Clinical trial NCT03886220
Conditions: Uterine Fibroids
Keywords: Elagolix ABT-620 Uterine Fibroids Heavy Menstrual Bleeding (HMB)
Sponsor: AbbVie
Start date: 2019-04-12; Completion date: 2021-04-28
Enrollment: 82 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objective of this study is to assess safety and efficacy of elagolix compared to placebo in reducing heavy menstrual bleeding (HMB) associated with uterine fibroids in premenopausal women. The primary hypothesis is that elagolix, compared to placebo, reduces HMB associated with uterine fibroids in premenopausal women.

Detailed description:

Arms: arm 1: Elagolix 150 mg once daily (QD) arm 2: Placebo QD
Interventions: intervention 1: Elagolix intervention 2: Placebo
Intervention descriptions: intervention 1: Oral; Tablet intervention 2: Oral; Tablet

Protocol documents:
Prot_000.pdf: 
NCT03886220


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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
7
2.1
BACKGROUND AND RATIONALE
7
2.2
BENEFITS AND RISKS TO SUBJECTS
7
3
STUDY OBJECTIVES AND ENDPOINTS
8
3.1
OBJECTIVES
8
3.2
PRIMARY ENDPOINT
8
3.3
ADDITIONAL ENDPOINTS
8
3.4
SAFETY ENDPOINTS
9
3.5
PHARMACOKINETIC AND PHARMACODYNAMIC ENDPOINTS
9
3.6
BIOMARKER RESEARCH SAMPLES
9
4
INVESTIGATIONAL PLAN
9
4.1
OVERALL STUDY DESIGN AND PLAN
9
5
STUDY ACTIVITIES
12
5.1
ELIGIBILITY CRITERIA
12
5.2
CONTRACEPTION RECOMMENDATIONS
17
5.3
PROHIBITED MEDICATIONS AND THERAPY
17
5.4
PRIOR AND CONCOMITANT THERAPY
19
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
20
5.6
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY
22
5.7
STUDY DRUG
22
5.8
RANDOMIZATION/DRUG ASSIGNMENT
23
5.9
PROTOCOL DEVIATIONS
24
6
SAFETY CONSIDERATIONS
24
6.1
COMPLAINTS AND ADVERSE EVENTS
24
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
27
7.1
STATISTICAL AND ANALYTICAL PLANS
27
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7.2
DEFINITION FOR ANALYSIS POPULATIONS
28
7.3
STATISTICAL ANALYSES FOR EFFICACY
28
7.4
STATISTICAL ANALYSES FOR SAFETY
28
7.5
STATISTICAL ANALYSES FOR PHARMACOKINETICS/PHARMACODYNAMICS
29
7.6
OVERALL TYPE I ERROR CONTROL
29
7.7
SAMPLE SIZE DETERMINATION
29
8
ETHICS
29
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
29
8.2
ETHICAL CONDUCT OF THE STUDY
29
8.3
SUBJECT CONFIDENTIALITY
30
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
30
10 DATA QUALITY ASSURANCE
30
11 COMPLETION OF THE STUDY
30
12 REFERENCES
30
LIST OF TABLES
TABLE 1.
WASHOUT INTERVALS FOR EXCLUSIONARY HORMONAL/ANTI-HORMONAL THERAPY
16
TABLE 2.
PROHIBITED MEDICATIONS
18
TABLE 3.
TREATMENTS ADMINISTERED DURING THE DOUBLE-BLIND TREATMENT PERIOD
23
TABLE 4.
IDENTITY OF INVESTIGATIONAL PRODUCTS
23
LIST OF FIGURES
FIGURE 1.
STUDY M16-824 SCHEMATIC
10
LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
32
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APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
36
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
37
APPENDIX D.
STUDY ACTIVITIES SCHEDULE
38
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
44
APPENDIX F.
OPERATIONS MANUAL
45
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
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 (US).1,2  Uterine fibroids may develop in African-
American women on average 10 years earlier than in white women.3  The overall cost of symptomatic 
uterine fibroids exceeds $2 billion per year in the US.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 women.3  The most common symptom and the most common reason for hysterectomy in 
women with uterine fibroids is heavy or prolonged menstrual bleeding.  Non-bleeding symptoms, such 
as pelvic pain, are also a common reason for hysterectomy.
While there are numerous surgical options available to manage heavy bleeding or other symptoms due 
to uterine fibroids, until recently there was no Food and Drug Administration (FDA)-approved long-term 
medical treatment for symptomatic uterine fibroids.
Elagolix sodium (hereinafter "elagolix," also referred to as ABT-620) is a novel, oral, short-acting, 
nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist that competitively inhibits the GnRH 
receptors in the pituitary gland.  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.  To support long-term therapy with elagolix at 
higher doses, hormonal add-back therapy would be required to mitigate changes in bone mineral 
density (BMD) and minimize other hypoestrogenic adverse effects of estradiol (E2) suppression (e.g., hot 
flush).  A detailed discussion of the preclinical toxicology, metabolism, pharmacology, and 
pharmacokinetics (PK) of elagolix in humans and a summary of clinical studies can be found in the 
Investigator's Brochure.6
This study is being conducted to provide an option of elagolix 150 mg once daily (QD) for 
premenopausal women with HMB associated with uterine fibroids who are not suitable for or prefer not 
to use hormonal add-back therapy and/or desire an option of once a day dosing.
Clinical Hypothesis
Elagolix 150 mg QD will be effective in reducing HMB compared to placebo in premenopausal women 
with uterine fibroids.
2.2 Benefits and Risks to Subjects
Elagolix (Oriahnn®) capsules 300 mg with 1.0 mg E2 and 0.5 mg Norethindrone acetate (NETA) has been 
approved by the US FDA on 29 May 2020 for the management of HMB associated with uterine fibroids.  
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Completed Phase 2 studies and preliminary results from the Phase 3 studies of elagolix for the 
management of HMB associated with uterine fibroids show reduction in HMB in women with uterine 
fibroids compared with placebo.  The overall safety profile from Phase 2 showed elagolix is well 
tolerated.  Safety results for the Phase 3 studies in uterine fibroids are consistent with the Phase 2 safety 
results.  Elagolix 150 mg is approved for the management of moderate to severe pain associated with 
endometriosis.7  Thus, the benefit/risk profile for the study is favorable.
For further details, please see findings from completed studies, including safety data in the elagolix 
Investigator's Brochure.6
3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
To assess the safety and efficacy of elagolix 150 mg QD compared to placebo in reducing HMB 
associated with uterine fibroids in premenopausal women.  The primary hypothesis is that elagolix 150 
mg QD, compared to placebo, reduces HMB associated with uterine fibroids in premenopausal women.   
3.2 Primary Endpoint
The primary endpoint will be the proportion of subjects meeting the following conditions:
!
Menstrual blood loss (MBL) volume < 80 mL at the Final Month (the last 28 days of treatment), 
and
!
≥50% reduction in MBL volume from Baseline to the Final Month (the last 28 days of 
treatment).
3.3 Additional Endpoints
!
Proportion of subjects with suppression of bleeding at the Final Month and each month during 
the Treatment Period
!
Proportion of subjects with amenorrhea at the Final Month and each month during the 
Treatment Period
!
Change and percent change from Baseline in MBL volume at the Final Month and each month 
during the Treatment Period
!
Change and percent change from Baseline in hemoglobin concentration at each month during 
the Treatment Period 
!
Patient Global Impression of Change – Menstrual Bleeding (PGIC-MB) at each month during the 
Treatment Period
!
Change from Baseline in Uterine Fibroid Symptoms Quality of Life (UFS-QoL) at each scheduled 
assessment
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3.4 Safety Endpoints
The safety endpoints will be based on the following evaluations: physical examinations, vital signs
measurements, electrocardiogram (ECG) variables, clinical laboratory testing (including hematology, 
chemistry, urinalysis, and lipid panel), and adverse event (AE) monitoring.
3.5 Pharmacokinetic and Pharmacodynamic Endpoints
Pharmacokinetic Endpoints
Exposures of elagolix will be summarized, and elagolix concentrations may be combined with other 
studies and used to develop a population PK model.  Additional parameters may be calculated if useful 
for the interpretation of the data.
Pharmacodynamic Endpoint
Serum E2 concentrations will be determined at designated visits throughout the study and summarized.  
Additional pharmacodynamic parameters may be calculated if useful in the interpretation of the data.  
Estradiol data may be combined with data from other studies and used for exposure-response analysis.
3.6 Biomarker Research Samples
Optional samples (whole blood, serum, and plasma) will be collected at specified time points (Appendix 
D) throughout the study to evaluate known and/or novel disease-related or drug-related biomarkers.  
Types of biomarkers may include nucleic acids, proteins, lipids, and/or metabolites. The objective of 
research is to analyze samples for biomarkers that will help in the understanding of uterine fibroids, 
related conditions, response to treatment with elagolix (or similar compounds), and changes in BMD.  
Research may also include changes in epigenetics, gene expression, and proteomics that may be 
associated with uterine fibroids, related conditions, or the subject's response to treatment.  This 
research is exploratory in nature and the results may not be included with the clinical study report.  
Biomarker samples will be collected only from subjects who consent to the optional exploratory 
analyses, unless precluded by local regulations or restrictions.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a Phase 4, randomized, double-blind, 6-month placebo-controlled, parallel-group, multicenter 
study.  Premenopausal women 18 to 51 years of age with uterine fibroids and HMB, as evidenced by 
MBL > 80 mL during 1 menses in Screening as measured by the alkaline hematin method, will be 
selected for this study.  See Section 5.1 for information regarding eligibility criteria.
Once eligibility is established during the Screening Period, eligible subjects will be randomly assigned in 
the double-blind period at the baseline visit to receive either elagolix 150 mg QD or placebo in a 
2:1 ratio for 6 months.  Following the double-blind Treatment Period, there will be a 1 month Post-
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Treatment Follow-Up (PTFU) Period.  The study will be conducted in approximately 45 sites in the US 
(including Puerto Rico).
Total study duration can be up to 9 months (Screening Period of approximately 1.5 to 2.5 months prior 
to Study Day 1 [Baseline]).  The study consists of the following 4 study periods:
!
Washout Period:  up to 10 months prior to Screening (only applicable if subject is taking 
exclusionary medication at the time of consent); duration is based on the excluded medication
(Table 1).
!
Screening Period:  approximately 1.5 to 2.5 months prior to Study Day 1 (Baseline).  Screening-
related procedures to assess for eligibility must be conducted within first 1.5- to 2.5-month
duration.  However, in the event the cycle or product collection is not complete within 
2.5 months during the Screening Period, the Screening Period may be extended with prior 
approval from AbbVie therapeutic area medical director (TA MD) and would result in a longer 
duration of participation for the subject than outlined.
!
Treatment Period:  duration of 6 months (double-blind).  For all subjects who meet eligibility 
criteria during the Screening Period, each subsequent visit during the Treatment Period should 
be scheduled based on the date of the Day 1 (randomization) visit.
!
PTFU Period:  One month following the last dose of study drug.  All subjects are expected to 
enter the 1-month PTFU after completing Treatment Month 6 or once a subject prematurely 
discontinues from the treatment period.  
The schematic of the study is shown in Figure 1.  Further details regarding study procedures are located 
in Appendix F, Operations Manual.
Figure 1.
Study M16-824 Schematic
M = month; QD = once daily; PTFU = Post-Treatment Follow-up; SPCV = Screening Product Collection Visit
*
The Screening Period may be extended in certain circumstances (e.g., heavy menstrual bleeding < 80 mL) by obtaining 
sponsor approval.
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Rescreening
Subjects who screen fail for this study (Study M16-824) may be rescreened with the TA MD's approval.  
The TA MD will determine which procedures need to be repeated if the subject was a screen failure for 
this study.  The subject must re-consent and meet all eligibility criteria at the time of re-screening to 
qualify for the study.
Choice of Control Group
The control group consists of subjects randomly assigned to receive placebo.  
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All clinical and 
laboratory procedures in this study are standard and generally accepted.
For efficacy assessments, validated questionnaires will be used to query study subjects about symptoms 
that occur commonly in patients with uterine fibroids or how uterine fibroids affects daily tasks and 
activities.
Suitability of Subject Population
Premenopausal women 18 to 51 years of age with uterine fibroids who have HMB (> 80 mL during 1
menses in Screening) are selected for this study.  The lower age limit (18 years) was chosen based on the 
relative paucity of adolescent females with symptomatic uterine fibroids before 18 years of age; the 
upper age limit (51 years) 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.
Selection of Doses in the Study
The dose of elagolix 150 mg QD was selected to provide optimum efficacy while maintaining an 
acceptable safety profile in women with HMB and uterine fibroids not suitable for or prefer not to 
receive hormonal add-back therapy and/or desire an option of once a day dosing for HMB with uterine 
fibroids.
Based on preliminary integrated PK exposure-response analysis for efficacy from Phase 2 studies in 
women with HMB and uterine fibroids 
 
