Conditions: Heavy Menstrual Bleeding Uterine Fibroids
Keywords: Elagolix Sodium Heavy Menstrual Bleeding (HMB) Heavy Uterine Bleeding Leiomyomata Menorrhagia Elagolix + Norethindrone Acetate Elagolix + E2/NETA Elagolix Safety Efficacy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 478
Healthy volunteers: no

Brief summary:
This randomized multicenter phase 3b study seeks to evaluate the safety of elagolix in combination with estradiol/norethindrone acetate for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women. This study was double-blind (DB) during the first 12 months and open-label (OL) for the next 36 months.

Detailed description:
478 participants were randomly assigned at a ratio of 2:1 to the following treatment groups:

1. Elagolix 300 mg twice daily (BID) plus estradiol 1.0 mg/norethindrone acetate 0.5 mg (E2/NETA) once daily (QD) for 48 months, followed by 12 months PTFU
2. Placebo for 12 months, followed by elagolix 300 mg BID plus E2/NETA QD for 36 months, followed by 12 months PTFU

This study was double-blinded during the first 12 months and open-label for the next 36 months. Participants entered up to 12 months of PTFU after completing treatment Month 48 (or at any time a participant prematurely discontinued treatment).

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Elagolix intervention 2: Estradiol /norethindrone acetate (E2/NETA) intervention 3: E2/NETA Placebo intervention 4: Elagolix Placebo
Intervention descriptions: intervention 1: Film-coated 300 mg tablets intervention 2: Estradiol 1 mg/norethindrone acetate 0.5 mg capsules intervention 3: Placebo capsules intervention 4: Film-coated placebo tablets

Protocol document:
Prot_000.pdf: 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions 
Protocol 
Date
Original
17 May 2017
Amendment 1
29 June 2017
Amendment 2
24 May 2018
Administrative Change 1
09 May 2019
Administrative Change 2
13 May 2020
Amendment 3
05 September 2019
Amendment 4
16 November 2020
Amendment 5
08 October 2021
The purpose of this amendment is to:
●
Update Section 5.3.1.1, Study Procedures, Endometrial Biopsy and 
Appendix C, Study Activities.
Rationale:  Based on FDA correspondence to elagolix-AB IND 115528
(April 21, 2022, FDA Advice/Information Request, Reference ID:  4971727), 
the endometrial biopsy at Month 36 was reinstated and the criteria revised so 
that the endometrial biopsy is required regardless of endometrial thickness.
●
Correct administrative and typographical errors throughout the document.
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M16-283
Name of Study Drug:  Elagolix (ABT-620)
Phase of Development:  3b
Name of Active Ingredient:  Elagolix sodium
Date of Protocol Synopsis:  02 May 2022
Protocol Title:  A Phase 3b Study to Evaluate the Long-Term 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 safety of elagolix 300 mg BID in combination with 
E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg QD) compared to placebo at 12-months in 
premenopausal woman with heavy menstrual bleeding associated with uterine fibroids, 2) to characterize 
the impact of elagolix 300 mg BID with E2/NETA on bone mineral density (BMD) in women with 
heavy menstrual bleeding associated with uterine fibroids after up to 48-months of treatment.
Investigators:  Multicenter
Study Sites:  Approximately 175 sites
Study Population:  Premenopausal female subjects (aged 18 to 50 years, inclusive) with uterine fibroids 
and HMB (> 80 mL blood loss per menstrual cycle).
Number of Subjects to be Enrolled:  Approximately 500
Methodology:  
This Phase 3b, sequential, randomized, 12-month double-blind placebo-controlled, 36-month open-label, 
multi-center study is designed to evaluate the long term safety of elagolix with add back therapy in 
women with HMB associated with uterine fibroids.  Approximately 500 subjects will be randomized in a 
2:1 ratio to one of the following two treatment groups:
1.
Elagolix 300 mg BID plus E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg QD) (n = 335) 
for 48-months
2.
Placebo (n = 165) for 12-months, followed by elagolix 300 mg BID plus E2/NETA (estradiol 
1.0 mg/norethindrone acetate 0.5 mg QD) for 36-months
Subjects randomized to elagolix 300 mg BID plus E2/NETA in the 12-month Treatment Period will 
receive the same treatment during the open label Treatment Period.  Subject randomized to placebo in 
the 12-month Treatment Period will switch to elagolix 300 mg BID plus E2/NETA during the open label 
Treatment Period after completing the 12-month Treatment Period.
Study Duration:
The total duration for this study is up to 77 months.
The study consists of 4 periods:

Washout Period – up to 10 months prior to Screening (only applicable if subject is taking 
exclusionary medication at the time of consent; duration of washout depends on the type of 
exclusionary medication being taken).

Screening Period – approximately 2.5 to 5 Months prior to first dose of study drug.

Treatment Period – up to 48-month treatment duration.
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
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Study Duration (Continued):  

Post-Treatment Follow-Up Period – up to 12-month duration following the last dose of the 
study drug.  Subjects are expected to enter Post-Treatment Follow-Up after completing 
Treatment Month 48, or at any time a subject prematurely discontinues during the Treatment 
Period.
Washout Period:
Following informed consent, subjects, who have been taking exclusionary medications, must enter a 
Washout Period.  Subjects must complete the Washout Period and then have at least 1 menses (refer to 
Table 2) after completion of washout, prior to entering the Screening Period.  The duration of washout 
period is based on the excluded medication as described in the protocol.  The following study procedures 
may be performed:  medical, social and gynecological history, a physical examination with vital signs, 
urine pregnancy testing; protocol-related adverse event review and documentation of current 
medications and 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.  Subjects will also begin the use of dual non-hormonal contraception and receive counseling on 
the importance of consistent, appropriate and effective use of birth control and will have contraceptives 
dispensed as necessary.
Screening Period:
Following informed consent (if Washout was not required), subjects will enter into the approximately 
2.5 to 5 Months Screening Period to establish eligibility based on inclusion and exclusion criteria, 
including the following assessments:  a pelvic ultrasound (TAU and TVU); a saline infusion 
sonohysterography (SIS); an endometrial biopsy; a Pap test; a mammogram in subjects 39 years of age 
or older (at the time of randomization) if one was not performed within 3 months prior to Screening; a 
dual energy x-ray absorptiometry (DXA) scan (for BMD).  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 
(with or without visible blood) on days with menstrual bleeding or spotting, and must return the products 
to the site within approximately 5 days after cessation of menses.  Subjects are required to use dual non-
hormonal contraception (as applicable), contraceptive counseling will be provided and contraceptives 
dispensed, as necessary.
Year 1 Treatment Period:
The Treatment Period begins with Day 1, which will occur between cycle 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.
On Day 1 of the 12-month Treatment Period, subjects will be randomized to receive either placebo 
(n = 165), or elagolix 300 mg BID plus E2/NETA (n = 335).  Study drug kits will be dispensed to 
subjects at each on-site visit.  Subjects entering the 12-month Treatment Period will have on-site visits at 
Day 1, Months 3, 6, 9 and 12; phone visits will be made at Months 1, 2, 4, 5, 7, 8, 10 and 11.
A mammogram, pelvic ultrasound (TAU and TVU) and endometrial biopsy (based on TVU finding) will 
be performed in subjects at Month 12 or Premature Discontinuation Visit, if applicable; DXA scan will 
be performed at the Months 6, 12 and Premature Discontinuation Visit (if applicable); Vital signs 
assessments will be conducted at all on-site study visits, and a baseline ECG will be obtained.
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
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Year 1 Treatment Period (Continued):
During Months 1 to 12, subjects will be asked to complete the following patient-reported outcome 
questionnaires:  (UFS-QoL), Patient Global Impression of Change (PGIC based on menstrual bleeding 
(PGIC-MB), Site Staff will administer the and the C-SSRS – Since Last Visit questionnaire.  The 
Investigator will complete the Physician Surgery Questionnaire (PSQ).
A urine pregnancy test will be performed at each visit throughout the Treatment Period.  Home urine 
pregnancy test kits will be provided to subjects for use at home for the study visits when subjects are not 
required to come to the site.  Subjects will self-administer the test and report the results to the site during 
the scheduled phone contact visits.  A positive urine pregnancy test must be confirmed with a serum 
pregnancy test.  If a serum pregnancy test result is positive at any time during the Treatment Period, 
study drug will be discontinued.
Blood samples for Clinical Safety Labs will be performed at on-site visits throughout the 12-month
Treatment Period.  Subjects will be counseled at each visit on appropriate and effective forms of dual 
non-hormonal contraceptives to promote pregnancy prevention.
Blood samples will be collected for assay of serum estradiol and to measure plasma concentrations of 
elagolix and norethindrone.
Adverse event and concomitant medication review will be conducted at all visits (on-site and phone 
visit) during the Treatment Period.
Year 2, 3 4 (Open-Label) Treatment Period:
Subject randomized to placebo in the 12-month Treatment Period will switch to elagolix 300 mg BID 
plus E2/NETA during the open label Treatment Period after completing the 12-month Treatment Period.  
For subjects entering the open-label Treatment Period, visits will occur either by phone or on-site from 
Months 13 through 48.  The study drug will be dispensed every 3 months (during an on-site visit).  Study 
drug will be taken orally twice daily for the entire open label Treatment Period.  A morning dose of 
1 tablet (elagolix) and 1 capsule (E2/NETA) and an evening dose of 1 tablet (elagolix) should be taken 
each day approximately 12 hours apart.
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, will remind subjects 
of the importance of consistent use of appropriate and effective dual non-hormonal contraception.  
Subjects may begin taking hormonal contraceptive preparations only after completing the Treatment 
Period, being off study drug for at least 30 days and having a negative urine pregnancy test.  On-site 
visits will occur every three months starting at Month 15.
The following study procedures will be performed (as applicable); a pelvic ultrasound (TAU and TVU), 
Pap test, mammogram, and an endometrial biopsy starting at Month 24 to Month 48 or Premature 
Discontinuation Visit.  DXA scans will be obtained every 6 months starting at Month 18 or Premature 
Discontinuation Visit (if applicable).
Subjects will also be asked to complete patient-reported outcome questionnaires, throughout the 
36-month open-label Treatment period; the UFS-QoL and Site Staff will administer the C-SSRS – Since 
Last Visit.
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
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Year 2, 3 4 (Open-Label) Treatment Period (Continued):
A urine pregnancy test will be performed at each visit throughout the Treatment Period.  Home urine
pregnancy test kits will be provided to subjects for use at home for the study visits when subjects are not 
required to come to the site.  Subjects will self-administer the test and report the results to the site during 
the scheduled phone contact visits.  A positive urine pregnancy test must be confirmed with a serum 
pregnancy test.  If a serum pregnancy test result is positive at any time during the Treatment Period, 
study drug will be discontinued.  Subjects will be counseled at each visit on appropriate and effective 
forms of dual non-hormonal contraceptives to promote pregnancy prevention.
Subjects will continue to provide blood samples for Clinical Safety Labs, during the on-site visits.
Post-Treatment Follow-Up Period:
Subjects will enter the Post-Treatment Follow-Up Period for up to 12 months to assess bone recovery 
after up to 48 months of treatment.  Subjects who prematurely discontinue from the study at any time 
during the Treatment Period will enter the Post-Treatment Follow-Up Period.  DXA scans of the lumbar 
spine, total hip, and femoral neck will be obtained at Post-Treatment Follow-Up Months 6 and/or 12.
Pregnancy testing, samples for FSH and E2, Return to Menses questionnaire completion will be 
performed at designated study visits.  Adverse events and concomitant medication use will also be 
reviewed.  Subjects may begin taking hormonal contraceptive preparations only after completing the 
open-label Treatment Period, being off study drug for 30 days, having a negative urine pregnancy test
and returning to menses.
Central Laboratory and Central Imaging Vendors:
DXA, Ultrasound (TAU/TVU), SIS, MRI (if applicable), Endometrial biopsy, Pap test and safety 
clinical lab samples will be analyzed/evaluated using the central laboratories or vendors.  Assays for 
biomarkers, pharmacokinetics, and pharmacogenetics will be analyzed at AbbVie and those for the 
Alkaline Hematin will be analyzed by the Alkaline Hematin Laboratory.
Analysis of Menstrual Blood Loss:
This study will utilize the Alkaline Hematin method for measuring MBL during the Screening Period.  
Key Criteria for Inclusion/Exclusion:
Key Inclusion Criteria:

Subject is a premenopausal female 18 to 50 years of age at the time of Screening.

Subject has a diagnosis of uterine fibroids documented by a Pelvic Ultrasound (TAU, TVU) 
assessed by a central reader and verification that a uterine fibroid meets at least one of the 
following criteria:
o
Intramural, submucosal non-pedunculated fibroid with a diameter ≥ 2 cm (longest 
diameter).
o
Subserosal fibroid ≥ 4 cm (longest diameter).
o
Multiple fibroids with a total uterine volume of ≥ 200 cm3 to ≤ 2,500 cm3.

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.

Subject has a Screening FSH level of < 35 mIU/mL (35 IU/L).

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.
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
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Key Criteria for Inclusion/Exclusion (Continued):

Subject must agree to use two forms of non-hormonal contraception (dual contraception) 
consistently during the Washout (if applicable), Screening and Treatment Periods.  Acceptable 
methods of dual contraception include the following combinations:
o
Condom with spermicide (foam, gel or polymer film).
o
Diaphragm with spermicide (condom may or may not be used).
o
Cervical cap with spermicide (condom may or may not be used).
Subject is not required to use dual contraception methods if:
o
Sexual partner(s) is vasectomized, at least 6 months prior to Screening.
o
Subject practices total abstinence from sexual intercourse, as the preferred lifestyle of the 
subject; periodic abstinence is not acceptable.
o
Subject had a bilateral tubal occlusion or tubal ligation at least 4 months prior to Screening.
o
Subject is not sexually active with men; periodic sexual relationship(s) with men requires 
the use of dual non-hormonal contraception as noted above.

Subject has an adequate endometrial biopsy performed during Screening, the results of which 
show no clinically significant endometrial pathology.
Key Exclusion Criteria:

Subject has had menstrual cycles that are > 38 days in length for the past 3 consecutive months 
prior to Screening.

Subject has screening pelvic ultrasound or SIS results that show a clinically significant 
gynecological disorder such as:
o
A persistent simple ovarian cyst > 5 cm in longest diameter (if the pelvic ultrasounds 
shows a simple ovarian cysts > 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).
o
A complex ovarian cyst > 3.5 cm in diameter (longest diameter).
o
An endometrioma > 3.5 cm in diameter (longest diameter).
o
Large endometrial polyp ≥ 1 cm.
o
Intracavitary/submucosal pedunculated fibroid.

Subject ≥ 21 years of age at Screening (or age at which Pap smears are routinely performed 
according to local guidelines) has a Pap smear result that meets exclusionary criteria.

Subject's hemoglobin level is < 7 g/dL (subjects with initial screening hemoglobin results 
< 7 g/dL can be prescribed iron supplements and have their hemoglobin levels retested prior to 
Day 1).
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
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Key Criteria for Inclusion/Exclusion (Continued):

Subject has a history of osteoporosis or other metabolic bone disease, including:
o
Screening DXA results of the lumbar spine (L1 – L4), femoral neck, or total hip BMD 
corresponding to 2.0 or more standard deviations below normal (T-score ≤ –2.0).
o
Intercurrent bone disease (e.g., osteomalacia, osteogenesis imperfecta, etc.).
o
Condition that would interfere with obtaining adequate DXA measurements (e.g., history 
of spinal surgery, spinal hardware or severe scoliosis).
o
History or presence of a condition that is associated with a decrease in BMD 
(e.g., uncontrolled hyperthyroidism, uncontrolled hyperparathyroidism, anorexia nervosa, 
etc.).
o
History of low-trauma bone fracture (e.g., fracture resulting from a fall from a standing 
height or lower).
o
Bilateral hip replacement.
o
Clinically significant hypocalcemia, hypo- or hyperphosphatemia
o
Treatment with medication (excluding calcium and Vitamin D) for osteoporosis, 
osteopenia, or other bone disease associated with a decrease in BMD.

Subject has a history of major depression or post-traumatic stress disorder (PTSD) episode 
within 2 years of screening, OR a history of other major psychiatric disorder at any time 
(e.g., schizophrenia, bipolar disorder).

Subject is using any systemic corticosteroids for over 14 days within 3 months prior to 
Screening or is likely to require treatment with systemic corticosteroids during the course of the 
study.  Over-the-counter and prescription topical, inhaled, intranasal or intra-articular injectable 
(for occasional use) corticosteroids are allowed.
Investigational Products:
Elagolix sodium 300 mg tablets
Estradiol 1.0 mg/norethindrone acetate 0.5 mg
Doses:
Elagolix 300 mg BID plus E2/NETA (estradiol 1.0 mg/norethindrone 
acetate 0.5 mg QD) (n = 335)
Placebo (n = 165), switch to elagolix 300 mg BID plus E2/NETA after 
completing the 12-month Treatment Period
Reference Therapy:
Placebo to match Elagolix; Placebo to match E2/NETA
Mode of Administration:
Oral
Duration of Treatment:  Subjects will receive up to 48 months of treatment.
Duration of Post-Treatment Follow-Up: Subjects will receive up to 12 months of Post-Treatment 
Follow-Up
Criteria for Evaluation:
Efficacy:
Primary Efficacy Endpoint:
The objective of this study is to evaluate the long term safety of Elagolix 300 mg BID plus E2/NETA 
(estradiol 1.0 mg/norethindrone acetate 0.5 mg QD), and as such, no primary efficacy endpoint is 
defined.
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
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Criteria for Evaluation (Continued):
Questionnaires and Quality of Life Assessments:

Reason for Study Participation

PSQ

UFS-QoL Questionnaire

PGIC-MB

C-SSRS

Return to Menses
Safety:
Safety evaluations include physical examination, vital signs, ECG, BMD changes, endometrial 
assessments (endometrial thickness and biopsy), pelvic ultrasound (TAU/TVU), clinical laboratory tests 
(including hematology, chemistry, urinalysis and lipid panel) and adverse events monitoring.
Statistical Methods:
In general, data will be summarized for the 12-month double-blind Treatment Period, the 36-month 
open-label Treatment Period, and the Post-Treatment Follow-Up Period separately.
In the 12-month double-blind placebo-controlled Treatment Period, data will be summarized by 
treatment group (the elagolix 300 mg BID plus E2/NETA group and the placebo group).  Comparisons 
will be made between the elagolix 300 mg BID plus E2/NETA group and the placebo group in the 12-
month double-blind Treatment Period.
In the Year 2 to 4 open-label Treatment Period, summaries will be provided for each of the following 
groups of subjects.
1.
Subjects randomized to elagolix 300 mg BID plus E2/NETA in the 12-month double-blind
Treatment Period and continued to receive elagolix 300 mg BID plus E2/NETA in the open-label 
Treatment Period;
2.
Subjects randomized to placebo in the 12-month double-blind Treatment Period, and switched to 
elagolix 300 mg BID plus E2/NETA in the open-label Treatment Period.
No statistical tests will be made following the 12-month double-blind placebo-controlled Treatment 
Period.
Efficacy:
Efficacy Analysis:
The objective of this study is to evaluate the safety of elagolix 300 mg BID plus E2/NETA (estradiol 
1.0 mg/norethindrone acetate 0.5 mg QD), and as such, no primary efficacy endpoint is defined.
Analyses Other Efficacy Variables:
The change from baseline for UFS-QoL will be summarized by treatment group.  During the double 
blinded period, change from baseline will be analyzed using an analysis of covariance (ANCOVA) 
model with treatment group as the main effect and corresponding baseline value as a covariate.
For the PGIC-MB, the individual and combined response categories will be summarized during the 
double blinded period.  Comparison will be made using a Miettinen–Nurminen (M-N) test.
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
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Statistical Methods (Continued):
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, lipid panel, 
vital signs, endometrial safety via TVU/TAU and endometrial biopsy, and pregnancy results will be 
summarized.
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 
percentage change from baseline will generally be analyzed using a 1-way analysis of variance 
(ANOVA) with treatment as the main effect in the 12-month Treatment Period, unless otherwise 
specified.
Categorical data will be summarized with frequencies and percentages by treatment group.  Chi-square 
test or Fisher's exact test will be used to analyze treatment group differences for qualitative categorical 
variables as appropriate in the 12-month Treatment Period, unless otherwise specified.
The within-group percent change from baseline to Months 6, 12, 18, 24, 30, 36, 42 and 48 in BMD will 
be summarized for each treatment group.  The percent change from baseline to Month 6 and Month 12 in 
BMD will be compared between the elagolix 300 mg BID plus E2/NETA group and the placebo group.  
Sample Size:
Based on clinical review, a sample size of 500 was selected to gather long term safety exposure data in 
approximately 50 subjects completing 48 months of study drug dosing, with approximately 30 subjects 
receiving 48 months of active drug elagolix 300 mg BID plus E2/NETA 1/0.5 mg QD.
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 to develop a 
population pharmacokinetic model.  Exposure-response analyses may be conducted as appropriate.
Biomarker:
Serum concentrations of estradiol (E2) will be listed for each subject by visit day and dose regimen.
 


Elagolix (ABT-620)
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1.3
List of Abbreviations and Definition of Terms
Abbreviations
ABV
AbbVie
AE
Adverse Event
AESI
Adverse Event of Special Interest
AH
Alkaline Hematin
BID
Twice daily (bis in die)
BI-RADS
Breast Imaging Reporting and Data System
BMD
Bone Mineral Density
CIN
Cervical Intraepithelial Neoplasia
COVID-19
Coronavirus Disease - 2019
C-SSRS
Columbia-Suicide Severity Rating Scale
CSSR
Clinical Safety System Receipt
CU-IUD
Copper IUD
CYP3A
Cytochrome P450 3A
DFP
Direct-from-patient
DTP
Direct-to-patient
DXA
Dual energy X-Ray Absorptiometry
E2
Estradiol
E2/NETA
Estradiol/Norethindrone acetate
ECG
12-Lead Electrocardiogram
EDC
Electronic Data Capture
ePRO
Electronic Patient Reported Outcome
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GnRH
Gonadotropin releasing hormone
HAV-IgM
Hepatitis A virus immunoglobulin M
HBsAg
Hepatitis B surface antigen
HCV Ab
Hepatitis C virus antibody
HDL
High-density lipoprotein
Hgb
Hemoglobin
HIFU
High Intensity Focused Ultrasound
HIV
Human Immunodeficiency Virus
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
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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
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intra-Uterine Device
LDL
Low-density Lipoprotein
LNG-IUS
Levonorgestrel Intrauterine System
LSIL
Low-grade squamous intraepithelial lesion
M-N
Miettinen–Nurminen
M
Month (visit)
MBL
Menstrual Blood Loss
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
NBI
Neurocrine Biosciences Inc
NETA
Norethindrone acetate
Pap
Papanicolau 
PCV
Product Collection Visit
PGIC-MB
Patient Global Impression of Change – Menstrual Bleeding
PSQ
Physician Surgery Questionnaire
QD
Once a day
RANKL
Receptor activator of nuclear factor-κB ligand
SAE
Serious Adverse Event
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SGOT/ASAT
Serum glutamic-oxaloacetic transaminase/aspartate aminotransferase
SGPT/ALAT
Serum glutamic-pyruvic transaminase/alanine aminotransferase
SIS
Saline Infusion Sonohysterography
TA MD
Therapeutic Area Medical Director
TA SD
Therapeutic Area Scientific Director
TAU
Transabdominal Ultrasound
 


Elagolix (ABT-620)
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TEAEs
Treatment-emergent adverse events
TSH
Thyroid Stimulating Hormone
TVU
Transvaginal Ultrasound
UFS-QoL
Uterine Fibroid Symptom Quality of Life Questionnaire
Pharmacokinetic and Statistical Abbreviations
ANOVA
Analysis of variance
ANCOVA
Analysis of covariance
MMRM
Mixed-model with repeated measures
PD
Pharmacodynamic
PK
Pharmacokinetic
SAP
Statistical Analysis Plan
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 approximately 2.5 to 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.
Month
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 (during screening); visits 
should occur within approximately 5 days after the last sanitary 
product was collected during a bleeding and/or spotting 
episode.
Heavy Menstrual Bleeding
Menorrhagia or > 80 mL blood loss
 


Elagolix (ABT-620)
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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
1.2
Synopsis .....................................................................................................3
1.3
List of Abbreviations and Definition of Terms........................................11
2.0
Table of Contents...................................................................14
3.0
Introduction ...........................................................................19
3.1
Uterine Fibroids .......................................................................................19
3.2
Elagolix....................................................................................................20
3.2.1
Preclinical Experience..............................................................................20
3.2.1.1
Toxicology ...............................................................................................20
3.2.2
Clinical Experience..................................................................................20
3.2.3
Pregnancy in Elagolix Studies .................................................................27
3.3
Estradiol/Norethindrone Acetate..............................................................28
3.4
Differences Statement..............................................................................28
3.5
Benefits and Risks....................................................................................29
4.0
Study Objectives....................................................................30
5.0
Investigational Plan...............................................................30
5.1
Overall Study Design and Plan:  Description ..........................................30
5.2
Selection of Study Population..................................................................40
5.2.1
Inclusion Criteria .....................................................................................41
5.2.2
Exclusion Criteria ....................................................................................43
5.2.3
Prior and Concomitant Therapy...............................................................48
5.2.3.1
Prior Hormonal/Anti-Hormonal Medications..........................................49
5.2.3.2
Concomitant Therapy...............................................................................51
5.2.3.3
Iron Supplementation...............................................................................51
5.2.3.4
Concomitant Use of Corticosteroids........................................................52
5.2.3.5
Prohibited Therapy...................................................................................52
5.2.4
Contraception Recommendations ............................................................56
5.3
Efficacy, Pharmacokinetic, Biomarker, Optional Exploratory 
Research Samples and Safety Assessments/Variables.............................59
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................59
 


