Conditions: Uterine Fibroids Heavy Menstrual Bleeding
Keywords: Elagolix Elagolix Sodium Heavy uterine bleeding Heavy menstrual bleeding (HMB) Leiomyomata Menorrhagia ABT-620 Elagolix + E2/NETA (Elagolix + Norethindrone acetate)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 378
Healthy volunteers: no

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

Detailed description:

Arms:
arm 1: Placebo for both elagolix twice daily (BID) and norethindrone acetate (E2/ NETA) once daily (QD) arm 2: Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD arm 3: Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD

Interventions: intervention 1: Elagolix intervention 2: Placebo for Estradiol/Norethindrone Acetate intervention 3: Estradiol/Norethindrone Acetate intervention 4: Placebo for Elagolix
Intervention descriptions: intervention 1: Film-coated tablets intervention 2: Placebo capsules intervention 3: Commercially-available E2/NETA tablets were over-encapsulated to maintain study blinding. intervention 4: Film-coated placebo tablets

Protocol document:
Prot_000.pdf: 
Elagolix (ABT-620)
M12-817 Protocol Amendment 2
1
1.0
Title Page
Clinical Study Protocol M12-817
A Phase 3 Study to Evaluate the Efficacy and Safety 
of Elagolix in Combination with 
Estradiol/Norethindrone Acetate for the 
Management of Heavy Menstrual Bleeding 
Associated with Uterine Fibroids in Premenopausal 
Women
Incorporating Amendments 1 and 2
AbbVie Investigational
  Product:
Elagolix (ABT-620)
Date:
06 October 2017
Development Phase:
3
Study Design:
Phase 3, randomized, double-blind, multicenter, 
placebo-controlled study evaluating the efficacy, safety and 
tolerability of elagolix alone and in combination with 
estradiol/norethindrone acetate for the management of heavy 
menstrual bleeding associated with uterine fibroids in 
premenopausal women 18 to 51 years of age.
Investigators:
Multicenter Trial:  Investigator information is on file at AbbVie
Sponsor:
AbbVie
Sponsor/Emergency 
  Contact:
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.
NCT02691494


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
2
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
10 December 2015
Amendment 1
26 July 2016
Administrative Change 1
26 July 2017
The purpose of this Amendment is to:
●
Update Section 1.1 Protocol Amendment:  Summary of Changes from 
Appendix Q to Appendix R
Rationale:  To correct the typographical error
●
Update following Section 1.2, Synopsis, Section 1.3, List of Abbreviations and 
Definition of Terms, Section 3.2.3, Pregnancy in Elagolix Studies, and 
Section 5.1, Overall Study Design and Plan:  Description, to add 'approximate' 
2.5 to 3.5 month Screening Period
Rationale:  To accurately note the variability in screening period and 
maintain consistency across the protocol
●
Update Section 5.1, Overall Study Design and Plan:  Description to:
○
Clarifying rescreening of subject would be pertinent to Study M12-817
Rationale:  Clarify for this protocol that rescreening would apply to 
Study M12-817 only.
○
Add additionally, for subjects who underwent screening in the replicate 
pivotal Study M12-815 who were not Randomized due to enrollment 
closure in that study, may have an opportunity to transfer to 
Study M12-817 with Study Team approval.  Tests and procedures 
conducted in Study M12-815 will be transferred with the subject to 
Study M12-817 for the subject's continued participation in screening and 
will be used for eligibility to be Randomized into Study M12-817 without 
needing to repeat procedures unless otherwise indicated.


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
3
Rationale:  To clarify the process to which subjects from Study M12-815 
can be randomized into Study M12-817 for their continued participation.
●
Update Section 5.3.1.1, Study Procedures, Central Imaging Procedures to:
○
Clarify that the Month 6 endometrial biopsy and imaging procedures need 
to be performed 15 days prior to the visit to ensure that images or samples 
are accepted for review by the central vendor.
Rationale:  To clarify language that procedures need to be performed 
within the window, however not all results need to be reported by the 
central vendor to the site for subject eligibility prior to rollover into the 
extension study.
○
Clarify that the pelvic ultrasound report at Month 6 is only required for 
review if the endometrial biopsy cannot be performed or biopsy results are 
insufficient. 
Rationale:  To clarify the case when the ultrasound report needs to be 
reviewed at Month 6 prior to rollover into the extension study.
Update Section 5.3.1.1, Study Procedures, Qualifying Uterine Fibroids to 
revise from Multiple Small Fibroids to Multiple Fibroids
Rationale:  To include all multiple fibroids regardless of size.
●
Update Section 5.4, Removal of Subjects from Therapy or Assessment to 
clarify when in the Study, surgical interventions and elevated liver enzymes 
constitute study withdrawal.
Rationale:  Clarify which subjects require withdrawal during treatment and 
post-treatment follow up period
●
Update Section 5.4.4, Delays in Rollover into the Extension Study, to:
○
Add the '28-day' interval visit required for subjects awaiting eligibility for 
the extension study
Rationale:  To clarify the timing of the monthly interval for when the delay 
in rollover visit should occur.
○
Remove language to conduct assessments and procedures in Table 6
Rationale: To reflect the update that the procedures are performed at the 
28 day interval.


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
4
○
Clarify for subjects not entering the extension study that the next visit in 
the Post-Treatment Follow-up Period will be a Site Visit and not a Phone 
Visit
Rationale:  To correct the error in Amendment 2 which described the Post-
Treatment Follow-up Month 1 Visit as a Phone Visit.
●
Update Appendix C, Study Activities – Washout, Screening and Treatment 
Periods and Post-Treatment Follow-Up Period, to add footnotes for 
Endometrial Biopsy Pelvic Ultrasound, MRI and DXA at Month 6
Rationale:  Clarify which results need to be reported prior to rollover into the 
extension study.
●
Update Appendix D, BI-RADS Classification 
Rationale:  Updating classifications to align with the American College of 
Radiology BI-RADS Atlas Fifth Edition.
An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix R.


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
5
1.2
Synopsis
AbbVie Inc.
Protocol Number:  M12-817
Name of Study Drug:  Elagolix (ABT-620)
Phase of Development:  3
Name of Active Ingredient:  Elagolix sodium
Date of Protocol Synopsis:  06 October 2017
Protocol Title:  A Phase 3 Study to Evaluate the Efficacy and Safety of Elagolix in Combination with 
Estradiol/Norethindrone Acetate for the Management of Heavy Menstrual Bleeding Associated with 
Uterine Fibroids in Premenopausal Women
Objectives:  The objectives of this study are 1) to assess the efficacy, safety and tolerability of elagolix 
300 mg BID in combination with E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg QD), versus 
placebo to reduce heavy menstrual bleeding (HMB) associated with uterine fibroids in premenopausal 
women 18 to 51 years of age, and 2) to characterize the impact of E2/NETA on the safety/tolerability 
[including bone mineral density (BMD) and other hypoestrogenic side effects] and efficacy of elagolix.
Investigators:  Multicenter trial.  Investigator information is on file at AbbVie.
Study Sites:  Approximately 125 sites
Study Population:  Premenopausal female subjects (aged 18 to 51 years, inclusive) with uterine fibroids 
and HMB (> 80 mL blood loss per menstrual cycle).
Number of Subjects to be Enrolled:  Approximately 400
Methodology:  
This Phase 3, randomized, double-blind, multicenter, placebo-controlled study is designed to evaluate the 
efficacy, safety and tolerability of elagolix alone and in combination with E2/NETA in the management 
of premenopausal women with HMB associated with uterine fibroids.  Approximately 400 subjects will 
be randomized in a 1:1:2 ratio of placebo to active treatment alone and in combination with E2/NETA to 
one of the following three treatment groups:
!
placebo (n = 100)
!
elagolix 300 mg BID (n = 100)
!
elagolix 300 mg BID plus E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD 
(n = 200)
Study Duration:  The total duration for this study is approximately 21 months.
The study consists of 4 periods:
!
Washout Period prior to Screening (only applicable if subject is taking hormonal medication at 
the time of consent; duration of washout depends on the type of hormonal medication).
!
Screening Period – approximately 2.5 to 3.5 months prior to first dose of study drug.
!
Treatment Period – 6-month treatment duration.
!
Post-Treatment Follow-Up Period – 12-month period, OR instead of entering the 
Post-Treatment Follow-Up Period, subjects may enter into an extension study (Study M12-816) 
if they are willing and qualify, based on safety parameters, to receive an additional 6 months of 
treatment, followed by 12 months of follow-up.


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
6
Washout Period:
Following informed consent, subjects, who are taking or were taking exclusionary medications such as 
hormonal medications or antifibrinolytics prior to screening that require washout, must enter a Washout 
Period.  Subjects must complete the Washout Period and have had at least 1 menses after completion of 
washout, prior to entering the Screening Period.  The duration of the required washout period is based on 
the excluded hormonal medication that the subject is currently taking, or was taking.  Procedures such as 
medical, social and gynecological history, a complete physical examination (including height and weight) 
with vital signs and urine pregnancy testing, protocol-related adverse event review will be performed and 
current medications will be documented.  Contraceptive counseling will be provided, and contraceptives 
dispensed, as necessary.  A pelvic ultrasound (transabdominal [TAU] and transvaginal [TVU]) may be 
performed after obtaining informed consent and prior to a subject entering the Washout Period in order to 
establish the presence of a qualifying fibroid(s) or uterine volume to avoid an unnecessary and lengthy 
washout period.
Screening Period:
Following informed consent (if Washout was not required), subjects will enter into an approximate 2.5-
to 3.5-month Screening Period to establish eligibility based on inclusion and exclusion criteria. A pelvic 
ultrasound (TAU and TVU) will be performed to confirm the presence and size of qualifying uterine 
fibroids and uterine volume and to rule out exclusionary ovarian cysts.  In addition to the ultrasound, a 
saline infusion sonohysterography (SIS) will be conducted to rule out exclusionary gynecological 
disorders such as pedunculated submucosal fibroids and endometrial polyps.  An endometrial biopsy will 
be performed to rule out endometrial pathology.  A mammogram in subjects who will be 39 years of age 
or older at the time of randomization will be performed unless the subject had a mammogram performed 
within 3 months prior to Screening.  DXA scans will be performed to evaluate bone mineral density 
(BMD) for determination of eligibility.  During the Screening Period, subjects must demonstrate MBL of 
> 80 mL for each of two menses as measured by the alkaline hematin method which quantifies the 
amount of blood loss on sanitary products.  Subjects will be dispensed sanitary product collection kits for 
2 to 3 menstrual cycles and will be required to collect all sanitary products on days with menstrual 
bleeding or spotting, and must return the products to the site within approximately 5 days after cessation 
of menses.  Subjects must be instructed to collect and return all used or worn products even if there 
is no visible blood on the products.  Subjects will also complete the Screening-Baseline Columbia 
Suicide Severity Rating Scale (C-SSRS) questionnaire to assess suicidal behavior and ideation. 
Treatment Period:
The Treatment Period begins with Day 1, which will occur between Days 1 to 10 of the first day of 
menses (defined as full menstrual flow) for all subjects who meet eligibility criteria during the Screening 
Period.
Subjects will be randomized to receive either placebo (n = 100), elagolix 300 mg BID (n = 100) or 
elagolix 300 mg BID plus E2/NETA (n = 200).  All subjects will self-administer study medication or 
matching placebo twice daily (in the morning and in the evening approximately 12 hours apart) orally 
throughout the 6-month Treatment Period.  Subjects randomized into the study will visit the site during 
the 6-Month Treatment Period on Day 1, and then monthly (28-day intervals), at Month 1 through 
Month 6.  Additional study visits may occur either for subjects returning their sanitary products for 
analysis of alkaline hematin at a Product Collection Visit or for a Premature Discontinuation visit.


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
7
Treatment Period (Continued):
Treatment Period Assessments:
Sanitary product collection kits will continue to be dispensed at all Treatment Period visits.  Subjects will 
be required to collect all sanitary products on days with menstrual bleeding or spotting and return them to 
the clinical study site, either during a scheduled monthly visit or at a Product Collection Visit.  Subjects 
must be instructed to collect and return all used or worn products even if there is no visible blood 
on the products.  If a subject does not return a sanitary product collection keg at any site visit (scheduled 
monthly visit or Product Collection visit), the Site Staff will administer the Uterine Bleeding 
Questionnaire (UBQ) to record if she had any bleeding or spotting since the last study visit.  If the subject 
had bleeding or spotting since the last study visit, the Site Staff will record the subjects response 
indicating why she did not collect products or return a sanitary product collection keg.
A pelvic ultrasound will be performed in all subjects at Day 1, Month 3, Month 6 or Premature 
Discontinuation Visit, if applicable, to assess volume of the largest fibroid, uterine volume, endometrial 
thickness and potential presence of ovarian and uterine pathology.  During the Treatment Period, 
Magnetic Resonance Imaging (MRIs) in a subset of subjects will be conducted at Day 1 and Month 6 or 
Premature Discontinuation Visit, if applicable to assess fibroid and uterine volume.  An endometrial 
biopsy will be performed in all subjects at the Month 6 or premature discontinuation visit.  It is 
recommended that the pelvic ultrasound, MRI (if applicable) and endometrial biopsy procedures be 
performed within the – 15 day procedure window).
Subjects will be asked to complete several patient-reported outcome questionnaires, such as the 
EQ-5D-5L, Uterine Fibroid Symptom Questionnaire (UFS-QoL), Work Productivity and Activity 
Impairment (WPAI) questionnaire, Health Care Resource Utilization questionnaire (HCRU), C-SSRS –
Since Last Visit questionnaire and Patient Global Impression of Change (PGIC), based on bleeding and 
non-bleeding uterine fibroid symptoms.  Site Staff will administer the Uterine Bleeding Questionnaire 
(UBQ), as applicable and the HCRU.  The Investigator will complete the Physician Surgery 
Questionnaire.
Pregnancy (urine and/or serum) tests will be performed at each visit throughout the study.  Subjects will 
be counseled at each visit on appropriate and effective forms of dual non-hormonal contraceptives to 
promote pregnancy prevention.
During the Treatment Period, blood samples will be collected for assay of serum estradiol and 
progesterone, and to measure plasma concentrations of elagolix and NETA.
Subjects will provide blood samples for Clinical Safety Labs, (including lipid panel) and for subjects who 
consent, a DNA pharmacogenetic sample will be collected on Day 1 and an RNA pharmacogenetic 
sample will be collected on Day 1, Month 1, Month 3 and Month 6 or Premature Discontinuation.
DXA scans will be obtained at Month 6 of the Treatment Period.  Sites will be encouraged to schedule 
the Month 6 DXA as early as possible within the – 15-day Month 6 treatment window, allowing for the 
evaluation of BMD prior to entering post-treatment follow-up or the extension study, Study M12-816.  
Subjects with BMD decrease < 8% in spine, total hip and femoral neck will be eligible for entry into the 
extension study.  Subject's with ≥ 8% decrease in BMD in the spine, total hip or femoral neck at Month 6 
of the Treatment Period are ineligible for entry into the extension study and will enter into the Post-
Treatment Follow-up Period.


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
8
Post-Treatment Follow-Up Period:
Eligible subjects who complete the 6-month Treatment Period, may, following consent, enter a separate 
extension study for 6 additional months of treatment with elagolix (for further details, refer to the 
Study M12-816 protocol synopsis). Subjects who prematurely discontinue from treatment, decline to 
participate in, or do not qualify for the extension study, will enter 12-month the Post-Treatment 
Follow-Up Period.
For subjects entering the 12-month Post-Treatment Follow-Up Period, visits will be conducted either by 
phone or on-site from Month 1 through Month 12.  (Subjects who prematurely discontinue from the 
Treatment Period prior to the Month 3 Study visit, are not required to have the pelvic ultrasound, MRI [if 
applicable] or DXA [unless the reason for discontinuation was due to BMD decrease or occurrence of 
fracture] performed in the Post-Treatment Follow-up Period and will complete the study at the 
Post-Treatment Follow-up Month 6 visit.)  Post-Treatment Follow-up Months 1, 3, 6, 9 and 12 are on-site 
visits while Post-Treatment Follow-up Months 2, 4, 5, 7, 8, 10 and 11 are Phone Visits.
During the phone visits, site personnel will discuss adverse events, concomitant medications, if 
applicable, obtain the results of the subject's self-administered urine pregnancy test and will remind 
subjects of the importance of consistent use of appropriate and effective dual non-hormonal contraception 
through the Post-Treatment Follow-Up Period.  Subjects may begin taking hormonal contraception or 
Tranexamic Acid (Lysteda, Cyklokapron, Cyclo-f) after completing the Post-Treatment Follow-Up 
Month 2 Visit and having returned to first full menses in the Post-Treatment Follow-up Period.
Subjects will be required to collect sanitary products for the first full menses in the Post-Treatment 
Follow-up Period.  Subjects will return the sanitary products at a Product Collection Visit within 
approximately 5 days after cessation of bleeding or spotting.
During the Post-Treatment Month 3 and Post-Treatment Month 6 on-site visits, procedures such as TAU, 
TVU, MRI (if applicable), DXA, clinical safety labs and pregnancy testing will be performed.  At the 
Post-Treatment Period Month 12 visit, procedures including vital signs, lipid panel, Apolipoprotein A 
and B and DXA will be performed.
Adverse event and concomitant medication review will be conducted at all visits during the 
Post-Treatment Follow-Up Period, including the phone visits.  
Central Laboratory and Central Imaging Vendors:
DXA, Ultrasound, SIS, MRI (if applicable), safety clinical lab samples including Apo A, and Apo B, 
endocrine panels, and alkaline hematin will be analyzed/evaluated using central laboratories or vendors.  
Assays for PK, PD and PG will be analyzed at AbbVie.
Analysis of Menstrual Blood Loss:
This study will utilize the alkaline hematin (AH) method for measuring MBL from screening through the 
first full menses in the Post-Treatment Follow-up Period.  Alkaline hematin is an objective and reliable 
measurement of total MBL based on the quantitation of menstrual blood collected on sanitary products.  


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
9
Key Criteria for Inclusion/Exclusion:
Key Inclusion Criteria:
1.
Subject has voluntarily signed and dated the informed consent form (ICF), approved by an 
Institutional Review Board/Ethics Committee (IRB/EC), prior to washout (if applicable), or initiation 
of any screening or study-specific procedures.
2.
Subject is a premenopausal female 18 to 51 years of age at the time of Screening.
3.
Subject has a diagnosis of uterine fibroids documented by a Pelvic Ultrasound (TAU, TVU) assessed 
by a central reader and verification that a fibroid present meets at least one of the following criteria:
!
Intramural, submucosal non-pedunculated fibroid with a diameter ≥ 2 cm (longest diameter).
!
Subserosal fibroid ≥ 4 cm.
!
Multiple fibroids with a total uterine volume of ≥ 200 cm3 to ≤ 2,500 cm3.
4.
Subject has HMB associated with uterine fibroids as evidenced by MBL > 80 mL during each of 
two screening menses as measured by the alkaline hematin method.
5.
Subject has a Screening FSH level of < 35 mIU/mL (35 IU/L).
6.
Subject has a negative urine and/or serum pregnancy test(s) during the Washout (if applicable) and/or 
Screening Periods, and has a negative urine pregnancy test just prior to first dose.
7.
Subject must agree to use two forms of non-hormonal contraception (dual contraception) consistently 
during the Washout (if applicable), Screening, Treatment and Post-Treatment Follow-Up Periods.  
(Subject may start hormonal contraception after completion of the Post-Treatment Month 2 Visit and 
return to first full menses).  Acceptable methods of dual contraception include the following 
combinations:
!
Condom with spermicide (foam, gel or polymer film).
!
Diaphragm with spermicide (condom may or may not be used).
!
Cervical cap with spermicide (condom may or may not be used).
Subject is not required to use dual contraception methods if:
!
Sexual partner(s) is vasectomized, at least 6 months prior to Screening.
!
Subject practices total abstinence from sexual intercourse, as the preferred lifestyle of the 
subject; periodic abstinence is not acceptable.
!
Subject had a bilateral tubal occlusion (including ligation and blockage methods such as 
Essure®), at least 4 months prior to Screening.
!
Subject is not sexually active with men; periodic sexual relationship(s) with men requires the 
use of dual non hormonal contraception as noted above.
8.
Subject has an adequate endometrial biopsy performed during Screening, the results of which show 
no clinically significant endometrial pathology.
9.
Subject ≥ 39 years of age at the time of randomization has a normal mammogram (BI-RADS 
Classification 1 to 3 or equivalent) during Screening or within 3 months prior to Screening.  
10. Subject must agree to the Washout Intervals for hormonal therapies, including any other medication 
that may require washout.
11. Subject has not taken exclusionary hormonal therapies within the specified washout interval prior to 
the initiation of any screening procedures and must have returned to at least 1 menses after 
completion of washout, prior to initiation of any screening procedures.


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
10
Key Criteria for Inclusion/Exclusion (Continued):
Rationale For Inclusion Criteria:
1
This is standard criterion in accordance with harmonized Good Clinical Practice (GCP)
2, 3, 4, 5
These criteria were selected to ensure an appropriate subject population of premenopausal 
women with HMB associated with uterine fibroids.  (prognostic and predictive)
6, 7
The impact of elagolix on pregnancies or breastfed infants is unknown and there is a 
possible risk of miscarriage due to changes in hormone levels; therefore, these criteria 
ensure pregnant women are not enrolled into the study and adequate precautions are taken 
to avoid pregnancy during study participation.  (prognostic and risk)
8, 9
These are standard criteria to ensure general good health and the safety of the subjects.  
(risk)
10, 11
To avoid bias for the evaluation of efficacy and safety by concomitant use of other 
medications.  (predictive and risk)
  
Key Exclusion Criteria:
1.
Subject has had menstrual cycles that are > 38 days in length for the past 3 months prior to 
Screening.
2.
Subject has screening pelvic ultrasound or SIS results that show a clinically significant gynecological 
disorder such as:
!
A persistent simple ovarian cyst > 5 cm in longest diameter (If the initial pelvic ultrasound 
shows a simple ovarian cyst > 5 cm and ≤ 7 cm an ultrasound of the ovaries may be repeated in 
4 to 6 weeks; however, the results must be evaluated prior to Day 1 and not meet exclusion).  
!
A complex ovarian cyst > 3.5 cm in diameter (longest diameter)
!
An endometrioma > 3.5 cm in diameter (longest diameter)
!
Large endometrial polyp ≥ 1 cm
!
Intracavitary/submucosal pedunculated fibroid
3.
Subject had a myomectomy, uterine artery embolization or high intensity focused ultrasound within 
6 months prior to Screening.
4.
Subject had an endometrial ablation within 1 year prior to Screening.
5.
Subject ≥ 21 years of age at Screening (or age at which Pap smears are routinely performed 
according to local or country guidelines) has a Pap smear result that meets exclusionary criteria.
6.
Subject has active pelvic inflammatory disease (PID).
7.
Subject's weight exceeds the limit of the DXA machine used for this study.
8.
Subject's hemoglobin level is < 8 g/dL (subjects with initial screening hemoglobin results < 8 g/dL 
can be prescribed iron supplements and have their hemoglobin levels retested prior to Day 1).
9.
Subject had two or more blood transfusions (separate events) within 9 months prior to Screening or 
required a blood transfusion within 60 days prior to Day 1.


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
11
Key Criteria for Inclusion/Exclusion (Continued):
Key Exclusion Criteria (Continued):
10. Subject has clinically significant abnormalities in clinical chemistry, hematology, or urinalysis 
(excluding findings that are associated with the disease under study such as low hemoglobin or low 
hematocrit) or a serum creatinine > 2.0 mg/dL at Screening.  Clinically significant laboratory 
abnormalities may be retested prior to Day 1; however the results must meet entry criteria to be 
eligible for randomization.
11. Subject has moderate to severe hepatic impairment including aspartate aminotransferase 
(ASAT/SGOT) or alanine aminotransferase (ALAT/SGPT) or bilirubin (unless known diagnosis of 
Gilbert's disease) ≥ 2.0 times the upper limit of the reference range.
12. 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).
13. Subject has clinically significant abnormal ECG or ECG with QT interval corrected for heart rate 
(QTc) > 450 msec at Screening using either Fridericia's correction (QTcF) or Bazett's correction 
(QTcB).
14. Subject is less than 6 months post-partum, post-abortion, post-pregnancy, or post lactation at the time 
of entry into the Screening Period, is pregnant or breastfeeding or is planning a pregnancy within the 
next 24 months.
15. Subject was diagnosed with a hereditary blood coagulation disorder (e.g., Von Willebrand disease, 
Factor V Leiden), or has a history of surgery-related severe bleeding or severe and prolonged 
bleeding associated with dental work.
16. Subject has a history of osteoporosis or other metabolic bone disease, including:
!
Screening DXA results of the lumbar spine (L1-L4), femoral neck, or total hip BMD 
corresponding to 1.5 or more standard deviations below normal (T-score ≤ –1.5).
!
Intercurrent bone disease (e.g., osteomalacia, osteogenesis imperfecta, etc.).
!
Condition that would interfere with obtaining adequate DXA measurements (e.g., history of 
spinal surgery, spinal hardware or severe scoliosis).
!
Presence of a condition that is associated with a decrease in BMD (e.g., uncontrolled 
hyperthyroidism, uncontrolled hyperparathyroidism, anorexia nervosa, etc.).
!
History of low-trauma bone fracture (e.g., fracture resulting from a fall from a standing height or 
lower).
!
History of bilateral hip replacement.
!
Clinically significant hypocalcemia, hypo- or hyperphosphatemia
!
Treatment with medication (excluding calcium and Vitamin D) for osteoporosis, osteopenia, or 
other bone disease associated with a decrease in BMD.
17. Subject has a history of major depression or post-traumatic stress disorder (PTSD) within 2 years of 
screening, OR a history of other major psychiatric disorder at any time (e.g., schizophrenia, bipolar 
disorder).  
18. 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 Day 1, 
prior to randomization.


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
12
Key Criteria for Inclusion/Exclusion (Continued):
Key Exclusion Criteria (Continued):
19. Subject has a clinically significant medical condition that requires intervention OR an unstable 
medical condition that makes the subject an unsuitable candidate for the study in the opinion of the 
investigator.
20. Subject has active vein thrombosis, pulmonary embolism or history of these conditions.
21. Subject has active arterial thromboembolic disease (e.g., stroke, myocardial infarction) or history of 
these conditions.
22. Subject has history of or active malignancy (except basal cell carcinoma of the skin) with or without 
systemic chemotherapy.
23. Subject has a history of clinically significant condition(s) or documented history of a severe, 
life-threatening or other significant sensitivity to any drug.
24. Subject has a surgical history of:
!
Hysterectomy (with or without oophorectomy).
!
Bilateral oophorectomy.
!
Bariatric surgical procedures of any type within 6 months of Screening.
25. Subject cannot tolerate estrogen- or estrogen plus progestin-containing preparations (e.g., oral 
contraceptives), or these preparations are contraindicated due to medical reasons.
26. Subject used any known moderate or strong inducers (e.g., cyclosporine, rifampin, carbamazepine, 
St. John's Wort) of cytochrome P450 3A (CYP3A) as indicated in Table 3 within 1 month prior to
randomization.
27. Subject is using a copper intra-uterine device (CU-IUD) or levonorgestrel intrauterine system 
(LNG-IUS).  If LNG-IUS is removed and subject completes washout or the CU-IUD is removed and 
the subject returns to 1 menses after completion of washout for LNG-IUS or after removal of the CU-
IUD, the subject can be screened for eligibility.
28. Subject is using any systemic corticosteroids for over 14 days within 3 months prior to Screening or 
is likely to require treatment with systemic corticosteroids during the course of the study.  
Over-the-counter and prescription topical, inhaled, intranasal or injectable (for occasional use) 
corticosteroids are allowed.
29. Subject is using oral retinoid preparations such as Accutane® (isotretinoin).  Topical isotretinoin 
applications are permitted.
30. Subject has a history of drug abuse and/or alcohol abuse within 12 months prior to Screening.
31. Subject was previously enrolled (randomized) in an elagolix study.
32. Subject is currently participating in another investigational study (drug or device) or has participated 
in an investigational drug study (i.e., receiving or has received investigational product) within 
1 month or 5 times the investigational drug half-life, whichever is longer, prior to Screening 
procedures.
33. Subject, who in the judgment of the investigator, will be unable or unwilling to comply with 
study-related assessments and procedures, including collection of sanitary products.


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
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Key Criteria for Inclusion/Exclusion (Continued):
Rationale for Exclusion Criteria:
1 – 4, 24
These criteria were selected to ensure an adequate subject population of women 
with HMB and uterine fibroids and no clinically significant gynecological 
disorders.  (prognostic and predictive)
5 – 13, 15 – 23, 
29, 30
These are standard criteria to ensure general good health and the safety of the 
subjects.  (prognostic and risk)
14
The impact of elagolix on pregnancies or breastfed infants is unknown and there is 
a possible risk of miscarriage due to changes in hormone levels; therefore, these 
criteria ensure adequate precautions are taken to avoid pregnancy or breastfeeding 
while receiving elagolix.  (risk)
31, 32
This criterion was selected to avoid bias for the evaluation of efficacy and safety 
by prior participation in an elagolix study.  (predictive and risk)
25 – 28
These criteria were selected to ensure that efficacy can be adequately assessed.  
(predictive and risk)
33
This criterion was added to ensure the population of subjects enrolled will comply 
with study-related procedures and subject collection requirements throughout the 
entire study.  (predictive)
  
Investigational Products:
Elagolix sodium 300 mg tablets
Estradiol 1.0 mg/norethindrone acetate 0.5 mg
Doses:
Placebo
Elagolix 300 mg BID alone
Elagolix 300 mg BID plus estradiol/norethindrone acetate (E2 
1.0 mg/NETA 0.5 mg) QD
Reference Therapy:
Placebo to match Elagolix; Placebo to match E2/NETA
Mode of Administration:
Oral
Duration of Treatment:  Subjects will receive 6 months of treatment.
Duration of Post-Treatment Follow-Up:  12 months (applicable to subjects not entering the extension 
study, Study M12-816).


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
14
Criteria for Evaluation:
Efficacy:
The analysis will compare 6 months of treatment with elagolix with and without add-back therapy, 
estradiol/norethindrone acetate (E2/NETA) to placebo.
Primary Efficacy Endpoint:
The primary endpoint will be the percentage of subjects meeting a composite endpoint consisting of these 
two bleeding assessments:
!
MBL volume < 80 mL during the Final Month (the last 28 days of treatment), AND
!
50% or greater reduction in MBL volume from baseline to the Final Month (the last 28 days of 
treatment).
A subject who prematurely discontinues the study drug due to adverse events, "lack of efficacy," or 
"requires surgery or invasive intervention for treatment of uterine fibroids" will be considered as a 
non-responder regardless whether she meets the two aforementioned responder criteria or not.
Secondary Efficacy Variables:
!
MBL volume assessed using alkaline hematin methodology and UBQ
!
Suppression of bleeding
!
Hemoglobin concentration 
!
Fibroid and uterine volume
!
UFS-QoL Questionnaire
!
EuroQol (EQ-5D-5L) Questionnaire
!
Health Care Resource Utilization (HCRU) Questionnaire
!
Patient Global Impression of Change (PGIC) Questionnaires
!
Work Productivity and Activity Impairment (WPAI) Questionnaire
Safety:
Safety evaluations include physical examination, vital signs, ECG, BMD changes, endometrial 
assessment (endometrial thickness and biopsy), clinical laboratory tests (hematology, chemistry, 
urinalysis, lipid panel) and adverse event monitoring.


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
15
Statistical Methods:
Efficacy:
Primary Efficacy Analysis:
The primary analysis will be based on the modified intent-to-treat (mITT) analysis set which is 
comprised of all randomized subjects who took at least one dose of the study drug and have at least 
one post-baseline visit in this study.
The baseline MBL volume will be defined as the mean of MBL volume from the qualified menstrual 
cycles during the Screening Period prior to the first study drug dose date, in which the total MBL volume 
is from all validated and non-validated sanitary products that subjects returned and where the total MBL 
volume of validated sanitary products only (excluding non-validated sanitary products) is greater than 
80 mL.  All menstrual cycles during the Screening Period in which the total MBL volume of validated 
sanitary products only is less than or equal to 80 mL are not qualified to be considered for baseline.
Final Month is defined as the last 28 days of treatment prior to and including the last dose date.
The primary endpoint will be analyzed using a logistic regression model including treatment as the main 
effect and baseline MBL volume as a covariate.  Missing Final Month MBL volume will be imputed 
using multiple imputation.
The primary efficacy comparison will be between the elagolix 300 mg BID plus E2/NETA group and the 
placebo group.  Therefore, no multiplicity adjustment is necessary.
Analyses for Secondary Efficacy Variables:
In general, data will be summarized for the Treatment Period and Post-Treatment Period separately.  Data 
for the Treatment Period will be summarized for each treatment group and compared between each 
elagolix treatment group and the placebo group.
The percentage of subjects with MBL volume < 80 mL and 50% or greater reduction in MBL volume 
from baseline during the Treatment Period will be summarized for each treatment group and compared 
between each elagolix treatment group and the placebo group.  Also, the individual component (the 
percentage of subjects with MBL volume of < 80 mL as well as the percentage of subjects with ≥ 50% 
reduction in MBL volume from baseline) will be summarized. 
The change and percent change from baseline in MBL volume to each month and to the Final Month, 
will be summarized for each treatment group and compared between each elagolix treatment group and 
the placebo group.
The percentage of subjects with suppression of bleeding and the percentage of subjects with amenorrhea 
will be summarized by monthly intervals throughout the Treatment Period.  In addition, the cumulative 
percentage of subjects with suppression of bleeding and the cumulative percentage of subjects with 
amenorrhea will be summarized by treatment group.


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
16
Statistical Methods (Continued):
Efficacy (Continued):
Analyses for Secondary Efficacy Variables (Continued):
The change from baseline to monthly intervals in number of bleeding days will be summarized by 
treatment group.  In addition, the change from baseline in total number of sanitary products will be 
summarized by treatment group. 
The change and percent change from baseline in hemoglobin concentration will be summarized for each 
treatment group and compared between each elagolix treatment group and the placebo group.
The change and percent change from baseline in primary fibroid volume, total fibroid volume, and 
uterine volume will be summarized for each treatment group and compared between each elagolix 
treatment group and the placebo group.  The change from baseline for quality of life assessments 
(e.g., UFS-QoL, EQ-5D-5L) will be summarized for each treatment group and compared between each 
elagolix treatment group and the placebo group. 
For the PGIC-MB and PGIC-NBUFS, the number and percentage of subjects in each response category 
will be summarized by treatment group.
Safety
All randomized subjects who took at least one dose of the study drug will be included in the safety 
analyses.  The number and percentage of subjects having adverse events will be tabulated by primary 
SOC and MedDRA Preferred Term with a breakdown by treatment group.  Hematology, chemistry, 
urinalysis, lipid panel, vital signs and endometrial biopsy variables will be summarized.
To evaluate BMD change, the percent change from baseline to Month 6 in the Treatment Period using 
aggregated data from two pivotal studies (Studies M12-815 and M12-817) will be compared between 
each elagolix treatment group and the placebo group as well as between the elagolix 300 mg BID group 
and the elagolix 300 mg BID plus E2/NETA group using analysis of co-variance (ANCOVA) with 
treatment as the main effect and baseline BMD as a covariate.  Two-sided 95% confidence intervals will 
be constructed for the differences in percent change from baseline to Month 6 in BMD.
Sample Size:
Approximately 400 subjects will be randomized (1:1:2) to placebo (N = 100), elagolix 300 mg BID 
(N = 100), or elagolix 300 mg BID plus E2/NETA (N = 200) for 24 weeks of dosing.  The sample size 
will provide at least 90% power to detect a difference between the elagolix 300 mg BID plus E2/NETA 
group and the placebo group in the percentage of subjects with MBL volume < 80 mL during the Final 
Month (the last 28 days of treatment) and 50% or greater reduction in MBL volume from baseline to the 
Final Month under the assumption of responder rates being 60% and 30% for elagolix 300 mg BID plus 
E2/NETA and placebo, respectively.
Pharmacokinetic:
Plasma concentrations of elagolix and norethindrone will be listed for each subject by visit day and dose 
regimen.  Pharmacokinetic data may be combined with data from other studies in women.  
Exposure-response analyses may be conducted as appropriate.
Pharmacodynamic:
Serum concentrations of estradiol, progesterone, FSH, and LH will be listed for each subject by visit day 
and dose regimen.


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
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Study Schematic:
  


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
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1.3
List of Abbreviations and Definition of Terms
Abbreviations
Ab
Antibody
ABT
Abbott/AbbVie
AE
Adverse Event
AGC
Atypical Glandular Cells
AH
Alkaline Hematin
APO A
Apolipoprotein A
APO B
Apolipoprotein B
ASC-H
Atypical Squamous Cells cannot exclude High grade squamous intraepithelial 
lesion
ASC-US
Atypical Squamous Cells of Undetermined Significance
AESI
Adverse Event of Special Interest
BID
Twice daily (bis in die)
BI-RADS
Breast Imaging Reporting and Data System
BMD
Bone Mineral Density
BUN
Blood Urea Nitrogen
CIN
Cervical Intraepithelial Neoplasia
CRF
Case Report Form
C-SSRS
Columbia-Suicide Severity Rating Scale
CU-IUD
Copper IUD
CYP3A
Cytochrome P450 3A
D&C
Dilation and curettage
DNA
Deoxyribonucleic acid
DXA
Dual energy X-Ray Absorptiometry
E2
Estradiol
ECG
12-Lead Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EQ-5D-5L
EuroQol-5D-5L
FDA
US Food and Drug Administration
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
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GLP
Good Laboratory Practices
GnRH
Gonadotropin releasing hormone
HAV-IgM
Hepatitis A Virus Immunoglobulin M
HBsAg
Hepatitis B Surface Antigen
HCRU
Health Care Resource Utilization
HCV Ab
Hepatitis C Virus Antibody
Hgb
Hemoglobin
HIFU
High Intensity Focused Ultrasound
HIV
Human Immunodeficiency Virus
HIV Ab
Human Immunodeficiency Virus Antibody
HMB
Heavy Menstrual Bleeding
HPV
Human Papilloma Virus
HSIL
High-Grade Squamous Intraepithelial Lesion 
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICL
Imaging Core Lab
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IR
Immediate Release
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intra-Uterine Device
K2EDTA
K2-ethylenediaminetetraacetic acid
LDL
Low-density Lipoprotein
LH
Luteinizing Hormone
LNG-IUS
Levonorgestrel Intrauterine System
LSIL
Low-grade squamous intraepithelial lesion
M
Month (visit)
MAD
Multiple Ascending Dose
MBL
Menstrual Blood Loss
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Cell volume of RBC
MedDRA
Medical Dictionary for Regulatory Activities


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
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MRI
Magnetic Resonance Imaging
NETA
Norethindrone acetate
NBI
Neurocrine Biosciences Inc
P
Progesterone
Pap
Papanicolau 
PCV
Product Collection Visit
PD
Premature Discontinuation 
PGIC-MB
Patient Global Impression of Change – Menstrual Bleeding
PGIC-NBUFS
Patient Global Impression of Change – Non-Bleeding Uterine Fibroid Symptoms
PID
Pelvic Inflammatory Disease
P-gp
P-glycoprotein
PK
Pharmacokinetic
POC
Proof-of-Concept
PRO
Patient Reported Outcome
PSQ
Physician Surgery Questionnaire 
PTSD
Post-Traumatic Stress Disorder
QD
Once a day (quaque die)
QoL
Quality of Life
RANKL
Receptor activator of nuclear factor-κB ligand
RBC
Red Blood Cell
RR
Respiration Rate
RNA
Ribonucleic acid
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SGOT/ASAT
Serum glutamic-oxaloacetic transaminase/aspartate aminotransferase
SIS
Saline Infusion Sonohysterography
SGPT/ALAT
Serum glutamic-pyruvic transaminase/alanine aminotransferase
SPRM
Selective Progesterone Receptor Modulator
TA MD
Therapeutic Area Medical Director
TAU
Transabdominal Ultrasound
TDD
Total Daily Dose
TBG
Thyroxine-Binding Globulin
TSH
Thyroid Stimulating Hormone
TEAEs
Treatment-emergent adverse events


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
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TVU
Transvaginal Ultrasound
UBQ
Uterine Bleeding Questionnaire
UFS-QoL
Uterine Fibroid Symptom Quality of Life Questionnaire
WBC
White Blood Cells
WHO
World Health Organization
WPAI
Work Productivity and Activity Impairment 
Pharmacokinetic and Statistical Abbreviations
ANOVA
Analysis of variance
ANCOVA
Analysis of covariance
AUC
Area under the plasma concentration-time curve
Cmax
Maximum concentration in plasma
LOCF
Last Observation Carried Forward
NOAEL
No observed-adverse-effect levels
PD
Pharmacodynamic
PK
Pharmacokinetic
SAP
Statistical Analysis Plan
Tmax
Time to maximum observed plasma concentration


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
22
Definition of Terms
Washout Period 
(if applicable)
The minimum interval of time for washout of hormonal therapy or other 
prohibited medications (if applicable).
Screening Period
The approximate 2.5 to 3.5 month period prior to randomization on Day 1, 
when screening procedures are performed to establish eligibility.  Subjects 
may either enter the Screening Period directly, if no washout is required, 
or enter after completing the Washout Period (if applicable).
Day 1 (Randomization) or 
Treatment Period Day 1
The day a subject takes her first dose of study drug.  Day 1 will occur 
between the first and tenth day of the onset (first day with full menstrual 
flow) of menses.
Monthly Visits:  Treatment 
Period Months 1 through 6 
and Post-Treatment Period 
Months 1 through 12
A month is defined as 28 days.
Product Collection Visits 
(PCVs)
Visits at which subjects return used sanitary products for assessment of 
alkaline hematin levels (either during screening or the treatment period); 
visits should occur within approximately 5 days after the last sanitary 
product was collected during a bleeding and/or spotting episode.
Home Product Collection 
Visits (Home PCVs)
Product Collection Visit conducted at home by a Home Health Care Agent 
who will go to the subject's home to draw a venous blood sample and 
retrieve the collection keg to return to the study site.
Heavy Menstrual Bleeding
Menorrhagia or > 80 mL blood loss
Vasomotor Symptoms
e.g., hot flush and night sweats


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
23
2.0
Table of Contents
1.0
Title Page ...............................................................................1
1.1
Protocol Amendment:  Summary of Changes ......................................... 2
1.2
Synopsis................................................................................................. 5
1.3
List of Abbreviations and Definition of Terms...................................... 18
2.0
Table of Contents ................................................................ 23
3.0
Introduction......................................................................... 29
3.1
Uterine Fibroids ................................................................................... 29
3.2
Elagolix................................................................................................ 30
3.2.1
Preclinical Experience .......................................................................... 31
3.2.1.1
Toxicology........................................................................................... 31
3.2.2
Clinical Experience .............................................................................. 32
3.2.3
Pregnancy in Elagolix Studies .............................................................. 40
3.3
Estradiol/Norethindrone Acetate........................................................... 45
3.4
Differences Statement .......................................................................... 45
3.5
Benefits and Risks................................................................................ 46
4.0
Study Objective ................................................................... 46
5.0
Investigational Plan.............................................................47
5.1
Overall Study Design and Plan:  Description ........................................ 47
5.2
Selection of Study Population............................................................... 56
5.2.1
Inclusion Criteria.................................................................................. 57
5.2.2
Exclusion Criteria................................................................................. 59
5.2.3
Prior and Concomitant Therapy............................................................ 64
5.2.3.1
Prior Hormonal/Anti-Hormonal Medications........................................ 64
5.2.3.2
Concomitant Therapy........................................................................... 66
5.2.3.3
Iron Supplementation ........................................................................... 67
5.2.3.4
Concomitant Use of Corticosteroids ..................................................... 67
5.2.3.5
Prohibited Therapy............................................................................... 68
5.2.4
Contraception Recommendations and Pregnancy Testing ..................... 71
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, Pharmacogenetic 
and Safety Assessments/Variables ........................................................ 75
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ............... 75


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
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5.3.1.1
Study Procedures.................................................................................. 75
5.3.1.2
Blood Samples for Pharmacogenetic Analysis .....................................109
5.3.1.3
Collection and Handling of Pharmacodynamic Variables ....................110
5.3.2
Drug Concentration Measurements......................................................111
5.3.2.1
Collection of Samples for Analysis......................................................111
5.3.2.2
Measurement Methods ........................................................................111
5.3.3
Efficacy Variables...............................................................................111
5.3.3.1
Primary Efficacy Variable ...................................................................111
5.3.3.2
Secondary Efficacy Variable ...............................................................112
5.3.4
PRO and Quality of Life Variables ......................................................112
5.3.5
Safety Variables ..................................................................................112
5.3.6
Pharmacodynamic Variables ...............................................................113
5.3.7
Pharmacokinetic Variables ..................................................................113
5.3.8
Pharmacogenetic Variables..................................................................113
5.3.9
Independent Data Monitoring Committee............................................114
5.4
Removal of Subjects from Therapy or Assessment ..............................114
5.4.1
Discontinuation of Individual Subjects ................................................115
5.4.2
Discontinuation of Entire Study...........................................................116
5.4.3
Treatment Interruption.........................................................................117
5.4.4
Delays in Rollover into the Extension Study........................................118
5.5
Treatments ..........................................................................................120
5.5.1
Treatments Administered.....................................................................120
5.5.2
Identity of Investigational Products .....................................................122
5.5.2.1
Packaging and Labeling.......................................................................123
5.5.2.2
Storage and Disposition of Study Drug................................................124
5.5.3
Method of Assigning Subjects to Treatment Groups ............................124
5.5.4
Selection and Timing of Dose for Each Subject ...................................125
5.5.5
Blinding of Investigational Product .....................................................125
5.5.6
Treatment Compliance ........................................................................125
5.5.7
Drug Accountability ............................................................................127
5.6
Discussion and Justification of Study Design.......................................128
5.6.1
Discussion of Study Design and Choice of Control Groups .................128
5.6.2
Appropriateness of Measurements.......................................................128