, elagolix 150 mg QD is predicted to provide clinically meaningful efficacy in reduction of 
HMB.  Elagolix has been evaluated extensively in women with HMB and uterine fibroids in Phase 2 
studies.  No safety signals were observed in Phase 2a and 2b studies, and safety results from Phase 2 
and Phase 3 studies show that elagolix is generally well tolerated.  Refer to the elagolix Investigator's 
Brochure for further details.
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5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.
Consent
1. Subject has voluntarily signed and dated the informed consent form (ICF), approved by an 
institutional review board (IRB)/independent ethics committee (IEC), prior to washout (if 
applicable) or initiation of any screening or study-specific procedures.
2. Table 1Subject agrees to the washout intervals for hormonal therapies, including any other 
medication that may require washout (Table 1).
3. Subject is not taking exclusionary therapies (Table 2) within the specified washout interval 
prior to the initiation of any screening procedures.
4. Subject must be willing to comply with study-related assessments and procedures and in the 
judgment the investigator is a suitable candidate for the study.
5. Subject must agree to the use of at least 2 forms of non-hormonal contraception (dual 
contraception) consistently throughout Washout (if applicable), Screening, Treatment, and PTFU 
Periods.  
6. Subject should agree to not participating in other investigational trials (drug or device) 
throughout the study.
Demographics
7. Subject is a premenopausal female, 18 to 51 years of age at the time of Screening.
8. Criterion has been removed.
9. Uterine fibroids documented by a pelvic ultrasound (transabdominal ultrasound [TAU], 
transvaginal ultrasound [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
10. HMB associated with uterine fibroids as evidenced by MBL > 80 mL during 1 menses in 
Screening as measured by the alkaline hematin method.
Laboratory Assessments and Other Tests
11. Laboratory values must meet the following criteria at Screening (unless otherwise specified):
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!
Hemoglobin ≥ 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).
!
Serum creatinine ≤ 2.0 mg/dL at Screening.
!
Aspartate aminotransferase (AST) or alanine transaminase (ALT) < 3 × times the upper limit 
of the reference range and bilirubin < 2 times the upper limit of the reference range (unless 
known diagnosis of Gilbert's disease).
!
Screening follicle-stimulating hormone (FSH) level of < 35 mIU/mL (35 IU/L).
!
Negative urine and/or serum pregnancy test(s) during the Washout (if applicable) and/or 
Screening Periods, and a negative urine pregnancy test immediately before administration 
of the first dose of study drug.
12. Subjects must not have hepatitis B nor C based on the presence of the following:
!
Hepatitis B surface antigen (HBsAg)
!
Hepatitis C virus antibody (HCV Ab) with reactive ribonucleic acid (RNA) test
13. No clinically significant abnormalities in clinical chemistry, hematology, or urinalysis 
(excluding findings associated with the disease under study such as low hemoglobin or low 
hematocrit).  Clinically significant laboratory abnormalities may be retested once prior to Day 1.  
For further retesting, contact the TA MD.
14. An adequate endometrial biopsy performed during screening or final report of endometrial 
biopsy done within 3 months prior to Screening available for Principal Investigator (PI) review 
showing no clinically significant endometrial pathology at Screening.
15. Subject ≥ 21 years of age at Screening (or age at which Papanicolaou [Pap] smears are 
routinely performed according to local or country guidelines) has a Pap smear result that meets 
eligibility criteria as indicated in Operations Manual Figure 1, Pap Test Eligibility (Operations 
Manual [Appendix F]) during Screening or within 3 months prior to Screening.
16. Subject ≥40 years of age at the time of informed consent has a normal mammogram (Breast 
Imaging Reporting and Data System [BI-RADS] Classification 1 to 3 or equivalent) during 
Screening or within 3 months prior to Screening.
17. No clinically significant abnormal ECGs during Screening.
Subject History
18. Menstrual cycles with interval of 24 to 38 days in length for the 3 consecutive months prior 
to Screening.
19. Must not have clinically significant gynecological finding from screening ultrasound or saline 
infusion sonohysterography (SIS) or MRI (if SIS is unevaluable), including:
!
Persistent simple ovarian cyst > 5 cm in longest diameter (If the pelvic ultrasound shows a 
simple ovarian cyst > 5 cm and ≤ 7 cm, an ultrasound of the ovaries may be repeated in 
approximately 4 to 6 weeks; however, the results must be evaluated prior to Day 1 and 
meet eligibility criteria.)
!
Complex ovarian cyst > 3.5 cm in diameter at longest point
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!
An endometrioma > 3.5 cm in diameter (longest diameter)
!
Large endometrial polyp (≥ 1 cm)
!
Intracavitary submucosal pedunculated fibroid
20. Must not have a myomectomy, uterine artery embolization, or high-intensity focused 
ultrasound (HIFU) within 6 months prior to Screening or an endometrial ablation within 
6 months prior to Screening.
21. Must not have active pelvic inflammatory disease.
22. Must be > 6 months post-partum, post-abortion, post-pregnancy, and post lactation at the 
time of entry into the Screening Period.
23. Must not be pregnant or breastfeeding or planning a pregnancy until completion of the 
study.
24. No diagnoses or history of:
!
Hereditary blood coagulation disorder (e.g., Von Willebrand disease, Factor V Leiden).
!
History of surgery-related severe bleeding or severe and prolonged bleeding associated with 
dental work.
!
Two separate events of blood transfusions within 9 months prior to Screening (with 
exception of transfusions associated with low hemoglobin or low hematocrit due to uterine 
fibroids) or blood transfusions within 60 days prior to Day 1.
!
Active malignancy or history of malignancy (except basal cell carcinoma of the skin) with or 
without systemic chemotherapy.
!
Documented history of a severe, life-threatening, or other significant sensitivity to any drug.
25. No osteoporosis, osteopenia, or other metabolic bone disease, including:
!
Intercurrent bone disease (e.g., osteomalacia, osteogenesis imperfecta).
!
History or presence of a condition 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.
26. No history of:
!
A newly diagnosed, clinically significant medical condition requiring therapeutic intervention 
(e.g., new onset hypertension) that has not been stabilized prior to Day 1.
!
A clinically significant medical condition anticipated to require intervention during the 
course of the study participation (e.g., anticipated major elective surgery).
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!
An unstable medical condition making the subject an unsuitable candidate for the study in 
the opinion of the investigator.
!
Any suicide attempts "ever" or subject answers "yes" to questions 4 or 5 on the suicidal 
ideation portion (referring to within the last year) of the Columbia-Suicide Severity Rating 
Scale (C-SSRS) when administered during Screening or prior to dosing on Study Day 1.
!
Drug abuse and/or alcohol abuse within 12 months prior to Screening.
!
Major depression or post-traumatic stress disorder (PTSD) episode within 2 years prior to 
Screening.
!
Other major psychiatric disorders at any time (e.g., schizophrenia, bipolar disorder).
27. No surgical history of:
!
Hysterectomy (with or without oophorectomy)
!
Bilateral oophorectomy
!
Bariatric surgical procedures of any type within 6 months prior to Screening
28. Must not be using:
!
Medications as identified inTable 1 Table 2
!
Copper intrauterine device (CU-IUD)
!
For a subject using a contraceptive sub-dermal implant or CU-IUD:
!
The contraceptive sub-dermal implant must be removed, and subject must 
complete the Washout per Table 1 and subsequently have 1 menses after 
completion of Washout.
!
The CU-IUD must be removed and subsequently have 1 menses after completion of 
Washout.
!
Levonorgestrel intra-uterine system (LNG-IUS) is allowed.  If a subject has LNG-IUS in 
place, the LNG-IUS must be in place for 6 months or longer before the subject will 
be screened, and the LNG-IUS should remain throughout the Treatment Period and 
the PTFU Month 1 visit.  If a subject does not have LNG-IUS in place at the beginning 
of Screening period or Washout Period (if applicable), therapy with LNG-IUS cannot 
be started until the subject has completed the Treatment Period and the PTFU 
Month 1 visit.
!
Systemic corticosteroids for > 14 days within 3 months prior to Screening or is likely to 
require use of systemic corticosteroids for > 7 days yearly during study participation.
!
Over-the-counter and prescription topical, inhaled, intranasal, or intra-articular 
injectable (for occasional use) corticosteroids are allowed.
29. Regarding other study participation, subjects must not be:
!
Currently participating in another investigational study (drug or device)
!
Participating in an investigational drug study (i.e., receiving or has received investigational 
product) within 1 month or 5 times the investigational drug half-life, whichever is longer, 
prior to screening procedures.
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!
If a subject has participated in an investigational trial with hormonal treatment, the 
washout interval specified in Table 1 applies.
!
Previously enrolled in either an elagolix study or a study involving another investigational 
oral GnRH antagonist within 3 months from last dose of study drug to Screening in 
Study M16-824.  May not re-enroll in this study after receiving at least 1 dose of study drug.
Table 1.
Washout Intervals for Exclusionary Hormonal/Anti-Hormonal Therapy
Therapya
Minimum 
Interval for 
Washout
Number of Mensesb
Required AFTER 
Completion of Washout 
Period (Prior to Initial 
Screening Visit)
Medroxyprogesterone acetate injection (Depo-Provera®; Sayana®)
10 months 
from injection
2 menses
GnRH antagonist and agonist (exception Synarel nasal spray and 
1-month depot is 1 month)
Selective progesterone receptor modulators (e.g., ulipristal 
acetate, vilaprisan)
3 months
1 menses
Danazol (Cyclomen®)
Aromatase inhibitors
Oral contraceptivesc
1 month
Oral, transdermal, or intravaginal estrogen preparations
Synarel® Nasal Spray
GnRH agonist – 1 month depot (e.g., Lupron Depot 3.75 mg)
Hormonal and, sub-dermal progestin implant (e.g., Nexplanon®)
1 month after 
removal
NuvaRing®
Progesterone-containing intrauterine system (if subject chooses to 
remove within 1 month of Screening)
Antifibrinolytics
2 weeks
GnRH = gonadotropin-releasing hormone; TA MD = therapeutic area MD
a.
If less than a full course of therapy is administered, the investigator should contact the AbbVie TA MD to discuss and 
confirm the required washout interval.
b.
Subjects must complete the mandatory month of washout and subsequently have a menses.  Bleeding due to withdrawal 
of the hormonal therapy cannot be considered the required menses.
c.
Levonorgestrel 1.5 mg or ulipristal acetate 30 mg will be used for emergency contraception.
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5.2 Contraception Recommendations
Subject must agree to the use of at least 2 forms of nonhormonal contraception (dual contraception) 
consistently throughout the Washout (if applicable), Screening, and Treatment Periods and through the 
end of PTFU Period.  Subjects may begin taking hormonal contraception after completing the PTFU 
Month 1 Visit and having returned to first full menses in the PTFU Period.
Acceptable methods of dual nonhormonal contraception include:
!
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 has an LNG-IUS in place at least 6 months prior to the Screening visit and remains in 
place throughout the Treatment Period and PTFU Month 1 visit.
!
Subject practices total abstinence from sexual intercourse, as the preferred lifestyle of the 
subject; periodic abstinence is not acceptable and requires dual nonhormonal contraception.
!
Subject had a bilateral tubal ligation or bilateral tubal occlusion ≥4 months prior to Screening.
!
Subject is not sexually active with men; however, periodic sexual relationship(s) with men 
requires the use of study-defined dual nonhormonal contraception.
5.3 Prohibited Medications and Therapy
The medications listed in Table 2 should not be taken during the Washout (if applicable), Screening, 
Treatment, and PTFU Periods (if applicable).
Due to the extensive list of herbal remedies and supplements, please contact the AbbVie TA MD for any 
that may be prohibited.  Generally-speaking, any supplements or herbal remedies used to treat 
premenstrual or gynecological problems, such as black cohosh, are excluded.
If a prohibited medication is used to treat an AE or a pre-existing condition other than uterine fibroids to 
prevent immediate hazard during treatment period, details must be recorded in source documents and 
the electronic case report form (eCRF).
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Information regarding potential drug interactions with elagolix can be located in the elagolix 
Investigator's Brochure.
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 entering 
Washout will be required to undergo study-specific procedures, as outlined in Appendix D, Study 
Activities.
The minimum washout intervals for hormonal medications prior to Screening are described in Table 1.  If 
the type of hormonal product and the length of Washout Period are not listed in Table 1, a washout 
duration of 5 half-lives is recommended, or consult the AbbVie TA MD.
Iron Supplementation
Excessive blood loss from heavy menses may result in iron deficiency anemia.  Anemia is defined by the 
World Health Organization (WHO) as a hemoglobin (Hgb) concentration < 12 g/dL (120 g/L) for 
nonpregnant women, 15 years of age and above, at sea level.8  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.
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 they have not required a blood transfusion within 60 days prior to Day 1.  All 
iron supplements taken during the study, from Screening through the Final Visit, must be recorded on 
the concomitant medications eCRF.
Concomitant Use of Corticosteroids and Other Medications
Chronic use (> 14 days) of systemic corticosteroids within 3 months prior to Screening through PTFU 
period is prohibited.  Short-term use (no longer than 1 week [total of 7 days] per occurrence) of systemic 
glucocorticoids/corticosteroids to manage acute conditions is allowed during the Treatment Period.  A 
maximum of 14 days over the 6-month Treatment Period is allowed during a subject's participation.  
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.
5.5 Withdrawal of Subjects and Discontinuation of Study
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 AE or noncompliance with the protocol.  
Subjects who withdraw from the study will not be replaced unless the investigator and AbbVie mutually 
agree in writing.  Subjects may voluntarily withdraw or will be withdrawn from study drug treatment 
and/or the study at any time for reasons including, but not limited to, the following:
!
The subject decides to withdraw consent for any reason.
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!
The investigator believes it is in the best interest of the subject.
!
Clinically significant deterioration of the subject's medical status as determined by the 
investigator.
!
The subject requires surgical intervention for treatment of uterine fibroids and menstrual 
bleeding or other procedures including hysterectomy, myomectomy, uterine artery 
embolization, high-intensity focused ultrasound (HIFU), endometrial ablation, dilation and 
curettage (D&C), etc. during the Treatment Period.  In the post treatment period, these 
procedures do not warrant withdrawal if performed during the PTFU Period unless a 
hysterectomy with bilateral salpingo-oophorectomy (BSO) is performed and the subject does 
not plan to use hormone replacement therapy within 1 month of the surgery date.
!
The subject becomes pregnant or has a positive serum pregnancy test.
!
The subject has ALT or AST elevation ≥ 5 × upper limit of normal (ULN), confirmed upon repeat 
testing during the Treatment Period.
!
The subject develops clinically significant gynecological findings or condition that in the 
investigator's or AbbVie TA MD's opinion would preclude the subject from continuing in the 
Treatment Period due to safety reasons.
!
If subject experiences a nontraumatic bone fracture during Treatment Period. 
!
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.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  At a minimum, 2 telephone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation.
Treatment Interruption
AbbVie or the investigator may request that a subject temporarily discontinue study drug 
administration, which will be referred to as a "treatment interruption."  The following are examples for 
reasons of treatment interruption (not all inclusive):
!
AE that, based on clinical judgment, requires temporary suspension of treatment or prevents a 
subject from taking study drug
!
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).
!
Subject forgets to take study drug, lost study drug, etc.
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If the subject has missed 10 or more consecutive days of study drug dosing, the AbbVie TA MD must be 
consulted to determine whether the subject may resume study drug administration or continue in the 
Treatment Period.
In the event a subject withdraws consent from the clinical study, biomarker research will continue 
unless the subject explicitly requests analysis to be stopped.  When AbbVie is informed that samples are 
withdrawn from research, samples will not be analyzed, no new biomarker analysis data will be 
collected, and the samples will be destroyed.  A subject may withdraw consent for optional biomarker 
research at any time and remain in the clinical study.  Data generated from clinical study and/or optional 
biomarker research, before subject withdrawal of consent, will remain part of the study results.
Study Discontinuation
AbbVie may terminate this study prematurely, either in its entirety or at any site. The investigator may 
also stop the study at his/her site if he/she has safety concerns.  If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the investigator.
5.6 Follow-Up for Subject Withdrawal from Study
To minimize missing data for efficacy and safety assessments, subjects who prematurely discontinue 
study drug treatment should complete the procedures outlined for the Premature Discontinuation visit 
(PD visit) as soon as possible, preferably within 2 to 7 days of study drug discontinuation.
Subjects should be advised on the continued scientific importance of their PTFU data even if they 
discontinue treatment with study drug early.  All subjects should have an onsite PTFU visit 30 days after 
study drug discontinuation to ensure all treatment-emergent AEs/serious adverse events (SAE) have 
been resolved.
All subjects who prematurely discontinue will enter the 1-month PTFU Period unless the subject decides 
to discontinue the study participation entirely (withdrawal of informed consent).
All attempts must be made to determine the date of the last study drug dose and the primary reason for 
discontinuation of study drug and/or study participation.  The information will be recorded on the 
appropriate eCRF page.  However, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the investigator considers necessary to treat the subject's 
condition.  Following discontinuation of study drug, the subject will be treated in accordance with the 
investigator's best clinical judgment, irrespective of whether or not the subject decides to continue 
participation in the study.
5.7 Study Drug
Eligible subjects will be randomly assigned to receive elagolix 150 mg QD or placebo for the 6-month 
double-blind Treatment Period.  The treatment administration is presented in Table 3.
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Table 3.
Treatments Administered During the Double-Blind Treatment Period
Treatment Group
Dosing Time
Elagolix Tablet
Matching Elagolix 
Placebo Tablet
Elagolix 150 mg QD
AM
1
0
Placebo
AM
0
1
QD = once daily
Double-Blind Treatment Period
The study drug, consisting of elagolix 150 mg film-coated tablets, or matching placebo film-coated 
tablets, will be supplied in a carton with 5 blister cards.  Subjects will be instructed to self-administer 
their study drug throughout the 6-month double-blind Treatment Period.  The first dose of study drug 
will be administered at the site.
Identity of Investigational Product
Information about the drug formulations to be used in this study is presented in Table 4.
Table 4.
Identity of Investigational Products
Investigational Product Active
Investigational Product Placebo
Investigational product name
Elagolix 150 mg
Matching Elagolix 150 mg placebo
Active ingredient
Elagolix 
None
Mode/Route of administration 
Oral
Oral
Formulation
RC2
RC2
Dosage form
Film-coated tablet
Film-coated tablet
Dose and units
150 mg tablet
N/A
Frequency of administration
QD
QD
Storage conditions
15° to 25°C
15° to 25°C
N/A = not applicable; QD = once daily; RC2 = roller compaction
Compliance
During the Treatment Period visits or PD 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 (Month 3 and Month 6).  The subject-reported data will be recorded in source and in the eCRF.
5.8 Randomization/Drug Assignment
All subjects will be randomly assigned to receive either elagolix 150 mg QD or placebo centrally using an 
interactive response technology (IRT).  Before the study is initiated, contact information and user 
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guidelines for IRT will be provided to each site. Study drug will be dispensed at the study visits outlined 
in Appendix D.
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.
Once the subject's eligibility has been confirmed 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 5.7 upon entry into the Day 1 to Month 6 Treatment 
Period.
Study drug must not be dispensed unless the IRT is contacted.  Study drug may only be dispensed to 
subjects enrolled in the study according to kit numbers provided by the IRT.
The randomization schedule will be computer-generated by the statistics department at AbbVie, North 
Chicago, IL, prior to the start of the study.  A copy of all of the randomization schedules will be kept by 
the statistics department at AbbVie and a copy will be forwarded to the IRT provider.
Breaking Blind
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's conditions (e.g., antidote is available).  AbbVie must then 
be notified within 24 hours after the blind is broken.  The date and reason that the blind was broken 
must be recorded in the source documents and eCRF, as applicable.
5.9 Protocol Deviations
The investigator is responsible for complying with all protocol requirements, written instructions, and 
applicable laws regarding protocol deviations.  Protocol deviations are prohibited except when 
necessary to eliminate an immediate hazard to study subjects.  If a protocol deviation occurs (or is 
identified), the investigator is responsible for notifying IEC/IRB, regulatory authorities (as applicable), 
and AbbVie.
6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
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.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
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Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 1 business day of the study site's knowledge of the event.  Product complaints occurring during 
the study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE, therefore, can 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.  Laboratory abnormalities and changes in vital signs are considered to be AEs only if they result 
in discontinuation from the study, necessitate therapeutic medical intervention, and/or if the 
investigator considers them to be AEs.
The investigators will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study.  All AEs will be followed to a satisfactory conclusion.
An elective surgery/procedure scheduled to occur during a study will not be considered an AE 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 AE.
If an AE, whether associated with study drug or not, meets any of the following criteria, it is to be 
reported to AbbVie clinical pharmacovigilance as an SAE within 24 hours of the site being made aware of 
the SAE (refer to Section 4.3 of the Operations Manual (Appendix F), for reporting details and contact 
information):
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.
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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).
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.
Serious adverse events and protocol-related nonserious AEs will be collected beginning when the 
subject signs the study-specific informed consent.  From the time of study drug administration until 
PTFU Month 1 visit, all AEs, adverse events of special interest (AESIs), and SAEs will be collected whether 
solicited or spontaneously reported by the subject.  
AbbVie will be responsible for suspected unexpected serious adverse reactions (SUSAR) reporting for 
the investigational medicinal product (IMP) in accordance with global and local requirements.
AEs will be monitored throughout the study to identify any of special interest that may indicate a trend 
or risk to subjects.
Adverse Events of Special Interest
The following AESIs will be monitored during the study:
!
Bone fractures
!
Mood and depression-related events
!
Hepatic transaminase elevations
During the study, AbbVie may require additional information on AEs, SAEs, and/or AESIs to be collected 
and recorded in the eCRF.
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Adverse Event Severity and Relationship to Study Drug
The investigator will use the following definitions to rate the severity of each AE:
Mild
The AE is transient and easily tolerated by the subject.
Moderate
The AE causes the subject discomfort and interrupts the subject's usual 
activities.
Severe
The AE causes considerable interference with the subject's usual activities 
and may be incapacitating or life threatening.
The investigator will use the following definitions to assess the relationship of the AE 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.
Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 1 working day of the 
sites being made aware of the pregnancy and study drug must be discontinued (Section 5.5).  A positive 
urine pregnancy test result must be confirmed with a quantitative serum pregnancy test.  If the subject 
has a positive serum pregnancy test during the Treatment Period, no additional study procedures will be 
conducted; however, an ultrasound examination will be performed (and read locally) as early as possible 
during the first trimester of pregnancy to assess the gestational age and document an intrauterine 
pregnancy.
Pregnancies identified during the Treatment Period, although not AEs, will be monitored for fetus, 
pregnancy, and infant outcomes.  The pregnancy outcome of an elective or spontaneous abortion, 
stillbirth or congenital anomaly is considered an SAE and must be reported to AbbVie within 24 hours of 
the site's being made aware of the event.  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.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
There will be only 1 database lock and 1 analysis after all subjects complete or prematurely discontinue 
from the study.  The statistical methods provided in this protocol will be focused on primary efficacy 
analysis.  Complete and specific details of the statistical analysis will be described in the Statistical 
Analysis Plan (SAP).  
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7.2 Definition for 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 baseline and efficacy analyses.
The Safety Analysis Set includes all randomized subjects who received at least 1 dose of study drug.  The 
data from the safety analysis set will be presented by the treatment actually received regardless of 
which treatment group was assigned at the time of randomization.  If a subject takes more than 
1 treatment, the subject will be analyzed in the safety analysis set as taking the treatment to which she 
is randomized.  All safety analyses will be performed based on Safety Analysis Set.
7.3 Statistical Analyses for Efficacy
Primary Efficacy Analysis
The primary efficacy analysis will be based on the FAS, and the primary endpoint will be the proportion 
of responders meeting the following conditions:
!
MBL volume < 80 mL at the Final Month (the last 28 days of treatment)
!
≥50% reduction in MBL volume from Baseline to Final Month (the last 28 days of treatment)
Subjects whose primary reason for prematurely discontinuing study drug is "lack of efficacy," or 
"requires surgery or invasive intervention for treatment of uterine fibroids" will be considered as non-
responders.
The primary endpoint will be analyzed using a logistic regression model including treatment as the main 
effect and baseline MBL volume as a covariate.  Missing Final Month MBL volume will be imputed using 
multiple imputation.  For subjects who prematurely discontinue the Treatment Period prior to Month 6, 
the Final Month (the last 28 days prior to and including the last dose date) will be used in the primary 
analysis.
Additional Efficacy Analyses
Details on other efficacy analyses are provided in the SAP.
7.4 Statistical Analyses for Safety
Analysis of safety parameters will include the following:
!
The number and percentage of subjects with AEs
!
A summary of laboratory values
The full list of safety endpoints and corresponding analyses will be presented in the SAP.
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7.5 Statistical Analyses for Pharmacokinetics/Pharmacodynamics
Plasma concentrations of elagolix 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 and exposure-response analyses may be conducted as appropriate.  For example, if PK 
exposures are estimated, analyses may be conducted to assess the relationship between PK parameters 
or estradiol concentrations and efficacy and safety responses.  Additional analyses will be performed if 
useful and appropriate.
7.6 Overall Type I Error Control
No multiplicity adjustment is needed for this study as there is only 1 endpoint being analyzed and there 
is only 1 analysis of this endpoint.
7.7 Sample Size Determination 
Approximately 48 subjects will be randomly assigned (in a 2:1 ratio) to receive either elagolix 150 mg QD 
(N = 32) or placebo (N = 16).  The sample size will provide at least 80% power to detect a difference 
between the elagolix 150 mg QD group and the placebo group in the percentage of subjects meeting the 
primary endpoint on MBL at the Final Month of the placebo-controlled Treatment Period, with a final 
volume < 80 mL and an improvement of ≥ 50% from Baseline, assuming response rates of 10% for the 
placebo group and 55% for the elagolix 150 mg QD group with a 2-sided α = 0.05.  The above sample size 
was calculated using nQuery Advanced 8.1.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the ICF must be 
obtained before any subject is enrolled.  Any amendment to the protocol will require review and 
approval by the IEC/IRB before the changes are implemented to the study.  In addition, all changes to 
the consent form(s) will be IEC/IRB approved.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation (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 investigator are specified in Appendix B.
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8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH good clinical practice (GCP), and applicable local regulatory 
requirement(s).
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
11
COMPLETION OF THE STUDY
The end of study is defined as the date of the last subject's last visit/last procedure.
12
REFERENCES
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 for Elagolix.
7.
ORILISSA™ (eligolix) Prescribing Information.  AbbVie Inc.  July 2018.
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8.
WHO.  Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity.  
Vitamin and Mineral Nutrition Information System.  Geneva, World Health Organization, 2011 
(WHO/NMH/NHD/MNM/11.1) (http://www.who.int/vmnis/indicators/haemoglobin.pdf, 
accessed [15 November 2018]).
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APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AE
adverse event
AESI
adverse event of special interest
AGC
atypical glandular cells
ALT
alanine aminotransferase
APSI
active pharmaceutical ingredient
ASC-H
atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion
ASC-US
atypical squamous cells of undetermined significance
AST
aspartate aminotransferase
ATEMS
AbbVie Temperature Excursion Management System
BID
twice daily
BI-RADS
Breast Imaging Reporting and Data System
BMD
bone mineral density
BSO
bilateral salpingo-oophorectomy
BUN
blood urea nitrogen
CIN
cervical intraepithelial neoplasia
COVID-19
Coronavirus disease 2019
C-SSRS
Columbia-Suicide Severity Rating Scale
CU-IUD
copper intrauterine device
CYP3A
cytochrome P450 3A
DB
double-blind
D&C
dilation and curettage
DNA
deoxyribonucleic acid
DTP
direct-to-patient
DXA
dual x-ray absorptiometry
E2
estradiol
ECC
endocervical curettage
ECG
electrocardiogram
eCRF
electronic case report form
EC/TZ
endocervical/transformational zone
FAS
full analysis set
FDA
Food and Drug Administration
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
FDC
fixed-dose capsule
FSH
follicle-stimulating hormone
GCP
good clinical practice
GnRH
gonadotropin-releasing hormone
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV Ab
hepatitis C virus antibody
HDL-C
high-density lipoprotein cholesterol
Hgb
hemoglobin
HIFU
high-intensity focused ultrasound
HMB
heavy menstrual bleeding
HPV
human papilloma virus
HSIL
high-grade squamous intraepithelial lesion 
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
independent ethics committee
IM
intramuscular
IMP
investigational medicinal product
IRB
institutional review board
IRT
interactive response technology
IU
international unit
IUD
intrauterine device
IV
intravenous
K2EDTA
potassium ethylenediaminetetraacetic acid
LDL-C
low-density lipoprotein cholesterol
LNG-IUS
levonorgestrel intrauterine system
LSIL
low-grade squamous intraepithelial lesion
M
month
MBL
menstrual blood loss
MCH
mean corpuscular hemoglobin
MCV
mean cell volume
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NETA
norethindrone acetate
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NILM
negative intraepithelial lesion or malignancy
OATP
organic anion transporting polypeptide
Pap
Papanicolaou 
PCV
Product Collection Visit
PD
premature discontinuation
PD visit
Premature Discontinuation visit
PGE1
prostaglandin E1
PGIC-MB
Patient Global Impression of Change – Menstrual Bleeding
PGIC-NBUFS
Patient Global Impression of Change - Non-Bleeding Uterine Fibroids Symptoms
PI
principal investigator
PK
pharmacokinetic
PRO
patient-reported outcome
PSQ
Physician Surgery Questionnaire
PT
post-treatment
PTFU
Post-Treatment Follow-Up
PTSD
post-traumatic stress disorder
QD
once a day
RANKL
receptor activator of nuclear factor kappa-B ligand (also known as tumor necrosis 
factor ligand)
RBC
red blood cells
RNA
ribonucleic acid
rPTH 
recombinant human parathyroid hormone
RSI
Reference Safety Information
SAE
serious adverse event
SAP
statistical analysis plan
SIS
saline infusion sonohysterography
SOC
system organ class
SPCV
Screening Product Collection Visit
SUSAR
suspected unexpected serious adverse reactions
TA MD
Therapeutic Area Medical Director
TAU
transabdominal ultrasound
TEAEs
treatment-emergent adverse events
TIBC
total iron binding capacity
TSH
thyroid-stimulating hormone
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TVU
transvaginal ultrasound
UBQ
Uterine Bleeding Questionnaire
UFS-QoL
Uterine Fibroid Symptoms Quality of Life Questionnaire
ULN
upper limit of normal
UNSCH
Unscheduled Visit
US
United States
WBC
white blood cells
WHO
World Health Organization
WO
Washout
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M16-824:  A Phase 4 Study to Evaluate the Safety and Efficacy of Elagolix for the Management 
of Heavy Menstrual Bleeding Associated with Uterine Fibroids in Premenopausal Women
Protocol Date:  12 June 2020
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site 
location.  In signing the Investigator Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
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., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
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 protocol and all of its amendments.
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. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Clinical Program Development
Medical Writing
Clinical Development
Clinical Development
Data and Statistical Sciences
Data and Statistical Sciences
Clinical Pharmacology
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APPENDIX D. STUDY ACTIVITIES SCHEDULE
The required study activities are shown in the following table.  Individual activities are described in 
detail in the Operations Manual (Appendix F).
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions 
Protocol 
Date
Version 1.0
27 November 2018
Version 2.0
28 August 2019
Version 3.0
17 October 2019
Administrative Change 1
11 May 2020
The purpose of this version is to truncate assessments in a clinically appropriate manner, as this will now 
become an exploratory study to evaluate the effectiveness of the 150 mg elagolix alone dose to reduce 
HMB associated with uterine fibroids.  Other administrative revisions and minor clerical errors were 
corrected for consistency throughout the protocol in addition to the following:
!
Removal of dual x-ray absorptiometry (DXA) scan from all timepoints in the study.  Monitoring 
of BMD in the study will not be included as part of protocol-specified procedures.   
Rationale: This study evaluates the low dose regimen of 150 mg QD for uterine fibroids 
administered for 6 months.  There is sufficient safety data for BMD at the 150 mg QD dose. 
!
Removal of the Day 1 and Month 6 pelvic ultrasound (TAU and TVU).  
Rationale:  Pelvic ultrasound will only be used to determine eligibility.  Fibroid and uterine 
volume are no longer endpoints in the study.
!
The PTFU Period was shortened from 12 months to 1 month.  
Rationale:  An extended PTFU period is no longer necessary due to removal of DXA/BMD 
assessment. 
!
Removal of secondary endpoints in the study 
Rationale:  Study changed to exploratory study.
!
Reduction of sample size from 150 to 48
Rationale:  Study changed to exploratory study.
!
Additional directions for protocol modifications related to the Coronavirus disease 2019 
(COVID-19) pandemic were added to Operations Manual Section 2.2, Section 3.7, Section 3.8, 
Section 3.11, Section 3.22, Section 3.24, and Section 6.1.  
Rationale:  To describe alternative processes that may be needed because of the COVID-19 
pandemic.
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APPENDIX F. OPERATIONS MANUAL
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-824 Version 4.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 CONTACTS
Sponsor/
Emergency 
Medical Contact
Clinical Development
AbbVie Inc.
1 North Waukegan Road 
North Chicago, IL 60064
Office:
Mobile:
Fax:
Email:
EMERGENCY 24 hour Number:  +1 (973) 784-6402
Safety Concerns
Men's and Women's Health Safety 
Team
Dept. R48S, Bldg. AP31-1
1 North Waukegan Road
North Chicago, IL 60064 
Phone:
+1 847 935-7577
Email: 
GPRD_SafetyManagement_Hormones@abbvie.com 
SAE Reporting 
outside of RAVE
Email: 
PPDINDPharmacovigilance@abbvie.com 
Fax:
1 847-938-0660
Protocol 
Deviations
Clinical Development
AbbVie Inc.
1 North Waukegan Road 
North Chicago, IL 60064
OR
AbbVie Inc.
1 North Waukegan Road
North Chicago, IL 60064
Office:
Mobile:
Fax:
Email:
Phone:
Email:
Certified Clinical 
Lab
Covance CLS
8211 SciCor Drive
Indianapolis, IN 46214
Phone:
+1 317-273-7872 
Fax:
+1 317-616-4572 
Pharmacokinetic 
(Bioanalytical) 
Lab
Bioanalysis 
Dept. R46W, Bldg AP13A
Room 2326
AbbVie Inc.
1 North Waukegan Road
North Chicago, IL 60064 
Phone:
+1 847-936-1382 
Fax:
+1 847-938-9898 
Biomarker 
Sample Lab
Genomic Technologies, Genomics 
Resource Center (GRC)
AbbVie Inc.
1 North Waukegan Road
North Chicago, IL 60064 
Phone:
Email:
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-824 Version 4.0
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TABLE OF CONTENTS
1
CONTACTS
2
2
PROTOCOL ACTIVITIES BY VISIT
5
2.1
INDIVIDUAL WASHOUT/SCREENING PERIOD VISIT ACTIVITIES
5
2.2
INDIVIDUAL TREATMENT PERIOD VISIT ACTIVITIES
7
2.3
POST-TREATMENT FOLLOW-UP VISIT ACTIVITIES
14
3
STUDY PROCEDURES
15
3.1
SUBJECT INFORMATION AND INFORMED CONSENT
15
3.2
ELIGIBILITY CRITERIA
16
3.3
MEDICAL HISTORY
16
3.4
GYNECOLOGICAL/OBSTETRICAL AND UTERINE FIBROID HISTORY
16
3.5
ADVERSE EVENT ASSESSMENT
17
3.6
PRIOR AND CONCOMITANT THERAPY
17
3.7
PATIENT-REPORTED OUTCOMES AND RATING SCALES
17
3.8
CLINICAL LABORATORY TESTS
19
3.9
PHARMACOKINETIC AND PHARMACODYNAMIC SAMPLING
21
3.10 BIOMARKER RESEARCH SAMPLING
22
3.11 CONTRACEPTION COUNSELING/DISPENSE CONTRACEPTIVES
22
3.12 HEIGHT AND WEIGHT
23
