Clinical trial NCT03951077
Conditions: Polycystic Ovary Syndrome
Keywords: Polycystic Ovary Syndrome Hormone Elagolix
Sponsor: AbbVie
Start date: 2019-08-12; Completion date: 2021-02-10
Enrollment: 118 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will assess the potential impact of elagolix on disordered pituitary and ovarian hormones in women with polycystic ovary syndrome (PCOS).

Detailed description:
This is a phase 2, multicenter, double-blind (sponsor-unblinded), randomized, placebo-controlled study to assess the safety and efficacy of elagolix in women with PCOS. PCOS is one of the most common hormonal disorders in women of reproductive age, yet few treatment options are available. This study will help determine if elagolix can impact disordered hormonal dynamics in women with PCOS and at what dosage.

Arms: arm 1: Placebo taken orally twice a day (BID) arm 2: Elagolix 25 mg taken orally BID plus placebo arm 3: Elagolix 50 mg taken orally QD plus placebo arm 4: Elagolix 75 mg taken orally BID plus placebo arm 5: Elagolix 150 mg taken orally QD plus placebo arm 6: Elagolix 300 mg taken orally QD plus placebo
Interventions: intervention 1: Elagolix intervention 2: Placebo
Intervention descriptions: intervention 1: Capsule administered orally intervention 2: Capsule administered orally