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
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5.6.3
Suitability of Subject Population .........................................................128
5.6.4
Selection of Doses in the Study ...........................................................129
6.0
Complaints......................................................................... 129
6.1
Medical Complaints ............................................................................130
6.1.1
Definitions ..........................................................................................130
6.1.1.1
Adverse Event.....................................................................................130
6.1.1.2
Serious Adverse Events.......................................................................131
6.1.1.3
Adverse Events of Special Interest.......................................................132
6.1.2
Adverse Event Severity .......................................................................132
6.1.3
Relationship to Study Drug..................................................................133
6.1.4
Adverse Event Collection Period.........................................................133
6.1.5
Adverse Event Reporting.....................................................................134
6.1.6
Pregnancy............................................................................................136
6.2
Product Complaint...............................................................................137
6.2.1
Definition............................................................................................137
6.2.2
Reporting ............................................................................................137
7.0
Protocol Deviations ........................................................... 138
8.0
Statistical Methods and Determination of Sample 
Size ..................................................................................... 139
8.1
Statistical and Analytical Plans............................................................139
8.1.1
General Considerations........................................................................139
8.1.2
Data Sets Analyzed .............................................................................139
8.1.3
End-of-Treatment Period Analysis.......................................................140
8.1.4
Independent Data Monitoring Committee............................................140
8.1.5
Demographic, Baseline Characteristics and Concomitant 
Medications.........................................................................................141
8.1.6
Time Points, Time Windows and Time Periods for Analysis ...............142
8.1.7
Efficacy...............................................................................................142
8.1.7.1
Primary Efficacy Variable ...................................................................142
8.1.7.1.1
Primary Analysis.................................................................................142
8.1.7.1.2
Derivation of Primary Efficacy Endpoint.............................................143
8.1.7.1.3
Multiple Imputation.............................................................................144
8.1.7.1.4
Sensitivity Analysis of the Primary Efficacy Variable..........................145


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
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8.1.7.2
Secondary Efficacy Variables..............................................................145
8.1.7.2.1
Reduction of Bleeding.........................................................................146
8.1.7.2.2
Hemoglobin Concentration..................................................................147
8.1.7.2.3
Fibroid and Uterine Volume ................................................................147
8.1.7.2.4
Quality of Life.....................................................................................148
8.1.7.2.5
Patient Global Impression of Change (PGIC) ......................................148
8.1.7.2.6
Work Productivity and Activity Questionnaire (WPAI) .......................149
8.1.7.2.7
Health Care Resource Utilization Questionnaire (HCRU)....................149
8.1.7.2.8
Multiple Comparisons .........................................................................149
8.1.8
Safety..................................................................................................149
8.1.8.1
General Considerations........................................................................149
8.1.8.2
Adverse Events....................................................................................150
8.1.8.3
Analysis of Laboratory Data and Vital Signs .......................................151
8.1.8.4
Bone Mineral Density..........................................................................151
8.1.8.5
Post-Treatment Analysis of Menstruation............................................152
8.1.8.6
Endometrial Biopsy.............................................................................152
8.1.8.7
Pelvic Ultrasound ................................................................................152
8.1.8.8
Columbia Suicide Severity Rating Scale (C-SSRS) .............................153
8.1.9
Pharmacokinetic/Pharmacodynamic Analysis......................................153
8.2
Determination of Sample Size .............................................................153
9.0
Ethics.................................................................................. 154
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ........................................................................................154
9.2
Ethical Conduct of the Study...............................................................154
9.3
Subject Information and Consent.........................................................155
10.0
Source Documents and Case Report Form 
Completion ........................................................................ 155
10.1
Source Documents...............................................................................155
10.2
Case Report Forms..............................................................................156
11.0
Data Quality Assurance .................................................... 157
12.0
Use of Information ............................................................ 158
13.0
Completion of the Study ................................................... 160
14.0
Investigator's Agreement.................................................. 161


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
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15.0
Reference List.................................................................... 162
List of Tables
Table 1.
Visit and Assessment Windows............................................................ 56
Table 2.
Washout Intervals for Exclusionary Hormonal/Anti-Hormonal 
Therapy................................................................................................ 66
Table 3.
Prohibited Medications......................................................................... 69
Table 4.
Clinical Laboratory Tests ..................................................................... 96
Table 5.
Menstrual Blood Loss Volume Eligibility............................................102
Table 6.
Schedule of Assessments – Delays in Roll-Over into Extension 
Study...................................................................................................119
Table 7.
Treatments Administered.....................................................................121
Table 8.
Identity of Investigational Products .....................................................123
List of Figures
Figure 1.
Study Schematic................................................................................... 48
Figure 2.
Pap Test Eligibility............................................................................... 80
Figure 3.
Management of BMD % Decrease at Month 6 of Treatment 
Period and Eligibility for Inclusion in the Extension Study ................... 93
Figure 4.
Management of BMD % Decrease:  Post-Treatment Follow-Up 
Month 12.............................................................................................. 95
Figure 5.
Sanitary Product Dispensation and Collection .....................................100
Figure 6.
Adverse Event Collection....................................................................134
Figure 7.
Flow-Chart for Deriving Primary Endpoint..........................................144
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.........................................164
Appendix B.
List of Protocol Signatories .................................................................166
Appendix C.
Study Activities – Washout, Screening and Treatment Periods and 
Post-Treatment Follow-Up Period .......................................................167
Appendix D.
BI-RADS Classification ......................................................................175


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
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Appendix E.
Reason for Study Participation – SAMPLE .........................................176
Appendix F.
Physician Surgery Questionnaire Version 1.0 – SAMPLE ...................177
Appendix G.
Uterine Bleeding Questionnaire(UBQ) – Treatment Period –
SAMPLE.............................................................................................178
Appendix H.
Uterine Bleeding Questionnaire (UBQ) Post-Treatment Follow-
Up Period – SAMPLE .........................................................................179
Appendix I.
Uterine Fibroid Symptom Quality of Life Questionnaire (UFS-
QoL) – SAMPLE ................................................................................180
Appendix J.
Patient Global Impression of Change – Menstrual Bleeding 
(PGIC-MB) SAMPLE .........................................................................181
Appendix K.
Patient Global Impression of Change Non-Bleeding Uterine 
Fibroid Symptoms (PGIC-NBUFS) – SAMPLE ..................................182
Appendix L.
Work Productivity and Activity Impairment Questionnaire: 
Uterine Fibroids V2.0 (WPAI:UF) – SAMPLE....................................184
Appendix M.
EurolQol (EQ-5D-5L) – SAMPLE ......................................................186
Appendix N.
Columbia-Suicide Severity Rating Scale (C-SSRS) –
Baseline/Screening – SAMPLE...........................................................188
Appendix O.
Columbia-Suicide Severity Rating Scale (C-SSRS) – Since Last 
Visit – SAMPLE .................................................................................191
Appendix P.
Health Care Resource Utilization Questionnaire (HCRU)
Version 2.0 – SAMPLE.......................................................................194
Appendix Q.
Health Care Resource Utilization Questionnaire (HCRU) 
Version 1.0 – SAMPLE.......................................................................200
Appendix R.
Protocol Amendment:  List of Changes ...............................................202


Elagolix (ABT-620)
M12-817 Protocol Amendment 2
29
3.0
Introduction
3.1
Uterine Fibroids
Uterine fibroids (leiomyomata) are the most common benign tumors in women and occur 
in up to 80% of women of reproductive age.1  The incidence increases with age, and 
uterine fibroids are the most common reason for hysterectomy in the United States.1,2  
Uterine fibroids may develop in African-American women on average 10 years earlier 
than in white women.3  The overall cost of symptomatic uterine fibroids exceeds 
$2 billion per year in the United States.4
The growth of uterine fibroids is highly dependent on both estrogen and progesterone.5  
Although often asymptomatic, fibroids may cause symptoms severe enough to warrant 
therapy in 20% to 50% of women3 and the most common symptom is heavy or prolonged 
menstrual bleeding.  Other symptoms may include anemia, pelvic pressure and pelvic 
organ compression, back pain, and adverse reproductive outcomes.  Heavy menstrual 
bleeding (HMB) (menorrhagia, defined as > 80 mL per menstrual cycle)1 is extremely 
inconvenient, can significantly impact quality of life and may lead to iron-deficiency 
anemia.
The choice of treatment is based on individual symptoms, patient preference, and the 
desire to preserve either fertility or the uterus or both.  Historically, hysterectomy or 
myomectomy were the preferred treatment options for women with symptomatic uterine 
fibroids.2  However, surgery is also associated with risks such as infections, bleeding 
complications, thromboembolic effects, scarring/adhesions, and even increased mortality.6  
As more women delay pregnancy into their 30s and 40s, there is a growing need for 
alternatives to surgical treatments, especially hysterectomy.  To meet this demand, during 
the past 2 decades many new uterus-sparing therapies have been proposed and studied 
including semi-invasive procedures, such as uterine artery embolization and magnetic 
resonance imaging (MRI)-guided high-intensity focused ultrasound ablation therapy as 
well as nonsurgical, medical treatments.  There is no long-term medical treatment for 


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


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The initial 3-month, Phase 2a, dose-finding, Proof-of-Concept (POC) study 
(Study M12-663) evaluated total daily doses (TDDs) of elagolix of 200, 400, and 600 mg 
in premenopausal women with HMB associated with uterine fibroids.  Data from this 
study indicated that an elagolix TDD of 600 mg best met the agreed-upon dose selection 
criteria for Phase 2b and Phase 3 (predicated on a dose in Phase 2a that provided the most 
robust response [responder rates of approximately > 80% for the composite bleeding 
assessment] and an acceptable safety and bleeding profile for the majority of women).  It 
was known that to support long-term dosing with elagolix at these higher doses, low dose 
hormonal add-back therapy would be required to mitigate bone loss and minimize other 
hypoestrogenic adverse events, e.g., hot flush.
Subsequently, a 6-month safety and efficacy Phase 2b study (Study M12-813) evaluating 
elagolix TDD of 600 mg (administered as 300 mg BID [twice daily] in Cohort 1 or 
600 mg QD in Cohort 2) with and without add-back therapy was conducted.  As add-back 
therapy, the study evaluated two doses of E2/NETA (low dose, 0.5 mg/0.1 mg and 
standard dose, 1.0 mg/0.5 mg).  Preliminary results from Cohort 1 demonstrated that 
treatment with elagolix 300 mg BID alone and in combination with E2/NETA provided 
robust efficacy in controlling HMB associated with uterine fibroids and provided an 
acceptable safety/tolerability profile that could potentially support the proposed chronic 
use indication.  While similar efficacy results were noted in Cohort 2 (elagolix 600 mg 
QD), review of the totality of data (preclinical, Phase 1 and Phase 2) comparing 
two dosing regimens support selection of the 300 mg BID + standard dose E2/NETA as 
the regimen for Phase 3.  
Additional details on rationale for dose selection are included in Section 5.6.4.
3.2.1
Preclinical Experience
3.2.1.1
Toxicology
Elagolix has been well characterized in repeated-dose animal toxicity studies of up to 
15 weeks in mouse, 28 weeks in rat, 39 weeks (9 months) in dog and 13 weeks in 
monkey.  


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The safety margin for the 200 mg BID human dose for the endometriosis indication is 
approximately 8.6 (28 week rat study) and 7.5 (9 month dog study).  
There were no significant findings from in vitro and in vivo genotoxicity studies. Also, 
there was no significant increase in tumors in the 2-year mouse carcinogenicity study with 
elagolix sodium.  In the 2-year rat carcinogenicity study, increase in thyroid or liver 
tumors was rat specific with no risk anticipated for human.
Elagolix is not teratogenic (no fetal abnormalities in preclinical studies) based on data 
from the rat and rabbit Segment II studies.  However, there were non-teratogenic findings, 
e.g., observations of abortions in rabbit and post-implantation loss in rat at higher doses.  
These could either be due to maternal toxicity or related to indirect pharmacological 
activity.  
Please refer to the most recent edition of the elagolix Investigator Brochure for complete 
information on toxicology studies for elagolix.
3.2.2
Clinical Experience
Refer to Edition 15 of the elagolix Investigator's Brochure (April 2016 or the most recent 
version) for the complete information on clinical studies, exposure to study drug, and 
safety.
Clinical Program Overview
As of 31 January 2016, a total of 3,417 subjects have received at least 1 dose of elagolix 
in clinical studies conducted by NBI and AbbVie (30 Phase 1 studies, 6 Phase 2 
endometriosis studies, 2 Phase 2 uterine fibroid studies [Studies M12-663 and M12-813], 
2 Phase 3 endometriosis studies [Studies M12-665 and M12-667] and 2 ongoing Phase 3 
endometriosis extension studies [Studies M12-667 and M12-821]).  More than 1,000 of 
these subjects were dosed for ≥ 6 weeks.  Of the 3,417 subjects, 95 were healthy men, 
795 were healthy women, 1,857 were women with endometriosis, 645 were women with 
uterine fibroids, 16 were women with hepatic impairment, and 9 were women with renal 


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impairment.  In ongoing studies (including 2 extension studies mentioned above and 
excluding Study M12-671), more than 1,625 subjects have received at least 1 dose of 
elagolix.
Twelve Phase 1 clinical studies (7 in healthy men and 5 in healthy women) and 6 Phase 2 
studies (in women with endometriosis) were completed by NBI.  To date, 18 Phase 1 
studies have been completed by AbbVie.  The Phase 3 endometriosis registration program 
consists of 2 replicate 6-month pivotal studies, Study M12-665 and Study M12-671 and 
2 extension studies, Study M12-667 and Study M12-821, respectively.  In women with 
HMB associated with uterine fibroids, 2 Phase 2 studies have been completed by AbbVie, 
Study M12-663 and Study M12-813.  The Phase 3 uterine fibroid registration program 
consists of 2 pivotal studies, Study M12-815 and Study M12-817, and a single planned 
associated 6-month safety/efficacy extension study, Study M12-816.
Clinical Pharmacokinetic and Pharmacodynamic Summary
Clinical pharmacokinetic (PK) studies indicate that elagolix is rapidly absorbed from the 
gastrointestinal (GI) tract with time to maximum plasma concentration (Tmax) of 
approximately 1 hour for immediate release (IR) tablet formulation.  The following points 
are key findings of elagolix PK:
●
Elagolix exposure (area under the plasma concentration versus time curve 
[AUC] and maximum concentration in plasma [Cmax]) appears to be 
approximately dose-proportional across the daily dose range studied (25 to 
400 mg).  At single daily doses of 600 mg and above, more than dose 
proportional increases in elagolix exposures were observed.
●
Elagolix displays biphasic disposition with a terminal elimination half-life of 
approximately 4 to 6 hours.  Little or no accumulation resulted from twice 
daily (BID) (400 mg BID) or once daily (QD) (400 mg QD) dosing at steady 
state.
●
Food decreases the AUC of the immediate-release tablet formulation by 
approximately 25%.


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●
Elagolix is a substrate of CYP3A and P-gp and may be a weak inducer of 
CYP3A enzymes.
●
Elagolix is primarily excreted in feces as metabolites (64%) and parent 
compound (26%).  Less than 3% is excreted unchanged in the urine.  Plasma 
exposure of elagolix metabolites was low (< 3% of each metabolite) relative to 
the parent.
Pharmacodynamic data from the AbbVie multiple-ascending dose (MAD) study, 
Study M12-790, in premenopausal healthy female subjects showed a dose-dependent 
suppression of E2, reaching maximum suppression at approximately 200 mg BID.  
Anovulatory progesterone levels were observed through Day 21 in all subjects at doses as 
low as 100 mg BID.  In addition, luteinizing hormone (LH) and follicle-stimulating 
hormone (FSH) decline in a dose dependent manner, with maximal suppression and near 
maximal suppression, respectively, at 300 mg BID.  The elagolix 400 mg BID dose not 
appear to result in substantial additional E2 suppression compared with the 300 mg BID 
dose.
Effects on Ovulation
Elagolix is not a contraceptive and data on ovulation rates from the 3-month 
folliculogenesis study, Study M12-673, showed that the 100 mg BID, 150 mg QD, and 
200 mg QD doses do not appear to differentiate.  The percentage of subjects with at least 
1 ovulation during the 3 months of elagolix treatment was 47.4% to 57.1%, and the 
percentage of subjects with ovulation was 28.1% to 33.3% within each month (28-day 
period).  In contrast, when ovulation rates are counted by subject or by month, the 200 mg 
BID dose appears to decrease ovulation rates to almost half of that observed with the 
150 mg QD dose.
The 300 mg BID dose appeared to have a slightly lower ovulation rate than 200 mg BID 
(27% versus 32%), and when the standard-dose estradiol 1.0 mg/norethindrone acetate 
0.5 mg (standard-dose E2/NETA) was co-administered with elagolix 300 mg BID, the 
ovulation rate decreased further to approximately 10%.


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


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


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


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subjects had a 3 to ≤ 5% BMD decrease, 25% had > 5% to < 8% BMD decrease, and 8% 
had a ≥ 8% BMD decrease.
While the addition of low-dose E2/NETA partially prevented BMD loss at the lumbar 
spine at Month 6 of treatment compared to the elagolix alone group (mean change from 
baseline –1.5% versus –3.6%), the E2/NETA (estradiol 1.0 mg/norethindrone acetate 
0.5 mg) more substantially mitigated BMD loss at the lumbar spine at Month 6 compared 
with the elagolix alone group (mean change from baseline –0.1% versus –3.6%).  In the 
E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) group 8.2% of subjects had a 3 
to ≤ 5% BMD decrease, 1 subject (2%) had a 5% – 8% BMD decrease and no subjects 
(0%) had ≥ 8% BMD decrease at the lumbar spine. 
Effects of Elagolix on Clinical Laboratory Parameters
Data from the Phase 2 studies with elagolix in women with uterine fibroids showed dose-
dependent increases in serum lipid parameters, corresponding to the degree of estrogen 
suppression and similar to those seen with other GnRH analogs.  Changes in serum lipids, 
in particular total cholesterol and low-density lipoprotein cholesterol (LDL-C), were 
observed in this study, similar to those observed in postmenopausal women9 and these 
changes, as expected, were somewhat attenuated by E2/NETA in a dose dependent 
manner.  Mean percentage increases from Baseline in total cholesterol, high density 
lipoprotein cholesterol (HDL-C), LDL-C, and triglycerides were observed across each of 
the elagolix treatment groups over the 6-month treatment duration.  Ongoing clinical trials 
with elagolix suggest similar findings, again which are consistent with those noted with 
other GnRH analogs.  While the significance of these lipid changes in premenopausal 
women with low-risk baseline lipid values is unknown, further monitoring and evaluation 
is needed.  In all these studies, the increased lipid values usually occur during the first 1 to 
2 months of elagolix use, stabilize or plateau, and return to pretreatment baseline levels 
within 1 to 3 months after elagolix is discontinued. 


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


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3.2.3
Pregnancy in Elagolix Studies
Pregnancies (Across the Entire Elagolix Clinical Development Program) 
The mechanism of action of elagolix, bleeding pattern, and the indirect evidence for 
follicular escapes (high E2 and progesterone values) indicate that elagolix does not 
consistently inhibit ovulation and as discussed in Section 3.2.2, Clinical Pharmacokinetic 
and Pharmacodynamic Summary, elagolix is not a contraceptive.
As of 05 February 2016, 172 pregnancies have been reported among women participating 
in elagolix clinical trials, including 104 that occurred off-treatment (58 during Screening 
and 46 during Post-Treatment [had a conception date more than 30 days after the last dose 
of study drug]) and 68 On-Treatment (i.e., had conception date during the Treatment 
Period with study drug or were deemed to have a conception date within 30 days after the 
last dose of study drug).  Among the 68 on-treatment pregnancies, 21 subjects had no 
exposure to elagolix (20 subjects treated with placebo only and 1 subject treated with oral 
contraceptives only).  The remaining 47 on-treatment pregnancies were in elagolix-treated 
subjects, and 21were carried to term, with 18 subjects delivering live infants without 
complications (1 pair of twins).  One subject delivered an infant with meconium 
aspiration pneumonia (MedDRA preferred term = congenital pneumonia).  Two subjects 
who received 150 mg elagolix QD in Phase 2 endometriosis studies delivered infants with 
congenital anomalies:  1 infant with tracheoesophageal fistula with findings of patent 
ductus arteriosus, tricuspid valve incompetence, and pneumothorax and 1 infant with cleft 
soft palate.  Internal and external causality assessment of these malformations supported 
that both congenital malformation cases were unlikely to be related to elagolix.
In Phase 3 studies in endometriosis 14 pregnancies have been reported in Study M12-665 
and 6 have been reported in Study M12-671.  In the aforementioned Phase 2b UF study, 
1 on-treatment pregnancy has been reported.  
Extensive counseling on pregnancy prevention along with a requirement for dual 
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trials.  Women are also counseled on the unknown, thus potential, risk to children born to 
mothers exposed to elagolix during pregnancy, including the possibility of malformations.
Pregnancies must be reported immediately and study drug discontinued.  Information on 
the outcome of the pregnancy will be collected.  For live infant births, information on the 
health of the infant will be collected 6 to 12 months after delivery.
Pregnancy outcomes must also be monitored vigilantly across the entire development
program, including adverse events related to pregnancy outcomes.  Women should also be 
counseled on the unknown, thus potential, risk to children born to mothers exposed to 
elagolix during pregnancy, including the possibility of malformations.
Efficacy in Phase 2 Uterine Fibroid Studies
The main objectives of the uterine fibroids Phase 2 program in premenopausal women 
were as follows:  1) to select the most appropriate dose(s) of elagolix to evaluate in 
Phase 2b and Phase 3 from both an efficacy and safety perspective, and 2) to assess the 
need for, adequacy, and type of add-back therapy to be used in conjunction with elagolix.  
The first objective was accomplished in the 3-month Phase 2a, dose-ranging POC study, 
Study M12-663, and the second objective was accomplished in both Phase 2 studies (need 
for and type of add-back in Phase 2a and adequacy of add-back therapy in Phase 2b 
[6-month safety and efficacy study]).  
The Phase 2a dose-finding, POC study evaluated TDDs of elagolix of 200, 400, and 
600 mg in premenopausal women with HMB associated with uterine fibroids.  While it 
was anticipated that some women would likely benefit (reduction in menstrual bleeding), 
even with low doses (TDD of 200 mg) of elagolix, the agreed-upon dose selection criteria 
for Phase 2b was predicated on a dose in Phase 2a that provided the most robust response 
(responder rates of approximately > 80% for the composite bleeding assessment) and an 
acceptable safety and bleeding profile for the majority of women.  It was known that to
support long-term dosing with elagolix at these higher doses, hormone add back therapy 
would be required for all of these.


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


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


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Preliminary results from Study M12-813 show that all treatment arms (both doses of 
elagolix [300 mg BID and 600 mg QD] alone or in combination with either strength of 
E2/NETA) met the primary endpoint, which is the proportion of subjects who achieved an 
MBL volume of < 80 mL at the Final Month and 50% or greater reduction in MBL 
volume from Baseline to the Final Month compared to that of placebo (all P < 0.001), as 
measured by the alkaline hematin method.
AbbVie Ongoing Phase 3 Clinical Studies
Endometriosis
The Phase 3 endometriosis clinical development program is comprised of two 6-month 
replicate, randomized, double-blind, placebo-controlled pivotal studies (Studies M12-665 
and M12-671), each with complimentary 6-month safety/efficacy extension studies 
(Studies M12-667 and M12-821).  The extension studies are ongoing.  The primary 
objective of the pivotal studies are to evaluate the safety, tolerability, and efficacy, of 
elagolix, administered QD or BID compared to placebo, in the management of moderate 
to severe endometriosis-associated pain while taking into account the use of rescue 
analgesics.  Secondary efficacy objectives include assessments of other endometriosis-
related symptoms, analgesic use, as well as quality of life (QoL) endpoints.  The 6-month 
extension studies assess the long-term safety and efficacy of elagolix for a total treatment 
duration of up to 12 months.
Phase 3 Clinical Development Program for Uterine Fibroids
The overall objective of the registration clinical development program is to generate 
requisite safety, tolerability, and efficacy data in 2 replicate 6-month Phase 3 pivotal 
studies and 1 safety and efficacy extension study (total 12-month treatment period) to 
support use of elagolix 300 mg BID with E2/NETA (estradiol 1.0 mg/norethindrone 
acetate 0.5 mg) for the intended indication of the chronic management of HMB associated 
with uterine fibroids.  Furthermore, the goal is to generate data that supports long-term 
use with this treatment regimen.


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The primary objective of these pivotal studies is to evaluate the efficacy and safety of 
elagolix 300 mg BID in combination with add-back therapy (E2/NETA) as compared to 
placebo to reduce HMB associated with uterine fibroids.  Given the difficulties with 
extending placebo for periods beyond 6 months, the elagolix 300 mg BID alone arm 
serves as a reference arm, which will be useful in fully understanding the protective 
effects of standard dose E2/NETA on BMD over a 12-month treatment period.
Subjects who complete either pivotal study (Studies M12-815 or M12-817) will have the 
option to enter into the extension study (Study M12-816) to receive an additional 
6 months of therapy, for a total of up to 12 months of active treatment for those 
randomized in the pivotal studies to active treatment and a total of 6 months of treatment 
for those randomized to placebo in the pivotal studies.
Subjects who discontinue or complete treatment in either pivotal study and choose not to 
participate in or are ineligible for entry into the extension study will enter into the 
12-month Post-Treatment Follow-Up Period of their respective study.
3.3
Estradiol/Norethindrone Acetate
E2/NETA (1.0 mg E2 and 0.5 mg NETA) is a continuous combined oral 
estrogen/progestin regimen.  E2/NETA is approved in the United States as 
postmenopausal hormone replacement therapy for the treatment of moderate to severe 
vasomotor symptoms associated with menopause and the prevention of postmenopausal 
osteoporosis.  E2/NETA is also approved in the United States for the treatment of 
moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause.
3.4
Differences Statement 
Phase 2 studies in women with HMB associated with uterine fibroids demonstrated that 
elagolix 300 mg BID provides the most robust efficacy in reducing HMB and E2/NETA 
is the optimal regimen for managing and limiting BMD loss, such that longer term dosing 
is feasible. 


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Continued assessments of this treatment regimen in the pivotal Phase 3 trials will provide 
the requisite data to support registration of elagolix 300 mg BID + E2/NETA as safe and 
efficacious treatment for the chronic management of HMB associated with uterine 
fibroids.  
3.5
Benefits and Risks
The most common symptom of premenopausal women with uterine fibroids is heavy 
menstrual bleeding (HMB).  A safe and effective chronic pharmacologic therapy for 
symptomatic uterine fibroids, as an alternative to hysterectomy or other surgical 
intervention, has not yet been approved, which is the objective of the elagolix Phase 3 
clinical development program.  Results from Phase 2 studies in women with HMB 
associated with uterine fibroids demonstrated that treatment with elagolix 300 mg BID 
alone and in combination with E2/NETA provided robust efficacy in reducing HMB 
associated with uterine fibroids.  Importantly, when co-administered with elagolix 300 mg 
BID, E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD mitigated BMD loss 
observed with elagolix 300 mg BID alone and substantially other hypoestrogenic adverse 
events such as hot flushes.  Also co-administration of elagolix and E2/NETA attenuated 
increases in serum lipid parameters observed with elagolix 300 mg BID alone.  
Furthermore, there was no evidence of endometrial safety concerns and the overall safety 
profile remained unchanged, with no new or unexpected findings to date.
This therapeutic approach, if successful, could provide an alternative to surgical 
interventions, and/or semi-invasive procedures as a chronic pharmacologic treatment for 
HMB associated with uterine fibroids.  Based on the totality of data to date from the 
Phase 2 clinical development program, the overall benefit/risk profile of elagolix 300 mg 
BID with E2/NETA appears to be favorable for the chronic management of HMB 
associated with uterine fibroids, and will be further defined in this Phase 3 trial.
4.0
Study Objective
The objectives of this study are to:


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●
Assess the efficacy, safety and tolerability of elagolix 300 mg BID in 
combination with E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg 
QD), versus placebo to reduce HMB associated with uterine fibroids in 
premenopausal women 18 to 51 years of age.  
●
The study will also characterize the impact of E2/NETA on the 
safety/tolerability (including BMD and other hypoestrogenic side effects) and 
efficacy of elagolix.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This Phase 3, randomized, double-blind, multicenter, placebo-controlled study is designed 
to evaluate the efficacy, safety and tolerability of elagolix alone and in combination with 
E2/NETA in the management of premenopausal women with HMB associated with 
uterine fibroids.  Approximately 400 subjects will be randomized in a 1:1:2 ratio to 1 of 
the following 3 treatment groups:
●
placebo (n = 100)
●
elagolix 300 mg BID (n = 100)
●
elagolix 300 mg BID plus E2/NETA (estradiol 1.0 mg/norethindrone acetate 
0.5 mg) QD (n = 200)
This study is designed to enroll approximately 400 subjects across approximately 
125 clinical study sites to meet scientific and regulatory objectives without enrolling an 
undue number of subjects in alignment with ethical considerations.  If the target number 
of enrolled subjects has been met, there is a possibility that additional subjects in 
screening will not be enrolled.
The study consists of 4 periods as follows:  
1.
Washout Period prior to Screening (if applicable)


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2.
Screening Period of approximately 2.5 to 3.5 months prior to first dose of study 
drug
3.
6-month Treatment Period 
4.
12-month Post-Treatment Follow-Up Period (OR Subjects may enter an extension 
study [Study M12-816] if they are willing and qualify, based on safety parameters, 
to receive an additional 6 months of treatment, followed by 12 months of 
follow-up).
Subjects will visit the site for assessments and testing during the Washout Period, if 
applicable, during the Screening Period (Initial Screening Visit, Screening Product 
Collection Visits [PCVs] for assessment of menstrual blood loss) and Treatment Period 
(Day 1 [Randomization] and monthly during Month 1 through Month 6).  Following the 
6-month Treatment Period, subjects will enter into a 12-month Post-Treatment Follow-Up 
Period or an extension study.  The Study Periods are illustrated in Figure 1.
Figure 1.
Study Schematic
Washout Period
Following informed consent, subjects, who are taking or were taking exclusionary 
medications such as hormonal medications or antifibrinolytics, prior to screening that 
require washout, must enter a Washout Period.  Subjects must complete the Washout 


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Period and have had at least 1 menses after completion of washout, prior to entering the 
Screening Period.  The duration of the required washout period is based on the excluded 
medication that the subject is currently taking, or was taking.  The requirements for 
washout are provided in detail in Section 5.2.3.1, Prior Hormonal/Anti-Hormonal 
Medications and the assessments to be performed are specified in Appendix C, Study 
Activities.
A pelvic ultrasound (transabdominal [TAU] and transvaginal [TVU]) may be performed 
after informed consent is obtained and prior to a subject entering the Washout Period in 
order to establish the presence of a qualifying fibroid(s) or uterine volume to avoid the 
subject unnecessarily undergoing a lengthy washout of hormonal medications.  Subjects 
will begin the use of non-hormonal dual contraception and receive counseling on the 
importance of consistent, appropriate and effective use of birth control.  
Screening Period
Subjects who do not require washout will enter directly into the approximate 2.5- to 
3.5-month Screening Period and will provide written informed consent before any study-
related procedures are performed.  Subjects will undergo screening procedures 
(e.g., safety labs, pelvic ultrasound [TAU/TVU], DXA) as specified in Appendix C, Study 
Activities, to establish eligibility based on inclusion and exclusion criteria.  
Subjects will be required to use dual non-hormonal contraception and will receive 
counseling on the importance of consistent, appropriate and effective use of birth control 
throughout the Screening Period.  
A pelvic ultrasound (TAU and TVU) will be performed, if not performed in the Washout 
Period, to determine the presence and size of qualifying uterine fibroids and uterine 
volume and to rule out exclusionary criteria; in addition to the ultrasound, a saline 
infusion sonohysterography (SIS) will be conducted to rule out exclusionary 
gynecological disorders such as intracavitary submucosal pedunculated fibroids and 
endometrial polyps. 


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Subjects who have qualifying uterine fibroids and uterine volume as assessed by 
ultrasound; however, have SIS images which are unable to fully assess the endometrial 
cavity, may undergo additional imaging modalities such as MRI for further evaluation in 
Screening.
Eligibility based on MBL (> 80 mL for each of 2 menstrual cycles) will be established 
using the alkaline hematin method.  Sanitary products and sanitary product collection kits 
will be dispensed during screening and training will be provided to ensure collection of 
sanitary products for menstrual bleeding assessment at the start of the subject's 
first menses in the Screening Period (Screening Menstrual Cycle 1).  Subjects will be 
required to collect all used or worn sanitary products (including products with no visible 
blood on them) on days with menstrual bleeding or spotting over the course of 2 or 
3 menstrual cycles during Screening to determine eligibility for entry into the Treatment 
Period.  Sanitary products will be returned to the site within approximately 5 days after 
cessation of menses for each menstrual cycle at a Screening Product Collection Visit.  
Reminders regarding the consistent use of acceptable forms of dual non-hormonal birth 
control and collection of all used or worn sanitary products on days with bleeding or 
spotting will be provided on a routine basis by the Study Staff.
Subjects who screen fail may be re-screened into the Study M12-817 on a case-by-case 
basis after consulting the AbbVie TA MD for approval.
Additionally, for subjects who underwent screening in the replicate pivotal 
Study M12-815 study who were not Randomized due to enrollment closure in that study, 
may have an opportunity to transfer to the Study M12-817 with TA MD approval.  Tests 
and procedures conducted in Study M12-815 will be transferred with the subject to 
Study M12-817 for the subject's continued participation in screening and will be used for 
eligibility to be Randomized into Study M12-817 without needing to repeat procedures 
unless otherwise indicated.


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Screening Sanitary Product Collection Visits
At each Screening Product Collection Visit, sanitary products to measure menstrual blood 
loss will be collected and a venous blood sample will be obtained.  The site will submit 
the sanitary products and venous blood sample to the alkaline hematin laboratory for 
analysis of blood loss to determine eligibility. 
Vital signs, a urine pregnancy test, contraception counseling and adverse event and 
concomitant medication review will also be performed during these visits.  Additional 
sanitary collection kits and contraceptives will be dispensed at each visit.  
There may be an option for subjects to have a Product Collection Visit conducted at home 
by a Home Health Care Agent who will go to the Subject's home to draw a venous blood 
sample and retrieve the collection keg to return to the site.
Treatment Period
The Treatment Period begins with Day 1, which will occur between Days 1 to 10 of the 
first day of menses (defined as the first day with full menstrual flow) for all subjects who 
meet eligibility criteria during the Screening Period.  
Subjects will be randomized to receive either placebo (n = 100), elagolix 300 mg BID 
(n = 100) or elagolix 300 mg BID plus E2/NETA QD (n = 200).  The first dose of study 
drug will be administered at the study site on Day 1.  Subjects will be instructed to 
self-administer study medication or matching placebo twice daily (in the morning and in 
the evening approximately 12 hours apart) orally without regard to food throughout the 
6-Month Treatment Period.  Subjects randomized into the study will visit the site during 
the 6-Month Treatment Period on Day 1, and then monthly (28-day intervals) from 
Month 1 through Month 6.  Additional study visits may occur, either for subjects 
returning their sanitary products for analysis of alkaline hematin at a Product Collection 
Visit or for a Premature Discontinuation Visit (if applicable).


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


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Eligible subjects who complete the 6-month Treatment Period, qualify and provide 
informed consent will be allowed to participate in a 6-month extension study in which all 
subjects will receive active treatment with either elagolix 300 mg BID alone or elagolix 
300 mg BID plus E2/NETA.  All activities for these subjects are outlined in the extension 
study protocol (Study M12-816).  The Month 6 Treatment Visit in this study may be 
conducted over several days to allow for eligibility to be confirmed prior to participation 
in the extension study.
Post-Treatment Follow-Up Period
For subjects entering the 12-month Post-Treatment Follow-Up Period, visits will occur 
either by phone or on-site from Months 1 through 12.  
During the phone visits, site personnel will discuss adverse events, concomitant 
medications, if applicable, obtain the results of the subject's self-administered urine 
pregnancy test and will remind subjects of the importance of consistent use of appropriate 
and effective dual non-hormonal contraception throughout the Post-Treatment Follow-Up 
Period.  Subjects may begin taking hormonal contraceptive preparations only after 
completing the Post-Treatment Follow-Up Month 2 Visit and having returned sanitary 
products for a full menses (menses with full menstrual flow) in the Post-Treatment 
Follow-up Period.  If the subject's full menses has not returned by the Post-Treatment 
Follow-Up Month 2 Visit, an adverse event of amenorrhea should be documented.
During the on-site visits, Post-Treatment Month 1, 3, 6, 9 and 12, procedures will be 
performed as specified in Appendix C, Study Activities.
Subjects will be required to collect sanitary products for their first menses with full 
menstrual flow in the Post-Treatment Follow-up Period.  If the subject misses collecting 
sanitary products for her first full menses, she will be required to collect sanitary products 
for her next full menses.  Subjects will return the sanitary products at a Product Collection 
Visit within approximately 5 days after cessation of bleeding or spotting.  The Post-
Treatment UBQ will be administered by Site Staff at each Phone or Site Visit until the 


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subject has returned sanitary products from her one full menses in the Post-Treatment 
Follow-up Period.  Once a subject returns sanitary products from a full menses in the 
Post-Treatment Follow-up Period, the Post-Treatment UBQ no longer needs to be 
completed.
Subjects who prematurely discontinued from the Treatment Period prior to the Month 3 
Study Visit, (e.g., subjects who received < 3 months of study drug), will enter into the 
Post-Treatment Follow-Up Period, however, the number of procedures/assessments 
performed in the Post-Treatment Period will be reduced and these subjects will complete 
the study at the Post-Treatment Follow-up Month 6 visit (unless the reason for premature 
discontinuation was due to BMD decrease or an adverse event of fracture).  
Procedures/assessments should be performed as specified in Appendix C, Study 
Activities.
Unscheduled Visit and Unscheduled Visits for Delays in Roll-Over
In the event an Unscheduled Visit is necessary during the Treatment or Post-Treatment 
Follow-Up Period, the site will perform at minimum, the UBQ and an assessment of 
adverse events and concomitant medications.  Unscheduled visits should be limited to 
when a subject is required to return to the office or off-site facility to repeat a procedure or 
to conduct a procedure to assess safety and the visit is not occurring at the same time 
when other study related procedures are scheduled to occur.  For unscheduled visits when 
study drug is dispensed (e.g., to replenish lost or damaged study drug), the subject will
also be required to have a negative urine pregnancy test result prior to dispensing.  
Clinical judgment should dictate when other safety assessments (such as vital signs and/or 
symptom-directed physical examination) should be conducted and should also support the 
reason for the unscheduled visit.
Subjects awaiting test results to determine eligibility into the extension study may be 
required to remain in the Treatment Period to receive additional study drug until results 
become available.  Visits associated with this waiting period will be documented as 
Unscheduled Visits and subjects will continue to undergo study-related assessments and 


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procedures as outlined in Appendix C and Section 5.4.4 Delays in Rollover into the 
Extension Study.
Visit Windows
Visit windows will be allowed for the monthly visits during the Treatment and 
Post-Treatment Follow-Up Periods.  Each subsequent monthly visit should be scheduled 
based on the date of the Day 1 (Randomization) visit.  At the Month 6 Treatment Period 
Visit, a –4 or +6 day visit window will be allowed in order to collect sanitary products 
from the last episode of menstrual bleeding or spotting prior to the Month 6 visit if 
menstrual bleeding starts immediately prior to or coincides with the scheduled visit.  The 
subject will be instructed to continue taking study drug from the extra blister card until 
she returns for the Month 6 visit.
Specific assessment-related visit windows are allowed.  Please refer to Table 1, Visit and 
Assessment Windows, for assessment-specific visit windows.


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Table 1.
Visit and Assessment Windows
Study Visit Windows
Study Visit
Visit Windows
Day 1 (Days 1 – 10 of the start of menses)
No visit windows*
Treatment Period:  Months 1 – 5
±4 days
Treatment Period:  Month 6
–4 or +6 days
Post-Treatment Follow-Up Period:  Months 1 – 12
±7 days
Assessment-Specific Windows for Treatment and Post-Treatment Period
Study Visit/Assessment
Visit Windows
Treatment Period
Day 1:  Ultrasound
±7 days
Day 1:  MRI (if participating in MRI subset)
±7 days (unless an MRI was required in 
Screening.  If MRI required in 
Screening, the Day 1 MRI will not be 
performed)
Month 3:  Ultrasound
±7 days
Month 6:  Ultrasound, MRI (if participating in MRI subset) 
DXA Scan and endometrial biopsy
–15 or +4 days
Post Treatment Follow-Up Period
Month 3:  Ultrasound, MRI (if participating in MRI subset)
–15 or +4 days
Month 6:  Ultrasound, DXA Scan
–15 or +4 days
Month 12:  DXA Scan
–15 or +4 days
*
Randomization must occur between Days 1 – 10 of the onset (first day of full menstrual flow) of menses.
5.2
Selection of Study Population
Premenopausal female subjects (aged 18 to 51 years, inclusive) with HMB (> 80 mL 
blood loss per menstrual cycle) associated with uterine fibroids who meet the inclusion 
criteria and do not meet any of the exclusion criteria will be eligible for randomization 
into the study.
Each Investigator will employ their clinical judgment in conjunction with protocol 
specified inclusion/exclusion criteria to determine if subject meets eligibility.  Questions 


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should be directed to the AbbVie Therapeutic Area Medical Director (TA MD) listed in 
Section 6.1.5 if further clarification is required.
Due to the long Screening Period, eligibility should be assessed throughout the Screening 
Period and just prior to Randomization to ensure that subject continues to meet eligibility.
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 51 years of age at the time of Screening.
3.
Subject has a diagnosis of uterine fibroids documented by a Pelvic Ultrasound 
(TAU, TVU) assessed by a central reader and verification that a fibroid present 
meets at least one of the following criteria:
●
Intramural, submucosal non-pedunculated fibroid with a diameter ≥ 2 cm 
(longest diameter)
●
Subserosal fibroid ≥ 4 cm
●
Multiple fibroids with a total uterine volume of ≥ 200 cm3 to ≤2,500 cm3
4.
Subject has HMB associated with uterine fibroids as evidenced by MBL > 80 mL 
during each of two menses in Screening as measured by the alkaline hematin 
method.
5.
Subject has a Screening FSH level of < 35 mIU/mL (35 IU/L).
6.
Subject has a negative urine and/or serum pregnancy test(s) during the Washout (if 
applicable) and/or Screening Periods, and has a negative urine pregnancy test just 
prior to first dose.
7.
Subject must agree to use two forms of non-hormonal contraception (dual 
contraception) consistently during the Washout (if applicable), Screening, 
Treatment and Post-Treatment Periods (Subject may start hormonal contraception 
after completion of the Post-Treatment Month 2 Visit provided her menses has 


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returned).  Acceptable methods of dual contraception include the following 
combinations:
●
Condom with spermicide (foam, gel or polymer film)
●
Diaphragm with spermicide (condom may or may not be used)
●
Cervical cap with spermicide (condom may or may not be used)
Subject is not required to use dual contraception methods if:
●
Sexual partner(s) is vasectomized, at least 6 months prior to Screening.
●
Subject practices total abstinence from sexual intercourse, as the preferred 
lifestyle of the subject; periodic abstinence is not acceptable.
●
Subject had a bilateral tubal occlusion (including ligation and blockage 
methods such as Essure®), at least 4 months prior to Screening.  
●
Subject is not sexually active with men; periodic sexual relationship(s) with 
men requires the use of dual non-hormonal contraception as noted above.
8.
Subject has an adequate endometrial biopsy performed during Screening, the 
results of which show no clinically significant endometrial pathology.
9.
Subject ≥ 39 years of age at the time of randomization has a normal mammogram 
(BI-RADS Classification 1 to 3 or equivalent) during Screening or within 3 months 
prior to Screening.  
10.
Subject must agree to the Washout Intervals for hormonal therapies, including any 
other medication that may require washout as specified in Section 5.2.3.1.
11.
Subject has not taken exclusionary hormonal therapies within the specified 
washout interval as specified in Section 5.2.3.1 prior to the initiation of any 
screening procedures and must have at least 1 menses prior to initiation of any 
screening procedures.
Rationale for Inclusion Criteria:
1
This is standard criterion in accordance with harmonized Good Clinical 
Practice (GCP).


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2 – 5
These criteria were selected to ensure an appropriate subject population of 
premenopausal women with HMB associated with uterine fibroids.  
(prognostic and predictive)
6, 7
The impact of elagolix on pregnancies or breastfed infants is unknown and 
there is a possible risk of miscarriage due to changes in hormone levels; 
therefore, these criteria ensure pregnant women are not enrolled into the study 
and adequate precautions are taken to avoid pregnancy during study 
participation.  (prognostic and risk)
8 – 9
These are standard criteria to ensure general good health and the safety of the 
subjects.  (risk)
10, 11
To avoid bias for the evaluation of efficacy and safety by concomitant use of 
other medications.  (predictive and risk)
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if she meets any of the following 
criteria:
1.
Subject has had menstrual cycles that are > 38 days in length for the past 3 months 
prior to Screening. 
2.
Subject has screening pelvic ultrasound or SIS results that show clinically 
significant gynecological findings such as:
●
A persistent simple ovarian cyst > 5 cm in longest diameter (if the pelvic
ultrasound shows a simple ovarian cyst > 5 cm and ≤ 7 cm, an ultrasound of 
the ovaries may be repeated in approximately 4 – 6 weeks; however, the 
results must be evaluated prior to Day 1 and not meet exclusion).
●
A complex ovarian cyst > 3.5 cm in diameter (longest diameter)
●
An endometrioma > 3.5 cm in diameter (longest diameter)
●
Large endometrial polyp (≥ 1 cm)
●
Intracavitary Submucosal pedunculated fibroid
3.
Subject had a myomectomy, uterine artery embolization or high intensity focused 
ultrasound within 6 months prior to Screening.