3.13 VITAL SIGNS
24
3.14 PHYSICAL EXAMINATION
24
3.15 GYNECOLOGICAL (PELVIC AND BREAST) EXAMINATION
24
3.16 PAP TEST
24
3.17 ENDOMETRIAL BIOPSY
26
3.18 12-LEAD ELECTROCARDIOGRAM
26
3.19 MAMMOGRAM
27
3.20 CENTRAL IMAGING PROCEDURES
27
3.21 COLLECTION OF SANITARY PRODUCTS
29
3.22 RETURN SANITARY PRODUCTS
29
3.23 RANDOMIZATION/DRUG ASSIGNMENT
30
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-824 Version 4.0
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3.24 DISPENSE STUDY DRUG
31
3.25 DRUG ACCOUNTABILITY
32
4
SAFETY MANUAL
32
4.1
METHODS AND TIMING OF SAFETY ASSESSMENT
32
4.2
RECORDING DATA AND ANALYSES OF SAFETY FINDINGS
33
4.3
REPORTING ADVERSE EVENTS AND INTERCURRENT ILLNESSES
33
4.4
PREGNANCY
34
5
COUNTRY-SPECIFIC REQUIREMENTS
35
5.1
SUSAR REPORTING
35
6
STUDY DRUG
35
6.1
TREATMENTS ADMINISTERED
35
6.2
PACKAGING AND LABELING
35
6.3
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS
36
6.4
SELECTION AND TIMING OF DOSE FOR EACH SUBJECT
37
7
REFERENCES
37
LIST OF TABLES
TABLE 1.
CLINICAL LABORATORY TESTS
20
TABLE 2
MENSTRUAL BLOOD LOSS VOLUME ELIGIBILITY
30
LIST OF FIGURES
FIGURE 1.
PAP TEST ELIGIBILITY
25
LIST OF APPENDICES
APPENDIX A.
REASON FOR STUDY PARTICIPATION
38
APPENDIX B.
PHYSICIAN SURGERY QUESTIONNAIRE (PSQ)
39
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-824 Version 4.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
signatories according to local requirements.  A copy of the signed informed consent 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.
Optional biomarker research samples will only be collected if the subject has voluntarily signed and 
dated a written consent form describing the exploratory research.  The written consent may be part of 
the main consent form.  If the subject does not consent to providing optional samples, the subject will 
still be allowed to participate in the study.
Information regarding benefits 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.
3.2 Eligibility Criteria
Each investigator will employ their clinical judgment in conjunction with protocol-specified eligibility 
criteria to determine if a subject is eligible for the study.  If further clarification is required, questions 
should be directed to the AbbVie Therapeutic Area Medical Director (TA MD) listed in Section 1. 
3.3 Medical 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.
3.4 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
!
Prior hormonal medications, including those taken for treatment of uterine fibroids or other 
gynecological conditions
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-824 Version 4.0
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!
Prior use of nonhormonal medications for the treatment of uterine fibroids and 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.
3.5 Adverse Event Assessment
Please refer to Section 6 of the study protocol.
3.6 Prior and Concomitant Therapy
Prior and concomitant medications will be assessed at the time points specified in Section 2 and as 
described in the protocol.
3.7 Patient-Reported Outcomes and Rating Scales
Prior to the start of the study, AbbVie and/or its designee will provide detailed instructions and training 
for study site staff administering these scales.  The objective of this training is to establish uniformity 
across sites in administration of these rating instruments.  The subjects and/or the investigator or site 
staff will complete the following questionnaires as appropriate at the time points indicated in Section 2; 
the questionnaires should be administered before any other study procedures are performed at that 
visit.  Subjects and site staff will be asked to record their responses electronically (which will then be 
entered into the electronic case report form (eCRF), as applicable).
In the event that a subject or study personnel cannot come to the site because of the COVID-19 
pandemic, patient-reported outcome entries may be administered by site staff over the phone and 
responses collected on paper (source) and transcribed into EDC or entered by site staff directly into an 
electronic system.  AbbVie should be notified.
Uterine Fibroid Symptoms Quality of Life (UFS-QoL) (4-Week Recall)
The UFS-QoL1 is a disease-specific self-administered questionnaire used to measure health-related 
quality of life in women with symptomatic uterine fibroids.  At the times specified in Section 2, each 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-824 Version 4.0
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subject will be asked to complete a modified (4-week recall) UFS-QoL Questionnaire to report fibroid-
related symptoms experienced during the previous 4 weeks.
Reason for Study Participation Questionnaire
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 (Appendix A of the Operations Manual).
Physician Surgery Questionnaire (PSQ)
Each physician will be asked to complete the 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 (Appendix B of the Operations Manual).  
Uterine Bleeding Questionnaire (UBQ)
Subjects who did not return a sanitary product collection keg (for alkaline hematin menstrual blood loss 
analysis) at applicable on-site visits (scheduled on-site visit, Product Collection Visit, Unscheduled, or the 
PD visit) during the study will be asked to indicate whether they had any uterine bleeding or spotting 
since their last study visit.  If the subject did not have uterine bleeding or spotting the site staff will 
indicate "No" on the UBQ.  If the subject did have bleeding or spotting, the subject will be asked the 
reason why they did not return sanitary product collection keg at the on-site visit.  This response will be 
recorded on the UBQ by the site staff.  Subjects who did not return the keg will be retrained on product 
collection.
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.
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS2 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 and to 
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.  Site staff will 
administer the Screening/Baseline C-SSRS questionnaire in Screening and on Day 1.  During the 
Treatment Period, site staff will administer the C-SSRS Since Last Visit questionnaire at the time points 
specified in Section 2.2.  The C-SSRS administered at the Day 1 Visit will serve as the Baseline for clinical 
assessment.
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.  In addition, any 
subject noted to have history of any suicide attempts "ever" on C-SSRS or via clinical interview, is not 
eligible for randomization.  If the subject expresses suicidal ideation or suicidal behavior on the C-SSRS 
or via clinical interview at any time during the study, the investigator should take appropriate action to 
protect the subject (including possible discontinuation from the study and referral for appropriate 
psychiatric care) and then notify the AbbVie TA MD.  
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-824 Version 4.0
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3.8 Clinical Laboratory Tests
Laboratory samples will be assessed using a certified central laboratory selected for this study.  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 12-lead ECG 
recording are conducted at a visit.  
In the event that the central laboratory cannot be used to test samples because of the COVID-19 
pandemic, samples may be obtained at a local laboratory or by a home health care service. AbbVie 
should be notified.
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.  
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 prior to Day 1 will serve as the Baseline for clinical assessment.
The central laboratory will provide the laboratory results to the investigative site where they will be 
reviewed, signed, and dated by the investigator.  The investigator will receive sponsor-defined alerts 
from the central laboratory.  For any value outside of the reference range and/or sponsor-defined alerts, 
the investigator will review and indicate on the report if the result is clinically significant or not clinically 
significant.  The investigator will evaluate clinically significant laboratory values per standard of care, 
which may include repeating the test to verify the out-of-range value.  Clinically significant laboratory 
abnormalities after randomization may be documented as AEs if they require discontinuation or at the 
discretion of the investigator (see protocol).
Samples will be obtained for the laboratory tests listed in Table 1 at the time points specified in 
Section 2.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-824 Version 4.0
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Table 1.
Clinical Laboratory Tests
Clinical Laboratory Tests
Hematology
Clinical Chemistry 
(After Minimum 8-Hour Fast)
Lipid Panel
(After Minimum 8-Hour Fast)
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 
Alanine aminotransferase 
Aspartate aminotransferase
Alkaline phosphatase
Screening only
Serum iron
Serum ferritin
Total iron binding capacity (TIBC)
Vitamin D
Low-density lipoprotein cholesterol 
(LDL-C) 
High-density lipoprotein cholesterol 
(HDL-C)
Triglycerides
Total cholesterol
Endocrine Panel (Screening Only)
Follicle-stimulating hormone 
(FSH)
Reflexive thyroid-stimulating 
hormone (TSH)
Urinalysis
Pregnancy Test
Other Tests (Screening Only)
Specific gravity
Ketones 
Protein
Blood
Glucose
pH
Serum pregnancy (only when 
urine pregnancy test is 
positive)
Hepatitis B surface antigen (HBsAg)
Hepatitis C virus antibody (HCV Ab)
Clinical Chemistry/Lipid Panel
Clinical chemistry and lipid panel samples should be obtained in the morning following an overnight fast 
(minimum of 8 hours); however, there may be circumstances when 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 nonfasting conditions.
Pregnancy Tests (Serum and Urine)
Urine pregnancy tests will be performed at the time points specified in Section 2, in all subjects 
regardless of sexual activity status or method of contraception, including subjects who are surgically 
sterilized.  
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-824 Version 4.0
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The urine pregnancy test result on Day 1 must be reviewed and confirmed to be negative prior to 
randomization.  
During treatment period, a positive urine pregnancy test result must be confirmed with a quantitative 
serum pregnancy test.  Study drug must not be dispensed if the subject has a positive urine pregnancy 
test result at any visit during the Treatment Periods (including Day 1 result).  The site will immediately 
inform the subject to discontinue study drug temporarily while the subject waits for the results of the 
serum pregnancy test.  If a serum pregnancy test result is positive, the subject will be prematurely 
discontinued from the study drug.  The site should instruct the subject to complete a Premature 
Discontinuation visit within 2 to 7 days of study drug discontinuation.  
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.  
If the subject becomes pregnant at any time after randomization up through 30 days after the last dose 
of study drug, an ultrasound examination will be performed as early as possible during the first trimester 
of pregnancy to assess the gestational age and estimated date of delivery.  Refer to Section 4.4 for 
instructions on reporting of a pregnancy to the sponsor and the required follow-up on the subject's 
fetus, pregnancy, and infant outcomes.
Urine Test for Gonorrhea and Chlamydia (Optional)
Gonorrhea and chlamydia testing can be ordered at the investigator's discretion to test for active 
gonorrhea or chlamydia before the endometrial biopsy is performed.  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 gonorrhea/chlamydia testing (per 
instructions from the central laboratory) can be performed after treatment at the investigator's 
discretion.
3.9 Pharmacokinetic and Pharmacodynamic Sampling
Blood samples for assay of elagolix, also known as pharmacokinetic samples, will be collected by 
venipuncture into 3-mL evacuated K2-ethylenediaminetetraacetic acid (K2EDTA)-containing collection 
tubes at the time points specified in Section 2.  Samples will be collected regardless of the time of last 
dose.  Sufficient blood will be collected to provide approximately 1 mL of plasma from each sample. 
Blood samples for assay of estradiol, also known as pharmacodynamic samples, will be collected by 
venipuncture into 4-mL evacuated collection tubes without anticoagulant (red cap, no gel separators to 
be used) at the time points specified in Section 2.  On Day 1, estradiol samples will be collected prior to 
dosing.  Samples collected at all visits other than Day 1 will be drawn at any time during the visit.  
Sufficient blood volume will be collected to provide approximately 1.6 mL of serum from each sample. 
The date and time of blood collections will be recorded on the Central Laboratory Requisition Form (see 
Section 5.7 of the protocol under compliance for recording the times of the last 4 doses prior to study 
visit).
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Refer to the study specific laboratory manual for detailed instructions on sample collection, 
handling/processing, and shipment.
The Bioanalysis Department at AbbVie will use validated assays to determine plasma concentrations of 
elagolix and serum concentrations of estradiol.
3.10 Biomarker Research Sampling
Optional biospecimens (whole blood, serum, and plasma) for biomarker research will be collected at the 
time points specified in Section 2.  All biomarker 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 biomarker samples and data in a 
secure storage space with adequate measures to protect confidentiality.  The samples may 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, or per local requirement.
3.11 Contraception Counseling/Dispense Contraceptives
The sponsor will train investigators and study staff on the importance of contraception in this clinical 
trial.  The investigator or designated study staff will counsel subjects (excluding those who have had a 
bilateral tubal ligation or bilateral tubal occlusion) at every on-site 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 at least 2 forms of nonhormonal contraception (dual contraception) as 
indicated in the protocol.  If a subject has used LNG-IUS at least 6 months prior to the Screening visit and 
that remains in place throughout the Treatment Period through the PTFU Month 1 visit, she is not 
required to use 2 forms of nonhormonal contraception. 
In the event that a subject or study personnel cannot come to the site for dispensing of nonhormonal 
contraceptive supplies because of the COVID-19 pandemic, nonhormonal contraceptive supplies may be 
provided to subjects via alternative means.  
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 nonhormonal 
contraception throughout her study participation.
2.
The investigator or designated study staff will counsel the subject that the study drug is not 
contraceptive, that ovulation may occur even though the study drug may have altered 
menstrual cycle patterns, and that fetal abnormalities have been reported in women who have 
received elagolix in clinical studies; however, it is unknown whether these abnormalities were 
the result of taking elagolix.
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3.
The sponsor will provide training materials to the sites for instructing subjects on the types of 
protocol-allowed contraception methods, their effectiveness, and proper use.
!
The sponsor will provide all investigative sites with a supply of materials to promote 
pregnancy prevention, including contraceptives (e.g., condoms and spermicides) to provide 
to subjects at no charge.  
!
Subjects 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 at the 
time points specified in Section 2, as necessary.  
!
The source documents will capture the date that 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 any 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.
!
For subjects who have had a bilateral tubal ligation or bilateral tubal occlusion, (including 
Essure®) or LNG-IUS, 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.
Monthly study contacts are used to promote frequent interaction with site staff and 
opportunities for continued education.
5.
At each Treatment Period visit (on-site), the proper use of contraception will be reinforced to 
address possible ineffective use and the risk of unexpected pregnancy due to unprotected 
sexual activity.
3.12 Height and Weight
Height and body weight will be measured at Screening (Section 2.1).  The subject will wear lightweight 
clothing and no shoes during weighing.  The weight measurement at Screening will serve as the Baseline 
for clinical assessment.
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3.13 Vital Signs
Vital sign determinations of systolic and diastolic blood pressure, pulse rate, and body temperature will 
be obtained at the time points specified in Section 2.  The blood pressure and heart rate measurements 
should be taken prior to scheduled blood collections (if applicable).  Subjects should be seated for a 
minimum of 5 minutes before vital signs are taken; subjects are to remain seated when vital signs are 
taken.  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. 
3.14 Physical Examination
A complete physical examination will be performed at the time points specified in Section 2.  The 
complete physical examination performed during Screening will serve as the Baseline for clinical 
assessment.  A brief, symptom-directed physical examination will be performed at the Day 1 visit.
Any significant physical examination findings after the first dose will be recorded as AE.  All findings, 
whether related to an AE or part of each subject's medical history, will be captured on the appropriate 
eCRF page.
3.15 Gynecological (Pelvic and Breast) Examination
A complete breast and pelvic examination, including external genitalia, will be performed at the time 
points specified in Section 2.  The complete breast and pelvic examination completed during Screening 
will serve as the Baseline for clinical assessment.
3.16 Pap Test
A Pap test will be performed in Subjects > 21 years of age during the Screening Period unless the Subject 
has had a Pap smear or colposcopy within 3 months of the start of Screening, and results are reviewed 
by the principal investigator and deemed to meet eligibility requirements as outlined in Figure 1, Pap 
Test Eligibility.  For those subjects who require a Pap smear during the Screening Period, the Pap test 
will be performed using the Thin Prep® Pap Test™ provided and analyzed by the central laboratory.  If 
the subject is experiencing uterine bleeding that precludes the performance of the Pap test, this 
procedure should be performed as soon as possible after the uterine bleeding has ended.  In the case of 
an unsatisfactory sample, the Pap test can be repeated.  The repeat Pap test should also be performed 
when the subject is not experiencing uterine bleeding.  In order to be enrolled in the study, the Pap test 
must meet eligibility requirements as outlined in Figure 1, Pap Test Eligibility.
Subjects who are 25 to 51 years of age, with the Pap diagnosis of atypical squamous cells of 
undetermined significance (ASC-US), or low grade squamous intraepithelial lesion (LSIL) and those 
> 30 years of age with negative intraepithelial lesion or malignancy (NILM) but absent or insufficient 
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endocervical/transformational zone (EC/TZ) component will have reflex human papillomavirus (HPV) 
testing as outlined in Figure 1.  Those with high-risk HPV, NILM with absent or insufficient EC/TZ, or LSIL 
with or without high-risk HPV will be screen failed and may undergo additional evaluation/colposcopy 
outside of the protocol per local guidelines or standard of care.
If a Subject has a colposcopy performed outside of the study, they may be rescreened if they have no 
other exclusionary criteria and has had an adequate colposcopy with a negative endocervical sample 
post colposcopy.  If biopsies are performed, they must show a histological diagnosis of cervical 
intraepithelial neoplasia (CIN) 1 or less with an adequate colposcopy and a negative endocervical sample 
post colposcopy. 
Subjects with the cytology screening result of high-grade squamous intraepithelial lesion (HSIL), atypical 
squamous cells cannot exclude HSIL (ASC-H), atypical glandular cells (AGC), or atypical endocervical cells 
are not eligible for the study.
Subjects should continue with recommended Pap testing outside of the protocol per standard of care 
and local guidelines during the study.
Figure 1.
Pap Test Eligibility
AGC = atypical glandular cells; ASC-H = atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion; 
ASC-US = atypical squamous cells of undetermined significance; CIN = cervical intraepithelial neoplasia; 
EC/TZ = endocervical/transformational zone; HPV = human papillomavirus; HSIL = high-grade squamous intraepithelial lesion; 
LSIL = low-grade squamous intraepithelial lesion; NILM = negative intraepithelial lesion or malignancy
*
If a colposcopy is performed outside the study, subject may be eligible to rescreen provided the colposcopy results show a 
histologically negative endocervical curettage (ECC), and if biopsies were performed, they must be CIN 1 or less.
#
Reflex performed only if subject is > 30 years of age.
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3.17 Endometrial Biopsy
An endometrial biopsy will be performed in all subjects during the Screening Period unless final report of 
endometrial biopsy done within 3 months of Screening are available and results are reviewed by the 
principal investigator and deemed to meet eligibility requirements.  Subjects must have a negative urine 
pregnancy test within 24 hours before undergoing the endometrial biopsy.
Instructions on endometrial biopsy collection and processing procedures for shipping will be provided by 
the central laboratory.  Sites can either use the endometrial biopsy instruments provided by the central 
laboratory or any other endometrial biopsy instruments available at the study site.
Pre-medication for the endometrial biopsy procedure is allowable and should be recorded in source 
documents and on the appropriate eCRF.  At the investigator's discretion, misoprostol for cervical 
dilatation is allowable.  
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, including SIS.
The investigator must obtain and review biopsy results from the central laboratory to ensure that 
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.  If there 
is a need for an office hysteroscopy to obtain the endometrial biopsy sample, the AbbVie TA MD 
(Section 1) should be consulted.  If biopsy needs to be repeated and SIS is pending or repeat SIS is 
requested by central reader, it is recommended that both procedures be planned together; the 
endometrial biopsy should be performed immediately after SIS.  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 be considered a screen 
failure, but may be rescreened after treatment per rescreening guidelines in the protocol.
3.18 12-Lead Electrocardiogram
12-lead ECG will be performed at the designated study visits as specified in Section 2.1.  The ECG should 
be performed prior to blood collection.
The ECGs will be evaluated by an appropriately trained physician at the site ("local reader").  The local 
reader from the site will sign and date all ECG tracings and will provide his/her global interpretation as a 
written comment on the tracing using the following categories:
!
Normal ECG
!
Abnormal ECG – not clinically significant
!
Abnormal ECG – clinically significant
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Only the local reader's evaluation of the ECG will be collected and documented in the subject's source 
folder.  The automatic machine reading (i.e., machine-generated measurements and interpretation that 
are automatically printed on the ECG tracing) will not be collected.
3.19 Mammogram
A mammogram will be obtained during Screening (only for subjects who will be 40 years of age or older 
at the time of consent) unless the subject had a mammogram performed within 3 months prior to 
Screening and results are reviewed by the principal investigator and deemed to meet eligibility 
requirements.  Local mammogram results and final interpretation must be entered into the eCRF upon 
receipt.
A local radiologist will read mammograms and that radiologist's interpretation will be used to determine 
if a subject meets eligibility criteria.
!
Subjects with normal or benign findings or Breast Imaging Reporting and Data System (BI-RADS) 
Classifications 1, 2, or 3 (via mammogram or other mode of imaging) will be eligible for the 
study.  
!
Subjects with an abnormal mammogram or BI-RADS 4, 5, or 6 will not be eligible for the study.  
If the repeat mammogram or other breast imaging results indicate further testing is required 
(e.g., breast biopsy) to rule out any potential exclusionary findings, the subject is not eligible for 
the study.  Any further imaging or testing will be performed outside of the protocol and should 
follow standard of care.  
!
If a subject's mammogram results are incomplete ([BI-RADS] 0) and need to be repeated, the 
AbbVie TA MD does not need to be contacted for approval before the repeat mammogram or 
other mode of imaging (e.g., ultrasound, spot compression) is conducted.  If results meet entry 
requirements, the subject will be allowed to continue in Screening.  
Subjects should continue with recommended mammography testing outside of the protocol per local 
guidelines and standard of care during the study.
3.20 Central Imaging Procedures
Pelvic Ultrasound:  TAU and TVU
The pelvic ultrasound (TAU, TVU, SIS) will be performed by the investigative sites' or affiliated radiology 
department.  If magnetic resonance imaging (MRI) is requested by central reader for further evaluation 
of endometrial cavity it 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 (still images and video clips as requested) should be transmitted to the central reader to 
determine eligibility for entry into the study.  
The principal investigator should review the pelvic ultrasound images or report to assess eligibility.  If no 
eligible fibroids are found on local read, the subject should be screen-failed, and no images should be 
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submitted to central reader for further assessment.  To maintain screening timelines, it is recommended 
that there be short turnaround time for local read. 
The investigator or designee is responsible for review of local ultrasound, SIS reports, and/or MRI 
images for subject safety.  Any abnormal findings that are clinically significant and that requires medical 
intervention should be reported as AE.  The interpretation of the local report and/or images will be filed 
or recorded in the subject's source documents.  Data and/or local interpretation from the local 
ultrasound and SIS images will not be recorded in the eCRF.
Central Reader 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
!
Volume of largest fibroid at Baseline in cubic centimeters
!
Uterine volume in cubic centimeters
!
Presence of ovarian cysts:  Number; size (cm); location (right/left ovary); simple/complex/corpus 
luteum
!
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 eligibility criteria based on the presence of focal intracavitary lesions including:
!
Large endometrial polyp (≥1 cm)
!
Intracavitary submucosal pedunculated fibroid (FIGO Type 0)
Subjects should have a negative urine pregnancy test within 24 hours before undergoing the SIS.  It is 
recommended that video clips be captured during SIS (see Imaging Acquisition Guidelines). 
The SIS should be performed as early as possible during the Screening Period to rule out any 
exclusionary findings.  For subjects entering Washout, a SIS will not be performed until the subject 
enters the Screening Period to limit the number of invasive procedures before her eligibility is fully 
determined.
If a subject has an endometrial polyp ≥ 1 cm and desires to have the polyp removed outside of the study 
(before 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/or uterine volume as assessed by central reader but 
do not have SIS images that adequately characterize the endometrial cavity, SIS may be repeated.  
Alternatively, an MRI may be performed in lieu of SIS if SIS cannot be performed (e.g., due to location or 
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size of fibroids) or images are unevaluable.  The AbbVie TA MD should be consulted if the investigator 
plans to perform MRI.
If SIS needs to be repeated and endometrial biopsy is pending or repeat endometrial biopsy is needed, it 
is recommended that both procedures be planned together; the endometrial biopsy be performed 
immediately after SIS.  
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).
3.21 Collection of Sanitary Products
Quantitative measurement of the volume of menstrual blood loss (MBL) will be performed using the 
alkaline hematin method.  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.  
Validated products have undergone analytical testing by the analytical lab to confirm the following 
characteristics:
!
adequate precision and accuracy of blood recovery
!
no or limited interference with the alkaline hematin method  
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
3.22 Return Sanitary Products
Subjects will be required to collect all sanitary products (with or without visible blood) on days with 
menstrual bleeding or spotting and return them to the clinical study site at visits during the Screening 
and Treatment periods of the study and at the Premature Discontinuation visit (Section 2).  There will be 
no product collection required during the Follow-up Period.  
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.
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Menstrual Cycle Product Collection Visit  
Subjects will visit the site within approximately 5 days after cessation of bleeding or spotting for 
Menstrual Cycle Product Collection Visit.  Sanitary products to measure MBL will be collected, and the 
site will submit the sanitary products to the alkaline hematin laboratory for analysis of MBL volume.  In 
addition, a venous blood sample will be obtained and sent with the collected products to the alkaline 
hematin laboratory.  It is recommended that site submit the sanitary products to alkaline hematin 
laboratory only after verifying that subject has qualifying fibroids per central reader based on the local 
ultrasound report.
In the event that a subject or study personnel cannot come to the site for venous blood sample 
collection and return of collected sanitary products because of the COVID-19 pandemic, a home health 
care service may be utilized to obtain such samples.  
If the first screening menstrual cycle does not qualify, an additional screening menstrual cycle may be 
permitted (Table 2).  Screening menstrual Cycle 1 for menstrual bleeding assessment begins with the 
first day of bleeding or spotting associated with menses.
Table 2
Menstrual Blood Loss Volume Eligibility
Screening Cycle 1 
Blood Loss
Screening Cycle 2 
Blood Loss
Eligible
> 80 mL
N/A
Yes
≤ 80 mLa
> 80 mL
Yes
N/A = not applicable
a.
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 to 80 mL may proceed 
to collect a second Screening Cycle to determine eligibility without prior approval.
Subjects will be required to collect all sanitary products from the first cycle collected in the Screening 
period continuously to the end of the placebo-controlled Treatment Period.
Subjects will return their sanitary products to the site at the scheduled on-site visit or at a Product 
Collection Visit.  A Product Collection Visit is only necessary if an on-site visit is not scheduled to occur 
within approximately 5 days after cessation of bleeding or spotting.  Sites should notify the subjects 
when to start collecting products after they are dispensed the product collection kit on site.  This 
schedule is repeated through the rest of the placebo-controlled Treatment Period.
3.23 Randomization/Drug Assignment
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 and used to identify each subject throughout the study.  
The registration of the first Screening Visit will trigger shipment of clinical drug supplies to the study site.  
Subjects will be randomly assigned by IRT to receive either elagolix 150 mg QD or placebo on Day 1; a 
unique randomization number will be provided via IRT.  
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During the Treatment Period, sites will register each onsite visit in IRT in order to obtain the appropriate 
amount of scheduled resupply 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.
All AbbVie personnel with direct oversight of the conduct and management of the trial (with the 
exception of the AbbVie Drug Supply Management Team), the investigator, study site personnel, and the 
subject will remain blinded to each subject's baseline to Month 6 treatment throughout the study.  To 
maintain the blind, the elagolix and respective matching placebo provided for the study will be identical 
in appearance.  The IRT will provide access to unblinded subject treatment information in the case of a 
medical emergency.
3.24 Dispense Study Drug
The site will dispense study drug at the time points specified in Section 2.2.  The subject will take the 
first elagolix 150 mg tablet or matching placebo at the study site on Day 1 (randomization) whether the 
subject's visit is scheduled in the morning or afternoon.  Subjects will be instructed to self-administer 
their study drug throughout the Treatment Period.
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 will be able to utilize Marken and/or another local courier for drug shipment.  AbbVie has set up an 
agreement with Marken (third-party vendor) for sites to use to ship study drug to subjects.
!
Sites will be responsible for meeting IRB reporting requirements and submitting the booking 
form (which will be provided) to the local IRB. 
The PI must discuss the DTP process with the subject: 
!
Obtain consent to provide delivery information to Marken and/or local courier and document 
this in the source.
!
Obtain consent to provide delivery information to Marken and/or local courier and document 
this in the source. 
!
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.
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3.25 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 or similar shipping document.  The shipment receipt must be 
acknowledged in IRT in order to become available for dispensing 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, clinical safety system receipt number, the number of blister cards/cartons dispensed, initials of 
person who dispensed the drug, and the date study drug was dispensed for each subject.  In addition to 
using IRT inventory, an accurate inventory of study drug can also be kept by the site.
An overall accountability of the study drug will be performed and verified by the site monitor via IRT 
throughout the study and at the study site closeout visit.  Throughout the study and upon completion or 
termination of the study, all used, unused, and unopened containers will be returned to AbbVie 
according to instructions from AbbVie.
The investigator or his/her designated representative agrees not to supply study medication to any 
persons not enrolled in the study.
4 SAFETY MANUAL
4.1 Methods and Timing of Safety Assessment
Serious adverse events (SAEs) and protocol-related nonserious AEs will be collected beginning when the 
subject signs the study-specific informed consent.  From the time of study drug administration until 
PTFU Month 1 visit, all AEs, adverse events of special interests (AESIs), and SAEs will be collected 
whether solicited or spontaneously reported by the subject.  
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examination will be performed (read locally) as early as possible during the first trimester of pregnancy 
to assess gestational age and document intrauterine pregnancy.  The following information 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.
5 COUNTRY-SPECIFIC REQUIREMENTS
5.1 SUSAR Reporting
AbbVie will be responsible for SUSAR reporting for the IMP in accordance with global and local 
guidelines and Appendix A of the investigator brochure will serve as the Reference Safety Information 
(RSI).  The RSI in effect at the start of a DSUR reporting period serves as the RSI during the reporting 
period.  For follow-up reports, the RSI in place at the time of occurrence of the "suspected" serious 
adverse reaction will be used to assess expectedness.
6 STUDY DRUG
6.1 Treatments Administered
Subjects will be centrally randomly assigned using an IRT.  Subjects randomly assigned to 1 of 
2 treatment groups in a 2:1 ratio to receive elagolix 150 mg film-coated tablet or respective matching 
placebo tablet by oral administration for 6 months in the Double-Blind Treatment Period.
The study drug will be dispensed in the form of tablets at the visits listed in Section 2.2.  Study drug 
should be taken with approximately 8 oz. (240 mL) of water without regard to food and should be taken 
at approximately the same time each morning to promote compliance.  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).
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.  Sites should not contact IRT for kit 
assignment until a subject is onsite for the visit and urine pregnancy test is negative.  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 a that a 
home urine pregnancy test was performed and the result was negative.  Study drug dispensing can then 
be undertaken as outlined in Section 3.24.
6.2 Packaging and Labeling
AbbVie will supply blinded study drug in monthly kits (i.e., cartons) for the 6-month Double-Blind 
Treatment Period.  Study drug is provided at each dispensing visit.  The study drug consists of elagolix or 
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
respective matching placebo tablets.  Each kit (carton) contains 4 weekly blister cards and 1 extra 
medication blister card.  Each kit supplies sufficient study medication for 4 weeks (28 days) of dosing, 
plus 1 week of extra medication.
Each individual blister card contains 7 tablets of elagolix or 7 tablets of matching placebo for a 7-day 
(weekly) supply of study medication.  
The kits will be assigned to a subject via IRT and will encode the appropriate study drug to be dispensed 
at the subject's corresponding study visit.
The study drug 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.
Storage and Disposition of Study Drug
Elagolix and respective matching placebo study drug must be stored at controlled temperature 15° to 
25°C (59° to 77°F).
The study drug storage temperature must be recorded on each business day.  Any temperature 
excursions must be entered into AbbVie Temperature Excursion Management System (ATEMS) 
immediately.  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.
6.3 Method of Assigning Subjects to Treatment Groups
This is a randomized, double-blind, 6-month placebo-controlled, parallel-group, multicenter study.  
Subjects randomized in the Double-Blind Treatment Period will receive elagolix 150 mg or matching 
placebo for the duration of the Treatment Period. 
At the Screening visit, all subjects will be assigned a unique subject number through the use of the IRT.  
Subjects will be randomly assigned by IRT to receive 1 of the treatments on the Day 1 visit.  For subjects 
who do not meet the study selection criteria, the site personnel must contact the IRT system and 
identify the subject as a screen failure.
Subjects who are enrolled will retain their subject number assigned at the Screening visit throughout the 
study.  After confirming that the subject has met eligibility criteria and prior to the Day 1 (initial 
randomization dose), a unique randomization number for treatment assignment will be provided via IRT. 
Contact information and user guidelines for IRT use will be provided to each site.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
6.4 Selection and Timing of Dose for Each Subject
All randomized subjects will take study drug orally once daily for the entire 6-month Treatment Period at 
the scheduled visits (Section 2.2).  For Day 1 to Month 6, subjects will take a blinded morning dose of 
elagolix (150 mg) tablet or matching placebo tablet.
7 REFERENCES
1.
Spies JB, Coyne K, Guaou Guaou N, et al.  The UFS-QoL, a new disease specific symptom and 
health-related quality of life questionnaire for leiomyomata.  Obstet and Gynecol.  
2002;99(2):290-6.
2.
Columbia-Suicide Severity Rating Scale (C-SSRS) [homepage on the Internet].  Columbia 
University Medical Center [cited March 9, 2018].  Available from:  http://cssrs.columbia.edu/.
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX A. REASON FOR STUDY PARTICIPATION
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX B. PHYSICIAN SURGERY QUESTIONNAIRE (PSQ)
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SAP_001.pdf: 
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M16-824 – Statistical Analysis Plan
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Statistical Analysis Plan for Study M16-824
Safety and Efficacy of Elagolix for the Management 
of Heavy Menstrual Bleeding Associated with 
Uterine Fibroids in Premenopausal Women
Date:  06 October 2020
Version 2.0
NCT03886220