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5.3.1.1
Study Procedures .....................................................................................60
5.3.1.2
Collection and Handling of Biomarker and Optional Exploratory 
Research Samples ....................................................................................89
5.3.2
Drug Concentration Measurements .........................................................90
5.3.2.1
Collection of Samples for Analysis .........................................................90
5.3.2.2
Measurement Methods.............................................................................91
5.3.3
Efficacy Variables....................................................................................91
5.3.3.1
Questionnaires and Quality of Life Variables..........................................91
5.3.4
Safety Variables.......................................................................................91
5.3.5
Pharmacokinetic Variables ......................................................................92
5.3.6
Biomarker and Exploratory Research Variables......................................92
5.4
Removal of Subjects from Therapy or Assessment.................................92
5.4.1
Discontinuation of Individual Subjects....................................................93
5.4.2
Discontinuation of Entire Study...............................................................95
5.4.3
Treatment Interruption.............................................................................95
5.5
Treatments................................................................................................96
5.5.1
Treatments Administered.........................................................................96
5.5.2
Identity of Investigational Product(s) ......................................................99
5.5.2.1
Packaging and Labeling.........................................................................100
5.5.2.2
Storage and Disposition of Study Drug(s) .............................................101
5.5.3
Method of Assigning Subjects to Treatment Groups.............................102
5.5.4
Selection and Timing of Dose for Each Subject....................................103
5.5.5
Blinding..................................................................................................103
5.5.5.1
Blinding of Investigational Product.......................................................103
5.5.6
Treatment Compliance...........................................................................104
5.5.7
Drug Accountability...............................................................................105
5.6
Discussion and Justification of Study Design........................................106
5.6.1
Discussion of Study Design and Choice of Control Groups..................106
5.6.2
Appropriateness of Measurements.........................................................106
5.6.3
Suitability of Subject Population ...........................................................107
5.6.4
Selection of Doses in the Study .............................................................107
6.0
Complaints ...........................................................................108
6.1
Medical Complaints...............................................................................108
 


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6.1.1
Definitions..............................................................................................108
6.1.1.1
Adverse Event........................................................................................108
6.1.1.2
Serious Adverse Events .........................................................................110
6.1.1.3
Adverse Events of Special Interest ........................................................111
6.1.2
Adverse Event Severity..........................................................................111
6.1.3
Relationship to Study Drug....................................................................112
6.1.4
Adverse Event Collection Period...........................................................113
6.1.5
Adverse Event Reporting.......................................................................113
6.1.6
Pregnancy...............................................................................................115
6.2
Product Complaint .................................................................................116
6.2.1
Definition ...............................................................................................116
6.2.2
Reporting................................................................................................117
7.0
Protocol Deviations..............................................................117
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................118
8.1
Statistical and Analytical Plans..............................................................118
8.1.1
General Considerations..........................................................................118
8.1.2
Data Sets Analyzed ................................................................................119
8.1.3
End of 12-Month Placebo-Controlled Treatment Period Analysis........120
8.1.4
Treatment Month 24, Month 36, Month 48 and Other Timepoints 
Analyses.................................................................................................120
8.1.5
Demographic, Baseline Characteristics and Concomitant 
Medications............................................................................................121
8.1.6
Efficacy..................................................................................................121
8.1.6.1
Primary Efficacy Variable .....................................................................121
8.1.6.1.1
Primary Analysis....................................................................................121
8.1.6.2
Other Efficacy Variables........................................................................122
8.1.7
Safety .....................................................................................................122
8.1.7.1
General Considerations..........................................................................122
8.1.7.2
Adverse Events ......................................................................................123
8.1.7.3
Analysis of Laboratory Data and Vital Signs ........................................124
8.1.7.4
Bone Mineral Density............................................................................125
8.1.7.5
Endometrial Biopsy ...............................................................................125
 


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8.1.7.6
Pelvic Ultrasound Findings....................................................................125
8.1.7.7
Columbia Suicide Severity Rating Scale (C-SSRS) ..............................126
8.1.8
Pharmacokinetic/Biomarker Analysis ...................................................126
8.2
Determination of Sample Size ...............................................................126
9.0
Ethics.....................................................................................126
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................126
9.2
Ethical Conduct of the Study.................................................................127
9.3
Subject Information and Consent...........................................................128
10.0
Source Documents and Case Report Form 
Completion ...........................................................................129
10.1
Source Documents .................................................................................129
10.2
Case Report Forms.................................................................................129
11.0
Data Quality Assurance ......................................................132
12.0
Use of Information...............................................................133
13.0
Completion of the Study .....................................................134
14.0
Investigator's Agreement....................................................136
15.0
Reference List ......................................................................137
List of Tables
Table 1.
Visit and Assessment Windows...............................................................39
Table 2.
Washout Intervals for Exclusionary Hormonal/Anti-Hormonal 
Therapy ....................................................................................................50
Table 3.
Prohibited Medications ............................................................................54
Table 4.
Clinical Laboratory Tests.........................................................................78
Table 5.
Menstrual Blood Loss Volume Eligibility...............................................85
Table 6.
Treatments Administered.........................................................................97
Table 7.
Identity of Investigational Products.......................................................100
List of Figures
Figure 1.
Study Schematic.......................................................................................33
 


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Figure 2.
Pap Test Eligibility ..................................................................................68
Figure 3.
Sanitary Product Dispensation and Collection ........................................83
Figure 4.
Adverse Event Collection ......................................................................113
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................138
Appendix B.
List of Protocol Signatories....................................................................140
Appendix C.
Study Activities......................................................................................141
Appendix D.
BI-RADS Classification.........................................................................156
 


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3.0
Introduction
3.1
Uterine Fibroids
Uterine fibroids (leiomyomata) are the most common benign tumors in women and occur 
in up to 80% of women of reproductive age.1  The incidence increases with age and 
uterine fibroids are the most common reason for hysterectomy in the United States.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 greater than 80 mL per menstrual cycle) is 
extremely inconvenient, can significantly impact quality of life and may lead to iron-
deficiency anemia.
While there are numerous surgical options available to manage symptomatic uterine 
fibroids, at present there is no long-term medical treatment for 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.
 


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3.2
Elagolix
Elagolix sodium (hereinafter "elagolix," also referred to as ABT-620) is a novel, oral, 
short-acting, non-peptide, gonadotropin-releasing hormone (GnRH) antagonist that 
competitively inhibits the GnRH receptors in the pituitary gland and is being developed 
by AbbVie for the management of endometriosis-related pain and the chronic 
management of heavy menstrual bleeding (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 nearly 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.6
3.2.1
Preclinical Experience
3.2.1.1
Toxicology
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 the most recent version of the Investigator's Brochure for the complete 
information on clinical studies, exposure to study drug, and safety.
Clinical Program Overview
As of 20 August 2018, a total of 4,569 subjects have received at least 1 dose of elagolix in 
clinical studies conducted by NBI and AbbVie (39 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 M12-671], 2 Phase 3 
 


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endometriosis extension studies [Studies M12-667 and M12-821]), and ongoing Phase 3 
endometriosis studies [Study M14-702 and Study M16-383].
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.  
The Phase 3 uterine fibroid registration program has 790 subjects.
Clinical Pharmacokinetic and Pharmacodynamic Summary
See Investigator Brochure Section for detailed discussion regarding the 
pharmacodynamics of elagolix including results of the multiple-ascending dose study, 
Study M12-790, in premenopausal healthy female subjects.
As discussed in the Investigator Brochure, treatment of women with elagolix does not 
block ovulation so women may become pregnant while taking elagolix.  There is a dose-
dependent inhibition of ovulation with increasing elagolix dosing such that, for example, 
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 
formulation for the current study, the ovulation rate decreased further to approximately 
10%.
Efficacy in Phase 2 Uterine Fibroid Studies
Please see the most recent version of Investigator Brochure for detailed description of the 
elagolix Phase 2b (Study M12-813) protocol and results.  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 both strengths of E2/NETA in the form of Activella) met the 
primary endpoint, which was the proportion of subjects who achieved a Menstrual Blood 
Loss (MBL) volume of < 80 mL at the Final Month and 50% or greater reduction in MBL 
 


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volume from Baseline to the Final Month compared to that of placebo (all P < 0.001), as 
measured by the alkaline hematin method.
Additional results from Cohort 1 demonstrated that treatment with elagolix 300 mg BID 
plus E2/NETA showed the following:
●
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.
The conclusion 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.
Adverse Events in Elagolix Uterine Fibroid Studies
Please see Investigator Brochure Section 8.3.3.1.5 for details of adverse events after 
elagolix treatment across the elagolix clinical program.  This section will summarize the 
adverse event data in the elagolix Uterine Fibroid Phase 2b study.
Data from the completed Phase 2b study, Study M12-813, represent the most extensive 
single study data set that examined the tolerability of elagolix at dosing to be used in 
Phase 3, including the present study and show that, overall, the percentage of subjects 
who reported treatment-emergent adverse events was generally similar across all 
 


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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%).  Estrogen-dependent 
adverse events from elagolix treatment were ameliorated significantly with the estrogen-
progestin add-back regimens as detailed below.
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 in elagolix clinical studies are discussed in the 
Investigator Brochure and include hot flush, cutaneous adverse events, ovarian-related 
events, BMD decrease, fractures, uterine bleeding, mood changing disorders (suicidality 
and depression) and changes in serum lipids.
In the completed Phase 2 studies in uterine fibroids, there were a higher percentage of 
women experiencing cutaneous/hypersensitivity events and hot flush with elagolix 
treatment compared with placebo.  Adverse events of special interest will continue to be 
monitored in all clinical studies including the present study.
Serious Adverse Events in the Elagolix Uterine Fibroid Program
Please see Investigator Brochure Section 9.2.3.1.1 for details regarding Serious Adverse 
Events seen across the elagolix clinical program.  This section will summarize the SAEs 
noted in the elagolix Phase 2b study, Study M12-813.
 


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In Cohort 1 of the Phase 2b study in women with HMB associated with uterine fibroids, 
there were 13 serious adverse events (SAEs) that either occurred during the Treatment 
Period or within 30 days of last dose in 8 subjects randomized to receive active treatment.  
There were six SAEs in placebo treated subjects (9.2%), 3 (4.6%) in the elagolix 300 mg 
BID group, 3 (4.7%) in the elagolix 300 mg BID + LD E2/NETA group, and 1 (1.5%) in 
the elagolix 300 mg BID + SD E2/NETA group.  Treatment-emergent SAEs were 
reported for 13 subjects in Cohort 2, including 1 subject (1.3%) in the placebo group, 
5 (6.5%) in the elagolix 600 mg QD group, 3 (3.9%) in the elagolix 600 mg QD + LD 
E2/NETA group, and 4 (5.2%) in the elagolix 600 mg QD + SD E2/NETA group.  In both 
cohorts, the majority of SAEs were reported by 1 subject each in any treatment group.
One subject in the elagolix 600 mg QD + LD E2/NETA group had an SAE of uterine 
leiomyoma that was considered reasonably possibly related to study drug.
Effects of Elagolix on Bone Mineral Density (BMD) in the Uterine Fibroid Phase 2b 
Study
In the 6-month Phase 2b study 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.
Results from the Phase 2b uterine fibroid study demonstrate that treatment with elagolix 
300 mg BID and 600 mg QD significantly decrease BMD, which is partially mitigated by 
addition of E2/NETA in a dose-dependent manner.  In Cohort 1, the mean percentage 
change from Baseline to Month 6 in BMD in the lumbar spine for the elagolix 300 mg 
BID alone group was –3.8% at Month 6; 19% of subjects had a 3 to ≤ 5% BMD decrease, 
29% had > 5% to < 8% BMD decrease, and 8% had a ≥8% BMD decrease.
In Cohort 2, the mean percentage change from Baseline to Month 6 in BMD in the lumbar 
spine for the elagolix 300 mg BID alone group was –3.4% at Month 6; 25% of subjects 
had a 3 to ≤ 5% BMD decrease, 21% had > 5% to < 8% BMD decrease, and 7% had a 
≥8% BMD decrease.  The addition of standard-dose E2 (estradiol 1.0 mg/norethindrone 
 


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acetate 0.5 mg) substantially mitigated BMD loss at the lumbar spine at Month 6 
compared with the elagolix alone group.  In Cohort 1 the mean change from baseline 
–0.1% versus –3.8%), while in Cohort 2 standard dose E2/NETA resulted in a mean 
change from baseline was –1.1% vs –3.4%.
After 6 months treatment in Cohort 1 in the standard E2/NETA (estradiol 
1.0 mg/norethindrone acetate 0.5 mg) group 6.3% of subjects had a 3 to ≤ 5% BMD 
decrease, 1 subject (2%) had a 5% – 8% BMD decrease and no subjects had ≥ 8% BMD 
decrease at the lumbar spine.  Similarly after 6 months treatment in Cohort 2 in the 
standard E2/NETA group 9.6% of subjects had a 3 to ≤ 5% BMD decrease, 3 subjects
(5.8%) had a 5% – 8% BMD decrease and 1 subject (1.9%) had ≥ 8% BMD decrease at 
the lumbar spine.
Taken together results from the Study M12-813 indicated that the standard E2/NETA 
dose would ameliorate bone loss observed during treatment of heavy menstrual bleeding 
in women with uterine fibroids using elagolix 300 mg BID.
Effects of Elagolix on Clinical Laboratory Parameters
In the Phase 2 studies, changes in serum lipids, in particular total cholesterol and low-
density lipoprotein cholesterol (LDL-C), were observed in this study, similar to those in 
which occur as women enter menopause7 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.  Generally these mean changes were changes within the normal range 
of these laboratory tests.  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.  Please 
see the latest version of the Investigator Brochure for details.
 


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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.
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, while the 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 
Endometrial biopsies were conducted at Baseline and at Month 6 in Study M12-813.  
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.
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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As would be expected from a molecule that decreases serum estradiol, there was no 
endometrial hyperplasia in women treated with elagolix alone in the Phase 2b uterine 
fibroid study nor was this observed after 6 months treatment with either addback arms.
3.2.3
Pregnancy in Elagolix Studies
Please refer to Section 8.3.3.10 of the most recent edition of the elagolix Investigator 
Brochure of a complete discussion of Pregnancies in the Elagolix Clinical Development 
Program.  As discussed above and in the Investigator Brochure, elagolix does not block 
ovulation although there is a dose dependent inhibition of ovulation with increasing 
dosage.
Pregnancies have been observed in the elagolix clinical studies.  Although there were no 
congenital malformations observed in the elagolix Phase 3 endometriosis program, earlier 
Phase 2 studies with elagolix did reveal 2 pregnancies with congenital malformations.
In the aforementioned Phase 2b UF (Study M12-813) study, 1 on-treatment pregnancy 
was reported.  In the elagolix Phase 3 studies 4 on-treatment pregnancies were observed.
Extensive counseling on pregnancy prevention along with a requirement for dual non-
hormonal barrier contraception is utilized in all ongoing and planned elagolix clinical 
trials.  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.
 


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Phase 3 Clinical Development Program for Uterine Fibroids
The overall objective of the Phase 3 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.
The primary objective of this current Phase 3b (Study M16-283) study in women with 
HMB associated with uterine fibroids is to obtain extended data on the safety of elagolix 
300 mg BID with standard dose E2/NETA.  All subjects will have the opportunity to be 
treated with elagolix 300 mg BID with standard dose E2/NETA for the second, third and 
fourth years of the study enabling a careful examination of the long term safety of this 
dose over 48 months, particularly with respect to bone loss compared to baseline.
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.  
The Phase 2b Study M12-813 demonstrated that elagolix 300 mg BID with full dose 
add-back therapy showed continued robust efficacy while mitigating bone loss in most 
study subjects.  For this reason estradiol 1.0 mg/norethindrone acetate 0.5 mg is the only 
add-back therapy in this long-term treatment study.
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 
 


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is the optimal regimen for managing and limiting BMD loss, such that longer term dosing 
is feasible.
Continued assessments of this treatment regimen in the pivotal Phase 3 trials will provide 
the requisite data to support registration of elagolix 300 mg BID + E2/NETA as safe and 
efficacious treatment for the chronic management of HMB associated with uterine 
fibroids.
This long-term study will demonstrate safety data of elagolix 300 mg BID plus estradiol 
1.0 mg/norethindrone acetate 0.5 mg versus placebo over a 12-month period and the long 
term safety of this dose over 48 months, particularly with respect to bone mineral density.
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 reduced 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 as a chronic pharmacologic treatment for heavy menstrual period associated 
with uterine fibroids.  Based on the totality of data to date from the Phase 2 clinical 
 


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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 established in the Phase 3 pivotal trials.  This Phase 3b study 
will extend understanding of the safety of elagolix 300 mg BID with E2/NETA compared 
to placebo for 12 months and the long term tolerability of this dose over 48 months, 
particularly with respect to bone mineral density compared to baseline.
Considering the coronavirus disease - 2019 (COVID-19) pandemic, the benefit and risk to 
subjects participating in this study has been re-evaluated.  Based on the information to 
date, no additional risk to study participants is anticipated with the use of elagolix in 
combination with E2/NETA.
4.0
Study Objectives
The objectives of this study are to:
1.
Assess the safety of elagolix 300 mg administered twice daily (BID) in 
combination with E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg QD) 
compared to placebo at 12 months in premenopausal women with heavy menstrual 
bleeding associated with uterine fibroids,
2.
Characterize the impact of elagolix 300 mg BID with E2/NETA on bone mineral 
density (BMD) in women with HMB associated with uterine fibroids after up to 
48 months of treatment.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
COVID-19 Pandemic-Related Acceptable Protocol Modifications
During the COVID-19 pandemic, it has been necessary to employ mitigation strategies to 
enable the investigator to ensure subject safety and continuity of care.  Acceptable 
mitigation strategies are identified and included throughout the protocol.
 


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The investigator should contact the TA MD before discontinuing a subject from the study 
for a reason other than "planned per protocol," (refer to Section 5.4) to ensure all 
acceptable mitigation steps have been explored.
This Phase 3b, randomized, sequential 12-month double-blind placebo-controlled, 
36-month open-label, multi-center study is designed to evaluate the safety of elagolix with 
add-back therapy in women with HMB associated with uterine fibroids.
Approximately 500 subjects will be randomized in a 2:1 ratio to one of the following 
2 treatment groups:
1.
Elagolix 300 mg BID plus E2/NETA (estradiol 1.0 mg/norethindrone acetate 
0.5 mg QD) (n = 335) for 48 months
2.
Placebo (n = 165) for 12 months
Subjects randomized to elagolix 300 mg BID plus E2/NETA in the 12-month Treatment 
Period will receive the same treatment during the open-label Treatment Period.  Subjects
randomized to placebo in the 12-month Treatment Period will switch to elagolix 300 mg 
BID plus E2/NETA during the open-label Treatment Period after completing the 
12-month Treatment Period.
The study was designed to enroll approximately 500 subjects across approximately 
175 clinical study sites to meet scientific and regulatory objectives without enrolling an 
undue number of subjects in alignment with ethical considerations.  Therefore, if the 
target number of subjects has been enrolled, there is a possibility that additional subjects 
in screening will not be enrolled.  The total duration for a subject's participation in this 
study is approximately 77 months, consisting of the following 4 study periods:
1.
Washout Period – up to 10 months prior to Screening (only applicable if subject is 
taking exclusionary medication at the time of consent; duration of washout depends 
on the type of exclusionary medication being taken).
 


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2.
Screening Period – approximately 2.5 to 5 months prior to first dose of study drug.
3.
Treatment Period – up to 48-month treatment duration
4.
Post-Treatment Follow-Up Period – up to 12 months duration following the last 
dose of study drug.  Subjects are expected to enter Post-Treatment Follow-Up after 
completing Treatment Period Month 48, or at any time a subject prematurely 
discontinues during the Treatment Period.
The Study Schematic is shown below in Figure 1.
 


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Figure 1.
Study Schematic
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  


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Washout Period
Following informed consent, subjects who have been taking exclusionary medications 
such as hormonal medications or antifibrinolytics must enter the Washout Period to 
discontinue medications that may confound efficacy analyses and which must be 
completed prior to the Screening Period.  The duration of the required washout period is 
based on the excluded medication that the subject had been taking.  Additional details 
about washout intervals for exclusionary medication is provided in Section 5.2.3.1.  Study 
procedures to be performed during the Washout Period are specified in Appendix C, 
Study Activities and described in Section 5.3.1.1.  Subjects must complete the Washout 
Period and then have at least 1 menses (refer to Table 2) prior to entering the Screening 
Period.  A pelvic ultrasound (transabdominal [TAU] and transvaginal [TVU]) may be 
performed prior to the Washout Period to establish the presence of a qualifying fibroid(s) 
or measure the uterine volume to avoid the subject unnecessarily undergoing a lengthy 
washout of hormonal medications.
Subjects will also begin the use of dual non-hormonal contraception during the Washout 
Period and receive counseling on the importance of consistent, appropriate and effective 
use of birth control and will have contraceptives dispensed, as necessary.
Screening Period
Subjects who do not require washout will enter the Screening Period (approximately 
2.5 to 5 months) and will provide written informed consent before any study-related 
procedures are performed.  Subjects will undergo screening procedures as outlined in 
Appendix C, Study Activities and described in Section 5.3.1.1, to establish eligibility 
based on inclusion and exclusion criteria.
A pelvic ultrasound (TAU and TVU) will be performed during screening, 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.  A saline infusion 
 


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sonohysterography (SIS) will be conducted to rule out exclusionary gynecological 
disorders such as intracavitary submucosal pedunculated fibroids and endometrial polyps.
Subjects who have qualifying uterine fibroids and uterine volume as assessed by 
ultrasound and have SIS images but are unable to fully assess the endometrial cavity after 
2 separate SIS attempts have been made, may undergo an MRI for further evaluation 
during Screening (per imaging vendor request).
Subjects with previous invasive testing (e.g., endometrial biopsy, pelvic ultrasound, Pap 
test and SIS) in addition to DXA assessments within the last 3 months prior to screening
and original results available may qualify to participate in this study.
Eligibility based on MBL (> 80 mL for each of 2 menstrual cycles) will be established 
using the alkaline hematin method.  Sanitary products and the collection kits will be 
dispensed during Screening.  Training will be provided to subjects 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 have signed the 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 SIS) 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 in the electronic Case Report Form (eCRF).
 


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Subjects who screen fail for this study or other AbbVie studies may be re-screened with 
the TA SD's approval.
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 on-site visit.
Year 1 Treatment Period
The Treatment Period begins with Day 1, which will occur between cycle 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 randomly assigned (in a 2:1 ratio) to receive either elagolix 300 mg BID 
plus E2/NETA (n = 335) or placebo (n = 165).  The first dose of study drug will be 
administered at the study site on Day 1 (whether subject has a morning or afternoon visit 
scheduled).  The subject will take her second dose on the first day that evening according 
to instructions.  Thereafter, subjects will be instructed to self-administer study medication 
or matching placebo twice daily (once in the morning and once in the evening 
approximately 12 hours apart) orally without regard to food throughout the 12-Month 
Year 1 Treatment Period.  Subjects entering the 12-month Treatment Period will have on-
site visits at Day 1 and Months 3, 6, 9 and 12.  Phone visits will be made at Months 1, 2, 
4, 5, 7, 8, 10, and 11.
A urine pregnancy test will be performed at each visit throughout the 12-month Treatment 
Period.  Subjects will be counseled at each visit on consistent, appropriate and effective 
 


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forms of dual non-hormonal contraception to promote pregnancy prevention.  A positive 
urine pregnancy test must be confirmed with a serum pregnancy test.  A positive serum 
pregnancy test at any time will necessitate discontinuation from the Treatment Period.
During the phone visits, site staff will assess ongoing adverse events, concomitant 
medications (if applicable), obtain the results of the subject's self-administered urine 
pregnancy test, and remind subjects of the importance of consistent use of appropriate and 
effective use of dual non-hormonal contraception.
A pelvic ultrasound (TAU and TVU) will be performed during the Treatment Period as 
outlined in Appendix C, Study Activities.
Subjects who prematurely discontinue at any time during the 12-month Treatment Period 
will be asked to complete Premature Discontinuation procedures as outlined in 
Appendix C, Study Activities Table and will enter the Post-Treatment Follow-Up Period.
Year 2, 3 and 4 (Open-Label) Treatment Period
Eligible subjects, who complete the 12-month Year 1 Treatment Period, will continue 
participation in the 36-month open label Treatment Period.  Subjects randomized to 
elagolix 300 mg BID plus E2/NETA or placebo in the 12-month Treatment Period will 
receive elagolix 300 mg BID plus E2/NETA during the open-label Treatment Period.
For subjects entering the open-label Treatment Period, visits will occur either by phone or 
on-site as outlined in Appendix C, Study Activities.
Subjects may begin taking hormonal contraceptive preparations only after completing the 
open-label Treatment Period and has a negative urine pregnancy test after 1 month off of 
study drug and return to menses.
Post-Treatment Follow-Up Period 
Subjects will enter the Post-Treatment Follow-Up Period for up to 12 months to assess 
bone recovery after up to 48 months of treatment.  Subjects who prematurely discontinue 
 


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from the study at any time during the Treatment Period will enter the Post-Treatment 
Follow-Up Period.
Adverse event collection and concomitant medication review is detailed in Section 6.1.4
and Appendix C.
DXA scans and additional detail regarding study procedures during the Post-Treatment 
Follow-Up Period is provided in Section 5.3.1.1 and Study Activities, Appendix C.
Study visits may be impacted due to the COVID-19 pandemic.  This may include changes 
such as phone or virtual visits, visits at alternative locations, or changes in the visit 
frequency and timing of study procedures, among others.  Additional details are provided 
for certain procedures.  Every effort should be made to ensure the safety of subjects and 
site staff, while maintaining the integrity of the study.  If visits cannot be conducted onsite 
due to travel restrictions or other pandemic-related reasons, study visits may be conducted 
over the phone where feasible and AbbVie should be notified.
Visit Windows
Visit windows will be allowed during the Treatment and Post Treatment Follow-Up 
Periods.  Each subsequent visit during the Treatment Period (Months 1 through 48) should 
be scheduled based on the date of the Day 1 (Randomization) 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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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 
should be directed to the AbbVie Therapeutic Area Scientific Director (TA SD) listed on 
the title page 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 
any study-specific procedures including washout or screening procedures.
2.
Subject is a premenopausal female 18 to 50 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 uterine fibroid 
meets at least one of the following criteria:
●
Intramural, submucosal non-pedunculated fibroid with a diameter ≥ 2 cm 
(longest diameter)
●
Subserosal fibroid ≥ 4 cm (longest diameter)
●
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).
 