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4.
Subject had an endometrial ablation within 1 year prior to Screening.
5.
Subject ≥ 21 years of age at Screening (or age at which Pap smears are routinely 
performed according to local or country guidelines) has a Pap smear result that
meets exclusionary criteria as indicated in Figure 2, Pap Test Eligibility.  
6.
Subject has active pelvic inflammatory disease (PID).
7.
Subject's weight exceeds the limit of the DXA machine used for this study.
8.
Subject's hemoglobin level is < 8 g/dL (subjects with initial screening hemoglobin 
results < 8 g/dL can be prescribed iron supplements and have their hemoglobin 
levels retested prior to Day 1).  
9.
Subject had two or more blood transfusions (separate events) within 9 months prior 
to Screening or required a blood transfusion within 60 days prior to Day 1.
10.
Subject has clinically significant abnormalities in clinical chemistry, hematology, 
or urinalysis (excluding findings that are associated with the disease under study 
such as low hemoglobin or low hematocrit) or a serum creatinine > 2.0 mg/dL at 
Screening.  Clinically significant laboratory abnormalities may be retested prior to 
Day 1; however the results must meet entry criteria to be eligible for 
randomization.
11.
Subject has moderate to severe hepatic impairment (including aspartate 
aminotransferase (ASAT/SGOT) or alanine aminotransferase (ALAT/SGPT) or 
bilirubin (unless known diagnosis of Gilbert's disease) ≥ 2.0 times the upper limit 
of the reference range.
12.
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).
13.
Subject has clinically significant abnormal ECG or ECG with QT interval corrected 
for heart rate (QTc) > 450 msec at Screening using either Fridericia's correction 
(QTcF) or Bazett's correction (QTcB).


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14.
Subject is less than 6 months post-partum, post-abortion, post-pregnancy, or post 
lactation at the time of entry into the Screening Period, is pregnant or breastfeeding 
or is planning a pregnancy within the next 24 months.
15.
Subject was diagnosed with a hereditary blood coagulation disorder 
(e.g., Von Willebrand disease, Factor V Leiden), or has a history of surgery-related 
severe bleeding or severe and prolonged bleeding associated with dental work.
16.
Subject has a history of osteoporosis or other metabolic bone disease, including:
●
Screening DXA results of the lumbar spine (L1-L4), femoral neck, or total hip 
BMD corresponding to 1.5 or more standard deviations below normal (T-score 
≤ –1.5)
●
Intercurrent bone disease (e.g., osteomalacia, osteogenesis imperfecta, etc.)
●
Condition that would interfere with obtaining adequate DXA measurements 
(e.g., history of spinal surgery, spinal hardware or severe scoliosis).
●
Presence of a condition that is associated with a decrease in BMD 
(e.g., uncontrolled hyperthyroidism, uncontrolled hyperparathyroidism, 
anorexia nervosa)
●
History of low-trauma bone fractures (e.g., fracture resulting from a fall from a 
standing height or lower)
●
History of bilateral hip replacement
●
Clinically significant hypocalcemia, hypo- or hyperphosphatemia
●
Treatment with medication (excluding calcium and vitamin D) for 
osteoporosis, osteopenia, or other bone disease associated with a decrease in 
BMD
17.
Subject has a history of major depression or post-traumatic stress disorder (PTSD) 
within 2 years of Screening, OR a history of other major psychiatric disorder at any 
time (e.g., schizophrenia, bipolar disorder). 
18.
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 Day 1, prior to randomization.


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19.
Subject has a clinically significant medical condition that requires intervention OR
an unstable medical condition that makes the subject an unsuitable candidate for 
the study in the opinion of the investigator (including, but not limited to, 
uncontrolled diabetes mellitus, uncontrolled hypertension, epilepsy requiring 
anti-epileptic medication, unstable angina, confirmed inflammatory bowel disease, 
hyperprolactinemia, clinically significant infection or injury or symptomatic 
endometriosis [confirmed by laparoscopy/laparotomy]).
20.
Subject has active vein thrombosis, pulmonary embolism or history of these 
conditions.
21.
Subject has active arterial thromboembolic disease (e.g., stroke, myocardial 
infarction) or history of these conditions. 
22.
Any history of or active malignancy (except basal cell carcinoma of the skin) with 
or without systemic chemotherapy.
23.
Subject has a history of clinically significant condition(s) or documented history of 
a severe, life-threatening or other significant sensitivity to any drug.
24.
Subject has a surgical history of:
●
Hysterectomy (with or without oophorectomy)
●
Bilateral oophorectomy
●
Bariatric surgical procedures of any type within 6 months of Screening
25.
Subject cannot tolerate estrogen- or estrogen plus progestin-containing preparations 
(e.g., oral contraceptives), or these preparations are contraindicated due to medical 
reasons.
26.
Subject used any known moderate or strong inducers (e.g., cyclosporine, rifampin, 
carbamazepine, St. John's Wort) of cytochrome P450 3A (CYP3A), as indicated in 
Table 3 within 1 month prior to randomization.
27.
Subject is using a copper intra-uterine device (CU-IUD) or levonorgestrel 
intra-uterine system (LNG-IUS).  If the LNG-IUS is removed and subject 
completes washout per Section 5.2.3.1, or the CU-IUD is removed and the subject 


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returns to 1 menses after completion of washout for LNG-IUS or after removal of 
the CU-IUD, the subject can be screened for eligibility to be considered for 
randomization.
28.
Subject is using any systemic corticosteroids for over 14 days within 3 months 
prior to Screening or is likely to require treatment with systemic corticosteroids 
during the course of the study.  Over-the-counter and prescription topical, inhaled, 
intranasal or injectable (for occasional use) corticosteroids are allowed.
29.
Subject is using oral retinoid preparations such as Accutane® (isotretinoin).  
Topical isotretinoin applications are permitted.
30.
Subject has a history of drug abuse and/or alcohol abuse within 12 months prior to 
Screening.
31.
Subject was previously enrolled (randomized) in an elagolix study.
32.
Subject is currently participating in another investigational study (drug or device) 
or has participated in an investigational drug study (i.e., receiving or has received 
investigational product) within 1 month or five times the investigational drug 
half-life, whichever is longer, prior to Screening procedures.  If a subject has 
participated in an investigational trial with hormonal treatment, the washout 
interval specified in Section 5.2.3.1 applies.
33.
Subject, who in the judgment of the investigator, will be unable or unwilling to 
comply with study-related assessments and procedures, including collection of 
sanitary products. 
Rationale for Exclusion Criteria: 
1 – 4, 24
These criteria were selected to ensure an adequate subject 
population of women with HMB and uterine fibroids and no 
clinically significant gynecological disorders.  (prognostic and 
predictive)
5 – 13, 15 – 23, 
29, 30
These are standard criteria to ensure general good health and the 
safety of the subjects.  (prognostic and risk)


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14
The impact of elagolix on pregnancies or breastfed infants is 
unknown and there is a possible risk of miscarriage due to changes 
in hormone levels; therefore, these criteria ensure adequate 
precautions are taken to avoid pregnancy or breastfeeding while 
receiving elagolix.  (risk)
31, 32
This criterion was selected to avoid bias for the evaluation of 
efficacy and safety by prior participation in an elagolix study.  
(predictive and risk)
25 – 28
These criteria were selected to ensure that efficacy can be 
adequately assessed.  (predictive and risk)
33
This criterion was added to ensure the population of subjects 
enrolled will comply with study-related procedures and subject 
collection requirements throughout the entire study.  (predictive)
5.2.3
Prior and Concomitant Therapy
Any medication administered to treat uterine fibroid symptoms or HMB associated with 
uterine fibroids within 6 months prior to Washout or Screening must be recorded in 
source documents and the electronic case report forms (eCRFs).  The date(s) of 
administration (including start and stop dates), dose, route, and reason for use and 
discontinuation must be recorded in source documents and on the Prior Uterine Fibroid 
Medication eCRFs.  
Please refer to Section 5.2.3.2 for details regarding concomitant medication use.
The AbbVie Therapeutic Area Medical Director (TA MD) should be contacted if there are 
any questions regarding concomitant or prior therapy.
5.2.3.1
Prior Hormonal/Anti-Hormonal Medications
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.  Subjects must also return to 1 menses after 
completion of Washout before entering into the Screening Period.  Subjects currently 


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using hormonal/anti-hormonal therapies will sign an ICF before they discontinue the 
hormonal medication.  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 required washout.  Subjects must 
also return to 1 menses after completion of Washout before the Screening Period can 
begin.  Discontinuation of hormonal contraception should be done according to 
prescribing information (e.g., complete current cycle of birth control pills).  
The minimum washout intervals for hormonal medications (including LNG-IUS) prior to 
Screening are described in Table 2.  Subjects entering washout will be required to undergo 
study specific procedures, as outlined in Appendix C, Study Activities.  Subjects may 
enter the Screening Period provided they have returned to 1 menses after the required 
washout period has been completed.  Subjects who have a CU-IUD and agree to have the 
CU-IUD removed may enter screening, however the subject must return to 1 menses after 
removal of the CU-IUD, prior to collecting sanitary products for assessment of menstrual 
blood loss as the removal of the CU-IUD may cause abnormal menstrual bleeding that 
may interfere with the assessment of eligibility criteria.  
If the type of hormonal product and the length of Washout Period are not listed in the 
table below, consult the AbbVie TA MD.


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Table 2.
Washout Intervals for Exclusionary Hormonal/Anti-Hormonal 
Therapy
Therapy
Minimum Interval 
for Washout**
Number of Menses Required 
AFTER Completion of 
Washout Period (Prior to 
Initial Screening Visit)
Medroxyprogesterone acetate injection (Depo-Provera®; 
Sayana®)
300 days from 
injection
2 menses
GnRH agonist 3 month depot (Lupron Depot® 11.25 mg)
90 days from 
injection
1 menses
GnRH antagonist
90 days
Selective Progesterone Receptor Modulators 
(e.g., Ulipristal acetate, Vilaprisan)
Nafarelin acetate
Danazol (Cyclomen®)
Aromatase inhibitors
Oral contraceptives
30 days
Oral, transdermal or intravaginal estrogen preparations*
Oral, intravaginal or transdermal progesterone/progestin 
preparations, including tibolone*
Synarel® (Nasal Spray)
Progesterone and LNG-IUS, sub-dermal progestin 
implant (e.g., Nexplanone®), GnRH agonist – 1 month 
depot
Exception:  levonorgestrel 1.5 mg or ulipristal acetate 
30 mg used for emergency contraception
30 days after removal 
or injection
Lupron Depot® 3.75 mg
NuvaRing®
Antifibrinolytics
2 weeks
*
E2/NETA will be taken by subjects randomized to the E2/NETA treatment group.
**
This is the minimum washout; however, subjects may not enter Screening until at least 1 menses (or at least 
2 menses for Medroxyprogesterone acetate injection) has occurred after completion of the Washout Period.  If less 
than a full course of therapy is administered, the investigator should contact the AbbVie TA MD listed in 
Section 6.1.5 to discuss and confirm the required washout interval.
5.2.3.2
Concomitant Therapy
All other medications or vaccines (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving at the time of entering 


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into the Washout Period (if required) or Screening Period and during the Treatment and 
Post-Treatment Follow-Up Periods must be recorded in source documents and on the 
Concomitant Medication eCRFs.  The reason for use, date(s) of administration (including 
start and end dates) and dosage information (including dose and frequency) must be 
recorded.
5.2.3.3
Iron Supplementation
Excessive blood loss from heavy menses may result in iron deficiency anemia.  Iron 
deficiency anemia is defined by the World Health Organization (WHO) as an Hgb 
concentration below 12 g/dL (120 g/L) for non-pregnant women.  Subjects entering the 
study with anemia or who develop anemia during the study, if not already taking iron 
supplements, should be prescribed iron supplementation by the Investigator, as per 
standard of care.  If the Investigator does not prescribe iron supplements for subjects with 
a Hgb < 12g/dL, the reason should be documented in source documents.
The recommended oral dose of ferrous sulfate is 300 to 325 mg following the diagnosis of 
anemia.  During Screening, all subjects with an Hgb level < 8 g/dL will be retested after 
receiving iron supplements; these subjects will only be eligible to randomize if their 
Hgb results meet eligibility prior to Day 1 (Randomization) and has not required a blood 
transfusion within 60 days prior to Day 1.  If a subject is unable to tolerate ferrous sulfate 
then ferrous gluconate, liquid iron or intravenous (IV) iron may be prescribed.  If subjects 
experience constipation from iron supplement use, stool softeners may be prescribed.  All 
iron supplements taken during the study, from Screening through the final visit, must be 
recorded on the concomitant medications eCRF.
Further instructions on the provision of iron supplementation and stool softeners will be 
provided separately from this protocol.
5.2.3.4
Concomitant Use of Corticosteroids
Chronic use (> 14 days) of systemic corticosteroids is prohibited during the Washout, 
Screening, Treatment and Post-Treatment Follow-Up Periods, however inhaled 


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corticosteroids for the treatment of asthma are permitted.  Over-the-counter and 
prescription topical, inhaled, intranasal or injectable (for occasional use) corticosteroids 
are allowed.  Subjects, who based on medical history, may potentially require long-term 
oral treatment with corticosteroids during the course of the study, should not be enrolled.  
If the subject requires systemic corticosteroid use for > 14 days, the AbbVie TA MD must 
be notified.
5.2.3.5
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 the Washout, Screening; Treatment Period and until the 
Post-Treatment Follow-Up Month 2 Visit and return to menses.  If the Subject has not 
returned to menses, she must continue the use of dual non-hormonal contraception.
For subjects who are prescribed/administered the emergency contraceptive pill during the 
study, the AbbVie TA MD must be informed.
Tranexamic acid should not be taken during the Screening, Treatment or Post-Treatment 
Follow-Up Period, however tranexamic acid, if necessary, can be prescribed following 
completion of the Post-Treatment Follow-up Month 2 visit and the subject has returned to 
first full menses.
Due to the extensive list of herbal remedies and supplements, please contact the AbbVie 
TA MD for any that may be prohibited.  Generally-speaking, any supplements or herbal 
remedies used to treat premenstrual or gynecological problems, such as black cohosh, are 
excluded.
The following medications should not be taken during the Washout (if applicable), 
Screening, Treatment and Post-Treatment Follow-Up Period.


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Table 3.
Prohibited Medications 
Prohibited During the Washout, Screening, Treatment and Post-Treatment Follow-Up Periods
Hormonal/Anti-Hormonal 
Medications%, such as:
GnRH agonists leuprolide acetate (Lupron®), nafarelin acetate 
(Synarel®), goserlin acetate (Zoladex®)
GnRH antagonists (other than elagolix)
Danazol (Danocrine®)
Medroxyprogesterone acetate (Depo-Provera®, Provera®)
Oral contraceptives
Estrogen preparations*
Testosterone preparations
Other progestins* (oral, vaginal, transdermal, implantable, IUD, 
or LNG-IUS, except emergency contraception)
HCG or HCG products
Glucocorticoids, oral or injectable (chronic use only)
Mifepristone
Selective Progesterone Receptor Modulators (e.g., Ulipristal 
acetate (except as emergency contraception, i.e., 30 mg) and 
Vilaprisan)
Tamoxifen
Bromocriptine (Parlodel®)
Cabergoline (Dostinex®)
Raloxifene (Evista®)
Aromatase Inhibitors (e.g., Anastrozole [Arimidex®], 
Exemestane [Aromasin®])
Non-hormonal estrogen 
supplements#
Natural Estrogen preparations (e.g., soy-containing supplements, 
black cohosh)
Antifibrinolytics%
Tranexamic acid (Lysteda, Cyklokapron, Cyclo-f)


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Table 3.
Prohibited Medications (Continued)
Prohibited During the Washout, Screening, Treatment and Post-Treatment Follow-Up Periods
Moderate or strong CYP3A 
Inducers,9 and Anti-epileptic 
medications, such as:
Strong Inducers:
St. John's Wort
Rifampin
Carbamazepine
Phenytoin
Dexamethasone chronic use
Moderate Inducers:
Bosentan
Efavirenz
Etravirine
Modafinil
Nafcillin
Bisphosphonates, RANKL 
inhibitors, Anabolic Bone Agents or 
rPTH, such as:
Fosamax®, Fosamax Plus D®, Binosto®, Boniva®, Reclast®, 
Zometa®, Prolia®, XGEVA®, Forteo®, Actonel®, Atelvia®, 
Miacalcin®, Fortical®
Synthetic Prostaglandin E1 (PGE1) 
Analogs, such as:
Misoprostol (Cytotec®, Arthrotec®)
Single use of PGE1 for cervical preparation prior to biopsy is 
allowed; chronic use is prohibited
Oral Retinoids (topical applications 
are permitted), such as:
Accutane® (isotretinoin)
*
E2/NETA will be taken by subjects randomized to the E2/NETA dose group.
#
Due to the extensive list of herbal remedies and supplements, please contact the AbbVie TA MD for any that may 
be prohibited.  
%
Subjects may begin the use of hormonal contraceptives following completion of the Post-Treatment Follow-up 
Month 2 Visit and return to menses.  Tranexamic acid, if necessary can be prescribed following completion of the 
Post-Treatment Follow-up Month 2 visit and the subject has returned to first full menses.
If a prohibited medication is necessary to treat an adverse event or a pre-existing 
condition other than uterine fibroids, the AbbVie TA MD noted in Section 6.1.5 should be 
consulted; however, if clinically required and to prevent an immediate hazard to the 
subject being treated, the AbbVie TA MD should be notified as soon as possible after the 
start of use.  Additionally, if a subject takes a prohibited medication during the study, 
except as permitted per protocol (hormonal medication taken after completion of the 
Post-Treatment Follow-Up Month 2 Visit and return to menses), her continued 


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participation in the study will be evaluated by the investigator and the AbbVie TA MD.  If 
there are any questions regarding prior or concomitant therapy, please contact your Study 
Monitor.
5.2.4
Contraception Recommendations and Pregnancy Testing
Contraception Counseling/Dispense Contraceptives
Investigators and Study Coordinators will be trained by the Sponsor on the importance of 
contraception in this clinical trial.  Subjects (excluding those subjects who have had a 
bilateral tubal ligation or bilateral tubal occlusion) will be counseled at every visit 
throughout their participation in the study on the importance of pregnancy prevention and 
the use of appropriate and effective methods of birth control during the Washout Period, if 
applicable, during the Screening, Treatment, and Post-Treatment Follow-Up Periods of 
the study.  
Subjects must agree to use two forms of non-hormonal contraception (dual contraception) 
consistently throughout the Washout (if applicable), Screening and Treatment Periods and 
Post-Treatment Follow-Up Periods (Subjects may begin the use of hormonal 
contraception (e.g., oral or IUD) after completing the Post-Treatment Follow-up Month 2 
Visit and after return to first full menses in the Post-Treatment Follow-up Period).  
Subjects using an LNG-IUS, who agree to have the LNG-IUS removed must complete 
washout per Section 5.2.3.1, and return to 1 menses after completion of washout prior to 
Screening.  Subjects using a CU-IUD, who agree to have the IUD removed may enter 
screening, however the subject must return to at least 1 menses after removal of the CU-
IUD prior to collecting sanitary products for assessment of menstrual blood loss as the 
removal of the CU-IUD may cause abnormal menstrual bleeding that may interfere with 
the assessment of eligibility criteria.  
Acceptable methods of dual non-hormonal contraception include the following 
combinations:


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●
Condom with spermicide (foam, gel or polymer film)
●
Diaphragm with spermicide (condom may or may not be used)
●
Cervical cap with spermicide (condom may or may not be used)
Subjects are not required to use dual contraception methods if:
●
Sexual partner(s) is vasectomized at least 6 months prior to screening
●
Subject practices total abstinence from sexual intercourse, as the preferred 
lifestyle of the subject; periodic abstinence is not acceptable
●
Subject had a bilateral tubal occlusion (including ligation and blockage 
methods such as Essure®) at least 4 months prior to screening.  
●
Subject is not sexually active with men; periodic sexual relationship(s) with 
men requires the use of dual non-hormonal contraception as indicated above.
Subjects may begin the use of hormonal contraception in place of dual non-hormonal 
contraception during the Post-Treatment Follow-up Period if they meet both of the 
following: 
●
Completed the Post-Treatment Follow-up Month 2 Visit
●
Returned to first full menses in the Post-Treatment Follow-up Period
If subject does not return to full menses she must continue use of dual non-hormonal 
contraception.
The following measures will be taken to help ensure pregnancy prevention during the 
study.
1.
The informed consent form will include an attestation requiring the subject to 
confirm in writing her full awareness that the potential risks of study drug 
(elagolix) on the unborn child are unknown and therefore she must not get pregnant 
during the entire time of study participation, and that she agrees to consistently use 
dual non-hormonal contraception throughout her study participation (during the 


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Washout Period, if applicable, Screening, Treatment and Post-Treatment Follow-
Up Period.
2.
The investigator or designated study staff will counsel the subject that the study 
drug is not contraceptive, that ovulation may occur even though the study drug may 
have altered menstrual cyclicity, and that fetal abnormalities have been observed in 
women who have received elagolix in clinical studies that were not deemed to be 
related to elagolix based on the totality of data; however, it is unknown whether 
these abnormalities were the result of taking elagolix.
3.
The Sponsor will provide training materials to the sites for instructing subjects on 
the types of protocol-allowed contraception methods, their effectiveness and proper 
use.
●
The Sponsor will provide sites with a supply of materials to promote 
pregnancy prevention, including contraceptives (condoms and spermicides), 
and lubricants to provide to subjects at no charge.  Subjects should only use 
the pregnancy prevention materials provided by the Sponsor as these products 
have undergone analytical testing by the analytical lab to confirm there is no or 
limited interference with the alkaline hematin method.
●
Subjects will be allowed to choose a contraception method of their choice from 
the contraceptives provided by the Sponsor and practice the allowable methods 
of dual contraception.  The site will assess the subject's basic understanding of 
the proper use through discussion and demonstration of proper techniques, 
including proper diaphragm use.
●
The site will dispense contraceptives to subjects throughout Washout, if 
applicable, Screening, Treatment, and through the Post-Treatment Follow-Up, 
as needed.  Subjects may begin the use of hormonal medication after 
completion of the Post Treatment Follow-up Month 2 visit and return to first 
full menses.
●
The source documents will capture date contraception counseling was 
performed, whether the subject is sexually active with men, the type of 
contraceptive used, a change in contraceptive method, use of a non-study 


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supply brand, contraceptives provided to the subject, and the date supplies 
were provided.
●
As appropriate, the subject will be asked to attest by signature at the time of 
consent, and in a stand-alone attestation form at Day 1 and at the Month 6 or 
Premature Discontinuation study visit that allowable methods of contraception, 
as described during the pregnancy prevention counseling, are being practiced.
●
For subjects who have had a bilateral tubal occlusion, attestation is only 
required to be collected once at the time of consent.
4.
Subjects will be reminded to use dual non-hormonal contraception.
5.
The study drug will be dispensed as a monthly supply at the beginning of each 
month during the Treatment Period to promote frequent interaction with site staff 
and opportunities for continued education.
6.
At each visit, subjects will be asked to name the type of contraception used since 
their last visit and will be reminded of the proper use of that type of method to 
prevent ineffective contraception and the risk of unexpected pregnancy due to 
unprotected sexual activity.
Pregnancy Tests and Reporting a Pregnancy
Urine and/or serum pregnancy tests will be performed as specified in Appendix C, in all 
subjects regardless of sexual activity status or method of contraception.  The subject must 
have a confirmed negative urine pregnancy test within 24 hours prior to performing the 
SIS and endometrial biopsy procedures.
The urine pregnancy test result on Day 1 must be reviewed and determined to be negative 
prior to randomization.  In addition, during the Treatment Period, the urine pregnancy test 
must be negative prior to providing subjects with their next monthly supply of study drug, 
(including an unscheduled visit at which study drug is dispensed).
Home pregnancy test kits will be provided to the subject at the Initial Screening Visit and 
Month 6 or Premature Discontinuation visit during the Treatment Period if logistically, a 


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urine pregnancy test cannot be performed at the study site or other medical facility within 
24 hours prior to an SIS and/or endometrial biopsy.  The subject must self-administer and 
report a negative urine pregnancy test result to the site within 24 hours prior to undergoing 
these procedures.
A positive urine pregnancy test result must be confirmed with a quantitative serum 
pregnancy test.  The subject should temporarily discontinue study drug administration 
while waiting for the results of the serum pregnancy test.  If a serum pregnancy test result 
is positive at any time during the Treatment Period, the site will immediately inform the 
subject to discontinue study drug (Section 6.1.6).  If a subject is confirmed as pregnant, 
the subject will be prematurely discontinued from the study. 
An ultrasound examination will be performed during the first trimester of pregnancy to 
assess the gestational age and estimated date of delivery if the subject becomes pregnant 
during the Treatment or Post-Treatment Follow-Up Periods of the study.  Refer to 
Section 6.1.6 for instructions on reporting of a pregnancy to the Sponsor and the required 
follow-up on the subject/fetus and live infant births.
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, 
Pharmacogenetic and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures during the Washout (if applicable), Screening, Treatment and 
Post-Treatment Follow-Up Periods described in this protocol are summarized in 
Appendix C.
5.3.1.1
Study Procedures
The study procedures outlined in Appendix C are discussed in detail in this section, with 
the exception of the monitoring of study drug accountability (Section 5.5.7) and the 
collection of concomitant medication and adverse event information (Section 5.2.3 and 


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Section 6.1, respectively).  Study data will be recorded in source documents and on 
eCRFs.
The Screening Period will occur within approximately 2.5 to 3.5 months prior to 
administration of the first dose of study drug on Day 1 (randomization).  For procedures 
performed during the Screening Period and subsequently repeated, the procedure 
performed closest to dosing will serve as a baseline for clinical assessment. 
Study procedures during the Treatment and Post-Treatment Follow-Up Periods may be 
performed within the visit windows specified in Table 1.  Scheduled monthly visits during 
the Treatment and Post-Treatment Follow-Up Period are based on a 28-day month.
It is recommended that the pelvic ultrasound, MRI (if applicable), DXA scan and 
endometrial biopsy for the Month 6 Visit be conducted within approximately 15 days 
prior to the scheduled Month 6 Visit to ensure the images are received and acceptable for 
review by the central vendor.  If eligibility into the extension study cannot be determined 
at the pivotal study Month 6 visit, an additional study drug kit will be dispensed to the 
subject at the Month 6 Visit.  Refer to Section 5.4.4, Delays in Roll-Over for the 
Extension Study for further instructions.
This protocol provides recommendations regarding the sequence of procedures to be 
performed during the study.  In no case should these recommendations outweigh clinical 
judgment or standard of care.  If the protocol indicates that the AbbVie TA MD is to be 
contacted prior to performing a procedure, yet the timing of the request would either 
interrupt a procedure or would interfere with standard of care and clinical judgment, then 
clinical judgment should prevail and the AbbVie TA MD should be notified afterwards.  
Due to the long Screening Period, eligibility should be assessed throughout the Screening 
Period, including just prior to randomization to ensure that the subject continues to meet 
eligibility and that the results from all screening procedures are available prior to 
randomization.  


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Informed Consent
The IRB/IEC approved informed consent will be signed by the subject before beginning 
any study-specific procedures or discontinuing any hormonal contraception/therapies or 
other prohibited medications.  Pharmacogenetic (PG) testing is optional and a subject 
must be provided a separate informed consent form for this blood collection.  Details 
about how informed consent will be obtained and documented are provided in Section 9.3.
Screen Failures and Re-Screening of Subjects
Subjects who have signed informed consent and did not randomize because they either did 
not complete the Washout Period (if applicable), did not complete the study-specific 
procedures during the Screening Period (e.g., TAU/TVU or endometrial biopsy) or did not 
meet all entry criteria will be considered Screen Failures.  The reason(s) for screen failure 
will be recorded in the source documents and will be captured in the eCRF.  Subjects who 
screen fail may be re-screened on a case-by-case basis after consulting the AbbVie TA 
MD for approval.
Medical/Social History
The following information will be collected after signing the informed consent, either 
during the Washout Period (if applicable) or during the Screening Period for those 
subjects who do not require washout.
●
Complete medical history, including documentation of any clinically 
significant medical conditions and medications
●
History of tobacco and alcohol use
The medical history will be reviewed and updated prior to dosing on Study Day 1 
(Randomization) and will serve as the baseline for clinical assessment.


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Gynecological/Obstetrical and Uterine Fibroid History
A detailed gynecological/obstetrical and uterine fibroid history will be collected either 
during the Washout Period (if applicable) or during the Screening Period for those who do 
not require washout, and will include the following:
Detailed gynecological/uterine fibroid history, including:
●
History of uterine fibroids, including year of diagnosis and uterine fibroid 
symptoms
●
History of endometriosis, ovarian cysts, endometrial polyps, or other relevant 
gynecological conditions
●
History of gynecological surgeries and gynecological diagnostic procedures
●
History of bleeding including average cycle length and average number of 
days with bleeding/cycle over the last 6 months and typical intensity of 
menstrual periods 
●
History of irregular bleeding or prolonged bleeding
●
Prior hormonal medications including those taken for treatment of uterine 
fibroids or other gynecological conditions
●
Prior use of non-hormonal medications for the treatment of uterine fibroids, 
including dates of use for 6 months prior to either Washout (if applicable) or 
Screening
●
History of sexually transmitted infections
●
Obstetrical History
●
Pregnancy history including:
○
Number of pregnancies
●
Number of live birth term pregnancies
●
Number of live birth pre-term pregnancies
○
Number of abortions including elective, therapeutic and spontaneous 
abortions 
○
Delivery outcomes (specifically, anomalies including congenital 
malformations and chromosomal abnormalities).


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The gynecological/obstetrical and uterine fibroid history will be reviewed and updated 
prior to dosing on Study Day 1 (Randomization) and will serve as the baseline for clinical 
assessment.
Gynecological (Pelvic and Breast) Examination
A complete breast, and pelvic examination, including external genitalia will be performed 
during the Screening Period and at the Month 6 or Premature Discontinuation visit in the 
Treatment Period.  A screening breast examination may be omitted, based on local or 
country guidelines, e.g., breast examinations are routinely or only conducted by breast 
specialists.  In these cases, source documentation should indicate reason not performed.
Pap Test
A Pap test will be performed in subjects ≥ 21 years of age during the Screening Period, 
using the Thin Prep® Pap Test™ provided and analyzed by the central laboratory.  If the 
subject is experiencing menstrual bleeding that precludes the performance of the Pap test, 
this procedure should be performed as soon as possible after the menstrual bleeding has 
ended.  In the case of an unsatisfactory sample, the Pap test can be repeated.  The repeat 
Pap test should also be performed when the subject is not experiencing menstrual 
bleeding.  In order to be enrolled in the study, the Pap test must meet eligibility 
requirements as outlined in Figure 2, Pap Test Eligibility. 
Subjects age 25 – 51 years old, with the Pap diagnosis of ASC-US (atypical squamous 
cells of undetermined significance) with high risk human papillomavirus (HPV), or 
low-grade squamous intraepithelial lesion (LSIL) and those > 30 years of age with 
negative (NILM) but absent or insufficient endocervical/transformational zone component 
will have reflex HPV testing as outlined in Figure 2.  Those with high risk HPV, LSIL 
with high risk HPV or LSIL negative for HPV, or subjects > 30 years of age with 
Negative Intraepithelial Lesion or Malignancy (NILM) but with negative or absent 
endocervical or transformation zone component with high risk HPV will undergo 
additional evaluation as outlined in Figure 2 with colposcopy and biopsy, if applicable per 
local guidelines or standard of care. 




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Endometrial Biopsy
Instructions on endometrial biopsy collection and processing procedures for shipping will 
be provided by the central laboratory.  Sites can either use the endometrial biopsy 
instruments provided by the Central Lab or any other endometrial biopsy instruments 
available at the study site.  Subjects must have a confirmed negative urine pregnancy test 
within 24 hours prior to undergoing the endometrial biopsy.  
Pre-medication for the endometrial biopsy procedure is allowable and should be recorded 
in source documents and on the appropriate eCRF.  Misoprostol for cervical dilatation is 
allowable.  An office hysteroscopy may be performed to obtain the endometrial biopsy 
sample if the endometrial biopsy cannot be performed because of anatomical reasons.  
During the Screening Period, an endometrial biopsy will be performed in all subjects.
If the endometrial biopsy is performed on the same day as the Pap smear or pelvic 
ultrasound, the endometrial biopsy should be performed after the Pap smear and pelvic 
ultrasound.
Biopsy results must be obtained before the subject can be randomized.  In case of an 
insufficient sample the biopsy may be repeated; however, results must be available prior 
to randomization.  Subjects must have an adequate endometrial biopsy, (i.e., results show 
no endometrial pathology to be eligible for randomization).
If an abnormal finding such as endometritis, hyperplasia (with or without atypia) or 
endometrial cancer is reported, subjects will not be eligible for randomization into the 
study.  If the Investigator determines that an abnormal finding can be treated outside of 
the protocol, the AbbVie TA MD must be contacted to obtain approval to perform a 
repeat biopsy.  The repeat biopsy must meet eligibility criteria prior to Study Day 1 
(Randomization).
During the Treatment Period, an endometrial biopsy will be performed at Month 6 visit or 
at the Premature Discontinuation visit (if subject prematurely discontinues after the 


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Month 3 Visit).  It is recommended that the biopsy for the Month 6 Visit is performed 
approximately 15 days prior to the scheduled Month 6 visit to ensure the results are 
received from the central laboratory in order to determine eligibility for inclusion into the 
extension study.  If biopsy results are not available by the Month 6 visit of the Treatment 
Period, refer to Section 5.4.4 for instructions on assigning additional study drug kits for 
delays in roll-over until eligibility is determined.  
If the Month 6 biopsy results are normal or the sample contains scant endometrium 
without abnormalities, the subject is eligible to enter the extension study.
In the event the Month 6 biopsy cannot be performed (e.g., due to a stenotic cervix or 
location of fibroids), or an insufficient biopsy sample is obtained and the concurrent TVU 
indicates a thickness of > 4 mm, a repeat biopsy must be performed.  If upon repeat, a 
sample cannot be obtained or remains insufficient, the AbbVie TA MD should be 
consulted.
If a repeat biopsy is performed and the results are normal or the sample contains scant 
endometrium without abnormalities, the subject is eligible to enter the extension study.
Subjects with abnormal endometrial pathology results (including, endometrial hyperplasia 
with or without atypia and endometrial cancer) at Treatment Month 6 are not eligible to 
enter the extension study and instead will enter the Post-Treatment Follow-up Period.  
The endometrial pathology should be managed according to standard of care.
Physical Examination
A complete physical examination will be performed during the Washout Period (if 
applicable) or Screening Period and will include height and weight measurements (the 
subject should not wear shoes).  Subjects who entered washout will only be required to 
have a symptom-directed physical examination performed when they enter the Screening 
Period.  


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During the Treatment Period and Post-Treatment Follow-Up Periods, a complete physical 
examination will be performed at Day 1 (prior to dosing), Month 6 and Post-Treatment 
Follow-up Month 6 or Premature Discontinuation.  The complete physical examination at 
Day 1, Month 6 or Premature Discontinuation will include weight measurements.  
Symptom Directed Physical Examinations will be performed as specified in Appendix C.
Clinically significant physical examination findings prior to randomization will be 
recorded as medical history.  Any clinically significant physical examination findings 
after dosing will be recorded in the source documents and in the eCRFs as adverse events.
Vital Signs
Vital sign determination of heart rate, blood pressure, respiratory rate and body 
temperature will be obtained at all visits during the study as indicated in Appendix C.  
The blood pressure and heart rate measurements should be taken prior to scheduled blood 
collections.  Body temperature measurements should be assessed using the same modality 
consistently throughout the study, e.g., oral, aural, axillary, etc., and the modality will be 
reported in the source documents and eCRF.
The vital signs measurements prior to dosing on Day 1 will serve as the baseline 
measurements for clinical assessment.
12-Lead Electrocardiogram (ECG)
A resting 12-lead ECG will be conducted during the Screening Period and at the 
Treatment Month 6 Visit or Premature Discontinuation visit (if applicable) of the 
Treatment Period, as indicated in Appendix C.  
For any abnormal screening test results, the ECG may be repeated at a later date, however 
the subject must meet eligibility prior to Study Day 1 (Randomization).  Final results will 
be entered into the eCRF.
The Investigator or qualified designee at the study site will determine if any findings 
outside the normal physiological variation are clinically significant (in consultation with a 


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cardiologist if necessary), and document this on the ECG tracing/report, sign and date it.  
The original ECG tracing or a certified copy of the original tracing with the physician's 
assessment will be retained in the subject's records at the study site.  For ECG with QT 
interval corrected for heart rate (QTc) > 450 msec, the correction formula used 
(i.e., Bazett's or Fridericia's) should be recorded in source documents and the eCRF.  The 
study site should use the same correction formula consistently throughout the study.  
Mammogram
A mammogram will be obtained during Screening only for subjects who will be 39 years 
of age or older at the time of randomization unless the subject had a mammogram 
performed within 3 months prior to Screening.  Local mammogram results and final 
interpretation must be entered into the eCRF.
If a subject's mammogram results are incomplete (BI-RADS 0) and needs to be repeated, 
the AbbVie TA MD does not need to be contacted for approval prior to conducting the 
repeat mammogram or other mode of imaging (e.g., ultrasound, spot compression).  If 
results meet entry requirements, subject would be allowed to continue in the study.  
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 randomization.  Any further imaging or testing will be performed outside 
of the protocol and should follow standard of care.  Subjects may be re-screened on a case 
by case basis after review of the results and consulting the AbbVie TA MD for approval.
The local radiologist's interpretation will be used to determine if a subject meets 
eligibility.  Subjects with normal or benign findings or BI-RADS Classifications 1, 2 or 3 
as outlined in Appendix D will be eligible for randomization.  Subjects with an abnormal 
mammogram or BI-RADS 0, 4 or 5, will not be eligible for randomization into the study.  
Subjects should continue with recommended mammography screening outside of the 
protocol per local guidelines and standard of care during the study.


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Central Imaging Procedures
Fibroid and uterine assessments will be obtained using pelvic ultrasound (TAU and TVU) 
throughout the study, and SIS at Screening.  In addition to the TAU and TVU, an MRI 
will be performed in a subset of subjects during the Treatment and Post-Treatment 
Follow-up Period who consent to participate in the MRI Subset.  The goal of the MRI 
subset is to evaluate uterine fibroid size and volume and uterine volume using another 
technique in addition to ultrasound.  All ultrasound and MRI images will be sent to the 
Central Imaging Core Lab (ICL) for review to determine eligibility for randomization and 
to monitor safety during the Treatment and Post Treatment Follow-Up Periods.
The pelvic ultrasound (TAU, TVU, and SIS) and MRI (if applicable) will be performed 
by the investigative sites' or affiliated Radiology Department.  The ultrasonographer at 
each investigative site will be required to acquire the ultrasound, SIS and MRI (if 
applicable) images according to the Imaging Acquisition Guidelines provided by the ICL.  
Images should be sent/transmitted to the ICL to determine eligibility for entry into the 
study and for subject evaluation during the course of the study.  Refer to the Image 
Acquisition Guidelines for instructions on submitting images to the ICL.
The pelvic ultrasound (TAU, TVU and SIS) and MRI (if applicable) will be assessed both 
locally and by the ICL.  The ICL will issue an Eligibility Form based on review of the 
pelvic ultrasound and SIS indicating the presence or absence of a qualifying fibroid and/or 
uterine volume and whether any exclusionary pathology was present.  If images are 
unevaluable, the ICL will inform the investigative site and additional images will need to 
be resubmitted.  If there is a discrepancy between the local assessment and the central 
reader's assessment, this should be brought to AbbVie's attention and AbbVie will discuss 
the findings with the local site and central reader on a case-by-case basis to determine 
eligibility.  
The Investigator or designee should consult the local ultrasound and SIS reports and/or 
images in order to make any eligibility and safety-related judgments concerning the 
subject.  The interpretation of the local report and/or images will be filed or recorded in 


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the subject's source documents.  Data and/or local interpretation from the local ultrasound 
and SIS images will not be recorded in the eCRF.
The ICL will only issue a report for pelvic ultrasound at Treatment Month 6.  A report for 
all other Treatment and Post-Treatment timepoints for pelvic ultrasound and MRI will 
only be issued if any significant changes are observed that may affect subject safety 
during the study.  In these cases, the Investigator should review the local ultrasound 
and/or MRI images and treat as per standard of care.
The pelvic ultrasound, SIS and MRI (if applicable) will be performed as specified in 
Appendix C.
It is recommended that the pelvic ultrasound and MRI (if applicable) performed for the 
Month 6 Visit are conducted approximately 15 days prior to the scheduled Month 6 Visit 
to ensure the images are received and acceptable for review by the central vendor.  The 
central pelvic ultrasound report is only required prior to rollover in the event the Month 6 
endometrial biopsy cannot be performed or biopsy results are insufficient.  In this case the 
central pelvic ultrasound is required to determine if the endometrial thickness is ≥ 4 mm 
in which case the subject needs a repeat biopsy prior to rollover (see Section 5.3.1.1
Endometrial Biopsy).  If the results are not available by the Month 6 visit of the Treatment 
Period to determine need for a repeat endometrial biopsy, refer to Section 5.4.4 for 
instructions until results are available to determine eligibility into the extension study.  
Qualifying Uterine Fibroids:
The following types of uterine fibroids will qualify a subject for randomization: 
Fibroid size/uterine volume:  
●
At least 1 fibroid with a diameter ≥ 2 cm (longest diameter)
OR
●
Multiple fibroids with a total uterine volume of ≥ 200 cm3 to ≤2,500 cm3 as 
documented by centrally read imaging vendor


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Type of fibroid/fibroid location:
●
Intramural fibroids
●
Submucosal non-pedunculated fibroids
●
Large (≥ 4 cm) subserosal fibroid
The following types of uterine fibroids are exclusionary:
●
Intracavitary pedunculated submucosal fibroids
●
Solitary pedunculated subserosal fibroids
●
Small (< 4 cm) solitary subserosal fibroids
Pelvic Ultrasound:  TAU and TVU
A pelvic ultrasound (TAU and TVU) will be performed early in the Screening Period and 
as early in the menstrual cycle as possible in all subjects, or in the Washout Period, if 
applicable.  Subsequent pelvic ultrasounds will be performed at the time points indicated 
in Appendix C, Study Activities.  The pelvic ultrasound will determine the presence of 
qualifying uterine fibroids and uterine volume.  The TAU and TVU will be used to 
confirm the presence of qualifying uterine fibroids (at least 1 fibroid with diameter ≥ 2 cm 
(longest diameter), or multiple small fibroids with a uterine volume of ≥ 200 cm3 to
≤2,500 cm3, and to obtain measurements of the dimensions of the uterus and of the 
largest fibroid.  The TVU will be used to assess gynecological disorders, such as ovarian 
cysts, endometriomas.  However, these assessments can also be made by TAU, if 
necessary.
Assessments for the pelvic ultrasound include, but are not limited to the following:
●
Endometrial thickness 
●
Presence of abnormal endometrial appearance or endometrial pathology
●
Presence of uterine fibroids
●
Number of uterine fibroids
●
Volume and location of the 3 largest fibroids


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●
Uterine volume in cubic centimeters
●
Presence of ovarian cysts 
○
Number
○
Size (cm)
○
Location (right or left ovary)
○
Simple versus complex
●
Endometrioma > 3.5 cm longest diameter
●
Solid ovarian lesions > 1.5 cm longest diameter
Saline Infusion Sonohysterography (SIS)
In addition to the pelvic ultrasound, an SIS will also be performed in all subjects during 
the Screening Period, to assess exclusion criteria based on the presence of focal 
intracavitary lesions including:
●
Endometrial polyp ≥1 cm 
●
Intracavitary submucosal pedunculated fibroid
The SIS should be performed as early as possible during the Screening Period to rule out 
any exclusionary findings; for subjects entering washout, an SIS will not be performed 
until the subject enters the Screening Period in order to limit the number of invasive 
procedures prior to fully determining eligibility.  The subject must have a confirmed 
negative urine pregnancy test result within 24 hours prior to undergoing the SIS.  It is 
advised that the SIS be performed post-menses to Day 10 of the menstrual cycle.  
Ibuprofen and antibiotics may be administered prior to conducting the SIS, if standard of 
care.  
If a subject is known to have an endometrial polyp ≥ 1 cm, and desires to have the polyp
removed outside of the study, prior to entering Screening the subject must have a negative 
pathology report and return to one normal menses prior to screening.


