month 6 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 6, 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 


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the Treatment Month 6 study visit or at the Premature Discontinuation visit (if prior to 
Treatment Month 6).
Subjects will use the e-Diary to record assessments of DYS or NMPP, dyspareunia, 
menstrual period, uterine bleeding, Daily Diary endometriosis-associated pain score via 
NRS, as well as the use of protocol-allowed rescue analgesic medications for 
endometriosis-associated pain.  Scores from applicable daily assessments collected during 
Screening will be used to evaluate subject eligibility for the study prior to Open Label 
Run-In period on Day 1 E-Diary assessments will continue to be completed daily through 
Month 6 of the Treatment Period or until a subject prematurely discontinues from the 
Treatment Period (if they discontinue prior to Treatment Month 6).  
Subject responses to the Daily Diary endometriosis-associated pain score via NRS will be 
used at Treatment Month 3 and Month 6 to determine subject status of efficacy responder 
and incomplete efficacy responder. 
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.


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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.
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.


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Daily Diary Endometriosis-Associated Pain Score via Numeric Rating Scale (NRS)
Beginning at Screening, subjects will complete the Daily Diary endometriosis-associated 
pain score via NRS through Month 6.  Subjects will assess in the e-Diary their 
endometriosis-associated pain during the past 24 hours on a scale of 0 – 10, with 0 = no 
pain and 10 = worst pain ever.  
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 6.  Subjects will report 
whether they have taken pain medication and document the total number of pills taken 
within each class (NSAIDs and/or opioids) of protocol-allowed rescue analgesic during 
the last 24-hour period.
The use of protocol-allowed rescue analgesic medications taken during Treatment 
Months 7 – 24 will be recorded in the subjects' source documents and eCRF.
Patient Reported Outcomes (PRO) and Outcomes Rating Scales
Prior to the start of the study, instructions and training for study site staff administering 
these rating scales will be provided by AbbVie and/or its designee.  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).  
Overall Endometriosis-Associated Pain (7-Day Recall)
Beginning at Day 1 of the Treatment Period and at all monthly visits during the Treatment 
Period (on-site and telephone contacts), site staff will administer the overall 
endometriosis-associated pain questionnaire (Appendix E) (11-point NRS) assessing 


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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.
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 
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 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 a specific health problem.  The WPAI-SHP will be 
completed by subjects electronically via a tablet device, and the SHP referenced is
endometriosis-associated pain.


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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 using a tablet device:  very much improved, much 
improved, minimally improved, not changed, minimally worse, much worse or very much 
worse.
Health Endometriosis Treatment Satisfaction Questionnaire (ETSQ)14
This 6-item measure was developed to assess patient-reported satisfaction with effects on 
endometriosis pain, dysmenorrhea, dyspareunia, amount of bleeding tolerability and 
overall treatment satisfaction.  The ETSQ has a 7 point response scale.  Subject will 
complete this questionnaire on an electronic tablet device.
Health Care Resource Utilization (HCRU)
The Health Care Resource Utilization questionnaire captures subject visits to non-study 
Health Care Practitioners at Day 1 and during the Treatment Period.  At all study visits 
(on-site and telephone 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 (or the prior month for the Day 1 assessment).  The subject's 
responses will be recorded on the HCRU hard-copy worksheet by the site staff.
Additional Questionnaires
BMD Risk Factor Assessment Questionnaires (Appendix G)
Information will be obtained at study visits as outlined in Appendix C to help identify risk 
factors potentially associated with changes in BMD.  Subjects will be asked about 


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modifiable and non-modifiable risk factors, e.g., smoking and alcohol use, physical 
activity, and dietary intake of calcium.  Information about physical activity will be 
collected via the International Physical Activity Questionnaire Short Last 7 Days Self-
Administered format (IPAQ).15  As applicable per questionnaire, site staff will elicit 
subject responses and record appropriately or, subjects will be asked to enter their 
responses electronically.
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.  The C-SSRS Since Last Visit 
questionnaire should be administered by site staff during the Treatment Period as 
indicated in Appendix C.
Post-Treatment Assessment of Menstruation
Subjects will be asked about occurrence of post-treatment menses 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 had a post-treatment menses, site staff will continue to assess 
menstruation and repeat the questionnaire at subsequent follow-up visits, as applicable.  
The date when menses started since discontinuation of study drug will be documented in 
the source documents and eCRFs.
Assignment of Subject Numbers
The site will contact IRT during the Washout or Screening Period to obtain a subject 
(Screening) number after the subject has signed the informed consent.  Consecutive and 


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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 enrolled 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.
5.3.1.2
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 6 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 Day 1 and Treatment Months 3 and 6 samples will be obtained pre-dose; samples 
collected at all other visits can be drawn at any time during the visit.  The date and time of 
collection, as well as the dosing times of the two prior doses of study drug will be 
recorded in the subject's source documents and the eCRF.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
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.


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At Month 3 and Month 6, samples will be collected before the drug dispensation or 
administration of drug at the site (the first dose of study drug from the newly assigned 
study drug kit will be administered at the site at these visits).  At all other designated 
visits, samples will be collected regardless of the time of last dose.  A total of 
6 blood samples for pharmacokinetic analysis are planned to be collected per subject 
during study participation.  The date and time of collection, as well as the dosing times of 
the two prior doses of study drug, will be recorded in the source and the eCRF. 
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 Drug Analysis Department at 
AbbVie.  Plasma or serum concentrations of other possible metabolites may be 
determined with validated or non-validated methods.
5.3.3
Efficacy Variables
5.3.3.1
Primary Variables
The co-primary efficacy endpoints will be the proportion of responders (Figure 1, 
treatment Group B versus treatment Group C) 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 collected in the daily e-Diary will also be included in the 
responder definition.
5.3.3.2
Secondary Variables
The following efficacy variables will be collected in the daily e-Diary through Treatment 
Month 6 and will be summarized:
●
DYS
●
NMPP
●
Dyspareunia