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Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................5
2.1
Objectives and Hypotheses ........................................................................5
2.2
Study Design Overview .............................................................................6
2.3
Treatment Assignment and Blinding .........................................................7
2.4
Sample Size Determination........................................................................7
3.0
Endpoints..................................................................................8
3.1
Primary Endpoint(s)...................................................................................8
3.2
Other Efficacy Endpoint(s)........................................................................8
3.3
Safety Endpoint(s) .....................................................................................8
3.4
Additional Endpoint(s)...............................................................................9
4.0
Analysis Populations ...............................................................9
5.0
Subject Disposition..................................................................9
6.0
Study Drug Duration.............................................................10
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................10
7.1
Demographics and Baseline Characteristics............................................11
7.2
Medical History .......................................................................................12
7.3
Prior and Concomitant Medications ........................................................12
8.0
Efficacy Analyses...................................................................13
8.1
General Considerations............................................................................13
8.2
Handling of Missing Data........................................................................13
8.3
Primary Efficacy Endpoint(s) and Analyses............................................15
8.3.1
Primary Efficacy Endpoint(s) ..................................................................15
8.3.2
Handling of Missing Data for the Primary Efficacy Endpoint(s)............15
8.3.3
Primary Efficacy Analysis .......................................................................15
8.3.4
Additional Analyses of the Primary Efficacy Endpoint(s) ......................17
8.4
Additional Efficacy Analyses ..................................................................19
8.5
Efficacy Subgroup Analyses....................................................................25
9.0
Safety Analyses ......................................................................25
9.1
General Considerations............................................................................25