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Subjects who have qualifying uterine fibroids and uterine volume as assessed by 
ultrasound; however, have SIS images which are unable to fully assess the endometrial 
cavity, may undergo additional imaging modalities such as MRI for further evaluation.
An SIS may be performed during the Treatment Period if there is an intracavitary finding 
on ultrasound or MRI.
Magnetic Resonance Imaging (MRI) Subset:
A subset of subjects who consent to participate in the MRI Subset will have an MRI 
performed at the Day 1 (unless an MRI was performed in Screening as indicated below) 
and Month 6 or Premature Discontinuation visits during the Treatment Period and at the 
Post-Treatment Follow-Up Month 3 or Post-Treatment Premature Discontinuation Visit.  
If the Day 1 MRI cannot be performed within the specified assessment window per 
Table 1, the MRI should not be performed and the subject will not participate in the MRI 
Subset.  Subjects who have qualifying uterine fibroids and uterine volume as assessed by 
ultrasound; however, have SIS images which are unable to fully assess the endometrial 
cavity, may undergo additional imaging modalities such as MRI for further evaluation in 
Screening.
Subjects who had an MRI prior to Day 1 and agree to be part of the MRI subset, will not 
have an MRI repeated at Day 1; instead, subjects will have MRIs performed at the 
Month 6 visit during the Treatment Period and at the Post-Treatment Follow-Up Month 3 
Visit.  
Assessments for the MRI include, but are not limited to the following:
●
Fibroid volume in cubic centimeters (of 3 largest fibroids) 
●
Fibroid location
●
Uterine volume in cubic centimeters
●
Presence of adenomyosis (diffuse adenomyosis as the dominant condition 
versus focal) 


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●
Presence of any concerning findings
If the subject prematurely discontinued prior to Month 3, i.e., received < 3 months of 
study drug during the Treatment Period, an MRI will not be performed at the Premature 
Discontinuation visit during the Treatment or Post-Treatment Follow-Up Period.
Depending on the size of the uterus, MRI images of the abdominal cavity may need to be 
submitted to measure uterine volume and to assess for safety.  It is recommended to 
follow standard of care when determining which anatomical sections are to be included in 
order to prevent incomplete views, thus leading to repeat procedures.  Please refer to the 
Image Acquisition Guidelines for further details.
Intracavitary Uterine Findings
An SIS may be performed during the Treatment or Post-Treatment Follow-Up Periods if 
the pelvic ultrasound (TAU and TVU) or MRI (if applicable) results suggest an 
intracavitary lesion such as a polyp.  The finding of a polyp during the Treatment or 
Post-Treatment Periods should be documented as an adverse event if the Investigator 
considers it to be clinically significant.  
The AbbVie TA MD should be notified of the subject's management plan for any 
clinically significant pathologic findings during the Treatment and Post-Treatment 
Periods.
Ovarian Findings:
During Screening, if the initial pelvic ultrasound shows a simple ovarian cyst > 5 and 
≤7 cm in longest diameter, an ultrasound of the ovaries may be repeated in approximately 
4 to 6 weeks.  The repeat results must be evaluated prior to Day 1, Randomization, and 
not meet exclusion criteria (i.e., persistent simple ovarian cyst > 5 cm).
In Screening, if any of the adnexal structures, such as an ovary, cannot be visualized on 
the pelvic ultrasound due to, for example, fibroid location and/or fibroid size, the subject 
may be eligible for randomization provided there are no exclusionary findings.


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During Treatment or Post-Treatment, if the pelvic ultrasound shows a simple ovarian cyst 
> 5 cm or a complex ovarian cyst (including endometriomas) > 3.5 cm in longest diameter 
the findings should be documented as an adverse event if the Investigator considers them 
to be clinically significant.  
Bone Mineral Density (DXA Scan)
DXA scans of the spine, femoral neck and total hip will be performed by qualified 
technologist/radiologists utilizing GE Lunar or Hologic equipment and sent to an ICL for 
review and analysis.  Site training and qualifications, including assessment of instruments, 
will be completed prior to screening the first subject.  Instructions on calibration and 
standardization of instruments will be specified in a manual that will be provided to all 
study sites.  Sites will need to obtain approval from the ICL prior to initiating study scans.  
A DXA scan will be performed during the Screening Period to determine eligibility based 
on BMD measurements from the ICL.  Subjects with a T-score of ≤ –1.5 at the lumbar 
spine, total hip or femoral neck on the screening DXA scan will not be eligible for 
randomization into the study.  
During the Treatment Period, a DXA scan will be performed at Month 6 or Premature 
Discontinuation visit (Subjects who prematurely discontinue treatment prior to Month 3 
will not have a DXA at the Premature Discontinuation Visit unless the premature 
discontinuation was related to BMD decrease or the occurrence of a fracture).  In the 
event there is a change in DXA machine for a subject between baseline and a subsequent 
time point, the AbbVie TA MD must be notified.
It is recommended that the bone scan performed for the Month 6 Visit is conducted 
approximately 15 days prior to the scheduled Month 6 Visit to ensure the results are 
received from the central vendor in order to determine eligibility for inclusion into the 
extension study.  If DXA results are not available by the Month 6 visit of the Treatment 
Period, refer to Section 5.4.4 for instructions until results are available to determine 
eligibility into the extension study.


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During the Post-Treatment Follow-Up Period, DXA scans will be performed in all 
subjects at the Month 6 and Month 12 visits in the Post-Treatment Follow-Up Period.  
However, if the subject prematurely discontinued prior to the Treatment Month 3 visit, 
i.e., received < 3 months of study drug during the Treatment Period, Post-Treatment DXA 
scans will not be performed (unless the premature discontinuation was related to BMD or 
the occurrence of a fracture) and the subject will complete the study at the Post-Treatment 
Month 6 visit.  
A BMD decrease at any anatomic location (spine, total hip or femoral neck) during the 
Treatment or Post-Treatment Follow-up period that leads to discontinuation from study or 
a BMD decrease at any anatomic location with a T-score < –1.5 should be reported as AE.
Determination of BMD Eligibility for Inclusion into the Extension Study:
Inclusion of subjects for BMD criteria in the extension study will be based on the 
parameters specified below and illustrated in Figure 3. 
●
Subjects with BMD decrease < 8% in the spine, total hip and femoral neck will 
be eligible based on DXA for entry into the extension study.
●
Subjects with ≥ 8% BMD decrease at any location at Month 6 of the Treatment 
Period are not eligible for entry into the extension study and will instead enter 
into the Post-Treatment Follow-Up Period and continue with BMD evaluation 
as illustrated in Figure 4.


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Figure 3.
Management of BMD % Decrease at Month 6 of Treatment Period 
and Eligibility for Inclusion in the Extension Study
Management of BMD for Subjects Entering the Post-Treatment Follow-Up Period
For subjects entering the Post-Treatment Follow-Up Period of this study, DXA scans are 
required at Month 6 and Month 12 of the Post-Treatment Follow-Up Period.
A Post-Treatment Month 6 or Month 12 DXA will not be performed in subjects who 
prematurely discontinued prior to the Treatment Month 3 visit, i.e., received < 3 months 
of study drug during the Treatment Period (unless the premature discontinuation was 
related to BMD decrease or the occurrence of a fracture).
Management of BMD % Decrease at Post-Treatment Follow-up Month 12
Management of subjects with BMD % decrease at Post-Treatment Follow-Up Month 12 is 
outlined below and illustrated in Figure 4.


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Subjects with Post-Treatment Month 12 BMD % decrease of < 3% in the spine, femoral 
neck and total hip and no decrease in any region from Post-Treatment Follow-up Month 6 
to Month 12 will not require a referral to a bone specialist.
Subjects will be referred to a Bone Specialist at Post-Treatment Follow-up Month 12, 
even if the overall BMD decrease from baseline is < 3%, if they meet the following 
criteria:
●
Subject had Post-Treatment Month 6 BMD decrease compared to baseline in 
any region and demonstrates further BMD decrease at Month 12 in the same 
region (between Post-Treatment Month 6 and Month 12) and, subject meets 
one of the following:
○
Subject was ≥ 45 years of age at the time of last dose of study drug in the 
Treatment Period 
OR
○
Subject has not had a menses in the past 12 months
●
Subjects with Post-Treatment Month 12 BMD % decrease of ≥ 3% in the 
spine, femoral neck or total hip and a T-score < –1.0 OR T-score < –1.5 will 
be referred to a bone specialist for further management, and will be followed 
on an individual basis.  
The management plan for subjects referred to a Bone Specialist (e.g., Endocrinologist, 
Rheumatologist, International Society for Clinical Densitometry (ISCD) certified 
physician) will be reviewed with the AbbVie TA MD, with follow-up information 
provided on the subject evaluation, treatment, and outcome.  Follow-up information from 
the initial evaluation will be recorded in the eCRF.  It is recommended that the Bone 
Specialist should be someone other than the Principal Investigator or Sub-Investigator.  


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Figure 4.
Management of BMD % Decrease:  Post-Treatment Follow-Up 
Month 12
Clinical Laboratory Tests
Samples will be obtained for the laboratory tests listed in Table 4, at the time points 
indicated in Appendix C, Study Activities.


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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
Inorganic phosphorus
Magnesium
Total protein
Albumin
Total bilirubin 
Serum glutamic-pyruvic transaminase 
(SGPT/ALAT)
Serum glutamic-oxaloacetic transaminase 
(SGOT/ASAT)
Alkaline phosphatase
Uric acid
Lactate dehydrogenase 
Creatine Phosphokinase 
Serum iron
Serum ferritin
Total iron binding capacity (TIBC)
Specific gravity
Ketones 
Protein
Blood
Glucose
pH
Microscopic Exam
Urine%
Gonorrhea
Chlamydia
Lipid Panel (After Minimum 
8-Hour Fast)
LDL cholesterol
HDL cholesterol
Triglycerides
Total cholesterol
Lipid Profile
Apolipoprotein A and B
Pregnancy Test
Serum pregnancy
Endocrine Panel
Serology Testing
PK and PD Assay/PG 
Analysis
Follicle-stimulating hormone 
(FSH)
Luteinizing Hormone (LH)
Reflexive Thyroid Stimulating 
Hormone (TSH)
Thyroxine Binding Globulin (TBG)
HAV-IgM
HbsAg
HCV Ab
HIV Ab
Elagolix and NETA*
E2 and P*
DNA and RNA*
*
Samples will be shipped to the Central Laboratory by the Study Site and then shipped by the Central Laboratory to 
AbbVie for analysis.
%
Optional – ordered at Investigator's discretion.  Samples will be shipped to the Central Laboratory.
All laboratory samples (hematology, chemistry, urinalysis, endocrine panel, lipid panel) 
will be assessed using a certified central laboratory and these data will be used for data 
analysis.  The central laboratory will provide instructions regarding the collection 
(including any fasting requirements), processing and shipping of samples.  Blood draws 


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should be performed after vital signs and ECG recordings are conducted at a visit.  All 
clinical laboratory samples will be shipped to the central laboratory, with the exception of 
the venous blood sample for alkaline hematin analysis which will be sent to the alkaline
hematin lab.  Residual serum samples remaining after chemistry testing has been 
performed will be stored frozen at the central laboratory for possible repeat testing or 
further analysis upon AbbVie's request.
The laboratory results (except Apo A and Apo B) will be provided by the central 
laboratory to the investigative site where they will be reviewed, signed and dated by the 
Investigator.  For any value outside of the reference range, the Investigator will indicate 
on the report if the result is clinically significant (CS) or not clinically significant (NCS).  
The Investigator will assess clinically significant laboratory values per standard of care 
which may include repeating the test to verify the out-of-range value.  Clinically 
significant laboratory abnormalities post-randomization may be documented as adverse 
events, depending on the interpretation of the Investigator (Section 6.1).
All screening laboratory results must be reviewed prior to randomization, including any 
repeated test results.  Subjects will not be randomized if laboratory results are clinically 
significant.  The laboratory test results obtained from the Day 1 pre-dose samples will 
serve as the baseline for clinical assessment.
The Investigator will receive Sponsor defined alerts from the central lab.  The Investigator 
will review the lab alerts and assess clinical significance for potential events.
Blood samples for Pharmacogenetic (PG), Pharmacokinetic (PK), and Pharmacodynamic 
(PD) analysis will be collected and processed as indicated in Section 5.3.1.2 (PG), 
Section 5.3.1.3 (PD) and Section 5.3.2 (PK).
Safety Laboratory Tests
Clinical safety laboratory tests consist of hematology, clinical chemistry, including lipid 
panel and urinalysis samples.  The clinical chemistry and lipid panel samples should be 
obtained in the morning following an overnight fast (minimum of 8 hours); however, 


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there may be circumstances when a sample is obtained later in the day and/or not under 
fasting conditions.  If a sample was obtained with less than 8 hours of fasting, the Source 
Documents and the lab requisition should be marked to indicate that the sample was 
obtained under non-fasting conditions.
Lipid Panel
If, during the Treatment or through Post-Treatment Period Month 12 Visit the lipid panel 
results for LDL cholesterol, Triglycerides, Total cholesterol are more than 3 × the upper 
limit of normal range and the sample was not obtained under fasting conditions (minimum 
8 hour fast), the subject will return to the office as soon as possible to have the panel 
repeated under fasting conditions. 
Apolipoprotein A and B, (Apo A and Apo B)
Blood samples for Apo A and Apo B will be collected as part of the chemistry panel.  The 
Apo A and Apo B data are exploratory and results will not be provided to the 
investigative site.
Serology Testing for Hepatitis and HIV
Subjects will be tested for HAV-IgM, HBsAg, HCV Ab HIV and anti-HIV Ab by the 
central laboratory 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.
HIV testing will be conducted by ELISA; if the test result is reactive, testing will 
automatically reflex to Multispot assay.  If results are negative or indeterminate, HIV-1 
TMA assay is performed to complete the confirmation with results of:  Not Detected or 
Detected.  If the HIV ELISA test result is reactive or TMA assay results are detected, the 
subject will be screen-failed.   
The results of the HIV and anti-HIV Ab testing will be retained confidentially by the 
study site.


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Urine Test for Gonorrhea and Chlamydia (Optional) 
Gonorrhea and chlamydia testing can be ordered at the Investigator's discretion during the 
Screening Period, to test for active gonorrhea or chlamydia prior to undergoing the 
endometrial biopsy and SIS.  Any treatment provided will occur outside of the protocol.
Endocrine Panel
The endocrine panel consists of the following analytes:  FSH, LH, reflexive TSH and 
thyroxine-binding globulin (TBG).  
Sanitary Product Collection for Alkaline Hematin Assay
Quantitative measurement of the volume of MBL will be performed using the alkaline 
hematin method.  Menstrual blood loss will be assessed in all subjects using validated 
sanitary products, also referred to as "validated" products.  Validated products have 
undergone analytical testing by the analytical lab to confirm adequate precision and 
accuracy of blood recovery as well as no or limited interference with the alkaline hematin 
method.  
Subjects will start to collect their sanitary products in the Screening Period over the 
course of 2 to 3 menstrual cycles to determine eligibility for randomization based on 
MBL.  Subjects will continue to collect sanitary products after eligibility based on MBL 
in Screening is determined.  There will be no interruption in collection of sanitary 
products between Screening and Randomization and the Subject should be instructed to 
collect sanitary products starting in Screening and throughout the 6-month Treatment 
Period to determine the change from baseline in MBL volume, and up through their 
first menses with full menstrual flow in the Post-Treatment Follow-up Period to assess 
return to menses.
Starting in Screening, subjects will be dispensed sanitary collection kits that consist of 
validated sanitary products, product collection bags, bar-coded labels and a keg with 
screw-on lid for storage as provided by the vendor.  It is important that only the sanitary 


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products provided for use during the study are used.  Validated sanitary products may 
include:
●
Tampax tampons (Regular, Super or Super-Plus absorbency)
●
Stayfree Maxi Pads (Regular, Super Long or Overnight absorbency)
●
Carefree Original Long Unscented pantiliners 
Subjects will be required to collect and retain all sanitary products on days with menstrual 
bleeding or spotting (subjects must be instructed to collect and return all used or 
worn products even if there is no visible blood on the products or if non-validated 
products were used) as described in the Alkaline Hematin Laboratory Manual.
The dispensation and collection requirements in the Screening, Treatment and 
Post-Treatment Periods are outlined in Figure 5.
Figure 5.
Sanitary Product Dispensation and Collection
•
SPCV= Screening Cycle Product Collection Visits (1, 2 and 3)
•
All products should be returned to the study site within approximately 5 days after all bleeding and/or spotting has ended
•
SCPCV3 may not be required depending on amount of blood loss during  SPCV 1 and SPCV2
•
Subjects will continue collecting sanitary products from Screening through the first menses with full menstrual flow  in the Post-
Treatment Follow-up Period.  There will be no break in collection between Screening and Randomization.
Initial 
Screening
Visit
Day 1
(Day 1-10
of menses)
M1
M2
M3
M4
M5
M6
SPCV1
SPCV2
SPCV3 
(only if required)
Collect sanitary products 
from Day 1 through Month 6
M3
M6
Treatment Period
Screening Period
Post-treatment 
Follow-up Period
Collect sanitary products 
for 2-3 Screening 
Menstrual Cycles
Collect sanitary products until 
first menses with full menstrual 
flow in the Post-Treatment 
Follow-up Period
M9
M12


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Screening Product Collection Visits
Subjects will be dispensed a product collection kit and will collect sanitary products on 
days with bleeding or spotting.  Subjects will visit the site within approximately 5 days 
after cessation of bleeding or spotting for Screening Menstrual Cycles 1 and 2, and if 
applicable, Cycle 3 Product Collection Visits.  At each Screening Product Collection 
Visit, sanitary products to measure MBL will be collected and a venous blood sample will 
be obtained.  The site will submit the sanitary products and venous blood sample to the 
Alkaline Hematin Laboratory for analysis of MBL volume to determine eligibility.  To be 
eligible for the study based on MBL, a subject must demonstrate > 80 mL for each of 2 
menses in Screening.
Under very limited conditions, additional screening menstrual cycles may be permitted; 
however the situation must be discussed with AbbVie prior to allowing additional product 
collections.  Screening Menstrual Cycle 1 for menstrual bleeding assessment begins with 
the first day of bleeding or spotting associated with menses.  If a subject has a known 
history of HMB and her first screening MBL amount is ≤ 80 mL due to a variety of 
factors that may include missed collection of products, submission of non-validated 
products (products that have not been tested to determine the level of interference with the 
alkaline hematin assay), or an atypical menstrual cycle, or if a subject misses the 
collection of sanitary products for one of the screening menstrual cycles, the Study Site 
must consult with AbbVie for further instructions, which may include the collection of 
sanitary products for an additional menstrual cycle.  The subject may still be eligible for 
randomization if she demonstrates blood loss > 80 mL during at least 2 screening 
menstrual cycles.  Table 5 provides an overview of eligibility based on MBL.


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Table 5.
Menstrual Blood Loss Volume Eligibility
Screening Cycle 1 
Blood Loss
Screening Cycle 2 
Blood Loss
Screening Cycle 3#
Blood Loss
Eligible
> 80 mL
> 80 mL
Not needed
Yes
> 80 mL
≤ 80 mL
> 80 mL
Yes
≤ 80 mL*
> 80 mL
> 80 mL
Yes
*
Study site must consult AbbVie for approval to collect sanitary products for additional menstrual cycles in 
screening.
#
There may be instances when a 4th cycle needs to be collected due to certain circumstances.  Study Site must also 
consult AbbVie for approval in the event a 4th cycle is needed to determine eligibility based on MBL.
Sites will contact the Interactive Response Technology (IRT) at the Screening Cycle 2 
Product Collection Visit to register the date of the visit for the first subject who completes 
the Screening Cycle 2 Product Collection Visit.  The registration of this visit will trigger 
the initial shipment of study drug to the study site.
Sanitary Product Collection During the Treatment Period
During the Treatment Period, Subjects will continue to collect sanitary products on all 
days with menstrual bleeding or spotting.  
As in Screening, sanitary products collected during the Treatment Period will be returned 
by the Subject within approximately 5 days after cessation of menstrual bleeding or 
spotting and a venous sample will be obtained at either a scheduled monthly visit or at a 
Product Collection Visit, as appropriate.  
Treatment Period Product Collection Visits
Product Collection Visits are only necessary if a monthly visit is not scheduled to occur 
within approximately 5 days after cessation of menstrual bleeding or spotting.  During the 
Product Collection Visits, subjects will have a venous blood sample, urine pregnancy test, 
vital signs, contraception counseling, as well as adverse event and concomitant 
medication assessment.  Product Collection Visits during the Treatment Period should be 


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numbered in sequential order (e.g., Product Collection Visit 1, Product Collection Visit 2, 
etc.) and entered into the eCRF.
Subjects who do not return a sanitary product collection keg at a site visit (scheduled 
monthly visit, PCV or Unscheduled Visit) will be administered the UBQ by the Site Staff.  
The Site Staff will ask the subject if she had any bleeding or spotting since the previous 
visit.  If the subject did have bleeding or spotting since the previous visit, the site staff 
will ask why the subject did not return sanitary products.  Responses to these questions 
will be documented on the UBQ by the Site Staff.
Sanitary Product Collection During the Post-Treatment Follow-Up Period
Subjects will be required to collect sanitary products on days with menstrual bleeding or 
spotting for their first menses with full menstrual flow in the Post-Treatment Follow-up 
Period.  If the subject misses collecting sanitary products for her first full menses, she will 
be required to collect sanitary products for her next full menses.  Once a subject has 
submitted sanitary products from her first full menses in the Post-Treatment Follow-up 
Period, she will no longer be required to collect sanitary products during her subsequent 
menses. 
Subjects who have not returned to their first full menses and have not returned a sanitary 
product collection keg in the Post-Treatment Follow-up Period will be administered the 
UBQ by the Site Staff.  The Site Staff will ask the subject if she had any bleeding or 
spotting since the previous visit.  If the subject did have bleeding or spotting since the 
previous visit, the site staff will ask why the subject has not returned for a Post-Treatment 
Product Collection Visit to return her sanitary products.  Responses to these questions will 
be documented on the UBQ by the Site Staff.  Once a Subject returns sanitary products 
from a full menses in the Post-Treatment Follow-up Period, the Post-Treatment UBQ no 
longer needs to be completed.


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Return of Sanitary Products to Alkaline Hematin Vendor
The site will submit the sanitary products and venous blood sample collected at the 
scheduled monthly visits or Product Collection Visits to the Alkaline Hematin Lab for 
analysis as outlined in the Alkaline Hematin Laboratory Manual.  
Home Visits
There may be an option for subjects to have a Product Collection Visit conducted at home 
by a Home Health Care Agent who will go to the Subject's home to draw a venous blood 
sample and retrieve the collection keg to return to the site.  
Use of Non-Validated Products
All subjects are to only use validated products, however in cases when a subject used 
non-validated (a product not provided for use in the study), the subject should be 
instructed to collect and submit the non-validated products to the Study Site.  
Subjects Pending Results for Eligibility into the Extension Study
Site Staff should continue to dispense sanitary products and sanitary product collection 
kits to subjects if results for entry into the extension study are pending at the time of the 
Month 6 visit.  
Sanitary products collected after the Month 6 visit will be returned to the site within 
approximately 5 days after cessation of menstrual bleeding or spotting as a Product 
Collection Visit and this collection will be numbered sequentially (refer to the Treatment 
Period Product Collection Visit section above).
Refer to Figure 5, Sanitary Product Dispensation and Collection for details on 
dispensation and collection requirements.


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Patient Reported Outcomes (PRO) Rating Scales
Prior to the start of the study, Site Personnel will be trained on all rating scales used in 
this study.  The objective of this training is to establish uniformity across sites in 
administration of these rating instruments.  The following questionnaires will be 
completed by the Subjects and/or the Investigator or Site Staff, as appropriate at the time 
points indicated in Appendix C.  Subjects and Site Staff will be asked to record their 
responses directly onto paper questionnaires and enter into the eCRF.
Reason for Study Participation
In order to better understand the reason(s) why a study participant has decided to enroll in 
this study, subjects will complete the single-question Reason for Study Participation 
Questionnaire (Appendix E) at the Day 1 Visit.  
Physician Surgery Questionnaire
Each physician will be asked to complete the Physician Surgery Questionnaire (PSQ) 
(Appendix F) at the Day 1 Visit.  
The PSQ evaluates the likelihood that the Physician would consider surgery or a surgical 
procedure as one of the treatment options related to uterine fibroids for the subject.  
Uterine Bleeding Questionnaire (Treatment – UBQ)
Subjects who did not return a Sanitary Product Collection Keg (for alkaline hematin 
analysis) at a site visit (scheduled monthly visit, PCV or Unscheduled Visit) during the 
Treatment Period, will be asked to indicate whether they had any uterine bleeding or 
spotting since their last study visit.  If the subject did not have uterine bleeding or spotting 
the site staff will indicate "No" on the UBQ.  If the subject did have bleeding or spotting, 
the subject will be asked the reason they did not return sanitary product collection keg.  
This response will be recorded on the UBQ (Appendix G) by the Site Staff.


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Post-Treatment Uterine Bleeding Questionnaire (Post-Treatment-UBQ)
Subjects who have not collected and returned sanitary products for their first menses with 
full menstrual flow in the Post-Treatment Follow-up Period, will be asked at each visit 
before sanitary products are returned if they had any bleeding or spotting since their last 
visit.  If the subject did not have uterine bleeding or spotting the site staff will indicate 
"No" on the UBQ.  If the subject did have bleeding or spotting, the subject will be asked 
the reason she did not return the sanitary product collection keg.  This response will be 
recorded on the UBQ (Appendix H) by the Site Staff.  Once a Subject returns sanitary 
products from a full menses in the Post-Treatment Follow-up Period, the Post-Treatment 
UBQ no longer needs to be completed.
Uterine Fibroid Symptoms Quality of Life (UFS-QoL) (4-Week Recall)
The UFS-QoL (Appendix I) is a disease-specific self-administered questionnaire used to 
measure health-related quality of life in women with symptomatic uterine fibroids.  Each 
subject will be asked to complete a modified (4-week recall) UFS-QoL Questionnaire10 to 
report fibroid-related symptoms experienced during the previous 4 weeks.
Patient Global Impression of Change – Menstrual Bleeding (PGIC-MB)
Subjects will use the PGIC-MB (Appendix J) to assess the change in their severity of 
menstrual bleeding (from very much improved to very much worse) since initiation of 
study drug by choosing one of seven responses.
Patient Global Impression of Change – Non-Bleeding Uterine Fibroids Symptoms 
(PGIC-NBUFS) 
Subjects will complete the PGIC-NBUFS (Appendix K) to document the presence of and 
to assess the change in the overall severity of non-bleeding uterine fibroid symptoms and 
the severity of specific non-bleeding uterine fibroid symptoms (from very much improved 
to very much worse) since initiation of study drug.


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Work Productivity and Activity Impairment Questionnaire (WPAI)
The WPAI questionnaire (Appendix L) will consist of questions measuring the impact of 
uterine fibroid symptoms on work productivity and daily activities during the previous 
7 days.  The questionnaire will be completed by Study Subjects at the Day 1 and Month 6 
visits.
EuroQol-5D 5 level (EQ-5D-5L™)11
The EQ-5D-5L (Appendix M) is a standardized measure comprised of 5 questions, 
measuring 5 dimensions of health status (mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression).  Subjects will be asked to select a response to 
each category that best describes their current health.  The EQ-5D-5L also contains a 
visual analogues scale that provides quantitative measure of health as judged by the 
individual respondents.  Subjects will also be asked to rate their current health on a scale 
of 0 – 100.   
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 (Appendix N) questionnaire 
will be administered in Screening and Day 1.  During the Treatment Period, the C-SSRS, 
Since Last Visit (Appendix O) questionnaire will be administered as specified in 
Appendix C. 
During Screening or at the Day 1 visit, prior to randomization, any subject noted to have 
suicidal ideation with plan within the last year, either via answering "yes" to question 4 
and/or question 5 to the suicidal ideation portion of the C SSRS, or via clinical interview,
is not eligible for randomization.  If the subject expresses suicidal ideation on the C-SSRS 
or via clinical interview at any time during the study, the Investigator should take 


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appropriate action and then notify the AbbVie TA MD.  Appropriate steps will be taken to 
protect the subject (including possible discontinuation from the study and referral for 
appropriate psychiatric care).  The C-SSRS will be administered at the times outlined in 
Appendix C.  The C-SSRS administered at the Day 1 Visit will serve as the baseline for 
clinical assessment.
Health Care Resource Utilization (HCRU)
The Health Care Resource Utilization questionnaire (Appendix P) will be used to capture 
routine/general health care visits (that are not associated with an adverse event) to non-
study Health Care Providers during the Treatment Period.  Subjects will be asked to 
provide information on any visits to non-study Health Care Practitioners in the past 
4 weeks for routine/general health visits including any diagnostic or therapeutic 
procedures that were performed.  The responses will be recorded on the HCRU by the Site 
Staff.  Health care resource use related to an Adverse Event or Serious Adverse Event will 
be captured as part of the Adverse Event, independent of the HCRU, and recorded in the 
eCRF.
Complete HCRU Version 1.0 (Appendix Q) for subjects randomized on Day 1 under 
Original Protocol at the time points listed in Appendix C, Study Activities. 
Complete HCRU Version 2.0 (Appendix P) for subjects randomized on Day 1 under 
Protocol Amendment 1 at the time points listed in Appendix C, Study Activities. 
Phone Contact During the Post-Treament Follow-Up Period
During the Post-Treatment Follow-Up Period at Follow-Up Months 2, 4, 5, 7, 8, 10, and 
11, site staff will telephone subjects who have not discontinued from the Follow-Up 
Period.  Site staff will assess ongoing adverse events, concomitant medications, provide 
contraception counseling and obtain the result of the subject administered urine pregnancy 
test.  Site staff will also assess return to full menses and administration of the Post-
Treatment UBQ, as applicable.  The phone call and pregnancy test result will be
documented in source documents and eCRF.


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Randomization and 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 
unique subject numbers will be assigned.  The same subject number will be used to 
identify the subject throughout the Screening, Treatment and Post-Treatment Follow-Up 
Periods.  In Screening, the site will contact IRT at the Screening Cycle 2 Product
Collection Visit to register the date of the visit for the first subject who completes the 
Screening Cycle 2 Product Collection Visit.  The registration of this visit will trigger 
shipment of clinical drug supplies to the study site.  If the subject is not randomized into 
the study, the reason for screen failure will be documented in the eCRF and the site will 
register the subject as a screen failure in IRT.
At the Day 1 Visit, eligible subjects will be randomized to 1 of 3 treatment groups by 
using IRT and providing the subject number the subject received during Screening or 
Washout.  During the randomization contact, a randomization number and kit number will 
be assigned by the IRT according to a randomization schedule generated by the statistics 
department at AbbVie.
During the Treatment Period, sites will register each monthly visit in IRT in order to 
obtain a scheduled re-supply of study drug to dispense to each subject.  In the event study 
drug becomes lost or damaged, the site can contact IRT to obtain an unscheduled 
re-supply of study drug kit numbers to dispense.  Sites will register subjects as 
"Completed" or "Discontinued" (if the subject prematurely discontinues) at the end of the 
Treatment Period and will also indicate whether the subject will enter the Post-Treatment 
Follow-Up Period or the Extension Study M12-816.
5.3.1.2
Blood Samples for Pharmacogenetic Analysis
One 4 mL whole blood sample for DNA isolation will be collected on Day 1 from each 
subject with consent.  If the sample is not collected on Day 1, it may be collected at any 
time throughout the study.


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Additionally, one 2.5 mL whole blood sample for RNA isolation will be collected on 
Day 1, Month 1, Month 3, and Month 6 or premature discontinuation with consent.  The 
procedure for obtaining and documenting informed consent is discussed in Section 9.3.
The samples will be minimally labeled with study ID, subject ID, and time-point.  Please 
refer to the Lab manual for instructions on collection and processing of samples.
Samples will be shipped frozen to the central laboratory and later shipped to AbbVie for 
DNA/RNA extraction.  
AbbVie will store the DNA and RNA samples in a secure storage space with adequate 
measures to protect confidentiality.  The samples will be retained while research on 
ABT-620 (or drugs of this class) continues, but no longer than 20 years.
5.3.1.3
Collection and Handling of Pharmacodynamic Variables
Blood Samples for Estradiol (E2) and Progesterone (P) Assay 
A single blood sample will be collected at each time point indicated in Appendix C to be 
used for the pharmacodynamic analysis of E2 and P.  The blood samples for assay of 
estradiol and progesterone will be collected in one 9 mL evacuated collection tube without 
anticoagulant (red cap, no gel separators to be used).  Sufficient blood volume will be 
collected to provide approximately 4 mL serum from each sample.
Refer to the study specific laboratory manual for detailed instructions on sample 
collection, processing and shipment. 
On Day 1, estradiol and progesterone samples will be collected prior to dose.  The date 
and time of collection will be recorded on the Central Laboratory Requisition Form.  
Samples collected at all visits other than Day 1 will be drawn at any time during the visit.


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5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood Samples for Elagolix and Norethindrone Assay
Blood samples for assay of Elagolix and norethindrone, also known as PK samples, will 
be collected by venipuncture into 3 mL evacuated K2-ethylenediaminetetraacetic acid 
(K2EDTA)-containing collection tubes at the time points indicated in Appendix C.  
Sufficient blood will be collected to provide approximately 1 mL plasma from each 
sample. 
Refer to the study specific laboratory manual for detailed instructions on sample 
collection, processing and shipment.
The date and time of collection will be recorded on the Central Laboratory Requisition 
Form.  The Day 1 visit sample should be collected approximately 1 hour after the 
first dose of study drug is administered; samples collected on other visit days will be 
collected at any time during the visit.
5.3.2.2
Measurement Methods
Plasma concentrations of elagolix and norethindrone and serum concentrations of 
estradiol and progesterone will be determined using validated methods by the Drug
Analysis Department at AbbVie.  Plasma or serum concentrations of other possible 
metabolites may be determined with validated or non-validated methods.
5.3.3
Efficacy Variables
5.3.3.1
Primary Efficacy Variable
The primary endpoint will be the percentage of subjects meeting a composite endpoint 
consisting of these two bleeding assessments:
●
MBL volume of < 80 mL during the Final Month (the last 28 days of 
treatment), AND


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●
50% or greater reduction in MBL volume from baseline to the Final Month 
(the last 28 days of treatment)
A subject who prematurely discontinues the study drug due to adverse events, "lack of 
efficacy" or "requires surgery or invasive intervention for treatment of uterine fibroids" 
will be considered as a non-responder regardless whether she meets the 
two aforementioned responder criteria or not.
5.3.3.2
Secondary Efficacy Variable
The following will be considered secondary variables:
●
MBL volume assessed using AH methodology and UBQ
●
Suppression of bleeding
●
Hemoglobin concentration
●
Fibroid and uterine volume
5.3.4
PRO and Quality of Life Variables
●
UFS-QoL Questionnaire
●
Physician Surgery Questionnaire
●
EuroQol (EQ-5D-5L) Questionnaire
●
Health Care Resource Utilization (HCRU)
●
Patient Global Impression of Change (PGIC) Questionnaires
●
Work Productivity and Activity Impairment (WPAI) Questionnaire
●
Reason for Study Participation Questionnaire
5.3.5
Safety Variables
●
Change from baseline to Month 6 in bone mineral density measured by DXA
●
Number and percentage of subjects reporting treatment-emergent adverse 
events (TEAEs)


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●
Number and percentage of subjects reporting adverse events of special interest 
(AESI) (e.g., hypoestrogenic adverse events)
●
Time to the first post-treatment menses
●
Change from baseline in clinical laboratory parameters
●
Change from baseline in vital signs
●
Endometrial biopsy and pelvic ultrasound findings
●
Columbia Suicide Severity Rating Scale (C-SSRS)
5.3.6
Pharmacodynamic Variables
Concentrations of E2, P, LH and FSH will be obtained throughout the Screening and 
Treatment Periods.  Additional pharmacodynamic parameters may be calculated if useful 
in the interpretation of the data.
5.3.7
Pharmacokinetic Variables
Exposures of elagolix and norethindrone, may be determined using a population PK 
approach.  Additional parameters may be calculated if useful in the interpretation of the 
data.
5.3.8
Pharmacogenetic Variables
DNA and RNA samples may be sequenced and data analyzed for RNA expression and 
genetic factors contributing to the subject's response to elagolix, or other study treatment, 
in terms of pharmacokinetics, efficacy, tolerability and safety.  Such genetic factors may 
include genes for drug metabolizing enzymes, drug transport proteins, genes within the 
target pathway, or other genes believed to be related to drug response.  Some genes 
currently insufficiently characterized or unknown may be understood to be important at 
the time of analysis.  The samples may be analyzed as part of a multi-study assessment of 
genetic factors involved in the response to elagolix or drugs of this class.  The samples 
may also be used for the development of diagnostic tests related to elagolix (or drugs of 
this class).  The results of pharmacogenetic analyses may not be reported with the study 
summary.


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5.3.9
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) will be employed for this Phase 3 
study and will have the usual responsibilities for safeguarding the interests of study 
participants and monitoring the overall study conduct.  The IDMC will provide 
recommendations about continuing, modifying, or stopping the trial for safety reasons.  
The IDMC membership and responsibilities will be documented in its charter.  After each 
IDMC meeting, the IDMC will communicate its recommendations to the sponsor, as 
described in the IDMC charter.
5.4
Removal of Subjects from Therapy or Assessment
Each subject has the right to withdraw from the study at any time.  In addition, the 
Investigator may discontinue a subject from the study at any time if the Investigator 
considers it necessary for any reason, including the occurrence of an adverse event or 
noncompliance with the protocol.  Subjects who withdraw from the study will not be 
replaced unless it is mutually agreed upon, in writing, by the Investigator and AbbVie.  
Each subject will be withdrawn from the study if any of the following occur:
●
The subject decides to withdraw consent for any reason.
●
The investigator believes it is in the best interest of the subject.
●
Clinically significant deterioration of the subject's medical status as 
determined by the investigator.
●
The subject requires surgical intervention for treatment of uterine fibroids and 
menstrual bleeding or other procedures including hysterectomy, myomectomy, 
uterine artery embolization, high intensity focused ultrasound (HIFU), 
endometrial ablation, dilation and curettage (D&C), etc. during the Treatment 
Period.  In the post treatment period these procedures do not warrant 
withdrawal if performed during the Post-Treatment Period unless a 
hysterectomy with bilateral salpingo-oophorectomy (BSO) is performed and 
the Subject does not plan to use Hormone Replacement Therapy within 
1 month of the surgery date.
●
The subject becomes pregnant.


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●
The subject has (SGPT/ALAT) or SGOT/ASAT elevation > 5 times the upper 
limit of normal confirmed upon repeat during the Treatment Period.
●
The subject's legally acceptable representative decides to withdraw consent for 
any reason.
●
Heavy menstrual bleeding during the Treatment Period that requires a blood 
transfusion at any time after having taken 28 days of study drug.  If a subject 
has a blood transfusion during the Post-Treatment Period, the AbbVie TA MD 
should be contacted to determine if the subject can remain in the study.
●
Any other medical reason that AbbVie or the study investigator deems 
appropriate.
5.4.1
Discontinuation of Individual Subjects
In the event that a subject withdraws or is prematurely discontinued from study drug 
treatment, the subject should complete the Treatment Period Premature Discontinuation 
Visit as soon as possible (preferably within 2 – 7 days of last dose of study drug, if 
possible) and undergo study procedures as outlined in Appendix C.  Subjects who 
prematurely discontinue during the Treatment Period are expected to enter the 12-Month 
Post-Treatment Follow-Up Period.
In the event that a subject withdraws or is prematurely discontinued during the 
Post-Treatment Follow-Up period, the subject should complete the Post-Treatment 
Premature Discontinuation Visit as soon as possible and undergo study procedures as 
outlined in Appendix C.  These procedures should not interfere with the initiation of any 
new treatments or therapeutic modalities the Investigator determines are necessary to treat 
the subject's condition.  The reason(s) for the discontinuation from the study will be 
recorded in the eCRFs.
All used and unused study drug containers will be returned to the study site.
If a subject becomes pregnant during the Treatment or Post-Treatment Follow-Up 
Periods, no additional study procedures, except an ultrasound will be conducted.  Refer to 


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Section 6.1.6 for instructions on reporting of a pregnancy to the Sponsor and the required 
follow-up on the subject/fetus and live births.
Subjects who prematurely discontinue from treatment and enter Post-Treatment 
Follow-Up and received study drug for < 3 months or the procedure was performed in the 
past two months are not required to undergo the following procedures during the 
Post-Treatment Period, unless requested by the AbbVie TA MD or based on clinical 
judgment:
Post-Treatment Period Month 3:
●
TAU/TVU
●
MRI
Post-Treatment Period Month 6:
●
TAU/TVU
●
DXA (unless the premature discontinuation was related to BMD decrease or 
the occurrence of a fracture)
If a subject is discontinued from the study with an ongoing adverse event or an unresolved
laboratory result that is clinically significant (as determined by the Investigator), the 
Investigator will attempt to provide follow-up until a satisfactory clinical resolution of the 
laboratory result or adverse event is achieved.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The Investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 


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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 in writing the Investigator as well as regulatory 
authorities of the decision and give detailed reasons for the discontinuation.
●
The Investigator must promptly notify the IRB/IEC and give detailed reasons 
for the discontinuation.
●
The Investigator must promptly notify the enrolled subjects of the premature 
discontinuation and administer appropriate treatments such as replacement of 
the treatment regimen, if applicable, by other appropriate regimens.
5.4.3
Treatment Interruption
AbbVie or the Investigator may request that a subject temporarily discontinue study drug 
administration, which will be referred to as "treatment interruption."  The following are 
examples for reasons when the AbbVie TA MD must be notified in order to assess 
whether a subject should undergo temporary treatment interruption:  
●
Adverse event, that based on clinical judgment, requires temporary suspension 
of treatment or prevents a subject from taking study drug
●
Due to malfunction of barrier contraception or unprotected intercourse
Additionally, there may be times when a subject has had treatment interruption due to 
having forgotten to take study medication, lost study medication, etc.  If the subject has 
missed 7 or more consecutive days of dosing (with either ABT-620/Placebo or 
E2/NETA/Placebo), the AbbVie TA MD must be consulted to determine whether the 
subject may resume study drug administration or continue in the Treatment Period.  
These examples are not all-inclusive; if the Investigator has any questions, these should be 
directed to the AbbVie TA MD.


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5.4.4
Delays in Rollover into the Extension Study
Subjects may be required to remain in the Treatment Period following the completion of 
the Month 6 visit if results to determine eligibility into the Extension Study are not 
available at the time of the Month 6 visit.  Subjects will return to the study site at the same 
28-day monthly visit intervals if eligibility for the extension study has not been 
determined before then.  Subjects will continue to take study drug until eligibility has 
been established.  These visits will be documented as and registered as Unscheduled 
Visits.  Sites should register Unscheduled Visits in IRT in order to obtain additional kits 
of study drug.  Procedures/assessments to be performed during the Unscheduled Visit 
while the subject is waiting for the determination of eligibility into the extension study, 
are indicated in the Table 6.


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Table 6.
Schedule of Assessments – Delays in Roll-Over into Extension Study
Schedule of Assessments – Delays in Roll-Over into Extension Study
Procedure 
Perform Monthly
Symptom-directed Physical Examination
X
Vital Signs
X
Clinical/Safety Laboratory Tests:  Hematology, Chemistrya
X
Urine Pregnancy Testb
X
Endocrine Panel:  FSH, LH 
X
Pharmacodynamic Sample (PD):  Serum Estradiol (E2) and Progesterone (P)
X
Contraception Counseling and Dispense Contraceptives as necessary
X
Dispense Sanitary Products and Collection Kits (Keg, Collection Bags etc.)
X
Collect and Return Sanitary Products
X
Register Visits in IRT
X
Study Drug:  Dispense (D) and Return (R)c
X
Study Drug Accountability
X
Study Drug Compliance
X
Adverse Event Monitoring
X
Concomitant Medication Monitoring
X
Questionnaires
UBQd
X
C-SSRS – Since Last Visit
X
HCRU
X
a.
Eight (8) hour minimum fast for Clinical Safety Laboratory Tests; Chemistry and Lipid Panels.
b.
A positive urine pregnancy test result must be confirmed with a quantitative serum pregnancy test.  For any subject 
who has a positive serum pregnancy test result, a TVU must be conducted as early as possible in the first trimester 
in order to assess the gestational age and estimated due date.  The subject will be discontinued from the study at the 
point the pregnancy was confirmed.
c.
Urine pregnancy test must be negative prior to providing subjects with their next monthly supply of study drug.
d.
The Uterine Bleeding Questionnaire (UBQ) is to be completed by Site Staff at every scheduled monthly visit (or 
PCV) only if the subject did not return a sanitary product collection keg at the visit.
Once eligibility for entry into the extension study has been determined:
Subject Entering the Extension Study:
●
Subject will return to the study site as soon as possible


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●
Subject will discontinue taking study drug from the pivotal study just prior to 
entering the extension study, i.e., subjects are to continue taking study drug 
until they have returned to the site for their roll-over visit
●
Record transition of study subject into the extension study in IRT
Subject NOT Entering the Extension Study:
●
Subject will discontinue taking study drug
●
Subject will return to the study site as soon as possible
●
Record transition of study subject into the Post-Treatment Follow-up Period in 
IRT
●
The next scheduled visit will be the Month 1 Site Visit
5.5
Treatments
5.5.1
Treatments Administered
Subjects will be randomly assigned by IRT to receive one of the following treatment 
groups for a total of 6 months of treatment:
●
placebo (n = 100)
●
elagolix 300 mg BID (n = 100)
●
elagolix 300 mg BID plus E2/NETA (estradiol 1.0 mg/norethindrone acetate 
0.5 mg) QD (n = 200)
The treatment administration is presented in Table 7.