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●
Daily Diary endometriosis-associated pain score via NRS
●
Rescue analgesic medication use
In addition, the following efficacy variables will be collected and summarized:
●
PGIC
●
Overall Endometriosis-Associated Pain via NRS (7-day recall)
●
Patient reported outcome (PRO) and Outcomes Rating Scales questionnaires
5.3.4
Safety Variables
BMD Assessments:
BMD assessments will be summarized.  Modifiable and non-modifiable risk factors will 
be assessed as they relate to baseline BMD and changes in BMD over time, including:  
smoking and alcohol use, physical activity (IPAQ), previous use of calcium and 
vitamin D, prior medications, race, age, height and weight (BMI), family history of 
fracture and family history of osteoporosis.
Other Safety Assessments:
Safety evaluations will also include physical examinations, AEs and concomitant 
medications, clinical laboratory tests and vital sign measurements.  Endometrial health 
will be assessed via TVU and biopsy.
5.3.5
Pharmacodynamic Variables
Concentrations of estradiol will be obtained at designated visits throughout the study.  
Additional pharmacodynamic parameters may be calculated if useful in the interpretation 
of the data.  Estradiol data may be combined with data from other studies and may be 
used for exposure-response analysis.


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5.3.6
Pharmacokinetic Variables
Plasma concentrations of elagolix and norethindrone will be listed for each subject by 
visit.  Elagolix and norethindrone exposures will be summarized.  Elagolix 
pharmacokinetic data may be combined with data from other studies to conduct 
population pharmacokinetic analysis and may be used in exposure-response analysis.
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 the study drug treatment and or 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 
prior to Month 24, 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/Scientific Director would preclude the subject from 
continuing in the Treatment Period due to safety reasons
●
The results of any post-baseline DXA prior to Month 24 document a Z-score 
(for subjects < 40 years of age ) or T-score (for subjects ≥ 40 years of age)
< –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


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●
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/Scientific Director
●
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/Scientific Director.
●
The subject requires or elects surgical intervention for treatment of 
endometriosis or uterine bleeding (e.g., laparoscopy, hysterectomy, ovarian 
cystectomy)
●
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, or prematurely discontinue due to the occurrence of a fracture or any newly 
diagnosed bone condition are expected to enter the Follow-Up Period for up to 12 months 
unless discontinuing due to pregnancy.
If a subject becomes pregnant during the Treatment 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.


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If a subject requires or elects surgery (e.g., laparoscopy, hysterectomy, ovarian 
cystectomy) for the management of her 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, TVU, Pap test, or endometrial biopsy does not need to be performed.
DXA scans are needed if the reason for premature discontinuation is due to the occurrence 
of a fracture or any newly diagnosed bone condition.
In addition, if a subject is being discontinued from the study due to a documented Z-score 
or T-score result of < –2.5, or a BMD decrease of > 8% from baseline, 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 and e-Diaries 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.  
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 


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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
All subjects will be administered elagolix 150 mg QD at Day 1 through Treatment 
Month 3.  Subjects will be administered the following open-label treatment regimen for 
3 months as indicated in Table 5:  
Table 5.
Treatments Administered (Day 1 – Month 3)
Investigational Product
Treatment Group
Dosing Time
Elagolix 150 mg Tablets QD
Elagolix 150 mg QD 
AM
1
PM
0
Based on the efficacy responder status as determined at the Treatment Month 3 Visit each 
subject will be assigned by the IRT to one of the following treatment groups:
●
Elagolix 150 mg QD.  This includes subjects who are efficacy responders at 
Month 3 (Group A), and subjects who are incomplete efficacy responders and 
randomized to receive 150 mg QD (Group B)


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●
Elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD.  This includes 
subjects who are incomplete efficacy responders at Month 3 and randomized to 
receive 200 mg BID plus E2/NETA 1/0.5 mg QD (Group C)
At the Treatment Month 6 Visit, the efficacy responder status will again be reassessed in 
the same blinded manner as at Month 3.  Each subject will be assigned by the IRT to one 
of the following treatment groups:
●
Elagolix 150 mg QD.  This includes:
○
Subjects who are efficacy responders at Treatment Month 3 and continue 
treatment through Month 24 (Group A), and 
○
Subjects who are incomplete efficacy responders at Treatment Month 3, 
randomized to receive 150 mg QD and are efficacy responders at 
Treatment Month 6 and continue treatment through Month 24 (Group E) 
●
Elagolix 200 mg BID plus E2/NETA.  This includes
○
subjects who are incomplete efficacy responders at Treatment Month 3, 
randomized to receive 200 mg BID plus E2/NETA 1/0.5 mg QD and 
continue treatment through Month 24 (Group C), and 
○
subjects who are incomplete efficacy responders to elagolix 150 mg QD at 
Treatment Month 3, randomized to elagolix 150 mg QD treatment group 
and are incomplete efficacy responders at Treatment Month 6, and dose 
increased to elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD 
through Month 24 (Group D).
The treatment administration for treatment Months 4 through 24 is presented in Table 6.


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Table 6.
Treatments Administered (Month 4 – Month 24)
Investigational Product
Treatment Group
Dosing 
Time
E2/NETA 
Capsules
E2/NETA 
Placebo 
Capsules
Elagolix 
150 mg 
Tablets
Elagolix 
150 mg 
Placebo 
Tablets
Elagolix 
200 mg 
Tablets
Elagolix 
200 mg 
Placebo 
Tablets 
Elagolix 150 mg 
QD plus Placebo 
to match Elagolix 
200 mg BID and 
E2/NETA QD
AM
0
1
1
0
0
1
PM
0
0
0
0
0
1
Elagolix 200 mg 
BID plus 
E2/NETA 
(1 mg/0.5 mg) QD 
plus Placebo to 
match Elagolix 
150 mg
AM
1
0
0
1
1
0
PM
0
0
0
0
1
0
The elagolix study drug, consisting of open-label elagolix 150 mg (Day 1 – Treatment 
Month 3 only), will be supplied in a carton.  The subject will take the elagolix dose orally 
in the morning at the study site on Day 1.  Subjects will be instructed to thereafter self-
administer their study drug throughout the 3 month Open-Label Run-In Period.  After 
Treatment Month 3, elagolix study drug consisting of elagolix 150 mg or placebo, and 
elagolix 200 mg BID plus E2/NETA (1 mg/0.5 mg) QD or placebo will be supplied in a 
carton.
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 – 24, a 3 month supply will be dispensed at each on-
site visit (Months 12, 15, 18, and 21), with enough to supply subjects until the next 
scheduled on-site visit.  