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9.2
Adverse Events ........................................................................................26
9.2.1
Treatment-Emergent Adverse Events ......................................................26
9.2.2
Adverse Event Overview .........................................................................26
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................27
9.2.4
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................28
9.2.5
Adverse Events of Special Interest ..........................................................28
9.3
Analysis of Laboratory Data....................................................................28
9.4
Analysis of Vital Signs ............................................................................32
9.5
Endometrial Biopsy .................................................................................33
9.6
Columbia Suicide Severity Rating Scale (C-SSRS) ................................33
9.7
Pregnancy Results....................................................................................34
10.0
Interim Analyses....................................................................34
11.0
Overall Type-I Error Control ..............................................34
12.0
Version History......................................................................35
13.0
References...............................................................................36
List of Tables
Table 1.
Monthly Analysis of Bleeding for Amenorrhea ......................................21
Table 2.
Categorical Summary of Incidence and Cumulative Incidence of 
Amenorrhea..............................................................................................22
Table 3.
SAP Version History Summary...............................................................35
List of Figures
Figure 1.
Study Schematic.........................................................................................7
List of Appendices
Appendix A.
Protocol Deviations..................................................................................37
Appendix B.
Definition of Adverse Events of Special Interest ....................................38
Appendix C.
Exceptions to Standard CTC Lab Grading Criteria for Elagolix 
Studies......................................................................................................39