Protocol documents:
Prot_000.pdf: 
NCT03951077


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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
KEY SECONDARY ENDPOINT
8
3.4
ADDITIONAL ENDPOINTS
8
3.5
SAFETY ENDPOINTS
9
3.6
PHARMACOKINETIC ENDPOINTS
9
3.7
PHARMACODYNAMIC ENDPOINTS
9
3.8
BIOMARKER SAMPLING
9
4
INVESTIGATIONAL PLAN
10
4.1
OVERALL STUDY DESIGN AND PLAN
10
4.2
DISCUSSION OF STUDY DESIGN
11
5
STUDY ACTIVITIES
12
5.1
ELIGIBILITY CRITERIA
12
5.2
CONTRACEPTION
17
5.3
PROHIBITED MEDICATIONS AND THERAPY
18
5.4
PRIOR AND CONCOMITANT THERAPY
21
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
21
5.6
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY
23
5.7
STUDY DRUG
23
5.8
RANDOMIZATION/DRUG ASSIGNMENT
26
5.9
PROTOCOL DEVIATIONS
26
6
SAFETY CONSIDERATIONS
27
6.1
COMPLAINTS AND ADVERSE EVENTS
27
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7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
30
7.1
STATISTICAL AND ANALYTICAL PLANS
30
7.2
DEFINITION FOR ANALYSIS POPULATIONS
30
7.3
STATISTICAL ANALYSES FOR EFFICACY
30
7.4
STATISTICAL ANALYSES FOR SAFETY
31
8
ETHICS
31
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
31
8.2
ETHICAL CONDUCT OF THE STUDY
32
8.3
SUBJECT CONFIDENTIALITY
32
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
32
10 DATA QUALITY ASSURANCE
32
11 COMPLETION OF THE STUDY
33
12 REFERENCES
33
LIST OF TABLES
TABLE 1.
WASHOUT INTERVALS FOR EXCLUSIONARY HORMONAL/ANTI-HORMONAL THERAPY
17
TABLE 2.
PROHIBITED MEDICATIONS
19
TABLE 3.
TREATMENT ADMINISTERED
24
TABLE 4.
IDENTITY OF INVESTIGATIONAL PRODUCTS
25
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
11
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
34
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
37
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APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
38
APPENDIX D.
ACTIVITY SCHEDULE
39
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
46
APPENDIX F.
OPERATIONS MANUAL
47
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine and metabolic disorder 
characterized by chronic oligo-anovulation, androgen excess, and polycystic ovaries.  Despite being 
one of the most common hormonal disorders in women of reproductive age, few therapeutic options 
are available for women with PCOS.
Elagolix sodium (hereinafter "elagolix,") is an 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.  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.1
Elagolix has the potential to improve the disordered pituitary and ovarian hormonal dynamics in women 
with PCOS.
Clinical Hypothesis
Elagolix will lower luteinizing hormone (LH) secretion while maintaining follicle-stimulating hormone 
(FSH) secretion and consequently:
1.
Lower serum testosterone concentrations
2.
Restore normal menstrual cycles in women with PCOS
3.
Improve ovulation
4.
Improve hyperandrogenic symptoms
2.2 Benefits and Risks to Subjects
Women with PCOS have symptoms of oligomenorrhea, hirsutism, and anovulation due to excess LH 
secretion.  Elagolix has the potential to improve this symptom complex by reducing LH secretion and 
potentially restoring a normal LH/FSH ratio.  Preliminary data show that at low doses of elagolix, LH is 
preferentially inhibited compared with FSH.  As of 20 August 2018, 4569 subjects have been exposed to 
elagolix; the safety profile of elagolix is well established even at doses higher than those planned for 
administration in this study.  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.1
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Considering the coronavirus disease-2019 (COVID-19) pandemic, the benefit and risk to subjects 
participating in this study has been re-evaluated.  Based on the limited information to date, no 
additional risk to study participants is anticipated with the use of elagolix.
3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
The objective of the study is to assess the PK, pharmacodynamics (PD), safety, and efficacy of elagolix in 
women with PCOS.
3.2 Primary Endpoint
The primary endpoint is the proportion of menstrual cycle responders.
3.3 Key Secondary Endpoint
Change from Baseline to Week 1 in the area under the LH serum concentration-time curve (AUC).
3.4 Additional Endpoints
1.
Proportion of complete menstrual cycle responders
2.
Change from Baseline in the LH serum AUC at each scheduled assessment during the Treatment 
Period
3.
Change from Baseline in the FSH serum AUC at each scheduled assessment during the 
Treatment Period 
4.
Change from Baseline in total and free testosterone serum concentration at each scheduled 
assessment during the Treatment Period
5.
Number of menstrual bleeding episodes during the Treatment Period
6.
Number of ovulations based on weekly serum progesterone level during the Treatment Period
7.
Proportion of subjects with at least 2 ovulations during the Treatment Period
8.
Endpoints related to hyperandrogenism – Patient Global Impression (PGI) for both acne and 
hirsutism; change from Baseline at each scheduled assessment during the Treatment Period for 
the following:  acne measured with total lesion count and investigator's global assessment (IGA), 
hirsutism measured with Ferriman–Gallwey (FG) score
9.
Endpoints related to metabolic features - change from Baseline at each scheduled assessment 
during the Treatment Period for the following:  glycated hemoglobin (HbA1c), fasting 
insulin/glucose, body mass index (BMI), lipids, waist circumference
10. Change from Baseline at each scheduled assessment during the Treatment Period for additional 
hormones:  androstenedione, anti-Mullerian hormone (AMH), estradiol (E2), progesterone
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11. Change from Baseline in ovarian volume at each scheduled assessment during the Treatment 
Period
12. Endpoints related to the subject's quality of life:  change from Baseline in domains from the 
Polycystic Ovary Syndrome Questionnaire (PCOSQ) (emotions, body hair, weight, infertility 
problems, and menstrual problems) and the Menstrual Bleeding Questionnaire (MBQ) at each 
scheduled assessment during the Treatment Period.
3.5 Safety Endpoints
Safety evaluations include physical examination, vital signs, pelvic ultrasound (includes both 
transabdominal ultrasound [TAU] and transvaginal ultrasound [TVU]), MRI (if required), clinical 
laboratory tests (including hematology, chemistry, urinalysis, and lipid panel), bone mineral density 
(BMD) via dual energy x-ray absorptiometry (DXA) examinations, and adverse event (AE) monitoring for 
the entire study duration.
3.6 Pharmacokinetic Endpoints
Plasma concentrations of elagolix will be determined at designated visits, and the concentrations may 
be used to develop a population PK model.  The population PK model may be linked with data from the 
PD endpoints for PK/PD analyses.
3.7 Pharmacodynamic Endpoints
LH and FSH concentrations will be determined at designated visits throughout the study and 
summarized.  Serum AUC0-t of LH and FSH will be calculated using non-compartmental methods and 
summarized.  Serum concentrations of other endocrine hormones may be determined and summarized 
if useful for the interpretation of the study results.  Additional PD parameters may be calculated if useful 
in the interpretation of the study results.
3.8 Biomarker Sampling
Optional whole blood, serum, and plasma samples 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 this 
research is to analyze samples for biomarkers that may help to understand PCOS, related conditions, 
and the subject's response to elagolix.  Research may also include epigenetic changes in 
deoxyribonucleic acid (DNA) that may associate with the subject's response to treatment or disease.  
Samples for ribonucleic acid (RNA) may be used to research if any genetic variants result in changes to 
gene expression.  This research is exploratory in nature and the results may not be included with the 
clinical study report.
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4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a Phase 2, randomized, double-blind (sponsor-unblinded), 6-month, placebo-controlled, parallel 
group, multicenter study designed to assess the PK and PD of elagolix and to demonstrate the safety and 
efficacy of elagolix in women with PCOS.
The duration of the study could be up to 42 weeks, which includes an 8-week Washout (if necessary), a 
6-week Screening Period, a 24-week Treatment Period, and a 30-day Post-Treatment Follow-up Period.
The Screening Period may be extended in certain circumstances (e.g., repeat TVU is needed) following 
consultation with the sponsor. 
Study Visits and Assessments:  Study visits for safety, efficacy, PK, and PD assessments will be scheduled 
as listed in the activity schedule (Appendix D).  Sites will have the option to participate in sparse PK 
sampling of elagolix.  Optional sparse PK sampling will take place on the scheduled visits at Week 1 and 
Week 4 of the Treatment Period, as listed on the activity schedule (Appendix D), and includes 5 lab 
draws over 6 hours.  If sites choose not to participate in the optional sparse PK sampling, a single PK 
sample will be required at the scheduled visits.  At other study visits (other than the optional sparse PK 
sampling study visits), a single PK sample will be collected as per the activity schedule.
Required intensive PD sampling of LH and FSH will occur at Baseline, and the scheduled visits at Week 1, 
Week 4, and Week 16 of the Treatment Period, as listed on the activity schedule (Appendix D).  Required 
intensive PD sampling includes 7 to 9 lab draws over 3 to 4 hours (taken every 30 minutes).  At other 
study visits (other than intensive PD study visits), a single PD sample will be collected, per the activity 
schedule.
Washout Period for subjects on oral contraceptives (OCPs):  a 2-month Washout Period will be required 
for subjects who are on OCPs.  Washout Period for subjects on metformin:  a 1-month Washout Period 
will be required for subjects on metformin.  A full list of Washout Periods for other medications is 
presented in Table 1.
During Screening, subjects will undergo procedures and activities as listed in the Activities Schedule to 
ensure they meet eligibility requirements.
Beginning at Screening and throughout the Treatment Period, each subject will complete an electronic 
daily bleeding diary.  The subjects will also undergo weekly blood draws for progesterone levels.  A 
progesterone level ≥ 3 ng/mL will be used to indicate ovulation.
Subjects will undergo procedures and activities as listed in the Activities Schedule at the 30-day 
post-treatment follow-up visit.  An unscheduled visit may occur when the subject returns to the clinic at 
any time for the evaluation of symptoms, changes in concomitant medications, or any AEs.
The study schematic is presented in Figure 1.  Further details regarding study procedures are located in 
the Operations Manual (Appendix F).  See Section 5 for information regarding eligibility criteria.  Study 
sites and subjects will remain blinded for the duration of the study.
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Figure 1.
Study Schematic
BID = twice daily; M = month; PTFU = post-treatment follow-up; QD = once daily
Some of the study visits and visit activities (including but not limited to clinical laboratory tests and 
concomitant medication assessment) may be conducted in the home or non-hospital/clinic environment 
by qualified individuals at the investigator's request and with the subject's agreement where local 
regulation allows.
Rescreening
Subjects who screen fail for this study may be rescreened.  Prior to rescreening a subject, the 
investigator should consult with the AbbVie Therapeutic Area Medical Director (TA MD).  The TA MD will 
determine which procedures will need to be repeated if the subject was a screen failure for this study or 
another AbbVie elagolix study.  The subject must re-consent and meet all eligibility criteria at the time of 
rescreening to qualify for the study.
4.2 Discussion of Study Design
Choice of Control Group
The control group consists of subjects randomly assigned to receive placebo.  No therapy is currently 
approved for treatment of PCOS.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  The safety 
assessments used in this study are standard and generally recognized as reliable, accurate, and relevant 
within the context of this study design.
DXA is a standard accepted measure of BMD and will be utilized to assess the effect of elagolix therapy 
on BMD.
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Suitability of Subject Population
Women 18 to 35 years of age with PCOS are selected for this study.  The lower age limit (18 years) was 
chosen based on the youngest adult age; the upper age limit (35 years) was chosen in order to limit the 
study to women earlier in the disease process.  No studies in females outside of the reproductive years 
are necessary for this proposed indication.
This study will enrich for subjects who have PCOS with menstrual abnormalities and hyperandrogenic 
features by using criteria for enrollment that require elevated testosterone as well as oligomenorrhea.
Selection of Doses in the Study
The effects of elagolix on gonadotropic and ovarian hormones were evaluated in premenopausal 
healthy women in 2 Phase 1 studies over 21 days in a multiple-ascending dose study (Study M12-790), 
and over a period of 3 months in a folliculogenesis study (Study M12-673).  In these studies, the 
evaluated elagolix dosages ranged from 100 mg once daily (QD) to 400 mg twice daily (BID).  In the 
21-day multiple-ascending dose study, dose-dependent suppression of gonadotropic and ovarian 
hormones was observed.  Based on the results from the 2 studies, elagolix exhibited partial suppression 
of LH up to 100 mg BID (200 mg total daily dose), and near maximal suppression at 200 mg BID and 
higher.  However, elagolix showed differential FSH suppression compared with LH, where no or minimal 
suppression was observed up to 200 mg total daily dose and near maximal or maximal suppression at 
200 mg BID and higher.  In the 3-month folliculogenesis study, ovulatory progesterone concentrations 
(> 5 nmol/L) were observed more often at lower elagolix dosages (100 to 200 mg QD, 100 mg BID) 
correlating with higher ovulation rates.  In Study M12-790, when the same total daily dose was 
evaluated as QD or BID (i.e., 100 mg BID versus 200 mg QD), BID regimens appeared to provide more 
suppression of hormones compared with QD regimens.  Testosterone suppression was also observed 
with elagolix dosages (100 mg BID, 200 mg BID, and 300 mg BID).
Based on the totality of the data from the Phase 1 and exploratory dose-response modeling, a total daily 
dose range of 50 mg to 300 mg with various dosing regimens (i.e., QD and BID) would provide an 
opportunity to study and explore a dose range finding in women with PCOS by targeting partial 
suppression of LH levels without inhibition of FSH and suppressed testosterone to achieve the desired 
clinical endpoints in women with PCOS.  The lowest effective dose that would allow establishment or 
improvement in menstrual regularity is desired.  The upper dose range in the study would also allow 
evaluation of maximum ability of elagolix to achieve improvement in hyperandrogenic features.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria to be included in the study.  
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 any study-specific 
procedures including washout or screening procedures.
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2. Subject agrees to the washout intervals for hormonal therapies, including any other 
medication that may require washout (Table 1) (if a subject has participated in an investigational 
trial with hormonal treatment, the washout interval applies as listed in
Table 1).
3. Subject is not taking exclusionary therapies.  The medications listed in Table 2 should not be 
taken during Washout (if applicable), Screening, Treatment Period, and Post-Treatment 
Follow-up Period.
4. Subject must be willing to comply with study-related assessments and procedures, including 
completion of the daily electronic diary (e-Diary) and avoid use of all hair removal procedures 
and products throughout the required time periods.  Laser hair removal is prohibited 
throughout the entire duration of the study (see Operations Manual [Appendix F] Section 3.5). 
Demographic and Laboratory Assessments
5. Adult female, 18 to 35 years of age, inclusive, at the time of Screening.
6. Body mass index (BMI) 18.5 to 38 kg/m2, inclusive at the time of Screening
7. A diagnosis of PCOS with subject meeting each of the following historical criteria:
!
Clinical hyperandrogenism or biochemical hyperandrogenism based on physical examination
or laboratory findings; and 
!
History of ovarian dysfunction indicated by menstrual irregularity:  oligomenorrhea 
(menstrual interval > 35 days or ≤8 menstrual cycles per year) or amenorrhea (no menses in 
6 consecutive months or greater); and
!
Cycle length > 35 days in the 3 months prior to Baseline based on subject self-report.
8. Laboratory values must meet the following criteria within the Screening Period prior to the 
first dose of study drug:
!
Must not have FSH level > 10 IU/L 
!
Elevated testosterone (total testosterone or free testosterone calculated by central 
laboratory)
!
Aspartate aminotransferase (AST) and alanine aminotransferase (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).
!
Negative urine and/or serum pregnancy test(s) during the Washout (if necessary) and/or 
Screening Periods, and a negative urine pregnancy test immediately before administration 
of the first dose of study drug.
!
Subjects must have neither hepatitis B nor C based on the presence of the following:
!
Hepatitis B surface antigen (HBsAg)
!
Hepatitis C virus antibody (HCV Ab) and detectable HCV RNA 
!
Equivocal viral test results should be repeated.
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!
No clinically significant abnormalities in clinical chemistry, hematology, or urinalysis 
(excluding findings associated with the disease under study).  
!
Screening labs may be retested once prior to Baseline; for further retesting, contact the TA 
MD.
!
An adequate endometrial biopsy that shows no clinically significant endometrial pathology 
during Screening (or within 12 months prior to Screening if documentation provided) or 
endometrial thickness < 5 mm on Screening TVU.
!
Must have a normal Papanicolaou (Pap) smear result as described in, Operations Manual 
(Appendix F), Pap Test Eligibility (applies to subjects ≥ 21 years of age at Screening or age at 
which Pap smears are routinely performed according to local guidelines).
!
Must not have active pelvic inflammatory disease at the time of Screening.
Subject History
9. No history of irregular menstrual bleeding associated with conditions other than PCOS 
(e.g., uterine polyps or submucosal uterine fibroids, adenomyosis)
10. Must be more than 6 months post-partum, post-abortion, post-pregnancy, and 
post-lactation at the time of entry into the Screening Period.
11. Must not have had laser hair removal within the 6 months prior to Baseline.
12. Must not have clinically significant gynecological finding from screening ultrasound or MRI if 
required, 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 Baseline and 
meet eligibility criteria.)
!
Complex ovarian cyst > 3.5 cm in diameter at longest point
!
Large endometrial polyp (≥ 1 cm)
!
Submucosal fibroid 
!
Endometrioma > 3.5 cm in diameter (longest diameter)
13. Must not be pregnant or breastfeeding or planning a pregnancy until completion of the 
study.
14. Must not have any clinically significant abnormal findings on electrocardiogram (ECG)
obtained during Screening.
15. No diagnoses of:
!
Cushing's syndrome
!
Late onset congenital adrenal hyperplasia (or elevated screening 17-OH-P); the investigator 
should determine the applicable reference range for the subject as noted in central 
laboratory report to determine subject eligibility
!
Androgen-secreting tumors (or total testosterone > 200 ng/dL at Screening)
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!
Uncontrolled thyroid disease (or abnormal thyroid-stimulating hormone [TSH] and 
tetraiodothyronine (T4) at Screening)
*Note:  An abnormal TSH will reflex to test T4.  If the T4 result is within normal limits, the 
TSH test can be repeated one time.  TSH and T4 must be normal prior to Baseline. 
!
Hyperprolactinemia (or elevated prolactin at Screening)
!
Diabetes mellitus (or abnormal fasting glucose ≥ 126 mg/dL (7.0 mmol/L) or HbA1c values 
≥6.5 percent (48 mmol/mol) at Screening).
!
Major depression or post-traumatic stress disorder episode within 2 years prior to 
Screening, or a history of other major psychiatric disorder at any time (e.g., schizophrenia, 
bipolar disorder).
!
Active malignancy or history of malignancy (except basal cell carcinoma of the skin) with or 
without systemic chemotherapy
16. No osteoporosis or other metabolic bone disease, or any condition that would interfere with 
obtaining adequate DXA measurements: 
!
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). 
!
History of low-trauma hip or vertebral fractures (e.g., fracture resulting from a fall from a 
standing height or lower)
!
Bilateral hip replacement
!
History of spinal surgery, spinal hardware
!
Severe scoliosis
!
Subject does not meet the limits/specifications of the local DXA machine being used for this 
study
!
Clinically significant hypocalcemia, hypo- or hyperphosphatemia
!
Treatment with medication (excluding calcium and vitamin D) for bone disease associated 
with a decrease in BMD
17. Results of subject's Screening DXA of the lumbar spine (L1 - L4) and total hip/femoral neck 
must demonstrate adequate BMD as follows:
!
Z-score ≥ –2.0 
18. No history of: 
!
A newly diagnosed, clinically significant medical condition requiring therapeutic intervention 
(e.g., new onset hypertension) that has not been stabilized at least 30 days prior to Baseline
!
A clinically significant medical condition anticipated to require intervention during the 
course of the study participation (e.g., anticipated major elective surgery)
!
An unstable medical condition making the subject an unsuitable candidate for the study in 
the investigator's opinion (including, but not limited to, uncontrolled hypertension, epilepsy 
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requiring anti-epileptic medication, unstable angina, confirmed inflammatory bowel disease, 
hyperprolactinemia, clinically significant infection or injury)
!
Drug abuse and/or alcohol abuse within 12 months prior to Screening
!
Any suicide attempts ever or answered "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 Baseline.
19. No surgical history of: 
!
Hysterectomy 
!
Unilateral or bilateral oophorectomy
!
Ovarian wedge resection or ovarian drilling as treatment for PCOS
!
Bariatric surgical procedures of any type within 12 months of Screening
!
Major surgery within 3 months prior to the initial Screening visit
!
Minor surgery within 1 month prior to the initial Screening visit
20. Must not be using:
!
Medications identified in Section 5.3 Table 2 during Washout, Screening, Treatment or 
Post-Treatment Follow-Up Periods.
!
Copper intrauterine device (CU-IUD), levonorgestrel intrauterine system (LNG-IUS), or 
implant.  If the CU-IUD, LNG-IUS, or implant is removed, and subject completes the required 
washout if applicable, the subject may be considered for Screening for the study.
!
Systemic corticosteroids for over 14 days within 3 months prior to Screening or anticipate 
require use of systemic corticosteroids for more than 7 days during the study.  Over-the-
counter and prescription topical, inhaled, intranasal, or intra-articular (for occasional use) 
corticosteroids are allowed.
!
Oral retinoid preparations such as Accutane® (isotretinoin) within the last 12 months prior 
to Screening.  Topical isotretinoin applications are also not permitted within the last 28 days 
prior to Screening.
21. Regarding other study participation, subjects must not be: 
!
Previously treated in either an elagolix study or a study involving another investigational 
GnRH antagonist, within the last 3 months prior to entry into the Screening Period
!
Currently participating in another investigational study (drug or device)
!
Participating in an investigational drug study (i.e., receiving or has received investigational 
product) within 28 days or 5 times the investigational drug half-life, whichever is longer, 
prior to Screening procedures
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Table 1.
Washout Intervals for Exclusionary Hormonal/Anti-Hormonal Therapy
Therapy
Minimum Interval for Washouta
Medroxyprogesterone acetate injection (Depo Provera®; Sayana®)
12 months from injection
GnRH antagonists and GnRH agonists
3 months
Aromatase inhibitors
3 months
Selective progesterone receptor modulators (e.g., ulipristal acetate, 
vilaprisan)
3 months
Danazol (Cyclomen®)
Clomiphene 
Gonadotropins 
Antiandrogens 
Oral, intramuscular or intravenous glucocorticoids
Oral contraceptivesb
2 months
Oral, transdermal, or intravaginal estrogen preparations
Oral, intravaginal or transdermal progesterone/progestin preparations, 
including tibolone
Hormonal and nonhormonal IUD, sub-dermal progestin implant 
(e.g., Nexplanon®)
2 months after removal
NuvaRing®
Moderate (bosentan, efavirenz, etravirine, modafinil) or strong inducers 
(phenytoin, rifampin, carbamazepine, St. John's Wort, mitotane) of 
cytochrome P450 3A (CYP3A) 
Moderate (cimetidine, ciprofloxacin, erythromycin, fluconazole) or strong 
(itraconazole, ketoconazole, grapefruit juice, clarithromycin, diltiazem) 