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From Treatment Month 3 through Treatment Month 24, study drug will be taken orally 
twice daily.  A morning dose of 1 tablet elagolix 150 mg or placebo, 1 tablet elagolix 
200 mg or placebo, and 1 capsule of E2/NETA or placebo, and an evening dose of 
1 capsule elagolix 200 mg or placebo 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 to promote compliance.
If the subject forgets to take the morning dose during treatment Months 1 – 3, the subject 
should be instructed to take the morning dose as soon as possible.  If the subject forgets to 
take the morning dose during treatment Months 4 – 24 the subject 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.  For study visits at Treatment Months 3 and 6, 
the first doses from the newly assigned study drug kit will be administered on-site.  The 
evening dose will be taken from the newly dispensed supply of study drug.  Subjects must 
return all study drug containers at each on-site visit.
5.5.2
Identity of Investigational Products
Information about the drug formulations to be used in this study is presented in Table 7.


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Table 7.
Identity of Investigational Products
Study Drug
Formulation
Route of 
Administration
Manufacturer
Elagolix (ABT-620) 
150 mg Film coated 
tablets
Oral
AbbVie
Matching Elagolix 
(ABT-620) Placebo
Placebo FilmCoated 
tablets
Oral
AbbVie
E2/NETA*
Estradiol 1 mg/ 
Norethindrone acetate 
0.5 mg Hard Gelatin 
Capsule
Oral
Novo Nordisk, A/S
Matching (E2/NETA 
Placebo
Placebo Hard Gelatin 
Capsule
Oral
AbbVie
Elagolix (ABT-620)
200 mg Film Coated 
Tablet
Oral
AbbVie
Matching Elagolix 
(ABT-620) Placebo
Placebo Film Coated 
Tablet 
Oral
AbbVie
*
Note:  Commercially available as Activella® 1 mg/0.5 mg.
5.5.2.1
Packaging and Labeling
AbbVie will supply open label and blinded study drug in monthly kits (i.e., cartons).  For 
the open label kit, one kit consists of Elagolix 150 mg.  Each kit will contain 
5 weekly blister cards, with each blister card containing 7 days of study medication;
4 blister cards for the 28 days of drug administration and 1 blister card in case of 
lost/damaged medication, late visit, etc.  
For blinded supplies, subjects will receive two kits:
●
One kit of elagolix 150 mg or matching placebo tablet and elagolix 200 mg or 
matching placebo tablet.  The kit will contain morning and evening doses
●
One kit of E2/NETA (1 mg/0.5 mg) capsule or matching placebo.  The kit will 
only contain the morning dose.


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Each kit will contain 5 weekly blister cards, with each blister card containing 7 days of 
study medication; 4 blister cards for the 28 days of drug administration and 1 blister card 
in case of lost/damaged medication, late visit, etc.
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°C to 25°C (59° to 77°F).
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
On Study Day 1, all subjects will begin dosing with Elagolix 150 mg QD.  The first dose 
of study drug will be administered at the study site on Day 1 and study drug kits will be 
dispensed to subjects to continue daily dosing.  At the Treatment Month 3 study visit, 
subjects will be assessed as either an 'efficacy responder' or an 'incomplete efficacy 
responder' based on responses entered in the e-Diary on the Daily Diary endometriosis-
associated pain score via NRS.  The status of a subject will be determined in the IRT 
system and will remain blinded.  The Daily Diary endometriosis-associated pain score via 


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NRS data within the e-Diary system will transfer into IRT on a daily basis with a blinded 
calculation as follows: 
●
Efficacy responder:  the mean of the responses on the Daily Diary 
endometriosis-associated pain score via NRS for the 35 days prior to the 
Treatment Month 3 visit demonstrate ≥ 30% decrease (improvement) from the 
mean of the responses 35 days prior to the first dose of study drug (Baseline 
Daily Diary endometriosis-associated pain score via NRS)
●
Incomplete efficacy responder:  the mean of the responses on the Daily Diary 
endometriosis-associated pain score via NRS for the 35 days prior to the 
Treatment Month 3 visit does not demonstrate ≥ 30% decrease (improvement) 
from the mean of the responses 35 days prior to the first dose of study drug 
(Baseline Daily Diary endometriosis-associated pain score via NRS)
Following conclusion of the Open-Label Run-In Period, treatment arm assignment for all 
subjects will become and remain blinded for the remainder of the 24-month Treatment 
Period.  To preserve the blind, at Treatment Months 3 and 6, IRT will be utilized for 
treatment assignment of all subjects regardless of treatment assignment.
At the Treatment Month 3 visit (i.e., the end of the Open-Label Run-In Period), in a 
blinded manner, the efficacy response for a subject will be assessed via the Daily Diary 
endometriosis-associated pain score via NRS.  Subjects assessed as "efficacy responders" 
will continue dosing in Treatment Group A in a blinded manner for the remainder of the 
Treatment Period.  All other subjects (assessed as "incomplete efficacy responders") will 
be assigned randomly (in an equal ratio) via IRT in a blinded manner to either Treatment 
Group B or Treatment Group C for 3 months.  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.  At the Treatment Month 6 study 
visit, in a blinded manner, subjects will again be assessed for efficacy response via the 
Daily Diary endometriosis-associated pain score via NRS in a similar manner as was done 


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at the Treatment Month 3 visit.  All Month 3 "incomplete efficacy responders" that were 
randomly assigned to be on Treatment Group B who become "efficacy responders" will 
continue dosing in Treatment Group E in a blinded manner.  All other Month 3 
'incomplete efficacy responder' subjects on Treatment Group B who are assessed as 
'incomplete efficacy responders' at Month 6 will escalate dosing to Treatment Group D.  
To preserve the blind, at Month 6, IRT will be utilized for treatment assignment of all 
subjects; however, only Month 3 'incomplete efficacy responder' subjects on Treatment 
Group B for the additional 12 weeks after Treatment Month 3 will have a chance for dose 
modification.  The subject number assigned via IRT at Washout of Screening does not 
change throughout the study.  
The treatment assignments following the Treatment Month 6 study visit will continue for 
all subjects for the duration of the Treatment Period in a blinded manner.  There will not 
be further dose adjustments following the Treatment Month 6 visit for any subject.
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 
assigned or randomized into treatment groups as appropriate described in Section 5.5.1.
Study drug will be administered at the study site on Day 1 and subjects will be instructed 
thereafter self-administer study drug once a day in the morning with approximately 8 oz 
(240 mL) of water.  The first dose of study drug from the newly dispensed study drug 
kit(s) will be administered at the study site at Treatment Months 3 and 6.  Starting at 
Treatment Month 3, 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 