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Appendix D.
Details for Historical Data Borrowing.....................................................40


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for elagolix 
Study M16-824 titled "Safety and Efficacy of Elagolix for the Management of Heavy 
Menstrual Bleeding Associated with Uterine Fibroids in Premenopausal Women."
Study M16-824 examines the efficacy and safety of elagolix for the management of heavy 
menstrual bleeding associated with uterine fibroids in premenopausal women.
The analyses of pharmacokinetic endpoints, pharmacodynamic endpoints, and biomarker 
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 9.3 (SAS 
Institute Inc., Cary, NC  27513) or later under the UNIX operating system.
This SAP includes changes to analyses based on the changes in study design and 
procedures in the protocol amendment 4.  Details are outlined in Section 13.0.
2.0
Study Design and Objectives
2.1
Objectives and Hypotheses
The objective of this study is to assess the safety and efficacy of elagolix 150 mg QD 
compared to placebo in reducing HMB associated with uterine fibroids in premenopausal 
women.
The primary hypothesis is that elagolix 150 mg QD, compared to placebo, reduces HMB 
associated with uterine fibroids in premenopausal women.


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2.2
Study Design Overview
This is a Phase 4, randomized, double-blind, 6-month placebo-controlled, parallel-group, 
multicenter study.  Premenopausal women 18 to 51 years of age with uterine fibroids and 
HMB, as evidenced by MBL > 80 mL during 1 menses in Screening as measured by the 
alkaline hematin method, will be selected for this study.
Once eligibility is established during the Screening Period, eligible subjects will be 
randomly assigned in the double-blind period at the baseline visit to receive either 
elagolix 150 mg QD or placebo in a 2:1 ratio for 6 months.  Following the double-blind 
Treatment Period, there will be a 1-month Post-Treatment Follow-Up (PTFU) Period.  
The study will be conducted in approximately 45 sites in the US (including Puerto Rico).
Total study duration, excluding the Washout Period, can be up to 9.5 months (including a 
Screening Period of approximately 1.5 to 2.5 months prior to Study Day 1 [Baseline]).  
The study consists of the following 4 study periods:
●
Washout Period:  up to 10 months prior to Screening (only applicable if subject 
is taking exclusionary medication at the time of consent).
●
Screening Period:  approximately 1.5 to 2.5 months prior to Study Day 1 
(Baseline).  
●
Treatment Period:  duration of 6 months (double-blind).  
●
PTFU Period:  One month following the last dose of study drug.  All subjects 
are expected to enter the 1-month PTFU after completing Treatment Month 6 
or once a subject prematurely discontinues from the treatment period.
The schematic of the study is shown in Figure 1.


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Figure 1.
Study Schematic
M = month; QD = once daily; PTFU = Post-Treatment Follow-up; SPCV = Screening Product Collection Visit
*
The Screening Period may be extended in certain circumstances (e.g., heavy menstrual bleeding < 80 mL) by 
obtaining sponsor approval.
2.3
Treatment Assignment and Blinding
Subjects will be randomly assigned in the double-blind period at the baseline visit to 
receive either elagolix 150 mg QD or placebo in a 2:1 ratio for 6 months.
2.4
Sample Size Determination
Approximately 48 subjects will be randomly assigned (in a 2:1 ratio) to receive either 
elagolix 150 mg QD (N = 32) or placebo (N = 16). The sample size will provide at least 
80% power to detect a difference between the elagolix 150 mg QD group and the placebo 
group in the percentage of subjects meeting the primary endpoint on MBL at the Final 
Month of the placebo-controlled Treatment Period, with a final MBL volume < 80 mL 
and a reduction in MBL volume of ≥ 50% from Baseline, assuming response rates of 10% 
for the placebo group and 55% for the elagolix 150 mg QD group with a 2-sided α = 0.05. 
The above sample size was calculated using nQuery Advanced 8.1.


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3.0
Endpoints
3.1
Primary Endpoint(s)
The primary endpoint will be the proportion of subjects meeting both of the following 
conditions:
●
Menstrual blood loss (MBL) volume < 80 mL at the Final Month (the last 
28 days of treatment), and
●
≥ 50% reduction in MBL volume from Baseline to the Final Month (the last 
28 days of treatment).
3.2
Other Efficacy Endpoint(s)
The additional efficacy endpoints are:  
●
Proportion of subjects with suppression of bleeding (as defined in Section 8.4) 
at the Final Month and each month during the Treatment Period
●
Proportion of subjects with amenorrhea (as defined in Section 8.4) at the Final 
Month and each month during the Treatment Period
●
Change and percent change from Baseline in MBL volume at the Final Month 
and each month during the Treatment Period
●
Change and percent change from Baseline in hemoglobin concentration at each 
month during the Treatment Period 
●
Patient Global Impression of Change – Menstrual Bleeding (PGIC-MB) at each 
month during the Treatment Period
●
Change from Baseline in Uterine Fibroid Symptoms Quality of Life (UFS-
QoL) at each scheduled assessment.
3.3
Safety Endpoint(s)
The safety endpoints will be based on the following evaluations:
●
Adverse events monitoring


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●
Clinical laboratory testing
●
Vital signs measurements
●
Electrocardiogram (ECG) variables
●
Columbia Suicide Severity Rating Scale (C-SSRS)
●
Pregnancy 
3.4
Additional Endpoint(s)
The analyses of pharmacokinetic endpoints, pharmacodynamic endpoints, and biomarker 
research endpoints will not be covered in this SAP.
4.0
Analysis Populations
The following population sets will be used for the analyses.
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 baseline and efficacy analyses.
The Safety Analysis Set includes all randomized subjects who received at least 1 dose of 
study drug.  The data from the safety analysis set will be presented by the treatment 
actually received regardless of which treatment group was assigned at the time of 
randomization.  If a subject takes more than 1 treatment, the subject will be analyzed in 
the safety analysis set as taking the treatment to which she is randomized.  All safety 
analyses will be performed based on Safety Analysis Set.
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 each treatment group:


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●
Subjects randomized in the study;
●
Subjects who took at least one dose of study drug;
●
Subjects who completed protocol-specified treatment;
●
Subjects who prematurely discontinued study drug (all reasons and primary 
reason);
●
Subjects in each analysis population, as applicable.
For end of study participation, the number and percentage of subjects who completed the 
protocol defined follow-up period (or did not with associated reasons) will be summarized 
overall and by treatment group.
6.0
Study Drug Duration
For the safety analysis set population, duration of treatment will be summarized for each 
treatment group and for both groups combined.  Duration of treatment is defined for each 
subject as last dose date minus first dose date + 1.  Duration of treatment will be 
summarized using the number of subjects treated, mean, standard deviation, median, 
minimum and maximum.  In addition, the number and percentage of subjects treated with 
study drug for a duration in each treatment duration interval (1 – 28 days, > 28 – 56 days, 
> 56 – 84 days, > 84 – 112 days, > 112 – 140 days, > 140 – 168 days, > 168 days) will be 
summarized.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline or disease characteristics, medical history, and prior and 
concomitant medications will be summarized for the FAS overall and by treatment group.  
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).


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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 (≤ 35, 
> 35 years), BMI (< 25, 25 – < 30, ≥ 30 kg/m2), tobacco user (current, former, never, 
unknown), and alcohol user (current, former, never, unknown).
Continuous baseline characteristics include MBL volume, hemoglobin concentration, 
International Federation of Gynecology and Obstetrics (FIGO) classification,1 fibroid and 
uterine volume.  Categorical baseline characteristics include Physician Surgery 
Questionnaire (PSQ), Reason for Study Participation Questionnaire, and hemoglobin 
concentration (≤ 10.5, > 10.5 – ≤ 12, and > 12 g/dL). 
Baseline Fibroid and Uterine Volume
Fibroid and uterine volume data will be summarized at Baseline with data as observed; 
missing data will not be imputed.  
For each subject, the fibroid with the largest volume at Baseline is considered as the 
primary fibroid for the subject.  Baseline average fibroid volume is calculated using the 
average volume of fibroids with measurements available at Baseline.
FIGO Classification 
The number and percentage of subjects with fibroids at each location (e.g., intramural, 
subserosal, submucosal non-pedunculated, and subserosal pedunculated) according to the 
FIGO classification1 will be summarized for each treatment group at Baseline.  For each 
subject, the lowest FIGO classification among all measurements of all fibroids before or 
on Day 1 (or before Day 8 if there is no measurement before or on Day 1) will be 
considered as the Baseline FIGO for the subject.


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7.2
Medical History
Medical 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 overall and by treatment group.  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).  Non-gynecological medical 
history, gynecological medical history, menstrual and obstetrical history will be 
summarized and presented separately. 
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name.  A prior 
medication is defined as any medication taken prior to the date of the first dose of study 
drug.  A concomitant medication is defined as any medication that started prior to the date 
of the first dose of study drug and continued to be taken after the first dose of study drug 
or any medication that started on or after the date of the first dose of study drug, but not 
after the date of the last dose of study drug.  A medication will be considered a 
concomitant medication where one of the following three cases occurs (1) the start date is 
missing and the end date is either after or on the first study drug dose date; (2) the start 
date is prior to or on the last dose of study drug and the end date is missing; (3) both the 
start date and the end date are missing. 
The number and percentage of subjects taking medications will be summarized by generic 
drug name based on the World Health Organization (WHO) Drug Dictionary for both 
prior and concomitant medications.


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8.0
Efficacy Analyses
8.1
General Considerations
All efficacy analyses will be conducted in the FAS Population.  All tests will be 2-sided at 
an alpha level of 0.05.
Unless otherwise specified, categorical data will be summarized by frequency and 
percentage; descriptive summaries of continuous data will display the mean, SD, median, 
minimum, and maximum.
For continuous variables, when the analyses of change and/or percent change from 
Baseline to post-baseline visit(s) are performed, the within-group change from Baseline to 
each applicable visit will be summarized by treatment group with the mean, SD (or SE), 
and 95% Confidence Intervals (CIs).  The between-group differences will be summarized 
with the mean, SE, 95% CIs, and P value when applicable.  At each post-baseline visit, 
the Baseline mean and post-baseline visit mean will be calculated for all subjects with 
baseline and post-baseline value at that visit by treatment group.
Final Month is defined as the last 28 days prior to and including the last dose day.
Unless otherwise specified, there is no hypotheses testing for efficacy endpoints in the 
Post-Treatment Follow-up Period.
Information regarding corresponding statistical methods for analyses and any additional 
statistical measures required for a specific variable/endpoint will be provided in relevant 
sections.  
8.2
Handling of Missing Data
Multiple Imputation (MI) will be used in the primary analysis for the primary endpoint.  
Missing Final Month MBL volume will be imputed using multiple imputation.  First, M
"semi complete" datasets of monthly MBL volume (Month 1 [Day 2 – Day 28], Month 2 


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[Day 29 – Day 56], Month 3 [Day 57 – Day 84], Month 4 [Day 85 – Day 112], Month 5 
[Day 113 – Day 140], and Month 6 [Day 141 – Day 168]) with monotone missing data 
pattern will be generated via MCMC option using SAS PROC MI.2  Then, for each of the 
M "semi complete" datasets with monotone missing data, a "complete" dataset of monthly 
MBL volume from Month 1 to Month 6 will be generated via MONOTONE REG option 
using SAS PROC MI.  M represents the number of imputations and we set M = 30.  The 
random seed 12345 will be used.
Mixed-Effect Model Repeat Measurement (MMRM) will be used for the analyses of 
change and percent change from Baseline in MBL volume to each month.  The repeated 
measures analysis will be conducted using a mixed model including observed 
measurements at all visits for each month being analyzed.  The mixed model includes the 
categorical fixed effects of treatment, month and treatment-by-month interaction, and the 
continuous fixed covariate of baseline measurement.  The REPEATED statement will be 
used for month in PROC MIXED with blocks in the covariance matrix identified by 
subject nested within treatment group.  An unstructured variance covariance matrix will 
be used.  Parameter estimation is based on the assumption of data being missing at 
random and using the method of restrictive maximum likelihood (REML).
Missing data will be imputed using the following methods for the sensitivity analyses of 
the primary efficacy endpoint:
●
Non-Responder Imputation (NRI):  All subjects who have missing Final Month 
MBL volume will be considered as non-responders.
●
Observed Cases (OC):  The OC analysis will not impute values for missing 
evaluations, and thus subjects who have missing Final Month MBL volume 
will be excluded from this analysis.