inhibitors of CYP3A
1 month
Metformin (and other insulin-sensitizing agents)
Statins (and other lipid-lowering agents)
GnRH = gonadotropin-releasing hormone; IUD = intrauterine device
a.
This is the minimum washout.  If less than a full course of therapy is administered, the investigator should contact the 
AbbVie TA MD listed on the cover page of this protocol to discuss and confirm the required washout interval.
b.
Exception:  levonorgestrel 1.5 mg or ulipristal acetate 30 mg used for emergency contraception.
5.2 Contraception 
Subject must agree to the use of at least 2 forms of nonhormonal contraception (dual contraception) 
consistently throughout the Washout (if applicable), Screening, Treatment Period, and Post-Treatment 
Follow-Up Period.  Acceptable methods of dual nonhormonal contraception include:
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Condom with spermicide (foam, gel, or polymer film).
!
Diaphragm with spermicide (condom may or may not be used).
!
Cervical cap with spermicide (condom may or may not be used).
!
Vaginal sponge impregnated with spermicide used with a condom.
Subject is not required to use dual contraception methods if:
!
Sexual partner(s) is vasectomized at least 6 months prior to Screening or is documented to be 
sterile for any reason.
!
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 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 Washout (if applicable), Screening, 
Treatment Period, and Post-Treatment Follow-Up Period.
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Any oral acne treatments and topical 
acne medications, such as:
Oral antibiotics, topical retinoids, benzoyl peroxide
CYP3A = cytochrome P450 3A isoform subfamily; GnRH = gonadotropin-releasing hormone; hCG = human chorionic 
gonadotropin; IM = intramuscular; IV = intravenous; LNG-IUS = levonorgestrel intrauterine system; OATP = organic anion 
transporting polypeptide; rPTH = recombinant human parathyroid hormone
5.4 Prior and Concomitant Therapy
Any medication administered to treat PCOS symptoms within 6 months prior to Washout or Screening 
must be recorded in source documents and in the electronic case report forms (eCRFs).  The date(s) of 
administration (including start and stop dates), dose, frequency, route, and reason for use and 
discontinuation must be recorded in source documents and on the appropriate eCRF.
All other medications or vaccines (including over-the-counter or prescription medicines, vitamins and/or 
herbal supplements) that the subject is receiving at the time of entering into the Washout Period (if 
required) or Screening Period and during the Treatment and Post-Treatment Follow-Up Periods must be 
recorded in source documents and on the Concomitant Medication eCRFs.  The reason for use, date(s) 
of administration (including start and end dates), and dosage information (including dose, frequency and 
route) must be recorded.
The AbbVie TA MD should be contacted if there are any questions regarding concomitant or prior 
therapies.  Information regarding potential drug interactions with elagolix can be located in the elagolix 
Investigator's Brochure.
Subjects must be able to safely discontinue any prohibited medications 5 half-lives or up to 8 weeks 
prior to initial study drug administration.  Subjects must be consented for the study prior to 
discontinuing any prohibited medications for the purpose of meeting study eligibility.
5.5 Withdrawal of Subjects and Discontinuation of Study
A subject may voluntarily withdraw or be withdrawn from the study at any time for reasons including, 
but not limited to, the following:
!
Clinically significant abnormal laboratory results or AEs, which rule out continuation of the study 
drug, as determined by the investigator or the AbbVie TA MD.
!
Clinically significant deterioration of the subject's medical status as determined by the 
investigator.
!
Any other medical reason that AbbVie or the investigator deems appropriate.
!
The investigator believes it is in the best interest of the subject.
!
The subject requests withdrawal from the study for any reason.
!
Eligibility criteria violation was noted after the subject started study drug and continuation of 
the study drug would place the subject at risk.
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Introduction of prohibited medications or dosages and continuation of the study drug would 
place the subject at risk.
!
The subject becomes pregnant or has a positive serum pregnancy test.
!
The subject experiences a nontraumatic bone fracture.
!
In the investigator's opinion, the subject is unable or unwilling to comply with study-related 
assessments and procedures, including completion of the e-Diary.
!
If any of the following hepatic function test criteria is met, study drug must be discontinued:
!
AST and/or ALT elevations > 8 × upper limit of normal (ULN)
!
AST and/or ALT elevations > 5 × ULN for more than 2 weeks
!
AST and/or ALT elevations > 3 × ULN, with total bilirubin > 2 × ULN
!
AST and/or ALT elevations > 3 × ULN, accompanied by clinical signs or symptoms suggestive 
for hepatic injury (e.g., fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia [> 5%]).
Isolated lab abnormalities in an otherwise well-appearing subject should be confirmed prior to 
study drug discontinuation.  A thorough investigation of potential etiologies for the elevated 
transaminases should be conducted (e.g., trauma, acetaminophen use, viral hepatitis, alcohol 
ingestion), and the subject should be followed closely for clinical progression.
Subjects for whom treatment is discontinued for elevated hepatic function tests should have 
transaminases and bilirubin levels repeated by the central laboratory within 48 to 72 hours of 
the initial finding if possible and then be monitored closely until levels normalize or return to 
Baseline.
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.
Discontinuation of Study
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.  If, in the judgment of the investigator and 
AbbVie, the continued exposure to the study drug represents an unexpected, significant, or 
unacceptable risk to subjects, the study will be stopped.  An example of such risk would be if 3 or more 
subjects developed active liver disease, as defined in the discontinuation criteria above.
Treatment Interruption
AbbVie or the investigator may request that a subject temporarily discontinue study drug 
administration, which will be referred to as "treatment interruption."  The following are examples for 
reasons when the AbbVie TA MD must be notified in order to assess whether a subject should undergo 
temporary treatment interruption:  
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Adverse event, 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).
COVID-19 Pandemic-Related Acceptable Protocol Modifications
During the COVID-19 pandemic, it has been necessary to employ mitigation strategies to enable the 
investigator to ensure subject safety and continuity of care.  Acceptable mitigation strategies are 
identified and included in the Operations Manual in Appendix F.
The investigator should contact the AbbVie medical contact before discontinuing a subject from the 
study for a reason other than "planned per protocol," to ensure all acceptable mitigation steps have 
been explored.
Refer to the Operations Manual in Appendix F for details on how to handle study activities/procedures.
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 continue to be followed for all regularly scheduled visits, unless subjects 
have decided to discontinue the study participation entirely (withdrawal of informed consent).  Subjects 
should be advised on the continued scientific importance of their data even if they discontinue 
treatment with study drug early.
If a subject prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the Premature Discontinuation visit (PD visit) should be completed as soon as 
possible, preferably within 2 weeks.  In addition, if subject is willing, a 30-day follow-up phone call after 
the last dose of study drug may be completed to ensure all treatment-emergent AEs/serious adverse 
events (SAEs) have been resolved.
All attempts must be made to determine the date of the last study drug dose and the reason for 
discontinuation of study drug 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
Subjects will be randomly assigned to elagolix or matching placebo.
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The treatment administration is presented in Table 3.
Table 3.
Treatment Administered
Treatment Group
Investigational Product
Dosing 
Time
Elagolix 25 mg 
Capsule
Elagolix 75 mg 
Capsule
Elagolix 150 mg 
Capsule
Matching 
Placebo 
Capsule
Elagolix 25 mg BID 
AM
1
0
0
1
PM
1
0
0
0
Elagolix 50 mg QD
AM
2
0
0
0
PM
0
0
0
1
Elagolix 75 mg BID
AM
0
1
0
1
PM
0
1
0
0
Elagolix 150 mg QD
AM
0
0
1
1
PM
0
0
0
1
Elagolix 300 mg QD
AM
0
0
2
0
PM
0
0
0
1
Placebo
AM
0
0
0
2
PM
0
0
0
1
BID = twice daily; QD = once daily
The study drug, consisting of elagolix 25 mg, 75 mg, 150 mg capsules (identical in appearance), or 
respective matching placebo capsules, will be supplied in a carton with 5 blister cards.  Subjects will be 
instructed to self-administer their study drug.
Identity of Investigational Product
Information about the drug formulations to be used in this study is presented in Table 4.
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Table 4.
Identity of Investigational Products
Investigational Product Active
Investigational Product Placebo
Investigational 
Product Name
Elagolix 25 mg hard gelatin capsule
Elagolix 75 mg hard gelatin capsule
Elagolix 150 mg hard gelatin capsule
Universal placebo hard gelatin capsule
Active Ingredient
Elagolix
N/A
Mode/Route of 
Administration 
Oral
Oral
Formulation
RC2 tablet over-encapsulated in Size #0 
hard gelatin capsule shells
N/A
Dosage Form
Hard Gelatin Capsule
Hard gelatin capsule
Dose and Units
25 mg, 75 mg, and 150 mg
Universal placebo capsule
Drug 
Preparation/Pack
aging
Blister card
Blister card
Blinding
Blinded, capsules
Blinded, capsules
Frequency of 
Administration
50 mg, 150 mg, 300 mg:  QD
25 mg, 75 mg:  BID
Matching placebo regimen
Storage 
Conditions
15 to 25°C
15 to 25°C
BID = twice daily; N/A = not applicable; QD = once daily; RC2 = roller compaction 2
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If a subject is unable to come to the study site to pick up their study drug due to COVID-19, a 
direct-to-patient (DTP) study drug shipment can be made from the study site to the subject and 
direct-from-patient (DFP) transfer will be available if allowed by local regulations.  AbbVie will submit 
any required notifications to the regulatory authority as applicable.  Refer to the Operations Manual in 
Appendix F for details on DTP shipment of study drug.
Compliance
During the Treatment Period visits or Premature Discontinuation visit, the subject will be asked to 
confirm whether doses were taken and to provide the dates and approximate times of the last 4 doses 
of study drug prior to elagolix PK samples as noted in Appendix D, Activity Schedule.  The subject-
reported data will be recorded in source and in the eCRF.
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5.8 Randomization/Drug Assignment
All subjects will be randomly assigned to receive either elagolix or placebo centrally using an interactive 
response technology (IRT).  Before the study is initiated, contact information and user guidelines for IRT 
will be provided to each site.  Study drug will be dispensed at the study visits outlined in Appendix D, 
Activity Schedule.
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.  For subjects who rescreen, the screening number assigned by the IRT at the 
initial washout or screening visit should be used.  
Once the subject's eligibility has been confirmed and prior to the Baseline (randomization) dose, a 
unique randomization number will be provided via IRT.  Stratified Randomization will be performed by a 
ratio of 2:2:2:2:2:3 to the following treatments:  25 mg BID, 50 mg QD, 75mg BID, 150 mg QD, 300 mg 
QD, or placebo (20 subjects in each active treatment group and 30 subjects in the placebo group).  
Subject randomization will be stratified based on FG score (< 8, ≥ 8) and BMI (< 30, ≥30).
Study drug must not be dispensed without contacting IRT.  Study drug may only be dispensed to subjects 
enrolled in the study according to kit numbers provided by the IRT.
The randomization schedule will be computer generated by the statistics department at AbbVie, North 
Chicago, IL, prior to the start of the study.  A copy of all of the randomization schedules will be kept by 
the statistics department at AbbVie and a copy will be forwarded to the IRT provider.
Breaking Blind
Blind break transaction is performed in the study IRT system.  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, including those that may be due to the COVID-19 pandemic), the investigator is responsible 
for notifying IEC/IRB, regulatory authorities (as applicable), and AbbVie.
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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.
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 can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product.
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 AE can result from use of the drug as stipulated in the protocol or approved labeling, as well as from 
accidental or intentional overdose, drug abuse, or drug withdrawal.  Any worsening of a pre-existing 
condition or illness is considered an AE.  Worsening in severity of a reported AE should be reported as a 
new AE.  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.
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 
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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 or contract research organization (CRO) (as appropriate) 
as an SAE within 24 hours of the site's being made aware of the SAE (refer to Section 4.3 of the 
Operations Manual 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.
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.
All AEs reported from the time of study drug administration until 30 days after discontinuation of study 
drug administration will be collected, whether solicited or spontaneously reported by the subject.  In 
addition, SAEs and protocol-related nonserious AEs will be collected from the time the subject signs the 
study-specific informed consent.
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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.
Adverse events 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 AEs of special interest will be monitored during the study:
!
Elevated hepatic transaminases
!
BMD decrease/fractures
!
Mood and depression-related events
Of note, all pregnancy outcomes will be monitored (see below).
Adverse Event Severity and Relationship to Study Drug
The investigators will rate the severity of each AE as mild, moderate, or severe.
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 after 
the site becomes aware of the pregnancy.  Subjects who become pregnant after receiving at least 
one dose of study drug during the Treatment Period or within 30 days of last dose of study drug of the 
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study must be discontinued (Section 5.5).  If a pregnancy occurs in a study subject, information 
regarding the pregnancy and the outcome will be collected.
If a subject has a positive serum pregnancy test during the Treatment Period, no additional 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.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
Study sites and subjects will remain blinded for the duration of this double-blind study.  The sponsor, 
however, will be unblinded for the entirety of the study.
Complete and specific details of the statistical analysis will be described and fully documented in the 
Statistical Analysis Plan (SAP).  The SAP will be finalized prior to database lock.  The statistical analyses 
will be performed using SAS (SAS Institute Inc., Cary, North Carolina, USA).
7.2 Definition for Analysis Populations
The full analysis set (FAS) consists of all randomly assigned subjects who have received at least one 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 the 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 consists of all subjects who received at least one dose of study drug.  The data 
from the safety analysis set will be presented by the treatment actually received no matter what 
treatment group was assigned at the time of randomization.  If a subject takes more than one 
treatment, the subject will be analyzed in the safety analysis set as taking the treatment to which she 
was randomized.  All safety analyses will be performed based on the safety analysis set.
7.3 Statistical Analyses for Efficacy
Primary Analysis
The primary endpoint is the proportion of menstrual cycle responders.  A subject is considered a 
menstrual cycle responder if she has at least 2 normal menstrual cycles during the final 4 months of the 
Treatment Period.  In addition, a subject is considered a complete menstrual cycle responder if she has 
normal menstrual cycles beginning at or before Month 3 that are maintained through Month 6 during 
the Treatment Period.  The proportion of complete menstrual cycle responders will be considered an 
additional endpoint.
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For the primary efficacy endpoint, the pairwise comparisons for the difference in proportion of 
responders between each treatment group and placebo group will be analyzed using the Cochran-
Mantel-Haenszel test (CMH) adjusted for FG score (< 8, ≥ 8) and BMI (< 30, ≥ 30) at Baseline.  
Additionally, the CMH-based 95% confidence interval for the difference in proportion of responders 
within each FG score (< 8, ≥ 8) and BMI (< 30, ≥ 30) at Baseline will be calculated based on normal 
approximation. 
The primary analysis will be based on observed cases only; missing data will not be imputed for the 
primary endpoint.
Details on the primary and other efficacy analyses are provided in the SAP.
Sample Size Estimation
Approximately 130 subjects:  20 subjects per elagolix treatment group and 30 subjects assigned to 
placebo.
The sample size will provide at least 85% power to detect a difference between each elagolix group and 
the placebo group in the proportion of menstrual cycle responders, assuming response rates of 10% for 
the placebo group and 50% for the elagolix group with 2-sided α = 0.05.  The above sample size was 
calculated using nQuery advisor 7.0. 
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
!
A summary of DXA results
The full list of safety endpoints and corresponding analyses will be presented in the SAP.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, ICF(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(s) 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.
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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.
In the event of a state of emergency due to the COVID-19 pandemic leading to difficulties in performing 
protocol-specified procedures, AbbVie will engage with study site personnel in efforts to ensure the 
safety of subjects, maintain protocol compliance, and minimize risks to the integrity of the study while 
trying to best manage subject continuity of care.  This may include alternative methods for assessments 
(e.g., phone contacts or virtual site visits), alternative locations for data collection (e.g., use of a local 
laboratory instead of a central laboratory), and shipping investigational product and/or supplies direct 
to subjects to ensure continuity of treatment where allowed.  Refer to the Operations Manual in 
Appendix F for additional details.  In all cases, these alternative measures must be allowed by local 
regulations and permitted by IRB/IEC.  Investigators should notify AbbVie if any urgent safety measures 
are taken to protect the subjects against any immediate hazard.
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).  During the COVID-19 pandemic, remote monitoring of data may be employed if allowed 
by the local regulatory authority, IRB/IEC, and the study site.
10
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.
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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.
AbbVie.  Elagolix Investigator's Brochure.
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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
17-OH-P
17-OH-progesterone
AE
Adverse event
AGC
Atypical glandular cells
ALT
Alanine aminotransferase
AMH
Anti-Mullerian hormone
ASC-H
Atypical squamous cells cannot exclude HSIL
ASC-US
Atypical squamous cells of undetermined significance
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
BID
Twice daily
BMD
Bone mineral density
BMI
Body mass index
CIN
Cervical intraepithelial neoplasia
CMH
Cochran-Mantel-Haenszel
COVID-19
Coronavirus disease-2019
CRF
Case report form
CRO
Contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CU-IUD
Copper intrauterine device
DHEAS
Dehydroepiandrosterone sulfate
DNA
Deoxyribonucleic acid
DFP
Direct-from-patient
DTP
Direct-to-patient
DXA
Dual energy X-ray absorptiometry
E2
Estradiol
ECG
Electrocardiogram
eCRF
Electronic case report form
EC/TZ
Endocervical/transformational zone
EDC
Electronic data capture
FAS
Full analysis set
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FG
Ferriman–Gallwey
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GnRH
Gonadotropin-releasing hormone
HbA1c
Glycated hemoglobin
HBsAg
Hepatitis B surface antigen
HCV Ab
Hepatitis C virus antibody
HDL-C
High-density lipoprotein cholesterol
HPV
Human papillomavirus
HSIL
High-grade squamous intraepithelial lesion
ICF
Informed consent form
ICH
International Council for Harmonisation
IEC
Independent ethics committee
IGA
Investigator's global assessment
IRB
Institutional review board
IRT
Interactive response technology
IUD
Intrauterine device
LDL-C
Low-density lipoprotein cholesterol
LH
Luteinizing hormone
LNG-IUS
Levonorgestrel intrauterine system
LSIL
Low-grade squamous intraepithelial lesion
MBQ
Menstrual Bleeding Questionnaire
MedDRA
Medical Dictionary for Regulatory Activities
NILM
Negative intraepithelial lesion or malignancy
OCPs
Oral contraceptives
Pap
Papanicolaou
PCOS
Polycystic ovary syndrome
PCOSQ
Polycystic Ovary Syndrome Questionnaire
PD
Premature discontinuation/Pharmacodynamic(s)
PGI
Patient Global Impression
PK
Pharmacokinetic(s)
QD
Once daily
RNA
ribonucleic acid
RSI
Reference safety information
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SAE
Serious adverse event
SAP
Statistical analysis plan
SHBG
Sex hormone binding globulin
SOC
System organ class
SUSAR
Suspected unexpected serious adverse reactions
T4
tetraiodothyronine
TA MD
Therapeutic Area Medical Director
TAU
Transabdominal ultrasound
TSH
Thyroid-stimulating hormone
TVU
Transvaginal ultrasound
ULN
Upper limit of normal
USA
United States
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M16-837:  Phase 2, Multicenter, Double-blind (Sponsor-unblinded), Randomized, Placebo-
Controlled Study of the Safety and Efficacy of Elagolix in Women with Polycystic Ovary Syndrome
Protocol Date:  02 October 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
Clinical Development
Clinical Development
Data and Statistical Sciences
Data and Statistical Sciences
Clinical Pharmacology and Pharmacometrics 
Medical Writing
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
11 January 2019
Version 2.0
02 May 2019
Version 3.0
21 October 2019
The purpose of this version is to correct minor clerical errors for consistency throughout the protocol
and Operations Manual, and to clarify information in addition to the following:
!
Remove "at time of diagnosis" in Protocol Section 5.1, eligibility criterion 7
Rationale: Physical examination or laboratory findings documenting clinical hyperandrogenism 
or biochemical hyperandrogenism can be documented during screening, not necessarily at the 
time of diagnosis.
!
Remove "Bilateral tubal ligation, bilateral tubal occlusion, or bilateral salpingectomy" in Protocol 
Section 5.1, eligibility criterion 19
!
Rationale: Subjects are required to use 2 nonhormonal forms of contraception in this study.
Bilateral tubal ligation, bilateral tubal occlusion or bilateral salpingectomy are forms of 
nonhormonal permanent contraception; therefore, these subjects will not be excluded from the 
study.
!
Add procedures related to breaking the blind in Protocol Section 5.8
Rationale: Clarification that the blind break transaction is performed in the study IRT system.
!
Add sampling windows for PK and PD samples to Section 3.6 and Section 3.7, respectively, in the 
Operations Manual 
Rationale: Sampling windows were added to define acceptable times of serial sample 
collections to provide sites flexibility in performing sparse PK sampling and intensive PD 
sampling.
!
Add directions for protocol modifications related to the coronavirus disease-2019 (COVID-19) 
pandemic in Protocol Section 2.2, Section 5.5, Section 5.7, Section 5.9, Section 8.2, Section 9, 
and Appendix D, and to Operations Manual Section 2, Section 2.2, Section 3.1, Section 3.5, 
Section 3.6, Section 3.7, Section 3.8, Section 3.9, Section 3.11, Section 3.12, Section 3.13, 
Section 3.14, Section 3.17, Section 3.18, Section 3.19, Section 4.4, and Section 6.1, to describe 
alternative processes that may be needed.
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 M16-837 Version 4.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 CONTACTS
Sponsor/Therapeutic 
Area Medical 
Director (TA MD)/
Emergency Medical 
Contact
 