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6.
Subject must have a negative urine and/or serum pregnancy test(s) during the 
Washout (if applicable) and/or Screening Periods, and a negative urine pregnancy 
test just prior to administration of the first dose of study drug.
7.
Subject must agree to use two forms of non-hormonal contraception (dual 
contraception) consistently during the Washout (if applicable), Screening, 
Treatment Periods and through the end of Month 1 of the Post-Treatment Follow-
Up Period.  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 and requires dual 
non-hormonal contraception.
●
Subject had a bilateral tubal ligation or bilateral tubal occlusion, at least 
4 months prior to Screening.
●
Subject is not sexually active with men; however, periodic sexual 
relationship(s) with men require the use of study defined dual non-hormonal 
contraception.
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.
 


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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).
2 – 5
These criteria were selected to ensure an appropriate subject population of 
premenopausal women with HMB associated with uterine fibroids
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
8 – 9
These are standard criteria to ensure general good health and the safety of 
the subjects
10, 11
To avoid bias for the evaluation of safety by concomitant use of other 
medications
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 consecutive 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 
ultrasounds shows a simple ovarian cysts  > 5 cm and ≤ 7 cm, an ultrasound of 
 


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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 (HIFU) 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 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 < 7 g/dL (subjects with initial screening hemoglobin 
results < 7 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 aspartate aminotransferase (ASAT/SGOT) or alanine aminotransferase 
(ALAT/SGPT) ≥ 3.0 times the upper limit of the reference range or bilirubin 
 


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(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.
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 48 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 2.0 or more standard deviations below normal 
(T-score ≤ –2.0)
●
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).
●
History or presence of a condition that is associated with a decrease in BMD 
(e.g., uncontrolled hyperthyroidism, uncontrolled hyperparathyroidism, 
anorexia nervosa) or requires chronic treatment with systemic corticosteroids.
●
History of low-trauma bone fractures (e.g., fracture resulting from a fall from a 
standing height or lower)
●
Bilateral hip replacement
●
Clinically significant hypocalcemia, hypo- or hyperphosphatemia
●
Treatment with medication (excluding calcium and vitamin D) for bone disease 
associated with a decrease in BMD
 


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17.
Subject has a history of major depression or post-traumatic stress disorder (PTSD) 
episode 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) within the last 1 year at Screening or Day 1, prior to randomization.
19.
Subject has either:
●
A newly diagnosed, clinically significant medical condition that requires 
therapeutic intervention (e.g., new onset hypertension) that has not been 
stabilized 30 days prior to Randomization on Day 1, OR
●
A clinically significant medical condition that is anticipated to require 
intervention during the course of the study participation (e.g., anticipated major 
elective surgery), OR
●
An unstable medical condition that makes the subject an unsuitable candidate 
for the study in the opinion of the investigator (including, but not limited to, 
uncontrolled diabetes mellitus, uncontrolled hypertension, epilepsy requiring 
anti-epileptic medication, unstable angina, confirmed inflammatory bowel 
disease, hyperprolactinemia, clinically significant infection or injury 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 hypersensitivity, documented allergy to or is unable to tolerate 
norethindrone, norethindrone acetate or estradiol, or these preparations 
(e.g., Activella) or are otherwise intolerant of the estrogens or progestins in 
hormonal contraceptives or contraindicated for medical reasons.
 


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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 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 returns to 
1 menses, the subject can be screened for eligibility to be considered for 
randomization.
26.
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 intra-articular injectable (for occasional use) corticosteroids are 
allowed.
27.
Subject is using oral retinoid preparations such as Accutane® (isotretinoin).  
Topical isotretinoin applications are permitted.
28.
Subject has a history of drug abuse and/or alcohol abuse within 12 months prior to 
Screening that may affect the safety, data collection, or have an adverse effect on 
the study participation.
29.
Subject previously received Elagolix/an investigational GnRH antagonist less than 
1 year prior to entry into the Screening period.
30.
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.
 


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31.
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 and consistent use of dual non-hormonal contraception 
throughout the required time period.
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
5 – 13, 15 – 23, 28
These are standard criteria to ensure general good health and 
the safety of the subjects
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
25 – 30
These criteria were selected to ensure that safety can be 
adequately assessed
31
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
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 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.
 


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The AbbVie TA MD should be contacted if there are any questions regarding concomitant 
or prior therapy(ies).
5.2.3.1
Prior Hormonal/Anti-Hormonal Medications
Subjects using hormonal contraception or other hormonal/anti hormonal therapies may be 
considered for study participation provided they complete the required washout.  Subjects 
must have at least 1 menses after completion of Washout before entering into the 
Screening Period.  Subjects currently 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.  Discontinuation of hormonal contraception should be done 
according to prescribing information (e.g., complete current cycle of birth control pills) 
and per the investigator's discretion.
Subjects entering washout will be required to undergo study specific procedures, as 
outlined in Appendix C, Study Activities.
Subjects using an LNG-IUS, who agree to have the LNG-IUS removed, must complete 
the washout period and have at least 1 menses during the washout prior to Screening.  
Subjects using a CU-IUD, who agree to have the IUD removed may also enter screening 
(no washout required) and must have 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 and also to ensure there is no pregnancy.
The minimum washout intervals for hormonal medications (including LNG-IUS) prior to 
Screening are described in Table 2.  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), goserelin acetate (Zoladex®)
180 days from 
injection
1 menses
Synarel® (Nasal Spray)
Nafarelin acetate
GnRH agonist – 1 month depot (including Lupron 
Depot® 3.75 mg)
120 days
Non-oral GnRH antagonist
90 days
Selective Progesterone Receptor Modulators 
(e.g., Ulipristal acetate, Vilaprisan)
Danazol (Cyclomen®)
Aromatase inhibitors
Oral contraceptives***
30 days
Oral, transdermal or intravaginal estrogen preparations*
Oral, intravaginal or transdermal progesterone/progestin 
preparations, including tibolone*
Hormonal, sub-dermal progestin implant (e.g., 
Nexplanon®)
30 days after 
removal
NuvaRing®
Moderate or strong inducers (e.g., cyclosporine, 
rifampin, carbamazepine, St. John's Wort) of 
cytochrome P450 3A (CYP3A)
30 days prior to 
randomization
Antifibrinolytics
2 weeks
*
E2/NETA will be taken by subjects randomized to the E2/NETA treatment group.  Exception:  levonorgestrel 
1.5 mg or ulipristal acetate 30 mg used for emergency contraception.
**
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.
*** Subjects must complete the mandatory month of washout from oral contraceptives and subsequently have a 
menses.  Bleeding due to withdrawal of the oral contraceptives cannot be considered the required menses.
 


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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 
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.
Given the ongoing COVID-19 pandemic, selected non-live vaccines (e.g., mRNA, non-
replicating viral vector, protein subunit, etc.) to prevent SARS-CoV-2 infection may be 
administered during the Treatment and Post-Treatment Follow-Up Periods, as long as 
components of the vaccine are not contraindicated.
The decision to receive a locally available vaccine should be based on local guidance and 
an individual discussion between the treating physician and the subject.
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 < 7 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 
 


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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 and Treatment Period, however inhaled corticosteroids for the treatment of 
asthma are permitted.  Over-the-counter and prescription topical, inhaled, intranasal or 
intra-articular 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 Periods and until the 
Post-Treatment Follow-Up Period Month 1.  Subjects may start hormonal contraception 
after completion of Post-Treatment Follow-Up Period Month 1, and having a negative 
urine pregnancy test after 1 month off of study drug and returned to menses.  If the 
Subject has not returned to menses by Month 1 in the Post-Treatment Follow-Up Period, 
the Investigator would use acceptable medical practice to reinitiate hormonal 
contraceptive (e.g., pregnancy test, FSH, induction of withdrawal bleed, etc.).
For subjects who are prescribed/administered the emergency contraceptive pill during the 
study, the information should be captured in the source documents and eCRF and the 
AbbVie TA MD must be informed.
 


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Tranexamic acid should not be taken during the Screening and Treatment Periods, 
however tranexamic acid, if necessary, can be prescribed following completion of the 
Treatment Period and the subject has returned to first full menses.  Should the subject be 
prescribed tranexamic acid during the Treatment Period, they will be discontinued and 
will enter the Post-Treatment Follow-Up Period.
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, and the Treatment Periods.
 






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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 on the title page 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, her continued participation in the study will be evaluated 
by the Investigator and the AbbVie TA MD.  If there are any questions regarding prior or 
concomitant therapy, please contact your Study Monitor.
5.2.4
Contraception Recommendations
Contraception Counseling/Dispensing Contraceptives
Investigators and study staff will be trained by the Sponsor on the importance of 
contraception in this clinical trial.  Subjects (excluding those subjects who have had a 
bilateral tubal ligation or bilateral tubal occlusion) will be counseled by the Investigator or 
designated study staff at every visit throughout study participation on the importance of 
pregnancy prevention and the use of appropriate and effective methods of contraception.
Subjects must agree to use two forms of non-hormonal contraception (dual contraception) 
consistently throughout the Washout (if applicable), Screening and Treatment Periods and 
the first month of the Post-Treatment Follow-Up Period.  Subjects may begin the use of 
hormonal contraception (e.g., oral or IUD) after completion of the Post-Treatment 
Follow-Up Month 1 visit and has a negative urine pregnancy test after 1 month off study 
drug and return to menses.
Acceptable methods of dual non-hormonal contraception include the following 
combinations:
●
Condom with spermicide (foam, gel or polymer film)
●
Diaphragm with spermicide (condom may or may not be used)
●
Cervical cap with spermicide (condom may or may not be used)
 


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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 ligation or bilateral tubal occlusion at least 
4 months prior to screening.
●
Subject is not sexually active with men; however, periodic sexual 
relationship(s) with men requires the use of dual non-hormonal contraception 
as indicated above.
●
Subject has begun the use of hormonal contraception after the Post-Treatment 
Follow-Up Month 1 visit.
●
Subjects may begin the use of hormonal contraception after the Post-Treatment 
Follow-Up Month 1 visit, provided she has a negative urine pregnancy test 
1 month off of study drug and has returned to menses.  If the Subject has not 
returned to menses by Month 1, the Investigator would use acceptable medical 
practice to reinitiate hormonal contraceptive (e.g., pregnancy test, FSH, 
induction of withdrawal bleed).
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 (via signature) her full awareness that the potential risks of study 
drug on the unborn child are unknown and therefore she must not get pregnant 
during the entire time of study participation, and that she agrees to consistently use 
protocol required dual non-hormonal contraception throughout her study 
participation.
2.
The Investigator or designated study staff will counsel the subject that the study 
drug is not contraceptive, that ovulation may occur even though the study drug may 
have altered menstrual cycle patterns, and that fetal abnormalities have been 
 


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reported in women who have received elagolix in clinical studies however, it is 
unknown whether these abnormalities were the result of taking elagolix.
3.
The Sponsor will provide training materials to the sites for instructing subjects on 
the types of protocol-allowed contraception methods, their effectiveness and proper 
use.
●
The Sponsor will provide all investigative sites with a supply of materials to 
promote pregnancy prevention, including contraceptives (e.g., condoms and 
spermicides) to provide to subjects at no charge.
●
Subjects 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 an acceptable contraception method of their 
choice from the contraceptives provided by the Sponsor and will be expected to 
consistently practice the allowable methods of contraception.  The site will 
assess the subject's basic understanding of the proper contraceptive use through 
discussion and demonstration of proper techniques, if needed, including proper 
diaphragm use.
●
The site will provide contraceptives (and other supplies (e.g., lubricants) to 
subjects throughout Washout, if applicable, Screening and Treatment Periods, 
as needed.
●
The source documents will capture date initial contraception counseling was 
performed, whether the subject meets protocol criteria for not requiring use of 
dual contraception and the type of contraceptive provided to the subject (as 
applicable). At subsequent study visits, the source documents will capture if 
there was a change in contraceptive method, use of a non-study supply brand, 
and whether additional contraceptives were provided to the subject.
●
The subject will be asked to attest by signature at the time of consent, and 
subsequently in a stand-alone attestation form at all on-site study visits that 
allowable methods of contraception, as described during the pregnancy 
prevention counseling, are being practiced.
 


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●
For subjects who have had a bilateral tubal ligation or bilateral tubal occlusion, 
(including Essure®), attestation is only required to be collected once during the 
study prior to randomization, ideally at the time of consent.  Additionally, these 
subjects do not require contraception counseling at any study visit or the 
associated documentation of that counseling.
4.
On-site and phone visits are used to promote frequent interaction with site staff and 
opportunities for continued education.
5.
At each Treatment Period visit (on-site and phone visits), the proper use of 
contraception will be reinforced to address possible ineffective use and the risk of 
unexpected pregnancy due to unprotected sexual activity.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to come on-site, the 
contraception counseling should be conducted during the phone visits (as applicable). 
The site should ship a reasonable quantity of contraceptive supplies for subject use until 
next on-site visit.  The type and quantity of contraceptives shipped to the subject must be 
documented along with the shipping tracking number and documentation.  When subject 
is able to go to the site, site should make sure that enough contraceptives are dispensed to 
the subject.
5.3
Efficacy, Pharmacokinetic, Biomarker, Optional Exploratory 
Research Samples 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.
 


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5.3.1.1
Study Procedures
The study procedures outlined in Appendix C are discussed in detail in this section, with 
the exception of monitoring study drug accountability (Section 5.5.7), contraception 
counseling/contraceptive dispensing (Section 5.2.4), the collection of concomitant 
medication (Section 5.2.3) and adverse event information (Section 6.0).  All study data 
will be recorded on the eCRFs with the exception of the select ePRO data and data from 
the central lab/imaging vendor.
The Screening Period will occur within approximately 2.5 to 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 (as allowed per 
protocol or at the discretion of the AbbVie TA SD), 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 should be 
performed within the visit windows specified in Table 1.  Scheduled monthly visits during 
the Treatment and Post-Treatment Follow-Up Periods are based on a 28-day month.
This protocol provides recommendations regarding the sequence of procedures to be 
performed during the study.  In no case should these recommendations outweigh clinical 
judgment or standard of care.  If the protocol indicates that the AbbVie TA SD or 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.  Exploratory research testing is optional and a subject must 
be provided a separate informed consent option for this blood collection.  Details about 
how informed consent will be obtained and documented are provided in Section 9.3.
Medical/Social History
A complete medical history, including documentation of any clinically significant medical 
conditions and medications, history of tobacco and alcohol use, and drug abuse will be 
collected during the Washout Period (if applicable) or during the Screening Period for 
those subjects who do not require washout.  The medical history will be reviewed and 
should be updated if significant clinical findings are noted on Day 1 prior to dosing and 
will serve as the baseline for clinical assessment.
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:
●
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
 


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●
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:
○
Total number of pregnancies
○
Number of live births
○
Number of abortions (including elective, therapeutic and spontaneous 
abortions)
○
Delivery outcomes (specifically, anomalies including congenital 
malformations and chromosomal abnormalities).
The gynecological/obstetrical and uterine fibroid history will be reviewed and should be 
updated if needed prior to dosing on Day 1 (Randomization) and will serve as the baseline 
for clinical assessment.
Physical Examination
A complete physical examination will include height (at Screening only) and weight 
measurements (the subject should wear lightweight clothing and not wear shoes) and will 
serve as the baseline for clinical assessment.
A brief, symptom-directed physical examination will be performed at Washout (if 
applicable), Day 1 and Post Treatment Follow-Up Month 1.
Visits requiring either the complete physical examination (including weight) or a brief, 
symptom-directed physical examinations are outlined in the Study Activities Table, 
Appendix C.
 


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Clinically significant physical examination findings prior to randomization will be 
recorded as medical history.  Any clinically significant physical examination findings 
after initiation of dosing will be recorded in the source documents and in the eCRFs as 
adverse events.  The complete physical examination performed during Screening will 
serve as the baseline for clinical assessment.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to come on-site for the physical 
exam, it can be delayed up to 1 month from their scheduled time. Should the delay be 
longer, AbbVie should be notified.
Gynecological (Pelvic and Breast) Examination
A complete breast and pelvic examination, including external genitalia, will be performed 
during the Screening and Treatment periods as listed in Appendix C.  Timing of brief 
symptom-directed gynecologic examinations are outlined in Appendix C, but may also be 
performed at any time throughout the study as deemed clinically necessary.  The complete 
breast and pelvic examination completed during Screening will serve as the baseline for 
clinical assessment.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to come on-site for the 
gynecological exam, it can be delayed up to 1 month from their scheduled time. Should 
the delay be longer, AbbVie should be notified.
Vital Signs
Vital sign determination of pulse, blood pressure, respiratory rate, and body temperature 
will be obtained at all on-site visits during the study as indicated in Appendix C.  The 
blood pressure and heart rate measurements should be taken prior to scheduled blood 
 


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collections (if applicable).  Measurements should be assessed consistently throughout the 
study and will be recorded in the source documents and eCRF.
The vital signs measurements obtained prior to dosing on Day 1 will serve as the baseline 
measurements for clinical assessment.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to come on-site for the vital 
signs, it can be delayed up to 1 month from their scheduled time. Should the delay be 
longer, AbbVie should be notified.
12-Lead Electrocardiogram (ECG)
A resting 12-lead ECG will be conducted during the Screening Period.  The ECG should 
be obtained prior to any blood collection.
For any abnormal screening test results, the ECG may be repeated one time prior to/on 
Day 1, however the subject may not be enrolled if any clinically significant findings are 
noted on the repeat ECG.  Final results (i.e., results used to determine eligibility) will be 
entered into the eCRF.
The Investigator or qualified designee at the study site will determine if any findings are 
clinically significant (in consultation with a cardiologist if necessary), and document this 
on the ECG tracing/report, sign and date it.  The original ECG tracing or a certified copy 
of the original tracing with the physician's assessment will be retained in the subject's 
records at the study site.
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), and at Months 12, 24, 36, 48 and 
 


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Premature Discontinuation Visit (if applicable).  Local mammogram results and final 
interpretation must be entered into the eCRF upon receipt.
If a subject's screening mammogram results are incomplete (BI-RADS 0) and need to be 
repeated, the AbbVie TA MD does not need to be contacted for approval prior to 
conducting the repeat mammogram or other mode of imaging (e.g., ultrasound, spot 
compression).  If results meet entry requirements, subject would be allowed to continue in 
Screening.
If the repeat mammogram or other breast imaging results indicate further testing is 
required (e.g., breast biopsy) to rule out any potential exclusionary findings, the subject is 
not eligible for the study.  Any further imaging or testing will be performed outside of the 
protocol and should follow standard of care.
Mammograms will be read locally and the local radiologist's interpretation will be used to 
determine if a subject meets eligibility criteria.  Subjects with normal or benign findings 
or BI-RADS Classifications 1, 2 or 3 (via mammogram or other mode of imaging) as 
outlined in Appendix D will be eligible for randomization on Day 1.  Subjects with an 
abnormal mammogram or BI-RADS 4, 5 or 6 will not be eligible for randomization into 
the study.  Subjects should continue with recommended mammography testing outside of 
the protocol per local guidelines and standard of care during the study.
During the Treatment Period, mammograms will also be performed for subjects who are 
39 years of age or older at the time of the scheduled study visit at Months 12, 24, 36, 48 
and Premature Discontinuation Visit (if applicable).  A mammogram is not required for 
prematurely discontinued subjects if the subject had a mammogram within approximately 
6 months prior to the PD visit.  All mammograms will be read locally.  If a subject has a 
clinically significant mammogram finding in the opinion of the investigator, or BI-RADS 
Classifications 4, 5, or 6, or there is a recommendation for additional testing, the AbbVie 
TA MD should be notified for additional guidance and approval.
 


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COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to come on-site for the 
mammogram, it can be delayed up to 1 month from their scheduled time. Should the 
delay be longer, AbbVie should be notified.
Pap Test
Pap test will be performed on all subjects at the visits listed in Appendix C.  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.
After colposcopy, subjects who have a histological diagnosis of CIN 1 or less with an 
adequate colposcopy and a negative endocervical sample post colposcopy may continue in 
Screening.  For subjects with no lesion identified on colposcopy or when colposcopy 
 


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examination is unsatisfactory, endocervical sampling must be performed to confirm a 
negative/benign endocervical sample.
Subjects with the cytology screening result of atypical squamous cells cannot exclude 
HSIL (ASC-H), high-grade intraepithelial lesion (HSIL), or atypical glandular cells 
(AGC), atypical endocervical cells or histological diagnosis of CIN 2 or 3 are not eligible 
for the study.
During the Treatment Period, a Pap Test will be performed at Months 24, 48 and the 
Premature Discontinuation visit (if applicable).  During Treatment, if the subject has an 
abnormal pap test that indicates a clinically significant finding in the opinion of the 
investigator and requires additional testing (e.g., colposcopy or biopsy) as follow-up, the 
AbbVie TA MD should be notified for additional guidance and approval.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to come on-site for the pap test, it 
can be delayed up to 1 month from their scheduled time. Should the delay be longer, 
AbbVie should be notified.
 




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misoprostol for cervical dilatation is allowable.  In addition, Lidocaine may be used as 
local anesthesia on the cervix.  Any medications used for the procedure should be 
recorded in source documents and on the appropriate eCRF.  If there is a need for 
consideration for an office hysteroscopy to obtain the endometrial biopsy sample, the TA 
MD should be consulted.
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 from the central laboratory must be obtained and reviewed by the 
Investigator to ensure eligibility criteria are met before the subject can be randomized on 
Day 1.  In case of an insufficient sample the biopsy 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 subject will need to be screen failed and can be re-screened.
An endometrial biopsy is not required during the Treatment Period if the ultrasound 
findings at Treatment Months 12 or 24 indicate an endometrial thickness < 4 mm.  If the 
ultrasound findings during the Treatment Period Months 12 or 24 indicate an endometrial 
thickness ≥ 4 mm, then the subject must have an endometrial biopsy performed at these 
time points.
For this amendment (Amendment 6) based upon FDA feedback, endometrial biopsy at 
Month 36 and 48 is required regardless of the TVU findings at the corresponding visit.
Specifically, for subjects who have completed Month 36 study visit without the 
endometrial biopsy, subjects should return for an interval endometrial biopsy as an 
Unscheduled Visit.  Refer to Appendix C, Study Activities, for more information.
 


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If the Month 12, 24, or 36 biopsy results are normal or the sample contains scant 
endometrium without abnormalities, the subject may continue in the remaining of the 
open-label Treatment Period.
In the event the Month 12 or 24 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.  In the event 
that the Month 36 or 48 biopsy cannot be performed, or an insufficient biopsy sample is 
obtained, a repeat biopsy must be performed.
If the repeat biopsy is performed and the results are normal or the sample contains scant 
endometrium without abnormalities, the subject may continue the open-label Treatment 
Period.
If the repeat biopsy sample cannot be obtained or remains insufficient, the AbbVie TA 
MD should be consulted.
An additional endometrial biopsy should be performed if clinically indicated for 
breakthrough bleeding, taking into account of the subject's previous biopsy results, TVU 
findings, patient compliance with study drugs and recognizing subjects are receiving a 
daily dose of progestin.
Subjects with abnormal endometrial pathology results (including, endometrial hyperplasia 
with or without atypia and endometrial cancer) during the Treatment Period should be 
discontinued and instead will enter the Post-Treatment Follow-up Period.  The 
endometrial pathology should be managed according to standard of care.
In addition, if there is an abnormal endometrial pathology at Treatment Month 48, this 
should be managed according to standard of care.
 


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COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to come on-site for the 
endometrial biopsy, it can be delayed up to 1 month from their scheduled time. Should 
the delay be longer, AbbVie should be notified.
Central Imaging Procedures
Fibroid and uterine assessments will be obtained using pelvic ultrasound (TAU and TVU) 
at Washout (if applicable), Screening, Months 12, 24, 36, 48 or Premature 
Discontinuation Visit and SIS at Screening.  All ultrasound images will be sent to the 
Central Imaging Core Lab (central reader) for review to determine eligibility for 
randomization and to monitor safety during the Treatment Period.
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 central reader.  
Images should be sent/transmitted to the central reader 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 central reader.
The pelvic ultrasound (TAU, TVU and SIS) and MRI (if applicable) will be assessed both 
locally and by the central reader.  The central reader 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 central reader 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 TA MD will discuss the findings with the local site and central reader on a 
case-by-case basis to determine eligibility.
 