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8.3
Primary Efficacy Endpoint(s) and Analyses
8.3.1
Primary Efficacy Endpoint(s)
The primary endpoint is the percentage of responders, defined as subjects meeting the 
following two conditions:
●
MBL volume < 80 mL at the Final Month, and
●
50% or greater reduction in MBL volume from Baseline to the Final Month 
Subjects whose primary reason for prematurely discontinuing study drug is "lack of 
efficacy," or "requires surgery or invasive intervention for treatment of uterine fibroids" 
will be considered as non-responders.
8.3.2
Handling of Missing Data for the Primary Efficacy 
Endpoint(s)
See Section 8.2 for the handling of missing data for the primary analysis and sensitivity 
analyses for the primary efficacy endpoint.
8.3.3
Primary Efficacy Analysis
The primary analysis of the primary endpoint will be performed using the full analysis set 
population.
If a subject has missing observed Final Month MBL volume, the Final Month MBL 
volume will be imputed using multiple imputation as described in Section 8.2.
The primary analysis of the primary efficacy endpoint with multiple imputation will be 
carried out in the following steps:
1.
Multiple Imputation:  30 "complete" datasets of monthly MBL volume from 
Month 1 to Month 6 will be generated using SAS PROC MI as described above.  
The following covariates will be used in the imputation model: 
a.
Baseline MBL volume


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b.
Randomized treatment group
c.
Baseline hemoglobin 
d.
MBL volume in prior months
e.
Age of the subject at Baseline
2.
Impute Final Month MBL Volume:  In each of the 30 generated datasets, 
subject's missing Final Month MBL volume will be imputed using the MBL 
volume from the "complete" dataset with Month 1 – 6 MBL volume by looking at 
the corresponding month of the last dose day using analysis time window.  
Subjects whose last dose day are the same as Study Day 1 will have their Final 
Month MBL volume imputed using their Month 1 MBL volume.  
3.
Impute Responder Status:  The responder status (yes/no) will be derived from 
"complete" (observed or imputed) Final Month MBL volume, using the criteria as 
described in Section 8.3.1.  Subjects whose primary reason for prematurely 
discontinuing study drug is "lack of efficacy," or "requires surgery or invasive 
intervention for treatment of uterine fibroids" will be considered as non-
responders. 
4.
Analysis:  Each of the 30 imputed datasets will be analyzed separately using a 
logistic regression model including treatment as the main effect and Baseline MBL 
volume as a covariate to compare the elagolix treatment group to placebo.
5.
Pooling:  Estimates of the proportions of responders in each treatment group and 
the difference between the proportions from the 30 imputed datasets obtained from 
step 3 will be combined into one overall result using PROC MIANALYZE in 
SAS.3,4


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8.3.4
Additional Analyses of the Primary Efficacy Endpoint(s)
Sensitivity Analyses
The sensitivity analyses for the primary endpoint use different approaches to handle 
prematurely discontinued subjects, missing Final Month MBL volume, and AH data from 
validated versus unvalidated products.
The analysis set used for sensitivity analyses is the full analysis set.  Each of the following 
sensitivity analyses for the primary endpoint will be performed using a logistic regression 
model including treatment as the main effect and Baseline MBL volume as a covariate to 
compare the elagolix treatment group to placebo. 
Unless otherwise specified, subjects whose primary reason for prematurely discontinuing 
study drug is "lack of efficacy," or "requires surgery or invasive intervention for treatment 
of uterine fibroids" will be considered as non-responders. 
1.
The primary analysis will be repeated with all subjects categorized as 
responders/non-responders based on observed or imputed MBL volume data only 
(without taking into account their reasons for premature discontinuation of study 
drug).  Multiple imputation will be performed the same way as in the primary 
analysis. 
2.
Non-responder imputation (NRI):  All subjects who have missing Final Month 
MBL volume will be considered as non-responders.  No multiple imputation will 
be performed.
3.
Observed cases:  The primary analysis will be repeated with the observed Final 
Month MBL volume.  Subjects who have missing Final Month MBL volume will 
be excluded from this analysis.
4.
The primary analysis will be repeated using the total MBL volume collected from 
validated products only.  All subjects will be categorized as responders/non-
responders in the same manner as done in the primary analysis (i.e., using the 


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multiple imputation described in Section 8.3.3) with the exception that all AH data 
(including that for Baseline MBL volume) will be based on the total MBL volume 
collected from validated products only.
Additional Analyses
Each of the two response criteria that is a component of the primary endpoint, 
i.e., (1) MBL volume of < 80 mL at the Final Month; and (2) 50% or greater reduction in 
MBL volume from Baseline to the Final Month will be analyzed separately in the same 
way as for the primary analysis.  Baseline and Final Month MBL volumes obtained for 
the primary analysis via MI will be used.  The number and percentage of subjects meeting 
each criterion at the Final Month will be summarized by treatment group.  The 
comparison between the elagolix treatment group and placebo will be made using a 
logistic regression model including treatment as the main effect and Baseline MBL 
volume as a covariate.
Besides the method in the primary analysis, the number and percentage of subjects 
meeting each criterion at the Final Month will also be analyzed in the same way as in each 
sensitivity analysis for the primary endpoint.
The number and percentage of subjects satisfying either (1) MBL volume < 80 mL, or 
(2) 50% or greater reduction in MBL volume from Baseline, or both will be summarized 
for every 28-day interval by treatment group based on observed MBL volume.  This 
summary will also be provided at Final Month of the Treatment Period for subjects who 
prematurely discontinue study drug due to "lack of efficacy," or "requires surgery or 
invasive intervention for treatment of uterine fibroids" as the primary reason.  Cross-
tabulation of the two bleeding criteria above for each 28-day interval in the Treatment 
Period will be provided by treatment group based on observed MBL volume.  
Plots will be provided by treatment group using the MBL volume data for the primary 
analysis (after multiple imputation):


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●
Proportion of responders at Final Month. 
Additional supportive analysis of the primary efficacy endpoint using Bayesian historical 
borrowing may be explored.  Historical data of placebo subjects from AbbVie M12-815 
and M12-817 studies may be incorporated in the analysis based on the consistency and 
similarity between historical placebo data and current placebo data. Details of the 
historical borrowing method are provided in Appendix D.
8.4
Additional Efficacy Analyses
MBL Volume
The change and percent change from Baseline to the Final Month in MBL volume 
obtained from the primary analysis after multiple imputation will be summarized by 
treatment group and compared between the elagolix treatment group and placebo, using 
one-way ANCOVA with treatment as the main effect and Baseline MBL volume as a 
covariate.  Baseline and Final Month MBL volumes obtained for the primary analysis will 
be used.
The comparison of change or percent change from Baseline in MBL volume to each 
month between the elagolix treatment group and placebo will be performed using a Mixed 
Model Repeated Measures (MMRM) model with observed MBL volume, as described in 
Section 8.2.
For the analysis above using observed MBL volume in each 28-day interval, only subjects 
who did not prematurely discontinue in or before this 28-day interval will be included.  
For example, for Study Days 29 – 56, it includes subjects who were on treatment for at 
least 56 days.
Plots will be provided by treatment group using the MBL volume data for the primary 
analysis (multiple imputation):
●
Cumulative distribution function for MBL volume at Final Month; 


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Cumulative distribution function for percent reduction from Baseline to Final 
Month in MBL volume;
●
Cumulative distribution function for reduction from baseline to Final Month in 
MBL volume.
Plots will be provided by treatment group using observed MBL volume data: 
●
Mean change from Baseline in MBL volume over time.
Amenorrhea
The number and percentage of subjects who achieve amenorrhea will be calculated for 
each treatment group.  The amenorrhea analysis includes subjects on study drug for at 
least 38 days.  For each subject, amenorrhea at the Final Month is defined as having 
0 days of bleeding or spotting during the last 28 days prior to and including the last dose 
day, with the interval starting at or beyond Study Day 11.  If a subject does not have 
evaluable AH data during the last 28 days and no bleeding or spotting or "There was no 
visible blood on the sanitary products" is indicated on UBQ, then she is considered 
amenorrheic.  The denominator will be the number of subjects with at least 38 days on 
study drug and having an amenorrhea status at the Final Month.  The number and 
percentage of subjects with amenorrhea at Final Month will be summarized by treatment 
group and compared between the elagolix treatment group and placebo using the 
Miettinen-Nurminen (M-N) method.
Time to amenorrhea is defined as the number of days from the first study drug dose date 
to the day a subject achieves amenorrhea (i.e., the day a subject achieves amenorrhea –
the first study drug dose date + 1).  For a subject who achieves amenorrhea, the day she 
achieves amenorrhea is defined as the next day of the last bleeding/spotting day during the 
Treatment Period.  The median, Q1, and Q3 of time to amenorrhea will be calculated for 
subjects who achieve amenorrhea using Kaplan-Meier method.


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In the monthly analysis of bleeding for amenorrhea, the numerator will be the number of 
subjects on treatment who do not bleed or have spotting during the specified time window 
specified in Table 1 (but may have begun bleeding or spotting thereafter) and the 
denominator will be the number of subjects on study drug for the full window and having 
an amenorrhea status for that month.  
Table 1.
Monthly Analysis of Bleeding for Amenorrhea
Time Interval
Amenorrheic Status
Month 1
(Days 2 – 28)
Subject do not bleed or have spotting during Study Days 2 – 28 
(Truncated, 27-day window)
Month 2
(Days 29 – 56)
Subject do not bleed or have spotting during Study Days 29 – 56
Month 3
(Days 57 – 84)
Subject do not bleed or have spotting during Study Days 57 – 84
Month 4
(Days 85 – 112)
Subject do not bleed or have spotting during Study Days 85 – 112
Month 5
(Days 113 – 140)
Subject do not bleed or have spotting during Study Days 113 – 140
Month 6
(Days 141 – 168)
Subject do not bleed or have spotting during Study Days 141 – 168
Final Month
(last 28 days prior to and 
including the last dose day)
Subject do not bleed or have spotting during the last 28 days prior to and 
including the last dose day
Incidence and cumulative incidence of amenorrhea by last bleeding/spotting day at each 
month will be reported using the categories specified in Table 2.
The summary will be provided including all subjects who have at least 38 days on study 
drug.  If a subject meets the criteria for amenorrhea but discontinues, this subject's 
amenorrheic status will be carried forward to the time points after the subject has 
discontinued study drug.  The denominator will be the number of subjects who have at 
least 38 days on study drug and have an amenorrhea status at Final Month.
Plots will be provided by treatment group for percentage of subjects with incidence and 
cumulative incidence of amenorrhea during the Treatment Period, respectively.


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In all the analysis for amenorrhea above, if the observed MBL volume over a window (but 
treat "Subject only had spotting that did not require the use of sanitary products" on UBQ 
the same as bleeding) is 0 mL for a subject, then the subject is considered as no 
bleeding/spotting during that interval.  Last bleeding/spotting day refers to the last day 
with observed AH data > 0 mL or the last day with UBQ indicating bleeding or spotting.
Table 2.
Categorical Summary of Incidence and Cumulative Incidence of 
Amenorrhea
Analysis
Time Interval
Numerator Calculation
Incidence
Month 2
(≤ Study Day 56)
Last bleeding/spotting day occurs during Study Days 1 – 28
Month 3
(Study Day 57 – 84)
Last bleeding/spotting day occurs during Study Days 29 – 56
Month 4
(Study Day 85 – 112)
Last bleeding/spotting day occurs during Study Days 57 – 84
Month 5
(Study Day 113 – 140)
Last bleeding/spotting day occurs during Study Days 85 – 112 
Month 6 and after
(Study Day ≥ 141)
Last bleeding/spotting day occurs after Study Day 113
Cumulative
Month 2
(≤ Study Day 56)
Last bleeding/spotting day occurs before Study Day 29
Month 3
(Study Day 57 – 84)
Last bleeding/spotting day occurs before Study Day 57
Month 4
(Study Day 85 – 112)
Last bleeding/spotting day occurs before Study Day 85
Month 5
(Study Day 113 – 140)
Last bleeding/spotting day occurs before Study Day 113
Month 6 and after
(Study Day ≥ 141)
Last bleeding/spotting day occurs after Study Day 113
Suppression of bleeding
Suppression of bleeding is defined similarly to amenorrhea except that spotting is 
allowed.  For each subject, achieving suppression of bleeding at the Final Month is 
defined as having 0 days of bleeding (spotting allowed) during the last 28 days prior to 
and including the last dose day with the interval starting at or beyond Study Day 11.  The 


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suppression of bleeding analysis includes subjects with at least 38 days on study drug.  If 
a subject does not have evaluable AH data during the last 28 days and no bleeding is 
indicated on UBQ ("Subject only had spotting that did not require the use of sanitary 
products" or "There was no visible blood on the sanitary products" is allowed), then the 
subject will be considered having achieved suppression of bleeding.  The denominator 
will be the number of subjects with at least 38 days on study drug and having a 
suppression of bleeding status at the Final Month.
The number and percentage of subjects achieving suppression of bleeding at Final Month 
will be summarized by treatment group and compared between the elagolix treatment 
group and placebo using the Miettinen-Nurminen (M-N) method. 
Time to suppression of bleeding is defined as the number of days from the first study drug 
dose date to the day a subject achieves suppression of bleeding (i.e., the day a subject 
achieves suppression of bleeding – the first study drug dose date + 1).  For a subject who 
achieves suppression of bleeding, the day she achieves suppression of bleeding is defined 
as the next day of the last bleeding day during the Treatment Period.  The median, Q1, 
and Q3 of time to suppression of bleeding will be calculated for subjects who achieve 
suppression of bleeding using Kaplan-Meier method.
Monthly analysis of bleeding for suppression of bleeding, incidence and cumulative 
incidence of suppression of bleeding will be provided in the same way as will be done for 
amenorrhea in Table 1 and Table 2.  Plots will be provided by treatment group for 
percentage of subjects with incidence and cumulative incidence of suppression of 
bleeding during the Treatment Period, respectively.
In all the analysis for suppression of bleeding above, if the observed MBL volume over a 
window is 0 mL for a subject, then the subject is considered as no bleeding during that 
interval; if the observed MBL volume over a window is > 0 mL but there is no single 
daily observed AH data > 2 mL, the subject is also considered as no bleeding during that 
interval.  Last bleeding day refers to the last day with observed AH data > 2 mL or the last 
day with UBQ indicating bleeding.


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Hemoglobin Concentration
Hemoglobin (Hgb) concentration data will be summarized as observed; missing data will 
not be imputed.
Baseline Hgb concentration is defined as the last measurement prior to or on the first dose 
date of study drug.  The change and percent change from Baseline in Hgb concentration to 
each of Months 1 – 6 during the Treatment Period will be analyzed with one-way 
ANCOVA with treatment group as the main effect and Baseline as a covariate.
PGIC on Menstrual Bleeding Questionnaire
For PGIC on menstrual bleeding (PGIC – MB), the number and percentage of subjects in 
each response category will be summarized at each applicable visit by treatment group.  
Missing data will not be imputed.  No statistical tests will be performed.
For PGIC – MB, the response categories of "Very Much Improved" and "Much 
Improved" will be combined and 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 each applicable visit by treatment group.  Comparisons will be made using 
the Miettinen-Nurminen (M-N) method for each applicable visit in the Treatment Period.
Uterine Fibroid Symptoms Quality of Life (UFS-QoL)
Improvement in quality of life will be assessed on the UFS-QoL Questionnaire (4-week 
recall).  The change from Baseline to each applicable visit during the Treatment Period 
will be calculated and summarized by treatment group for each of the UFS QoL subscales 
(symptom severity, concern, activities, energy/mood, control, self-conscious, and sexual 
function) and the HRQL total.  The change from Baseline to each applicable visit in the 
Treatment Period will be analyzed using ANCOVA with treatment as the main effect and 
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to placebo.  Missing items within a subscale will be handled using the methods specified 
in the UFS QoL Scoring Manual.  Missing data across visits will not be imputed.
8.5
Efficacy Subgroup Analyses
For the primary endpoint, the following subgroups will be explored to assess potential 
differences in treatment effect across subgroup levels.
●
Baseline weight (< median, ≥ median)
●
Baseline BMI (< median, ≥ median)
●
Baseline BMI (< 25 kg/ m2, 25 – < 30 kg/m2, ≥ 30 kg/m2)
●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
●
Race (Black or African American, Not Black or African American)
●
Baseline MBL volume (< median, ≥ median)
●
Baseline FIGO classification as determined by TAU/TVU (0 – 3, 4, 5 – 8)
●
Baseline uterine volume as determined by TAU/TVU (< median, ≥ median)
●
Baseline primary fibroid volume as determined by TAU/TVU (< median, 
≥median)
Within each level of a subgroup variable, the proportions of responders, difference 
between proportions, and 95% CIs will be summarized within each subgroup level.  No p-
value will be provided for subgroup analysis.  The data set after multiple imputation for 
the primary analysis as in Section 8.3.3 will be used for the subgroup analyses.  For 
Baseline BMI, in case of small sample size at a subgroup level, the level of "< 25 kg/ m2" 
and "25 – < 30 kg/m2" may be collapsed.
9.0
Safety Analyses
9.1
General Considerations
Safety data will be summarized for the Safety Analysis Set.  Safety summaries will be 
presented by treatment group.  For the safety analysis, subjects are assigned to a treatment 
group based on the treatment actually received, regardless of the treatment randomized. If 


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a subject received more than one type of study drug, safety data will be analyzed in the 
treatment group to which she was randomized to.  All safety analyses will be based on 
observed data.  For analyses of safety endpoints, subjects who are missing an evaluation 
will not be included in the analysis of that particular parameter/visit, unless otherwise 
specified.  
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 AEs are defined as any AE with the onset that is after the first dose 
of study drug.  AEs starting more than 30 days following discontinuation of study drug 
will not be included in summaries of treatment-emergent AEs.  Events where the onset 
date is the same as the study drug start date are assumed to be treatment-emergent.  All 
treatment-emergent AEs will be summarized overall, as well as by primary MedDRA 
SOC and PT.  The SOCs will be presented in alphabetical order, and the PTs will be 
presented in alphabetical order within each SOC.  The number and percentage of subjects 
experiencing treatment-emergent AEs will be summarized.
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:


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●
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
●
All deaths
9.2.3
Treatment-Emergent Adverse Events by SOC and/or 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.
When summarizing AEs by relationship or severity, if a subject has an event with 
unknown severity or relationship then the subject will be counted in the 
severity/relationship category of "unknown" even if the subject has a second occurrence 
of the same event with a severity/relationship present.  The only exception is if the subject 
has a second occurrence of the same event with the most extreme severity (i.e., "severe") 
or the most extreme relationship category (i.e., "reasonable possibility").  In this case, the 
subject will be counted under these most extreme severity/relationship categories.
In addition, treatment-emergent adverse events will be summarized by PT and sorted by 
decreasing frequency for the elagolix treatment group.