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examples for reasons when the investigator may consider 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 Scientific Director who will discuss with AbbVie TAMD and 
provide a recommendation.
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 during the 
blinded portion of the study (starting at the Treatment Month 3 visit and will continue 
until the end of the Treatment Period Month 24).
The IRT will provide access to blinded subject treatment information during the blinded 
portion of 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 (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.


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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 on-site study visits throughout the Treatment 
Period, or Premature Discontinuation visit (if applicable).  The study site personnel will 
assess dosing 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 for Day 1 –
Treatment Month 3 and the same time in the morning and evening each day for Treatment 
Months 4 – 24.
5.5.7
Drug Accountability
The study Investigator or designee will verify via direct recording in IRT and/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 treatment.
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/returned for each subject.  In addition to using IRT 
inventory, an accurate inventory of study drug may also be kept by the site.


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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.
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.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This is a Phase 3 study to investigate the long term safety and efficacy of elagolix in 
management of endometriosis with -associated moderate to severe pain in addition to 
providing efficacy data on dose adjustment of elagolix in women who are incomplete 
responders to elagolix 150 mg QD.  This 24 month study will determine the impact of 
24 months of elagolix 150 mg QD on bone mineral density as well as the long term 
impact of 200 mg BID and E2/NETA on bone mineral density (as measured by DXA).  
Additionally the study will evaluate women at risk for greater decreases in DXA based on 
modifiable risk factors.
5.6.2
Appropriateness of Measurements
The co-primary efficacy endpoints for this trial will be 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 allowed rescue analgesic medication for 
endometriosis-associated pain will be included in the responder definition of the primary 
endpoints.  Additional secondary efficacy measures of DYS and NMPP, dyspareunia, and 
the PGIC are widely used in endometriosis as assessment tools.  In addition to assessment 
of pain reduction, the effects of treatment can be assessed using evidence of impact on 
subjects' functioning and overall well-being as well as subjects' utilization of health 


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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 plus E2/NETA.  Given the known relationship between 
estradiol levels and bone loss, serum E2 measurements will also be utilized to assess 
potential bone effects of elagolix plus E2/NETA.
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 with associated 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 
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 


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mitigate BMD decrease.  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 with associated 
pain, similar to the ongoing Phase 3 registration program.
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 Sections 6.1
through 6.1.5.  For product complaints, please refer to Section 6.2.
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 


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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 
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 


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


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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject 
and may require medical or surgical intervention to 
prevent any of the outcomes listed above (i.e., death of 
subject, life-threatening, hospitalization, prolongation of 
hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any 
elective or spontaneous abortion or stillbirth is considered 
an important medical event.  Examples of such events 
include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or 
drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.1.1.3
Adverse Events of Special Interest
Some adverse events, such as 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 (e.g., 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 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, another 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 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:  
FAX to:  


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For safety concerns, contact the Men's and Women's Health Safety Team at:
Men's and Women's Health Safety Team
1 North Waukegan Road
North Chicago, IL  60064
Men's and Women's Health Safety Line
Phone:
Fax:
Email:
For any subject safety concerns, please contact the AbbVie Therapeutic Area Scientific 
Director listed below who will discuss with the AbbVie TA Medical Director as needed.
In emergency situations involving study subjects when the primary Therapeutic Area 
Scientific Director is not available by telephone, please contact the 24-hour AbbVie 
Medical Escalation Hotline where your call will be re-directed to a designated backup 
AbbVie TA MD:
Phone:  


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6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Subjects who become pregnant during the Treatment 
or 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.  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 completion of the 
Follow-Up Month 1 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 becomes pregnant during the study, no additional study procedures, 
including protocol required DXA scans, will be conducted.  However, an 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.  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 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.


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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.
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 24 hours of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and 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 


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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.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.  The Principal Investigator 
is responsible for complying with all protocol requirements, and applicable global and 
local laws regarding protocol deviations.  If a protocol deviation occurs (or is identified) 
after a subject has been enrolled, the principal investigator is responsible for notifying 
Independent Ethics Committee (IEC)/Independent Review Board (IRB) regulatory 
authorities (as applicable), and their assigned Clinical Monitor or the following AbbVie 
Clinical Study Team Members:
Primary Contact:
Alternate Contact:
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.


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8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analysis Plans
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 0.05 unless otherwise specified.  The primary efficacy comparisons 
will be at Treatment Month 6 between the elagolix 200 mg BID plus E2/NETA treatment 
group (Group C) and elagolix 150 mg QD group (treatment Group B) in patients who are 
incomplete responders to elagolix 150 mg QD treatment at Month 3.  
8.1.2
Data Sets Analyzed
The full analysis set is comprised of all enrolled subjects who took at least one dose of the 
study drug and subjects will be analyzed in the treatment regimen to which she was 
assigned.  For the Open-label Run-in period (through Treatment Month 3) of the study, all 
subjects who receive at least 1 dose of study drug during the Open-label Run-in period 
will be included in the Open-label full analyses.  For the Double-blind Period of the study 
(Months 4 – 24), all subjects who receive at least 1 dose of study drug during the Double-
blind Period will be included in the Double-blind full analyses.  The full analysis set will 
be used for all analyses unless otherwise specified in the SAP.
8.1.3
Demographic, Baseline Characteristics and Concomitant 
Medications
Demographic and baseline characteristics will be summarized by treatment groups as well 
as the following two groups:
●
Subjects discontinued prior to the Double-blind Period.
●
Subjects treated in the Double-blind Period.