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The Investigator or designee should consult the local ultrasound and SIS reports and/or 
images in order to determine if any exclusionary criteria are present and make safety-
related judgments concerning the subject.  The interpretation of the local report and/or 
images will be filed or recorded in the subject's source documents.  Data and/or local 
interpretation from the local ultrasound, DXA, SIS and MRI (if applicable) images will 
not be recorded in the eCRF.
During the Treatment and Post-Treatment Follow-Up Periods, the central reader may 
issue a report if any significant changes are observed that may affect subject safety during 
the study.  In these cases, the Investigator should review the local ultrasound, SIS and/or 
MRI (if applicable) images and treat as per standard of care.
The pelvic ultrasound, SIS and MRI (if applicable) will be performed as outlined in 
Appendix C, Study Activities.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to come on-site or to the imaging 
facility, the DXA and TAU/TVU can be delayed up to 1 month from their scheduled time. 
Should the delay be longer, AbbVie should be notified.
Pelvic Ultrasound:  TAU and TVU
A pelvic ultrasound (TAU and TVU) will be performed early in the Screening Period and 
should ideally be performed during the subject's early proliferative phase of the menstrual 
cycle (approximately Days 4 – 8 of the cycle), 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 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 
 


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cysts and 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
●
Uterine volume in cubic centimeters
●
Presence of ovarian cysts 
o
Number
o
Size (cm)
o
Location (right or left ovary)
o
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 
 


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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.
Subjects who have qualifying uterine fibroids and uterine volume as assessed by 
ultrasound but have SIS images that are unable to fully assess the endometrial cavity after 
2 separate SIS attempts have been made, may undergo an MRI (per imaging vendor 
request) for further evaluation.
Intracavitary Uterine Findings
An SIS may be performed during the Treatment Period if the pelvic ultrasound (TAU and 
TVU) results suggest an intracavitary lesion such as a polyp.  The finding of a polyp 
during the Treatment Period 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 Period.
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 
 


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may be eligible for randomization provided there are no exclusionary findings based on an 
alternate imaging that can evaluate that adnexa such as an MRI (per central reader 
agreement).
During the Treatment Period, 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 lumber spine, femoral neck and total hip will be performed by qualified 
technologist/radiologists at the site or affiliated imaging facility utilizing GE Lunar or 
Hologic equipment and per the acquisition guidelines provided by the Central Imaging 
Core Lab (central reader).  The DXA technologist/radiologist or designee for each 
investigative site should electronically submit the subject's DXA images to the central 
reader for review and analysis following acquisition.  Subject eligibility and treatment 
management will be made based on the central reader review.  Sites will receive reports 
from the central reader detailing the results (including T-scores and BMD % change from 
baseline, as applicable) of the DXA scans performed.  Site training and qualifications, 
including assessment of instruments, will be evaluated/approved by the central reader 
prior to screening the first subject.  Instructions on calibration and standardization of 
instruments and any additional required information will be specified in a manual from 
the central reader that will be provided to all study sites.  Sites will need to obtain 
approval from the central reader prior to initiating study scans.
A DXA scan will be performed during Screening Period and sent to the central reader to 
determine eligibility and serve as the baseline scan for subject management.  Subjects 
with a T-score of < –2.0 at the lumber spine, total hip or femoral neck on the screening 
DXA scan will not be eligible to enter the study.
 


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During the Treatment Period, DXA scans will be performed for all subjects at Months 6, 
12, 18, 24, 30, 36, 42 and 48 and will be submitted to the central reader for review and 
analysis.  The central reader will be blinded to the subject's treatment assignment (in the 
12-month Treatment Period), but not to the corresponding time point.
If the results of any post-baseline DXA prior to and including Month 48, as read by the 
central reader selected for the study, document a T-score of < –2.5 in the lumbar spine, 
total hip or femoral neck, the subject must be discontinued from study drug dosing and 
will enter the Follow-Up Period.
Subjects with a BMD decrease of > 8% in the lumbar spine, total hip, or femoral neck 
(any of the three regions) on any DXA scan performed during the Treatment Period 
(i.e., Months 6, 12, 18, 24, 30, 36, and 42) must be discontinued from study drug dosing 
and will enter the Post-Treatment Follow-Up Period.
DXA scans are also required if a subject premature discontinues for the following reasons:
●
Subjects who discontinue prior to the Treatment Month 6 visit only if the
reason for premature discontinuation is due to the occurrence of a fracture or 
any newly diagnosed bone condition
●
Subjects who discontinue any time at the time of or after the Treatment 
Month 6 visit unless a DXA scan has been performed within 3 months of
Premature Discontinuation.
However, if a subject is being discontinued from the study due to a T-score of < –2.5 in 
any region (the lumber spine, total hip or femoral neck), BMD decrease from baseline of 
> 8% in any region, or TA MD assessment, additional DXA scans do not need to be 
performed as a part of the Premature Discontinuation visit procedures.  In these 
circumstances, the subject would enter into the Post-Treatment Follow-Up Period and 
continue with required BMD evaluations.
 


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DXA scans of the lumbar spine, total hip, and femoral neck will be obtained at Post-
Treatment Follow-Up Period at Months 6 and/or 12, except for subjects who prematurely 
discontinued less than 3 months during the Treatment Period.
If the BMD percent change from baseline of any post-baseline DXA cannot be provided 
by the central reader (i.e., due to scanner changes), then the TA MD must be consulted to 
confirm if the subject can continue study drug dosing.  A BMD decrease at any anatomic 
location (lumber spine, total hip or femoral neck) that results in discontinuation from the 
study should be reported as an adverse event (Section 6.1.1).
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
Total protein
Albumin
Total bilirubin 
Serum glutamic-pyruvic 
transaminase (SGPT/ALAT)
Serum glutamic-oxaloacetic 
transaminase (SGOT/ASAT)
Alkaline phosphatase
Serum iron1
Serum ferritin1
Total iron binding capacity (TIBC)1
Vitamin D Testing1
Specific gravity
Ketones 
Protein
Blood
Glucose
pH
Lipid Panel
(After Minimum 8-Hour Fast)
Low-density Lipoprotein (LDL) 
cholesterol
High-density Lipoprotein 
(HDL) cholesterol
Triglycerides
Total cholesterol
Endocrine Panel
Follicle-stimulating hormone 
(FSH)
Reflexive Thyroid Stimulating 
Hormone (TSH)
Pregnancy Test
Serum pregnancy (only 
completed if urine 
pregnancy test is 
positive)
1.
To be completed at Screening visit only.
Laboratory samples indicated in Table 4 will be assessed using a certified central 
laboratory selected for this study and these data will be used for data analysis.  The central 
laboratory will provide instructions regarding the collection (including any fasting 
requirements), processing and shipping of samples.  Blood draws should be performed 
after vital signs and ECG recording are conducted at a visit.
Clinical chemistry samples should be obtained in the morning following an overnight fast 
(minimum of 8 hours); however, there may be circumstances when the sample is obtained 
later in the day and/or not under fasting conditions.  If the sample was obtained with less 
 


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than 8 hours of fasting, the source documents and the lab requisition should be marked to 
indicate that the sample was obtained under non-fasting conditions.
All clinical laboratory samples will be shipped to the central laboratory, with the 
exception of the venous blood sample for alkaline hematin analysis which will be sent to 
the Alkaline Hematin Laboratory during screening.
The laboratory results will be provided by the central laboratory to the investigative site 
where they will be reviewed, signed and dated by the Investigator.  For any value outside 
of the reference range, the Investigator will review and indicate on the report if the result 
is clinically significant (CS) or not clinically significant (NCS).  The Investigator will 
evaluate clinically significant laboratory values per standard of care which may include 
repeating the test to verify the out-of-range value.  Clinically significant laboratory 
abnormalities post randomization may be documented as adverse events, depending on 
the interpretation of the Investigator (Section 6.0).
All screening laboratory results must be reviewed prior to randomization, including any 
repeated test results.  Screening laboratory tests may be repeated one time prior to Day 1, 
however, results must satisfy entry criteria prior to randomization.  Subjects will not be 
randomized on Day 1 if Screening laboratory results do not meet entry criteria or are 
assessed as clinically significant by the Investigator.  The laboratory test results obtained 
from the Day 1 pre-dose samples will serve as the baseline for clinical assessment.
The Investigator will receive Sponsor defined alerts from the central lab.  The Investigator 
will review the lab alerts and assess clinical significance for potential adverse events.
Blood samples for biomarker, exploratory research, and Pharmacokinetic (PK) analysis 
will be collected and processed as indicated in Section 5.3.1.2 and Section 5.3.2 (PK).  
Samples will be shipped to the Central Laboratory by the Study Site and then shipped by 
the Central Laboratory to AbbVie for analysis.
 


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COVID-19 Pandemic-Related Acceptable Protocol Modifications
If travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic prevent the subject from having blood drawn for laboratory testing at the study 
site, subject can be rescheduled to return within 30 days to have blood drawn.
Study drug administration may be continued provided the investigator has reviewed all 
prior laboratory results and confirms and discusses with the subject that there are no 
safety concerns for the subject to continue use of the study drug in the absence of current 
labs. If the Investigator has any concerns the TA MD should be contacted.
Lipid Panel
The lipid panel consists of LDL cholesterol, HDL cholesterol, triglycerides and total 
cholesterol; and should be obtained in the morning following an overnight fast (minimum 
of 8 hours); however, there may be circumstances when the sample is obtained later in the 
day and/or not under fasting conditions.  If the 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.
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 for all subjects during the Screening Period.  If any of these tests are 
positive or reactive, the subject is excluded from study participation.  Borderline hepatitis 
test results should be repeated.
The results of the HIV and anti-HIV Ab testing will be retained confidentially by the 
study site.
Optional Testing for Gonorrhea and Chlamydia
Gonorrhea and chlamydia testing can be ordered at the Investigator's discretion during the 
Screening and Treatment Periods, to test for active gonorrhea or chlamydia prior to 
 


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performing the endometrial biopsy.  These samples will be sent to the central laboratory 
for analysis.  If the Investigator determines that an abnormal test result can be treated, 
treatment will be outside of the protocol.  Follow-up chlamydia/gonorrhea testing (per 
instructions from the central lab) can be performed after treatment at the Investigator's 
discretion.
Endocrine Panel
The endocrine panel consists of the following analytes:  FSH and reflexive TSH.
Pregnancy Testing
Urine pregnancy tests will be performed as outlined in Appendix C, in all subjects 
regardless of sexual activity status or method of contraception, including subjects who are 
surgically sterilized.
The urine pregnancy test result on Day 1 must be reviewed and confirmed to be negative 
prior to randomization.  Prior to performing the SIS and endometrial biopsy procedures, 
the subject must have a confirmed and documented negative urine pregnancy test within 
24 hours of the procedure(s).  In addition, during the Treatment Period, the urine 
pregnancy test must be negative prior to providing subjects with their next supply of study 
drug, (including an unscheduled visit at which study drug is dispensed).
Home urine pregnancy test kits will be provided to subjects during the Treatment Period 
for use at home when subjects are not required to come to the site (e.g., phone contact 
visits and prior to certain study procedures).  Subjects will self-administer the tests and 
report the result to the site during phone visits or within 24 hours prior to undergoing 
certain study procedures.  Subjects reported test results will be entered in the source and 
eCRF.
A positive urine pregnancy test result (including a home urine pregnancy test) must be 
confirmed with a quantitative serum pregnancy test.  The subject should temporarily 
discontinue study drug administration while waiting for the results of the serum 
 


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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.
If the subject becomes pregnant at any time after randomization up through 30 days post 
last dose of study drug, an ultrasound examination will be performed during the 
first trimester of pregnancy to assess the gestational age and estimated date of delivery.  
Refer to Section 6.1.6 for instructions on reporting of a pregnancy to the Sponsor and the 
required follow-up on the subject's fetus, pregnancy and infant outcomes.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event that a subject or study personnel cannot come to the site for a study visit 
requiring a urine pregnancy test because of the COVID-19 pandemic, home pregnancy 
test kits may be provided to subjects to self-administer at home and report results to study 
site over the phone. Sites should document the results in source.  If a urine pregnancy test 
cannot be completed, the site will need to reach out to the TA MD to determine further 
action and if study drug should be discontinued.
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.
 


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Starting in Screening, subjects will be dispensed sanitary collection kits that consist of 
validated sanitary products, product collection bags and a keg with screw-on lid for 
storage as provided by the vendor.  It is important that only the sanitary products provided 
by the Sponsor are used during the study.  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 Period is outlined in 
Figure 3.
Figure 3.
Sanitary Product Dispensation and Collection
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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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, Screening Menstrual 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.  Subjects will continue to collect 
sanitary products in screening until the results confirm a second eligible menstrual cycle 
has been met.
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 but is not limited to the following:
●
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 
 


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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.
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
#
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.
*
If Screening Cycle 1 blood loss is ≤ 60 mL, study site must consult AbbVie for approval to collect sanitary 
products for additional menstrual cycles in screening.  Subjects with a Screening Cycle 1 blood loss between 
60 and 80 mL may collect Screening Cycle 2 to determine eligibility.
Sites will contact the Interactive Response Technology (IRT) 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.
Return of Sanitary Products to Alkaline Hematin Laboratory
The site will submit the sanitary products and applicable venous blood sample collected 
during the screening period to the Alkaline Hematin Laboratory for analysis as outlined in 
the Alkaline Hematin Laboratory Manual.
Use of Non-Validated Products
All subjects are required to only use validated products provided by the Sponsor, however 
in cases when a subject used non-validated products (a product not provided for use in the 
study), the subject should be instructed to collect and submit the non-validated products to 
the site.  Site staff is to ensure subject is re-educated on the use of validated products and 
should be source documented.
 


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Electronic Questionnaires and Quality of Life Assessments
Prior to the start of the study, detailed instructions and training for study site staff 
administering these scales will be provided by AbbVie and/or its designee.  The objective 
of this training is to establish uniformity across sites in administration of these rating 
instruments.  The following questionnaires will be completed by the Subjects and/or the 
Investigator or Site Staff, as appropriate at the time points indicated in Appendix C, Study 
Activities, and should be administered prior to any other study procedures being 
performed at that visit.  Subjects and Site Staff will be asked to record their responses 
directly into the electronic device provided to site.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event that a subject or study personnel cannot come to the site because of the 
COVID-19 pandemic, subject visits may be conducted via phone or video conference.  
The C-SSRS, UFS-QoL and PGIC-MB may be administered by site staff over the phone 
or video conference.  In this situation, sites will read the PRO questions and response 
options to the subject, record the subject's responses on paper (source), and transcribe into 
the electronic device provided to the site.  The subject's ability to view the PRO to 
understand the questions and response options should be preserved. Sites may share the 
questionnaire by video conference or send the questionnaires (email or hard copy) to the 
subjects to allow them to read/understand the questions and responses when the subject is 
providing responses over the phone.  The date and time of PRO data collection should be 
recorded in the source along with who collected the information.
Reason for Study Participation
In order to better understand the reason why a study participant has decided to enroll in 
this study, subjects will complete the single-question Reason for Study Participation 
Questionnaire at the Day 1 Visit.
 


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Physician Surgery Questionnaire
Each physician will be asked to complete the Physician Surgery Questionnaire (PSQ) to 
evaluate 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 Fibroid Symptoms Quality of Life (UFS-QoL) (4-Week Recall)
The UFS-QoL 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 UFS-QoL Questionnaire8 using 4-week recall 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 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.
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/Since Last Visit C-SSRS 
questionnaire will be administered by the site staff using the electronic tablet at the time 
points 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 
 


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or via clinical interview at any time during the study, the Investigator should take 
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 by site staff at the time 
points outlined in Appendix C.  The C-SSRS administered at the Day 1 Visit will serve as 
the baseline for clinical assessment.
Return to Menses
Subjects will be asked about return to menses using the Return to Menses Questionnaire 
in the Post-Treatment Follow-Up Period, as outlined in the Study Activities, Appendix C.  
Site staff will ask subjects if they have had a menstrual period since discontinuation of 
study drug and record subjects' responses on the site tablet.  If the subject indicates she 
has not returned to full menses, site staff will continue assess menstruation and repeat the 
questionnaire at subsequent post-treatment follow-up visits, as applicable.  The date when 
full menses returned will be documented in the source documents and eCRFs.
Randomization and Assignment of Subject Numbers
The site will contact Interactive Response Technology (IRT) during the Washout or 
Screening Period to obtain a subject (Screening) number after the subject has signed the 
informed consent.  Consecutive and unique subject numbers 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 2 treatment groups by 
using IRT and providing the subject number the subject received during Screening or 
 


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Washout.  During the randomization contact session, a unique randomization number and 
study drug kit numbers 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 on-site visit in IRT in order to obtain 
the appropriate amount of 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 to the subject.  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.
5.3.1.2
Collection and Handling of Biomarker and Optional 
Exploratory Research Samples
Samples for biomarker and optional exploratory research will be collected.  Subjects will 
have the option to provide samples for exploratory research.  Subjects may still participate 
in the main study even if they decide not to participate in this optional exploratory 
research.
All research samples should be collected, labeled, and shipped as outlined in the study 
specific lab manual.  AbbVie (or people or companies working with AbbVie) will store 
the samples in a secure storage space with adequate measures to protect confidentiality.  
The samples will be retained while research on Elagolix (or drugs of this class) or uterine 
fibroids and related conditions continues, but for no longer than 20 years after study 
completion.  The procedure for obtaining and documenting informed consent for 
exploratory research samples is discussed in Section 9.3.
Biomarker Blood Samples for Estradiol (E2) Assay 
A single blood sample will be collected at each time point indicated in Appendix C to be 
used for the analysis of E2.  The blood samples for assay of estradiol will be collected in 
one 6 mL evacuated collection tube without anticoagulant (red cap, no gel separators to be 
 


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used).  Sufficient blood volume will be collected to provide approximately 3 mL serum 
from each sample.
On Day 1, estradiol 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.
Samples for Pharmacogenetic Exploratory Research (Optional)
Optional whole blood samples for DNA (Deoxyribonucleic acid)  and RNA (Ribonucleic 
acid) isolation will be collected on Day 1, Month 12 and Premature Discontinuation Visit 
(if applicable) from each subject who consents to provide samples for exploratory 
research.
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 4 mL evacuated K2-ethylenediaminetetraacetic acid 
(K2EDTA)-containing collection tubes at the time points indicated in Appendix C, Study 
Activities.  Sufficient blood will be collected to provide approximately 2 mL plasma from 
each sample.
Refer to the study specific laboratory manual for detailed instructions on sample 
collection, processing and shipment.
Samples will be collected regardless of the time of last dose.  The date and time of 
collection will be recorded on the Central Laboratory Requisition Form.
 


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5.3.2.2
Measurement Methods
Plasma concentrations of elagolix and norethindrone and serum concentrations of 
estradiol 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
The objective of this study is to evaluate the long term safety and tolerability of elagolix 
300 mg BID with E2/NETA, and as such, no primary efficacy endpoint is defined.
5.3.3.1
Questionnaires and Quality of Life Variables
●
UFS-QoL Questionnaire
●
Physician Surgery Questionnaire
●
Patient Global Impression of Change (PGIC)-MB Questionnaire
●
Reason for Study Participation Questionnaire
5.3.4
Safety Variables
●
Change from baseline in BMD measured by DXA
●
Number and percentage of subjects reporting treatment-emergent adverse 
events (TEAEs)
●
Number and percentage of subjects reporting adverse events of special interest 
(AESI)
●
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)
 


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5.3.5
Pharmacokinetic Variables
Exposures of elagolix and norethindrone will be summarized and elagolix concentrations 
may be used to develop a population PK model.  Additional parameters may be calculated 
if useful for the interpretation of the data.
5.3.6
Biomarker and Exploratory Research Variables
The types of biomarkers to be analyzed may include, but are not limited to, nucleic acids, 
proteins, lipids, metabolites or hormone levels (E2).  The samples may be analyzed as part 
of a multi-study assessment of factors influencing the subjects' response to Elagolix (or 
drugs of the same or similar class) or the development and progression of uterine fibroids 
or related conditions.  The samples may also be used to develop new diagnostic tests, 
therapies, research methods or technologies.  The results from these analyses are 
exploratory in nature and may not be included with the study report.
5.4
Removal of Subjects from Therapy or Assessment
Each subject has the right to withdraw from the study at any time.  In addition, the 
Investigator may discontinue a subject from the study at any time if the Investigator 
considers it necessary for any reason, including the occurrence of an adverse event or 
noncompliance with the protocol.  Subjects who withdraw from the study will not be 
replaced unless it is mutually agreed upon, in writing, by the Investigator and AbbVie.  
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 Follow-Up Period these procedures do not 
 


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warrant withdrawal if performed during the Post-Treatment Follow-Up Period 
unless a hysterectomy with bilateral salpingo-oophorectomy (BSO) is 
performed in the Post-Treatment Follow-Up Period and the subject does not 
plan to use Hormone Replacement Therapy within 1 month of the surgery date.
●
The subject becomes pregnant or has a positive serum pregnancy test.
●
The subject has SGPT/ALAT or SGOT/ASAT elevation > 5 times the upper 
limit of normal, confirmed upon repeat testing during the Treatment Period.
●
The subject develops clinically significant gynecological findings or condition 
on either the TAU/TVU (confirmed by repeat TAU/TVU and/or SIS and/or 
office hysteroscopy) or endometrial biopsy that in the opinion of the 
Investigator or AbbVie TA MD would preclude the subject from continuing in 
the Treatment Period due to safety reasons.
●
The results of any post-baseline DXA prior to Month 48 document a T-score 
< –2.5 in the lumbar spine, total hip or femoral neck, a BMD decrease of > 8% 
in the lumbar spine, total hip, or femoral neck, or due to TA MD assessment 
when the BMD percent change from baseline cannot be provided by the central 
reader.
●
The subject requires use of prohibited medications to manage or treat bone 
mineral density changes during the Treatment Period as described in 
Section 5.2.3.5.  Subject continuation in the Post-Treatment Follow-Up Period 
is at the discretion of the AbbVie TA MD.
●
Heavy menstrual bleeding during the Treatment Period that requires a blood 
transfusion at any time after having taken 28 days of study drug.
●
In the Investigator's opinion, the subject is unable or unwilling to comply with 
study-related assessments and procedures.
●
Any other medical reason that AbbVie or the Investigator deems appropriate.
5.4.1
Discontinuation of Individual Subjects
In the event that a subject withdraws or is prematurely discontinued from study drug 
treatment, the subject should complete the Premature Discontinuation Visit as soon as 
possible (preferably within 2 – 7 days of last dose of study drug, if possible) and undergo 
 


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study procedures as outlined in Appendix C.  Subjects who prematurely discontinue 
during the Treatment Period are expected to enter the Post Treatment Follow-Up Period 
for up to 12 months unless discontinuation is due to pregnancy.
These procedures should not interfere with the initiation of any new treatments or 
therapeutic modalities the Investigator determines are necessary to treat the subject's 
condition.  The reason(s) for the discontinuation from the Treatment Period will be 
recorded in source and in the eCRFs.
If a subject becomes pregnant during the Treatment Period or within 30 days of the last 
dose of study drug, no additional study procedures, except an ultrasound will be 
conducted.  Refer to Section 6.1.6 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 will have a DXA scan performed at the Premature 
Discontinuation Visit:
●
Subjects who discontinue prior to the Treatment Month 6 visit only if the 
reason for premature discontinuation is due to the occurrence of a fracture or 
any newly diagnosed bone condition.
●
Subjects who discontinue any time at the time of or after the Treatment 
Month 6 visit, unless a DXA scan has been performed within the prior 
3 months of Premature Discontinuation.
Subjects who prematurely discontinue from treatment and enter Post-Treatment Follow 
Up Period and have had a TAU/TVU and DXA within the prior 3 months will not be 
required to repeat these procedures at the Premature Discontinuation Visit.
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.
 


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Upon discontinuation from the Treatment Period, all used, unused and unopened study 
drug containers will be returned to the study site.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The Investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
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
 


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●
Due to malfunction of barrier contraception or unprotected intercourse
●
After a positive urine pregnancy test, while waiting for results of the serum test
●
Clinical laboratory findings that require repeating or confirmation of a 
clinically significant value (e.g., may necessitate discontinuation from the 
study).
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 10 or more consecutive days of dosing (with either elagolix/E2/NETA or 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 who will provide a recommendation.
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 up to 48 months of treatment:
●
elagolix 300 mg BID plus E2/NETA (estradiol 1.0 mg/norethindrone acetate 
0.5 mg QD) (n = 335) for 48 months 
●
placebo (n = 165) for the first 12 months, then switch to elagolix 300 mg BID 
plus E2/NETA QD for the remaining 36 months
Safety of using elagolix (300 mg BID) in combination with estradiol 
1.0 mg/norethindrone acetate 0.5 mg has already been evaluated in clinical studies of 
6-month duration as discussed earlier in Section 3.2.3.
The treatment administration is presented in Table 6.
 


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Table 6.
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 
plus E2/NETA QD
AM
1
0
1
0
PM
1
0
0
0
A 3-month supply of each study drug plus extra medication will be dispensed beginning at 
Day 1 throughout the treatment period.
Year 1 Treatment Period
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) whether 
the subjects visit is scheduled in the morning or afternoon.  Subjects will be instructed to 
self-administer their study drug throughout the 12-month Treatment Period.
Year 2, 3 and 4 (Open-Label) Treatment Period
Study drug treatment after Treatment Month 12 will be open-label in which study drug 
will be dispensed every 3 months (during the on-site visits).  The elagolix study drug will 
be supplied in a carton and the E2/NETA study drug will be supplied in a separate carton.
Study drug will be taken orally twice daily for the entire 48-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 
 


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without regard to food.  Study drug should be taken at approximately the same time each 
morning and evening to promote compliance.
If the subject forgets to take the morning dose, she should be instructed to take the 
morning dose as soon as possible and take the evening dose as scheduled.  If the subject 
forgets to take the evening dose, she should be instructed to take the evening dose as soon 
as possible; if the subject misses the evening dose completely (until the next morning), the 
subject should only take the next morning dose.
On days when the subject visits the study site for the scheduled visits, she 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 
scheduled visit.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Depending on the local regulations, provisioning of study drug for direct-to-patient (DTP) 
and direct-from‑patient (DFP) transfer because of the COVID-19 pandemic will be 
available per request.  AbbVie should be notified.
Sites can utilize Marken and/or another local courier for drug shipment in such 
circumstances.  Shipments may also include other study supplies (e.g., pregnancy tests, 
paper copies of PROs).  AbbVie has set up an agreement with Marken (third-party 
vendor) for sites to use to ship study drug to (and from as applicable) subjects.  Shipments 
of study drugs from the study site to a subject's home will be appropriately temperature-
controlled (qualified shipper or temperature monitoring) within the labeled storage 
conditions.  Signature is required upon delivery; due to COVID-19 related social 
distancing, this may be provided by the courier after delivery.  Documentation of the 
shipment is to be retained by the clinical site.
●
Sites will be responsible for meeting IRB reporting requirements and 
submitting the booking form to the local IRB (as applicable).
 