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9.2.4
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
Treatment-emergent SAEs (including deaths) and AEs leading to study drug 
discontinuation will be summarized by SOC and PT and in listing format.
A listing of all deaths will be generated. 
9.2.5
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, CMQs, or PMQs).  Adverse 
events of special interest are listed in Appendix B.
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 (e.g., 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.
Laboratory Data in the Treatment Period
Mean change from baseline to each applicable post-baseline visit will be summarized for 
selected laboratory variables, with the number of observations, baseline mean, and visit 
mean.  The change from baseline mean, standard error, and 95% confidence interval will 
be presented for the mean change from baseline within each treatment group and 
difference between treatment groups (elagolix vs. placebo).  The selected laboratory 
variables include the following:  lipid variables, liver variables (alkaline phosphatase, 


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ALT, AST, bilirubin), glucose, hemoglobin, hematocrit, platelet count, and Red Blood 
Cell (RBC) count.  For lipid variables, in addition to low-density lipoprotein cholesterol 
(LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol, and 
triglycerides (TG), 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 either by 
NCI CTC criteria or categorized as low, normal, or high based on the normal ranges of the 
laboratory used for each sample.  For those analytes that are not reflected in the NCI CTC
criteria, exceptions to standard CTC lab grading criteria for elagolix studies will be used 
as specified in Appendix C. 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 and 4 will be summarized.
The number and percentage of subjects meeting the following criteria will be summarized 
at Baseline and each applicable visit by treatment group in the Treatment Period:
●
Total cholesterol:  ≤ 300, > 300 – ≤ 400, > 400 – ≤ 500, and > 500 mg/dL
●
HDL-C:  < 40 and ≥ 40 mg/dL
●
LDL-C:  < 130, ≥ 130 – < 160, ≥ 160 – < 190, and ≥ 190 mg/dL
●
TG:  ≤ 150, > 150 – ≤ 300, > 300 – ≤ 500, > 500 – ≤ 1000, and > 1000 mg/dL
●
LDL-C/HDL-C ratio:  ≤ 3, and > 3
●
Total cholesterol/HDL-C ratio:  ≤ 4.5, and > 4.5.
Laboratory abnormalities will be evaluated based on Potentially Clinically Important 
(PCI) criteria as below.  For each laboratory PCI criterion, the number and percentage of 
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group.  Listings will be provided to summarize subject-level laboratory data for subjects 
meeting PCI criteria.
The PCI criteria for lipid parameters during the Treatment Period are:
●
Total cholesterol > 200 mg/dL
●
LDL-C > 130 mg/dL
●
LDL-C > 160 mg/dL
●
HDL-C < 40 mg/dL
●
TG > 150 mg/dL
●
TG/HDL-C ratio > 3.5
●
LDL-C/HDL-C ratio > 4.
Plots will be provided by treatment group for HDL-C, LDL-C, triglycerides, and 
hemoglobin during the Treatment Period:
●
Final post-baseline lab values vs. Baseline lab values;
●
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;
●
Worst post-baseline lab values vs. Baseline lab values for subjects with NCI 
CTC Grade 3 or 4
Plots will be provided by treatment group for HDL-C, LDL-C, and triglycerides during 
the Treatment Period:
●
Mean percent change from Baseline in lipid parameters over time.
Plots of mean lab values over time during the Treatment Period will be provided for 
hemoglobin, total cholesterol, HDL-C, LDL-C, triglycerides (TG), LDL-C/HDL-C ratio, 
ALT, AST, bilirubin, apolipoprotein A and B.


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Listings of subjects with at least one ALT/AST assessment meeting CTC grade 3 or 4 
during the Treatment Period, subjects with at least one HDL C/LDL-C/TG/total 
cholesterol assessment meeting CTC grade 3 or 4 during the Treatment Period will be 
provided.
Assessment of Hepatotoxicity
The number and percentage of subjects in each treatment group with maximum on 
treatment laboratory values meeting the following criteria compared to the upper limit of 
normal (ULN) will be summarized by treatment group during the Treatment Period 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 × ULN.
The maximum ratio relative to the ULN will be used to determine if subjects meet 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 will be counted if the post-baseline laboratory value during the Treatment Period 
meets the above criteria regardless of Baseline laboratory value (i.e., the post-baseline 
laboratory value does not need to be worse than Baseline laboratory value).


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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.
eDISH (evaluation of drug-induced serious hepatotoxicity) plots will be provided by 
treatment group for values during the Treatment Period:
●
Peak AST vs. peak bilirubin;
●
Peak ALT vs. peak bilirubin.
9.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, and body 
temperature will be summarized.
Each vital sign variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum.  Mean change from baseline to each applicable post-baseline 
visit will be summarized for 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 treatment groups (elagolix vs. placebo).
The number and percentage of subjects who have PCS vital sign values meeting the 
following criteria will be summarized by treatment group and a listing of these subjects 
will be provided.  All increase/decrease will be calculated from Baseline to a post-
baseline visit in the Treatment Period.
The number and percentage of subjects who have a sustained PCS vital sign value 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 in the Treatment Period.
●
Diastolic blood pressure
○
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○
> 90 mmHg and ≥ 15 mmHg increase
○
≥ 100 mmHg
●
Systolic blood pressure
○
≤ 90 mmHg and ≥ 20 mmHg decrease
○
≥ 140 mmHg and ≥ 20 mmHg increase
○
≥ 160 mmHg
●
Pulse rate
○
≤ 45 bpm and ≥ 15 bpm decrease
○
> 100 bpm and ≥ 15 bpm increase
○
≥ 120 bpm
9.5
Endometrial Biopsy
The number and percentage of subjects in each category of endometrial biopsy results will 
be summarized at Baseline by treatment group.  If multiple assessments exist for a 
subject, all assessments will be displayed.
9.6
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS data will be summarized as observed by treatment group.
The C-SSRS – Baseline/Screening measured at Day 1 will be considered as Baseline 
C-SSRS.  Baseline C-SSRS will be summarized by treatment group.  Other analyses of 
C-SSRS only include subjects who have at least 1 post-baseline C-SSRS measurement, 
regardless of whether they have a baseline C-SSRS measurement.  The number of 
subjects with suicidal ideation, suicidal behavior, and self-injurious behavior without 
suicidal intent at each scheduled assessment during Treatment Period will be 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 Treatment Period will be summarized.  No statistical test will be 
performed.
A listing of subjects with suicidal ideation, suicidal behavior, or self-injurious behavior 
without suicidal intent based on the C-SSRS during treatment period will provided.
9.7
Pregnancy Results
A listing of subjects with positive pregnancy test results during the Treatment and Post-
Treatment Follow-up Periods will be provided.  In addition, listings of pregnancy 
information, fetal/newborn, infant post-delivery assessments, and infant during 6 -
12 month follow-up assessment will be provided.
The annualized pregnancy rate during the Treatment Period will be reported by treatment 
group.
10.0
Interim Analyses
There is no interim analysis for this study.
11.0
Overall Type-I Error Control
No adjustment of the type I error rate (alpha) for primary analysis of the single primary 
endpoint is needed.


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12.0
Version History
Table 3.
SAP Version History Summary
Version
Date
Summary
1.0
02 Dec 2019
Original version
2.0
06 Oct 2020
Updates made based on protocol amendment 4 (dated 
12 Jun 2020)
!
Description of study design and objectives 
updated to match protocol 
!
Secondary efficacy endpoints removed to 
match protocol; Change and percent change 
from Baseline in fibroid and uterine volume at 
Month 6 removed from other efficacy 
endpoints since post-baseline TVU/TAU not 
performed
!
Safety endpoints updated to match protocol
!
End-of-Treatment Period analysis removed 
since not to be performed 
!
Criteria for primary efficacy endpoint updated 
to match protocol
!
Efficacy subgroup analyses updated due to 
clinical relevance of subgroup variables and 
reduced sample size  
!
Analyses for post-treatment AEs and post-
treatment labs removed since Post-Treatment 
Follow-up changed to only 1 month 
!
Analyses of bone mineral density removed 
since DXA not performed
!
Analyses of ovarian cysts and endometrial 
thickness removed since post-baseline 
TVU/TAU not performed.
Supportive analysis of the primary efficacy endpoint 
using Bayesian historical borrowing method added to 
support analysis of the primary endpoint. 
List of AESIs is updated for consistency with other 
Elagolix studies.


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13.0
References
1.
Munro MG, Critchley HO, Broder MS, et al.  FIGO Working Group on Menstrual 
Disorders.  FIGO classification system (PALM-COEIN) for causes of abnormal 
uterine bleeding in nongravid women of reproductive age.  Int J Gynaecol Obstet.  
2011;113(1):3-13.
2.
SAS Institute Inc.  2015.  SAS/STAT® 14.1 User's Guide, The MI Procedure.  
Cary, NC:  SAS Institute Inc.
3.
SAS Institute Inc.  2015.  SAS/STAT® 14.1 User's Guide, The MIANALYZE 
Procedure.  Cary, NC:  SAS Institute Inc.
4.
Ratitch B, Lipkovich I, O'Kelly M.  Combining Analysis Results from Multiply 
Imputed Categorical Data. PharmaSUG 2013-Paper SP03, 2013.
5.
Schlaff WD, Ackerman RT, Al-Hendy A, et al.  Elagolix for Heavy Menstrual 
Bleeding in Women with Uterine Fibroids.  N Engl J Med. 2020;382:328-40.
6.
Neuenschwander B, Capkun-Niggli G, Branson M, et al. Summarizing historical 
information on controls in clinical trials.  Clin Trials.  2010;7(1):5-18.
7.
DerSimonian R, Laird N.  Meta-analysis in clinical trials.  Control Clin Trials.  
1986;7(3):177-88.


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Appendix A.
Protocol Deviations
The number and percentage of subjects who reported at least one of the following 
protocol deviation categories will be provided.
●
Subject entered into the study even though she did not satisfy entry criteria.
●
Subject developed withdrawal criteria during the study and was not withdrawn.
●
Subject received wrong treatment or incorrect dose of study.
●
Subject took prohibited concomitant medication.


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Appendix B.
Definition of 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 outcomes
All pregnancies will be followed up to 6 to 12 months post-delivery 
and reviewed at least quarterly and as they occur
Obstetrical complications (maternal and 
infant)
Pregnancy, labor, and delivery complications and risk factors 
(excluding abortions and stillbirths) SMQ
Psychiatric events
Depression and suicide/self-injury SMQ
Cardiovascular events
Cardiac arrhythmias SMQ, Cardiomyopathy SMQ, 
and Ischemic heart disease SMQ
Thromboembolic events
Embolic and thrombotic events SMQ
Alopecia 
Alopecia, diffuse alopecia, androgenic alopecia
Hepatic events
Drug related hepatic disorders comprehensive SMQ, Enhanced 
pharmacovigilance hepatic terms CMQ
Hormonally mediated malignancies
Breast neoplasms, malignant and unspecified SMQ
Uterine and fallopian tube neoplasms, malignant and unspecified SMQ
Ovarian neoplasms, malignant and unspecified SMQ


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


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Appendix D.
Details for Historical Data Borrowing
For the placebo control group, historical data of the observed proportion of responders for 
the primary endpoint from appropriate studies (M12-815 (n=94, proportion of 
responders=0.074),5 M12-817 (n=88, proportion of responders=0.102)5 were used for 
meta-analysis-predictive summary.6 The meta-analytic predicted proportion of responders 
is 0.09 (95% CI [0.06, 0.14]) based on DerSimonian & Laird estimator.7  Between-trial 
variability is small, and the historical effective sample size (the maximum number of 
subjects we could borrow) is 182. 
Figure D-1.
Meta-Analysis for Historical Placebo Data
For this supportive analysis of the primary endpoint, the principle for borrowing historical 
sample size is not to exceed the total sample size in the current study while keeping 
reasonable type I error rate and power with borrowing.  Thus, for placebo control 
borrowing, assuming approximately 90% of subjects with observed primary endpoint 
data, the historical placebo borrowing sample size will not exceed 42.  
Successful hypothesis testing for the primary endpoint will be claimed from Bayesian 
approach if the posterior probability of rate difference > 0 is larger than 97.5%, i.e.,:
	
 −
 > 0 > 0.975.


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Table D-1.
Bayesian Type I Error (One-Sided) and Power for Elagolix vs. Placebo 
(sample size = 28:14, placebo arm rate = 10%, elagolix arm rate = 55%)
Control 
Rate
Bias
Error/Power
Borrowing 7 
subjects
Error/Power
Borrowing 
14 subjects
Error/Power
Borrowing 21 
subjects
Error/Power
Borrowing 28 
subjects
Error/Power
Borrowing 42 
subjects
0.055
-0.034
0.008/0.985
0.002/0.992
0.002/0.995
0.002/0.998
0.002/0.998
0.064
-0.025
0.012/0.983
0.003/0.992
0.004/0.995
0.004/0.998
0.004/0.998
0.072
-0.017
0.017/0.981
0.005/0.991
0.006/0.995
0.006/0.998
0.006/0.998
0.081
-0.008
0.022/0.979
0.007/0.991
0.009/0.995
0.009/0.998
0.009/0.998
0.089
0.000
0.028/0.977
0.010/0.991
0.013/0.995
0.013/0.998
0.013/0.999
0.098
0.009
0.033/0.976
0.014/0.991
0.018/0.996
0.019/0.998
0.019/0.999
0.106
0.017
0.038/0.974
0.017/0.991
0.023/0.996
0.025/0.998
0.025/0.999
0.115
0.026
0.043/0.973
0.022/0.991
0.030/0.996
0.033/0.999
0.033/0.999
0.123
0.034
0.046/0.971
0.026/0.991
0.036/0.996
0.040/0.999
0.041/0.999
0.132
0.043
0.050/0.970
0.031/0.991
0.044/0.996
0.050/0.999
0.050/0.999
0.140
0.051
0.053/0.969
0.036/0.991
0.051/0.997
0.059/0.999
0.060/0.999
Table D-1 shows the Bayesian type I error rate (one-sided) and power for different 
number of borrowing and different bias from -3.4% to 5.1% (corresponding to true 
unknown placebo group rate from 5.5% to 14.0%) given sample size = 28:14 (assuming 
90% of subjects with observed primary endpoint data), placebo arm rate = 10%, and 
elagolix arm rate = 55%.  With the sample size of 28:14 for elagolix and placebo 
respectively, 14 historical placebo subjects could be borrowed while controlling one-sided 
type I error rate < 2.5% (when bias is not exceeding 2.6%) and not exceeding the study 
total sample size.  For example, for true placebo arm rate =10.6%, borrowing 14 will 
control one-sided type I error rate at 1.7%.
Therefore, for this supportive analysis with historical data borrowing, we would borrow 
14 historical subjects (smaller than effective sample size 182 and the current study 
placebo assumed observed sample size 42).  Beta (1.24, 12.76), with mean 0.09, will be 
assumed as informative prior for placebo group.  For the elagolix group, a Jeffrey's prior 
for binomial distribution Beta (0.5, 0.5) will be assumed.