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Medical history, protocol deviations, premature discontinuations, concomitant 
medications, and study drug exposure will be summarized.  No treatment group 
comparisons will be made.  Unless noted otherwise, the baseline values will be defined as 
the last value obtained prior to the first dose of the study drug during the Open-label Run-
in Period.
8.1.4
Efficacy
8.1.4.1
General Considerations
Analysis details for Months 1 through 24 of the Treatment Period will be specified in the 
SAP.
The primary efficacy comparisons will be at Treatment Month 6 between the Elagolix 
200 mg BID plus E2/NETA treatment group (Group C) and elagolix 150 mg QD group 
(treatment Group B) in patients who are incomplete responders to elagolix 150 mg QD 
treatment at Month 3.  
For efficacy data collected during Month 7 – 24 of the treatment period, summaries will 
be provided for the following treatment groups.
●
Efficacy responders to elagolix 150 mg QD at Month 3 and continue treatment 
through Month 24 (Group A).
●
Incomplete efficacy responders to elagolix 150 mg QD at Month 3 and 
randomized to elagolix 200 mg BID plus E2/NETA 1 mg/0.5 mg QD 
treatment group and continue treatment through Month 24 (Group C).
●
Incomplete efficacy responders to elagolix 150 mg QD at Month 3, 
randomized to elagolix 150 mg QD treatment group and remain incomplete 
efficacy responders at Month 6, dose increased to elagolix 200 mg BID plus 
E2/NETA 1 mg/0.5 mg QD through Month 24 (Group D). 
●
Incomplete efficacy responders to elagolix 150 mg QD at Month 3, 
randomized to elagolix 150 mg QD treatment group and are efficacy 
responders at Month 6 continue treatment through Month 24 (Group E).


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8.1.4.2
Primary Efficacy Variable
8.1.4.2.1
Primary Analysis
The primary analysis of the co-primary endpoints will be performed using the Double-
blind full analysis set.
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 using the daily e-Diary. 
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 
the average pain score as well as no increased analgesic rescue use for endometriosis-
associated pain.
The subjects will record use of these rescue analgesic medications on a daily basis in the 
e-Diary for the first 6 months of the treatment period.
The definition of increased analgesic use is as follows:
●
For the primary endpoints of DYS and NMPP, subjects will be considered 
non-responders if they have a 15% or greater increase from baseline in average 
pill count of rescue analgesics (endometriosis-associated) as further specified 
in Appendix H.
For the first 6 months, the rescue analgesic use for any defined period will be based on the 
average pill count during the analysis window for each class of rescue analgesics:  
NSAIDs, opioids, and any (NSAIDs and/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 number of pills within each class of rescue analgesic 
(NSAID or opioid) will be considered equivalent, regardless of specific pill choice, 


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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.
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 a 35 day window.  
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), not changed (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 
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.


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The ROC analysis may identify different response thresholds for DYS and NMPP.  The 
results of the ROC analysis, containing the determined thresholds, will be included in the 
final SAP prior to blind break.
The primary analysis of the co-primary endpoints will be based on a logistic regression 
model including treatment as the main factor and baseline pain score as a covariate to 
compare the proportion of responders at Month 6 between the incomplete responder 
groups that were randomized at Month 3 to either the elagolix 200 mg BID plus 
E2/NETA treatment group (Group C) or elagolix 150 mg QD group (Group B).  
The primary analysis will be repeated where the responder/non-responder categorization 
will use percent change from baseline in pain reduction.  ROC thresholds based on 
percent change from baseline in the average pain score will be conducted in the same 
manner as for the change from baseline.
Full details regarding the ROC analysis will be provided in the SAP.
8.1.4.3
Secondary Efficacy Variables
Key Secondary Efficacy Endpoints
The following key secondary efficacy endpoints based on data collected during the 
first 6 months of the treatment period will be summarized by treatment regimen:
●
Change from baseline in DYS
●
Change from baseline in NMPP
●
Change from baseline in dyspareunia
●
Change from baseline in Daily Diary endometriosis-associated pain score via 
NRS 
●
Change from baseline in rescue analgesic use across both classes of rescue 
analgesics based on average pill counts 
●
Percentage of subjects with 30% or more reduction from baseline based on the 
35 day mean of the Daily Diary endometriosis-associated pain score via NRS 


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Additional details regarding the key secondary efficacy endpoints will be provided in the 
SAP.
Additional Secondary Efficacy Endpoints
Additional secondary efficacy endpoints based on data collected during the first 6 months 
of the treatment period will include the following.  
●
Proportion of responders as assessed by change and percent change from 
Baseline in average pain score and rescue analgesic use monthly for DYS, 
NMPP, dyspareunia, and Daily Diary endometriosis-associated pain score via 
NRS, respectively. 
●
Proportion of responders as assessed by change and percent change from 
Baseline in average pain score alone (i.e., not taking into consideration of 
analgesic use) monthly for DYS, NMPP, dyspareunia, and Daily Diary 
endometriosis-associated pain score via NRS respectively. 
●
Change and percent change from Baseline, in the monthly average pain score 
(DYS, NMPP, dyspareunia), and Daily Diary endometriosis-associated pain 
score via NRS.
●
Change from Baseline in rescue analgesic use (average pill counts) to treat 
endometriosis-related pain, as assessed using information from the e-Diary. 
●
Proportion of analgesic use responders monthly (based only on reduction of 
rescue analgesics used).
Additional secondary efficacy endpoints during the 24 months treatment period will 
include the following.  
●
Patient Global Impression of Change (PGIC).
●
Monthly site administered overall endometriosis-associated pain questionnaire 
(7-day recall).
●
Patient reported outcome (PRO) and outcomes Rating Scales questionnaires.