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The investigator must discuss the DTP/DFP process with the subject:
●
Obtain consent to provide delivery information to Marken and/or local courier 
and document this in the source.
●
Obtain results of required safety procedures (e.g., urine pregnancy testing) 
before registering subject dispensation of study drug in IRT.
●
Confirm that the subject will be available to accept delivery.
●
The site will follow up with the subject after shipment is received.
●
The subject should maintain the drug containers, as well as any unused drug for 
return to site.
Sites will be required to retain documentation of the shipment for the IP accountability 
and monitoring.  AbbVie will not receive subject identifying information related to these 
shipments, as the site will work directly with the courier.
5.5.2
Identity of Investigational Product(s)
Information about the drug formulations to be used in this study is presented in Table 7.
 


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Table 7.
Identity of Investigational Products
Study Drug
Formulation
Route of 
Administration
Manufacturer
Elagolix 
Film-coated 300 mg tablets
Oral
AbbVie
Matching Elagolix 
Placebo
Film-coated Placebo tablets
Oral
AbbVie
E2/NETA
Estradiol 
1.0 mg/Norethindrone acetate 
0.5 mg tablet
Oral
Pharmaceutics 
International, Inc
Or
Novo Nordisk
Or
Amneal Pharmaceuticals
E2/NETA*
Estradiol 
1.0 mg/Norethindrone acetate 
0.5 mg capsules*
Oral
Commercial Tablets: 
Pharmaceutics 
International, Inc
Or
Novo Nordisk
Or
Amneal Pharmaceuticals
Matching E2/NETA 
Placebo
Placebo capsules
Oral
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) for the 12-month
Treatment Period using compliance packaging.  Study drug is provided at each dispensing 
visit.  The study drug consists of elagolix or matching placebo tablets and the other study 
drug consists of E2/NETA or matching placebo capsules.  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.
 


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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.
AbbVie will supply open-label study drug in 3-monthly kits (i.e., cartons) for the Year 2, 
3 and 4 Treatment Period which will not include the compliance packaging.  Two kits of 
study drug will be provided at each dispensing visit.  One kit consists of elagolix tablets 
and the other kit consists of E2/NETA tablets.  The elagolix kit contains 12 weekly blister 
cards and 1 extra medication blister card for a total of 13 blister cards.  Each individual 
elagolix blister card contains 14 tablets for a 7-day (weekly) supply study medication.
The E2/NETA kit contains 3-monthly blister cards or dial packs and 1 extra blister card or 
dial pack, with each blister card or dial pack containing 28 days 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 study medication is labeled as per country requirements.  All blank spaces on the 
label will be completed by the site staff prior to dispensing to the subject.  Labels must 
remain affixed to the study drug containers.  Adequate supplies of study drug will be 
provided to each study site automatically via IRT.
5.5.2.2
Storage and Disposition of Study Drug(s)
Elagolix, E2/NETA and respective matching placebo study medication must be stored at 
controlled room temperature 15° to 25°C (59° to 77°F).
The open label E2/NETA blister card or dial pack must be stored in the outer carton for 
protection from light.
The study medication storage temperature must be recorded each business day.  
Temperature excursion must be entered into AbbVie Temperature Excursion Management 
 


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System (ATEMS) immediately by the site staff and study drug should not be dispensed 
until ATEMS or AbbVie deems the drug as acceptable.
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 upon entry into the 12-month Treatment Period.  At the Year 1 
Treatment Month 12, all subjects will be re-assigned by IRT to receive open label elagolix 
300 mg BID plus E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg QD), 
including subjects previously randomized to placebo.  Subjects re-assigned by IRT will 
not be assigned new subject numbers.
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.
 


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The randomization schedule will be computer generated by the Statistics Department at 
AbbVie, North Chicago, IL prior to the start of the study.  A copy of all of the 
randomization schedules will be kept by the Statistics Department at AbbVie and a copy 
will be forwarded to the IRT provider.
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 to one of the two 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, unused or unopened) at the 
subsequent on-site visit.
5.5.5
Blinding
5.5.5.1
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 staff and subject will remain blinded to each subject's double-blind treatment 
assignment 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.
 


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5.5.6
Treatment Compliance
The Investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
Subjects will be instructed to return all study drug kits (used/unused/unopened) to the 
study site staff at study visits throughout the Treatment Period or Premature 
Discontinuation visit (if applicable).
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.
During 12-month Treatment Period, daily recordings of study drug dosing will be 
obtained using a compliance packaging blister card for all subjects (for both 
elagolix/E2/NETA and matching placebo).
During the Treatment Period, on-site or phone visit or Premature Discontinuation visit, 
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 should instruct subjects not to remove extra or multiple medications from the blister 
cards all at once (e.g., transferring multiple doses into a separate pill organizer) and 
should only remove the study drug from the blister when it is the time to take the dose.  If 
the subject has removed 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.
Compliance packaging will be used in the 12-month Treatment Period only and data 
collected from kit scanning will be used for exposure response analyses.
 


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During the Treatment Period, the site staff will review study drug compliance with 
subjects either during an on-site or phone visits.  During the phone visits, subjects will be 
asked if they are taking the study drug as indicated and information will be documented in 
source.
During on-site visits any discrepancies in 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 and appropriate information, including re-training if provided, 
should be recorded in the source documents.
If a subject missed more than 10 consecutive days of taking study drug, the AbbVie TA 
SD should be notified to determine whether the subject may continue.
5.5.7
Drug Accountability
The study Investigator or designee will verify via direct recording in IRT or by signature 
and date that study drug supplies are received intact and in the correct amounts indicated 
on the shipping document Clinical Site Shipment Request (CSSR) or similar shipping 
document.  The shipment receipt must be acknowledged in IRT in order to become 
available for dispensation to subjects.  The IRT must also be contacted when any subject 
completes or discontinues study drug.
The IRT will maintain a current and accurate inventory of all clinical drug supplies, 
accountability, reconciliation, returns and destruction for each site.  The IRT will also 
include the lot number, kit number, CSSR 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, unused and unopened 
containers will be returned to AbbVie according to instructions from AbbVie.
 


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The study investigator or his/her designated representative agrees not to supply study 
medication to any persons not enrolled in the study or not named as a sub-investigator.
Study drug will be dispensed at the study visits summarized in Appendix C, Study 
Activities.  Returned study drug should not be re-dispensed to the subject.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event that a subject cannot come to the site because of the COVID-19 pandemic, 
the site may contact the IRT for kit assignment after ensuring subject is eligible to 
continue with study drug dosing and confirming that a home urine pregnancy test was 
performed and the result was negative.  Study drug dispensing can then be undertaken as 
outlined in Section 5.5.1.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This Phase 3b study will be conducted as a randomized, sequential, 12-month double-
blind placebo-controlled, 36-month open-label, multi-center study in premenopausal 
women 18 to 50 years of age with HMB associated with uterine fibroids.
This study will evaluate the long-term safety of elagolix 300 mg BID plus E2/NETA in 
subjects with HMB associated with uterine fibroids.  The study will also assess the impact 
of elagolix 300 mg BID plus E2/NETA on BMD in women with HMB associated with 
uterine fibroids after up to 48 months of treatment.
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 
 


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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 50 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 
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 50 is included to reduce the risk of subjects 
becoming menopausal during the study.  No studies in females outside of the reproductive 
years are necessary for this proposed indication.
5.6.4
Selection of Doses in the Study
The results of the 3-month Phase 2a dose finding, Proof-of-Concept (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.
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.
 


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6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Section 6.1
through Section 6.1.6.  For product complaints, please refer to Section 6.2.
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 staff, or reported spontaneously by the subject will 
be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
 


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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 changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, and/or if the investigator considers them to be adverse events.
A BMD decrease at any anatomic location (lumber spine, total hip or femoral neck) 
during the Treatment Period that leads to discontinuation from study drug 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.
 


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


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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject 
and may require medical or surgical intervention to 
prevent any of the outcomes listed above (i.e., death of 
subject, life-threatening, hospitalization, prolongation of 
hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any 
elective or spontaneous abortion or stillbirth is considered 
an important medical event.  Examples of such events 
include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or 
drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.1.1.3
Adverse Events of Special Interest
For some adverse events, such as SAEs and adverse events of special interest (AESI), 
such as elevated liver transaminases, bone mineral density decrease/fractures, and mood 
and depression-related events, hot flashes and other non-bone hypoestrogenic events, lipid 
abnormalities, cardiovascular events, thromboembolic events, hormonally sensitive 
malignancies, and alopecia, 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
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information) to suggest a 
causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is insufficient evidence (information) to suggest a 
causal relationship
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an Other cause of event must be provided by the Investigator for the serious 
adverse event.
 


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6.1.4
Adverse Event Collection Period
All adverse events reported from the time of study drug administration until 30 days 
following discontinuation of study drug administration have elapsed will be collected, 
whether solicited or spontaneously reported by the subject.  All nonserious adverse events 
of bone fracture, clinically significant BMD loss, or newly diagnosed medically-related 
bone condition will be collected during the Post-Treatment Follow-Up Period, until the 
subject discontinues from study participation.  In addition, serious adverse events and 
protocol-related nonserious adverse events will be collected from the time the subject 
signed the study-specific informed consent.
Adverse event information will be collected as shown in Figure 4.
Figure 4.
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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Phone:  +1 (973) 784-6402 
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Supplemental study case report forms should be completed in the event of COVID-19 
related missed/virtual visits, study drug interruptions or discontinuations, or adverse 
events (including capture of specific signs/symptoms of infection and testing results).
COVID-19 infections should be captured as adverse events.  If the event meets the criteria 
for a serious adverse event (SAE), then follow the SAE reporting directions per the 
protocol and above.  The following COVID-19 related supplemental eCRFs should be 
completed:
●
COVID-19 Supplemental Signs/Symptoms
●
COVID-19 Status Form
If a subject has a confirmed or suspected COVID-19 infection and study drug 
was interrupted, the Investigator should contact the Sponsor emergency 
medical contact listed above before reintroducing study drug.
6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 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.  While waiting for the results of the serum pregnancy test, study drug 
should be temporarily discontinued pending results of the serum pregnancy test.  If a 
serum pregnancy test result is positive at any time during the Treatment Period of the 
study, the site will immediately inform the subject to discontinue study drug.  However, 
an ultrasound examination will be performed as early as possible during the first trimester 
of pregnancy to assess the gestational age and document an intrauterine pregnancy.  
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
 


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pregnancy will be collected for any study subject with a positive serum pregnancy test 
after receiving at least one dose of study drug through 30 days following the last dose of 
study drug.  The site will report a positive pregnancy test to the Sponsor, will follow the 
course of the subject's pregnancy, and report to the Sponsor on the health of the subject 
and fetus at each trimester, the newborn at the first post-delivery pediatrician visit and the 
infant 6 – 12 months post-delivery.
If the subject has a positive serum pregnancy test during the Treatment or Post-Treatment 
Follow-Up Periods of the study, no additional study procedures, including protocol 
required DXA scans, will be conducted.  The following information on the outcome of the 
pregnancy should be collected:  fetal outcome (e.g., spontaneous or elective abortion, live 
infant or still birth), date and mode of delivery, birth weight, birth length, gender, any 
congenital anomaly and medically significant complications during pregnancy or labor or 
delivery.  For live infant births, information on the health of the infant will be collected 
from the first post-delivery pediatrician visit and at 6 to 12 months after delivery.
For each subject with a confirmed pregnancy, the Investigator will provide information 
about the option to participate in an elagolix pregnancy registry (P18-954) for pregnancy 
outcomes.  The contact information for the Bloom Pregnancy Registry is in the 
Oriahnn/Orilissa label (pregnancy registry telephone number: 1-833-782-7241).
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome for mother or infant, meeting any serious criteria including an elective or 
spontaneous abortion, stillbirth or congenital anomaly is considered a serious adverse 
event and must be reported to AbbVie within 24 hours of the site becoming aware of the 
event.
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.
 


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For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality by the product to the 
events outlined directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and documented in source as required by the Sponsor.  Product 
Complaints associated with adverse events will be reported in the study summary.  All 
other complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition (investigational product).  In instances where a return is requested, every effort 
should be made by the investigator to return the product within 30 days.  If returns cannot 
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, 
 




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In general, data will be summarized for the 12-month placebo-controlled double-blind 
Treatment Period, the open-label Treatment Period, and the Post-Treatment Follow-Up 
Period separately.
In the 12-month placebo-controlled double-blind Treatment Period, data will be 
summarized by treatment group (the elagolix 300 mg BID plus E2/NETA group and the 
placebo group).  Comparisons of safety will be made between the elagolix 300 mg BID 
plus E2/NETA group and the placebo group in the 12-month Treatment Period.
In the open-label Treatment Period, summaries will be provided for each of the following 
treatment groups of subjects.
1.
Subjects randomized to elagolix 300 mg BID plus E2/NETA in the 12-month
Treatment Period and continued to receive elagolix 300 mg BID plus E2/NETA in 
the open-label Treatment Period;
2.
Subjects randomized to placebo in the 12-month Treatment Period, and switched to 
elagolix 300 mg BID plus E2/NETA in the Open-label Treatment Period.
Statistical tests will only be made in the double-blind Treatment Period.  No statistical 
tests will be made in the Open-label Treatment Period and the Post-Treatment Follow-Up 
Period.
8.1.2
Data Sets Analyzed
Full Analysis Set
The full analysis set which is comprised of all randomized subjects who took at least 
one dose of the study drug will be used for all efficacy analyses and baseline analyses 
unless otherwise specified in the Statistical Analysis Plan (SAP).  The data from the full 
analysis set will be presented by the treatment group assigned at the time of 
randomization.
 


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Safety Analysis Set
The safety analysis set includes all randomized subjects who took at least one dose of the 
study drug.  Subjects will be analyzed according to the treatment they actually received, 
defined as the randomized treatment if the patient took at least one dose of that treatment 
during the 12-month placebo-controlled double-blind Treatment Period, or the first 
treatment received if the randomized treatment was never received during the 12-month 
placebo-controlled double-blind Treatment Period.  All safety analyses will be performed 
based on the safety analysis set unless otherwise specified in the SAP.
The All Elagolix plus E2/NETA Analysis Set is defined as subjects who received at least 
1 dose of elagolix plus E2/NETA in the study (either in the placebo-controlled or open-
label Treatment Periods).  Subjects will be summarized based on the actual treatment 
received at the time of randomization (elagolix plus E2/NETA or placebo).
8.1.3
End of 12-Month Placebo-Controlled Treatment Period 
Analysis
An end-of-placebo-controlled treatment period analysis will be performed after the last 
subject completes the 12-Month placebo-controlled Treatment Period.  These analyses 
will include data collected during the Treatment Period (placebo-controlled and open-
label Treatment Periods) and the Follow-Up Period up to the data cut-off for the interim 
lock.  The database will be versioned for an interim lock and any discrepant data will be 
clarified before the versioning.  Analyses will be performed by AbbVie.
Since this end-of-placebo-controlled treatment period analysis is the only and final 
analysis for the comparison between treatment and placebo group at 12 months of safety 
and efficacy endpoints, no additional adjustment of alpha-level is necessary.
8.1.4
Treatment Month 24, Month 36, Month 48 and Other 
Timepoints Analyses
At the end of Treatment Month 24, Month 36, Month 48 or other timepoints during the 
open-label period, analysis of the safety and efficacy safety variables may be performed 
 


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after the last subject completes the Treatment Month 24, Month 36, Month 48 visit or 
other timepoint during the open-label period, respectively.  For subjects who prematurely 
discontinued during the treatment period, their data collected during the Follow-up Period 
will be included in the analysis, as appropriate.  The database will be versioned for an 
interim lock and any discrepant data will be clarified before the versioning.  Analyses will 
be performed by AbbVie.
8.1.5
Demographic, Baseline Characteristics and Concomitant 
Medications
Demographic and baseline characteristics will be summarized by treatment group.
Medical history and gynecological medical/surgical history data will be coded using 
system organ classes (SOCs) and preferred terms (PTs) from the Medical Dictionary for 
Regulatory Activities (MedDRA) by treatment group.  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.
Unless noted otherwise, the baseline values will be defined as the last non-missing 
assessment obtained prior to the initiation of the study drug unless otherwise specified.
8.1.6
Efficacy
8.1.6.1
Primary Efficacy Variable
8.1.6.1.1
Primary Analysis
As the objective of this study is to evaluate the long-term safety and tolerability of 
elagolix 300 mg BID with E2/NETA, no primary or secondary efficacy endpoint is 
defined.
 


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8.1.6.2
Other Efficacy Variables
Other assessments during the placebo-controlled double-bind 12-month Treatment Period 
include the following:
●
PGIC for Menstrual Bleeding Symptom;
●
Change from baseline for the UFS-QoL.
UFS-QoL
Improvement in quality of life will be assessed on the UFS-QoL Questionnaire (4-week 
recall).  The change from baseline to each scheduled assessment 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 Health Related Quality 
of Life Questionnaire (HRQoL) total.  The change from Baseline to Month 6 and 
Month 12 during the double-blind Treatment Period will be analyzed using ANCOVA 
with treatment as the main effect and corresponding Baseline UFS-QoL as a covariate to 
compare the elagolix dose group to placebo.
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 at Month 3, Month 6, Month 9 and Month 12 by treatment group.  The 
number and percentage of subjects with response of (a) "Very Much Improved" or "Much 
Improved," and (b) "Otherwise" will be summarized by treatment group in the 12-month 
Treatment Period.  Comparisons will be made using a Miettinen–Nurminen (M-N) test.
8.1.7
Safety
8.1.7.1
General Considerations
All randomized subjects who took at least one dose of the study drug will be included in 
the safety analyses.
 


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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 in the 12-month Treatment Period unless 
otherwise specified in the SAP.
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 
used to analyze treatment group differences for qualitative categorical variables in the 
12-month Treatment Period unless otherwise specified in the SAP.
Missing safety data will not be imputed.
Analysis details will be specified in the SAP.
8.1.7.2
Adverse Events
Unless otherwise specified, all summaries/analyses involving AEs will only include 
treatment-emergent adverse events (TEAEs).  TEAEs are defined as any AE with an onset 
or increased severity after the first dose of study drug and no more than 30 days after the 
last dose date of study drug.  AEs where the onset date is the same as the first dose date of 
study drug are assumed to be treatment-emergent, unless the first dose time of study drug 
and the AE start time are collected and the AE start time is prior to the first dose time of 
study drug.  If an incomplete onset date was collected for an AE, the AE will be assumed 
to be treatment-emergent unless there is evidence that confirms that the AE was not 
treatment-emergent (e.g., the AE end date was prior to the first dose date of study drug).
AEs starting more than 30 days following discontinuation of the study drug will not be 
included in the summaries of TEAEs.
TEAEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 19.0 or higher.  TEAEs will be summarized using MedDRA system organ classes 
(SOCs) and preferred terms (PTs) and grouped by treatment group.
 


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For each TEAE summary, the number and percentage of subjects experiencing at least 
one TEAE will be presented.  Subjects reporting more than one TEAE within a SOC will 
be counted only once for that SOC.  Subjects reporting more than one TEAE for a PT will 
be counted only once for that PT.
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 TEAE
●
Any TEAE reasonably possibly related to study drug
●
Any TEAE leading to discontinuation of study drug
●
Any treatment-emergent serious AE (SAE)
●
Any SAE reasonably related to study drug
●
Any AESI (e.g., hypoestrogenic adverse events)
8.1.7.3
Analysis of Laboratory Data and Vital Signs
Changes from baseline in laboratory and vital sign parameters will be summarized by 
treatment group during the Treatment Periods.
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.
 


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Analysis details will be specified in the SAP.
8.1.7.4
Bone Mineral Density
The within-group percent change from baseline to Months 6, 12, 18, 24, 30, 36, 42 and 48 
in BMD will be summarized for each treatment group with mean, standard deviation and 
two-sided 95% confidence interval.  The between-group differences in percent change 
from baseline to Month 6 and Month 12 in BMD will be summarized with mean and 
standard error.  The percent change from baseline to Month 6 and Month 12 in BMD will 
be compared between the elagolix 300 mg BID plus E2/NETA group and the placebo 
group using a model based approach.  Two-sided 95% confidence intervals will be 
constructed for the between group differences in percent change from baseline to Month 6 
and Month 12 in BMD.
The number and percentage of subjects with categorized percent change from baseline in 
BMD decrease will be summarized by treatment group during the Treatment Periods.
Analysis details will be specified in the SAP.
8.1.7.5
Endometrial Biopsy
The number and percentage of subjects in each category of endometrial biopsy result will 
be summarized.
8.1.7.6
Pelvic Ultrasound Findings
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 by treatment group during the Treatment Periods.  The change from baseline 
in endometrial thickness will be summarized for each treatment group during the 
Treatment Periods.
 


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8.1.7.7
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS will be summarized by treatment group according to published scoring 
guidelines.
8.1.8
Pharmacokinetic/Biomarker Analysis
Plasma concentrations of elagolix and norethindrone and serum concentrations of 
estradiol will be listed for each subject by visit day and dose regimen, as applicable.  
Pharmacokinetic data may be combined with data from other studies in women.  
Exposure-response analyses may be conducted as appropriate.  For example, if 
pharmacokinetic exposures are estimated, analyses may be conducted to assess the 
relationship of pharmacokinetic parameters and estradiol concentrations, versus efficacy 
and safety.  Additional analyses will be performed if useful and appropriate.
8.2
Determination of Sample Size
Approximately 500 subjects will be randomized (2:1) to elagolix 300 mg BID plus 
E2/NETA (N = 335) and placebo (N = 165).
Based on clinical review, a sample size of 500 was selected to gather long term safety 
exposure data in approximately 50 subjects completing 48 months of study drug dosing, 
with approximately 30 subjects receiving 48 months of active drug elagolix 300 mg BID 
plus E2/NETA 1/0.5 mg QD.
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.  
 


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IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.  During the COVID-19 pandemic, virtual/remote monitoring of data may be 
employed if allowed by the local regulatory authority, IRB/IEC, and the study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to ICH GCP and all other 
applicable regulatory requirements.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
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.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event of a state of emergency due to the COVID-19 pandemic leading to difficulties 
in performing protocol-specified procedures, AbbVie will engage with study site 
personnel in efforts to ensure the safety of subjects, maintain protocol compliance, and 
minimize risks to the integrity of the study while trying to best manage subject continuity 
of care.  This may include alternative methods for assessments (e.g., phone contacts or 
virtual site visits), and shipping investigational product and/or supplies direct to subjects 
 


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to ensure continuity of treatment where allowed.  Refer to the Study Procedures sections 
for additional details.  In all cases, these alternative measures must be allowed by local 
regulations and permitted by IRB/IEC.  Investigators should notify AbbVie if any urgent 
safety measures are taken to protect the subjects against any immediate hazard.
9.3
Subject Information and Consent
The Investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
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.
In the event a subject withdraws consent to participate from the study, stored biomarker 
and exploratory research samples will continue to be used for research and analysis.  In 
the event that a subject would like to withdraw consent for research using these samples, 
the subject may request that their samples be withdrawn.  Once AbbVie receives the 
request, remaining samples will be destroyed.  If the subject changes her consent, and the 
samples have already been tested, those results will still remain as part of the overall 
research data.
An informed consent, approved by an IRB/IEC, must be voluntarily signed and dated 
before samples are collected and analyzed for optional exploratory research.  The nature 
of the testing should be explained and the subject given an opportunity to ask questions.  
 


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If the subject does not consent to provide samples for the optional exploratory research, it 
will not impact their participation in the study.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, it is possible that additional protocol modifications not 
outlined in this protocol may become necessary.  If this situation arises, in addition to the 
study informed consent, additional verbal consent must be obtained prior to these 
adaptations or substantial changes in study conduct in accordance with local regulations.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded to the appropriate 
source document.  The Investigator Awareness Date (SAE CRF) may serve as the source 
for this data point.  This adverse event data point required for eCRF completion can be 
entered directly in the eCRF.
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 
 


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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 staff 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 staff 
(or their representatives).  AbbVie (or their representatives) will also be allowed access to 
all source documents pertinent to the study in order to verify eCRF entries.  The principal 
investigator will review the eCRFs for completeness and accuracy and provide his or her 
electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
Electronic Patient Reported Outcomes (ePRO)
Patient reported data must be completed for each subject screened/enrolled in this study.  
Some of these data are being collected with an Electronic Patient Reported Outcome 
(ePRO) system called Trialmax®, provided by the technology vendor CRF Health of 
 


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Plymouth Meeting, PA, USA.  The ePRO system is in compliance with Title 21 CFR 
Part 11.  The documentation related to the system validation of the ePRO system is 
available through the vendor, CRF Health, while the user acceptance testing of the study 
specific PRO design will be conducted and maintained at AbbVie.
The subject will be entering the data on an electronic device; these data will be uploaded 
to a server.  The data on the server will be considered source, and maintained and 
managed by CRF Health.
Internet access to the ePRO data will be provided by CRF Health for the duration of the 
study.  This access will be available for the duration of the study to the site investigator, as 
well as delegated staff.  Such access will be removed from investigator sites following the 
receipt of the study archive.  Data from the ePRO 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 ePRO data.  It will be possible for the investigator to make paper print-
outs from that media. 
The ePRO data will be collected by the following methods:
Diary Based
●
The (instrument/scale) will be collected electronically via a handheld device 
into which the subject will record the required pieces of information on a daily
basis.  The electronic device will be programmed to allow data entry for diary 
data being collected outside of the study site.  All data entered on the device 
will be immediately stored to the device itself and manually/automatically 
uploaded to a central server administrated by CRF Health.  The Investigator 
and delegated staff will be able to access all uploaded subject entered data via a 
password protected website, up until the generation, receipt and confirmation of 
the study archive.
 