AbbVie Inc.
1 North Waukegan Road
North Chicago, IL 60064
EMERGENCY 24 hour Number:  
+1 (973) 784-6402
Office:
Mobile:
Fax:
Email:
Safety Concerns
Men's and Women's Health 
Safety Team
Dept. R48S, Bldg AP31
1 North Waukegan Road
North Chicago, IL 60064
Phone: +1 847-935-7577
Email: 
GPRD_SafetyManagement_Hormones@abbvie.com
SAE Reporting 
outside of RAVE
Pharmacovigilance
Fax:
+1 847-938-0660
Email:
PPDINDPharmacovigilance@abbvie.com
Protocol Deviations
AbbVie Inc.
1 North Waukegan Road 
North Chicago, IL 60064
or
AbbVie Inc.
1 North Waukegan Road
North Chicago, IL 60064
Office:
Fax:
Email:
or
Office:
Fax:
Email:
Certified Clinical Lab
Covance CLS
8211 SciCor Drive
Indianapolis, IN 46214
Phone: +1 866-762-6209
Pharmacokinetic Lab
Bioanalysis
AbbVie Inc.
Dept. R46W, Bldg. AP13A
Room 2326
1 North Waukegan Road
North Chicago, IL 60064
Syneos Health, Inc. (formerly 
inVentiv)
2500 rue Einstein
Quebec, Canada
G1P0A2
Phone: +1 847-936-1382
Fax:
+1 847-938-9898
Phone: +1 418-527-4000
Fax:
+1 418-527-3456
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-837 Version 4.0
CONFIDENTIAL INFORMATION
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Exploratory 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 M16-837 Version 4.0
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
TABLE OF CONTENTS
1
CONTACTS
2
2
PROTOCOL ACTIVITIES BY VISIT
6
2.1
INDIVIDUAL WASHOUT/SCREENING PERIOD VISIT ACTIVITIES
6
2.2
INDIVIDUAL TREATMENT PERIOD VISIT ACTIVITIES
8
2.3
INDIVIDUAL POST-TREATMENT PERIOD VISIT ACTIVITIES
17
3
STUDY PROCEDURES
17
3.1
SUBJECT INFORMATION AND INFORMED CONSENT
17
3.2
MEDICAL HISTORY
18
3.3
GYNECOLOGICAL/OBSTETRICAL AND PCOS HISTORY
18
3.4
ADVERSE EVENT ASSESSMENT
19
3.5
PATIENT-REPORTED OUTCOMES AND RATING SCALES
19
3.6
PHARMACOKINETIC SAMPLING
22
3.7
PHARMACODYNAMIC SAMPLING
23
3.8
BIOMARKER RESEARCH SAMPLING
23
3.9
CONTRACEPTION COUNSELING/DISPENSE CONTRACEPTIVES
23
3.10 12-LEAD ELECTROCARDIOGRAM (ECG)
25
3.11 HEIGHT, WEIGHT, AND WAIST CIRCUMFERENCE
25
3.12 VITAL SIGNS
25
3.13 PHYSICAL EXAMINATION
25
3.14 GYNECOLOGICAL (PELVIC AND BREAST) EXAMINATION
26
3.15 PAPANICOLAOU (PAP) TEST
26
3.16 ENDOMETRIAL BIOPSY
27
3.17 CENTRAL/LOCAL IMAGING PROCEDURES
28
3.18 DISPENSE STUDY DRUG
30
3.19 CLINICAL LABORATORY TESTS
31
3.20 SUBJECT WITHDRAWAL FROM STUDY
34
4
SAFETY MANUAL
35
4.1
METHODS AND TIMING OF SAFETY ASSESSMENT
35
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-837 Version 4.0
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4.2
RECORDING DATA AND ANALYSES OF SAFETY FINDINGS
35
4.3
REPORTING ADVERSE EVENTS AND INTERCURRENT ILLNESSES
36
4.4
PREGNANCY
37
5
COUNTRY-SPECIFIC REQUIREMENTS
38
5.1
SUSAR REPORTING
38
6
STUDY DRUG
38
6.1
TREATMENTS ADMINISTERED
38
6.2
PACKAGING AND LABELING
38
6.3
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS
39
6.4
SELECTION AND TIMING OF DOSE FOR EACH SUBJECT
39
7
REFERENCES
39
LIST OF TABLES
TABLE 1.
CLINICAL LABORATORY TESTS
32
LIST OF FIGURES
FIGURE 1.
PAP TEST ELIGIBILITY
27
FIGURE 2.
ADVERSE EVENT COLLECTION
35
LIST OF APPENDICES
APPENDIX A.
E-DIARY FOR BLEEDING
40
APPENDIX B.
PATIENT GLOBAL IMPRESSION FOR ACNE AND HIRSUTISM
41
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-837 Version 4.0
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present to confirm eligibility.  Results of the endocrine hormones/test must be 
received and reviewed by site for eligibility prior to Baseline.
2.2 Individual Treatment Period Visit Activities
This section presents a list of activities performed during each visit, organized by visit.  The dot pattern 
on the upper right indicates the place of the visit in the overall Treatment Period Activity Schedule.
Activities are grouped by category (Interview, Exam, etc.).  Further information about each activity is 
provided in Section 3.
Scheduled monthly visits during the Treatment Period are based on a 28-day month.  All scheduled visits 
after Baseline through Week 4 should occur within ± 1 day of the projected date.  All scheduled visits 
after Week 4 should occur within ± 3 days of the projected date.  However, the TVU and DXA scan may 
be performed within approximately ± 15 days around the scheduled visit.
In the event that a subject or study personnel cannot come to the site because of the COVID-19 
pandemic, study visits may be conducted over the phone where feasible.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-837 Version 4.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
the informed consent statement will be reviewed, signed, and dated by the subject or their legally 
authorized representative, the person who administered the informed consent, and any other
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.
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.
Optional biomarker research samples will only be collected if the subject has voluntarily signed and 
dated a written consent form describing the research.  The written consent for biomarker research 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.  A subject may withdraw consent for optional 
biomarker samples at any time and remain in the main study.  Data generated from the optional 
biomarker samples before subject withdrawal of consent will remain part of the study results.
Due to the COVID-19 pandemic, it is possible that additional protocol modifications not outlined in the
protocol or operations manual may become necessary.  If this situation arises, in addition to the study 
informed consent, additional verbal consent may be obtained prior to these adaptations or substantial 
changes in study conduct in accordance with local regulations.
3.2 Medical History
A complete medical history including demographics, history of tobacco, alcohol, and drug use will be 
taken at Washout (if applicable) or during the Screening Period for those subjects who do not require
washout.  The medical history will be reviewed and updated at Screening.  The subject's medical history 
will be updated at the Baseline visit.  This updated medical history will serve as the baseline for clinical 
assessment.
3.3 Gynecological/Obstetrical and PCOS History
A detailed gynecological/obstetrical and PCOS 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 PCOS, including year of diagnosis and PCOS symptoms
!
History of endometriosis, ovarian cysts, endometrial polyps, or other relevant gynecological 
conditions
!
History of gynecological surgeries and gynecological diagnostic procedures
!
History of bleeding, including average cycle length and average number of days with 
bleeding/cycle over the last 6 months and typical intensity of menstrual periods 
!
History of irregular bleeding or prolonged bleeding
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-837 Version 4.0
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!
Prior hormonal medications, including those taken for treatment of PCOS or other gynecological 
conditions
!
Prior use of nonhormonal medications for the treatment of PCOS including pain medication, 
including dates of use for 12 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 PCOS history will be reviewed and should be updated if needed prior 
to dosing on Baseline (randomization) and will serve as the Baseline for clinical assessment.
3.4 Adverse Event Assessment
Please refer to Section 4.2.
3.5 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 2.2 and Section 2.3; 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 
either electronically or on paper (which will then be entered into the electronic case report form 
[eCRF]), as applicable.
Site staff should review all subject-completed questionnaires for logic and completeness before the 
subject leaves the study site. 
Subjects will complete the self-administered patient-reported outcome (PRO) instrument (when allowed 
per local regulatory guidelines).  Subjects should be instructed to follow the instructions provided with 
the instrument and to provide the best possible response to each item.  Site personnel shall not provide 
interpretation or assistance to subjects other than encouragement to complete the tasks.  Subjects who 
are functionally unable to read any of the instruments may have site personnel read the questionnaire 
to them.  Site personnel will encourage completion of the instrument at all specified visits and will 
ensure that a response is entered for all items.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-837 Version 4.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video conference.  The 
MBQ, PGIA/PGIH, PCOSQ, and C-SSRS may be administered by site staff via phone or video conference.  
In this situation, sites will read the PRO questions and response options to the subject, record the 
subject's responses on paper (source), and transcribe into the electronic data capture (EDC) system.  The 
subject's ability to view the PRO to understand the questions and response options should be preserved.  
Sites may share the questionnaire by video conference or send the questionnaires (email or hard copy) 
to the subjects to allow them to read/understand the questions and responses when the subject is 
providing responses over the phone.  The date and time of PRO data collection should be recorded in 
the source along with who collected the information.
Electronic Daily Diary (e-Diary) for Uterine Bleeding
An electronic patient-reported outcomes device (e-Diary) will be provided to all subjects during 
Screening after informed consent is obtained.  The e-Diary contains training information for the subject, 
but the site staff may also provide training on the required entries in the e-Diary.  Subjects will also be 
instructed to complete the diary at approximately the same time every day throughout the study.
Site staff should review subject e-Diary data regularly throughout the entire study beginning at 
Screening to ensure subject completion.  Subject noncompliance should be addressed by the site in a 
timely manner and subject retraining documented at the site.  Subjects who fail Screening will be 
instructed to return the e-Diary device to the site.  All subjects will be instructed to return the e-Diary 
device to the site at the last study visit or Premature Discontinuation visit.
Subjects will use the e-Diary to record assessments of uterine bleeding (Appendix A).
Menstrual Bleeding Questionnaire (MBQ)
The MBQ is a 20-item questionnaire to evaluate heavy menstrual bleeding.  The higher the score the 
heavier the menstrual bleeding burden.
The MBQ should be completed prior to any discussion of AEs or any review of laboratory findings at all 
applicable visits (Activity Schedule, Protocol Appendix D).
The subject should complete the questionnaire before site personnel perform any clinical assessments 
and before any interaction with site personnel has occurred to avoid biasing the subject's response.
Patient Global Impression for Acne and Hirsutism (PGIA and PGIH)
The Patient Global Impression of Acne (PGIA) and Patient Global Impression of Hirsutism (PGIH) will be 
measured using a 5-point scale and the scores will be used to assess the subject's opinion on how her 
symptoms have changed since starting medication.  The PGIA and PHIH should be completed prior to 
any discussion of AEs or any review of laboratory findings at all applicable visits (Appendix B).
Polycystic Ovary Syndrome Questionnaire (PCOSQ)
This study will utilize the PCOSQ developed by Cronin et al.1  The PCOSQ is a 26-item questionnaire 
broken up into 5 domains:  emotions, body hair, weight, infertility problems, and menstrual problems.  
Responses are scored on a 7-point Likert scale, with low scores reflecting worse quality of life.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-837 Version 4.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The PCOSQ should be completed prior to any discussion of AEs or any review of laboratory findings at all 
applicable visits (Activity Schedule, Protocol Appendix D).
The subject should complete the questionnaire before site personnel perform any clinical assessments 
and before any interaction with site personnel has occurred to avoid biasing the subject's response.
FG Score
The FG score will be used to quantify hirsutism.2  Sites will instruct the subject to refrain from any and all 
hair removal for at least 14 days prior to applicable visits.  Laser hair removal is prohibited throughout 
the duration of the study.  Each of the 9 body areas that is most sensitive to androgen is assigned a 
score from 0 (no hair) to 4 (frankly virile), and these are summed to provide a hormonal hirsutism score.  
"Focal" hirsutism (score 1 to 7) is a common normal variant, whereas generalized hirsutism (score of 8 or 
more) is abnormal in the general United States population. The FG Score assessment will be performed 
by the investigator.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to come on-site, the FG Score can be performed 
at the next on-site visit.
Acne Lesion Assessment
Acne severity will be measured by:
1).  Acne lesion count:  Investigators will count the number of non-inflammatory lesions (comedones) 
and number of inflammatory lesions (papules, pustules, and nodules) on the subject's face and sum the 
values for a total number.   
2).  Investigator's global assessment (IGA) scale.  The IGA scale is as follows:
0 – Clear or normal skin (no evidence of acne)
1 – Almost clear skin (some non-inflammatory acne is present with some non-inflamed papules.  
Papules may be developing but are not yet pinkish-red in color)
2 – Some non-inflammatory acne can be found with a few pustules and/or papules.  There are
no cystic acne lesions yet.
3 – Non-inflammatory acne dominates the area and a few inflammatory lesions can be found.  
There may or may not be one small cystic acne lesion in the area.
4 – Non-inflammatory and inflammatory acne lesions are more visible.  There may or may not 
be a few cystic acne lesions.
5 – Severe inflammatory acne dominates the area.  Several numbers of comedones, pustules, 
papules, and cystic acne are also present.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-837 Version 4.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to come on-site, the Acne Lesion Assessment 
and IGA can be performed at the next on-site visit.
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS3 is a systematically administered instrument developed to track suicidal AEs 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 during Screening and on Baseline.  During the Treatment 
Period, site staff will administer the C-SSRS Since Last Visit questionnaire at the time points specified in 
Section 2.2 and Section 2.3.  The C-SSRS administered at the Baseline Visit will serve as the Baseline for 
clinical assessment.
During Screening or at the Baseline visit, prior to randomization, any subject noted to have any suicide 
attempt ever or suicidal ideation with plan within the last year, either via answering "yes" to question 4 
and/or question 5 to the suicidal ideation portion of the C-SSRS, or via clinical interview, is not eligible 
for randomization.  If the subject expresses suicidal ideation on the C-SSRS or via clinical interview at any 
time during the study, the investigator should take appropriate action and then notify the AbbVie TA 
MD.  Appropriate steps will be taken to protect the subject (including possible discontinuation from the 
study and referral for appropriate psychiatric care).  
3.6 Pharmacokinetic Sampling
Sparse PK sampling (for sites that opt in to this activity):  Serial blood samples for the elagolix assay will 
be collected before the morning dose (0 hour) and at 1 (± 5 minutes), 2 (± 15 minutes), 4 (± 15 minutes), 
and 6 hours (± 15 minutes) after dosing on Study Weeks 1 and 4 (if sites choose not to participate in the 
optional sparse PK sampling, a single blood sample will be collected anytime upon subject's arrival at the 
site on Study Weeks 1 and 4).  "Intensive PK sampling" was changed in Protocol Version 3.0 to "sparse 
PK sampling."  The labels and references to "Intensive PK" in the study supplies and laboratory kits 
remain unchanged.
Single PK sample (for all sites):  In addition, a single blood sample will be collected anytime upon 
subject's arrival at the site as indicated in the Activity Schedule (Protocol Appendix D).  The samples will 
be assayed for elagolix concentration and exposures of elagolix will be summarized.
Plasma concentrations of elagolix will be determined by the Bioanalysis Department at AbbVie using a 
validated method.  Refer to the Laboratory Manual for sample collection and shipment instructions.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to come on-site, the sparse PK sampling or single 
PK sample can be collected at the next on-site visit.
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3.7 Pharmacodynamic Sampling
Intensive PD sampling:  Serial blood samples for LH and FSH assay will be collected at Baseline according 
to the following schedule:  0 hour, 0.5 (± 5 minutes), 1 (± 5 minutes), 1.5 (± 5 minutes), 2 (± 15 minutes), 
2.5 (± 15 minutes), 3 (± 15 minutes), 3.5 (± 15 minutes), and 4 (± 15 minutes) hours.  On Study Weeks 1, 
4, and 16, serial blood samples will be collected before the morning dose (0 hour) and at 
0.5 (± 5 minutes), 1 (± 5 minutes), 1.5 (± 5 minutes), 2 (± 15 minutes), 2.5 (± 15 minutes), 
3 (± 15 minutes), 3.5 (± 15 minutes), and 4 (± 15 minutes) hours after dosing.
In addition, a single blood sample will be collected anytime upon subject's arrival at the site on Study 
Weeks 8, 12, 20, and 24.  The samples will be assayed for LH and FSH concentrations, and exposures of 
both hormones will be summarized.
Serum concentrations of LH, FSH, and other relevant hormones and laboratory tests will be determined 
by AbbVie (or people or companies working with AbbVie).  Refer to the Laboratory Manual for sample 
collection and shipment instructions.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to come on-site, the intensive PD sampling or 
single PD sample can be collected at the next on-site visit.
3.8 Biomarker Research Sampling
Optional biomarker samples for DNA and RNA isolation from whole blood, serum, and plasma will be 
collected from consenting subjects 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 optional 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 PCOS and related conditions continues, but 
for no longer than 20 years after study completion, or per local requirement.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to come on-site, the optional biomarker samples 
can be collected at the next on-site visit.
3.9 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 at every visit as noted in the 
Activity Schedule (Protocol Appendix D) throughout study participation on the importance of pregnancy 
prevention and the use of appropriate and effective methods of contraception.  
Subjects must agree to use 2 forms of nonhormonal contraception (dual contraception) as indicated in 
the protocol.
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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 a 
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.
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.
(1)
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.  
(2)
Subjects should only use the pregnancy prevention materials provided by the sponsor.
(3)
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.
(4)
The site will provide contraceptives and other supplies (e.g., lubricants) to subjects at the 
time points specified in Section 2, as necessary.  
(5)
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.
(6)
The subject will be asked to attest by signature at the time of consent, and subsequently 
in a stand-alone attestation form at study visits specified in the Activity Schedule (Protocol 
Appendix D) that allowable methods of contraception, as described during the pregnancy 
prevention counseling, are being practiced.
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.
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to come on-site, the contraception counseling 
should be conducted during the phone visits (as applicable). The site should ship a reasonable quantity 
of contraceptive supplies for subject use until next on-site visit.  The type and quantity of contraceptives 
shipped to the subject must be documented along with the shipping tracking number and 
documentation. When the subject is able to go to the site, site should make sure that enough 
contraceptives are dispensed to the subject.
3.10 12-Lead Electrocardiogram (ECG)
A resting 12-lead ECG will be obtained during the Screening Period to confirm subject eligibility for the 
study unless the subject had one performed within 6 months of Screening and has documentation of the 
requirements.  The principal investigator or designee at the study site will sign and date the ECGs, 
determine whether any findings outside the normal physiological variation are clinically significant (in 
consultation with a cardiologist if necessary), and document this on the ECG report.  The original ECG 
tracing with the physician's assessment will be retained in the subject's records at the study site.
3.11 Height, Weight, and Waist Circumference
Height will be measured at Screening only.  Waist circumference should be measured at the umbilicus at 
visits as specified in Section 2.  Body weight will be measured at scheduled visits as specified in 
Section 2.  The subject will wear lightweight clothing and no shoes during weighing.  BMI will be 
calculated in EDC at the Screening visit.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to come on-site, height, weight, and waist 
circumference can be collected at the next on-site visit.
3.12 Vital Signs
Vital sign determinations of systolic and diastolic blood pressure, pulse, and temperature will be 
obtained at visits as specified in Section 2.  Blood pressure should be measured after the subject has 
been sitting for at least 5 minutes.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to come on-site, vital signs can be collected at 
the next on-site visit.
3.13 Physical Examination
A complete physical examination will be performed at the designated study visits as specified in 
Section 2.  The physical examination performed on Study Baseline will serve as the baseline physical 
examination for the entire study.  Any clinically significant physical examination findings after the 
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first dose will be recorded as AEs.  All findings, whether related to an AE or part of each subject's 
medical history, will be captured on the appropriate eCRF page.
At any time, a symptom-directed physical examination can be performed as deemed necessary by the 
investigator.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to come on-site, physical examination can be 
performed at the next on-site visit.
3.14 Gynecological (Pelvic and Breast) Examination