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Summaries for Secondary Efficacy Variables
Unless otherwise specified, no statistical tests will be performed for secondary efficacy 
endpoints. 
Analysis details will be specified in the SAP.
8.1.4.3.1
Dysmenorrhea and Non-Menstrual Pelvic Pain
The proportion of responders, mean change and percent change from baseline to each visit 
during the first 6 months treatment period in DYS and NMPP will be summarized for 
each monthly visit.
8.1.4.3.2
Dyspareunia
The proportion of responders, mean change and percent change from baseline to each visit 
during the first 6 months of the Treatment Period in dyspareunia will be summarized 
similar to the method for DYS and NMPP.  
8.1.4.3.3
Rescue 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 6 months of the Treatment Period.
The rescue analgesic for endometriosis-associated pain taken by the subject will be 
summarized for the following analgesic categories:  (a) NSAID or opioid, (b) opioid and 
(c) NSAID.  
Baseline will be calculated as percentage of days of endometriosis rescue analgesic use 
for each analgesic category during the last 35 calendar days prior to and including Day 1 
during the Screening Period.  For the purposes of the rescue analgesic analysis, the 
number of pills within each class of rescue analgesic (NSAID or opioid) will be 
considered equivalent, regardless of specific pill choice, e.g., average NSAID pill count 
will consider all protocol specified NSAIDs specified in Table 3 and will not be 
conducted separately by NSAID type.


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The average pill count for each class of rescue analgesic for each visit during the 
first 6 months of the treatment period will be calculated by adding the daily pill count of 
the corresponding class of rescue analgesic in the analysis 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.  For Month 4, 
average values will be based on data collected between Month 3 reference study day and 
Month 4 reference study day.
8.1.4.3.4
Daily Diary Endometriosis-Associated Pain Score via NRS
The proportion of responders, mean change and percent change from baseline to each visit 
during the first 6 months treatment period in Daily Diary endometriosis-associated pain 
score via NRS will be summarized for each monthly visit.
8.1.4.3.5
Additional Endpoints
The additional variables including PGIC, overall endometriosis-associated pain via NRS 
(11-point NRS, 7-day recall), EHP-30, EQ-5D-5L, WPAI, HCRU, ETSQ and PROMIS 
Fatigue short Form 6a will be summarized during the 24 months treatment period.
8.1.5
Safety
8.1.5.1
General Considerations
All enrolled subjects who took at least one dose of the study drug will be included in the 
safety analyses.  
Data collected during the 3 month Open-Label Run-In Period will be summarized for all 
subjects combined.
For safety data collected during Treatment Months 4 – 6, summaries will be presented for 
the following groups.
●
Subjects who are responders to Elagolix 150 mg QD treatment group at 
Month 3 (Group A) and subjects who are incomplete responders to Elagolix 


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150 mg QD treatment group at Month 3 and randomized to Elagolix 150 mg 
QD treatment group at Month 3 (Group B) will be combined 
●
Subjects who are incomplete responders to Elagolix 150 mg QD treatment 
group at Month 3 and randomized to Elagolix 200 mg BID plus E2/NETA 
treatment group at Month 3 (Group C).
For safety data collected during Treatment Months 7 – 24, summaries will be presented 
for the following group.
●
Subjects who are responders to Elagolix 150 mg QD treatment group at 
Month 3 (Group A) and subjects who are incomplete responders to Elagolix 
150 mg QD treatment group at Month 3 and randomized to Elagolix 150 mg 
QD treatment group at Month 3 and are responders at Month 6 and continue to 
receive Elagolix 150 mg QD (Group E) will be combined.
●
Subjects who are incomplete responders to Elagolix 150 mg QD treatment 
group at Month 3 and randomized to Elagolix 150 mg QD treatment group at 
Month 3 and are incomplete responders at Month 6 and are switched to 
Elagolix 200 mg BID plus E2/NETA (Group D).
●
Subjects who are incomplete responders to Elagolix 150 mg QD treatment 
group at Month 3 and randomized Elagolix 200 mg BID plus E2/NETA 
treatment group at Month 3 (Group C).
Baseline for all subjects will refer to the data obtained prior to dosing on Day 1 of the 
Open-label Run-in Period.  
In general, for continuous variables, descriptive statistics (mean, standard deviation, 
median, minimum and maximum) will be summarized by treatment group.  Categorical 
data will be summarized with frequencies and percentages by treatment group.  Unless 
otherwise specified, no statistical tests will be performed.
Analysis details will be specified in the SAP.


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8.1.5.2
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.  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 AESIs (e.g., hypoestrogenic adverse events)
8.1.5.3
Analysis of Laboratory Data and Vital Signs
Changes in laboratory and vital sign parameters will be summarized as specified in the 
SAP.  
8.1.5.4
Bone Mineral Density
The key BMD evaluations are lumbar spine at Month 12 and Month 24.  Secondary BMD 
endpoints include total hip and femoral neck.
The Z- and T-scores and BMD percent change from baseline values during the 24 month 
treatment period will be summarized.  Factors associated with a change in BMD will be 


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explored.  Unless otherwise specified, no statistical comparisons on BMD assessment will 
be performed between treatment groups.
Full analysis details will be provided in the SAP.
Post-treatment bone mineral density scans will be summarized similarly, as appropriate.
8.1.5.5
Uterine Bleeding
Descriptive statistics for uterine bleeding as collected in the daily e-Diary will be 
presented.
8.1.5.6
Endometrial Variables
Endometrial biopsy result and ultrasound assessments will be summarized.
8.2
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.
8.3
Determination of Sample Size
This study plans to enroll approximately 890 subjects to ensure a sufficient number of 
subjects receive elagolix 150 mg QD for 24 months. 
Assuming the efficacy responder rate for the Daily Diary endometriosis-associated pain 
score via NRS is 50% during the open label elagolix 150 mg QD group at Month 3, 50% 
of subjects who complete Month 3 of the open-label period and are incomplete responders 
to 150 mg QD will be randomized in equal ratio to 150 QD and 200 BID plus E2/NETA.  