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Table 7.
Treatments Administered
Investigational Product
Treatment Group
Dosing 
Time
Elagolix 
300 mg 
Tablets
Elagolix 
Placebo 
Tablets
E2/NETA 
Capsules
Matching 
E2/NETA 
Placebo 
Capsules
Placebo
AM
0
1
0
1
PM
0
1
0
0
Elagolix 300 mg BID
AM
1
0
0
1
PM
1
0
0
0
Elagolix 300 mg BID 
plus E2/NETA QD
AM
1
0
1
0
PM
1
0
0
0
The elagolix study drug, consisting of elagolix or matching placebo, will be supplied in a 
carton.  The E2/NETA study drug, consisting of E2/NETA or matching placebo, will be 
supplied in a separate carton.  The subject will take the first elagolix dose (morning dose) 
and first E2/NETA dose of study drug at the study site on Day 1 (Randomization).  
Subjects will be instructed to self-administer their study drug throughout the 6-month 
Treatment Period.  
A 1-month supply of each study drug (plus 1 week extra) will be dispensed during the 
Treatment Period at the Day 1 (randomization) Visit, and at the Month 1, 2, 3, 4 and 5 
visits. 
Study drug will be taken orally twice daily for the entire 6-month Treatment Period.  A 
morning dose of 1 tablet (elagolix or placebo) and 1 capsule (E2/NETA or placebo) and 
an evening dose of 1 tablet (elagolix 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 in order to promote compliance.
If the subject forgets to take the morning dose, she should be instructed to take the 
morning dose as soon as possible and take the evening dose as scheduled.  If the subject 


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forgets to take the evening dose, she should be instructed to take the evening dose as soon 
as possible; if the subject misses the evening dose completely (until the next morning), the 
subject should only take the morning dose. 
On days when the subject visits the study site for the scheduled visits, she will take her 
morning dose at home, prior to the visit.  The evening dose will be taken from the newly 
dispensed supply of study drug.  Subjects must return all study drug containers at each 
monthly visit.
At the Month 6 visit, a –4 or +6 day visit window will be allowed in order to collect 
sanitary products from the last menstrual bleeding cycle prior to the Month 6 visit if 
menstrual bleeding starts immediately prior to or coincides with the scheduled visit.  If the 
+6 day window is needed, the subject will be instructed to continue taking study drug 
from the extra blister card (1 week supply) until she returns for the Month 6 Visit.
Subjects awaiting results to determine eligibility into the extension study will continue to 
be dispensed study drug until results are available.  Refer to Section 5.4.4 for further 
details on dispensing and registering subjects during this waiting period.
5.5.2
Identity of Investigational Products
Information about the drug formulations to be used in this study is presented in Table 8.


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Table 8.
Identity of Investigational Products
Study Drug
Formulation
Route of 
Administration
Trademark
Manufacturer
Elagolix 
Film-coated 300 mg 
tablets
Oral
N/A
AbbVie
Matching Elagolix 
Placebo
Film-coated Placebo 
tablets 
Oral
N/A
AbbVie
E2/NETA* 
Estradiol 
1.0 mg/Norethindrone 
acetate 0.5 mg 
capsules*
Oral
N/A
Commercial 
Tablets:  
Pharmaceutics 
International, Inc 
Matching E2/NETA 
Placebo 
Placebo capsules
Oral
N/A
AbbVie
*
Commercially-available E2/NETA tablets are over-encapsulated to maintain study blinding.
5.5.2.1
Packaging and Labeling
AbbVie will supply blinded study drug in monthly kits (i.e., cartons).  Two kits of study 
drug will be provided at each dispensing visit.  One kit consists of Elagolix or matching 
placebo and the other kit consists of E2/NETA capsules or matching placebo. Each kit 
contains 5 blister cards, with each blister card containing 7 days of study medication.  
There are 4 weekly blister cards and 1 extra medication blister card in each kit to supply 
enough medication for 4 weeks (28 days) of dosing, plus an extra week's supply.  
Each individual elagolix or matching placebo blister card contains 14 tablets for a 7-day 
(weekly) supply study medication.  Also, each E2/NETA or matching placebo blister card 
contains 7 capsules for a 7-day (weekly) supply of study medication.  
The kits will be assigned to a subject via IRT and will encode the appropriate study drug 
to be dispensed at the subject's corresponding study visit.
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.


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5.5.2.2
Storage and Disposition of Study Drug
Elagolix, E2/NETA and respective matching placebo study medication must be stored at 
controlled room temperature 15° to 25°C (59° to 77°F).  Additionally, E2/NETA and 
matching placebo study medication must be protected from light.
The investigational products are for investigational use only and are to be used only 
within the context of this study.  The study drug supplied for this study must be 
maintained under adequate security and stored under the conditions specified on the label 
until dispensed for subject use or returned to AbbVie.  Returned study drug should not be 
re-dispensed to the subject.
5.5.3
Method of Assigning Subjects to Treatment Groups
All subjects will be centrally randomized using an IRT.  Before the study is initiated, 
contact information and user guidelines for IRT will be provided to each site.  Study drug 
will be dispensed at the study visits outlined in Appendix C, Study Activities.
As subjects enter into either the Washout Period or the Screening Period, a unique subject 
number will be assigned to each subject by the IRT.  This unique subject number will be 
used for each subject throughout the study.
After confirming that the subject has met randomization criteria and prior to the Day 1 
(randomization) dose, a unique randomization number will be provided via IRT.
Subjects will be randomly assigned by IRT to receive one of the treatment groups as 
outlined in Section 5.5.1 for a total of 6 months of treatment.
Study drug must not be dispensed without contacting IRT.  Study drug may only be 
dispensed to subjects enrolled in the study according to kit numbers provided by the IRT.
The randomization schedule will be computer generated by the Statistics Department at 
AbbVie, North Chicago, IL prior to the start of the study.  A copy of all of the 


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randomization schedules will be kept by the Statistics Department at AbbVie and a copy 
will be forwarded to the IRT provider.
5.5.4
Selection and Timing of Dose for Each Subject
Selection of the doses used for this study is discussed in Section 5.6.4.  Subjects will be 
randomized into one of the three treatment groups as described in Section 5.5.1.
Study drug will be initiated at the study site on Day 1 (randomization).  Subjects will be 
instructed to self-administer study drug twice a day (once in the morning and once in the 
evening approximately 12 hours apart) with approximately 8 oz (240 mL) of water.  
Subjects must return all study drug containers (used or unused) at the subsequent visit.
5.5.5
Blinding of Investigational Product
Each active elagolix dose will be identical in appearance to its matched placebo; each 
active E2/NETA dose will be identical in appearance to its matched placebo.  The study 
site personnel and subject will remain blinded to each subject's treatment throughout the 
course of the study.  The IRT will provide access to blinded subject treatment information 
during the study.
AbbVie must be notified before the blind is broken, unless identification of the study drug 
is required for medical emergency; i.e., situation in which the knowledge of the specific 
blinded treatment will affect the immediate management of the subject/patient's 
conditions (e.g., antidote is available).  AbbVie must then be notified within 24 hours of 
the blind being broken.  The date and reason that the blind was broken must be recorded 
in the source documents and eCRF, as applicable.
5.5.6
Treatment Compliance
Subjects will be instructed to return all study drug kits (used or unused) to the study site 
personnel at the Month 1, Month 2, Month 3, Month 4, Month 5 and Month 6 or 
Premature Discontinuation Visits during the Treatment Period.  The study site personnel 
will document compliance.


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The investigator or his/her designated and qualified representatives will dispense study 
drug only to subjects enrolled in the study in accordance with the protocol.  The study 
drug must not be used for reasons other than those described in the protocol.
Subjects should be advised of the importance of treatment compliance.  Study drug should 
be taken consistently at approximately the same time in the morning and evening each 
day.  Daily recordings of study drug dosing will be obtained using a compliance 
packaging blister card for all subjects (for both elagolix/matching placebo and 
E2/NETA/matching placebo).  AbbVie will provide training and study drug compliance 
materials to sites for instructing subjects on study drug compliance.
Sites will be provided scanning technology for direct access to the dosing compliance 
data; sites are expected to scan all returned blister cards (used/unused/unopened) to obtain 
the dosing information at each of the Treatment Period visits when study drug is returned 
to the site by the subject.  Any unused/unopened blister cards should be documented as 
such in the scanning technology source documentation.  Sites are expected to use the 
compliance data to guide them in discussions with the subject regarding compliance.  
Upon reviewing the dosing data, if the date(s) and time(s) for any of the last 4 doses of 
study drug (elagolix or E2/NETA or placebo) prior to the monthly Treatment Period visit 
or Premature Discontinuation visit are missing, the subject will be asked to confirm 
whether doses were taken and to provide the dates and approximate times of the last 
4 scheduled doses prior to the study visit.  The subject reported data will be recorded in 
source and in the eCRF.  Sites will document when the blister cards are not returned or 
when blister cards cannot be scanned.
Sites should instruct subjects not to remove extra or multiple medications from the blister 
cards all at once and should only remove the study drug from the blister when it is the 
time to take the dose.  If the compliance data shows incidence of removing a number of 
extra medications, sites should re-train the subjects on the importance of only removing 
study medication when it is time to take the dose and record re-training in the source 
documents.


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During review of the study drug compliance with the study subject, if the number of 
tablets/capsules to be taken and the number of tablets/capsules returned do not add up to 
the number of tablets/capsules dispensed, an explanation should be provided by the 
subject and recorded in the source documents.  
If a subject missed more than 7 consecutive days of taking study drug, the AbbVie TA 
MD should be notified to determine whether the subject may continue.
Compliance packaging data will be used for exposure response analysis.
5.5.7
Drug Accountability
The study Investigator or designee will verify by signature and date that study drug 
supplies are received intact and in the correct amounts indicated on the shipping document 
Proof of Receipt or similar shipping document or via direct recording in IRT.  The 
shipment receipt must be acknowledged in IRT in order to become available for 
dispensation to subjects.  The IRT must also be contacted when any subject discontinues 
study drug.
The IRT will maintain a current and accurate inventory of all clinical drug supplies, 
accountability, reconciliation, returns and destruction for each site.  The IRT will also 
include the lot number, kit number, Proof of Receipt number, the number of blister 
cards/cartons dispensed, initials of person who dispensed the drug, and the date study 
drug was dispensed for each subject.  In addition to using IRT inventory, an accurate 
inventory of study drug can also be kept by the site.
An overall accountability of the study drug will be performed and verified by the site 
monitor via IRT throughout the study and at the study site closeout visit.  Throughout the 
study and upon completion or termination of the study, all used and unused containers 
will be returned to AbbVie according to instructions from AbbVie.
The study investigator or his/her designated representative agrees not to supply study 
medication to any persons not enrolled in the study or not named as a sub-investigator.


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Study drug will be dispensed at the study visits summarized in Appendix C, Study 
Activities.  Returned study drug should not be re-dispensed to the subject.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This Phase 3 study will be conducted as a randomized, double-blind, multi-center, 
placebo-controlled study in premenopausal women 18 to 51 years of age with HMB 
associated with uterine fibroids.  The randomized, double-blind, placebo-controlled study 
design is the standard for unbiased assessments of treatment group differences.
This study will evaluate the safety and efficacy of elagolix 300 mg BID alone and elagolix 
300 mg BID in combination with E2/NETA QD (1.0 mg/0.5 mg) versus placebo in 
subjects with HMB associated with uterine fibroids.  The study will also assess the impact 
of E2/NETA on the efficacy, safety, and tolerability of elagolix, including hypoestrogenic 
side effects such as BMD decrease and vasomotor symptoms.  
5.6.2
Appropriateness of Measurements
The safety assessments used in this study are standard, widely used and generally 
recognized as reliable, accurate and relevant within the context of this study design.
Regarding efficacy measures, HMB is the most common symptom of women with uterine 
fibroids.  The quantitation of menstrual blood loss using the alkaline hematin method on 
sanitary products has been validated by the analytical testing laboratory.  Pelvic 
ultrasound and SIS are standard methods for assessing uterine fibroid size, fibroid and 
uterine volume.  Endometrial biopsy is a standard method for assessing endometrial 
safety.  DXA is the established gold standard method to assess changes in BMD.
5.6.3
Suitability of Subject Population
Premenopausal women 18 to 51 years of age with HMB (> 80 mL per menstrual cycle) 
and uterine fibroids were selected for this study because that is the population who suffer 


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from HMB associated with uterine fibroids.  The lower bound of the age limit (18) was 
chosen based on the relative paucity of adolescent females with symptomatic uterine 
fibroids prior to age 18, and the upper age of 51 is included to reduce the risk of subjects 
becoming menopausal during the study.  No studies in males or in females outside of the 
reproductive years are necessary for this proposed indication.
5.6.4
Selection of Doses in the Study
The preliminary results of the 3-month Phase 2a dose finding, POC Study indicate that 
elagolix 300 mg BID was the most effective dose in reducing HMB associated with 
uterine fibroids.  The 6-month Phase 2b safety/efficacy study confirmed these results and 
also demonstrated that E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD was 
effective in preventing BMD loss and ameliorating vasomotor symptoms due to estrogen 
suppression.  The data (PK/PD) from the multiple ascending dose (MAD) and 
folliculogenesis studies in healthy subjects also provide additional support for the targeted 
elagolix dose.  All of these studies have demonstrated an acceptable safety and tolerability 
profile to date.
Based on the totality of safety and efficacy data, elagolix 300 mg BID with E2/NETA 
(estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD was selected for further evaluation in 
Phase 3.  The maximum elagolix dose administered in this study will not exceed a total 
daily dose of 600 mg.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Section 6.1
through 6.1.5.  For product complaints, please refer to Section 6.2


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All adverse events will be followed to a satisfactory conclusion.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide an Other cause of the event.  For adverse events to be considered 
intermittent, the events must be of similar nature and severity.  Adverse events, whether in 
response to a query, observed by site personnel, or reported spontaneously by the subject 
will be recorded.
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities, and vital signs are considered to be adverse events only 
if they result in discontinuation from the study, necessitate therapeutic medical 
intervention and/or if the investigator considers them to be adverse events.


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An adverse event of amenorrhea will be reported for subjects who do not return to menses 
by the Post-Treatment Follow-up Month 2 Phone Visit and the adverse event will be 
followed until resolution.  The onset date of the adverse event will be the date of the 
Follow-up Month 2 Visit.  
A BMD decrease at any anatomic location (spine, total hip or femoral neck) during the 
Treatment or Post-Treatment Follow-up period that leads to discontinuation from study or 
a BMD decrease at any anatomic location with a T-score < –1.5 should be reported as an 
adverse event.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
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.


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


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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.
6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an "Other" cause of event must be provided by the investigator for the serious 
adverse event.
6.1.4
Adverse Event Collection Period
All adverse events reported from the time of study drug administration through Month 6 
or Month 12 in the Post-Treatment Follow-Up Period, (if applicable) will be collected, 
whether solicited or spontaneously reported by the subject.  In addition, serious adverse 
events and protocol-related nonserious adverse events will be collected from the time the 
subject signed the study-specific informed consent.


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If a subject prematurely discontinues from the study, i.e., either prematurely discontinues 
from Treatment Period and does not enter the Post-Treatment Follow-Up Period or 
prematurely discontinues from the Post-Treatment Follow-Up Period, adverse events and 
serious adverse events will be collected up to 30 days after the last dose of study drug.
Adverse event information will be collected as shown in Figure 6.
Figure 6.
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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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 emailing (preferred route) or faxing the appropriate 
serious adverse event forms to:
Email: 
FAX to
For safety concerns, contact the Men's and Women's Health Safety Team at:
Men's and Women's Health Safety Team
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Men's and Women's Health Safety Line
For any subject safety concerns, please contact the physician listed below:
Primary Therapeutic Area Medical Director (TA MD):


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In emergency situations involving study subjects when the primary AbbVie TA MD is not 
available by phone, please contact the 24-hour AbbVie Medical Escalation Hotline
where your call will be re-directed to a designated backup AbbVie medical monitor:
Phone: 
Email:
6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Subjects who become pregnant during the Treatment 
or Post-Treatment Follow-Up Periods of the study must be discontinued (Section 5.4 and 
Section 5.4.1).  A positive urine pregnancy test result must be confirmed with a serum 
pregnancy test.  If a serum pregnancy test result is positive at any time during the 
Treatment Period of the study, the site will immediately inform the subject to discontinue 
study drug.  Information regarding a pregnancy occurrence in a study subject and the 
outcome of the pregnancy will be collected for any study subject with a positive serum 
pregnancy test from the signing of the informed consent (i.e., washout [if applicable]) or 
screening) through the Post-Treatment Follow-Up Period.  The site will report a positive 
pregnancy test to the Sponsor, will follow the course of the subject's pregnancy, and 
report to the Sponsor on the health of the subject and fetus at each trimester and at the 
first post-delivery pediatrician visit.
If the subject becomes pregnant during the Treatment or Post-Treatment Follow-Up 
Periods of the study, an ultrasound examination will be performed as early as possible 
during the first trimester of pregnancy to assess the conception date and document an 
intrauterine pregnancy.  The following information on the outcome of the pregnancy that 
occurred after signing of the informed consent, regardless of when the subject became 
pregnant (i.e., either during the Washout, Screening, Treatment or Post-Treatment 
Follow-Up Periods) should be collected:  fetal outcome (e.g., spontaneous or elective 
abortion, live infant or still birth), date of delivery, birth weight, birth length, gender, birth 


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defects, congenital anomaly and medically significant complications during pregnancy or 
labor or delivery.  For live infant births, information on the health of the infant will be 
collected 6 to 12 months after delivery.
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the 
site becoming aware of the event.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (e.g., printing illegible), missing 
components/product, or packaging issues.
Any information available to help in the determination of causality by the product to the 
events outlined directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and recorded in source documents as required by the Sponsor.  
Product Complaints associated with adverse events will be reported in the study summary.  
All other complaints will be monitored on an ongoing basis.


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Product Complaints may require return of the product with the alleged complaint 
condition (investigational product).  In instances where a return is requested, every effort 
should be made by the investigator to return the product within 30 days.  If returns cannot 
be accommodated within 30 days, the site will need to provide justification and an
estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
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 Analytical 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 safety and efficacy 
comparisons will be between the elagolix 300 mg BID plus E2/NETA treatment group 
and the placebo group.  Comparisons between the elagolix 300 mg BID alone treatment 
group and the placebo group are provided for a reference.
8.1.2
Data Sets Analyzed
Modified Intent-to-Treat (mITT) Analysis Set
The modified intent-to-treat (mITT) analysis set is comprised of all randomized subjects 
who took at least one dose of the study drug and have at least one post-baseline visit in 
this study.  The mITT analysis set will be used for all efficacy analyses unless otherwise 
specified in the Statistical Analysis Plan (SAP).
Safety Analysis Set
The safety analysis set includes all randomized subjects who took at least one dose of the 
study drug.  The data from the safety analysis set will be presented by the treatment 
actually received no matter what treatment group was assigned at the time of 
randomization.  If a subject takes more than one treatment, the subject will be analyzed in 
the safety analysis set as taking the treatment to which she is randomized to.  All safety 
analyses will be performed based on the safety analysis set unless otherwise specified in 
the SAP.


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8.1.3
End-of-Treatment Period Analysis
An end-of-treatment period analysis of the primary and secondary efficacy variables along 
with demographic and safety variables will be performed after the last subject randomized 
in this study completes the 6-Month Treatment Period of Study M12-817.  This 
end-of-treatment period analysis will include all treatment period data from all patients 
randomized into the study.  The data base will be versioned and any discrepant data will 
be clarified before the lock.  Analyses will be performed by an external Independent Data 
Analysis Center (IDAC).  Subjects completing Study M12-817 are eligible to be enrolled 
in the double-blind extension study.  The blinding at the subject level for the extension 
study will be maintained as the efficacy data analyses will only present overall treatment 
group results to the sponsor.  The sponsor will have access to the unblinded results at the 
treatment group level.  However, the blinded data at the subject level will not be included 
in the results of the demographic, efficacy, or safety endpoints provided to the sponsor.  
The randomization schedule for Study M12-817 will be provided to the IDAC by 
someone other than the project statistician, who is otherwise not involved with this study.  
All AbbVie study personnel will remain blinded until the blind is broken for the 
double-blind extension study.  The end-of-treatment period analysis will only include data 
collected during the 6-month treatment period of the study and will not include data 
collected during the post-treatment follow-up period.
Since this end-of-treatment period analysis is the only and final analysis of the primary 
and ranked secondary endpoints of Study M12-817, no adjustment of alpha-level is 
necessary.
8.1.4
Independent Data Monitoring Committee
The IDMC will receive an analysis summary by treatment group, which will include data 
on enrollment, baseline characteristics, and safety.


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8.1.5
Demographic, Baseline Characteristics and Concomitant 
Medications
Demographic and baseline characteristics will be summarized by treatment group.
Overall comparability among treatment groups will be performed using the following 
methods:  a one-way analysis of variance (ANOVA) with treatment group as the main 
effect for continuous variables, Fisher's exact test (or its generalization to r × c tables) for 
qualitative categorical variables and the Cochran-Mantel-Haenszel (CMH) row mean 
scores test for ordered categorical variables.
Medical history will be summarized by condition/diagnosis by treatment group (no 
treatment group comparisons will be made).  The duration of the study drug exposure will 
be summarized by treatment group.
Protocol deviations and reasons for discontinuation will be summarized.
Concomitant medications will be coded using the World Health Organization (WHO) 
dictionary and summarized with frequencies and percentages.
The baseline MBL volume will be defined as the mean of MBL volume from the qualified 
menstrual cycles during the Screening Period prior to the first study drug dose date, in 
which the total MBL volume is from all validated and non-validated sanitary products that 
subjects returned and where the total MBL volume of validated sanitary products only 
(excluding non-validated sanitary products) is greater than 80 mL.  All menstrual cycles 
during the Screening Period in which the total MBL volume of validated sanitary products 
only is less than or equal to 80 mL are not qualified to be considered for baseline.  The 
baseline for bleeding days will be based on the assessments from the qualified menstrual 
cycles that are used to calculate the baseline MBL volume.
The baseline values for other variables will be defined as the last non-missing assessment 
obtained prior to the initiation of the study drug unless otherwise specified.


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8.1.6
Time Points, Time Windows and Time Periods for Analysis
As appropriate, time windows for various safety and efficacy analyses will be defined in 
the SAP.
For randomized subjects who received at least one dose of the study drug, Study Day is 
defined as the number of days since (positive values) or prior (negative values) to the 
first study drug dose.  The day of the first study drug dose is defined as Study Day 1, 
while the last day prior to the first study drug dose is defined as Study Day –1.  There is 
no Study Day 0.
8.1.7
Efficacy
8.1.7.1
Primary Efficacy Variable
8.1.7.1.1
Primary Analysis
The primary analysis of the primary endpoint will be performed using the mITT analysis 
set.
The primary endpoint will be the percentage of subjects meeting a composite endpoint 
consisting of two bleeding assessments:
●
Menstrual blood loss (MBL) volume < 80 mL during the Final Month (the last 
28 days of treatment), and
●
50% or greater reduction in MBL volume from baseline to the Final Month 
(the last 28 days of treatment).
A subject who prematurely discontinues the study drug due to adverse events, "lack of 
efficacy," or "requires surgery or invasive intervention for treatment of uterine fibroids" 
will be considered as a non-responder regardless whether she meets the 
two aforementioned responder criteria or not.
Baseline MBL volume is described in Section 8.1.5.  The Final Month is defined as the 
last 28 days of treatment prior to and including the last dose date.


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The MBL volume used for the primary and sensitivity analyses is defined as the total 
combined volume of blood ascertained via the AH method from all used (validated and 
non-validated) sanitary products that a subject returns.  In case a subject does not return 
any used sanitary products and indicates on the UBQ that she experienced bleeding during 
the Final Month, the MBL volume will be imputed per the procedure described in 
Section 8.1.7.1.2.
The primary endpoint will be analyzed using a logistic regression model including 
treatment as the main effect and baseline MBL volume as a covariate.
8.1.7.1.2
Derivation of Primary Efficacy Endpoint
The Final Month MBL volume will be derived as follows:
●
If a subject has any AH data reported during the Final Month (i.e., she has at 
least 1 day of AH data during the last 28 days of treatment), then her primary 
endpoint will be based on AH data during the Final Month.  The subject's Final 
Month MBL volume will be the total MBL volume which is the sum of the 
observed MBL volume over the last 28 days of treatment.
●
If a subject is missing the Final Month AH data and the Uterine Bleeding 
Questionnaire is completed, then;
●
A value of 0 will be assigned to the Final Month MBL volume if no bleeding 
or spotting, "Subject only had spotting that did not require the use of sanitary 
products" or "There was no visible blood on the sanitary products" is indicated 
on the Uterine Bleeding Questionnaire (Appendix G).
●
Otherwise, the primary endpoint will be imputed using multiple imputation as 
described in Section 8.1.7.1.3.
A flow-chart showing how the primary endpoint will be derived is presented in Figure 7.


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Figure 7.
Flow-Chart for Deriving Primary Endpoint 
8.1.7.1.3
Multiple Imputation
The imputation model will include but is not limited to the following variables:  baseline
MBL volume, treatment group, and 28-day MBL volume at each post-baseline treatment 
cycle.  The final imputation model will be specified in the SAP.
First, M "semi-complete" datasets will be imputed to produce monotone missing data via 
MCMC using SAS PROC MI.  Then, M "complete" datasets for the Final Month MBL 
volume will be generated based on each "semi-complete" dataset via linear regression 
using SAS PROC MI.  M represents the number of imputed datasets and its value will be 
specified in the SAP.


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Each subject's responder status will be derived based on the imputed Final Month MBL 
volume from the M imputed datasets.  And the percentages of responders are analyzed 
using a logistic regression model including treatment as the main effect and baseline MBL 
volume as a covariate.
8.1.7.1.4
Sensitivity Analysis of the Primary Efficacy Variable
The sensitivity analyses for the primary endpoint will use different approaches for 
handling prematurely discontinued subjects and different approaches for dealing with 
missing Final Month MBL volume.  The details of the sensitivity analyses will be 
specified in the SAP.
Unless otherwise specified, the analysis dataset used for sensitivity analysis is the mITT 
analysis set.
8.1.7.2
Secondary Efficacy Variables
Ranked secondary efficacy measures during the Treatment Period include the following 
(the order of the ranked secondary efficacy endpoints will be specified in the SAP):
●
Change from baseline in MBL volume to the Final Month;
●
Monthly change from baseline in MBL volume;
●
Percentage of subjects with suppression of bleeding (no bleeding allowed, 
spotting allowed) at the Final Month;
●
Percentage of subjects with baseline hemoglobin ≤ 10.5 g/dL who have an
increase in hemoglobin > 2 g/dL at Month 6.
Non-ranked secondary efficacy measures during the Treatment Period include the 
following:
●
Change and percent change from baseline in MBL volume;
●
Percentage of subjects with MBL volume < 80 mL and 50% or greater
reduction in MBL volume from baseline during 28-day intervals throughout 
the Treatment Period;


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●
Change from baseline in total number of sanitary products used;
●
Change and percent change from baseline in hemoglobin concentration;
●
PGIC for Menstrual Bleeding and Non-Bleeding Uterine Fibroid Symptoms;
●
Change and percent change from baseline in fibroid and uterine volume;
●
Change from baseline for the UFS-QoL; 
●
Change from baseline for the EuroQoL-5D (EQ-5D-5L);
●
The HCRU;
●
Change from baseline for the WPAI.
Statistical Analyses for Secondary Efficacy Variables
For continuous variables, including change from baseline analyses, treatment group 
differences will be analyzed as appropriate using analysis of covariance (ANCOVA) 
models with treatment group as the main effect and baseline score as a covariate.  
Additionally, the mixed model repeated measures (MMRM) method for change from 
baseline to each post-baseline assessment during the Treatment Period will be conducted 
as appropriate.
Categorical data will be analyzed using CMH test, chi-square, Fisher's exact test or 
logistics regression as appropriate.
For the ranked secondary variables, a fixed-sequence approach will be applied to maintain 
the family-wise type I error rate.
Analysis details will be specified in the SAP.
8.1.7.2.1
Reduction of Bleeding
The percentage of subjects with MBL volume < 80 mL and 50% or greater reduction in 
MBL volume from baseline during the Treatment Period will be summarized for each 
treatment group and compared between each elagolix treatment group and the placebo 
group.  Also, the individual component (the percentage of subjects with MBL volume of 


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< 80 mL as well as the percentage of subjects with ≥ 50% in MBL volume reduction from 
baseline) will be summarized. 
The change and percent change from baseline in MBL volume to each month and to the 
Final Month will be summarized for each treatment group and compared between each 
elagolix treatment group and the placebo group.
The percentage of subjects with suppression of bleeding and the percentage of subjects 
with amenorrhea will be summarized by monthly intervals throughout the Treatment 
Period.  For each subject, suppression of bleeding will be defined as having no days of 
bleeding (spotting is allowed) during a 28-day interval.  Amenorrhea is defined as having 
no days of bleeding or spotting during a 28-day interval.  In addition, the cumulative 
percentage of subjects with suppression of bleeding and the cumulative percentage of 
subjects with amenorrhea will be compared between each elagolix treatment group and 
the placebo group.
The change and percent change from baseline to monthly intervals in number of bleeding 
days will be summarized by treatment group.  In addition, the change from baseline in 
total number of sanitary products will be summarized and compared between each 
elagolix treatment group and the placebo group.
8.1.7.2.2
Hemoglobin Concentration
The change and percent change from baseline in hemoglobin concentration will be 
summarized monthly for each treatment group and compared between each elagolix 
treatment group and the placebo group.  Shift tables from baseline to values over time will 
be summarized by anemia status.
8.1.7.2.3
Fibroid and Uterine Volume
The change and percent change from baseline in primary fibroid volume, total fibroid 
volume and uterine volume will be summarized for each treatment group and compared 
between each elagolix treatment group and the placebo group.


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The percentage of subjects with ≥ 25% reduction in total and primary fibroid volume and 
uterine volume will be summarized for each treatment group and compared between each 
elagolix treatment group and the placebo group.
8.1.7.2.4
Quality of Life
UFS-QoL
Improvement in quality of life will be assessed on the UFS-QoL Questionnaire (4-week 
recall).  The change from baseline will be calculated and summarized for each of the 
UFS-QoL subscales (symptom severity, concern, activities, energy/mood, control, 
self-conscious and sexual function) and the UFS-QoL total.  
EQ-5D-5L
The number and percentage of subjects with answers in each level for Mobility, Self-care, 
Usual activities, Pain/Discomfort, Anxiety/Depression will be summarized by treatment 
group.  
The change from baseline in subject health status will be summarized for each treatment 
group and compared between each elagolix treatment group and the placebo group.
8.1.7.2.5
Patient Global Impression of Change (PGIC)
PGIC for Menstrual Bleeding (PGIC-MB):
PGIC-MB is to assess the change in subjects' severity of menstrual bleeding.  The number 
and percentage of subjects in each response category based on PGIC-MB will be 
summarized by treatment group.  
PGIC for Non-Bleeding Uterine Fibroid Symptoms (PGIC-NBUFS):
PGIC-NBUFS is to assess the severity of overall non-bleeding symptoms and the severity 
of specific non-bleeding uterine fibroid symptoms.  The number and percentage of 


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subjects in each response category of each question based on PGIC-NBUFS will be 
summarized by treatment group.  
8.1.7.2.6
Work Productivity and Activity Questionnaire (WPAI)
The change from baseline for the WPAI will be summarized for each treatment group and 
compared between each elagolix treatment group and the placebo group.
8.1.7.2.7
Health Care Resource Utilization Questionnaire (HCRU) 
HCRU will be summarized for each treatment group.
8.1.7.2.8
Multiple Comparisons
The primary efficacy comparison will be between the elagolix 300 mg BID plus 
E2/NETA group and the placebo group.  The comparison between the elagolix 300 mg 
BID alone group and the placebo group will be used as a reference and to examine the 
validity of the study design.  Therefore, no multiplicity adjustment is necessary.  The 
order of ranked secondary endpoints will be specified in the SAP.
8.1.8
Safety
8.1.8.1
General Considerations
All randomized subjects who took at least one dose of the study drug will be included in 
the safety analyses.
For continuous variables, descriptive statistics (mean, standard deviation, median, 
minimum and maximum) will be summarized by treatment group.  The treatment group 
differences in change and percent change from baseline will be analyzed using a one-way 
ANOVA with treatment as the main effect unless otherwise specified.  
Categorical data will be summarized with frequencies and percentages by treatment 
group.  Chi-square test or Fisher's exact test (or its generalization to r × c tables) will be 


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used to analyze treatment group differences for qualitative categorical variables unless 
otherwise specified.
Missing safety data will not be imputed.
Analysis details will be specified in the SAP.
8.1.8.2
Adverse Events
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary.  Treatment-emergent adverse events (TEAEs) will be 
summarized for each treatment group.  TEAEs are defined as AEs with a start date on or 
after the first dose of the study drug and within 30 days of the last dose of the study drug.  
AEs starting more than 30 days following discontinuation of the study drug will not be 
included in the summaries of TEAEs.  AEs starting more than 30 days following 
discontinuation of the study drug will be summarized separately as Post-Treatment AEs.
When summarizing TEAEs by relationship or severity, if a subject has an event with 
unknown severity or relationship, then the subject will be counted in the 
severity/relationship category of "unknown," even if the subject has a second occurrence 
of the same event with a severity/relationship present.  The only exception is if the subject 
has a second occurrence of the same event with the most extreme severity (i.e., "severe") 
or a relationship category of "reasonable possibility."  In this case, the subject will be 
counted under these most extreme severity/relationship categories.
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


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●
Any event and by system organ class and preferred term for events resulting in 
study drug discontinuation
●
Any event and by system organ class and preferred term for serious events
●
Any event and preferred term for AESI's (e.g., hypoestrogenic adverse events)
The Post-Treatment AEs will be summarized in a similar manner as the TEAEs described 
above.
8.1.8.3
Analysis of Laboratory Data and Vital Signs
Changes from the baseline to each visit in continuous laboratory and vital sign parameters 
will be summarized by treatment group.  Treatment group differences for changes from 
baseline will be analyzed using a one-way ANOVA with treatment as the main effect.
Laboratory values will be categorized as low, normal or high based on normal ranges of 
the central laboratory used in this study.  Low or high laboratory values will be flagged in 
the data listings.  
Analysis details will be specified in the SAP.
8.1.8.4
Bone Mineral Density
The within-group percent change from baseline to Month 6 in BMD will be summarized 
for each treatment group with mean, standard deviation, median and two-sided 95% 
confidence interval.  The between-group differences in percent change from baseline to 
Month 6 in BMD will be summarized with mean and standard error.  The percent change 
from baseline to Month 6 in BMD will be compared between each elagolix treatment 
group and the placebo group as well as between the elagolix 300 mg BID group and the 
elagolix 300 mg BID plus E2/NETA group using (ANCOVA) with treatment as the main 
effect and baseline BMD as a covariate.  Two-sided 95% confidence intervals will be 
constructed for the between-group differences in percent change from baseline to Month 6 
in BMD.


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The number and percentage of subjects with categorized percent change from baseline in 
BMD (e.g., ≤ –3%, ≤ –5%, or ≤ –8%) will be summarized for each treatment group and 
comparison between each elagolix treatment  group and the placebo group as well as 
between the elagolix 300 mg BID group and the elagolix 300 mg BID plus E2/NETA 
group will be made.
In addition, to evaluate BMD change, the percent change from baseline to Month 6 in the 
Treatment Period using aggregated data from two pivotal studies (Studies M12-815 and 
M12-817) will be compared between each elagolix treatment group and the placebo group 
as well as between the elagolix 300 mg BID group and the elagolix 300 mg BID plus 
E2/NETA group using ANCOVA with treatment as the main effect and baseline BMD as 
a covariate.  Two-sided 95% confidence intervals will be constructed for the differences 
in percent change from baseline to Month 6 in BMD.
Analysis details will be specified in the SAP.
8.1.8.5
Post-Treatment Analysis of Menstruation
The time of the first post-treatment menses onset in days relative to the date of the last 
dose of the study drug will be calculated.  
8.1.8.6
Endometrial Biopsy
The number and percentage of subjects in each category of endometrial biopsy result will 
be summarized.
8.1.8.7
Pelvic Ultrasound
The number and percentage of subjects with complex ovarian cysts > 3.5 cm, as well as 
the number and percentage of subjects with simple ovarian cysts > 5 cm will be 
summarized for each treatment group at each time point.  The change from baseline to 
Month 6 in endometrial thickness will be summarized for each treatment group.


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8.1.8.8
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS will be summarized by treatment group according to published scoring 
guidelines.
8.1.9
Pharmacokinetic/Pharmacodynamic Analysis
Plasma concentrations of elagolix and norethindrone and serum concentrations of 
estradiol, progesterone, luteinizing hormone and follicle stimulating hormone will be 
listed for each subject by visit day and dose regimen, as applicable.  Pharmacokinetic data 
may be combined with data from other studies in women.  Exposure-response analyses 
may be conducted as appropriate.  For example, if pharmacokinetic exposures are 
estimated, analyses may be conducted to assess the relationship of pharmacokinetic 
parameters and estradiol and progesterone concentrations, versus efficacy and safety.  
Additional analyses will be performed if useful and appropriate.
8.2
Determination of Sample Size
Approximately 400 subjects will be randomized in a 1:1:2 ratio to placebo (N = 100), 
elagolix 300 mg BID (N = 100), or elagolix 300 mg BID plus E2/NETA (N = 200).  The 
sample size will provide at least 90% power to detect a difference between the elagolix 
300 mg BID plus E2/NETA group and the placebo group in the percentage of subjects 
with MBL volume < 80 mL during the Final Month (the last 28 days of treatment) and 
50% or greater reduction in MBL volume from baseline to the Final Month under the 
assumption of responder rates being 60% and 30% for elagolix 300 mg BID plus 
E2/NETA and placebo, respectively.  The sample size determination is primarily driven 
by the need for a sufficient number of patients for the safety database.  The above sample 
size was calculated using nQuery advisor 7.0.


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9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to ICH GCP.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.


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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 and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent form will be given to the subject and the original will be placed in 
the subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
Pharmacogenetic samples (DNA and RNA) will only be collected if the subject has 
voluntarily signed and dated a separate pharmacogenetic informed consent, approved by 
an IRB/IEC, after the nature of the testing has been explained and the subject has had an 
opportunity to ask questions.  The separate pharmacogenetic informed consent must be 
signed before the pharmacogenetic testing is performed.  If the subject does not consent to 
the pharmacogenetic testing, it will not impact the subject's participation in the study.
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 


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media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.
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, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.


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Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
Patient reported data must be completed for each subject screened/enrolled in this study
and entered into the eCRFs.  
11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
Prior to enrolling any subject in the study, a Site 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 
protocol and regulations.  In addition, ongoing review of the data will be conducted by a 
physician or representative at AbbVie.
Data entered into eCRFs will be electronically transferred to AbbVie and imported into 
the database using validated software throughout the study.  Computer logic checks will 
be run to identify such items as inconsistent study dates.  Any necessary corrections will 
be made to the eCRF.


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Routine hematology, serum chemistry, lipid and endocrine panels, urinalysis, Pap smears 
and endometrial biopsies will be analyzed using a central laboratory.  The data from these 
analyses will be electronically transferred from the central laboratory to the study 
database.
A review of all laboratory results will be conducted by a physician and clinical review 
team at AbbVie, the AbbVie monitors (or their representatives), the investigator and other 
appropriate personnel from AbbVie.
Alkaline hematin analysis will be performed by Alkaline Hematin central laboratory.  The 
data from these analyses will be electronically transferred from the Alkaline Hematin 
central laboratory to the study database.
PK and PD samples will be analyzed by the Drug Analysis Department at AbbVie and 
data will be loaded into the study database.
Pelvic ultrasound, SIS and MRI scans will be read by the Central Imaging Vendor.  The 
results of these scans will be electronically transferred from the Central Imaging Vendor 
to the study database.
DXA scans will be read by a Central DXA Reader.  The results of these scans will be 
electronically transferred from the Central DXA Reader to the study database.
12.0
Use of Information
All information concerning elagolix and AbbVie operations, such as AbbVie patent 
applications, formulas, manufacturing processes, basic scientific data, or formulation 
information, supplied by AbbVie and not previously published is considered confidential 
information.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of elagolix. 
This information may be disclosed as deemed necessary by AbbVie to other clinical 


Elagolix (ABT-620)
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investigators, other pharmaceutical companies, and to governmental agencies.  To allow 
for the use of the information derived from this clinical study and to ensure complete and 
thorough analysis, the investigator is obligated to provide AbbVie with complete test 
results and all data developed in this study and to provide direct access to source 
data/documents for study-related monitoring, audits, IEC/IRB review, and regulatory 
inspection.
This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie, and shall not be used except in 
the performance of this study.
The investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study, including each subject's name, subject number, address, phone 
number and emergency contact information.  This list will be maintained at the study site 
with other study records under adequate security and restricted access, and will not be 
retrieved by AbbVie.
Any pharmacogenetic research that may be done using DNA and RNA samples from this 
study will be experimental in nature and the results will not be suitable for clinical 
decision making or patient management.  Hence, neither the investigator, the subject, nor 
the subject's physician (if different from the Investigator) will be informed of individual 
subject pharmacogenetic results, should analyses be performed, nor will anyone not 
directly involved in this research.  Correspondingly, genetic 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 pharmacogenetic 
information from this study may be used in scientific publications or presented at medical 
conventions.  Pharmacogenetic information will be published or presented only in a way 
that does not identify any individual subject.


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13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The investigator must retain any records related to the study according to local 
requirements.  If the investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report.  The 
end-of-study is defined as the date of the last subject's last visit.


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


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


Elagolix (ABT-620)
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11.
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the 
new five-level version of EQ-5D (EQ-5D-5L).  Qual Life Res.  
2011;20(10):1727-36.
12.
ACR BI-RADS Atlas Fifth Edition.  p. 15-8.  Available from:  
https://www.acr.org/~/media/ACR/Documents/PDF/QualitySafety/Resources/BIR
ADS/01-Mammography/02--BIRADS-Mammography-Reporting.pdf?la=en.


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


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


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


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Appendix C.
Study Activities – Washout, Screening and Treatment Periods and Post-Treatment Follow-Up Period
Procedure
Washout (If Applicable) 
and Screening Period
Treatment Perioda
Washout 
Period
Screen 
Visit
Cycle 
1 – 3‡
PCVb
Day 
1c
Month 
1
Month 
2
Month 
3
Month 
4
Month 
5
Month 
6
PCVb,d
Unsch 
Visit
PD 
(if 
appl)
Informed Consent
X
X*
Medical/Social History
X
X*
Xe
Gynecological/Obstetrical and Uterine 
Fibroid History
X
X*
Xe
Gynecological (External Genitalia, Pelvic 
and Breast) Examinationf
X
X
X
Pap Test
X
Endometrial Biopsy
Xg
Xg,%,±,&
Xg,h
Complete Physical Examination; Height (H); 
Weight (W)
X 
(H, W)
X* 
(H, W)
Xe
(W)
X 
(W)
X 
(W)
Symptom-Directed Physical Examination
X*
X
X
X
X
X
Vital Signs (Temp, BP, Pulse, RR)
X
X
X
Xe
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram (ECG)
X
X
X
Mammogram
X∞
Pelvic Ultrasound@:  TAU, TVU
Xl
X*
X
X
X%,&
Xh
Saline Infusion Sonohysterography@ (SIS)
Xg
MRI (Subset of Subjects)@
Xj,k
Xk
X%
Xh
DXA Scan
X
X% ±
Xi


Elagolix (ABT-620)
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Procedure
Washout (If Applicable) 
and Screening Period
Treatment Perioda
Washout 
Period
Screen 
Visit
Cycle 
1 – 3‡
PCVb
Day 
1c
Month 
1
Month 
2
Month 
3
Month 
4
Month 
5
Month 
6
PCVb,d
Unsch 
Visit
PD 
(if 
appl)
Dispense Sanitary Products and Collection 
Kit (Keg, Collection Bags, etc.)
X
X
X
X
X
X
X
X
X^
X
X
Collect and return Sanitary Products; draw 
venous blood sample 
X
Xm
Xm
Xm
Xm
Xm
Xm
Xm
X
X
Clinical Safety Labs:  Chemistry, Lipid 
Panel and Hematology
X
Xe
X
X
X
X
X
X
X
Clinical Safety Labs: Creatinine 
Phosphokinase
X
X
X
X
X
Clinical Safety Labs:  Urinalysis
X
Xe
X
X
X
Apolipoprotein A and B 
Xe
X
X
X
Serology (Hepatitis and HIV Screens)
X
Endocrine:  FSH and LH
Xn
Xe
Xo
Xo
Xo
Xo
Xo
Xo
Xo
Endocrine:  Reflexive TSH and thyroxine-
binding globulin (TBG)
X
Xo,p
Xo,p
Pharmacodynamic Sample:  Serum Estradiol 
(E2) and Progesterone (P)
Xe
Xo
Xo
Xo
Xo
Xo
Xo
Xo
Pharmacokinetic Sample (PK):  Elagolix and 
NETA Plasma Concentration
Xq
Xo
Xo
Xo
Xo
Xo
Xo
Xo
Pharmacogenetic DNA Sample (Optional 
based on Subject consent)
Xo


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Procedure
Washout (If Applicable) 
and Screening Period
Treatment Perioda
Washout 
Period
Screen 
Visit
Cycle 
1 – 3‡
PCVb
Day 
1c
Month 
1
Month 
2
Month 
3
Month 
4
Month 
5
Month 
6
PCVb,d
Unsch 
Visit
PD 
(if 
appl)
Pharmacogenetic RNA Sample (Optional 
based on Subject consent)
Xo
Xo
Xo
Xo
Xo
Urine Pregnancy Testsr
X
Xs
X
Xe
X
X
X
X
X
Xs
X
Xs
Serum Pregnancy Tests
X
Xe
X
X
Contraception Counseling/Dispense 
Contraceptives as necessary
X
X
X
X
X
X
X
X
X
X
X
X
Birth Control Attestation
Xe
X
X


Elagolix (ABT-620)
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Procedure
Washout (If Applicable) 
and Screening Period
Treatment Perioda
Washout 
Period
Screen 
Visit
Cycle 
1 – 3‡
PCVb
Day 
1c
Month 
1
Month 
2
Month 
3
Month 
4
Month 
5
Month 
6
PCVb,d
Unsch 
Visit
PD 
(if 
appl)
PRO 
Questionnaires
Reason for Study 
Participation
Xe
EQ-5D-5L
Xe
X
X
UFS-QoL
Xe
X
X
X
PSQ
Xe
Work Productivity and 
Activity Questionnaire 
(WPAI)
X
X
UBQt
X
X
X
X
X
X
X
X
X
PGIC-MB
X
X
X
X
PGIC-NBUFS
X
X
X
X
Health Care Resource 
Utilization (HCRU)
X
X
X
X
X
X
X
C-SSRS –
Baseline/Screening
X
Xe
C-SSRS – Since Last Visit
X
X
X
X
X
X
X
Randomization
X
Interactive Response Technology (IRT)
X
X
X#
X
X
X
X
X
X
X
X
Drug Dispense
X
X
X
X
X
X
Xu
Drug Accountability
X
X
X
X
X
X
X
Adverse Event Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X


Elagolix (ABT-620)
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Procedure
Washout (If Applicable) 
and Screening Period
Treatment Perioda
Washout 
Period
Screen 
Visit
Cycle 
1 – 3‡
PCVb
Day 
1c
Month 
1
Month 
2
Month 
3
Month 
4
Month 
5
Month 
6
PCVb,d
Unsch 
Visit
PD 
(if 
appl)
Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
Delay in Roll-over Into Extension Study
Xv
‡
If the subject does not demonstrate blood loss > 80 mL during either Screening Cycle 1 or 2, she may qualify for a third cycle assessment of blood loss (Table 5).  If 
required, the subject will collect sanitary products for a third menstrual cycle and will visit the site for a Screening Cycle 3 Product Collection Visit.
*
If performed during Washout, do not repeat during Screening Period.  If a Complete Physical Examination was performed in Washout, only a Symptom-Directed Physical 
Examination will be performed in Screening.
%
Recommend performing approximately 15 days prior to Month 6 visit.
±
Results required to determine eligibility into the extension study.
&
Results required if endometrial biopsy at Month 6 cannot be performed or results are insufficient.
∞
Only in subjects ≥ 39 years of age at the time of randomization, unless the mammogram was performed within 3 months prior to Screening.
^
Sanitary products and Sanitary product collection supplies will be dispensed to subjects who are entering the extension study.  Subjects will be instructed to continue 
collecting sanitary products on days with menstrual bleeding or spotting throughout the Treatment Period of the extension study.
@
Subjects with a finding of polyp on pelvic ultrasound or MRI during the Treatment Period will undergo evaluation per standard of care which may include an SIS.  
#
Screening Cycle 2 Product Collection Visit will be registered in IRT for the first subject who completes the Screening Cycle 2 Product Collection Visit to activate drug 
shipment to the study site.
a.
Refer to Table 1, Visit and Assessment Windows, for allowable visit and assessment-specific windows during the Treatment Period.
b.
Visit to occur approximately 5 days after cessation of bleeding or spotting.
c.
Day 1 (Randomization) Visit to occur between Days 1 – 10 of the first day of menses (first day of menses is the first day with full menstrual flow).
d.
A Product Collection Visit is only necessary if a monthly visit is not scheduled to occur within approximately 5 days after cessation of bleeding or spotting.
e.
To either be updated or performed or collected prior to study drug administration.
f.
Screening breast examination may be omitted when, based on local or country guidelines, breast examinations are routinely or only conducted by breast specialists.  
g.
Subject must have a confirmed negative urine pregnancy test within 24 hours prior to the SIS and endometrial biopsy.  