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Tablet Based
●
The (instrument/scale) will be collected electronically via a Tablet/Laptop 
device into which the subject will directly enter the required pieces of 
information.  The electronic device will be programmed to allow data entry for 
only the visits specified in the protocol and will not allow for subjects to 
complete more than one of the same assessments at any one visit.  All data 
entered on the device will be immediately stored to the device itself and 
(manually/automatically) uploaded to a central server administrated by CRF 
Health.  The Investigator and delegated staff will be able to access all uploaded 
subject entered data via a password protected website, up until the generation, 
receipt and confirmation of the study archive.
11.0
Data Quality Assurance
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 
staff (and/or their representatives), the investigators, and the appropriate site staff.  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 staff 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 
 


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be run to identify such items as inconsistent study dates.  Any necessary corrections will 
be made to the eCRF.
Routine hematology, serum chemistry, lipid and endocrine panels, urine pregnancy tests, 
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 staff from AbbVie.
Alkaline hematin analysis will be performed by Alkaline Hematin Laboratory.  The data 
from these analyses will be electronically transferred from the Alkaline Hematin 
Laboratory to the study database.
PK and biomarker 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 (if applicable) 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
Any research that may be done using optional exploratory research samples from this 
study will be experimental in nature and the results will not be suitable for clinical 
decision making or patient management.  Hence, the subject will not be informed of 
individual results, should analyses be performed, nor will anyone not directly involved in 
this research.  Correspondingly, researchers will have no access to subject identifiers.  
 


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Individual results will not be reported to anyone not directly involved in this research 
other than for regulatory purposes.  Aggregate data from optional exploratory research 
may be used in scientific publications or presented at medical conventions.  Optional 
exploratory research information will be published or presented only in a way that does 
not identify any individual subject.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of elagolix.  
This information may be disclosed as deemed necessary by AbbVie to other clinical 
investigators, other pharmaceutical companies, and to governmental agencies.  To allow 
for the use of the information derived from this clinical study and to ensure complete and 
thorough analysis, the investigator is obligated to provide AbbVie with complete test 
results and all data developed in this study and to provide direct access to source 
data/documents for study-related monitoring, audits, IEC/IRB review, and regulatory 
inspection.
This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie, and shall not be used except in 
the performance of this study.
The investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study, including each subject's name, subject number, address, phone 
number and emergency contact information.  This list will be maintained at the study site 
with other study records under adequate security and restricted access, and will not be 
retrieved by AbbVie.
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 
 


Elagolix (ABT-620)
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IEC/IRB following conclusion of the study and will forward a copy of this report to 
AbbVie or their representative.
The investigator must submit, maintain, and archive any records related to the study 
according to ICH GCP and all other applicable regulatory requirements.  If the 
investigator is not able to retain the records, he/she must notify AbbVie to arrange 
alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.
 


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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 3b Study to Evaluate the Long-Term 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:
02 May 2022
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
 


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15.0
Reference List
1.
Baird DD, Dunson DB, Hill MC, et al.  High cumulative incidence of uterine 
leiomyoma in black and white women:  ultrasound evidence.  Am J Obstet 
Gynecol.  2003;188(1):100-7.
2.
Stewart EA.  Uterine fibroids.  Lancet.  2001;357(9252):293-8.
3.
Laughlin SK, Schroeder JC, Baird DD.  New directions in the epidemiology of 
uterine fibroids.  Semin Reprod Med.  2010;28(3):204-17.
4.
Rein MS, Barbieri RL, Friedman AJ.  Progesterone:  a critical role in the 
pathogenesis of uterine myomas.  Am J Obstet Gynecol.  1995;172(1 Pt 1):14-8.
5.
Buttram VC Jr, Reiter RC.  Uterine leiomyomata:  etiology, symptomatology, and 
management.  Fertil Steril.  1981;36(4):433-45.
6.
AbbVie.  Investigator's Brochure Edition 15.  07 April 2016.
7.
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.
8.
Spies JB, Coyne K, 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.
9.
Booth M.  Assessment of physical activity:  an international perspective. Res Q 
Exerc Sport.  2000;71 (2 Suppl):s114-20.
10.
Herdman M, Gudex C, Lloyd A, et al.  Development and preliminary testing of the 
new five-level version of EQ-5D (EQ-5D-5L).  Qual Life Res.  
2011;20(10):1727-36.
 


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


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


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


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Appendix C.
Study Activities
Procedure
WO (if Applicable) and 
Screening Period
Year 1 Treatment Perioda
WO 
Period
SCR
Visit
Cyc1e 1 
–3‡
PCVb
D
1c
M
1
M
2
M
3
M
4
M
5
M
6
M
7
M
8
M
9
M
10
M
11
M
12
Unsch 
Visit
PD
(If 
Appl.)
Informed Consent
X
X&
Phone Visitd
X
X
X
X
X
X
X
X
Medical/Social History
X
X&
Xe
Gynecological/
Obstetrical and Uterine Fibroid 
History
X
X&
Xe
Complete Physical Examination; 
Height (H); Weight (W)
X*
X
(H, W)$
X*,e
X
(W)$
X
(W)$
Gynecological (External Genitalia, 
Pelvic and Breast) Examination
X
X
X
Vital Signs
X
X
X
Xe
X
X
X
X
X
X
12-Lead Electrocardiogram (ECG)
X
Mammogram
X∞
Xf
Xg
Pap Test
X
Xg
Endometrial Biopsyh,i
X
X
Xg
Pelvic Ultrasound@:  TAU, TVU
Xj
X&
Xk
X
Xg
Saline Infusion Sonohysterography 
(SIS)i
X
MRI (if applicable)l
X 
DXA Scan
X
X
X
Xg
 


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Procedure
WO (if Applicable) and 
Screening Period
Year 1 Treatment Perioda
WO 
Period
SCR
Visit
Cyc1e 1 
–3‡
PCVb
D
1c
M
1
M
2
M
3
M
4
M
5
M
6
M
7
M
8
M
9
M
10
M
11
M
12
Unsch 
Visit
PD
(If 
Appl.)
Dispense Sanitary Products and 
Collection Kit (Keg, Collection 
Bags, etc.)
X
X^
Start Collection of Sanitary Products
X
Return Sanitary Products; draw 
venous blood sample 
X
Clinical Safety Labs:  Chemistry, 
Hematology, Lipid Panel and 
Urinalysis
X
X
X
X
Lipid Panel and Subset of Chemistry 
Labs:  ALT, AST, Bilirubin and 
Alkaline Phosphatase 
X
X
X
Urine Test for Gonorrhea and 
Chlamydia (Optional)
Xm
Vitamin D Testing
X
Serology (Hepatitis and HIV 
Screens)
X
Endocrine:  FSH and Reflexive TSH
X
Biomarker Sample:  Serum Estradiol 
(E2) 
Xe
Xn
Xn
Xn
Xn
Xn
Pharmacokinetic Sample (PK):  
Elagolix and NETA Plasma 
Concentration
Xn
Xn
Xn
Xn
Xn
 


Elagolix (ABT-620)
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Procedure
WO (if Applicable) and 
Screening Period
Year 1 Treatment Perioda
WO 
Period
SCR
Visit
Cyc1e 1 
–3‡
PCVb
D
1c
M
1
M
2
M
3
M
4
M
5
M
6
M
7
M
8
M
9
M
10
M
11
M
12
Unsch 
Visit
PD
(If 
Appl.)
Pharmacogenetic DNA and RNA 
Sample (PG) (Optional based on 
Subject consent)
Xn
Xn
Xn
Urine Pregnancy Testso,p
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contraception Counseling/Dispense 
Contraceptives as necessaryq
X
X
X
X^
X
X
X^
X
X
X^
X
X
X^
X
X
X^
X
Birth Control Attestation
X
X
X
X
X
X
Reason for Study Participation
Xe
PSQ
Xe
UFS-QoL
Xe
X
X
X
PGIC-MB
X
X
X
X
X
C-SSRS – Baseline/
Screening
X
Xe
C-SSRS – Since Last Visit
X
X
X
X
X
Randomization
X
Interactive Response Technology 
(IRT)
X
X
X#
X
X
X
X
X
X
Dispense Study Drug
X
X
X
X
Xr
Drug Accountabilityd
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Monitoringd 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medication Reviewd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 


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D = Day; M = Month; SCR Visit = Screening Visit; WO = Washout; PCV = Product Collection Visit; Unsch Visit = Unscheduled Visit; PD = Premature Discontinuation Visit
‡
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.  
*
Brief symptom-directed examination.
$
Complete physical examination; including weight (the subject should not wear shoes during weighing).
∞
Only in subjects ≥ 39 years of age at the time of randomization, unless the mammogram was performed within 3 months prior to Screening.  Results must be entered in EDC 
upon receipt.  
@
Subjects with a finding of polyp on pelvic ultrasound during the Treatment Period will undergo evaluation per standard of care which may include an SIS.
^
Site should dispense enough sanitary product collection kits during screening only.  In addition, sites should also dispense contraceptives to carry subject over to the next on-
site visit.
#
Screening Cycle 2 Product Collection Visit will be registered in IRT only 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 for Visit and Assessment Windows, for allowable visit and assessment-specific windows during the Year 1 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.
Site staff to evaluate subjects compliance with taking study drug per protocol, assess ongoing adverse events, concomitant medications (if applicable), obtain the results of the 
subject's self-administered urine pregnancy test, and remind subjects of the importance of consistent use of appropriate and effective use of dual non-hormonal contraception.
e.
To either be updated or performed or collected prior to study drug administration.  Measurements should be assessed consistently throughout the study.
f.
A Mammogram will be performed for all subjects who are 39 years of age or older at time of the scheduled study visit. 
g.
Mammogram, DXA, Pelvic Ultrasound, Pap test, or Endometrial Biopsy not required if subject prematurely discontinues prior to Treatment Month 6, i.e., received 
< 6 months of study drug.  Refer to Section 5.3.1.1, Study Procedures, Bone Mineral Density (DXA scan) for additional details on performing DXA scan at Premature 
Discontinuation Visit.
h.
An endometrial biopsy is not required during the Treatment Period if the TVU findings indicate an endometrial thickness < 4 mm.  If the TVU findings indicate an 
endometrial thickness ≥4 mm then the subject must have an endometrial biopsy performed.
i.
Subject must have a confirmed negative urine pregnancy test within 24 hours prior to performing the SIS and Endometrial Biopsy. 
j.
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.
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
145
k.
If subject has had a pelvic ultrasound (TAU/TVU) during washout or screening that is > 120 days from the date the procedure was performed, the pelvic ultrasound will need 
to be repeated on Day 1.
l.
Subjects who have SIS images which were unable to fully assess the endometrial cavity after 2 separate SIS attempts have been made may undergo an MRI for further 
evaluation in Screening (per imaging vendor request only).
m.
Optional urine test for gonorrhea or chlamydia should be performed prior to undergoing the endometrial biopsy.  Positive test results will be treated outside of the protocol.
n.
Biomarker sample (E2), Pharmacokinetic (PK) (elagolix and NETA) and Pharmacogenetic (DNA and RNA) samples can be drawn at any time during the visit.
o.
Study drug must not be dispensed if the subject has a positive urine pregnancy test result at any 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 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.
p.
Dispense home urine pregnancy test kits for subjects to self-administer during the Screening Period, prior to SIS and endometrial biopsy procedure, and for the Phone Visits 
during the Treatment Period.
q.
Subjects are required to use two forms of non-hormonal birth control throughout the Treatment Period. In addition, if the subject prematurely discontinues, the site should 
counsel the subject on the continued use of non-hormonal contraceptive use for at least 30 days after the last dose of study drug.
r.
Study drug kits will continue to be dispensed for those subjects continuing into the open–label Treatment Period.
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
146
Study Activities – Year 2 Open Label Treatment Period
Year 2 Treatment Perioda
Unsch 
Visit
PD
M
13
M
14
M
15
M
16
M
17
M
18
M
19
M
20
M
21
M
22
M
23
M
24
Phone Visitb
X
X
X
X
X
X
X
X
Pelvic Ultrasound@:  TVU, 
TAU
X
Xc
Endometrial Biopsyd
X
Xc
Pap Test
X
Xc
Complete Physical 
Examination:  including weight 
(W)
X
(W)*
X 
(W)*
Gynecological (External 
Genitalia, Pelvic and Breast) 
Examination
X
X 
Vital Signs 
X
X
X
X
X
X
Mammograme
X
Xc
DXA Scan
X
X
Xc
Clinical Safety Labs:  
Chemistry, Hematology, Lipid 
Panel and Urinalysis
X
X
Lipid Panel and Subset of 
Chemistry Labs:  ALT, AST, 
Bilirubin and Alkaline 
Phosphatase
X
X
X
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
147
Year 2 Treatment Perioda
Unsch 
Visit
PD
M
13
M
14
M
15
M
16
M
17
M
18
M
19
M
20
M
21
M
22
M
23
M
24
Biomarker Sample:  Serum 
Estradiol (E2)f
X
X
X
Pharmacokinetic Sample (PK):  
Elagolix and NETA Plasma 
Concentrationf
X
X
X
Urine Pregnancy Testg,h
X
X
X
X
X
X
X
X
X
X
X
X 
X
Contraception 
Counseling/Dispense 
Contraceptives as necessaryi
X
X
Xj
X
X
Xj
X
X
Xj
X
X
Xj
X
Birth Control Attestation
X
X
X
X
X
UFS-QoL
X
X
X
C-SSRS – Since Last Visit
X
X
X
X
X
Interactive Response 
Technology (IRT)
X
X
X
X
X
Dispense Study Drug
X
X
X
X
Drug Accountabilityb
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Monitoringb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medication 
Reviewb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
@
Subjects with a finding of polyp on pelvic ultrasound during the Treatment Period will undergo evaluation per standard of care which may include an SIS.
*
Complete physical examination; including weight (the subject should not wear shoes during weighing).
a.
Refer to Table 1 Visit and Assessment Windows, for allowable visit and assessment-specific windows during the Year 2 Treatment Period.
b.
Site staff to evaluate subjects compliance with taking study drug per protocol, assess ongoing adverse events, concomitant medications (if applicable), obtain the results of the 
subject's self-administered urine pregnancy test, and remind subjects of the importance of consistent use of appropriate and effective use of dual non-hormonal contraception.
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
148
c.
Premature Discontinuation prior to the time of the Treatment Month 18 does not require a Mammogram, DXA, Pelvic Ultrasound, Pap test, or Endometrial Biopsy, (i.e., 
received < 6 months of study drug during the Year 2 Treatment Period).  Refer to Section 5.3.1.1, Study Procedures, Bone Mineral Density (DXA scan) for additional details 
on performing DXA scan at Premature Discontinuation Visit.
d.
A negative urine pregnancy result should be obtained on the day of the endometrial biopsy, prior to performing the procedure.  An endometrial biopsy is not required during 
the Treatment Period if the TVU findings indicate an endometrial thickness < 4 mm.  If the TVU findings indicate an endometrial thickness ≥ 4 mm then the subject must 
have an endometrial biopsy performed.
e.
Mammograms will be performed for all subjects who are 39 years of age or older at time of the scheduled study visit.
f.
Biomarker sample (E2), Pharmacokinetic (PK) (elagolix and NETA) samples can be drawn at any time during the visit.
g.
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 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.
h.
Home pregnancy test kits will be dispensed at on-site visits and will be self-administered at home by the subject and results will be reported to site.
i.
Subjects are required to continue the use of two forms of non-hormonal birth control throughout the Treatment Period.  In addition, if the subject prematurely discontinues, 
the site should counsel the subject on the continued use of non-hormonal contraceptive use for at least 30 days after the last dose of study drug.
j.
Site should dispense enough contraceptives to carry subject over to the next on-site visit. 
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
149
Study Activities – Year 3 Open Label Extension
Year 3 Open Lab Treatment Perioda
M 
25
M 
26
M 
27
M 
28
M 
29
M 
30
M
31
M 
32
M 
33
M 
34
M 
35
M 
36
Unsch 
Visit
PD
Phone Visitb
X
X
X
X
X
X
X
X
Pelvic Ultrasound@:  TVU, 
TAU
X
Xc
Endometrial Biopsyd
X
Xc
Pap Test
Xc
Complete Physical 
Examination:  including 
weight (W)
X
(W)*
X 
(W)*
Gynecological (External 
Genitalia, Pelvic and Breast) 
Examination
X
X
Vital Signs 
X
X
X
X
X
X
Mammograme
X
Xc
DXA Scan
X
X
Xc
Clinical Safety Labs:  
Chemistry, Hematology, Lipid 
Panel and Urinalysis 
X
X
Lipid Panel and Subset of 
Chemistry Labs:  ALT, AST, 
Bilirubin and Alkaline 
Phosphatase
X
X
X
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
150
Year 3 Open Lab Treatment Perioda
M 
25
M 
26
M 
27
M 
28
M 
29
M 
30
M
31
M 
32
M 
33
M 
34
M 
35
M 
36
Unsch 
Visit
PD
Biomarker Sample:  Serum 
Estradiol (E2)f
X
X
X
Pharmacokinetic Sample (PK):  
Elagolix and NETA Plasma 
Concentrationf
X
X
X
Urine Pregnancy Testg,h
X
X
X
X
X
X
X
X
X
X
X
X
X
Contraception 
Counseling/Dispense 
Contraceptives as necessaryi
X
X
Xj
X
X
Xj
X
X
Xj
X
X
Xj
X
Birth Control Attestation
X
X
X
X
X
UFS-QoL
X
X
X
C-SSRS – Since Last Visit
X
X
X
X
X
Interactive Response 
Technology (IRT)
X
X
X
X
X
Dispense Study Drug
X
X
X
X
Drug Accountabilityb
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Monitoringb 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medication 
Reviewb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
@
Subjects with a finding of polyp on pelvic ultrasound during the Treatment Period will undergo evaluation per standard of care which may include an SIS.
*
Complete physical examination; including weight (the subject should not wear shoes during weighing).
a.
Refer to Table 1 Visit and Assessment Windows, for allowable visit and assessment-specific windows during the Year 3 Treatment Period.
b.
Site staff to evaluate subjects compliance with taking study drug per protocol, assess ongoing adverse events, concomitant medications (if applicable), obtain the results of the 
subject's self-administered urine pregnancy test, and remind subjects of the importance of consistent use of appropriate and effective use of dual non-hormonal contraception.
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
151
c.
Premature Discontinuation prior to the time of the Treatment Month 30 does not require a Mammogram, DXA, Pelvic Ultrasound, or Pap test (i.e., received < 6 months of 
study drug during the Year 3 Treatment Period).  Endometrial Biopsy is not required if the subject had an endometrial biopsy within the last 6 months.  Refer to Section 
5.3.1.1, Study Procedures, Endometrial Biopsy, and Bone Mineral Density (DXA scan) for additional details on performing DXA scan at Premature Discontinuation Visit.
d.
A negative urine pregnancy result should be obtained on the day of the endometrial biopsy, prior to performing the procedure.  Endometrial Biopsy is not required if the 
subject had an endometrial biopsy within the last 6 months. Refer to Section 5.3.1.1, Study Procedures, Endometrial Biopsy for additional details.
e.
A Mammogram will be performed for all subjects who are 39 years of age or older at time of the scheduled study visit.
f.
Biomarker sample (E2), Pharmacokinetic (PK) (elagolix and NETA) samples can be drawn at any time during the visit.
g.
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 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.
h.
Home pregnancy test kits will be dispensed at on-site visits and will be self-administered at home by the subject and results will be reported to site.
i.
Subjects are required to continue the use of two forms of non-hormonal birth control throughout the Treatment Period.  In addition, if the subject prematurely discontinues, 
the site should counsel the subject on the continued use of non-hormonal contraceptive use for at least 30 days after the last dose of study drug.
j.
Site should dispense enough contraceptives to carry subject over to the next on-site visit. 
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
152
Study Activities – Year 4 Open Label Extension
Year 4 Open Lab Treatment Perioda
M 
37
M 
38
M 
39
M 
40
M 
41
M 
42
M 
43
M 
44
M 
45
M 
46
M 
47
M 
48
Unsch 
Visit
PD
Phone Visitb
X
X
X
X
X
X
X
X
Pelvic Ultrasound@:  TVU, 
TAU
X
Xc
Endometrial Biopsyd
X
Xc
Pap Test
X
Xc
Complete Physical 
Examination:  including 
weight (W)
X
(W)*
X 
(W)*
Gynecological (External 
Genitalia, Pelvic and Breast) 
Examination
X
X
Vital Signs 
X
X
X
X
X
X
Mammograme
X
Xc
DXA Scan
X
X
Xc
Clinical Safety Labs:  
Chemistry, Hematology, Lipid 
Panel and Urinalysis 
X
X
Lipid Panel and Subset of 
Chemistry Labs:  ALT, AST, 
Bilirubin and Alkaline 
Phosphatase
X
X
X
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
153
Year 4 Open Lab Treatment Perioda
M 
37
M 
38
M 
39
M 
40
M 
41
M 
42
M 
43
M 
44
M 
45
M 
46
M 
47
M 
48
Unsch 
Visit
PD
Biomarker Sample:  Serum 
Estradiol (E2)f
X
X
X
Pharmacokinetic Sample (PK):  
Elagolix and NETA Plasma 
Concentrationf
X
X
X
Urine Pregnancy Testg,h
X
X
X
X
X
X
X
X
X
X
X
X
X
Contraception 
Counseling/Dispense 
Contraceptives as necessaryi
X
X
Xj
X
X
Xj
X
X
Xj
X
X
Xj
X
Birth Control Attestation
X
X
X
X
X
UFS-QoL
X
X
X
C-SSRS – Since Last Visit
X
X
X
X
X
Interactive Response 
Technology (IRT)
X
X
X
X
X
Dispense Study Drug
X
X
X
Drug Accountabilityb
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Monitoringb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medication 
Reviewb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
@
Subjects with a finding of polyp on pelvic ultrasound during the Treatment Period will undergo evaluation per standard of care which may include an SIS.
*
Complete physical examination; including weight (the subject should not wear shoes during weighing).
a.
Refer to Table 1 Visit and Assessment Windows, for allowable visit and assessment-specific windows during the Year 4 Treatment Period.
b.
Site staff to evaluate subjects compliance with taking study drug per protocol, assess ongoing adverse events, concomitant medications (if applicable), obtain the results of the 
subject's self-administered urine pregnancy test, and remind subjects of the importance of consistent use of appropriate and effective use of dual non-hormonal contraception.
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
154
c.
Premature Discontinuation prior to the time of the Treatment Month 42 does not require a Mammogram, DXA, Pelvic Ultrasound, or Pap test (i.e., received < 6 months of 
study drug during the Year 4 Treatment Period). Endometrial Biopsy is not required if the subject had an endometrial biopsy within the last 6 months.  Refer to 
Section 5.3.1.1, Study Procedures, Endometrial Biopsy, and Bone Mineral Density (DXA scan) for additional details on performing DXA scan at Premature Discontinuation 
Visit.
d.
A negative urine pregnancy result should be obtained on the day of the endometrial biopsy, prior to performing the procedure.  Endometrial Biopsy is not required if the 
subject had an endometrial biopsy within the last 6 months. Refer to Section 5.3.1.1, Study Procedures.
e.
A Mammogram will be performed for all subjects who are 39 years of age or older at time of the scheduled study visit.
f.
Biomarker sample (E2), Pharmacokinetic (PK) (elagolix and NETA) samples can be drawn at any time during the visit.
g.
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 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.
h.
Home pregnancy test kits will be dispensed at on-site visits and will be self-administered at home by the subject and results will be reported to site.
i.
Subjects are required to continue the use of two forms of non-hormonal birth control throughout the Treatment Period.  In addition, if the subject prematurely discontinues, 
the site should counsel the subject on the continued use of non-hormonal contraceptive use for at least 30 days after the last dose of study drug.
j.
Site should dispense enough contraceptives to carry subject over to the next on-site visit. 
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
155
Study Activities – Post-Treatment Follow-Up Period
Post-Treatment Follow-Upa
Month 1
Month 6
Month 12
On-site Visit
X
Phone Visit
X
X
Physical Examination
Xb
Return to Menses Questionnairec
X
X
DXA Scand
X
X
Pregnancy Teste
Urine (u), serum (s)
X (u, s)
Xf (u)
Xf (u)
Serum Estradiol (E2) and FSH 
sample
X
Lipid Panel and Subset of Chemistry 
Labs:  ALT, AST, Bilirubin and 
Alkaline Phosphatase
X
Review Adverse Events
Xg
Review Adverse Events of Special 
Interest (Bone)h
X
X
Review Concomitant Medication
X
X
X
a.
Refer to Table 1 Visit and Assessment Windows, for allowable visit and assessment-specific windows during the 
Post-Treatment Follow-Up Period.
b.
Brief, symptom-directed examination to assess any ongoing AEs for resolution.
c.
If the subject has a documented menstrual period after the last dose of study drug, the subject may begin the use of 
hormonal contraception (e.g., oral or IUD) in place of non hormonal birth control.
d.
Site staff to contact subjects to ensure Month 6 and 12 DXA scans are scheduled within the visit window (refer to 
Table 1).
e.
A positive urine pregnancy test result must be confirmed with a serum pregnancy test.  For any subject who has a 
positive serum pregnancy test result during the Post-Treatment Follow-Up Period, a TVU must be conducted as 
early as possible in the first trimester in order to assess the conception date.  The subject will be discontinued from 
the Post-Treatment Follow-Up Period at the point the pregnancy is confirmed. 
f.
A negative urine pregnancy test must be obtained within 2 days prior to performing the DXA.  A positive urine 
pregnancy test result must be confirmed with a serum pregnancy test.  For any subject who has a positive serum 
pregnancy test result, the DXA should not be performed.  The subject will be discontinued from the Follow-Up 
Period at the point the pregnancy is confirmed. 
g.
Any ongoing adverse events at the end of the Treatment Period will be reviewed for resolution during this visit.
h.
AESIs of bone fracture, clinically significant BMD loss, or newly diagnosed medically-related bone condition will 
be collected during the Post-Treatment Follow-Up Period. 
 