A complete breast and pelvic examination 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.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to come on-site, the gynecological examinations 
can be performed at the next on-site visit.
3.15 Papanicolaou (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 6 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 visit, the pap 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 35 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 
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 colposcopy performed outside of the study, they may be rescreened if they have no 
other exclusionary criteria and had an adequate colposcopy with a negative endocervical sample post 
colposcopy.  If biopsies are performed, they must show a histological diagnosis of cervical intraepithelial 
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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. 
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.
Note:
Only subjects ≤ 35 years of age are being enrolled in this study.
3.16 Endometrial Biopsy
An endometrial biopsy will be performed in all subjects during the Screening Period unless one has been 
performed within 12 months of the Screening visit and original results available qualify subject to 
participate in the study or endometrial thickness < 5 mm on Screening TVU (see Protocol Section 5.1).  
Endometrial biopsy should show no clinically significant endometrial pathology.  Subjects must have a 
confirmed negative urine pregnancy test within 24 hours before undergoing the endometrial biopsy.  
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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.
Premedication 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.  In addition, lidocaine may be used as local anesthesia on the cervix.  Any 
medications used for the procedure should be recorded in source documents and on the appropriate 
eCRF.  If there is a need for consideration for an office hysteroscopy to obtain the endometrial biopsy 
sample, the AbbVie TA MD (Section 1) should be consulted.  
If the endometrial biopsy is performed on the same day as the Pap smear or pelvic ultrasound, the 
endometrial biopsy should be performed after the Pap smear and pelvic ultrasound.
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 Baseline Visit.  In case of an 
insufficient sample, the biopsy may be repeated; however, results must be available prior to Baseline.  
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 per rescreening guidelines in the protocol.
3.17 Central/Local Imaging Procedures
Pelvic Ultrasound:  TAU and TVU
The pelvic ultrasound (TAU and TVU) will be performed by the investigative site's or affiliated radiology 
department at the time points specified in Section 2.  Images will be sent/transmitted to the central 
reader to determine subject eligibility for entry into the study and for subject evaluation during the 
course of the study.
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
!
Presence of ovarian cysts (to include number, size [cm], location [right or left ovary], simple 
versus complex)
!
Solid ovarian lesions > 1.5 cm longest diameter
!
Persistent simple ovarian cyst > 5 cm in longest diameter
!
Complex ovarian cyst > 3.5 cm in diameter at longest point
!
An endometrioma > 3.5 cm in diameter (longest diameter)
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A local reading will be performed to rule out pelvic masses or other significant pathologies.  The 
investigator should consult the local ultrasound report (or images if the report is not available) in order 
to make any safety-related judgments concerning the subject.  In this case, the local ultrasound reports 
will be maintained in the subject's source documents and copies may be collected upon request by the 
sponsor.  Data from the local ultrasound report will not be reported in the eCRF unless associated with 
an adverse event.
Ovarian Findings
During Screening, if the initial pelvic ultrasound shows a simple ovarian cyst > 5 cm 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 Baseline Visit (randomization) and not meet exclusion criteria 
(i.e., persistent simple ovarian cyst > 5 cm).  If the investigator notes endometrial thickness ≥ 5 mm, they 
may proceed to perform an endometrial biopsy based on the local read; however, the reading provided 
by the central reader should be used for entry into EDC.
In Screening, if any of the adnexal structures, such as an ovary, cannot be visualized on the pelvic 
ultrasound due to, for example, fibroid location and/or fibroid size, the subject may be eligible for 
randomization provided there are no exclusionary findings based on an alternate imaging that can 
evaluate that adnexa, such as a magnetic resonance imaging (per central reader request).  The central 
reader may also request a magnetic resonance imaging scan at the Week 24/premature discontinuation 
visit, if needed.  During the Screening Period, if the subject requires an MRI and the subsequent pelvic 
ultrasound is not readable, the subject will not continue to have pelvic ultrasounds.  An MRI will be 
completed at the final visit.
During the Treatment Periods, if the pelvic ultrasound shows a simple ovarian cyst > 5 cm or a complex 
ovarian cyst (including endometriomas) > 3.5 cm in longest diameter, the findings should be 
documented as an AE if the investigator considers them to be clinically significant.
Dual Energy X-ray Absorptiometry (DXA)
DXA scans of the lumber spine, femoral neck, and total hip will be performed at the time points 
specified in Section 2.  Site training and qualifications, which include assessment of instruments, will be 
evaluated/approved by the central reader prior to screening of the first subject. Instructions on 
calibration and standardization of instruments and any additional required information will be specified 
in a manual from the central reader that will be provided to all study sites. Sites will need to obtain 
approval from the central reader prior to initiating study scans.
The screening DXA scan will be sent to the central reader to determine eligibility and serve as the 
baseline scan for subject management.
During the Treatment Periods, DXA scans will be performed for all subjects at Week 24 and will be 
submitted to the central reader for review and analysis.  DXA scans will only be performed at the PD 
Visit if the subject has received study drug for at least 12 weeks.
DXA scans will be performed by qualified technologist/radiologists at the site or affiliated imaging facility 
using GE Lunar or Hologic equipment and per the acquisition guidelines provided by the Central Imaging 
Core Lab (central reader).  The DXA technologist/radiologist or designee for each investigative site 
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should electronically submit the subject's DXA images to the central reader for review and analysis 
following acquisition. The central reader will be blinded to the subject's treatment assignment, but not 
to the corresponding time point.
Subject eligibility will be made based on the central reader review. Sites will receive reports from the 
central reader that detail the results (including Z-scores and bone mineral density (BMD) % change from 
Baseline, as applicable) of the DXA scans performed.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, if the subject is unable to come on-site or to the imaging facility, the 
DXA and TAU/TVU can be delayed up to 1 month from their scheduled time.
3.18 Dispense Study Drug
The site will dispense study drug at the time points specified in Section 2.  The subject will take the 
first study drug dose the morning after the Baseline visit.  Subjects will be instructed to self-administer 
their study drug throughout the Treatment Period.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Depending on the local regulations, provisioning of study drug for direct-to-patient (DTP) and 
direct-from-patient (DFP) transfer because of the COVID-19 pandemic will be available per request.  
AbbVie will submit any required notifications to the regulatory authority as applicable. 
!
Sites will be responsible for meeting IRB reporting requirements and submitting the booking 
form to the local IRB (as applicable).
The investigator must discuss the DTP process with the subject:
!
Obtain consent to provide delivery information to local courier and document this in the source.
!
Obtain results of required safety procedures (e.g., urine pregnancy testing) before registering 
subject dispensation of study drug in IRT.
!
Confirm that the subject will be available to accept delivery.
!
The site will follow up with the subject after shipment is received.
!
The subject should maintain the drug containers, as well as any unused drug for return to site.
!
Sites will be required to retain documentation of the shipment for the IP accountability and 
monitoring.  AbbVie will not receive subject identifying information related to these shipments, 
as the site will work directly with the courier.
Shipments may also include other study supplies (e.g., pregnancy tests, paper copies of PROs).  
Instructions will be provided by AbbVie as to how a study site can initiate a DTP shipment using a local 
courier selected by AbbVie to provide this service when necessary.  Shipments of study drugs from the 
study site to a subject's home will be appropriately temperature-controlled (qualified shipper or 
temperature monitoring) within the labeled storage conditions.  Signature is required upon delivery; due 
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to COVID-19 related social distancing, this may be provided by the courier after delivery.  
Documentation of the shipment is to be retained by the clinical site.
3.19 Clinical Laboratory Tests
The blood samples for serum chemistry tests will be collected following a minimum 8-hour fast prior to 
study drug intake.  Subjects whose visits occur prior to the morning dose of study drug should be 
instructed to fast after midnight until the blood sample is collected in the morning and thereafter take 
their study drug with food.  Subjects whose visits occur after the morning dose of study drug should be 
instructed to fast after breakfast until the study visit occurs.  At the Baseline visit, a fasting blood sample 
should be collected.  Blood samples should still be drawn if the subject did not fast for at least 8 hours.  
Fasting or nonfasting status will be recorded in the source documents and on the laboratory requisition.  
The baseline laboratory test results for clinical assessment for a particular test will be defined as the last 
measurement prior to the initial dose of study drug.
A certified laboratory will be utilized to process and provide results for the clinical laboratory tests.  
Laboratory reference ranges will be obtained prior to the initiation of the study.
Instructions regarding the collection, processing, and shipping of these samples will be provided by the 
central laboratory and sent to the following certified laboratory addresses:
Covance CLS
8211 SciCor Drive
Indianapolis, IN 46214
If a laboratory test value is outside the reference range and the investigator considers the laboratory 
result to be clinically significant, the investigator will:
!
repeat the test to verify the out-of-range value;
!
follow the out-of-range value to a satisfactory clinical resolution; or
!
discontinue the subject from the study or require the subject to receive treatment; in this case, 
the laboratory result will be recorded as an AE.
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Table 1.
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)
Sodium
Potassium
Chloride
Bicarbonate
Blood urea nitrogen (BUN)
Serum creatinine
Glucose
Calcium
Total protein
Albumin
Total bilirubin 
Alanine aminotransferase 
Aspartate aminotransferase
Alkaline phosphatase
Uric acid
Low-density lipoprotein cholesterol 
(LDL-C)
High-density lipoprotein cholesterol 
(HDL-C)
Triglycerides
Total cholesterol
Endocrine Hormones/Tests
Follicle-stimulating hormone (FSH)
Luteinizing hormone (LH)
Fasting insulin
Glycated hemoglobin (HbA1c)
Testosterone
Sex hormone binding globulin 
(SHBG)
Progesterone
Androstenedione
Anti-Mullerian hormone (AMH)
Estradiol (E2)
Dehydroepiandrosterone sulfate 
(DHEAS)
Reflexive thyroid-stimulating
hormone
Prolactin
17-OH-progesterone (17-OH-P)
Urinalysis
Pregnancy Test
Other Tests (Screening Only)
Specific gravity
Ketones 
Leukocytes
Nitrites
Protein
Blood
Glucose
pH
Serum pregnancy
Urine pregnancy 
Hepatitis B surface antigen (HBsAg)
Hepatitis C virus antibody (HCVAb)
Hepatitis C virus RNA (HCV RNA)
Additional Blood Samples to be Collected
Elagolix single PK sample
LH/FSH single PD sample
Optional blood samples for exploratory research and validation studies.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If travel restrictions or other changes in local regulations in light of the COVID-19 pandemic prevent the 
subject from having blood drawn for laboratory testing at the study site, if possible, arrange for subjects 
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to have laboratory work done at a local lab, hospital, or other facility.  Local lab results should be 
obtained along with reference ranges and kept within the subjects' source documentation.  Local lab 
results should be reviewed by the investigator as soon as possible.
If laboratory samples cannot be collected, the site will need to reach out to the medical monitor to 
determine further action and if study drug should be discontinued.
Laboratory samples indicated in Table 1 will be sent to the certified central lab selected for this study.  
All laboratory samples listed above will be assessed using a certified laboratory selected for this study
and these data will be used for data analysis.  The central laboratory will provide instructions regarding 
the collection (including any fasting requirements), processing, and shipping of samples.  Blood draws 
should be performed after vital signs are conducted at a visit.
Clinical chemistry samples, insulin, and lipid panel 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.  
The central laboratory will provide the laboratory results to the investigative site where the investigator 
will review, sign, and date them.  For any value outside of the reference range, the investigator will 
review and indicate on the report if the result is clinically significant or not clinically significant.  The 
investigator will evaluate clinically significant laboratory values per standard of care which may include 
repeating the test to verify the out-of-range value.  Clinically significant laboratory abnormalities after 
randomization may be documented as AEs, depending on the investigator's interpretation.
All screening laboratory results must be reviewed prior to Baseline, including any repeated test results.  
Screening laboratory tests may be repeated one time prior to the Baseline Visit; however, results must 
satisfy entry criteria prior to randomization.  Subjects should not be randomized at Baseline Visit if 
screening laboratory results do not meet entry criteria or the investigator assesses them as clinically 
significant.  The most recent laboratory test results obtained prior to the Baseline Visit predose samples 
will serve as the Baseline for clinical assessment.
The investigator will receive sponsor-defined alerts from the central laboratory.  The investigator will 
review the lab alerts and assess clinical significance for potential AEs.
Serology Testing for Hepatitis
The central laboratory will test all subjects for hepatitis B surface antigen (HBsAg) and hepatitis C virus 
antibody (HCV Ab) during the Screening Period.  HCV RNA testing will be performed for those subjects 
with a positive HCV Ab.  A positive HBsAg or detectable HCV RNA will exclude subject from participation.  
Borderline hepatitis test results should be repeated.
Lipid Panel
The lipid panel consists of LDL-C, HDL-C, triglycerides, and total cholesterol; and should be obtained in 
the morning following an overnight fast (minimum of 8 hours); however, there may be circumstances 
when the sample is obtained later in the day and/or not under fasting conditions.  If the sample was 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-837 Version 4.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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 and/or serum 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.
The urine pregnancy test result on Baseline must be reviewed and confirmed to be negative prior to 
randomization.
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 Baseline 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 site should instruct the subject to complete a Premature 
Discontinuation visit within 2 to 7 days of study drug discontinuation.
If a subject is confirmed as pregnant, the subject will be prematurely discontinued from the study drug.  
For any subject who has a positive serum pregnancy test result, a transvaginal ultrasound (TVU) must be 
conducted as early as possible in the first trimester in order to assess the gestational age and estimated 
due date.
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 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.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event that a subject or study personnel cannot come to the site for a study visit requiring a urine 
pregnancy test because of the COVID-19 pandemic, home pregnancy test kits may be provided to 
subjects to self-administer at home and report results to study site over the phone.  If a urine pregnancy 
test cannot be completed, the site will need to reach out to the medical monitor to determine further 
action and if study drug should be discontinued.
Urinalysis
Urinalysis will be completed at all required visits.  Specified abnormal macroscopic urinalyses defined as 
leukocytes, nitrite, protein, ketones, or blood greater than negative, or glucose greater than normal will 
be followed up with a microscopic analysis at the central laboratory.
3.20 Subject Withdrawal from Study
All attempts must be made to determine the date of the last study drug dose and the primary reason for 
discontinuation of study drug 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 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-837 Version 4.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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
The study drug (elagolix or matching placebo) will be dispensed in the form of capsules at the visits 
listed in Section 2.2.
Study drug must not be dispensed without contacting the IRT system.  Study drug may only be 
dispensed to subjects enrolled in the study through the IRT system.  At the end of the Treatment Period 
or at the Premature Discontinuation visit, the site will contact the IRT system to provide visit date 
information and study drug return information for each kit.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event that a subject cannot come to the site because of the COVID-19 pandemic, the site may 
contact the IRT for kit assignment after ensuring subject is eligible to continue with study drug dosing 
and confirming that a home urine pregnancy test was performed and the result was negative.  Study 
drug dispensing can then be undertaken as outlined in Section 3.18.
6.2 Packaging and Labeling
All study drugs will be supplied in blister cards.
Each blister card will be labeled as required per country requirements.
The labels must remain affixed to the kit.  Upon receipt, study drug should be stored as specified on the
label and kept in a secure location.  Each kit will contain a unique kit number.  This kit number is 
assigned to a subject via IRT and encodes the appropriate study drug to be dispensed at the subject's 
corresponding study visit.  All blank spaces on the label will be completed by the site staff before 
dispensing to subjects.
Storage and Disposition of Study Drug
Elagolix and matching placebo study drug must be stored at controlled temperature 15° to 25°C (59° to 
77°F).  
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-837 Version 4.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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 Phase 2, multicenter, randomized, double-blind (sponsor-unblinded), placebo-controlled study.  
All eligible subjects will receive elagolix or matching placebo.
At the screening visit, all subjects will be assigned a unique subject number through the use of the IRT.  
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.  Upon receipt of study drug, the site will acknowledge receipt in the IRT system.
Contact information and user guidelines for IRT use will be provided to each site.
6.4 Selection and Timing of Dose for Each Subject
Study drug will be administered at the scheduled visits (Section 2.2) for the randomized subjects.  
Subjects will be instructed to take study drugs at the same time every day.
Study drug will be provided by AbbVie as capsules in dosages of 25 mg, 75 mg, 150 mg, and placebo 
capsules.
Study drug will be taken orally as 3 capsules each day.
7 REFERENCES
1.
Cronin G, Guyatt L, Griffith E, et al.  Development of a health-related quality-of-life 
questionnaire (PCOSQ) for women with polycystic ovary syndrome (PCOS).  J Clin Endocrin and 
Metab.  1998;83(6):1976-87.
2.
Hatch R, Rosenfield RS, Kim MH, et al.  Hirsutism:  implications, etiology, and management.  Am 
J Obstet Gynecol.  1981;140(7):815-30. 
3.
Columbia-Suicide Severity Rating Scale (C-SSRS) [homepage on the Internet].  Columbia 
University Medical Center [cited December 04, 2018].  Available from:  
http://cssrs.columbia.edu/.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-837 Version 4.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX A. E-DIARY FOR BLEEDING
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-837 Version 4.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX B. PATIENT GLOBAL IMPRESSION FOR ACNE AND 
HIRSUTISM
Patient Global Impression for Acne (PGIA)
Please choose the response below that best describes the overall change in your acne since you started 
taking the study medication. 
□ Much be_er 
□ A li_le be_er 
□ No change 
□ A li_le worse 
□ Much worse
Patient Global Impression for Hirsutism (PGIH)
Please choose the response below that best describes the overall change in your hair growth since you 
started taking the study medication. 
□ Much be_er 
□ A li_le be_er 
□ No change 
□ A li_le worse 
□ Much worse
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SAP_001.pdf: 
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M16-837 – Statistical Analysis Plan
Version 1.0 – 28 Oct 2019
1
Statistical Analysis Plan for Study M16-837
Phase 2, Multicenter, Double-blind (Sponsor-
unblinded), Randomized, Placebo-Controlled Study of 
the Safety and Efficacy of Elagolix in Women with 
Polycystic Ovary Syndrome
Date:  28 October 2019
Version 1.0
NCT03951077