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h.
Not required if subject prematurely discontinued prior to Treatment Month 3, i.e., received < 3 months of study drug.
i.
DXA scan is not required if subject prematurely discontinued prior to Treatment Month 3, i.e., received < 3 months of study drug (unless the premature discontinuation was 
related to BMD decrease or the occurrence of a fracture).
j.
Subjects who have SIS images which are unable to fully assess the endometrial cavity, may undergo an MRI for further evaluation in Screening.
k.
Subjects in the MRI subset who had an MRI during Screening will not repeat the MRI at Day 1. If the Day 1 MRI cannot be performed within the specified assessment 
window (Table 1), the MRI should not be performed and the subject will not participate in the MRI Subset.  
l.
Ultrasound may be performed prior to Washout (after informed consent is signed) to establish the presence of a qualifying fibroid(s) or uterine volume to avoid subjects from 
undergoing a lengthy washout of hormonal medications unnecessarily.
m.
If menstrual bleeding or spotting stops within approximately 5 days of a scheduled monthly visit, subject will return sanitary products at the scheduled monthly visit and a 
venous blood sample will be obtained.  The venous blood sample will be sent with collected products to the Alkaline Hematin laboratory.
n.
FSH only.
o.
Pharmacodynamic (E2 and P), Endocrine (FSH, LH, TBG), Pharmacokinetic (elagolix and NETA) and Pharmacogenetic (DNA and RNA) samples can be drawn at any time 
during the visit.
p.
TBG only.
q.
PK sample on Day 1 collected approximately 1 hour post study drug dosing.
r.
Study drug must not be dispensed if the subject has a positive urine pregnancy test result at a visit during the Treatment Period. A positive urine pregnancy test result must be 
confirmed with a quantitative serum pregnancy test.  For any subject who has a positive serum pregnancy test result, a TVU must be conducted as early as possible in the first 
trimester in order to assess the gestational age and estimated due date.  The subject will be discontinued from the study at the point the pregnancy was confirmed.
s.
Dispense home pregnancy test kit for subjects to self-administer during the Screening Period, prior to SIS and endometrial biopsy, if applicable, and for the Phone Visits 
during the Post Treatment Follow-Up Period.
t.
The UBQ is to be completed by Site Staff at a scheduled monthly visit, PCV or Unscheduled Visit only if the subject did not return a sanitary product collection keg at the 
visit.
u.
Subjects may require dispensation of additional study drug kits at the Month 6 visit if results from procedures are not available to determine eligibility into the extension 
study.
v.
Unscheduled Visits:  For delays in rollover into the Extension Study (Study M12-816), refer to Section 5.5.4, Table 6, for further details on assessments to be performed.


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Study Activities – 12-Month Post-Treatment Follow-Up Period 
12-Month Post-Treatment Follow-Up Perioda
PCV
PD#
Month 
1
Month 
2
Month 
3
Month 
4
Month 
5
Month 
6*
Month 
7
Month 
8
Month 
9
Month 
10
Month 
11
Month 
12
Phone Contact/Phone Visit
X
X
X
X
X
X
X
Pelvic Ultrasound@:  TVU, TAU
Xb
Xb
Xb
MRI (Subset of Subjects)@
Xb
Xb
Complete Physical Examination:  
including weight (W)
X (W)
X 
(W)
Symptom Directed Physical 
Examination
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
DXA Scan
Xc
Xc
Xc
Clinical Safety Labs:  Chemistry, 
Hematology, Lipid Panel and 
Urinalysis
X
X
X
X
Xd
X
Apolipoprotein A and B
X
X
X
X
X
X
Urine Pregnancy Teste
X
Xf
X
Xf
Xf
X
Xf
Xf
X
Xf
Xf
X
X
X
Serum Pregnancy Test
X
X
Return sanitary products for the 
first menses in Post-Treatment
Xg
Contraception Counseling/Dispense 
Contraceptivesh
X
X
X
X
X
X
X
X
X
X
X
X
X
PRO 
Questionnaires
UBQ (as 
applicable)
Xi
Xi
Xi
Xi
Xi
Xi
Xi
Xi
Xi
Xi
Xi
Xi
Xi
Xi
Adverse Event Monitoring
X
Xj
X
X
X
X
X
X
X
X
X
X
X
X


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12-Month Post-Treatment Follow-Up Perioda
PCV
PD#
Month 
1
Month 
2
Month 
3
Month 
4
Month 
5
Month 
6*
Month 
7
Month 
8
Month 
9
Month 
10
Month 
11
Month 
12
Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
*
Subjects who prematurely discontinue from the Treatment Period prior to the Month 3 Study Visit, i.e., who received < 3 months of study drug, will complete the study at the 
Post-Treatment Follow-up Month 6 visit.
#
Subjects who prematurely discontinue after the Post-Treatment Month 6 visit, should only complete procedures and assessments which are required for the Post-Treatment 
Follow-up Month 12 visit.
@
Subjects with a finding of polyp on pelvic ultrasound or MRI at during the Post-Treatment Period will undergo evaluation per standard of care which may include an SIS.
a.
Refer to Table 1, Visit and Assessment Windows, for allowable visit and assessment-specific windows during the Post-Treatment Period.
b.
Not required if performed within 2 months prior to PD or if subject prematurely discontinued prior to Treatment Month 3, i.e., received < 3 months of study drug during the 
Treatment Period.
c.
DXA scan is not required if subject prematurely discontinued prior to Treatment Month 3, i.e., received < 3 months of study drug during the Treatment Period (unless the 
premature discontinuation was related to BMD decrease or the occurrence of a fracture).
d.
Safety labs at Post-Treatment Follow-up Month 12:  Lipid Panel only.
e.
A positive urine pregnancy test result must be confirmed with a quantitative serum pregnancy test.  For any subject who has a positive serum pregnancy test result, a TVU 
must be performed during the first trimester of pregnancy to assess the gestational age and estimated date of delivery.  The site will immediately inform the subject to 
discontinue study drug and the subject will be discontinued from the study at the point the pregnancy is confirmed.
f.
Home pregnancy test kit will be self-administered at home by the subject.
g.
Subject should return sanitary products within approximately 5 days after cessation of bleeding or spotting from the first menses with full menstrual flow in the Post-
Treatment Follow-up Period at a Product Collection Visit or a scheduled site visit. The venous blood sample will be sent with collected products to the Alkaline Hematin 
laboratory.  If the subject misses collecting sanitary products for her first full menses, she will be required to collect sanitary products for her next full menses.  
h.
Subjects are required to continue the use of two forms of non-hormonal birth control throughout the Post-Treatment Follow-Up Period (After Month 2 in the Post-Treatment 
Follow-Up Period, provided the subject returned to menses, the subject may begin the use of hormonal contraception in place of non-hormonal birth control).
i.
Post-Treatment UBQ will only be completed if Subject has not returned sanitary products for her first full menses in the Post-Treatment Period at the time of the Phone or Site 
visit.  Once a Subject returns sanitary products from her first full menses in the Post-Treatment Follow-up Period, the Post-Treatment UBQ no longer needs to be completed.
j.
An adverse event of amenorrhea will be reported for subjects who do not return to menses by the Post-Treatment Follow-up Month 2 Phone Visit and the adverse event will 
be followed until resolution.


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Appendix D.
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
Reference:  ACR BI-RADS Atlas Fifth Edition.12


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Appendix E.
Reason for Study Participation – SAMPLE
We would like to ask you why you have agreed to participate in this clinical research 
study.  I am participating in this research study because (Please check one):
☐I would like to avoid surgery (hysterectomy)
☐I would like to delay surgery (hysterectomy)
☐I would like to avoid other surgeries or procedures (such as myomectomy or 
uterine artery embolization)
☐I would like to delay other surgeries or procedures (such as myomectomy or 
uterine artery embolization)
☐I prefer taking medication rather than surgery or procedures until I enter 
menopause when my symptoms, such as heavy menstrual bleeding, should 
improve and gradually go away
☐I would like to get pregnant after participating in the study
☐I don't know why
☐I don't want to answer
☐Other:  _________________________________________


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Appendix F.
Physician Surgery Questionnaire Version 1.0 – SAMPLE
Based on this subject's current presentation/profile as it relates to uterine fibroids, is 
surgery or surgical procedure one of the potential treatment options you would consider? 
 Yes 
 No
If yes, which surgery or surgical procedure would you consider?  Check all that apply.
 Hysterectomy
 Myomectomy
 Uterine Artery Embolization
 Other ____________


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Appendix G.
Uterine Bleeding Questionnaire(UBQ) – Treatment Period –
SAMPLE
(To be Completed by Site Staff)
Version 2.0
During site visits in the Treatment Period, subjects who did not return a Sanitary Product 
Collection Keg (for menstrual blood loss analysis) will be asked whether they had any 
uterine bleeding or spotting since their last study visit.
1.
Did the subject have any bleeding or spotting since her last study visit?
☐No    ☐Yes
If yes, why were sanitary products not collected/returned?  (Please select 
one response)
☐  Subject only had spotting that did not require the use of sanitary products*
☐  There was no visible blood on sanitary products*
☐  Subject forgot to/did not collect*
☐  Subject/Site discarded the sanitary products*
☐  Subject is still bleeding/spotting; will return when bleeding/spotting 
complete
☐  Subject collected sanitary products and did not bring them to this visit; will 
return sanitary products at a later date
☐  Other
* If this response is checked, remind subject to collect and return all used or worn sanitary 
products with or without visible blood.


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


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Appendix I.
Uterine Fibroid Symptom Quality of Life Questionnaire (UFS-QoL) 
– SAMPLE


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


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


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


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


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


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


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Appendix N.
Columbia-Suicide Severity Rating Scale (C-SSRS) –
Baseline/Screening – SAMPLE


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


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


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Appendix Q.
Health Care Resource Utilization Questionnaire (HCRU) 
Version 1.0 – SAMPLE
(To be completed by Site Staff)
Non-Study Visits for Routine/General Health Care
Complete Version 1.0 for Subjects who randomized under Original Protocol
Instructions to Site Staff:  At each scheduled monthly visit in the Treatment Period, please 
ask if the subject saw a Non-Study Health Care Practitioner (HCP) since her last 
scheduled monthly visit for a routine/general health care visit that is not associated with 
an adverse event.  
Only record routine/general health care visits with Non-Study HCPs below.
Record Non-Study HCP Visits associated with an adverse event on the Adverse Event 
form only.  Do not record below.  
1. Since the Subject's last scheduled monthly study visit, has she seen a non-study
Health Care Practitioner (e.g., Physician, Nurse Practitioner, Physician Assistant, Dentist, 
Physical Therapist) for a routine/general health care visit?  ☐No  ☐  Yes
If Yes, please complete questions 2 and 3 below to indicate the type(s) of Non-Study
Physician(s) seen and the number of times each Non-Study Physician was seen.


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2.   What type(s) of Non-Study Physician Specialty was 
the Subject seen by?  (Check all that apply)
3.  How many times was the subject 
seen by each Non-Study HCP
AUDIOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
ALLERGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
CARDIOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
DENTIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
DERMATOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
ENDOCRINOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
ENT
☐
☐1  ☐2  ☐3  ☐4  ☐5
FAMILY PRACTITIONER
☐
☐1  ☐2  ☐3  ☐4  ☐5
GASTROENTEROLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
GYNECOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
HEMATOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
HEPATOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
IMMUNOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
INFECTIOUS DISEASE SPECIALIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
INTERNAL MEDICINE SPECIALIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
INTERNIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
MEDICAL GENETICIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
NEPHROLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
NEUROSURGEON
☐
☐1  ☐2  ☐3  ☐4  ☐5
OPTHAMOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
ORTHOPEDIC SURGEON
☐
☐1  ☐2  ☐3  ☐4  ☐5
PHYSIATRIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
PLASTIC SURGEON
☐
☐1  ☐2  ☐3  ☐4  ☐5
PODIATRIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
PSYCHIATRIST 
☐
☐1  ☐2  ☐3  ☐4  ☐5
PSYCHOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
PULMONOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
RHEUMATOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
SURGEON
☐
☐1  ☐2  ☐3  ☐4  ☐5
UROLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
OTHER PHYSICIAN (specify type:  
________________________
☐
☐1  ☐2  ☐3  ☐4  ☐5


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Appendix R.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes
Section 1.2  Synopsis
Subsection Screening Period
First sentence previously read:
Following informed consent (if Washout was not required), subjects will enter into a 2.5-
to 3.5-month Screening Period to establish eligibility based on inclusion and exclusion 
criteria.
Has been changed to read:
Following informed consent (if Washout was not required), subjects will enter into an 
approximate 2.5- to 3.5-month Screening Period to establish eligibility based on inclusion 
and exclusion criteria.
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Definition of Terms
"Screening Period," first sentence previously read:
The 2.5 to 3.5 month period prior to randomization on Day 1, when screening procedures 
are performed to establish eligibility.  
Has been changed to read:
The approximate 2.5 to 3.5 month period prior to randomization on Day 1, when 
screening procedures are performed to establish eligibility.  
Section 3.2.3  Pregnancy in Elagolix Studies
Subsection Efficacy in Phase 2 Uterine Fibroid Studies
Fifth paragraph, second sentence previously read:
The study consisted of a 2.5- to 3.5-month Screening Period, a 6-month Treatment Period, 
and a 6-month Post-Treatment Follow-Up Period.  


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Has been changed to read:
The study consisted of an approximate 2.5- to 3.5-month Screening Period, a 6-month 
Treatment Period, and a 6-month Post-Treatment Follow-Up Period.  
Section 5.1  Overall Study Design and Plan:  Description
Subsection Screening Period
First paragraph, first sentence previously read:
Subjects who do not require washout will enter directly into the 2.5- to 3.5-month 
Screening Period and will provide written informed consent before any study-related 
procedures are performed.
Has been changed to read:
Subjects who do not require washout will enter directly into the approximate 2.5- to 
3.5-month Screening Period and will provide written informed consent before any study-
related procedures are performed.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Screening Period
Last paragraph previously read:
Subjects who screen fail may be re-screened on a case-by-case basis after consulting the 
AbbVie TA MD for approval.
Has been changed to read:
Subjects who screen fail may be re-screened into the Study M12-817 on a case-by-case 
basis after consulting the AbbVie TA MD for approval.
Additionally, for subjects who underwent screening in the replicate pivotal 
Study M12-815 study who were not Randomized due to enrollment closure in that study, 
may have an opportunity to transfer to the Study M12-817 with TA MD approval.  Tests 
and procedures conducted in Study M12-815 will be transferred with the subject to 
Study M12-817 for the subject's continued participation in screening and will be used for 


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204
eligibility to be Randomized into Study M12-817 without needing to repeat procedures 
unless otherwise indicated.
Section 5.3.1.1  Study Procedures
Fourth paragraph, first sentence previously read:
It is recommended that the Ultrasound, MRI (if applicable), DXA scan and endometrial 
biopsy for the Month 6 Visit be conducted within approximately 15 days prior to the 
scheduled Month 6 Visit to allow the results to be available from the central vendors in 
order to determine eligibility for inclusion into the extension study (Study M12-816).  
Has been changed to read:
It is recommended that the pelvic ultrasound, MRI (if applicable), DXA scan and 
endometrial biopsy for the Month 6 Visit be conducted within approximately 15 days 
prior to the scheduled Month 6 Visit to ensure the images are received and acceptable for 
review by the central vendor.  
Section 5.3.1.1  Study Procedures
Subsection Central Imaging Procedures
Fifth paragraph, first sentence previously read:
During the Treatment and Post-Treatment periods, the ICL may issue a report if any 
significant changes are observed that may affect subject safety during the study.  
Has been changed to read:
The ICL will only issue a report for pelvic ultrasound at Treatment Month 6.  A report for 
all other Treatment and Post-Treatment timepoints for pelvic ultrasound and MRI will 
only be issued if any significant changes are observed that may affect subject safety 
during the study.  


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Section 5.3.1.1  Study Procedures
Subsection Central Imaging Procedures
Last paragraph previously read:
It is recommended that the pelvic ultrasound and MRI (if applicable) performed for the 
Month 6 Visit are conducted approximately 15 days prior to the scheduled Month 6 Visit 
to ensure the results are received from the central vendor in order to determine eligibility 
for inclusion into the extension study.  If the results are not available by the Month 6 visit 
of the Treatment Period, refer to Section 5.4.4 for instructions until results are available to 
determine eligibility into the extension study.
Has been changed to read:
It is recommended that the pelvic ultrasound and MRI (if applicable) performed for the 
Month 6 Visit are conducted approximately 15 days prior to the scheduled Month 6 Visit 
to ensure the images are received and acceptable for review by the central vendor.  The 
central pelvic ultrasound report is only required prior to rollover in the event the Month 6 
endometrial biopsy cannot be performed or biopsy results are insufficient.  In this case the 
central pelvic ultrasound is required to determine if the endometrial thickness is ≥ 4 mm 
in which case the subject needs a repeat biopsy prior to rollover (see Section 5.3.1.1
Endometrial Biopsy).  If the results are not available by the Month 6 visit of the Treatment 
Period to determine need for a repeat endometrial biopsy, refer to Section 5.4.4 for 
instructions until results are available to determine eligibility into the extension study.  
Section 5.3.1.1  Study Procedures
Subsection Qualifying Uterine Fibroids:
Second paragraph, last bullet previously read:
Multiple small fibroids with a total uterine volume of ≥ 200 cm3 to ≤ 2,500 cm3 as 
documented by centrally read imaging vendor
Has been changed to read:
Multiple fibroids with a total uterine volume of ≥ 200 cm3 to ≤2,500 cm3 as documented 
by centrally read imaging vendor


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Section 5.4  Removal of Subjects from Therapy or Assessment
Fourth bullet previously read:
The subject requires surgical intervention for treatment of uterine fibroids and menstrual 
bleeding or other procedures including hysterectomy, myomectomy, uterine artery 
embolization, high intensity focused ultrasound (HIFU), endometrial ablation, dilation 
and curettage (D&C), etc.
Has been changed to read:
The subject requires surgical intervention for treatment of uterine fibroids and menstrual 
bleeding or other procedures including hysterectomy, myomectomy, uterine artery 
embolization, high intensity focused ultrasound (HIFU), endometrial ablation, dilation 
and curettage (D&C), etc. during the Treatment Period.  In the post treatment period these 
procedures do not warrant withdrawal if performed during the Post-Treatment Period 
unless a hysterectomy with bilateral salpingo-oophorectomy (BSO) is performed and the 
Subject does not plan to use Hormone Replacement Therapy within 1 month of the 
surgery date.
Section 5.4  Removal of Subjects from Therapy or Assessment
Sixth bullet previously read:
The subject has (SGPT/ALAT) or SGOT/ASAT elevation > 5 times the upper limit of 
normal confirmed upon repeat.
Has been changed to read:
The subject has (SGPT/ALAT) or SGOT/ASAT elevation > 5 times the upper limit of 
normal confirmed upon repeat during the Treatment Period.
Section 5.4.4  Delays in Rollover into the Extension Study
First paragraph, second sentence previously read:
Subjects will return to the study site at the same monthly visit intervals.  


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Has been changed to read:
Subjects will return to the study site at the same 28-day monthly visit intervals if 
eligibility for the extension study has not been determined before then.  
Section 5.4.4  Delays in Rollover into the Extension Study
Subsection Subject Entering the Extension Study:
Delete:  third bullet
Conduct the study assessments and procedures as outlined in Table 6, Delays in Roll-Over 
into Extension Study.
Section 5.4.4  Delays in Rollover into the Extension Study
Subsection Subject NOT Entering the Extension Study:
Delete:  third bullet
Conduct the study assessments and procedures as outlined in the Unscheduled Visit 
procedures above
Section 5.4.4  Delays in Rollover into the Extension Study
Subsection Subject NOT Entering the Extension Study:
Last bullet previously read:
The next scheduled visit will be the Month 1 Phone Visit
Has been changed to read:
The next scheduled visit will be the Month 1 Site Visit
Section 15.0  Reference List
Add:  new reference 12
ACR BI-RADS Atlas Fifth Edition.  p. 15-8.  Available from:  
https://www.acr.org/~/media/ACR/Documents/PDF/QualitySafety/Resources/BIRADS/0
1-Mammography/02--BIRADS-Mammography-Reporting.pdf?la=en.


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Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical Development
Global Drug Supply Management
Clinical Operations
Clinical Pharmacokinetics
Bioanalysis
Clinical Development
Statistics
Has been changed to read:
Name
Title
Functional Area
Clinical Development
Global Drug Supply Management
Clinical Operations
Clinical Pharmacokinetics
Bioanalysis
Clinical Development
Statistics


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Appendix C.  Study Activities – Washout, Screening and Treatment Periods and Post-Treatment Follow-Up Period
Procedure "Endometrial Biopsy," "Pelvic Ultrasound@:  TAU, TVU," and "DXA Scan" previously read:
Procedure
Washout (If Applicable) 
and Screening Period
Treatment Perioda
Washout 
Period
Screen 
Visit
Cycle 
1 – 3‡
PCVb
Day 
1c
Month 
1
Month 
2
Month 
3
Month 
4
Month 
5
Month 
6
PCVb,d
Unsch 
Visit
PD 
(if 
appl)
Endometrial Biopsy
Xg
Xg,%
Xg,h
Pelvic Ultrasound@:  TAU, TVU 
Xl
X*
X
X
X%
Xh
DXA Scan
X
X%
Xi
Has been changed to read:
Procedure
Washout (If Applicable) 
and Screening Period
Treatment Perioda
Washout 
Period
Screen
Visit
Cycle 
1 – 3‡
PCVb
Day 
1c
Month 
1
Month 
2
Month 
3
Month 
4
Month 
5
Month 
6
PCVb,d
Unsch 
Visit
PD 
(if 
appl)
Endometrial Biopsy
Xg
Xg,%,±,&
Xg,h
Pelvic Ultrasound@:  TAU, TVU 
Xl
X*
X
X
X%,&
Xh
DXA Scan
X
X%,±
Xi


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Appendix C.  Study Activities – Washout, Screening and Treatment Periods and 
Post-Treatment Follow-Up Period
Table note "%" previously read:
Recommend performing approximately 15 days prior to Month 6 visit to ensure results 
are available to determine eligibility into the extension study.
Has been changed to read:
%
Recommend performing approximately 15 days prior to Month 6 visit.
±
Results required to determine eligibility into the extension study.
&
Results required if endometrial biopsy at Month 6 cannot be performed or results are insufficient.
Appendix D.  BI-RADS Classification
Previously read:
The BI-RADS assessment categories are:
●
0 – Incomplete,
●
1 – Negative,
●
2 – Benign findings,
●
3 – Probably benign,
●
4 – Suspicious abnormality,
●
5 – Highly suspicious of malignancy,
●
6 – Known biopsy with proven malignancy
Has been changed to read:
The BI-RADS assessment categories are:
●
0 – Incomplete,
●
1 – Negative,
●
2 – Benign,
●
3 – Probably benign,
●
4 – Suspicious,


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●
5 – Highly suggestive of malignancy,
●
6 – Known biopsy – proven malignancy
Reference:  ACR BI-RADS Atlas Fifth Edition.12



SAP_001.pdf: 
Elagolix (ABT-620)
M12-817 – Statistical Analysis Plan
Version 1.0 – 02 Feb 2018
1
1.0
Title Page
Statistical Analysis Plan
Study M12-817
A Phase 3 Study to Evaluate the Efficacy and Safety 
of Elagolix in Combination with 
Estradiol/Norethindrone Acetate for the 
Management of Heavy Menstrual Bleeding 
Associated with Uterine Fibroids in Premenopausal 
Women
Date:  02 Feb 2018
Version 1.0
NCT02691494


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M12-817 – Statistical Analysis Plan
Version 1.0 – 02 Feb 2018
2
2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Introduction...........................................................................7
3.0
Study Objectives, Design and Procedures............................7
3.1
Objectives .............................................................................................. 7
3.2
Study Design.......................................................................................... 7
3.3
Sample Size............................................................................................ 9
3.4
End-of-Treatment Period Analysis.......................................................... 9
4.0
Analysis Populations ........................................................... 10
4.1
Definition for Analysis Populations ...................................................... 10
4.2
Variables Used for Stratification of Randomization .............................. 11
5.0
Protocol Deviation and Enrollment into Extension 
Study .................................................................................... 11
6.0
Analysis Conventions .......................................................... 11
6.1
Definition of Baseline........................................................................... 11
6.2
Definitions of Final Month and Final Visit ........................................... 13
6.3
Definition of Study Days (Days Relative to the First Dose of 
Study Drug) and Study End Days (Days Relative to the Last Dose 
of Study Drug) ..................................................................................... 13
6.4
Definition of Analysis Window ............................................................ 13
6.4.1
Treatment Period.................................................................................. 13
6.4.2
Post-Treatment Follow-Up Period ........................................................ 14
6.4.3
Details Regarding Visit Windows......................................................... 14
6.4.4
Handling of Multiple Assessments in a Specific Time Window............ 18
6.5
Dealing with Multiple Values on the Same Day.................................... 18
6.6
Definitions and Conventions of MBL Volume and Bleeding Days ....... 19
6.6.1
MBL Volume ....................................................................................... 19
6.6.1.1
Observed MBL Volume Over a Window.............................................. 19
6.6.2
Bleeding Days ...................................................................................... 20
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ................... 21
7.1
Demographic and Baseline Characteristics ........................................... 21


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7.1.1
Demographics ...................................................................................... 21
7.1.2
Baseline Characteristics........................................................................ 22
7.2
Medical History.................................................................................... 23
7.3
Prior, Concomitant, and Post-Treatment Medications ........................... 23
8.0
Subject Disposition..............................................................24
9.0
Study Drug Exposure.......................................................... 25
10.0
Efficacy Analysis .................................................................26
10.1
General Considerations......................................................................... 26
10.2
Primary Efficacy Analysis.................................................................... 27
10.2.1
Primary Efficacy Endpoint ................................................................... 27
10.2.2
Primary Analysis of Primary Efficacy Endpoint ................................... 27
10.2.2.1
Multiple Imputation.............................................................................. 28
10.2.3
Sensitivity Analyses of the Primary Efficacy Endpoint ......................... 30
10.2.3.1
Using Last Observation Carried Forward (LOCF) Imputation............... 31
10.2.4
Adenomyosis Subset ............................................................................ 31
10.3
Ranked Secondary and Other Efficacy Analyses................................... 32
10.3.1
Reduction of Bleeding.......................................................................... 33
10.3.2
Amenorrhea, Suppression and Control of Bleeding............................... 36
10.3.2.1
Amenorrhea.......................................................................................... 36
10.3.2.2
Suppression of Bleeding....................................................................... 38
10.3.2.3
Control of Bleeding.............................................................................. 39
10.3.3
Bleeding Days ...................................................................................... 40
10.3.4
Hemoglobin Concentration................................................................... 41
10.3.5
Fibroid and Uterine Volume, FIGO Classification, Adenomyosis, 
and Post-Treatment Menses.................................................................. 43
10.3.5.1
Fibroid and Uterine Volume ................................................................. 43
10.3.5.2
FIGO Classification.............................................................................. 43
10.3.5.3
Adenomyosis........................................................................................ 44
10.3.5.4
Post-Treatment Menses ........................................................................ 44
10.3.6
Quality of Life Questionnaire ............................................................... 45
10.3.6.1
Uterine Fibroid Symptoms Quality of Life (UFS-QoL)......................... 45
10.3.6.2
EQ-5D-5L............................................................................................ 46
10.3.6.3
Patient Global Impression of Change (PGIC) ....................................... 47


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10.3.6.3.1
PGIC on Menstrual Bleeding Questionnaire ......................................... 47
10.3.6.3.2
PGIC on Non-Bleeding Uterine Fibroid Symptoms Questionnaire........ 47
10.3.6.4
Work Productivity and Activity Questionnaire:  Uterine Fibroids 
(WPAI:UF) .......................................................................................... 48
10.3.6.5
Health Care Resource Utilization Questionnaire (HCRU)..................... 48
10.3.6.6
Number of Days in Hospital ................................................................. 48
10.4
Handling of Multiplicity....................................................................... 49
11.0
Safety Analysis.....................................................................49
11.1
General Considerations......................................................................... 49
11.2
Adverse Events..................................................................................... 50
11.3
Laboratory Variables............................................................................ 52
11.3.1
Analysis of Laboratory Variables ......................................................... 53
11.3.2
Assessment of Hepatotoxicity............................................................... 56
11.4
Bone Mineral Density........................................................................... 56
11.4.1
BMD in the Treatment Period............................................................... 57
11.4.2
BMD in the Post-Treatment Follow-Up Period..................................... 59
11.5
Vital Signs and Body Weight ............................................................... 60
11.6
Endometrial Biopsy.............................................................................. 62
11.7
Pelvic Ultrasound and MRI .................................................................. 62
11.7.1
Ovarian Cysts....................................................................................... 62
11.7.2
Endometrial Thickness ......................................................................... 63
11.8
Columbia Suicide Severity Rating Scale (C-SSRS) .............................. 63
11.9
Pregnancy Results ................................................................................ 64
12.0
References............................................................................64
List of Tables
Table 1.
Analysis Time Windows for Non-Bleeding Measurements 
Collected Monthly................................................................................ 15
Table 2.
Analysis Time Windows for Non-Bleeding Measurements 
Collected Every 3 Months in the Treatment Period............................... 16
Table 3.
Analysis Time Windows for Non-Bleeding Measurements 
Collected Every 6 Months in the Treatment Period (BMD)................... 16


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Table 4.
Analysis Time Windows for Non-Bleeding Measurements 
Collected Every 6 Months in the Treatment Period (MRI and 
Biopsy)................................................................................................. 16
Table 5.
Analysis Time Windows for Non-Bleeding Measurements 
Collected at Post-Treatment Month 1, 3, 6, 9, 12 .................................. 17
Table 6.
Analysis Time Windows for Non-Bleeding Measurements 
Collected at Post-Treatment Month 3 and 6.......................................... 17
Table 7.
Analysis Time Windows for Non-Bleeding Measurements 
Collected at Post-Treatment Month 3.................................................... 17
Table 8.
Analysis Time Windows for Non-Bleeding Measurements 
Collected at Post-Treatment Month 6 and 12 ........................................ 18
Table 9.
Monthly Analysis of Bleeding for Amenorrhea .................................... 37
Table 10.
Categorical Summary of Incidence and Cumulative Incidence of 
Amenorrhea.......................................................................................... 38
List of Figures
Figure 1.
Study Schematic..................................................................................... 9
Figure 2.
Flow-Chart for Deriving Final Month MBL Volume ............................ 28
List of Appendices
Appendix A.
UFS-QoL ............................................................................................. 66
Appendix B.
UFS-QoL Scoring Manual.................................................................... 69
Appendix C.
Patient Global Impression of Change (PGIC-MB) – SAMPLE ............. 71
Appendix D.
Patient Global Impression of Change, Non-Bleeding Uterine 
Fibroids Symptoms (PGIC-NBUFS) – SAMPLE.................................. 72
Appendix E.
EurolQol (EQ-5D-5L) – SAMPLE ....................................................... 75
Appendix F.
Reason for Study Participation ............................................................. 77
Appendix G.
Physician Surgery Questionnaire Version 1.0 – SAMPLE .................... 78
Appendix H.
Uterine Bleeding Questionnaire (UBQ) – Treatment Period –
SAMPLE.............................................................................................. 79
Appendix I.
Uterine Bleeding Questionnaire (UBQ) – Post-Treatment 
Follow-Up Period – SAMPLE.............................................................. 80


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Appendix J.
Work Productivity and Activity Impairment Questionnaire: 
Uterine Fibroids V2.0 (WPAI:UF) – SAMPLE..................................... 81
Appendix K.
WPAI:UF Scoring Rules ...................................................................... 83
Appendix L.
Columbia-Suicide Severity Rating Scale (C-SSRS) –
Baseline/Screening – SAMPLE............................................................ 85
Appendix M.
Columbia-Suicide Severity Rating Scale (C-SSRS) – Since Last 
Visit – SAMPLE .................................................................................. 88
Appendix N.
C-SSRS Scoring Rules ......................................................................... 91
Appendix O.
Health Care Resource Utilization Questionnaire (HCRU) 
Version 2.0 – SAMPLE........................................................................ 94
Appendix P.
Health Care Resource Utilization Questionnaire (HCRU) 
Version 1.0 – SAMPLE.......................................................................100
Appendix Q.
Adverse Events of Special Interest.......................................................102
Appendix R.
Exceptions to Standard CTCAE Lab Grading Criteria for Elagolix 
Studies ................................................................................................103


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3.0
Introduction
This statistical analysis plan (SAP) describes the planned statistical analyses for elagolix 
(ABT-620) Study M12-817 titled "A Phase 3 Study to Evaluate the Efficacy and Safety of 
Elagolix in Combination with Estradiol/Norethindrone Acetate for the Management of 
Heavy Menstrual Bleeding Associated with Uterine Fibroids in Premenopausal Women."  
The analysis plan was created based on the Study Protocol M12-817 Amendment 2 dated 
06 October 2017.
This analysis plan describes both the efficacy and safety analyses.  The pharmacokinetic 
data will be analyzed separately and is not addressed in this SAP.
The SAS System 9.2 or above will be used to perform the statistical analyses.  All 
statistical tests will be two-sided and a significance level of 0.05 will be used unless 
otherwise specified.  
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The objectives of this study are to:
●
Assess the efficacy, safety and tolerability of elagolix 300 mg BID in 
combination with E2/NETA (estradiol 1 mg/norethindrone acetate 0.5 mg 
QD), versus placebo to reduce heavy menstrual bleeding (HMB) associated 
with uterine fibroids in premenopausal women 18 to 51 years of age.  
●
The study will also characterize the impact of E2/NETA on the 
safety/tolerability (including bone mineral density [BMD] and other 
hypoestrogenic side effects) and efficacy of elagolix.
4.2
Study Design
This Phase 3, randomized, double-blind, multicenter, placebo-controlled study is designed 
to evaluate the efficacy, safety and tolerability of elagolix alone and in combination with 


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E2/NETA in the management of premenopausal women with HMB associated with 
uterine fibroids.  Approximately 400 subjects will be randomized in a 1:1:2 ratio to 1 of 
the following 3 treatment groups:
●
placebo (n = 100)
●
elagolix 300 mg BID (n = 100)
●
elagolix 300 mg BID plus E2/NETA (estradiol 1 mg/norethindrone acetate 
0.5 mg) QD (n = 200)
This study is designed to enroll approximately 400 subjects across approximately 
125 clinical study sites to meet scientific and regulatory objectives without enrolling an 
undue number of subjects in alignment with ethical considerations.  
The study consists of 4 periods as follows:  
1.
Washout Period prior to Screening (if applicable)
2.
Screening Period of approximately 2.5 to 3.5 months prior to first dose of study 
drug
3.
6-month Treatment Period
4.
12-month Post-Treatment Follow-up Period (OR Subjects may enter an extension 
study [Study M12-816] if they are willing and qualify, based on safety parameters, 
to receive an additional 6 months of treatment, followed by 12 months of 
follow-up).
Subjects will visit the site for assessments and testing during the Washout Period, if 
applicable, during the Screening Period (Initial Screening Visit, Screening Product 
Collection Visits [PCVs] for assessment of menstrual blood loss) and Treatment Period 
(Day 1 [Randomization] and monthly during Month 1 through Month 6).  Following the 
6-month Treatment Period, subjects will enter into a 12-month Post-Treatment Follow-up 
Period or an extension study.  The Study Periods are illustrated in Figure 1.


Elagolix (ABT-620)
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Version 1.0 – 02 Feb 2018
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Figure 1.
Study Schematic
4.3
Sample Size
Approximately 400 subjects will be randomized in a 1:1:2 ratio to placebo (N = 100), 
elagolix 300 mg BID (N = 100), or elagolix 300 mg BID plus E2/NETA (N = 200).  The 
sample size will provide at least 90% power to detect a difference between the elagolix 
300 mg BID plus E2/NETA group and the placebo group in the percentage of subjects 
with menstrual blood loss (MBL) volume < 80 mL during the Final Month (as defined in 
Section 7.2) and 50% or greater reduction in MBL volume from Baseline to the Final 
Month under the assumption of responder rates being 60% and 30% for elagolix 300 mg 
BID plus E2/NETA and placebo, respectively.  The sample size determination is primarily 
driven by the need for a sufficient number of patients for the safety database.  The above 
sample size was calculated using nQuery advisor 7.0.
4.4
End-of-Treatment Period Analysis
An end-of-treatment period analysis of the primary and secondary efficacy variables along 
with demographic and safety variables will be performed after the last subject completes 
the 6-Month Treatment Period of Study M12-817.  This end-of-treatment period analysis 
will include all treatment period data from all patients randomized into the study.  The 
data base will be versioned and any discrepant data will be clarified before the lock.  
Analyses will be performed by an external Independent Data Analysis Center (IDAC).  


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Subjects completing Study M12-817 are eligible to be enrolled in the double-blind 
extension study.  The blinding at the subject level for the extension study will be 
maintained as the efficacy data analyses will only present overall treatment group results 
to the sponsor.  The sponsor will have access to the unblinded results at the treatment 
group level.  However, the blinded data at the subject level will not be included in the 
results of the demographic, efficacy, or safety endpoints provided to the sponsor.  The 
randomization schedule for Study M12-817 will be provided to the IDAC by someone 
other than the project statistician, who is otherwise not involved with this study.  All 
AbbVie study personnel will remain blinded until the blind is broken for the double-blind 
extension study.  The end-of-treatment period analysis will only include data collected 
during the 6-month treatment period of the study and will not include data collected 
during the Post-Treatment Follow-up Period.
Since this end-of-treatment period analysis is the only and final analysis of the primary 
and ranked secondary endpoints of Study M12-817, no adjustment of alpha-level is 
necessary.
5.0
Analysis Populations
5.1
Definition for Analysis Populations
Full Analysis Set
The full analysis set is comprised of all randomized subjects who have received at least 
one dose of study drug in this study.  The data from the full analysis set will be presented 
by the treatment group assigned at the time of randomization, even if the subject does not 
receive the correct treatment or does not follow the protocol until completion.  The full 
analysis set will be used for all Baseline and efficacy analyses.  
Safety Analysis Set
The Safety Analysis Set will include all randomized subjects who received at least 
one dose of study drug.  The data from the safety analysis set will be presented by the 
treatment group as treated, independent of treatment group assignment at the time of 


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randomization.  If a subject receives more than one treatment, she will be analyzed in the 
treatment group to which she was randomized.  The Safety Analysis Set will be used for 
all safety analyses.  
5.2
Variables Used for Stratification of Randomization
There is no variable used for stratification of randomization.
6.0
Protocol Deviation and Enrollment into Extension 
Study
Protocol deviations will be summarized and listed by treatment group.  The number and 
percentage of subjects not enrolling into the extension study, and the reason for not 
enrolling into the extension study will be summarized by treatment group. 
7.0
Analysis Conventions
7.1
Definition of Baseline
Unless otherwise specified below, Baseline for a variable will be defined as the last non-
missing value obtained prior to or on Study Day 1.
MBL Volume Baseline
Baseline MBL volume will be defined as the mean of total MBL volume from all the 
qualified menstrual cycles during the Screening Period, in which the total MBL volume is 
from all validated and non-validated sanitary products that subjects returned and where 
the MBL volume of validated sanitary products only (excluding non-validated sanitary 
products) is greater than 80 mL.  All menstrual cycles during the Screening Period in 
which the total MBL of all validated products is less than or equal to 80 mL will not be 
included in the Baseline MBL volume calculation.  If the gap between two consecutive 
Screening menstrual cycles is 1 day apart or less (i.e., out of the two consecutive cycles, 
the start date of the second cycle – the end date of the first cycle ≤2), these two Screening 
menstrual cycles will be combined as one Screening menstrual cycle for the calculation of 
Baseline.