Elagolix (ABT-620)
M16-283 Protocol Amendment 6
156
Appendix D.
BI-RADS Classification
The BI-RADS assessment categories are:
●
0 – Incomplete,
●
1 – Negative,
●
2 – Benign findings,
●
3 – Probably benign,
●
4 – Suspicious abnormality,
●
5 – Highly suspicious of malignancy,
●
6 – Known biopsy with proven malignancy
 

SAP_001.pdf: 
Elagolix
M16-283 – Statistical Analysis Plan
Version 1.0 – 20 January 2021
1
Statistical Analysis Plan for Study M16-283
A Phase 3b Study to Evaluate the Long-Term Safety 
of Elagolix in Combination with 
Estradiol/Norethindrone Acetate for the 
Management of Heavy Menstrual Bleeding 
Associated with Uterine Fibroids in Premenopausal 
Women
Date:  20 January 2021
Version 1.0
 
NCT03271489


Elagolix
M16-283 – Statistical Analysis Plan
Version 1.0 – 20 January 2021
2
Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design, Objectives and Procedures.............................5
2.1
Objectives ..................................................................................................5
2.2
Study Design Overview .............................................................................6
2.3
Treatment Assignment and Blinding .........................................................8
2.4
Sample Size Determination........................................................................8
2.5
End of 12-Month Placebo-Controlled Treatment Period Analysis............9
2.6
Treatment Month 24, Month 36 and Month 48 Analyses..........................9
3.0
Endpoints................................................................................10
3.1
Primary Endpoint.....................................................................................10
3.2
Secondary Endpoint .................................................................................10
3.3
Other Efficacy Endpoints.........................................................................10
3.4
Safety Endpoints ......................................................................................10
4.0
Analysis Populations .............................................................11
5.0
Subject Disposition................................................................11
6.0
Study Drug Duration.............................................................12
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................14
7.1
Demographics and Baseline Characteristics............................................14
7.2
Medical History .......................................................................................15
7.3
Prior, Concomitant, and Post-Treatment Medications.............................15
7.4
Physician Surgery Questionnaire (PSQ)..................................................16
7.5
Reason for Study Participation Questionnaire.........................................16
8.0
Efficacy Analyses...................................................................16
8.1
General Considerations............................................................................16
8.2
Handling of Missing Data........................................................................17
8.3
Primary Efficacy Endpoint and Analyses ................................................17
8.4
Secondary Efficacy Endpoint and Analyses ............................................18
8.5
Other Efficacy Endpoints and Analyses ..................................................18
8.5.1
Patient Global Impression of Change (PGIC)..........................................18
8.5.2
Uterine Fibroid Symptoms Quality of Life (UFS-QoL)..........................18
 


Elagolix
M16-283 – Statistical Analysis Plan
Version 1.0 – 20 January 2021
3
9.0
Safety Analyses ......................................................................19
9.1
General Considerations............................................................................19
9.2
Adverse Events ........................................................................................20
9.2.1
Treatment-Emergent Adverse Events ......................................................20
9.2.2
Adverse Event Overview .........................................................................21
9.2.3
Treatment-Emergent Adverse Events by SOC and PT............................22
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure ..................................................................................................22
9.2.5
Serious Adverse Events (Including Deaths) and Adverse Events 
Leading to Study Drug Discontinuation ..................................................23
9.2.6
Adverse Events of Special Interest ..........................................................23
9.2.7
Post-Treatment Adverse Events...............................................................23
9.3
Analysis of Laboratory Data....................................................................24
9.4
Analysis of Vital Signs and Weights .......................................................27
9.5
Other Safety Analyses..............................................................................28
9.5.1
Columbia Suicide Severity Rating Scale (C-SSRS) ................................28
9.5.2
Bone Mineral Density..............................................................................29
9.5.2.1
Bone Mineral Density during the Treatment Period................................29
9.5.2.2
Bone Mineral Density during the Follow-up Period................................31
9.5.3
Transvaginal Ultrasound..........................................................................34
9.5.3.1
Ovarian Cysts...........................................................................................34
9.5.3.2
Endometrial Thickness.............................................................................34
9.5.4
Endometrial Biopsy .................................................................................35
9.5.5
Pregnancy Results....................................................................................35
10.0
Overall Type-I Error Control ..............................................37
11.0
Version History......................................................................38
12.0
References...............................................................................38
List of Tables
Table 1.
SAP Version History Summary...............................................................38
 


Elagolix
M16-283 – Statistical Analysis Plan
Version 1.0 – 20 January 2021
4
List of Figures
Figure 1.
Study Schematic.........................................................................................7
List of Appendices
Appendix A.
Definition of Adverse Events of Special Interest (AESI) Adverse 
Events of Special Interest.........................................................................39
 


Elagolix
M16-283 – Statistical Analysis Plan
Version 1.0 – 20 January 2021
5
1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for Study M16-283" 
A Phase 3b Study to Evaluate the Long-Term Safety of Elagolix in Combination with 
Estradiol/Norethindrone Acetate for the Management of Heavy Menstrual Bleeding 
Associated with Uterine Fibroids in Premenopausal Women."
Study M16-283 examines the long-term safety of elagolix 300 mg administered twice 
daily (BID) in combination with estradiol 1 mg/0.5 mg norethindrone acetate (E2/NETA 
1 mg/0.5 mg) in premenopausal women with heavy menstrual bleeding associated with 
uterine fibroids.
The analyses of pharmacokinetic endpoints, pharmacodynamic biomarker endpoints and 
exploratory research endpoints will not be covered in this SAP.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC  27513) or later under the UNIX operating system.
2.0
Study Design, Objectives and Procedures
2.1
Objectives
The objectives of this study are to:
●
Assess the safety of elagolix 300 mg administered twice daily (BID) in 
combination with E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg 
QD) compared to placebo at 12 months in premenopausal women with heavy 
menstrual bleeding associated with uterine fibroids,
●
Characterize the impact of elagolix 300 mg BID with E2/NETA on bone 
mineral density (BMD) in women with HMB associated with uterine fibroids 
after up to 48 months of treatment.
 


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2.2
Study Design Overview
This Phase 3b, randomized, 12-month double-blind placebo-controlled, 36 month open-
label, multi-center study is designed to evaluate the safety of elagolix with add-back 
therapy in women with HMB associated with uterine fibroids.
Approximately 500 subjects will be randomized in a 2:1 ratio to one of the following 
2 treatment groups:
1.
Elagolix 300 mg BID plus E2/NETA (estradiol 1.0 mg/norethindrone acetate 
0.5 mg QD) (n = 333) for 48 months
2.
Placebo (n = 167) for 12 months
Subjects randomized to elagolix 300 mg BID plus E2/NETA in the 12-month Treatment 
Period will receive the same treatment during the open-label Treatment Period.  Subject 
randomized to placebo in the 12-month Treatment Period will switch to elagolix 300 mg 
BID plus E2/NETA during the open-label Treatment Period after completing the 
12-month Treatment Period.
The total duration for a subject's participation in this study is approximately 77 months, 
consisting of the following 4 study periods:
1.
Washout Period – up to 10 months prior to Screening (only applicable if subject is 
taking exclusionary medication at the time of consent; duration of washout 
depends on the type of exclusionary medication being taken).
2.
Screening Period – approximately 2.5 to 5 months prior to first dose of study drug.
3.
Treatment Period – up to 48-month treatment duration
4.
Post-Treatment Follow-Up Period – up to 12 months duration following the last 
dose of study drug.  Subjects are expected to enter Post-Treatment Follow-Up after 
completing Treatment Period Month 48, or at any time a subject prematurely 
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The Study Schematic is shown below in Figure 1.
Figure 1.
Study Schematic
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


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Figure 1.
Study Schematic (Continued)
2.3
Treatment Assignment and Blinding
Approximately 500 subjects will be randomily assigned in a 2:1 ratio to one of the 
following 2 treatment groups:
1.
Elagolix 300 mg BID plus E2/NETA (estradiol 1.0 mg/norethindrone acetate 
0.5 mg QD) (n = 333)
2.
Placebo (n = 167) 
Unless otherwise specified, data will be summarized by group as listed above.
2.4
Sample Size Determination
Approximately 500 subjects will be randomily assigned (2:1) to elagolix 300 mg BID plus 
E2/NETA (N = 333) and placebo (N = 167).
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 


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Based on clinical review, a sample size of 500 was selected to gather long term safety 
exposure data in approximately 50 subjects completing 48 months of study drug dosing, 
with approximately 30 subjects receiving 48 months of active drug elagolix 300 mg BID 
plus E2/NETA 1/0.5 mg QD.
2.5
End of 12-Month Placebo-Controlled Treatment Period 
Analysis
An end-of-placebo-controlled treatment period analysis will be performed after the last 
subject completes the 12-Month placebo-controlled Treatment Period.  These analyses 
will include data collected during the full Treatment Period (placebo-controlled and open-
label Treatment Periods) and the Follow-Up Period up to the data cut-off for the interim 
lock.  The database will be versioned for an interim lock and any discrepant data will be 
clarified before the versioning.  Analyses will be performed by AbbVie.
Since this end-of-placebo-controlled treatment period analysis is the only and final 
analysis for the comparison between treatment and placebo group at 12 months of safety 
and efficacy endpoints, no additional adjustment of alpha-level is necessary.
2.6
Treatment Month 24, Month 36 and Month 48 Analyses
At the end of Treatment Month 24, Month 36 and Month 48, analysis of the safety and 
efficacy safety variables may be performed after the last subject completes the Treatment 
Month 24, Month 36 and Month 48 visit, respectively.  For subjects who prematurely 
discontinued during the treatment period, their data collected during the Follow-up Period 
will be included in the analysis, as appropriate.  The database will be versioned for an 
interim lock and any discrepant data will be clarified before the versioning.  Analyses will 
be performed by AbbVie.
 


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3.0
Endpoints
3.1
Primary Endpoint
As the objective of this study is to evaluate the long-term safety and tolerability of 
elagolix 300 mg BID with E2/NETA, no primary efficacy endpoint is defined.
3.2
Secondary Endpoint
As the objective of this study is to evaluate the long-term safety and tolerability of 
elagolix 300 mg BID with E2/NETA, no secondary efficacy endpoint is defined.
3.3
Other Efficacy Endpoints
Other efficacy endpoints include the following:
●
PGIC for Menstrual Bleeding Symptom at Month 3, Month 6, Month 9 and 
Month 12;
●
Change from baseline for the UFS-QoL at Month 6 and Month 12.
3.4
Safety Endpoints
The safety endpoints will be based on the following evaluations:
●
Dual energy X-ray absorptiometry (DXA) scan
●
Adverse events monitoring
●
Clinical laboratory tests
●
Vital signs
●
Endometrial biopsy
●
Pelvic ultrasound (transabdominal ultrasound [TAU]/transvaginal ultrasound 
[TVU])
●
Columbia Suicide Severity Rating Scale (C-SSRS)
●
Pregnancy
 


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4.0
Analysis Populations
The Full Analysis Set (FAS) is composed of all randomized subjects who have received at 
least 1 dose of study drug in this study.  The data from the FAS will be presented by the 
treatment group assigned at the time of randomization, even if a subject does not receive 
the correct treatment or does not follow the protocol until completion.  The FAS will be 
used for all efficacy and baseline analyses unless otherwise specified in the SAP.  
Subjects who do not continue into the open-label Treatment Period will be excluded from 
the analyses in the open-label Treatment Period.
The following populations will be used for safety analyses:
●
The Safety Analysis Set includes all randomized subjects who received at least 
1 dose of study drug. Subjects will be analyzed according to the treatment they 
actually receive, defined as the randomized treatment if the patient took at least 
one dose of that randomized treatment during the 12-month placebo-controlled 
double-blind Treatment Period, or the first treatment received if the randomized 
treatment was never received during the 12-month placebo-controlled double-
blind Treatment Period.  Subjects who do not continue into the open-label 
Treatment Period will be excluded from the analyses in the open-label 
Treatment Period.
●
The All Elagolix plus E2/NETA Analysis Set is defined as subjects who 
received at least 1 dose of elagolix plus E2/NETA in the study (either in the 
placebo-controlled or open-label Treatment Periods).  Subjects will be 
summarized based on the actual treatment received at the time of randomization 
(elagolix plus E2/NETA or placebo).
5.0
Subject Disposition
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized for all randomized subjects by 
treatment group and overall:
●
Subjects randomized in the study.
 


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●
Subjects who took at least one dose of study drug.
●
Subjects who completed the placebo-controlled Treatment Period.
●
Subjects who prematurely discontinued during the placebo-controlled 
Treatment Period.
●
Subjects who entered into the open-label Treatment Period.
●
Subjects who prematurely discontinued during the open-label Treatment 
Period.
●
Subjects who completed protocol-specified treatment.
●
Subjects who prematurely discontinued study drug (all reasons and primary 
reason).
●
Subjects who entered into the Follow-up Period.
●
Subjects who completed the Follow-up Period.
The number and percentage of subjects who discontinued study drug will be summarized 
by treatment group and overall as follows based on the Full Analysis Set:
●
By any reason for discontinuation
●
By primary reason for discontinuation
In addition, the number and percentage of subjects who discontinued study will be 
summarized for the FAS by treatment group and overall as follows:
●
By any reason for discontinuation
●
By primary reason for discontinuation
6.0
Study Drug Duration
Duration (days) of treatment will be summarized for the Safety Analysis Set using the 
number of subjects treated, mean, standard deviation, median, minimum and maximum.
Study drug duration will be summarized as follows:
 


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Placebo-controlled Treatment Period (Safety Analysis Set):
Duration of treatment during the placebo-controlled Treatment Period is defined as 
follow:
●
For subjects who did not continue into the open-label Treatment Period:
○
Last dose date during the placebo-controlled Treatment Period – First dose 
date during the placebo-controlled Treatment Period + 1
●
For subjects who continued into the open-label Treatment Period:
Minimum of
○
Last dose date during the placebo-controlled Treatment Period – First dose 
date during the placebo-controlled Treatment Period + 1
○
First dose date during the open-label Treatment Period – First dose date 
during the placebo-controlled Treatment Period.
In addition, the number and percentage of subjects in each treatment duration interval 
(1 – < 28 days, 28 – < 56 days, 56 – < 84 days, 84 – < 112 days, 112 – < 140 days, 
140 – < 168 days, 168 – < 196 days, 196 – < 224 days, 224 – < 252 days, 252 –
< 280 days, 280 – < 308 days, 308 – < 336 days, ≥336 days) will be summarized.
Open-label Treatment Period (Safety Analysis Set):
Duration of treatment during the open-label Treatment Period is defined as last dose date 
during the open-label Treatment Period minus first dose date during the open-label 
Treatment Period plus 1 day.
In addition, the number and percentage of subjects in each treatment duration interval 
(1 – < 84 days, 84 – < 168 days, 168 – < 252 days, 252 – < 336 days, 336 – < 420 days, 
420 – < 504 days, 504 – < 588 days, 588 – < 672 days, 672 – < 756 days, 756 –
< 840 days, 840 – < 924 days, 924 – < 1008 days, ≥ 1008 days) will be summarized.
 


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All Elagolix plus E2/NETA Analysis Set:
For subjects who received at least 1 dose of elagolix plus E2/NETA (either in the placebo-
controlled or open-label Treatment Period), the duration of treatment is defined as the last 
dose date of receiving elagolix plus E2/NETA minus the first dose date of receiving 
elagolix plus E2/NETA plus 1 day.
In addition, the number and percentage of subjects in each treatment duration interval 
(1 – < 84 days, 84 – < 168 days, 168 – < 252 days, 252 – < 336 days, 336 – < 420 days, 
420 – < 504 days, 504 – < 588 days, 588 – < 672 days, 672 – < 756 days, 756 –
< 840 days, 840 – < 924 days, 924 – < 1008 days, 1008 – < 1092 days, 1092 –
< 1176 days, 1176 – < 1260 days, 1260 – < 1344 days, ≥ 1344 days) will be summarized.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline characteristics, medical history, prior medications, concomitant 
medications, and post-treatment medications will be summarized by treatment group and 
overall using the Full Analysis Set.  Categorical variables will be summarized with the 
number and percentage of subjects; percentages will be calculated based on the number of 
non-missing observations.  Continuous variables will be summarized with descriptive 
statistics (number of non-missing observations, mean and standard deviation, median, 
minimum and maximum).
7.1
Demographics and Baseline Characteristics
Continuous demographic variables include age, weight, height, and body mass index 
(BMI).  Categorical demographic variables include sex, ethnicity, race, age (18 – 19, 
20 – 24, 25 – 29, 30 – 34, 35 – 39, 40 – 44, 45 – 49, ≥ 50 years), BMI (≤ 18.5, > 18.5 –
< 25, ≥25 – < 30, ≥ 30 – < 35, ≥ 35 – < 40, ≥ 40 kg/m2), tobacco use (current, former, 
never, unknown), and alcohol use (current, former, never, unknown).
 


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7.2
Medical History
Medical history and gynecological medical/surgical history data will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  The actual version of the 
MedDRA coding dictionary will be noted in the statistical tables and clinical study report.  
The number and percentage of subjects in each medical history category (by MedDRA 
system organ class and preferred term) will be summarized by treatment group and overall 
for the FAS.  The system organ class (SOC) will be presented in alphabetical order, and 
the preferred terms will be presented in alphabetical order within each SOC.  Subjects 
reporting more than one condition/diagnosis will be counted only once in each row (SOC 
or preferred term).
7.3
Prior, Concomitant, and Post-Treatment Medications
Prior, concomitant, and post-treatment medications will be summarized by generic name 
for the FAS.
Prior medications are those medications with a start date prior to the first study drug 
administration date.  Prior medications will be summarized separately for each treatment 
group and overall using ATC Classification and preferred terms from the World Health 
Organization (WHO) Drug Dictionary.
Concomitant medications are those medications, other than study drugs, taken during the 
treatment period 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 if any of the following three cases occur (1) the start 
date is missing and the end date is either after or on the first study drug dose date; (2) the 
start date is not missing and the end date is missing; (3) both the start date and the end 
date are missing.
Concomitant medications will be summarized using ATC Classification and preferred 
terms from the World Health Organization (WHO) Drug Dictionary with number and 
percentage for each treatment group and overall.
 


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Post-treatment medications are those medications with an end date after the last dose of 
study drug or ongoing at the end of study.  Post-treatment medications will be 
summarized 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.
7.4
Physician Surgery Questionnaire (PSQ)
For each of the PSQ questions, 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.
7.5
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.
8.0
Efficacy Analyses
8.1
General Considerations
All efficacy analyses will be conducted in the FAS Population.
Unless otherwise specified, during the 12-month placebo-controlled Treatment Period, 
elagolix plus E2/NETA group will be compared against placebo.  Statistical tests will be 
conducted at an alpha level of 0.05 (two-sided).  A test will be deemed significant if the 
P value rounded to three decimal places is less than or equal to 0.05 unless otherwise 
specified.
 


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Efficacy endpoints collected during each of the placebo-controlled and open-label 
Treatment Periods will also be summarized as observed cases (by treatment group); no 
comparisons or statistical tests will be performed.
The End of 12-Month Placebo-Controlled Treatment Period analyses will be performed 
after all ongoing subjects have completed the 12-month placebo-controlled Treatment 
Period and the database has been locked.  This will be the only and final analysis for the 
efficacy endpoints collected in the 12-Month Placebo-Controlled Treatment Period.
Unless otherwise specified, categorical data will be summarized by frequencies and 
percentages; continuous data will be summarized by the mean, standard deviation, 
median, minimum, and maximum.  For the analyses of change from baseline, the within-
group changes will be summarized with the mean, standard deviation or standard error, 
and 95% confidence intervals (CIs); between-group differences will be summarized with 
the mean, standard error, P value (as appropriate), and the 95% CIs.
For efficacy variables, the baseline during the 12-month placebo-controlled Treatment 
period (Months 1 – 12) will be the last non-missing value obtained prior to or on Study 
Day 1.
8.2
Handling of Missing Data
The primary objective of the study is to evaluate the long-term safety and tolerability of 
Elagolix plus E2/NETA.  The efficacy analyses will be based on the observed data.  The 
missing data will not be replaced or imputed.  Potential impact due to COVID-19 will be 
recorded in the database.  Listings will be provided to summarize AE and death related to 
COVID-19 infection, COVID-19 impacted visits, COVID-19 related study drug 
interruptions, COVID-19 status, and COVID-19 supplemental signs/symptoms.
8.3
Primary Efficacy Endpoint and Analyses
As the objective of this study is to evaluate the long-term safety and tolerability of 
elagolix 300 mg BID with E2/NETA, no primary efficacy endpoint is defined.
 


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8.4
Secondary Efficacy Endpoint and Analyses
As the objective of this study is to evaluate the long-term safety and tolerability of 
elagolix 300 mg BID with E2/NETA, no secondary efficacy endpoint is defined.
8.5
Other Efficacy Endpoints and Analyses
Other efficacy assessments include the following:
●
PGIC for Menstrual Bleeding Symptom;
●
Change from baseline for the UFS-QoL. 
8.5.1
Patient Global Impression of Change (PGIC)
For PGIC on menstrual bleeding (PGIC – MB), the number and percentage of subjects in 
each response category will be summarized at Month 3, Month 6, Month 9, Month 12 and 
Final Visit during the placebo-controlled double-blind 12-month Treatment Period by 
treatment group.
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 3, Month 6, Month 9, Month 12 and Final Visit during the placebo-controlled 
Treatment Period by treatment group.  Comparisons will be made using a Miettinen–
Nurminen (M-N) test [1] for Month 3, Month 6, Month 9, Month 12, and Final Visit 
assessments in placebo-controlled Treatment Period.  The p-value of the Miettinen-
Nurminen test will be reported.
8.5.2
Uterine Fibroid Symptoms Quality of Life (UFS-QoL)
Improvement in quality of life will be assessed on the UFS-QoL Questionnaire (4-week 
recall).  Each of the UFS-QoL subscales (symptom severity, concern, activities, 
energy/mood, control, self-conscious, and sexual function) and the HRQL total at 
 


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Month 6, Month 12, Month 18, Month 24, Month 30, Month 36, Month 42, Month 48, 
and Final Visit during the Treatment Period will be calculated and summarized by 
treatment group.  The change from Baseline to Month 6, Month 12, and Final Visit during 
the placebo-controlled Treatment Period will be analyzed using ANCOVA with treatment 
as the main effect and corresponding Baseline UFS-QoL as a covariate to compare 
elagolix dose group to placebo.
9.0
Safety Analyses
9.1
General Considerations
Safety summaries will be provided separately using the Safety Analysis Set during the 
placebo-controlled Treatment Period, Safety Analysis Set during the open-label Treatment 
Period, and All Elagolix plus E2/NETA Analysis Set as defined in Section 4.0.  Unless 
otherwise specified, no statistical comparisons or tests will be performed on Safety 
Analysis Set during the open-label Treatment Period or the All Elagolix plus E2/NETA 
Analysis Set.
Unless otherwise specified, the baseline for the 12-month placebo-controlled Treatment 
Period will be the last non-missing value obtained prior to or on Study Day 1.  The 
baseline during the open-label Treatment Period will be the last non-missing value 
obtained prior to or on the initiation day of elagolix plus E2/NETA.  The baseline for All 
Elagolix plus E2/NETA Analysis Set will be the last non-missing value obtained prior to 
or on the initiation day of elagolix plus E2/NETA.
All safety analyses will be based on observed data.  Unless otherwise specified, missing 
data will not be imputed.  The COVID-19 pandemic has interfered with the conduct of 
this study.  Potential impacts due to COVID-19 are recorded in the database.  Listings will 
be provided to summarize AE and death related to COVID-19 infection, COVID-19 
impacted visits, COVID-19 related study drug interruptions, COVID-19 status, and 
COVID-19 supplemental signs/symptoms.
 