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Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................5
2.1
Objectives ..................................................................................................5
2.2
Study Design Overview .............................................................................5
2.3
Treatment Assignment and Blinding .........................................................6
2.4
Sample Size Determination........................................................................6
3.0
Endpoints..................................................................................7
3.1
Primary Endpoint(s)...................................................................................7
3.2
Secondary Endpoint(s)...............................................................................7
3.3
Other Efficacy Endpoint(s)........................................................................7
3.4
Safety Endpoint(s) .....................................................................................8
4.0
Analysis Populations ...............................................................8
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............................................10
7.2
Medical History .......................................................................................11
7.3
Prior and Concomitant Medications ........................................................11
8.0
Efficacy Analyses...................................................................12
8.1
General Considerations............................................................................12
8.2
Handling of Missing Data........................................................................12
8.3
Primary Efficacy Endpoint(s) and Analyses............................................13
8.3.1
Primary Efficacy Endpoint(s) ..................................................................13
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) ......................16
8.4
Secondary Efficacy Analyses...................................................................17
8.5
Additional Efficacy Analyses ..................................................................17
8.5.1
Proportion of Complete Menstrual Cycle Responders ............................17
8.5.2
LH, FSH, testosterone and other hormones.............................................18


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8.5.3
Number of Menstrual Bleeding Episodes................................................18
8.5.4
Ovulations................................................................................................19
8.5.5
Change from baseline for other clinical efficacy endpoints ....................19
8.5.6
Patient Global Impression (PGI) for Acne and Hirsutism.......................20
9.0
Safety Analyses ......................................................................20
9.1
General Considerations............................................................................20
9.2
Adverse Events ........................................................................................21
9.2.1
Treatment-Emergent Adverse Events ......................................................21
9.2.2
Adverse Event Overview .........................................................................21
9.2.3
Treatment-Emergent Adverse Events by SOC and PT............................22
9.2.4
Deaths, Other Serious Adverse Events, and Adverse Events 
Leading to Study Drug Discontinuation ..................................................22
9.2.5
Adverse Events of Special Interest ..........................................................23
9.3
Analysis of Laboratory Data....................................................................23
9.4
Analysis of Vital Signs and Weight.........................................................25
9.5
Other Safety Analyses..............................................................................26
9.5.1
Columbia Suicide Severity Rating Scale (C-SSRS) ................................26
9.5.2
Bone Mineral Density..............................................................................27
9.5.3
Pregnancy Results....................................................................................28
10.0
Overall Type-I Error Control ..............................................28
11.0
Version History......................................................................28
12.0
References...............................................................................28
List of Tables
Table 1.
Examples of Menstrual Bleeding Episodes .............................................15
Table 2.
SAP Version History Summary...............................................................28
List of Figures
Figure 1.
Study Schematic.........................................................................................6