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Bleeding Days Baseline
Baseline for bleeding days (as defined in Section 7.6) will be the mean of total number of 
bleeding days over all the qualified Screening menstrual cycles that are used to calculate 
Baseline MBL volume.
Fibroid and Uterine Volume Baseline
Baseline for uterine volume, volume of the largest fibroid, total fibroid volume (3 largest 
fibroids), and endometrial thickness measured by ultrasound (transvaginal [TVU] or 
transabdominal [TAU]) or Magnetic Resonance Imaging (MRI) will be based on the last 
non-missing measurement collected during the Screening Period.  If there is no 
measurement collected on or prior to Study Day 1, the first measurement collected prior to 
Study Day 8 (Study Day 8 is not included) will be used as Baseline. 
Adenomyosis Baseline
Baseline for adenomyosis measured by TVU/TAU or MRI will be based on the last non-
missing measurement collected on or prior to Study Day 1.  If there is no measurement 
collected on or prior to Study Day 1, the first measurement collected prior to Study 
Day 15 (Study Day 15 is not included) will be used as Baseline.
Quality of Life Questionnaires Baseline
Baseline for quality of life questionnaires including Uterine Fibroid Symptom 
Questionnaire (UFS-QoL), EuroQoL-5D (EQ-5D-5L) questionnaire, Work Productivity 
and Activity Impairment (WPAI) questionnaire and Health Care Resource Utilization 
(HCRU) questionnaire will be based on the measurement collected on or before Study 
Day 1.  For UFS-QoL, EQ-5D-5L and HCRU, if there is no measurement collected on or 
before Study Day 1, the first measurement collected prior to Study Day 8 (Study Day 8 is 
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7.2
Definitions of Final Month and Final Visit
Final Month is defined as the last 28 days prior to and including the Reference Day, which 
is defined as the last visit date in the treatment period (last treatment visit date) or the last 
dose date if there is evaluable Alkaline Hematin (AH) data after the last treatment visit 
date and prior to or on the last dose date.
Final Visit is defined as the last non-missing assessment during the Treatment Period. 
Post-Treatment Final Visit is defined as the last non-missing assessment during the 
Post-Treatment Follow-up Period.
7.3
Definition of Study Days (Days Relative to the First Dose of 
Study Drug) and Study End Days (Days Relative to the Last 
Dose of Study Drug)
For randomized subjects who received at least one dose of study drug, the study day is 
defined as the number of days since (positive values) or prior to (negative values) the 
first study drug dose.  The day of the first study drug dose is defined as Study Day 1 while 
the last day prior to the first dose of study drug is defined as Study Day –1.  There is no 
Study Day 0.  Study end days are calculated based on the number of days relative to the 
last dose of study drug.  The first day following the last dose of study drug is defined as 
Study End Day 1. 
7.4
Definition of Analysis Window
7.4.1
Treatment Period
Data obtained more than 3 days after the subject's last dose of study drug in 
Study M12-817 will be excluded for all assessments performed at periodic intervals 
(monthly, every 3 months, or every 6 months) in the Treatment Period with the following 
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1.
For BMD, TVU/TAU, MRI, and endometrial biopsy assessments, data obtained 
more than 28 days after the last dose of study drug in Study M12-817 will be 
excluded from summaries/analyses in the Treatment Period.
2.
For Alkaline Hematin (AH) data, data obtained after the last dose of study drug in 
Study M12-817 will be excluded from the summaries/analyses in the Treatment 
Period.
7.4.2
Post-Treatment Follow-Up Period
For subjects who are not rolled over into the Extension Study M12-816 and continue to 
the Post-Treatment Follow-up Period, summaries for the Post-Treatment Follow-up 
Period will include data obtained more than 3 days after the subject's last dose of study 
drug for all assessments performed at periodic intervals (monthly, every 3 months, or 
every 6 months), with the following exceptions:
1.
For BMD, TVU/TAU, and MRI assessments, data obtained more than 28 days after 
the last dose of study drug will be included in the summaries during the Post-
Treatment Follow-up Period.
2.
For AH data, data obtained after the last dose of study drug in Study M12-817 will 
be included in the summaries during the Post-Treatment Follow-up Period.
7.4.3
Details Regarding Visit Windows
For analyses in the Treatment Period, time points and corresponding time windows are 
defined based on the time of exposure to study drug starting from Study Day 1.
The time windows described in this section will not be applied to bleeding assessments 
including AH data and Uterine Bleeding Questionnaire (UBQ).  Rules described in 
Section 7.4.1 and Section 7.4.2 will be applied prior to defining time windows.  Data 
considered as in the Treatment Period are not considered in the Post-Treatment Follow-up 


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Period as described in Section 7.4.1 and Section 7.4.2.  Any data considered as Baseline 
(see Section 7.1) will not be included in any post-baseline windows. 
Table 1 will be used for analyses of endpoints collected monthly in the Treatment Period 
and Post-Treatment Follow-up Period.
Table 1.
Analysis Time Windows for Non-Bleeding Measurements Collected 
Monthly
Visit
Nominal Day
(Study Day)
Time Window
(Study Days)
Month 1
28
> 1 – ≤ 42
Month 2
56
> 42 – ≤ 70
Month 3
84
> 70 – ≤ 98
Month 4
112
> 98 – ≤ 126
Month 5
140
> 126 – ≤ 154
Month 6
168
> 154 – ≤ 196
Nominal Day 
(Study End Day)
Time Window
(Study End Days)
Post-Treatment Month 1
28
> 3 – ≤ 42
Post-Treatment Month 2
56
> 42 – ≤ 70
Post-Treatment Month 3
84
> 70 – ≤ 98
Post-Treatment Month 4
112
> 98 – ≤ 126
Post-Treatment Month 5
140
> 126 – ≤ 154
Post-Treatment Month 6
168
> 154 –  ≤ 182
Post-Treatment Month 7
196
> 182 – ≤ 210
Post-Treatment Month 8
224
> 210 – ≤ 238
Post-Treatment Month 9
252
> 238 – ≤ 266
Post-Treatment Month 10
280
> 266 – ≤ 294
Post-Treatment Month 11
308
> 294 – ≤ 322
Post-Treatment Month 12
336
> 322 
Table 2 will be used for analyses of endpoints collected every 3 months in the Treatment 
Period.  If there is a scheduled Month 1 visit for the endpoint (e.g., PGIC-MB and 
PGIC-NBUFS), the first subtable will be used.  If there is no scheduled Month 1 visit for 


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the endpoint (e.g., TAU/TVU, creatinine phosphokinase, urinalysis, apolipoprotein A and 
B, UFS-QoL), the second subtable will be used.
Table 2.
Analysis Time Windows for Non-Bleeding Measurements Collected 
Every 3 Months in the Treatment Period
Visit
Nominal Day
(Study Day)
Time Window
(Study Days)
Month 1
28
> 1 – ≤ 56
Month 3
84
> 56 – ≤ 112
Month 6
168
> 112 – ≤ 196
Visit
Nominal Day
(Study Day)
Time Window
(Study Days)
Month 3
84
> 1 – ≤ 112
Month 6
168
> 112 – ≤ 196
Table 3 and Table 4 will be used for analyses of endpoints collected at Month 6 (biopsy, 
MRI, BMD) in the Treatment Period.
Table 3.
Analysis Time Windows for Non-Bleeding Measurements Collected 
Every 6 Months in the Treatment Period (BMD)
Visit
Nominal Day 
(Study Day)
Time Window
(Study Days)
Prior to Month 3
>1 – ≤ 84
Between Month 3 and Month 6
84
> 84 – ≤ 140
Month 6
168
> 140 – ≤ 196
Table 4.
Analysis Time Windows for Non-Bleeding Measurements Collected 
Every 6 Months in the Treatment Period (MRI and Biopsy)
Visit
Nominal Day 
(Study Day)
Time Window
(Study Days)
Prior to Month 6
70
> 1 – ≤ 140
Month 6
168
> 140 – ≤ 196


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Table 5 will be used for analyses of endpoints collected at Post-Treatment Month 1, 3, 6, 
9, and 12 (e.g., vital signs, clinical safety labs including chemistry, hematology, lipid 
panel and urinalysis, apolipoprotein A and B).  Table 6 will be used for analysis of 
endpoints collected at Post-Treatment Month 3 and 6 (e.g., TAU/TVU).  Table 7 will be 
used for analysis of endpoints collected at Post-Treatment Month 3 (e.g., MRI).  Table 8
will be used for analysis of endpoints collected at Post-Treatment Month 6 and 12 
(e.g., BMD).
Table 5.
Analysis Time Windows for Non-Bleeding Measurements Collected 
at Post-Treatment Month 1, 3, 6, 9, 12
Nominal Day
(Study End Day)
Time Window
(Study End Days)
Post-Treatment Month 1
28
> 3 – ≤ 42
Post-Treatment Month 3
84
> 42 – ≤ 126
Post-Treatment Month 6
168
> 126 – ≤ 210
Post-Treatment Month 9
252
> 210 – ≤ 294
Post-Treatment Month 12
336
> 294
Table 6.
Analysis Time Windows for Non-Bleeding Measurements Collected 
at Post-Treatment Month 3 and 6
Nominal Day 
(Study End Day)
Time Window
(Study End Days)
Post-Treatment Month 3
84
> 28 – ≤ 126
Post-Treatment Month 6
168
> 126 – ≤ 210
Post-Treatment Months 7 – 12
> 210
Table 7.
Analysis Time Windows for Non-Bleeding Measurements Collected 
at Post-Treatment Month 3
Nominal Day 
(Study End Day)
Time Window
(Study End Days)
Post-Treatment Month 3
84
> 28 – ≤ 126
Post-Treatment Months 4 – 12
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Table 8.
Analysis Time Windows for Non-Bleeding Measurements Collected 
at Post-Treatment Month 6 and 12
Nominal Day 
(Study End Day)
Time Window
(Study End Days)
Prior to Post-Treatment Month 6
> 28  – ≤ 140
Post-Treatment Month 6
168
> 140 – ≤ 196
Post-Treatment Months 7 – 11
> 196  – ≤ 308
Post-Treatment Month 12
336
> 308
7.4.4
Handling of Multiple Assessments in a Specific Time 
Window
For all parameters except MBL volume, multiple assessments in a specific time window 
will be handled as follows:
1.
For parameters other than BMD, TVU/TAU, MRI, and WPAI data, if more than 
one assessment is included in a time window, then the assessment performed 
closest to the scheduled study day (i.e., the nominal day) will be used in the 
analyses.  If more than 1 day is of equal proximity to the nominal day, then the data 
collected after the nominal day will be used in the analyses.
2.
For BMD, TVU/TAU, and MRI data, if multiple assessments exist in a specific 
time window, analyses of data will be based on the most conservative (worst) 
assessment.
3.
For WPAI data, if multiple assessments exist in a specific time window in the 
treatment period, analyses of data will be based on the last assessment during the 
treatment period. 
7.5
Dealing with Multiple Values on the Same Day
If multiple measurements are made on the same day for a laboratory parameter or a vital 
signs parameter, the average of the values will be used in analyses.  For summaries of 


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shifts from Baseline and potentially significant values, multiple values on the same day 
will not be averaged; all values will be considered for these analyses.
If multiple measurements for a particular parameter other than a laboratory parameter and 
a vital signs parameter are made on the same day for the same subject, the most 
conservative (worst) measurement will be used in analyses.
7.6
Definitions and Conventions of MBL Volume and Bleeding 
Days
7.6.1
MBL Volume
The MBL volume is based on validated and non-validated sanitary products unless 
otherwise specified (for some sensitivity analysis, the MBL volume will be based on 
validated sanitary products only).
Baseline MBL volume is based on observed AH data only.  No imputation will be made 
for Baseline MBL volume.
7.6.1.1
Observed MBL Volume Over a Window
If there were observed AH data between two study visits (Product Collection Visit or site 
visit with UBQ completed), then the MBL volume on the days with observed AH data 
will be the observed AH data and the MBL volume for the rest of days between the 
two study visits will be imputed as 0 by AH data.  
UBQ responses indicate if a subject has any bleeding or spotting since the last study visit 
(Product Collection Visit or site visit with UBQ completed).  If observed evaluable AH 
data is available over a window, then the UBQ will not be considered. 
If the AH data is reported as "NVB" (no visible blood, discarded without assay), "NO 
BLEED" (no collection due to no bleeding as indicated by subject or clinical site on assay 
requisition form), or "TL BQL" (total below low limit of quantitation), the numeric value 
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("NULL," "IN ERROR," "NO DATA," and etc.), the corresponding numeric value for the 
AH data will be set as missing.
The observed MBL volume over a window (such as the Final Month, Month 1 [Study 
Days 2 – 28], Month 2 [Day 29 – Day 56], Month 3 [Day 57 – Day 84], Month 4 
[Day 85 – Day 112], Month 5 [Day 113 – Day 140], and Month 6 [Study Days 141 –
168]) is defined as follows:
●
If a subject has any evaluable AH data reported in the window, then the 
subject's MBL volume in this window will be the total combined observed AH 
data of validated and non-validated sanitary products over this window.
●
If a subject is missing AH data or all AH data are unevaluable in the window 
and the UBQ is completed and indicates no bleeding or spotting, "Subject only 
had spotting that did not require the use of sanitary products" or "There was no 
visible blood on the sanitary products" and covers this window, then:
○
A value of 0 will be assigned to the MBL volume over this window.
●
If a subject is missing AH data or all AH data are unevaluable in the window 
and the UBQ is completed with no bleeding or spotting or "Subject only had 
spotting that did not require the use of sanitary products" or "There was no 
visible blood on the sanitary products" indicated but UBQ does not cover the 
full window, then:
○
A value of 0 will be assigned to the MBL volume over this window if the 
days not covered by UBQ response as described above have AH imputed 
MBL volume (see first paragraph in Section 7.6.1.1) being 0 for those 
days.
If there is still no value assigned after the imputation procedure described above, the 
observed MBL volume over the window is considered missing.
7.6.2
Bleeding Days 
A bleeding/spotting day is defined as a day having daily MBL volume of > 0 mL.
A spotting day is defined as a day having daily MBL volume of > 0 – 2 mL.


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A bleeding day is defined as a day having daily MBL volume of > 2 mL.
Bleeding intensity categories are
●
Daily MBL volume of > 2 – 10 mL.
●
Daily MBL volume of > 10 – 40 mL.
●
Daily MBL volume of > 40 – 80 mL.
●
Daily MBL volume of > 80 mL.
Please note that only observed AH data will be used for daily MBL volume categroies 
above.
8.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
8.1
Demographic and Baseline Characteristics
Demographics and Baseline characteristics will be summarized for all randomized 
subjects who received at least one dose of study drug by treatment group. 
8.1.1
Demographics
Continuous variables such as age, height, weight, and BMI will be summarized with the 
mean, standard deviation (SD), median, minimum, and maximum by treatment group and 
overall and also be compared among treatment groups using one-way analysis of variance 
(ANOVA).  Number and percentage will be computed by treatment group and overall for 
the following demographic parameters:  age group (18 – < 20 years old, 20 – < 25 years 
old, 25 – < 30 years old, 30 – < 35 years old, 35 – < 40 years old, 40 – < 45 years old, 
45 – < 50 years old, ≥ 50 years old), BMI (≤ 18.5 kg/m2, > 18.5 kg/m2 – < 25 kg/m2, 
25 kg/m2 – < 30 kg/m2, 30 kg/m2 – < 35 kg/m2, 35 kg/m2 – < 40 kg/m2, ≥ 40 kg/m2), sex, 
race, ethnicity, tobacco use (current, former, never, and unknown), and alcohol use 
(current, former, never, and unknown).  Categorical variables will be compared among 
treatment groups using a Fisher's exact test.  


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The number and percentage of subjects with Baseline presence of adenomyosis (as 
defined in Section 11.3.5.3) will be summarized by treatment group and overall.  No 
statistical tests will be performed.
Physician Surgery Questionnaire (PSQ)
For each of the PSQ questions (Appendix G), the number and percentage of subjects in 
each response category will be summarized at Baseline by treatment group and overall.  
No statistical tests will be performed.
Reason for Study Participation Questionnaire
Descriptive statistics will be presented for reasons for study participation for each 
treatment group.  No statistical tests will be performed.
8.1.2
Baseline Characteristics
Menstrual Blood Loss (MBL)
Baseline MBL measured by AH method as defined in Section 7.1 will be summarized for 
each treatment group and overall with mean, SD, median, minimum, and maximum 
values.  The baseline MBL values will be compared among treatment groups using 
one-way ANOVA.  
Bleeding Days
Baseline for bleeding days will be based on the observed daily AH data in Screening as 
defined in Section 7.1 and Section 7.6.
The numbers of bleeding days by intensity categories at Baseline will be summarized with 
mean, SD, median, minimum, and maximum for each treatment group and overall.
Hemoglobin Concentration
Baseline hemoglobin concentration will be summarized for each treatment group and 
overall with mean, SD, median, minimum, and maximum values.  The number and 


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percentage of subjects with Baseline hemoglobin concentration in the following 
categories will be summarized for each treatment group and overall:  ≤ 10.5 g/dL, 
> 10.5 – ≤ 12 g/dL, and > 12 g/dL.
Fibroid and Uterine Volume
Baseline uterine volume, Baseline volume of the largest fibroid, and Baseline total fibroid 
volume (3 largest fibroids) will be summarized for each treatment group and overall with 
mean, SD, median, minimum, and maximum values and will be compared between each 
elagolix dose group and placebo using one-way ANOVA. 
8.2
Medical History
Medical/surgical, gynecological, menstrual and obstetrical history will be summarized and 
presented using system organ classes (SOCs) and preferred terms (PTs) from the Medical 
Dictionary for Regulatory Activities (MedDRA) Version 19.0 or higher.  Subjects 
reporting more than one medical history within a SOC will be counted only once for that 
SOC.  Subjects reporting more than one medical history for a PT will be counted only 
once for that PT.  No statistical tests will be performed on medical history.
8.3
Prior, Concomitant, and Post-Treatment Medications
Medications with a start date prior to the first study drug dose date will be counted as 
prior medication.  
Concomitant medications are those medications, other than study drugs, taken during the 
treatment period with an end date after the first dose of study drug or ongoing at the end 
of study, and a start date prior to the last dose of study drug.  A medication will be 
considered a concomitant medication where one of the following three cases occur (1) the 
start date is missing and the end date is either after or on the first study drug dose date; 
(2) the start date is not missing and the end date is missing; (3) both the start date and the 
end date are missing.
No statistical tests will be performed on prior medications and concomitant medications.


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For prior medications administered to treat uterine fibroid symptoms, the following data 
are collected:  dates of administration (including start and stop dates), dose, route, and 
reason for discontinuation.  Prior medications will be summarized for all randomized 
subjects who received at least one dose of study drug with number and percentage for 
each treatment group and overall using ATC Classification and preferred terms from the 
World Health Organization (WHO) Drug Dictionary. 
Concomitant medications for all randomized subjects who received at least one dose of 
study drug will be summarized using ATC Classification and preferred terms from the 
World Health Organization (WHO) Drug Dictionary with number and percentage for each 
treatment group and overall.  
Other medications taken during the Post-Treatment Follow-up Period, which includes all 
medications with an end date after the last dose of study drug or ongoing at the end of 
study for subjects who did not enroll in the extension study, will be summarized by ATC 
Classification and WHO preferred term with number and percentage for each treatment 
group and overall.
A subject who reports two or more uses of the same medication will be counted only once 
within each WHO preferred term.  A subject with medications with more than one generic 
name will be counted only once in the overall total.  Prior medications, concomitant 
medications, and other medications during the Post-Treatment Follow-up Period will be 
summarized separately.
9.0
Subject Disposition
The number of subjects for each of the following categories will be summarized by 
treatment group and overall:
●
All randomized subjects
●
Subjects who took at least one dose of study drug
●
Subjects who completed the Treatment Period
●
Subjects who discontinued from the Treatment Period


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●
Subjects who enrolled in the extension study
●
Subjects who completed the Post-Treatment Follow-Up Period
●
Subjects who prematurely discontinued from the Post-Treatment Follow-Up 
Period
Premature discontinuation of the study drug by primary reason and by any reason will be 
summarized for each treatment group and overall, with number and percentage overall 
and by reason for discontinuation for all subjects who received at least one dose of study 
drug.  Subjects may have multiple reasons for prematurely discontinuing study drug, but 
will be counted no more than once for the total of "Any Reason."
Premature discontinuation during the Post-Treatment Follow-up Period by primary reason 
and by any reason will be summarized for each treatment group and overall, with number 
and percentage overall and by reason for discontinuation.  Subjects may have multiple 
reasons for prematurely discontinuing during the Post-Treatment Follow-up Period, but 
will be counted no more than once for the total of "Any Reason."
10.0
Study Drug Exposure
Exposure to study drug will be summarized for the safety analysis set.  The duration 
(days) of study drug treatment will be summarized with the mean, SD, median, minimum, 
and maximum for each treatment group and overall.  The duration of treatment is defined 
as the difference between the dates of the first and last doses of the treatment plus 1 day.  
The duration (days) of study drug treatment will also be summarized by treatment group 
and overall with number and percentage for the following categories:  1 – 28 days, > 28 –
56 days, > 56 – 84 days, > 84 – 112 days, > 112 – 140 days, > 140 – 168 days, > 168 –
196 days, and > 196 days.


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11.0
Efficacy Analysis
11.1
General Considerations
Unless otherwise stated, all statistical tests will be conducted at an alpha level of 
0.05 (two-sided).  A test will be deemed significant if the P value rounded to 
three decimal places is less than or equal to 0.05, unless otherwise specified.  For 
analyzing efficacy variables, each elagolix dose group will be compared with placebo.  
The elagolix dose groups will not be compared against each other unless otherwise 
specified.  The primary efficacy comparison will be between the elagolix 300 mg BID 
plus E2/NETA group and the placebo group.  The comparison between the elagolix 
300 mg BID alone group and the placebo group will be used as a reference and to 
examine the validity of the study design.
Unless otherwise specified, categorical data will be summarized by frequency and 
percentage; descriptive summaries of continuous data will display the mean, SD, median, 
minimum, and maximum.
For continuous variables, when the analyses of change and/or percent change from 
Baseline to post-baseline visit(s) are performed, the within-group change from Baseline to 
each relevant visit will be summarized by treatment group with the mean, SD, and 95% 
Confidence Intervals (CIs).  The between-group differences will be summarized with the 
mean, SE, 95% CIs, and P value when applicable.  At each post-baseline visit, the 
Baseline mean and post-baseline visit mean will be calculated for all subjects with 
baseline and post-baseline value at that visit by treatment group.
Information regarding corresponding statistical methods for analyses and any additional 
statistical measures required for a specific variable/endpoint are provided in the relevant 
sections.  
Unless otherwise specified, there will be no hypotheses testing for efficacy endpoints in 
the Post-Treatment Follow-up Period.


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11.2
Primary Efficacy Analysis
11.2.1
Primary Efficacy Endpoint
The primary endpoint will be the percentage of responders, defined as subjects meeting 
the following two conditions:
●
MBL volume < 80 mL at the Final Month (the last 28 days prior to and 
including the Reference Day), and
●
50% or greater reduction in MBL volume from Baseline to the Final Month 
(the last 28 days prior to and including the Reference Day)
Subjects who prematurely discontinue study drug due to "lack of efficacy," "requires 
surgery or invasive intervention for treatment of uterine fibroids," or adverse events will 
be considered as non-responders.  Only primary discontinuation reason is considered.
Baseline MBL volume is defined in Section 7.1.
Final Month is defined as in Section 7.2.  If a subject has less than or equal to 28 days of 
treatment prior to and including the Reference Day, then the Final Month will be the 
interval between Day 2 to the Reference Day.  The AH data on Day 1 will be included in 
the Baseline MBL volume calculation (provided it is part of a qualifying menstrual cycle) 
and will not be included in post-baseline MBL volume calculation.
11.2.2
Primary Analysis of Primary Efficacy Endpoint
The primary analysis of the primary endpoint will be performed using the full analysis set 
(Section 5.1).
If a subject has missing observed Final Month MBL volume (Section 7.6), the Final 
Month MBL volume will be imputed using multiple imputation as described in 
Section 11.2.2.1.
A flow-chart showing how Final Month MBL volume will be derived is presented in 
Figure 2.


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Figure 2.
Flow-Chart for Deriving Final Month MBL Volume
11.2.2.1
Multiple Imputation
Missing Final Month MBL volume will be imputed using multiple imputation.  
First, M "semi-complete" datasets of monthly MBL volume (Month 1 [Day 2 – Day 28, 
Month 2 [Day 29 – Day 56], Month 3 [Day 57 – Day 84], Month 4 [Day 85 – Day 112], 
Month 5 [Day 113 – Day 140], and Month 6 [Day 141 – Day 168]) with monotone 
missing data pattern will be generated via MCMC option using SAS PROC MI.8  Then, 
for each of the M "semi-complete" dataset with monotone missing data, "complete" 
dataset of monthly MBL volume from Month 1 to Month 6 will be generated via 
MONOTONE REG option using SAS PROC MI.  M represents the number of 
imputations and we set M = 20.  The random seed 76543 will be used. 


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The primary analysis with multiple imputation is carried out in the following steps:
1.
Multiple Imputation:  M "complete" datasets of monthly MBL volume from 
Month 1 to Month 6 will be generated using SAS PROC MI as described above.  
The following covariates will be considered in the imputation model: 
1) Baseline MBL volume
2) Randomized treatment group
3) Baseline Hemoglobin
4) MBL volume in prior months
5) Age of the subject at Baseline
2.
Impute Final Month MBL Volume:  In each of the M generated datasets, 
subject's missing Final Month MBL volume will be imputed using the MBL 
volume from the 'complete' dataset with Month 1 – 6 MBL volume by looking at 
the corresponding month of the Reference Day using analysis time window in 
Table 1.  For example, if the Reference Day of a subject is > Day 154, then the 
Month 6 MBL volume from 'complete' dataset will be used to impute Final Month 
MBL volume; if the Reference Day is > Day 126 and ≤Day 154, then the Month 5 
MBL volume will be used to impute Final Month MBL volume and so on.  
Subjects whose Reference Day is the same as Study Day 1 will have their Final 
Month MBL volume imputed using their Month 1 MBL volume.
3.
Impute Responder Status:  The responder status (yes/no) will be derived from 
"complete" Final Month MBL volume, using the criteria as described in 
Section 11.2.1.  If a subject's Final Month MBL volume is non-missing, then the 
observed Final Month MBL volume will be used in the analysis.  If the subject 
prematurely discontinued due to "lack of efficacy," "requires surgery or invasive 
intervention for treatment of uterine fibroids," or adverse event, the subject will be 
considered a non-responder, regardless if the Final Month MBL is observed or 
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4.
Analysis:  each of the M imputed datasets is analyzed separately using a logistic 
regression model including treatment as the main effect and Baseline MBL volume 
as a covariate to compare each elagolix dose group to placebo.
5.
Pooling:  estimates of the proportions of responders in each treatment group and 
the difference between the proportions from the M imputed datasets obtained from 
step 2 are combined into one overall result using PROC MIANALYZE in SAS.9,10
11.2.3
Sensitivity Analyses of the Primary Efficacy Endpoint
The sensitivity analyses for the primary endpoint will use different approaches to handle 
prematurely discontinued subjects and missing Final Month MBL volume.
Unless otherwise specified, the analysis dataset used for sensitivity analysis is the full 
analysis set.  Each of the following sensitivity analyses for the primary endpoint will be 
performed using a logistic regression model including treatment as the main effect and 
Baseline MBL volume as a covariate to compare each elagolix dose group to placebo. 
Unless otherwise specified, subjects who prematurely discontinue study drug due to "lack 
of efficacy," "requires surgery or invasive intervention for treatment of uterine fibroids," 
or adverse events will be considered as non-responders. 
1.
The primary analysis will be repeated with all subjects categorized as 
responders/non-responders based on observed or imputed MBL volume data only 
(without taking into account their reasons for premature discontinuation of study 
drug).  Multiple imputation will be performed the same way as in the primary 
analysis.
2.
Last observation carried forward (LOCF):  The primary analysis will be repeated 
with missing Final Month MBL volume imputed using LOCF (instead of multiple 
imputation) as described in Section 11.2.3.1.


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3.
Non-responder imputation (NRI):  All subjects who have missing Final Month 
MBL volume will be considered as non-responders.  No multiple imputation will 
be performed.
4.
Observed cases:  The primary analysis will be repeated with the observed Final 
Month MBL volume as defined in Section 7.6.  Subjects who have missing Final 
Month MBL volume will be excluded from this analysis.
5.
The primary analysis will be repeated using the total MBL volume collected from 
validated products only.  All subjects will be categorized as responders/non-
responders in the same manner as done in the primary analysis (i.e., using the 
multiple imputation described in Section 11.2.2) with exception that all AH data 
(including that for Baseline MBL volume) are based on the total MBL volume 
collected from validated products only.
11.2.3.1
Using Last Observation Carried Forward (LOCF) Imputation
For subjects who have missing Final Month MBL volume and are on study drug at least 
56 days prior to and including the Reference Day, their second to last 28 days (the 
preceding 28-day window prior to the Final Month) of observed MBL volume will be 
carried forward to the Final Month.  If the second to last 28 days of MBL volume is also 
missing and the subject has at least 84 days prior to and including the Reference Day, her 
third to last 28 days of observed MBL volume will be carried forward to the Final Month, 
and so on.
Subjects who have missing Final Month MBL volume and don't have a 28-day observed 
MBL volume to be carried forward will be excluded from the sensitivity analysis using 
the LOCF imputation.
11.2.4
Adenomyosis Subset
The proportion of responders and difference in proportions between each elagolix 
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with Baseline adenomyosis present, and repeated for the subjects with adenomyosis at any 
time during the Baseline or Treatment Period (see definition in Section 11.3.5.3).  No 
statistical tests will be performed. This will be calculated using the same imputed datasets 
as in the primary analysis, subset for the subjects identified in the adenomyosis subset of 
interest.
For each of the adenomyosis subsets defined in Section 11.3.5.3, the statistical 
comparison between each elagolix dose group and placebo for subjects with Baseline 
adenomyosis present will be made using a logistic regression model including treatment 
as the main effect and Baseline MBL volume as a covariate in the integrated summary of 
efficacy (ISE) setting together data from Studies M12-815 and M12-817.  The proportion 
of responders, difference in proportions between each elagolix treatment group and 
placebo and odds ratio with corresponding 95% CI, and p-values will be calculated.  This 
will be calculated using the same imputed datasets as in the primary analysis for each 
respective study, subset for the subjects identified in the adenomyosis subset of interest.  
11.3
Ranked Secondary and Other Efficacy Analyses
Ranked secondary efficacy endpoints during the Treatment Period include the following 
in the order specified below:
1.
Change from Baseline in MBL volume to the Final Month;
2.
Percentage of subjects with suppression of bleeding (no bleeding allowed, spotting 
allowed) at the Final Month;
3.
Change from Baseline in MBL volume to Month 6;
4.
Change from Baseline in MBL volume to Month 3;
5.
Percentage of subjects with Baseline hemoglobin ≤ 10.5 g/dL who have an increase 
in hemoglobin > 2 g/dL at Month 6;
6.
Change from Baseline in MBL volume to Month 1.


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Other efficacy endpoints during the Treatment Period include the following:
●
Change and percent change from baseline in MBL volume; 
●
Percentage of subjects with MBL volume < 80 mL and 50% or greater 
reduction in MBL volume from baseline during 28-day intervals throughout 
the Treatment Period;
●
Percentage of subjects with amenorrhea;
●
Percentage of subjects with control of bleeding;
●
The number of bleeding days;
●
Change and percent change from baseline in hemoglobin concentration;
●
Patient Global Impression of Change (PGIC) questionnaire for Menstrual 
Bleeding and Non-Bleeding Uterine Fibroid Symptoms;
●
Change and percent change from baseline in fibroid and uterine volume;
●
Change from baseline for the UFS-QoL; 
●
Change from baseline for the EuroQoL-5D (EQ-5D-5L);
●
The Health Care Resource Utilization (HCRU) questionnaire;
●
Change from baseline for the WPAI.
11.3.1
Reduction of Bleeding
The change and percent change from Baseline to the Final Month in MBL volume 
obtained from the primary analysis after multiple imputation will be summarized by 
treatment group and compared between each elagolix dose group and placebo, using 
one-way ANCOVA with treatment as the main effect and Baseline MBL volume as a 
covariate.  Baseline and Final Month MBL volumes obtained for the primary analysis will 
be used.  This analysis will be used for the first ranked secondary efficacy endpoint:  
change from Baseline in MBL volume to Final Month. 
The change and percent change from Baseline to each 28-day window starting at Study 
Day 2 up to Study Day 168 in observed MBL volume in the Treatment Period 
(i.e., Month 1 (Study Days 2 – 28), Month 2 (Study Days 29 – 56), Month 3 (Study 


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Days 57 – 84), Month 4 (Study Days 85 – 112), Month 5 (Study Days 113 – 140), and 
Month 6 (Study Days 141 – 168)) will be summarized by treatment group and compared 
between each elagolix dose group and placebo, using one-way ANCOVA with treatment 
as the main effect and Baseline MBL volume as a covariate.  The change and percent 
change from Baseline to Final Month in observed MBL volume will be performed 
similarly.
For observed MBL volume in each 28-day interval, only subjects who did not prematurely 
discontinue in or before this 28-day interval will be included.  For example, for Study 
Days 29 – 56, it includes subjects who were on treatment for at least 56 days.
The comparison of change or percent change from Baseline in MBL volume to each 
month between each of the elagolix dose groups and placebo will be performed using a 
Mixed Model Repeated Measures (MMRM) model with observed MBL volume.  The 
MMRM analysis will include the fixed categorical effects of treatment, month and 
treatment-by-month interaction, and the continuous fixed covariate of Baseline MBL 
volume.  The REPEATED statement will be used for month in PROC MIXED with 
blocks in the covariance matrix identified by subject nested within treatment group.  The 
following covariance structures will be used to model the variance-covariance matrix:  
Spatial Power, Compound Symmetry, and Unstructured.  For each efficacy parameter 
(change or percent change from Baseline), the covariance structure converging to the best 
fit, as determined by the smallest value for the Akaike Information Criterion (AIC), will 
be used as the covariance structure in the MMRM analysis for that efficacy parameter.  
This analysis will be used for the ranked secondary efficacy endpoints: change from 
Baseline in MBL volume to Month 6, Month 3, and Month 1. 
Each of the two response criteria that are components of the primary endpoint, 
i.e., (1) MBL volume of < 80 mL at the Final Month; and (2) 50% or greater reduction in 
MBL volume from Baseline to the Final Month will be analyzed separately in the same
way as for the primary analysis.  Baseline and Final Month MBL volumes obtained for 
the primary analysis will be used.  The number and percentage of subjects meeting each 
criterion at the Final Month will be summarized by treatment group.  The comparison 


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between each elagolix dose group and placebo will be made using a logistic regression 
model including treatment as the main effect and Baseline MBL volume as a covariate.
Besides the method in the primary analysis, the number and percentage of subjects 
meeting each criterion at the Final Month will also be analyzed in the same way as in each 
sensitivity analysis for the primary endpoint, and in the analysis for subjects identified in 
the adenomyosis subset of interest.
The number and percentage of subjects satisfying either (1) MBL volume < 80 mL, or 
(2) 50% or greater reduction in MBL volume from Baseline, or both will be summarized 
for every 28-day interval by treatment group based on observed MBL volume.  
Plots will be provided by treatment group using the MBL volume data for the primary 
analysis (multiple imputation): 
●
Cumulative distribution function for MBL volume at Final Month; 
●
Cumulative distribution function for percent change from Baseline to Final 
Month in MBL volume; 
●
Proportion of responders at Final Month; 
●
Cumulative distribution function for change from baseline to Final Month in 
MBL volume. 
Plots will be provided by treatment group using observed MBL volume data: 
●
Cumulative distribution function for change from baseline in MBL volume to 
Month 1, 3, and 6; 
●
Mean change in MBL volume over time. 


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11.3.2
Amenorrhea, Suppression and Control of Bleeding
11.3.2.1
Amenorrhea
The number and percentage of subjects who achieved amenorrhea will be calculated for 
each treatment group.  All amenorrhea analysis, including cumulative amenorrhea 
analysis, will include subjects on study drug for at least 38 days prior to and including the 
Reference Day.  For each subject, amenorrhea is defined as having 0 days of bleeding or 
spotting during the last 28 days prior to and including the Reference Day with the interval 
starting from Study Day 11.  If a subject did not have evaluable AH data during the last 
28 days and no bleeding or spotting or "There was no visible blood on the sanitary 
products" was indicated on UBQ, then she is considered amenorrheic.
The number and percentage of subjects with amenorrhea will be summarized by treatment 
group and compared between each of the elagolix dose groups and placebo using a 
Pearson's chi-square test or Fisher's exact test (if ≥ 20% of the cells have expected counts 
less than 5).
Time to amenorrhea is defined as the number of days from the first study drug dose date 
to the day a subject achieving cumulative amenorrhea (i.e., the day a subject achieving 
amenorrhea – the first study drug dose date + 1).  For a subject who achieved amenorrhea, 
the day she achieved amenorrhea is defined as the next day of the last bleeding/spotting 
day during the Treatment Period.  The median, Q1, and Q3 of time to amenorrhea will be 
calculated using Kaplan-Meier method.
In the monthly analysis of bleeding for amenorrhea, the numerator is the number of 
subjects on treatment who did not bleed during the specified time window (but may have 
begun bleeding thereafter) and the denominator is the number of subjects on drug for the 
full window.  For the final visit, the denominator is the number of subjects with at least 
38 days on study drug prior to and including the Reference Day. 


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Table 9.
Monthly Analysis of Bleeding for Amenorrhea
Time Interval
Amenorrheic Status
Month 1
(Days 2 – 28)
Subject did not bleed during Study Days 2 – 28 (Truncated, 27 day 
window)
Month 2
(Days 29 – 56)
Subject did not bleed during Study Days 29 – 56 
Month 3
(Days 57 – 84)
Subject did not bleed during Study Days 57 – 84 
Month 4
(Days 85 – 112)
Subject did not bleed during Study Days 85 – 112 
Month 5
(Days 113 – 140)
Subject did not bleed during Study Days 113 – 140 
Month 6
(Days 141 – 168)
Subject did not bleed during Study Days 141 – 168 
Final Month
(last 28 days prior to and 
including the Reference Day)
Subject did not bleed during the last 28 days prior to and including the 
Reference Day
Incidence and cumulative incidence of amenorrhea at each month will be reported using 
the categories specified in in Table 10.  
The summary will be provided in the following 2 ways:  (1) including only subjects who 
have at least 155 days (lower bound of Month 6 visit window as in Table 1) on study drug 
prior to and including the Reference Day.  The denominator is the number of subjects who 
have at least 155 days on study drug prior to and including the Reference Day.  (2) LOCF:  
including all subjects who have at least 38 days on study drug prior to and including the 
Reference Day.  If a subject meets the criteria for amenorrhea but discontinues, this 
subject's amenorrheic status was carried forward to the time points after the subject has 
discontinued study drug.  The denominator is the number of subjects who have at least 
38 days on study drug prior to and including the Reference Day.
Plots will be provided by treatment group for percentage of subjects with incidence and 
cumulative incidence of amenorrhea during the Treatment Period, respectively. 


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Table 10.
Categorical Summary of Incidence and Cumulative Incidence of 
Amenorrhea
Analysis
Time Interval
Numerator Calculation
Incidence
Month 2
(≤ Study Day 56)
Last bleeding/spotting day occurred during Study 
Days 1 – 28 and continued not bleeding/spotting every 
day thereafter until and including the Reference Day
Month 3
(Study Day 57 – 84)
Last bleeding/spotting day occurred during Study 
Days 29 – 56 and continued not bleeding/spotting every 
day thereafter until and including the Reference Day
Month 4
(Study Day 85 – 112)
Last bleeding/spotting day occurred during Study 
Days 57 – 84 and continued not bleeding/spotting every 
day thereafter until and including the Reference Day
Month 5
(Study Day 113 – 140)
Last bleeding/spotting day occurred during Study 
Days 85 – 112 and continued not bleeding/spotting every 
day thereafter until and including the Reference Day
Month 6
(Study Day 141 – 168)
Last bleeding/spotting day occurred during Study 
Days 113 – 140 and continued not bleeding/spotting 
every day thereafter until and including the Reference 
Day
Cumulative
Month 2
(≤ Study Day 56)
Last bleeding/spotting day occurred before Study Day 29 
and continued not bleeding/spotting every day thereafter 
until and including the Reference Day
Month 3
(Study Day 57 – 84)
Last bleeding/spotting day occurred before Study Day 57 
and continued not bleeding/spotting every day thereafter 
until and including the Reference Day
Month 4
(Study Day 85 – 112)
Last bleeding/spotting day occurred before Study Day 85 
and continued not bleeding/spotting every day thereafter 
until and including the Reference Day
Month 5
(Study Day 113 – 140)
Last bleeding/spotting day occurred before Study 
Day 113 and continued not bleeding/spotting every day 
thereafter until and including the Reference Day
Month 6
(Study Day 141 – 168)
Last bleeding/spotting day occurred before Study 
Day 141 and continued not bleeding/spotting every day 
thereafter until and including the Reference Day
11.3.2.2
Suppression of Bleeding
Suppression of bleeding is defined similarly to amenorrhea as in Section 11.3.2 except 
that spotting is allowed.  For each subject, achieving suppression of bleeding is defined as 


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having 0 days of bleeding during the last 28 days prior to and including the Reference 
Day with the interval starting from Study Day 11.  The suppression of bleeding analysis 
will include subjects with at least 38 days prior to and including the Reference Day.  If a 
subject did not have evaluable AH data during the last 28 days and no bleeding was 
indicated on UBQ ("Subject only has spotting that did not require the use of sanitary 
products" or "There was no visible blood on the sanitary products" was allowed), then the 
subject is considered having achieved suppression of bleeding. 
The number and percentage of subjects achieving suppression of bleeding will be 
summarized by treatment group and will be compared between each of the elagolix dose 
groups and placebo using a Pearson's chi-square test or Fisher's exact test (if ≥ 20% of the 
cells have expected counts less than 5). 
Time to suppression of bleeding is defined as the number of days from the first study drug 
dose date to the day a subject achieving suppression of bleeding (i.e., the day a subject 
achieving suppression of bleeding – the first study drug dose date + 1).  For a subject who 
achieved suppression of bleeding, the day she achieved suppression of bleeding is defined 
as the next day of the last bleeding day during the Treatment Period.  The median, Q1, 
and Q3 of time to suppression of bleeding will be calculated using Kaplan-Meier method.
Monthly analysis of bleeding for suppression of bleeding, incidence and cumulative 
incidence of suppression of bleeding will be provided in the same way as was done for 
amenorrhea in Table 9 and Table 10.  Plots will be provided by treatment group for 
percentage of subjects with incidence and cumulative incidence of suppression of 
bleeding during the Treatment Period, respectively. 
11.3.2.3
Control of Bleeding
For each subject, achieving control of bleeding is defined as having 0 days of bleeding 
and up to 1 day of spotting during the last 28 days prior to and including the Reference 
Day with the interval starting from Study Day 11.  The control of bleeding analysis will 
include subjects with at least 38 days prior to and including the Reference Day.  If a 


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subject did not have evaluable AH data during the last 28 days and no bleeding or spotting 
or "There was no visible blood on the sanitary products" was indicated on UBQ, then the 
subject is considered having achieved control of bleeding.  If the subject indicates 
bleeding or spotting on the UBQ, the subject does not meet the criteria for control of 
bleeding.
The number and percentage of subjects achieving control of bleeding will be summarized 
by treatment group and will be compared between each of the elagolix dose groups and 
placebo using a Pearson's chi-square test or Fisher's exact test (if ≥ 20% of the cells have 
expected counts less than 5).
11.3.3
Bleeding Days
The numbers of bleeding days by intensity categories (Section 7.6.2) will be calculated for 
each 28-day interval starting at Study Day 2 up to Study Day 168 in the Treatment Period 
(i.e., Study Days 2 – 28, Study Days 29 – 56, Study Days 57 – 84, Study Days 85 – 112, 
Study Days 113 – 140, and Study Days 141 – 168) and the first 28-day interval in the 
Post-Treatment Follow-up Period (i.e., Study End Days 1 – 28) for each treatment group.  
For each 28-day interval, each analysis includes subjects who did not premature 
discontinue in or before this 28-day interval.  For example, for Study Days 29 – 56, it 
includes subjects who were on treatment for at least 56 days.  For Final Month analysis, it 
includes subjects who were on treatment for at least 38 days prior to and including the 
Reference Day.  The summary of average number of bleeding days in a 28 day window 
during the Treatment Period will be provided for each treatment group by intensity 
categories.  No statistical tests will be performed.
A summary of average number of days by bleeding intensity categories in each 28-day 
interval during the treatment period will be provided for the following four populations, 
respectively:  1) the subjects with > 0 bleeding days in Month 1 (Study Days 2 – 28);
2) the subjects who did not bleed (0 bleeding days) in Month 1 (Study Days 2 – 28); 
3) the subjects with > 0 bleeding/spotting days in Month 1 (Study Days 2 – 28); 4) the 
subjects with 0 bleeding/spotting days in Month 1 (Study Days 2 – 28).  


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If a subject did not have evaluable AH data during an interval and no bleeding was 
indicated on UBQ ("Subject only has spotting that did not require the use of sanitary 
products" or "There was no visible blood on the sanitary products" was allowed), then the 
number of bleeding days over the interval is 0.  The number and percentage for each 
treatment group and overall will be provided for subjects who did not have evaluable AH 
data during an interval and bleeding was indicated on UBQ.
The change and percent change from Baseline in the numbers of bleeding/spotting days to 
each 28-day interval and Final Month in the Treatment Period and the first 28-day interval 
in the Post-Treatment Follow-up Period will be summarized for each treatment group, 
respectively.  The comparison between each elagolix dose group and placebo will be 
performed using a one-way ANCOVA method with treatment as the main effect and 
Baseline as a covariate for the Treatment Period only.  The same analysis will be 
performed for bleeding days as well. 
11.3.4
Hemoglobin Concentration
Hemoglobin (Hgb) concentration data will be summarized as observed; missing data will 
not be imputed.
Baseline Hgb concentration is defined as the last measurement prior to or on the first dose 
date of study drug.  The change and percent change from Baseline in Hgb concentration to 
Months 1 – 6 during the Treatment Period will be analyzed with one-way ANCOVA with 
treatment group as the main effect and Baseline as a covariate.
The number and percentage of subjects with changes in Hgb concentration from Baseline 
to Months 1 – 6 during the Treatment Period in each of the following categories will be 
summarized by treatment group and compared between each elagolix dose group and 
placebo, using a Pearson's chi-square test or Fisher's exact test (if ≥ 20% of the cells have 
expected counts less than 5).
●
Change from Baseline in Hgb ≤ –1.0 g/dL
●
–1.0 g/dL < Change from Baseline in Hgb ≤ –0.5 g/dL


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●
–0.5 g/dL < Change from Baseline in Hgb < 0.5 g/dL
●
0.5 g/dL ≤ Change from Baseline in Hgb < 1.0 g/dL 
●
1.0 g/dL ≤ Change from Baseline in Hgb < 1.5 g/dL
●
1.5 g/dL ≤ Change from Baseline in Hgb < 2.0 g/dL
●
Change from Baseline in Hgb ≥ 2.0 g/dL
Also, shift tables from Baseline to Month 3 and Month 6 will be summarized by the 
following categories.
●
Hgb ≤ 10.5 g/dL
●
10.5 g/dL < Hgb ≤ 12 g/dL
●
Hgb > 12 g/dL
The number and percentage of subjects who had Hgb Baseline ≤ 10.5 g/dL and have an 
increase in Hgb concentration > 2 g/dL from Baseline will be summarized for each month 
by treatment group and compared between each elagolix dose group and placebo, using a 
Pearson's chi-square test or Fisher's exact test (if ≥ 20% of the cells have expected counts 
less than 5).  The number and percentage of subjects who had Hgb Baseline ≤ 10.5 g/dL 
and have an increase in Hgb concentration > 1 g/dL from Baseline will be summarized for 
each month by treatment group and compared between each elagolix dose group and 
placebo, using a Pearson's chi-square test or Fisher's exact test (if ≥ 20% of the cells have 
expected counts less than 5). 
In addition, the number and percentage of subjects who have an increase in Hgb 
concentration > 1 g/dL from Baseline will be summarized for each month by treatment 
group and Baseline Hgb concentration categories as follows.  Same summary will be 
provided for increase in Hgb concentration > 2 g/dL from Baseline to each month.
●
Hgb ≤ 10.5 g/dL
●
10.5 g/dL < Hgb ≤ 12 g/dL
●
Hgb > 12 g/dL


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11.3.5
Fibroid and Uterine Volume, FIGO Classification, 
Adenomyosis, and Post-Treatment Menses
11.3.5.1
Fibroid and Uterine Volume
Fibroid and uterine volume data will be summarized as observed; missing data will not be 
imputed.  Analyses will be conducted separately for results obtained from TAU/TVU and 
MRI.
The change and percent change in the volume of the largest (primary) fibroid, the total 
fibroid volume (3 largest fibroids), and the uterine volume from Baseline to Month 3 (if 
applicable) and Month 6 during the Treatment Period will be summarized for each 
treatment group and compared between each elagolix dose group and placebo using an 
ANCOVA model with treatment as the main effect and Baseline as a covariate.  The 
change and percent change at Post-Treatment Month 3 and Post-Treatment Month 6 (if 
applicable) during the Post-Treatment Follow-up Period will also be summarized for each 
treatment group.
The number and percentage of subjects with ≥ 25% reduction from Baseline in total 
fibroid volume at Month 3 (if applicable) and Month 6 each during the Treatment Period 
will be summarized for each treatment group and analyzed using a logistic regression 
model, including treatment group as the main effect and Baseline volume as a covariate to 
compare each elagolix dose group to placebo.  The same analysis will be performed for 
largest (primary) fibroid volume and uterine volume, respectively.   
11.3.5.2
FIGO Classification
The number and percentage of subjects with fibroids at each location (e.g., intramural, 
subserosal, submucosal non-pedunculated, and subserosal pedunculated) according to the 
FIGO classification3 will be summarized for each treatment group at Baseline, Month 3 (if 
applicable) and Month 6 during the Treatment Period and Post-Treatment Month 3 and 
Post-Treatment Month 6 (if applicable) during the Post-Treatment Follow-up Period.  No 
statistical test will be performed.