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9.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock.  The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
study report.  Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise.  In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported.
9.2.1
Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) for each safety population are defined as 
follows:
TEAEs during the 12-month placebo-controlled Treatment Period on Safety 
Analysis Set during the placebo-controlled Treatment Period
TEAEs during the 12-month placebo-controlled Treatment Period are defined as any AEs 
with the onset that is on or after the first dose of study drug during the 12-month placebo-
controlled Treatment Period and no more than 30 days after the last dose of study drug for 
subjects who premature discontinue during the 12-month double-blind Treatment Period 
or until the first dose of study drug in the open-label Treatment Period for subjects who 
enter the open-label Treatment Period.  AEs starting more than 30 days following 
discontinuation of study drug will not be included in summaries of treatment-emergent 
AEs but will be summarized separately.
TEAEs during the open-label Treatment Period on the Safety Analysis Set during 
the open-label Treatment Period
TEAEs during the open-label Treatment Period are defined as any AEs with the onset that 
is on or after the first dose of study drug during the open-label Treatment Period and no 
 


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more than 30 days after the last dose of study drug in the study.  AEs starting more than 
30 days following discontinuation of study drug will not be included in summaries of 
treatment-emergent AEs but will be summarized separately.
TEAEs for All Elagolix plus E2/NETA Analysis Set
TEAEs for All Elagolix plus E2/NETA Analysis Set are defined as any AEs with the 
onset that is on or after the first dose of elagolix plus E2/NETA (either in the placebo-
controlled Treatment Period or open-label Treatment Period) and no more than 30 days 
after last dose of elagolix plus E2/NETA.  AEs starting more than 30 days following 
discontinuation of study drug will not be included in summaries of treatment-emergent 
AEs but will be summarized separately.
The number and percentage of subjects experiencing treatment-emergent AEs will be 
summarized overall, as well as by primary MedDRA SOC and PT by treatment group.  
The SOCs will be presented in alphabetical order, and the PTs will be presented in 
alphabetical order within each SOC.
9.2.2
Adverse Event Overview
An overview of treatment-emergent AEs will be presented consisting of the number and 
percentage of subjects experiencing at least one event for each of the following AE 
categories:
●
Any treatment-emergent AE
●
Any treatment-emergent AE related to study drug according to the investigator
●
Any severe treatment-emergent AE
●
Any serious treatment-emergent AE
●
Any treatment-emergent AE leading to discontinuation of study drug
●
Any treatment-emergent AE leading to death
●
Any treatment-emergent AE of special interest as specified in Appendix A
●
All deaths
 


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9.2.3
Treatment-Emergent Adverse Events by SOC and PT
Treatment-emergent adverse events will be summarized by SOC and PT; by maximum 
relationship to study drug as assessed by the investigator (e.g., reasonable possibility or no 
reasonable possibility) and SOC and PT; by maximum severity and SOC and PT; and by 
subject number and SOC and PT.  Specific adverse events will be counted once for each 
subject for calculating percentages, unless stated otherwise.  In addition, if the same 
adverse event occurs multiple times within a subject, the highest severity and level of 
relationship to investigational product will be reported.
In addition, treatment-emergent adverse events will be summarized by PT and sorted by 
decreasing frequency for the elagolix plus E2/NETA group.
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
An overview of AEs for All Elagolix plus E2/NETA Analysis Set will be presented per 
100 patient-years.  In addition, TEAEs for All Elagolix plus E2/NETA Analysis Set will 
be presented per 100 patient-years by SOC and PT.  AEs per 100 patient-years of 
exposure are defined as the number of AEs divided by the total exposure in 100 patient-
years.  Note that one event per preferred term per day per subject will be counted in the 
calculation of the number of AEs (i.e., a preferred term will not be counted twice on the 
same day for the same subject).
where total patient years are defined as the sum of the study drug exposure (defined as 
date of last dose of elagolix plus E2/NETA – date of first dose of elagolix plus E2/NETA 
+ 30 days) of all subjects normalized by 365.25, and rounded to one decimal place.
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 


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9.2.5
Serious Adverse Events (Including Deaths) and Adverse 
Events Leading to Study Drug Discontinuation
The number and percentage of subjects experiencing the following categories will be 
tabulated according to the primary MedDRA SOC and PT.  In addition, listing of subjects 
experiencing the following categories will be generated.
●
Treatment-emergent SAEs
●
Treatment-emergent AEs leading to discontinuation of study drug
●
Treatment-emergent AEs leading to death
9.2.6
Adverse Events of Special Interest
Adverse events of special interest will be summarized by SOC and PT and will be based 
on standardized or company MedDRA queries (SMQs or CMQs), or based on 
adjudication results.
Detailed information about the search criteria are provided in Appendix A.
9.2.7
Post-Treatment Adverse Events
Post-Treatment Adverse Events are defined as AEs starting more than 30 days following 
discontinuation of study drug in the Treatment Period.  The Post-Treatment AEs will be 
summarized as follows:
●
Overview of Post-Treatment AEs
●
Post-Treatment AEs by SOC and PT
●
Post-Treatment SAEs by SOC and PT
In addition, listing of subjects with Post-Treatment AEs by SOC and PT and Post-
Treatment SAEs by SOC and PT will be provided.
 


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9.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for Baseline where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded.  The 
clinical laboratory tests defined in the protocol operations manual (i.e., hematology and 
clinical chemistry) will be summarized.
Each laboratory variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum.  For selected laboratory variables including lipid variables, liver 
variables (alkaline phosphatase, ALT, AST, bilirubin), and hemotological variables 
(hemoglobin, hematocrit, platelet count, and red blood cell (RBC) count), mean change 
from baseline to each applicable post-baseline visit will be summarized, with the number 
of observations, baseline mean, and visit mean.  The change from baseline mean, standard 
error, and 95% confidence interval will be presented for the mean change from baseline 
within each treatment group and difference between elagolix group and placebo.  For lipid 
variables, in addition to low-density lipoprotein cholesterol (LDL-C), high-density 
lipoprotein cholesterol (HDL-C), total cholesterol, triglycerides (TG) and apolipoprotein 
A and B, the following ratios will be included:  the ratio of total cholesterol to HDL-C, 
the ratio of LDL-C to HDL-C, the ratio of TG to HDL-C, and the ratio of non-HDL-C 
(calculated as total cholesterol minus HDL-C) to HDL-C.
Changes in selected laboratory parameters will be tabulated using shift tables by NCI 
CTC criteria and categorized as low, normal, or high based on the normal ranges of the 
laboratory used for each sample.  A shift table from baseline either to the worse value 
(based on NCI CTC criteria) during treatment or to minimum and maximum value (based 
on normal range), will be created.  A similar shift table will be provided to summarize 
shifts from baseline to the final post-baseline value.
Laboratory abnormalities meeting CTC criteria grade 3 or 4 will be summarized.
 


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The number and percentage of subjects meeting the following sponsor-defined potentially 
clinically significant lipid values will be summarized at baseline and each relevant visit by 
treatment group in the appropriate Treatment Period:
●
Total cholesterol:  ≤ 300, > 300 – ≤ 400, > 400 – ≤ 500, and > 500 mg/dL
●
HDL-C:  < 40 and ≥ 40 mg/dL
●
LDL-C:  < 130, ≥ 130 – < 160, ≥ 160 – < 190, and ≥ 190 mg/dL
●
TG:  ≤ 150, > 150 – ≤ 300, > 300 – ≤ 500, > 500 – ≤ 1000, and > 1000 mg/dL
●
LDL-C/HDL-C ratio:  ≤ 3, and > 3
●
Total cholesterol/HDL-C ratio:  ≤ 4.5, and > 4.5
In addition, the number and percentage of subjects who have potentially clinically 
significant (PCS) lipid values meeting the following criteria any time during the 
appropriate Treatment Period will be summarized by treatment group.  Listings will be 
provided to summarize subject-level laboratory data for subjects meeting PCS criteria.
●
Total cholesterol > 200 mg/dL
●
LDL-C > 130 mg/dL
●
LDL-C > 160 mg/dL
●
HDL-C < 40 mg/dL
●
TG > 150 mg/dL
●
TG/HDL-C ratio > 3.5
●
LDL-C/HDL-C ratio > 4
The following plots will be provided by treatment group for HDL-C, LDL-C, and 
triglycerides during the appropriate Treatment Period:
●
Final post-baseline lab values vs. Baseline lab values
●
Final post-baseline lab values vs. Baseline lab values for subjects with NCI 
CTC Grade 3 or 4
●
Worst post-baseline lab values vs. Baseline lab values
 


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Worst post-baseline lab values vs. Baseline lab values for subjects with NCI 
CTC Grade 3 or 4
●
Mean percent change from baseline in lipid parameters over time
In addition, plots of mean lab values over time during the Treatment Period will be 
provided for hemoglobin, total cholesterol, HDL-C, LDL-C, triglycerides, LDL-C/HDL-C 
ratio, ALT, AST, bilirubin, apolipoprotein A and apolipoprotein B.
The number and percentage of subjects in each treatment group with maximum on 
treatment laboratory values meeting the following criteria compared to the upper limit of 
normal (ULN) during the appropriate Treatment Period will be summarized to assess 
potential hepatotoxicity.
●
ALT ≥ 3 × ULN and total bilirubin ≥ 2 × ULN
●
AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN
●
ALT and AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN
●
ALT ≥ 3 × ULN and total bilirubin < 2 × ULN
●
AST ≥ 3 × ULN and total bilirubin < 2 × ULN
●
ALT and AST ≥ 3 × ULN and total bilirubin < 2 × ULN
●
ALT ≥ 3 × ULN and total bilirubin ≥ 1.5 × ULN
●
AST ≥ 3 × ULN and total bilirubin ≥ 1.5 × ULN
●
ALT and AST ≥ 3 × ULN and total bilirubin ≥ 1.5 × ULN
●
ALT ≥ 3 × ULN, ≥ 5 × ULN, ≥ 10 × ULN, ≥ 20 × ULN
●
AST ≥ 3 × ULN, ≥ 5 × ULN, ≥ 10 × ULN, ≥ 20 × ULN
●
Total bilirubin ≥ 1.5 × ULN, ≥ 2.0 × ULN
The maximum ratio relative to the ULN is used to determine if subjects met the criteria 
listed above.  The ALT, AST, and total bilirubin values do not need to be concurrent in 
order to meet the defined criteria.  For ALT, AST, and total bilirubin, a subject is counted 
if the post-baseline laboratory value during the Treatment Period meets the above criteria 
 


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regardless of Baseline laboratory value (i.e., the post-baseline laboratory value does not 
need to be worse than Baseline laboratory value).
A listing of all ALT, AST, total bilirubin, and alkaline phosphatase values will be 
provided for each subject who meets any of the criteria defined above.
The following plots will be generated:  peak AST vs. peak bilirubin; peak ALT vs. peak 
bilirubin.
9.4
Analysis of Vital Signs and Weights
Vital sign measurements of pulse rate, sitting systolic blood pressure, and sitting diastolic 
blood pressure will be summarized.
Each vital sign variable and weight will be summarized for all time points (starting with 
Baseline) with the number of non-missing observations, mean and standard deviation, 
median, minimum and maximum.  Mean change from baseline to each applicable post-
baseline visit will be summarized for each vital sign variable, with the number of 
observations, baseline mean, and visit mean.  The change from baseline mean, standard 
error, and 95% confidence interval will be presented for the mean change from baseline 
within each treatment group and difference between elagolix group and placebo.
The number and percentage of subjects who have potentially clinically significant (PCS) 
vital sign and weight values meeting the following criteria will be summarized by 
treatment group.  All increase/decrease is calculated from Baseline to a post-baseline visit 
in the Treatment Period.
●
Diastolic blood pressure
○
≤ 50 mmHg and ≥ 15 mmHg decrease
○
> 90 mmHg and ≥ 15 mmHg increase
○
≥ 100 mmHg
●
Systolic blood pressure
○
≤ 90 mmHg and ≥ 20 mmHg decrease
 


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○
≥ 140 mmHg and ≥ 20 mmHg increase
○
≥ 160 mmHg
●
Pulse rate
○
≤ 45 bpm and ≥ 15 bpm decrease
○
> 100 bpm and ≥ 15 bpm increase
○
≥ 120 bpm
●
Weight
○
≥ 5% decrease
○
≥ 7% increase.
Listings will be provided to summarize subject-level vital sign and weight data for 
subjects meeting PCS criteria.
The number and percentage of subjects who had a sustained PCS vital sign and weight 
values will be summarized by treatment group and a listing of these subjects will be 
provided.  A sustained PCS value is defined as 3 consecutive PCS values.
9.5
Other Safety Analyses
9.5.1
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS data will be summarized as observed by treatment group for the Safety 
Analysis Set.
The C-SSRS – Baseline/Screening measured at Day 1 will be considered as Baseline 
C-SSRS.  Baseline C-SSRS will be summarized.  Other analysis of C-SSRS will only 
include subjects who have at least one post-baseline C-SSRS measurement, regardless of 
whether they had a baseline C-SSRS measurement.  The number of subjects with suicidal 
ideation, suicidal behavior, and self-injurious behavior without suicidal intent at each 
scheduled assessment during the appropriate Treatment Period will be summarized.  In 
addition, this table will be repeated for providing a summary of lifetime outcomes and 
past year outcomes at screening and Day 1.  No statistical test will be performed.
 


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The number of subjects with suicide-related treatment-emergent events based on the 
C-SSRS during the appropriate Treatment Period will be summarized.  No statistical tests 
will be performed.
A listing of subjects with suicidal ideation, suicidal behavior, or self-injurious behavior 
without suicidal intent based on the C-SSRS during treatment period will be provided.
9.5.2
Bone Mineral Density
All analyses and summaries of bone mineral density (BMD) will be performed for each 
anatomic location, i.e., femoral neck, lumbar spine, and total hip.  For subjects who had a 
right-side scan performed (rare instances), their data for right femoral neck and right 
femoral total hip will be included in the analysis with the data for the left femoral neck 
and left total hip, respectively (available for the majority of subjects).  If more than 
one scan is reported for an anatomic location within an analysis window, the worse (the 
lower value) of the multiple measurements will be used for analysis for each anatomic 
location.  Unless otherwise specified, the analysis of BMD at each post-baseline visit will 
exclude subjects who switch machine manufacturer type (Lunar or Hologic).
9.5.2.1
Bone Mineral Density during the Treatment Period
BMD
A summary of continuous BMD at each scheduled assessment will be provided during the 
appropriate Treatment Period.  This summary will include the sample size, mean, SD, 
median, minimum, and maximum.  This analysis will be repeated including subjects who 
switch machine manufacturer type (Lunar or Hologic), for subjects with scans only on 
Lunar machines, and for subjects with scans only on Hologic machines.
The analysis of percent change in BMD from baseline to each relevant visit during the 
Treatment Period will be based on an ANCOVA model with treatment as the main effect 
and baseline value of corresponding parameter as a covariate.  Elagolix plus E2/NETA 
group will be compared to placebo at Months 6 and 12 during the placebo-controlled 
 


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Treatment Period.  This analysis will be repeated including subjects who switch machine 
manufacturer type (Lunar or Hologic), for subjects with scans only on Lunar machines, 
and for subjects with scans only on Hologic machines.
The number and percentage of subjects with percent change from Baseline to each 
scheduled assessment during the Treatment Period in mutually exclusive categories of 
BMD decrease:  ≤ 0%, > 0% – ≤ 1.5%, > 1.5% – ≤ 3%, > 3% – ≤ 4%, > 4% – ≤ 5%, > 5% 
– < 8%, and ≥ 8% will be summarized by treatment group.  Elagolix plus E2/NETA group 
will be compared to placebo at Months 6 and 12 during the placebo-controlled Treatment 
Period using a chi-squared test.
Cross-tabulation of the DXA scans performed versus Treatment Period completion will be 
provided after all subjects complete the Treatment Period or premature discontinue from 
the Treatment Period.
Listings of subjects meeting the following criteria during the Treatment Period will be 
provided:
●
Listing of subjects with BMD decrease ≥ 8%
In addition, the following plot will be provided as needed:
●
Percent change from Baseline to each scheduled assessment (Months 6, 12, 18, 
24, 30, 36, 42, 48) during the Treatment Period in BMD vs. Baseline BMD 
values for subjects with greater than 8% BMD decrease at any location during 
the Treatment Period.
●
Cumulative distribution function of percent change from baseline in BMD at 
each scheduled assessment (Months 6, 12, 18, 24, 30, 36, 42, 48) during the 
Treatment Period.
●
Percent change from Baseline to each scheduled assessment (Months 6, 12, 18, 
24, 30, 36, 42, 48) in BMD during the Treatment period.
 


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Z-Score and T-Score
A continuous summary of the Z-score and T-score at each scheduled assessment will be 
provided by treatment group during the Treatment Period.  This summary will include the 
sample size, mean, SD, median, minimum, and maximum.
A categorical summary of Z-score will be provided at each scheduled assessment during 
the Treatment Period for the following categories:  ≤ –2.0, > –2.0 to ≤ –1.5, > –1.5 to
≤ –1.0, and > –1.0.  A categorical summary of T-score will be provided at each scheduled 
assessment during the Treatment Period for the following categories:  ≤ –2.5, > –2.5 to
< –1.0, and ≥ –1.0.  In addition, a categorical summary of the worst Z-score and T-score 
during the Treatment Period for the above categories will be provided.
9.5.2.2
Bone Mineral Density during the Follow-up Period
BMD
A summary of continuous BMD at each scheduled assessment will be provided by 
treatment group during the Follow-up Period.  This summary will include the sample size, 
mean, SD, median, minimum, and maximum.  This analysis will be repeated including 
subjects who switch machine manufacturer type (Lunar or Hologic), for subjects with 
scans only on Lunar machines, and for subjects with scans only on Hologic machines.
The analysis of percent change in BMD from baseline to each relevant visit during the 
Follow-up Period will be based on an ANCOVA model with treatment as the main effect 
and baseline value of corresponding parameter as a covariate.  No comparison will be 
performed during the Follow-up Period.  This analysis will be repeated including subjects 
who switch machine manufacturer type (Lunar or Hologic), for subjects with scans only 
on Lunar machines, and for subjects with scans only on Hologic machines.
The analysis of percent change in BMD from baseline will be repeated for the following 
subset of subjects:
 


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●
subjects who have a Treatment Month X (e.g., Month 12) scan and a Follow-up 
Month Y (e.g., Follow-up Month 6) scan and premature discontinue prior to 
next scheduled assessments.
The number and percentage of subjects with percent change from Baseline to each 
scheduled assessment during the Follow-up Period in mutually exclusive categories of 
BMD decrease:  ≤ 0%, > 0% – ≤ 1.5%, > 1.5% – ≤ 3%, > 3% – ≤ 4%, > 4% – ≤ 5%, > 5% 
– < 8%, and ≥ 8% will be summarized by treatment group.
In addition, the number and percentage of subjects with percent change from final on-
treatment to each scheduled assessment during the Follow-up Period in mutually 
exclusive categories of BMD decrease:  ≤ 0%, > 0% – ≤ 1.5%, > 1.5% – ≤ 3%, > 3% –
≤4%, > 4% – ≤ 5%, > 5% – < 8%, and ≥ 8% will be summarized by treatment group.
For the purpose of assessing post-treatment BMD recovery, the following summaries will 
be provided.  The "recovery" statistic was defined as:
Recovery at Follow-up Month X = 100 × ((% change from baseline to final) – (% change 
from baseline to Follow-up Month X))/(% change from baseline to final)
The "recovery" statistic is the proportion of BMD decrease at the final treatment scan 
recovered at Follow-up Month X.  For example, a subject who has a change of –2% at the 
end of treatment and has a change of –1% at Follow-up Month 6 has a recovery value of 
50% at Follow-up Month 6.  This statistic will only be defined for subjects who 
experienced a decrease from baseline at final treatment.
A continuous summary of recovery at each relevant visit during the Follow-up Period will 
be provided including mean, standard deviation, median, and a within-group 95% 
confidence interval for the following subset of subjects:
●
All subjects who experienced a decrease from baseline at final treatment;
●
Subjects who premature discontinue after Month 6 and on or prior to Month 12;
 


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Subjects who premature discontinue after Month 12 and on or prior to 
Month 18;
●
Subjects who premature discontinue after Month 18 and on or prior to 
Month 24;
●
Subjects who premature discontinue after Month 24 and on or prior to 
Month 30;
●
Subjects who premature discontinue after Month 30 and on or prior to 
Month 36;
●
Subjects who premature discontinue after Month 36 and on or prior to 
Month 42;
●
Subjects who premature discontinue after Month 42 or completed the 
Treatment Period.
Additionally, the number and percentage of subjects in each of the following categories 
will be provided for the subset of subjects listed above:  < 0%, 0 – 25%, > 25 – 50%, 
> 50 – 75%, > 75 – 100%, > 100%.
Bone loss will be defined as > 3% at the spine, > 4% at the total hip, or > 5% at the 
femoral neck.  The following listings will be provided:
●
Listing of subjects with bone loss from baseline to final on-treatment visit and 
continued bone loss from final on-treatment to Follow-up visits will be 
provided.  Subjects subsequently with an increase from Follow-up Month 6 to a 
subsequent Follow-up assessment will be excluded from this listing.
In addition, the following plots will be provided:
●
Cumulative distribution function of recovery at Follow-up Month 6 and 
Follow-up Month 12.
●
Percent change from baseline to treatment and follow-up months of interest.
 


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9.5.3
Transvaginal Ultrasound
9.5.3.1
Ovarian Cysts
The presence of ovarian cysts will be noted at Baseline and each relevant post-baseline 
visit during the placebo-controlled and open-label Treatment Periods.  The ovarian 
findings included complex ovarian cyst > 3.5 cm, simple ovarian cyst > 5 cm or 
endometriomas > 3 cm.  For the Safety Analysis Set, the number and percentage of 
subjects with the pre-defined complex ovarian cysts and simple ovarian cysts will be 
summarized by treatment group at each relevant visit during the Treatment Period.
For each TAU/TVU assessment, information for ovarian findings from the cysts 
assessment may be available for more than one cyst at more than one ovary location (left 
and/or right).  The subject with multiple cyst findings was counted once in the numerator 
and denominator when reporting the number and percentage of subjects in the relevant 
category of ovarian findings.  A listing included all results across multiple cysts findings 
from multiple assessments (where available) from subjects who had ovarian findings.
9.5.3.2
Endometrial Thickness
For the Safety Analysis Set, the endometrial thickness at each relevant visit during the 
Treatment Period will be summarized with descriptive statistics.  Additionally, analysis of 
change in endometrial thickness from Baseline to each relevant visit during the Treatment 
Period will be performed.  The mean change from Baseline each relevant visit during the 
12-month placebo-controlled Treatment Period will be compared between the elagolix 
treatment group and placebo using one-way ANOVA with treatment as the main effect; 
no comparison will be conducted during the open-label Treatment period.
In addition, the number and percentage of subjects with endometrial thickness of < 8 mm, 
≥ 8 mm and ≤ 12 mm, > 12 mm and ≤ 18 mm, and > 18 mm will be summarized by 
treatment group at each relevant visit during the Treatment Period.  Elagolix group will be 
compared to placebo using a Chi-squared test during the 12-month placebo-controlled 
 


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Treatment Period.  No comparisons will be conducted during the open-label Treatment 
Period.
9.5.4
Endometrial Biopsy
For the Safety Analysis Set, the number and percentage of subjects in each category of 
endometrial biopsy results will be summarized by treatment group at each relevant visit 
during the placebo-controlled and open-label Treatment Periods.  If multiple assessments 
existed in a specific time window, all assessments will be displayed.
9.5.5
Pregnancy Results
For the Safety Analysis Set, pregnancies and outcomes will be summarized by treatment 
group for the Treatment Period (placebo-controlled and open-label) and Follow-up Period.  
Subjects with conception date by sponsor more than 30 days after the last dose of study 
drug will be included in the summaries for the Follow-up Period.
Listings will be prepared of all pregnancy test results for any subject who ever had a 
positive pregnancy test at any time point during the study.
Positive pregnancy test results (serum, urine, and both) and a listing of all positive 
pregnancy test results will be provided.
Pregnancy outcome will be summarized by treatment group.  Additionally, a listing of 
pregnancy information will be provided.  Pregnancy outcome includes:
●
Number of pregnancies
●
Live births
○
Pre-term (extremely pre-term:  < 28 weeks; very pre-term:  28 –
< 32 weeks; moderate to late preterm:  32 – < 37 weeks)
○
Term (37 – < 42 weeks)
○
Post-term (≥ 42 weeks)
●
Spontaneous abortion (< 6, 6 – 13, > 13 weeks gestation)
●
Termination of pregnancy
 


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●
Ectopic pregnancy
●
Still birth
●
Congenital anomaly
●
Lost to follow-up
●
Subjects refused to provide information
●
Other
●
Ongoing (pregnancy ongoing at end of study)
●
Maternal exposure to Elagolix/Study drug (0, > 0 – 4, > 4 – 6, > 6 – 12, 
> 12 – 23, > 23 weeks)
●
Embryo/Fetal exposure to Elagolix/Study drug assessed by the sponsor 
(0, > 0 – 4, > 4 – 6, > 6 – 12, > 12 weeks)
Annualized pregnancy rate during treatment will be reported by treatment group.  The 
annualized pregnancy rate will be calculated as
Annualized pregnancy rate = (number of pregnancies/days of exposure to treatment) 
× 365
In addition, listings of fetal/newborn, infant post-delivery assessments, and infant during 
6 – 12 month follow-up assessment will be provided.
The above information will be summarized primarily based on data collected on the 
pregnancy case report form.  Information not directly obtained from the case report form 
will use the following definitions.
Gestation day
Gestation Day 0 was calculated by subtracting the gestational age provided according to 
the first trimester ultrasound date from the first trimester ultrasound date.  If no gestational 
age was provided, it will be imputed by subtracting 14 days from the midpoint between 
the subject's last negative pregnancy test date and the date of the positive pregnancy test.
 


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Gestational age 
Gestational age at delivery was calculated from gestation Day 0 to the date of delivery.  
Gestational age at abortion was calculated from gestation Day 0 to the date of abortion.
Conception date
Conception date by sponsor was calculated from the gestational age provided from the 
first trimester ultrasound, by adding 14 days to gestation Day 0.  If no gestational age was 
provided, the conception date by sponsor was imputed as the midpoint between the 
subject's last negative pregnancy test date and the date of the positive pregnancy test.
Maternal exposure
Maternal exposure to study drug was calculated as the last dose date of study drug – the 
first dose date of study drug + 1.
Embryo/fetal exposure
Embryo/fetal exposure to study drug by sponsor was calculated from the conception date 
by site/sponsor to the date of maternal last dose of study drug.
10.0
Overall Type-I Error Control
The objective of this study is to evaluate the long-term safety and tolerability of elagolix 
300 mg BID with E2/NETA.  No primary or secondary efficacy endpoint is defined.
Since the End of 12-Month Placebo-Controlled Treatment Period analysis is the only and 
final analysis for the comparison between treatment and placebo group at 12 months of 
safety and efficacy endpoints, no additional adjustment of alpha-level is necessary.
 


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11.0
Version History
Table 1.
SAP Version History Summary
Version
Date
Summary
1.0
20 January 2021
Original version
12.0
References
1.
Miettinen O, Nurminen M.  Comparative analysis of two rates.  Stat Med.  
1985;4(2):213-26.
 


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Appendix A.
Definition of Adverse Events of Special Interest (AESI) Adverse 
Events of Special Interest
Item of Safety Interest
Method of Surveillance
Hot flashes/night sweats
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
Bone fracture CMQ
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 outcome
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
Alopecia 
Alopecia, diffuse alopecia, androgenic alopecia
Hepatic events
Drug related hepatic disorders comprehensive SMQ, Enhanced 
pharmacovigilance hepatic terms PMQ
Hormonally mediated malignancies
Breast neoplasms, malignant and unspecified SMQ
Uterine and fallopian tube neoplasms, malignant and unspecified SMQ
Ovarian neoplasms, malignant and unspecified SMQ