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List of Appendices
Appendix A.
Definition of Adverse Events of Special Interest ....................................29


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for Elagolix 
Study M16-837 'Phase 2, Multicenter, Double-blind (Sponsor-unblinded), Randomized, 
Placebo-Controlled Study of the Safety and Efficacy of Elagolix in Women with 
Polycystic Ovary Syndrome.'
The analyses of pharmacokinetic endpoints, pharmacodynamic endpoints, and biomarkers 
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.
2.0
Study Design and Objectives
2.1
Objectives
The objective of the study is to assess the pharmacokinetics, pharmacodynamics, safety, 
and efficacy of elagolix in women with Polycystic Ovary Syndrome (PCOS).
2.2
Study Design Overview
This is a Phase 2, randomized, double-blind (sponsor-unblinded), 6-month, placebo 
controlled, parallel group, multicenter study designed to assess the PK and PD of elagolix 
and to demonstrate the safety and efficacy of elagolix in women with PCOS.
The duration of the study could be up to 42 weeks, which includes an 8-week Washout (if 
necessary), a 6-week Screening Period, a 24-week Treatment Period, and a 30-day Post-
Treatment Follow-up Period.
The schematic of the study is presented in Figure 1.


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Figure 1.
Study Schematic
BID = twice daily; M = month; PTFU = post-treatment follow-up; QD = once daily
2.3
Treatment Assignment and Blinding
Stratified randomization will be performed by a ratio of 2:2:2:2:2:3 to the following 
treatments:  25 mg BID, 50 mg QD, 75 mg BID, 150 mg QD, 300 mg QD, or placebo 
(20 subjects in each active treatment group and 30 subjects in the placebo group). Subject 
randomization will be stratified based on Ferriman-Gallwey (FG) score (< 8, ≥ 8) and 
body mass index (BMI) (< 30, ≥ 30).
2.4
Sample Size Determination
The planned total sample size is 130 subjects: 20 subjects per elagolix treatment group 
and 30 subjects assigned to placebo.
The sample size will provide at least 85% power to detect a difference between each 
elagolix group and the placebo group in the proportion of menstrual cycle responders 
based on a Pearson Chi-square test, assuming response rates of 10% for the placebo group 
and 50% for the elagolix group with 2-sided α = 0.05.  The above sample size was 
calculated using nQuery advisor 7.0.