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Among those, assuming Month 6 DYS and NMPP responder rates of 20% for subjects 
who are randomized to elagolix 150 mg QD group (Group B) and 50% for subjects who 
are randomized elagolix 200 mg BID plus E2/NETA treatment group (Group C), this 
sample size provides greater than 90% power to detect a difference in response rate 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.
Assuming 80% of incomplete responders to 150 mg QD who are randomized to 150 QD 
at Month 3 are switched to elagolix 200 mg BID plus E2/NETA at Month 6 and a 25% 
completion rate, the current sample size will provide at least 120 subjects who receive 
elagolix 150 mg QD treatment group for 24 months (Group A and E).
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.
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 and all other 
applicable regulatory requirements.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 


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Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed, 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.
In the event a subject withdraws consent to participate from the study, stored biomarker 
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 
that their samples be withdrawn.  Once AbbVie receives the request, remaining biomarker 


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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.
An 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 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 from the main study, optional exploratory research 
samples will continue to be stored and analyzed unless the subject specifically withdraws 
consent for the optional samples.  If consent is withdrawn for the optional sampling, the 
subject must inform their study doctor, and once AbbVie is informed, the optional 
samples will be destroyed.  However, if the subject withdraws his/her consent and the 
samples have already been tested, those results will still remain as part of the overall 
research data.
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 to the appropriate 
source document.  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.
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.
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 


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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.
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 diary 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 


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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, ETSQ and the 
PGIC questionnaires and some 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 monthly site administered Overall Endometriosis-Associated 
Pain via NRS (7-day recall) 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.
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.
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 


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protocol and regulations. Remote review of data will also be performed.  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.
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 


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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, telephone 
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.
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 


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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 Study to Evaluate Safety and Efficacy of Elagolix Alone or 
Elagolix with Hormonal Add-Back in Subjects with Endometriosis 
with Associated Moderate to Severe Pain
Protocol Date: 
29 September 2017
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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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 no. 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 16.  04 April 2017.
7.
Taylor HS, Guidice LS, Lessey BA, et al.  Treatment of endometriosis-associated 
pain with elagolix, an oral GnRH antagonist.  N Engl J Med.  2017;377(1):28-40.
8.
US Department of Health and Human Services Food and Drug Administration 
Center for Drug Evaluation and Research (CDER).  Guidance for Industry Drug 
Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and 
Labeling Recommendations.  February 2012.  Available from:  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
default.htm.
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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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 BB, Hays RD, Bjorner JB, et al; 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 Suppl 1):S22-31.
14.
Deal LS, Williams VS, DiBenedetti DB, et al.  Development and psychometric 
evaluation of the endometriosis treatment satisfaction questionnaire.  Qual Life 
Res.  2010;19(6):899-905.
15.
Booth M.  Assessment of physical activity:  an international perspective.  Res Q 
Exerc Sport.  2000;71 (2 Suppl):S114-20.


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


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


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Clinical Development
Clinical Operations
Clinical Pharmacokinetics
Bioanalysis
Clinical Development
Statistics


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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


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Activity
Washoutb
Screening
Treatment Perioda
Day 1c
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Subset of Chemistry Labs:  ALT, AST & 
Alkaline Phosphatase
X
Hepatitis/HIV Screen
X
Reflexive Thyroid Stimulating Hormone
X
Urine Test for Gonorrhea and Chlamydia 
(optional)n
X
Pharmacokinetic Sample (elagolix and 
norethindrone concentration) 
Xo
Xo
Pharmacodynamic Sample (E2)
Xp
X
X
Xo
X
X
Xo
E-Diary Daily Entry
Endometriosis Daily Pain Impact Diary, 
Daily Diary endometriosis-associated pain 
score via NRS, Dyspareunia, Uterine 
Bleeding, Rescue Analgesic Use for 
Endometriosis-Associated Pain
X
X
X
X
X
X
X
X
Endometriosis Health Profile-30 (EHP-30)
X
X
X
EuroQol-5D 5 level (EQ-5D-5L)
X
X
X
Endometriosis Treatment Satisfaction 
Questionnaire (ETSQ)
X
X
X
PROMIS Fatigue Short Form 6a,
Work Productivity and Activity Impairment 
Questionnaire:  Specific Health Problem 
(WPAI:SHP)
X
X


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Activity
Washoutb
Screening
Treatment Perioda
Day 1c
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
IPAQ and Dietary Calcium Intake 
Questionnaire
X
X
Health Care Resource Utilization (HCRU)
X
X
X
X
X
X
X
Overall endometriosis-associated pain via 
NRS (11-point NRS, 7-day recall)q
X
X
X
X
X
X
X
PGIC
X
X
X
X
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
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
Randomizationr
X
Dispense Study Drug
X
X
X
Xs
X
X
Xs


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Study Activities – Treatment Period (Continued)
Activity
Treatment Perioda
Month 7
Month 8
Month 9
Month 10
Month 11
Month 12
Telephone Contact
X
X
X
Physical Exam
Xh
Gynecological (External Genitalia, Pelvic and Breast) Exam
Xh
Vital Signs
X
X
X
TVUj
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)
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
X
Pharmacodynamic Sample (E2)
X
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)
!
ETSQ
X
IPAQ and Dietary Calcium Intake Questionnaire
X


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Activity
Treatment Perioda
Month 7
Month 8
Month 9
Month 10
Month 11
Month 12
Health Care Resource Utilization (HCRU)
X
X
X
X
X
X
Overall endometriosis-associated pain via NRS (11-point NRS, 7-day 
recall)q
X
X
X
X
X
X
PGIC
X
X
X
Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit
X
Review Adverse Events & Analgesic Rescue/Concomitant Medication
X
X
X
X
X
X
Contraceptive Counseling 
X
X
X
X
X
X
Contraceptive Dispensing (prn)/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
Telephone 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)
!
ETSQ
X
IPAQ and Dietary Calcium Intake Questionnaire
X
Health Care Resource Utilization (HCRU)
X
X
X
X
X
X


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Activity
Treatment Perioda
Month 13
Month 14
Month 15
Month 16
Month 17
Month 18
Overall endometriosis-associated pain via NRS (11-point NRS, 7-day 
recall)p
X
X
X
X
X
X
PGIC
X
X
Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit
X
Review Adverse Events & Analgesic Rescue/Concomitant Medication
X
X
X
X
X
X
Contraceptive Counseling 
X
X
X
X
X
X
Contraceptive Dispensing (prn)/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
PDt
Telehone Contact
X
X
X
X
Physical Exam
Xh
Xh
Gynecological (External Genitalia, Pelvic and Breast) 
Exam
Xh
Xg
Vital Signs
X
X
X
TVUj
X
Xt
DXAl
X
Xt
Pap test
X
Xt
Pregnancy Tests: j,k,l  urine (u) serum (s)
X (u)
X (u)
X (u, s)
X (u)
X (u)
X (u, s)
X (u, s)
Endometrial Biopsym
X
Xt
Clinical/Safety Labs:  Chemistry, Hematology, Lipid 
Panel & Urinalysis
X
X
Vitamin D testing
X
X
Subset of Chemistry Labs:  ALT, AST & Alkaline 
Phosphatase
X
Urine Test for Gonorrhea and Chlamydia (Optional)n
X
X
Pharmacokinetic Sample (elagolix and norethindrone 
concentration) 
X
X
Pharmacodynamic Sample (E2)
X
X
X
Health Care Resource Utilization (HCRU)
X
X
X
X
X
X
X