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


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menstrual cycle and the next post-treatment menstrual cycle) is 1 day apart or less 
(i.e., out of the two consecutive cycles, the start date of the second cycle – the end date of 
the first cycle ≤2), these two menstrual cycles will be combined as one menstrual cycle in 
determining the first post-treatment menses.
Volume of bleeding in a subject's first post-treatment menses will be calculated and 
summarized. 
Time to first post-treatment menses and volume of bleeding in first post-treatment menses 
will be summarized and analyzed separately for the following groups of subjects:
1.
All subjects who entered the Post-Treatment Follow-up Period.
2.
Subjects who entered the Post-Treatment Follow-up Period and were amenorrhiec 
at the Final Month in the Treatment Period.  Amenorrhea is defined as in 
Section 11.3.2.
3.
Subjects who entered the Post-Treatment Follow-up Period and achieved 
suppression of bleeding at the Final Month in the Treatment Period.  Suppression 
of bleeding is defined as in Section 11.3.3.
Based on the time to first post-treatment menses during the Post-Treatment Follow-up 
Period, each subject will be categorized into one of the following non-overlapping 
categories:  Study End Days 1 – 28, Study End Days 29 – 56, Study End Days 57 – 84, 
Study End Days 85 – 112, Study End Days 113 – 140, Study End Days 141 – 168, and 
Study End Days ≥168.  Summary tables will present the number and percentage of 
subjects in the specified categories.
11.3.6
Quality of Life Questionnaire
11.3.6.1
Uterine Fibroid Symptoms Quality of Life (UFS-QoL) 
Improvement in quality of life will be assessed on the UFS-QoL Questionnaire (4-week 
recall).  The change from Baseline to Month 3, Month 6, and Final Visit during the 


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Treatment Period will be calculated and summarized by treatment group for each of the 
UFS-QoL subscales (symptom severity, concern, activities, energy/mood, control, self-
conscious, and sexual function) and the HRQL total.  The change from Baseline in the 
Treatment Period will be analyzed using ANCOVA with treatment as the main effect and 
corresponding Baseline UFS-QoL as a covariate to compare each elagolix dose group to 
placebo.  Missing scores will be dealt with using the methods recommended by the 
UFS-QoL Scoring Manual.  The UFS-QoL questionnaire is presented in Appendix A, and 
the relevant UFS-QoL Scoring Manual is presented in Appendix B.
11.3.6.2
EQ-5D-5L
The EQ-5D-5L questions and relevant scoring rules are presented in Appendix E.
The number and percentage of subjects with answers in each category of the EQ-5D-5L 
(Mobility, Self-care, Usual activities, Pain/Discomfort, and Anxiety/Depression) domains 
will be summarized at Baseline, each planned assessment, and Final Visit during the 
Treatment Period by treatment group. 
Subject's responses to the EQ-5D-5L will be combined into a unique health state using a 
5-digit code with 1 digit from each of the 5 dimensions at Baseline, each planned 
assessment, and Final Visit during the Treatment Period.  The EQ-5D-5L states will be 
converted into a single preference-weighted health utility index score by applying 
country-specific weights if available or US weights if country-specific weights are 
unavailable.6,7
The EQ VAS scale is numbered from 0 – 100, with 100 indicating the best health that a 
subject can imagine, and 0 indicating the worst health that a subject can imagine.  
The change from Baseline to each planned assessment during the Treatment Period for 
health utility index score and EQ VAS will be analyzed using ANCOVA with treatment 
as the main effect and Baseline as a covariate to compare each elagolix dose group to 
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11.3.6.3
Patient Global Impression of Change (PGIC)
11.3.6.3.1
PGIC on Menstrual Bleeding Questionnaire
For PGIC on menstrual bleeding (PGIC – MB, Appendix C), the number and percentage 
of subjects in each response category will be summarized at Month 1, Month 3, Month 6, 
and Final Visit by treatment group.  No statistical tests will be performed.
For PGIC – MB, the response categories of "Very Much Improved" and "Much 
Improved" will be combined together.  The remaining five categories of the PGIC scale 
will be combined and labeled "Otherwise." The number and percentage of subjects with 
response of (a) "Very Much Improved" or "Much Improved," and (b) "Otherwise" will be 
summarized at Month 1, Month 3, Month 6, and Final Visit by treatment group.  
Comparisons will be made using a Pearson's chi-square test or Fisher's exact test (if 
≥20% of the cells have expected counts less than 5) for Month 1, Month 3, Month 6, and 
Final Visit assessments in the Treatment Period.
11.3.6.3.2
PGIC on Non-Bleeding Uterine Fibroid Symptoms 
Questionnaire
For each of the PGIC questions on non-bleeding uterine fibroids symptoms (PGIC –
NBUFS, Appendix D), the number and percentage of subjects in each response category 
will be summarized at Month 1, Month 3, Month 6, and Final Visit by treatment group.  
No statistical comparison will be performed.
For each of the PGIC – NBUFS questions, the response categories of "Very Much 
Improved" and "Much Improved" will be combined together.  The remaining 
five categories of the PGIC scale will be combined and labeled "Otherwise."  The number 
and percentage of subjects with response of (a) "Very Much Improved" or "Much 
Improved," and (b) "Otherwise" will be summarized at Month 1, Month 3, Month 6, and 
Final Visit by treatment group.  Comparisons will be made using a Pearson's chi-square 
test or Fisher's exact test (if ≥ 20% of the cells have expected counts less than 5) for 
Month 1, Month 3, Month 6, and Final Visit assessments in the Treatment Period.


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11.3.6.4
Work Productivity and Activity Questionnaire:  Uterine 
Fibroids (WPAI:UF)
For each of the measures as presented in the scoring guide Appendix K based on the data 
collected via the WPAI:UF, the change from Baseline to Month 6 and Final Visit during 
the Treatment Period will be summarized by treatment group.  Comparisons between each 
elagolix dose group and placebo for each of these specific measures will be performed 
using one-way ANCOVA with treatment as the main effect and the corresponding score at 
Baseline as a covariate.  The WPAI:UF is presented in Appendix J, and the WPAI:UF 
scoring guide is presented in Appendix K.
11.3.6.5
Health Care Resource Utilization Questionnaire (HCRU)
HCRU data will be summarized as observed; missing data will not be imputed.  HCRU 
data will be summarized by treatment group at Months 1 – 6 and Final Visit.  Version 1 
and Version 2 of HCRU will be summarized separately.  Descriptive statistics will be 
presented for the total number of Non-Study Health Care Practitioner Visits, overall and 
by the type of facility subjects were seen at.  The number and percentage of subjects will 
also be presented by the type of Non-Study Health Care Practitioner who administered 
care to the subject.
The number and percentage of subjects will be presented by the type of diagnostic or 
therapeutic procedures performed based on HCRU at Months 1 – 6 and Final Visit during 
the Treatment Period.  No statistical tests will be performed.
11.3.6.6
Number of Days in Hospital
Hospitalization related data will be summarized as observed; missing data will not be 
imputed.  Hospitalization data will be summarized by treatment group in the Treatment 
Period based on the Adverse Events eCRF.
The number and percentage of subjects who were hospitalized or had prolonged 
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had prolonged hospitalization multiple times during the Treatment Period, she will be 
counted only once. 
The number of hospitalizations will be summarized by treatment group.  The number of 
days in hospital (i.e., discharge date – admission date + 1) will be summarized by 
treatment group.  Only hospitalizations with an admission date on or after the first dose 
date and within 30 days following the last dose date (i.e., first dose date ≤ admission date 
≤ last dose date + 30) are included in the analysis of the number of days in hospital.  If 
discharge date or admission date is missing, then the hospitalization will be excluded from 
the analysis of the number of days in hospital.  No statistical tests will be performed.
11.4
Handling of Multiplicity
The primary comparison for all analyses will be made between elagolix 300 mg BID in 
combination with E2/NETA and placebo.  The elagolix 300 mg BID alone group serves as 
a reference arm. 
Therefore, no adjustment of the type I error rate (alpha) for primary analysis of the 
primary endpoint is needed.  Ranked secondary endpoints will follow a fixed-sequence 
testing procedure.11
12.0
Safety Analysis
12.1
General Considerations
Safety analyses will be carried out using the Safety Analysis Set, which includes all 
subjects who received at least one dose of study drug.  Safety data will be summarized by 
actual treatment received.  If a subject receives more than one type of study drug, safety 
data will be analyzed in the treatment group to which she was randomized to.  All safety 
analyses will be based on observed data.  For analyses of safety endpoints, subjects who 
are missing an evaluation will not be included in the analysis of that particular 
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For continuous variables, when the analyses of change and/or percent change from 
Baseline to post-baseline visit(s) are performed, the within-group change from Baseline to 
each relevant visit will be summarized by treatment group with the mean, SD, and 95% 
CIs.  The between-group differences will be summarized with the mean, SE, 95% CIs, 
and P value when applicable.  At each post-baseline visit, the Baseline mean and post-
baseline visit mean will be calculated for all subjects with baseline and post-baseline 
value at that visit by treatment group.  
For qualitative categorical variables, Fisher's exact test will be used to analyze between-
group differences when applicable.  Categorical data will be summarized by number and 
percentage of subjects by treatment group.  
Pregnancies and outcomes will also be summarized by treatment group.
Statistical comparisons will be performed between each elagolix dose group and placebo 
in the Treatment Period only, unless otherwise specified.  There will be no testing for 
safety endpoints in the Post-Treatment Follow-up Period.
Information regarding corresponding statistical methods for analyses and any additional 
statistical measures required for a specific variable/endpoint will be specified in the 
relevant sections.
12.2
Adverse Events
Adverse events (AEs) will be summarized using system organ classes (SOCs) and 
preferred terms (PTs) from the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 19.0 or higher.  
For each AE summary, the number and percentage of subjects experiencing at least 
one AE will be presented.  Subjects reporting more than one AE within a SOC will be 
counted only once for that SOC.  Subjects reporting more than one AE for a PT will be 
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Treatment-emergent AEs are defined as AEs with a start date on or after the first dose of 
study drug.  AEs starting more than 30 days following discontinuation of study drug will 
not be included in summaries of treatment-emergent AEs.  Post-Treatment AEs are 
defined as AEs starting more than 30 days following discontinuation of study drug in the 
Treatment Period of this study.  
When summarizing AEs by relationship or severity, if a subject has an event with 
unknown severity or relationship then the subject will be counted in the 
severity/relationship category of "unknown" even if the subject has a second occurrence 
of the same event with a severity/relationship present.  The only exception is if the subject 
has a second occurrence of the same event with the most extreme severity (i.e., "severe") 
or one of the two most extreme relationship categories (i.e., "probably related" or 
"possibly related").  In this case, the subject will be counted under these most extreme 
severity/relationship categories.
Treatment Period
The number and percentage of subjects with treatment-emergent AEs will be calculated 
by treatment group as follows:
●
Any AEs
●
Any AEs by system organ class (SOC) and preferred term (PT)
●
Any AEs occurring in ≥ 5% of subjects by system organ class (SOC) and 
preferred term (PT)
●
Any AEs by PT in descending frequency of elagolix 300 mg BID plus 
E2/NETA treatment group
●
Any AEs by maximum severity
●
Any AEs by maximum relationship
●
Any AEs reasonably possibly related to study drug 
●
Any AEs leading to study drug discontinuation
●
Any serious AEs (SAEs)
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●
Any SAEs leading to study drug discontinuation
●
Any AEs of special interest as specified in Appendix Q
●
Any AEs leading to death
A listing by treatment group of treatment-emergent AEs with subject IDs will be 
generated.  Listings of all treatment-emergent SAEs, AEs leading to death, and AEs 
leading to study drug discontinuation will be generated.
Summary of total number of hot flush and night sweat by subject-reported severity 
categories, summary of total number of hot flush and night sweat by maximum subject-
reported severity, and summary of time to first onset of hot flush and night sweat will be 
provided.  Listings of subjects associated with hot flush and night sweat will also be 
provided.
Post-Treatment Follow-Up Period
The Post-Treatment AEs will be summarized as follows:
●
Any AEs
●
Any SAEs.
12.3
Laboratory Variables
Hematology, clinical chemistry, urinalysis, and endocrine panel variables collected in this 
study are specified in the protocol.  An overall summary will be provided for all 
laboratory variables.  For all other analysis, analysis will be performed for the following 
laboratory variables:  lipid variables, liver variables (alkaline phosphatase, ALT, AST, 
bilirubin), hemoglobin, hematocrit, platelet count, and Red Blood Cell (RBC) count.
For lipid variables, in addition to low-density lipoprotein cholesterol (LDL-C), high-
density lipoprotein cholesterol (HDL-C), total cholesterol, triglycerides (TG), and 
apolipoprotein A and B, the following ratios will be included:  the ratio of total 


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cholesterol to HDL-C, the ratio of LDL-C to HDL-C, the ratio of TG to HDL-C, and the 
ratio of non-HDL-C (calculated as total cholesterol minus HDL-C) to HDL-C.
12.3.1
Analysis of Laboratory Variables
Treatment Period
All laboratory variables will be summarized with mean, median, standard deviation, 
minimum, and maximum by treatment group.
For continuous laboratory variables, the analyses of change (for all laboratory variables of 
interest) and percent change (only for lipid variables) from Baseline to each relevant visit 
in the Treatment Period will be performed.  The mean change from Baseline to each 
relevant visit in the Treatment Period will be compared between each of the elagolix dose 
groups and placebo using one-way ANOVA with treatment group as the main effect, 
unless otherwise specified.  
In the Treatment Period, the laboratory data will be categorized as low, normal, or high 
based on the normal ranges of the laboratory used in this study.  The low or high 
laboratory values will be flagged in the data listings.
In the Treatment Period, shift tables for change from Baseline according to the normal 
range will be provided for laboratory parameters mentioned above.  The shift tables will 
tabulate the number and percentage of subjects with baseline values of high or normal to 
post-baseline low, baseline values of low or normal to post-baseline high, baseline values 
of high or normal to final post-baseline low, baseline values of low or normal to final 
post-baseline high.  The final value in the Treatment Period refers to the last non-missing 
value collected within 3 days following the last dose of study drug.  
In the Treatment Period, shift tables for change from Baseline to the minimum, maximum, 
and final value will also be presented based on the Common Terminology Criteria for 
Adverse Events (CTCAE) v 4.0 grades5 for the laboratory tests.  For those analytes that 
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Elagolix Studies will be used as specified in Appendix R.  The final value in the 
Treatment Period is as defined above.  The number and percentage of subjects meeting the 
CTCAE will be summarized for hemoglobin and hemocrit by treatment group in the 
Treatment Period. 
The number and percentage of subjects meeting the following criteria will be summarized 
at Baseline and each relevant visit by treatment group in the Treatment Period:
●
Total cholesterol:  ≤ 300, > 300 – ≤ 400, > 400 – ≤ 500, and > 500 mg/dL
●
HDL-C:  < 40 and ≥ 40 mg/dL
●
LDL-C:  < 130, ≥ 130 – < 160, ≥ 160 – < 190, and ≥ 190 mg/dL
●
TG:  ≤ 150, > 150 – ≤ 300, > 300 – ≤ 500, > 500 – ≤ 1000, and > 1000 mg/dL
●
LDL-C/HDL-C ratio:  ≤ 3, and > 3
●
Total cholesterol/HDL-C ratio:  ≤ 4.5, and > 4.5.
In addition, the number and percentage of subjects who have potentially clinically 
significant (PCS) lipid values meeting the following criteria any time during the 
Treatment Period will be summarized by treatment group:
●
Total cholesterol > 200 mg/dL
●
LDL-C > 130 mg/dL
●
LDL-C > 160 mg/dL
●
HDL-C < 40 mg/dL
●
TG > 150 mg/dL
●
TG/HDL-C ratio > 3.5
●
LDL-C/HDL-C ratio > 4.
Plots will be provided by treatment group for HDL-C, LDL-C, triglycerides, and 
hemoglobin during the Treatment Period: 
●
Final post-baseline lab values vs. Baseline lab values; 


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Final post-baseline lab values vs. Baseline lab values for subjects with NCI 
CTCAE Grade 3 or 4; 
●
Maximum post-baseline lab values vs. Baseline lab values;
●
Maximum
Plots will be provided by treatment group for HDL-C, LDL-C, and triglycerides during 
the Treatment Period: 
●
Mean percent change from Baseline in lipid over month.
Post-Treatment Follow-Up Period
Laboratory data collected more than 3 days after the last dose of study drug in the 
Treatment Period will be included in the summary of data from the Post-Treatment 
Follow-up Period.  Baseline for summaries/analyses in the Post-Treatment Follow-up 
Period is the same as Baseline for summaries/analyses in the Treatment Period.
In the Post-Treatment Follow-up Period, the following summaries will be presented by 
treatment group:
●
During the Post-Treatment Follow-up Period, shift tables for change from 
Baseline to relevant Post-Treatment Follow-up visit(s) according to the normal 
ranges will be provided for LDL-C, HDL-C, TG, and total cholesterol.  
●
During the Post-Treatment Follow-up Period, shift tables for change from 
Baseline to relevant Post-Treatment Follow-up visit(s) will also be presented 
based on the CTCAE grades for LDL-C, HDL-C, TG, and total cholesterol.
●
Change in liver enzymes (SGPT/ALT, SGOT/AST, total bilirubin, and 
alkaline phosphatase) and lipid parameters (LDL-C, HDL-C, TG, and total 
cholesterol) from Baseline to relevant Post-Treatment Follow-up visit(s) will 
be summarized by treatment group with descriptive statistics.


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12.3.2
Assessment of Hepatotoxicity 
The number and percentage of subjects in each treatment group with maximum 
on-treatment laboratory values meeting the following criteria compared to the upper limit 
of normal (ULN) will be summarized by treatment group to assess potential 
hepatotoxicity.
●
ALT ≥ 3 × ULN and total bilirubin ≥ 2 × ULN
●
AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN
●
ALT and AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN
●
ALT ≥ 3 × ULN and total bilirubin < 2 × ULN
●
AST ≥ 3 × ULN and total bilirubin < 2 × ULN
●
ALT and AST ≥ 3 × ULN and total bilirubin < 2 × ULN.
The maximum ratio relative to the ULN is used to determine if subjects met the criteria 
listed above.  The ALT, AST, and total bilirubin values do not need to be concurrent in 
order to meet the defined criteria.  For ALT, AST, and total bilirubin, a subject is counted 
if the post-baseline laboratory value during the Treatment Period meets the above criteria 
regardless of Baseline laboratory value (i.e., the post-baseline laboratory value does not 
need to be worse than Baseline laboratory value).
A listing of all ALT, AST, total bilirubin, and alkaline phosphatase values will be 
provided for each subject who met any of the criteria defined above.
12.4
Bone Mineral Density
All analyses and summaries of bone mineral density (BMD) will be performed for each 
segment, i.e., femoral neck, lumbar spine, and total hip.  For subjects who had a right-side 
scan performed (rare instances), their data for right femoral neck and right femoral total 
hip were included in the analysis with the data for the left femoral neck and left total hip, 
respectively (available for the majority of subjects), and an additional analysis was 
performed using the left side only.  If more than one scan is reported for an anatomical 


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segment within an analysis window, the worse (the lower value) of the multiple 
measurements were used for analysis for each anatomical segment.
12.4.1
BMD in the Treatment Period
BMD
A continuous summary of BMD at Baseline, Between Month 3 and Month 6, Month 6, 
and Final Visit will be provided by treatment group.  This summary will include the 
mean, SD, median, minimum, maximum, and first and third quartiles.  This analysis will 
be repeated excluding subjects who switched machine manufacturer type (Lunar or 
Hologic), subjects with scans only on Lunar machines, and subjects with scans only on 
Hologic machines.
The analysis of percent change in BMD from Baseline to each relevant visit in the 
Treatment Period will be performed.  The mean percent change in BMD from baseline to 
Month 6 and Final Visit during the Treatment Period will be compared between each 
elagolix dose group and placebo, as well as between elagolix 300 mg BID group and 
elagolix 300 mg BID + E2/NETA group, using ANCOVA with treatment as the main 
effect and Baseline value of corresponding parameter as a covariate.  This analysis will be 
repeated excluding subjects who switched machine manufacturer type (Lunar or Hologic), 
subjects with scans only on Lunar machines, and subjects with scans only on Hologic 
machines.  
The number and percentage of subjects with percent change from Baseline to Between 
Month 3 and Month 6, Month 6, and Final Visit in the Treatment Period in mutually 
exclusive categories of BMD decrease:  ≤ 0%, > 0% – ≤ 1.5%, > 1.5% – ≤ 3%, > 3% –
≤5%, > 5% – < 8%, and ≥ 8% will be summarized by treatment group and comparison 
between each elagolix dose group and placebo, as well as between elagolix 300 mg BID 
group and elagolix 300 mg BID + E2/NETA group, will be made using Fisher's exact test.


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Z-Score and T-Score 
A continuous summary of the Z-score at Baseline, Between Month 3 and Month 6, 
Month 6, and Final Visit will be provided by treatment group.  This summary will include 
the mean, SD, median, minimum, maximum, and first and third quartiles.  A categorical 
summary of Z-score will be summarized at Baseline, Between Month 3 and Month 6, 
Month 6, and Final Visit for the following categories:  ≤ –2.0, > –2.0 to ≤ –1.5, > –1.5 to 
≤ –1.0, and > –1.0 for all subjects, subjects with BMD decrease ≥ 3% at Month 6, and 
subjects with BMD decrease < 3% at Month 6, respectively.  The categorical summary of 
worst Z-score at any time in the Treatment Period will be produced by treatment group for 
each anatomical region.
A continuous summary of the T-score at Baseline, Between Month 3 and Month 6, 
Month 6, and Final Visit will be provided by treatment group.  A categorical summary of 
T-score will be summarized at Baseline, Between Month 3 and Month 6, Month 6, and 
Final Visit for the following categories:  ≤ –2.5, > –2.5 to < –1.0, and ≥ –1.0 for all 
subjects, subjects with BMD decrease ≥ 3% at Month 6, and subjects with BMD decrease 
< 3% at Month 6, respectively.  The categorical summary of worst T-score at any time in 
the Treatment Period will be produced by treatment group for each anatomical region.
Plots will be provided by treatment group for:
●
Percent change from Baseline to Month 6 in BMD vs. Baseline BMD values;
●
Percent change from Baseline to Month 6 in BMD vs. Baseline BMD values 
for subjects with greater than 3% BMD decrease;
●
Percent change from Baseline in BMD at Month 6 vs. Baseline Z-score;
●
Maximum percent change from Baseline to Post-Baseline in BMD vs. 
Baseline Z-score;
●
Categorical summary of lumbar spine BMD percent change from Baseline to 
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A plot by treatment group of the cumulative distribution function of percent change from 
baseline in BMD at Month 6 and the Z-scores at Month 6 will be provided.  Additionally, 
the boxplots of Z-scores at baseline, Month 6, Post-Treatment Month 6, and Post-
treatment Month 12 will be provided by treatment group.  This will be repeated for 
T-scores.
Listings of subjects meeting the following thresholds during the treatment period will be 
provided:
●
Listing of subjects with bone decrease ≥ 8%
●
Listing of subjects with Z-score ≤ –1.5
●
Listing of subjects with T-score ≤ –1.5
●
Listing of subjects with Z-score ≤ –1.5 and bone decrease ≥ 8% in the same 
region
●
Listing of subjects with T-score ≤ –1.5 and bone decrease ≥ 8% in the same 
region.
12.4.2
BMD in the Post-Treatment Follow-Up Period
For subjects who do not enter the extension study, percent change from Baseline to Post-
Treatment Follow-up Month 6, Post-Treatment Follow-up Months 7 – 11, and Post-
Treatment Follow-up Month 12 will be summarized for each treatment group with 
descriptive statistics.  There will be no statistical testing of Post-Treatment Follow-up 
BMD values.
The analysis of percent change in BMD will be repeated to include only the subset of 
subjects who had a Treatment Month 6 and a Post-Treatment Follow-up Month 6 scan.  
Similarly, this analysis will be repeated to include only the subset of subjects who had a 
Treatment Month 6 and a Post-Treatment Follow-up Month 12 scan.
Percent change from Baseline in BMD to each of the Post-Treatment visits will be 
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BMD decrease:  ≤ 0%, > 0% – ≤ 1.5%, > 1.5% – ≤ 3%, > 3% – ≤ 5%, > 5% – < 8%, and 
≥8%.  
Cross-tabulations of the number and percentage of subjects in each of the previously 
noted categories of percent change from Baseline for the following:
●
Treatment Month 6 to Post-Treatment Follow-up Month 6
●
Treatment Month 6 to Post-Treatment Follow-up Month 12
●
Final Treatment to Post-Treatment Follow-up Month 6
●
Final Treatment to Post-Treatment Follow-up Month 12
●
Post-Treatment Follow-up Month 6 to Post-Treatment Follow-up Month 12.
The subjects included in these analyses will be limited to those who had values at these 
time points.
As described above for the Treatment Period, continuous and categorical summaries of 
the Z-score and T-score at each time point during the Post-Treatment Follow-up Period 
will be provided.
Listings of subjects meeting the following thresholds during the Post-Treatment Follow-
up period will be provided:
●
Listing of subjects with bone decrease ≥ 3% and T-score < –1.0 in the same 
region
●
Listing of subjects with T-score ≤ –1.5.
12.5
Vital Signs and Body Weight
Vital sign variables include pulse rate, sitting systolic blood pressure, sitting diastolic 
blood pressure, and oral body temperature.
Vital sign variables will be summarized with mean, median, standard deviation, 
minimum, and maximum by treatment group.


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Analyses of mean change from Baseline to each relevant visit during the Treatment Period 
in vital sign variables and weight will be performed.  The mean change from Baseline to 
each relevant visit in the Treatment Period will be compared between each elagolix dose 
group and placebo using one-way ANOVA with treatment as the main effect.  
The number and percentage of subjects who have PCS vital sign and weight values 
meeting the following criteria will be summarized by treatment group.  All 
increase/decrease is calculated from Baseline to a post-baseline visit in the Treatment 
Period.
The number and percentage of subjects who have a sustained PCS vital sign value and a 
listing of these subjects will be provided.  A sustained PCS value is defined as 
3 consecutive PCS values in the Treatment Period.
●
Diastolic blood pressure
○
≤ 50 mmHg and ≥ 15 mmHg decrease
○
> 90 mmHg and ≥ 15 mmHg increase
○
≥ 100 mmHg
●
Systolic blood pressure
○
≤ 90 mmHg and ≥ 20 mmHg decrease
○
≥ 140 mmHg and ≥ 20 mmHg increase
○
≥ 160 mmHg
●
Pulse rate
○
≤ 45 bpm and ≥ 15 bpm decrease
○
> 100 bpm and ≥ 15 bpm increase
○
≥ 120 bpm
●
Weight
○
≥ 5% decrease
○
≥ 7% increase.


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Change in vital signs from Baseline to relevant Post-Treatment Follow-up visit(s) (Post-
Treatment Month 1, Month 3, Month 6, Month 9, Month 12, and Final Visit) will be 
summarized by treatment group with descriptive statistics.
12.6
Endometrial Biopsy
The number and percentage of subjects in each category of endometrial biopsy results will 
be summarized at Baseline, Between Month 3 and Month 6, and Month 6 for each 
treatment group.
12.7
Pelvic Ultrasound and MRI
Analyses will be conducted separately for results obtained from TAU/TVU and MRI.  
The actual values and the change from Baseline to Month 3 (TAU/TVU only), Month 6, 
Follow-up Month 3 (TAU/TVU only), and Follow-up Month 6 will be summarized by 
treatment group with descriptive statistics.
12.7.1
Ovarian Cysts
The presence of ovarian cysts will be noted at Baseline and each relevant post-baseline 
visit in the Treatment Period and Post-Treatment Follow-up Period.  Significant ovarian 
findings include complex ovarian cyst > 3.5 cm or simple ovarian cyst > 5 cm.  The 
number and percentage of subjects with the pre-defined complex ovarian cysts and simple 
ovarian cysts will be summarized for each treatment group at each relevant visit in the 
Treatment Period.
For each TVU/TAU or MRI assessment, information for significant ovarian findings from 
the cysts assessment may be available for more than one cyst at more than one ovary
location (left and/or right).  For such assessments, the worst assessment based on the 
greatest of the three dimensions across the multiple cysts at the left and/or right ovary 
location within the same cyst type (i.e., simple or complex) will be included in the 
analyses/summary.  Additionally, the subject with multiple cyst findings will be counted 
once in the numerator and denominator when reporting the number and percentage of 
subjects in the relevant category of significant ovarian findings.  A listing will include all 


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results across multiple cysts findings from multiple assessments (where available) from 
subjects who have significant ovarian findings.
12.7.2
Endometrial Thickness 
Analysis of change in endometrial thickness from Baseline to Month 3 and Month 6 in the 
Treatment Period will be performed.  The mean change from Baseline to Month 3 
(TAU/TVU only) and Month 6 will be compared between each elagolix dose group and 
placebo using one-way ANOVA with treatment as the main effect.  
In addition, the number and percentage of subjects with endometrial thickness of < 8 mm, 
≥ 8 mm and ≤ 12 mm, > 12 mm and ≤18 mm, and > 18 mm in the Treatment and Post-
Treatment Follow-up Periods will be summarized by treatment group at each relevant 
visit in the Treatment Period.  No comparison will be made for the Post-Treatment 
Follow-up Period.
Change in endometrial thickness from Baseline to relevant Post-Treatment Follow-up 
visit(s) will be summarized by treatment group with descriptive statistics.
12.8
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS data will be summarized as observed by treatment group.  The C-SSRS –
Baseline/Screening and C-SSRS – Since Last Visit questionnaires and corresponding 
scoring rules are presented in Appendix L, Appendix M and Appendix N. 
The C-SSRS – Baseline/Screening measured at Day 1 will be considered as Baseline 
C-SSRS.  Baseline C-SSRS will be summarized by treatment group.  Other analysis of 
C-SSRS will only include subjects who have at least 1 post-baseline C-SSRS 
measurement, regardless of whether they had a baseline C-SSRS measurement.  The 
number of subjects with suicidal ideation, suicidal behavior, and self-injurious behavior 
without suicidal intent at each scheduled assessment during Treatment Period will be 
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outcomes and past year outcomes at screening and Day 1.  No statistical test will be 
performed.
The number of subjects with suicide-related treatment-emergent events based on the 
C-SSRS during Treatment Period will be summarized.  No statistical test will be 
performed. 
A listing of subjects with suicidal ideation, suicidal behavior, or self-injurious behavior 
without suicidal intent based on the C-SSRS during treatment period will be provided.
12.9
Pregnancy Results
Pregnancies and outcomes will be summarized by treatment group.  Listings will be 
prepared of all pregnancy test results for any subject who ever had a positive pregnancy 
test at any time point during the study.
13.0
References
1.
Schumacher U, Schumacher J, Mellinger U, et al.  Estimation of menstrual blood 
loss volume based on menstrual diary and laboratory data.  BMC Womens Health.  
2012;12:24.
2.
Heinze G, Schemper M.  A solution to the problem of separation in logistic 
regression.  Stat Med.  2002;21(16):2409-19.
3.
Munro MG, Critchley HO, Broder MS, et al; FIGO Working Group on Menstrual 
Disorders.  FIGO classification system (PALM-COEIN) for causes of abnormal 
uterine bleeding in nongravid women of reproductive age.  Int J Gynaecol Obstet.  
2011;113(1):3-13.
4.
Belsey EM, Machin D, d'Arcangues C.  The analysis of vaginal bleeding patterns 
induced by fertility regulating methods.  World Health Organization Special 
Programme of Research, Development and Research Training in Human 
Reproduction.  Contraception.  1986;34(3):253-60.


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5.
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
Published:  May 28, 2009 (v4.03:  June 14, 2010).  US DEPARTMENT OF 
HEALTH AND HUMAN SERVICES, National Institutes of Health, National 
Cancer Institute.
6.
Szende A, Williams A, editors.  Measuring self-reported population health:  an 
international perspective based on EQ-5D-5L.  EuroQol Group Monographs 
Volume 1.  SpringMed; 2004.
7.
Rabin R, Oemar M, Oppe M, et al.  EQ-5D-5L user guide:  basic information on 
how to use the EQ-5D-5L instrument Version 1.0.  April 2011.
8.
SAS Institute Inc.  2015.  SAS/STAT® 14.1 User's Guide, The MI Procedure.  
Cary, NC:  SAS Institute Inc.
9.
SAS Institute Inc.  2015.  SAS/STAT® 14.1 User's Guide, The MIANALYZE 
Procedure.  Cary, NC:  SAS Institute Inc.
10.
Ratitch B, Lipkovich I, O'Kelly M.  Combining analysis results from multiply 
imputed categorical data pharmaSUG.  2013-Paper SP03, 2013.
11.
Westfall PH, Krishen A.  Optimally weighted, fixed sequence and gatekeeper 
multiple testing procedures.  J Stat Plan Inference.  2001;99:25-40.


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Appendix A.
UFS-QoL


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


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Scale
Sum Item Values
Lowest and Highest 
Possible Raw Scores 
(Assuming All 
Related Scale Items 
are Answered)
Possible Raw Score 
Range (Assuming 
All Related Scale 
Items are 
Answered)
Concern
9 + 15 + 22 + 28 + 32
5, 25
20
Activities
10 + 11 + 13 + 19 + 20 + 27 + 29
7, 35
28
Energy/Mood
12 + 17 + 23 + 24 + 25 + 31 + 35
7, 35
28
Control
14 + 16 + 26 + 30 + 34
5, 25
20
Self-conscious
18 + 21 + 33
3, 15
12
Sexual Function
36 + 37
2, 10
8
HRQL Total
Sum of 6 Subscale Scores
29, 145
116
Formula for transformation of UFS-QoL raw scores ONLY:
Transformed Score = (Highest possible score – Actual raw score)/Possible raw score 
range × 100
HRQL total = Sum of 6 Subscale Scores.
Missing Items:
4.
For each subscale listed in the tables above, including the scale of Symptom 
Severity, if some of the answers for related scale items are missing (not to exceed 
50% of the scale items, details refer to Missing Items rule 2 below), then the lowest 
possible raw score = 1 × (total number of related scale items answered) and the 
highest possible raw score = 5 × (total number of related scale items answered).  
And the possible raw score range = the highest possible raw score – the lowest 
possible raw score.
5.
For the subscale analyses, if < 50% of the scale items are missing, the scale should 
be retained with the mean scale score of the items present used to impute a score 
for the missing items.  If ≥ 50% of the items are missing, no scale score should be 
calculated, the subscale score should be considered missing. If a subscale score is 
missing, the HRQL total cannot be calculated.


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


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


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2.
Since I started taking study medication, my abdominal or pelvic pressure has/is
☐
Very much improved
☐
Much improved
☐
Minimally improved
☐
Not changed
☐
Minimally worse
☐
Much worse
☐
Very much worse
3.
Since I started taking study medication, my abdominal or pelvic cramping has/is
☐
Very much improved
☐
Much improved
☐
Minimally improved
☐
Not changed
☐
Minimally worse
☐
Much worse
☐
Very much worse
4.
Since I started taking study medication, my back pain has/is
☐
Very much improved
☐
Much improved
☐
Minimally improved
☐
Not changed
☐
Minimally worse
☐
Much worse
☐
Very much worse


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5.
Since I started taking study medication, my abdominal bloating has/is
☐
Very much improved
☐
Much improved
☐
Minimally improved
☐
Not changed
☐
Minimally worse
☐
Much worse
☐
Very much worse
6.
Since I started taking study medication, my urinary problems (urinating too 
frequently or feeling a sudden need to urinate) has/is
☐
Very much improved
☐
Much improved
☐
Minimally improved
☐
Not changed
☐
Minimally worse
☐
Much worse
☐
Very much worse
7.
Overall since I started taking study medication, my non-bleeding symptoms
have/are
☐
Very much improved
☐
Much improved
☐
Minimally improved
☐
Not changed
☐
Minimally worse
☐
Much worse
☐
Very much worse


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


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Appendix F.
Reason for Study Participation
We would like to ask you why you have agreed to participate in this clinical research 
study.  I am participating in this research study because (Please check one):
☐I would like to avoid surgery (hysterectomy)
☐I would like to delay surgery (hysterectomy)
☐I would like to avoid other surgeries or procedures (such as myomectomy or 
uterine artery embolization)
☐I would like to delay other surgeries or procedures (such as myomectomy or 
uterine artery embolization)
☐I prefer taking medication rather than surgery or procedures until I enter 
menopause when my symptoms, such as heavy menstrual bleeding, should 
improve and gradually go away
☐I would like to get pregnant after participating in the study
☐I don't know why
☐I don't want to answer
☐Other:  _________________________________________


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Appendix G.
Physician Surgery Questionnaire Version 1.0 – SAMPLE
Based on this subject's current presentation/profile as it relates to uterine fibroids, is 
surgery or surgical procedure one of the potential treatment options you would consider? 
☐Yes 
☐No
If yes, which surgery or surgical procedure would you consider?  Check all that apply.
☐Hysterectomy
☐Myomectomy
☐Uterine Artery Embolization
☐Other ____________


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Appendix H.
Uterine Bleeding Questionnaire (UBQ) – Treatment Period –
SAMPLE
Version 2.0
During site visits in the Treatment Period, subjects who did not return a Sanitary Product 
Collection Keg (for menstrual blood loss analysis) will be asked whether they had any 
uterine bleeding or spotting since their last study visit.
1.
Did the subject have any bleeding or spotting since her last study visit?
☐No    ☐Yes
If yes, why were sanitary products not collected/returned?  (Please select 
one response)
☐Subject only had spotting that did not require the use of sanitary products*
☐There was no visible blood on sanitary products*
☐Subject forgot to/did not collect*
☐Subject/Site discarded the sanitary products*
☐Subject is still bleeding/spotting; will return when bleeding/spotting 
complete
☐Subject collected sanitary products and did not bring them to this visit; will 
return sanitary products at a later date
☐Other
*
If this response is checked, remind subject to collect and return all used or worn 
sanitary products with or without visible blood.


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


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


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


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


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Appendix L.
Columbia-Suicide Severity Rating Scale (C-SSRS) –
Baseline/Screening – SAMPLE


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


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


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Composite endpoints based on the above categories are defined below.
●
Suicidal ideation:  A "yes" answer at any time during treatment to any one of 
the five suicidal ideation questions (Categories 1 – 5) on the C-SSRS.
●
Suicidal behavior:  A "yes" answer at any time during treatment to any one of 
the five suicidal behavior questions (Categories 6 – 10) on the C-SSRS.
●
Suicidal behavior ideation or behavior:  A "yes" answer at any time during 
treatment to any one of the ten suicidal ideation and behavior questions 
(Categories 1 – 10) on the C-SSRS.
Comparative endpoints of interest are defined below.  "Treatment emergence" is used for 
outcomes that include events that first emerge or worsen.  "Emergence" is used for 
outcomes that include events that first emerge.
●
Treatment-emergent suicidal ideation compared to recent history:  An increase 
in the maximum suicidal ideation score during treatment from the maximum 
suicidal ideation category during a specified pre-treatment period (C-SSRS 
scales taken during the specified pre-treatment period; excludes "lifetime" 
scores from the Baseline C-SSRS scale or Baseline/Screening C-SSRS scale).
●
Treatment-emergent serious suicidal ideation compared to recent history:  An 
increase in the maximum suicidal ideation score to 4 or 5 on the C-SSRS 
during treatment from not having serious suicidal ideation (scores of 0 – 3) 
during a specified pre-treatment period (C-SSRS scales taken during the 
specified pretreatment period; excludes "lifetime" scores from the Baseline 
C-SSRS scale or Baseline/Screening C-SSRS scale).
●
Emergence of serious suicidal ideation compared to recent history:  An 
increase in the maximum suicidal ideation score to 4 or 5 on the C-SSRS 
during treatment from no suicidal ideation (scores of 0) during a specified pre-
treatment period (CSSRS scales taken during the specified pre-treatment 
period; excludes "lifetime" scores from the Baseline C-SSRS scale or 
Baseline/Screening C-SSRS scale).
●
Emergence of suicidal behavior compared to all prior history:  The occurrence 
of suicidal behavior (Categories 6 – 10) during treatment from not having 


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suicidal behavior (Categories 6 – 10) prior to treatment (includes "lifetime" 
and/or "screening" scores from the Baseline C-SSRS scale, Screening C-SSRS 
scale, or Baseline/Screening C-SSRS scale, and any "Since Last Visit" from 
the Since Last Visit C-SSRS scales taken prior to treatment)
●
Improvement in suicidal ideation at a time point of interest compared to 
baseline:  An improvement in this endpoint can be considered as a decrease in 
suicidal ideation score at the time point of interest (e.g., the last measurement 
during treatment) from the baseline measurement (e.g., the measurement taken 
just prior to treatment.  This analysis should only be performed for studies in 
which a baseline C-SSRS can be defined (i.e., having improvement from the 
worse event over a lifetime is not clinically meaningful).


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


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Appendix P.
Health Care Resource Utilization Questionnaire (HCRU) 
Version 1.0 – SAMPLE
(To be completed by Site Staff)
Non-Study Visits for Routine/General Health Care
Complete Version 1.0 for Subjects who randomized under Amendment 1
Instructions to Site Staff:  At each scheduled monthly visit in the Treatment Period, please 
ask if the subject saw a Non-Study Health Care Practitioner (HCP) since her last 
scheduled monthly visit for a routine/general health care visit that is not associated with 
an adverse event.  
Only record routine/general health care visits with Non-Study HCPs below.
Record Non-Study HCP Visits associated with an adverse event on the Adverse Event 
form only.  Do not record below.  
1.
Since the Subject's last scheduled monthly study visit, has she seen a non-study
Health Care Practitioner (e.g., Physician, Nurse Practitioner, Physician Assistant, 
Dentist, Physical Therapist) for a routine/general health care visit?
☐No ☐Yes 
If Yes, please complete questions 2 and 3 below to indicate the type(s) of Non-Study
Physician(s) seen and the number of times each Non-Study Physician was seen.


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2.   What type(s) of Non-Study Physician Specialty was 
the Subject seen by?  (Check all that apply)
3.  How many times was the subject 
seen by each Non-Study HCP
AUDIOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
ALLERGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
CARDIOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
DENTIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
DERMATOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
ENDOCRINOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
ENT
☐
☐1  ☐2  ☐3  ☐4  ☐5
FAMILY PRACTITIONER
☐
☐1  ☐2  ☐3  ☐4  ☐5
GASTROENTEROLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
GYNECOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
HEMATOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
HEPATOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
IMMUNOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
INFECTIOUS DISEASE SPECIALIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
INTERNAL MEDICINE SPECIALIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
INTERNIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
MEDICAL GENETICIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
NEPHROLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
NEUROSURGEON
☐
☐1  ☐2  ☐3  ☐4  ☐5
OPTHAMOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
ORTHOPEDIC SURGEON
☐
☐1  ☐2  ☐3  ☐4  ☐5
PHYSIATRIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
PLASTIC SURGEON
☐
☐1  ☐2  ☐3  ☐4  ☐5
PODIATRIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
PSYCHIATRIST 
☐
☐1  ☐2  ☐3  ☐4  ☐5
PSYCHOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
PULMONOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
RHEUMATOLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
SURGEON
☐
☐1  ☐2  ☐3  ☐4  ☐5
UROLOGIST
☐
☐1  ☐2  ☐3  ☐4  ☐5
OTHER PHYSICIAN (specify type:  
________________________
☐
☐1  ☐2  ☐3  ☐4  ☐5


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


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