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Activity
Treatment Perioda
Month 19
Month 20
Month 21
Month 22
Month 23
Month 24
PDt
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)
!
ETSQ
X
X
IPAQ and Dietary Calcium Intake Questionnaire
X
X (IPAQ 
only)
Overall endometriosis-associated pain via NRS 
(11-point NRS, 7-day recall)p
X
X
X
X
X
X
X
PGIC
X
X
X
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Since Last Visit
X
Review Adverse Events & Analgesic 
Rescue/Concomitant Medication
X
X
X
X
X
X
X
Contraceptive Counseling 
X
X
X
X
X
X
Xu
Contraceptive Dispensing (prn)/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.
b.
Subjects using exclusionary hormonal 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.


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c.
Day 1 will 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 ≥ 39 years of age or older at the start of screening, if no mammogram has been performed within 3 months.  If a subject has a mammogram performed 
during screening, annual mammograms should be performed during study participation.  Mammograms will be read locally.
j.
For any subject who has a positive serum pregnancy test result during the Treatment 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 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.  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 telephone contact visits.
m.
A negative urine pregnancy result should be obtained on the day of endometrial biopsy, prior to performing the procedure.  For subjects with an insufficient endometrial 
biopsy at Month 24 whose concurrent TVU indicates an endometrial thickness > 4 mm, a repeat biopsy should be performed.
n.
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.
To be collected prior to study drug dispensation/dosing at the site.
p.
On Day 1, the Pharmacodynamic sample should be collected with the safety labs prior to dosing.  
q.
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.
r.
Based on assessment for incomplete efficacy responders and subsequent blinded treatment assignment.
s.
Subjects will be administered the first dose of study drug from the new study drug kit(s) assigned at the investigative site (and prior to collection of PD sample).
t.
Premature Discontinuation prior to Month 6 does not require a DXA, TVU, Pap test, or endometrial biopsy.
u.
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
Activity
Follow-Up Perioda
Month 1
Month 6
Month 12
DXA
Xb
Xb
Physical Examc
X
Pharmacodynamic Sample (E2)
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
Follow up of Menstruation Questionnaireh
Xi
a.
The Follow-Up Period for the study will conclude for all subjects 30 days after the last Treatment Visit. 
b.
DXA scans of the lumbar spine, total hip, and femoral neck will be obtained at Follow-Up Months 6 and/or 12 for those subjects whose follow-up period visits occur prior to 
the study conclusion.
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.
Only 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 returned, 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 
●
3 – Probably benign
●
4 – Suspicious 
●
5 – Highly suggestive of malignancy
●
6 – Known biopsy-proven malignancy
Sickles EA, D'Orsi CJ, Bassett LW, et al.  ACR BI-RADS® Mammography.  In:  ACR 
BI-RADS® Atlas, Breast Imaging Reporting and Data System.  Reston, VA, American 
College of Radiology; 2013.


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Appendix E.
Overall Endometriosis-Associated Pain Questionnaire
On a scale of 0 – 10, 0 being no pain and 10 being worst pain ever, tell me the one number 
that describes your endometriosis pain at its WORST over the last 7 days.


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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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Appendix G.
BMD Risk Factor Assessment Questionnaire
This questionnaire will help estimate the amount of calcium you get from you what you 
eat and drink. 
Below is a list of some food items.  For each item in the list, please enter the number of 
servings you have eaten or drank, on a typical or average day, during the past week.
Please note that if you eat more than the listed serving size or amount, then you would 
increase the number of servings accordingly.  For example, if you have 1 cup of milk with 
breakfast and 1 cup of milk with dinner, you would enter 2 for the number of servings.  Or 
if you have 3 slices of cheese pizza, you would enter 3 for the number of servings.
Food Type
Standard Serving Size
Number of Servings 
on Average
Dairy
Skim Milk (non-fat)
8 ounces
Soy milk (calcium-fortified)
8 ounces
2% Milk 
8 ounces
Whole Milk
8 ounces
Milk (buttermilk, lowfat)
8 ounces
Yogurt (plain, low fat)
8 ounces
Yogurt (fruit, low fat)
8 ounces
Frozen yogurt (vanilla, soft serve)
½ cup
Ice cream (vanilla)
½ cup
Mozzarella cheese (part skim)
1½ ounces
Cheddar cheese
1½ ounces
Sour cream (reduced fat)
2 tablespoons
Cottage cheese (1% milk fat)
1 cup
Cream cheese (regular)
1 tablespoon


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Food Type
Standard Serving Size
Number of Servings 
on Average
Vegetables, Fruits, Nuts and Beans 
Turnip greens (fresh, boiled)
½ cup
Broccoli (raw)
½ cup
Kale (fresh, cooked)
1 cup
Kale (raw, chopped)
1 cup
Chinese cabbage (bok choy raw, shredded)
1 cup
Orange juice (with calcium)
6 ounces
Fish and Tofu
Sardines (canned in oil, with bones)
3 ounces
Canned pink salmon (with bones)
3 ounces
Tofu (soft, made with calcium sulfate)
½ cup
Tofu (firm, made with calcium sulfate)
½ cup
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


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Appendix H.
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
NSAID dose increases by more than 15% 
+ opioid analgesic use stops
Responder


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Use of NSAID and Opioid Analgesic at Baseline
Analgesics used at Baseline
Analgesic dose status at end of study
Responder?*
NSAID + opioid analgesic 
(continued)
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.
Assessment of dose is based on number of tablets of NSAIDS/opioids recorded in the Daily e-diary.