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3.0
Endpoints
3.1
Primary Endpoint(s)
The primary endpoint is the proportion of menstrual cycle responders as defined in 
Section 8.3.1.
3.2
Secondary Endpoint(s)
The secondary endpoint is change from Baseline to Week 1 in the area under the 
luteinizing hormone (LH) serum concentration-time curve (AUC) as defined in 
Section 8.4.
3.3
Other Efficacy Endpoint(s)
The primary and secondary efficacy endpoints are listed in Section 3.1 and Section 3.2, 
respectively. The additional efficacy endpoints are:
●
Proportion of complete menstrual cycle responders (normal menstrual cycles 
by the beginning of Month 3 and maintained thereafter each month through 
Month 6).
●
Change from Baseline in the LH serum AUC at each scheduled assessment 
during the Treatment Period.
●
Change from Baseline in the FSH serum AUC at each scheduled assessment 
during the Treatment Period. 
●
Change from Baseline in total and free testosterone serum concentration at 
each scheduled assessment during the Treatment Period.
●
Number of menstrual bleeding episodes during the Treatment Period.
●
Number of ovulations based on weekly serum progesterone level during the 
Treatment Period.
●
Proportion of subjects with at least 2 ovulations during the Treatment Period
●
Endpoints related to hyperandrogenism – Patient Global Impression (PGI) for 
both acne and hirsutism; change from Baseline at each scheduled assessment 
during the Treatment Period for the following:  acne measured with total lesion 


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count and investigator's global assessment (IGA), hirsutism measured with 
Ferriman–Gallwey (FG) score.
●
Endpoints related to metabolic features - change from Baseline at each 
scheduled assessment during the Treatment Period for the following:  glycated 
hemoglobin (HbA1c), fasting insulin/glucose, body mass index (BMI), lipids, 
waist circumference.
●
Change from Baseline at each scheduled assessment during the Treatment 
Period for additional hormones:  androstenedione, anti-Mullerian hormone 
(AMH), estradiol (E2), progesterone.
●
Change from Baseline in ovarian volume at each scheduled assessment during 
the Treatment Period.
●
Endpoints related to the subject's quality of life:  change from Baseline in 
domains from the Polycystic Ovary Syndrome Questionnaire (PCOSQ) 
(emotions, body hair, weight, infertility problems, and menstrual problems) 
and the Menstrual Bleeding Questionnaire (MBQ) at each scheduled 
assessment during the Treatment Period.
3.4
Safety Endpoint(s)
Safety evaluations include physical examination, vital signs, pelvic ultrasound 
(transabdominal ultrasound [TAU] and transvaginal ultrasound [TVU]), clinical 
laboratory tests (including hematology, chemistry, urinalysis, and lipid panel), bone 
mineral density (BMD) via dual energy X-ray absorptiometry (DXA) examinations, and 
adverse event (AE) monitoring for the entire study duration.
4.0
Analysis Populations
The following population sets will be used for the analyses.
The Full Analysis Set (FAS) consists of all randomly assigned subjects who have received 
at least one 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 the subject does not 


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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 consists of all subjects who received at least one dose of study 
drug.  The data from the safety analysis set will be presented by the treatment actually 
received no matter what treatment group was assigned at the time of randomization.  If a 
subject takes more than one treatment, the subject will be analyzed in the safety analysis 
set as taking the treatment to which she was randomized.  All safety analyses will be 
performed based on the safety analysis set.
5.0
Subject Disposition
The total number of subjects who were randomized and who completed the study will be 
summarized by treatment group and overall. In addition, reasons for study 
discontinuation will be summarized.
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:  
●
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;
The number and percentage of subjects who discontinued study drug will be summarized 
by treatment group and overall as follows:
●
By any reason for discontinuation;
●
By primary reason for discontinuation.
In addition, the number and percentage of subjects who discontinued study will be 
summarized by treatment group and overall as follows:


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●
By any reason for discontinuation;
●
By primary reason for discontinuation.
6.0
Study Drug Duration
For the Safety Analysis Set, duration of treatment will be summarized for each treatment 
group and for all investigational study drug dose 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 in each treatment duration interval (1 – 28, 29 – 56, 57 – 84, 85 – 112, 113 – 140, 
141 – 168, and > 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 by treatment group and overall using the 
FAS.  Categorical variables will be summarized with the number and percentage of 
subjects; percentages will be calculated based on the number of non-missing observations.  
Continuous variables will be summarized with descriptive statistics (number of 
non-missing observations, mean and standard deviation, median, minimum and 
maximum).
7.1
Demographics and Baseline Characteristics
Continuous demographic variables include age, weight, height, waist circumference, and 
body mass index (BMI).  Categorical demographic variables include sex, ethnicity, race, 
age (18 – 26, 27 – 35 years), BMI (18.5 – < 25, 25 – < 30, ≥ 30 kg/m2), tobacco use 
(current, former, never, unknown), and alcohol user (current, former, never, unknown).
Disease characteristics include menstrual and obstetrical history. Continuous variables 
include number of days bleeding. Categorical variables include cycle length (> 35 days 


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[yes/no]), typical intensity of menstrual periods (light, moderate, heavy), ever been 
pregnant (yes/no), and number of pregnancies (0, 1, 2, 3, 4, > 4), and congenital 
abnormality (yes/no).
7.2
Medical History
Medical history and gynecological medical/surgical history data will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  The actual version of the 
MedDRA coding dictionary will be noted in the statistical tables and clinical study report.  
The number and percentage of subjects in each medical history category (by MedDRA 
system organ class and preferred term) will be summarized by treatment group and 
overall.  The system organ class (SOC) will be presented in alphabetical order, and the 
preferred terms will be presented in alphabetical order within each SOC.  Subjects 
reporting more than one condition/diagnosis will be counted only once in each row (SOC 
or preferred term).
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name.
Prior medications are those medications with a start date prior to the first study drug 
administration date. 
Concomitant medications are those medications taken during the Treatment Period with 
an end date after the first dose of study drug or ongoing at the end of the study, and a start 
date prior to the last dose of study drug. A medication will be considered a concomitant 
medication where one of the following three cases occur (1) the start date is missing and 
the end date is either after or on the first study drug dose date; (2) the start date is not 
missing and the end date is missing; (3) both the start date and the end date are missing.
Prior and concomitant medications will be summarized by ATC Classification and 
preferred terms from the World Health Organization (WHO) Drug Dictionary with 
number and percentage for each treatment group and overall. A subject who reports two 


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or more uses of the same medication will be counted only once within each WHO 
preferred term. A subject with medications with more than one generic name will be 
counted only once in the overall total.
8.0
Efficacy Analyses
8.1
General Considerations
All efficacy analyses will be conducted using the FAS.  Unless otherwise specified, each 
elagolix dose group will be compared to placebo. All statistical tests will be conducted at 
an alpha level of 0.1 (two-sided). A test will be deemed significant if the P value rounded 
to three decimal places is less than or equal to 0.1 unless otherwise specified.
Unless otherwise specified, categorical data will be summarized by frequencies and 
percentages for each treatment group and overall; continuous data will be summarized by 
the mean, standard deviation, median, minimum, and maximum for each treatment group 
and overall. For the analyses of change from baseline, the within-group changes will be 
summarized with the mean, standard deviation, and the median; between-group 
differences will be summarized with the mean, standard error, P value, and the 90% CIs.
Baseline refers to the last non-missing value obtained prior to or on Study Day 1.
8.2
Handling of Missing Data
Missing data will be imputed using the following methods for the efficacy analyses:
Mixed-Effect Model Repeat Measurement (MMRM):  The repeated measures analyses 
will be conducted using mixed models including observed measurements at all visits.  The 
mixed model includes the categorical fixed effects of treatment, visit and treatment-by-
visit interaction, subject as a random effect, and the continuous fixed covariates of 
baseline measurement.  An unstructured variance covariance matrix will be used.  
Parameter estimation is based on the assumption of data being missing at random and 
using the method of restrictive maximum likelihood (REML). Missing data will not be 
imputed for MMRM analysis.


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Observed Cases (OC):  The OC analysis will not impute values for missing evaluations, 
and thus a subject who does not have an evaluation on a scheduled visit will be excluded 
from the OC analysis for that visit.  OC will exclude values after a subject prematurely 
discontinues from study drug.
Multiple Imputation (MI): The MI approach will be used as a sensitivity analysis for the 
primary endpoint. For the primary endpoint, 20 'complete' datasets will be generated 
using SAS PROC MI. The seed will be 123. Using the Cochran-Mantel-Haenszel 
(CMH) model adjusted for FG score (< 8, ≥ 8) and normal/obese status (BMI < 30, ≥ 30) 
at Baseline, the imputed endpoints will be analyzed using each of the 20 datasets.  SAS 
PROC MIANALYZE will be used to generate the final inferences of difference of 
proportion of menstrual cycle responders between each elagolix group and placebo.
8.3
Primary Efficacy Endpoint(s) and Analyses
8.3.1
Primary Efficacy Endpoint(s)
The primary efficacy endpoint is the proportion of menstrual cycle responders. 
A subject is considered as a menstrual cycle responder if she has at least 2 normal 
menstrual cycles during the final 4 months of the Treatment Period. For subjects who 
complete the treatment period this will be Month 3 to Month 6; for subjects who 
prematurely discontinue at Month X, where X is greater than or equal 4, this will be 
Month (X – 3) to Month X; for subjects who prematurely discontinue at Month X, where 
X is less than 4, this will be Month 1 to Month X.  A normal menstrual cycle will be
defined as follows:
a.
Subject has menstrual bleeding (excluding spotting only) AND
b. The length of the menstrual cycle is from 21 to 35 days.  Menstrual cycle length is 
defined as the length of time from the first day of one menstrual bleeding episode 
to the day before the next menstrual bleeding episode (calculated by [first day of 
the next menstrual bleeding episode] minus [the first day of the referenced 
bleeding episode]).


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A menstrual bleeding episode is defined with the following rules:
a.
A bleeding episode requires at least one of the following:
●
At least 2 consecutive days of bleeding, OR
●
At least 1 day of bleeding followed immediately by 1 day of spotting or 1 day 
of missing data then spotting or 1 day of missing data then bleeding, OR
●
At least 1 day of spotting followed immediately by 1 day of bleeding or 1 day 
of missing data then bleeding.
b. Consecutive days of spotting only with no days of bleeding are not considered as 
an episode.
c.
If consecutive days of spotting are adjacent to a day with bleeding, then these 
consecutive days with spotting are counted as part of the same bleeding episode.
d. One day of missing data between a spotting day and bleeding day or between 
2 bleeding days qualifies as part of the same bleeding episode.
Examples are presented in Table 1.




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two-sided p-value for the comparison of the proportion of menstrual cycle responders 
between that elagolix group and placebo is less than or equal to 0.1 and in favor of the 
elagolix group.
For the primary efficacy endpoint, the pairwise comparisons for the difference in 
proportion of menstrual cycle responders between each elagolix group and placebo will be 
analyzed using the Cochran-Mantel-Haenszel test (CMH) adjusted for FG score (< 8, ≥ 8) 
and normal/obese status (BMI < 30, ≥ 30) at Baseline. Additionally, the CMH-based 90% 
confidence interval for the difference in proportion of responders within each FG score 
(< 8, ≥ 8) and normal/obese status (BMI < 30, ≥ 30) at Baseline will be calculated based 
on normal approximation.
8.3.4
Additional Analyses of the Primary Efficacy Endpoint(s)
The following sensitivity analyses for the primary efficacy endpoint will be conducted:
1.
The menstrual cycle response for subjects who prematurely discontinue the study 
drug at or before Month 4 will be considered as missing. Multiple imputation (MI) 
approach will be used for the primary endpoint. Details regarding MI are in 
Section 8.2. 
2.
Subjects who prematurely discontinue study drug during the Treatment Period due 
to "lack of efficacy" or adverse event (AE) will be considered as non-responders, 
while subjects who discontinue study drug during the Treatment Period due to 
other reasons will be categorized as responders/non-responders in the same manner 
as done in the primary analysis.
3.
All subjects who prematurely discontinue the study drug at or before Month 4 will 
be considered as non-responders and the primary analysis will be repeated. 
Subjects who discontinue after Month 4 will be categorized as responders/non-
responders in the same manner as done in the primary analysis.
4.
The difference between each elagolix group and placebo group in proportion of 
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regression model with the responder/non-responder categorization as the dependent 
variable, treatment as the main effect, and baseline FG score (< 8, ≥ 8) and baseline 
normal/obese status (BMI < 30, ≥ 30) as the covariates. The proportion of 
menstrual cycle responders, difference in proportions between each elagolix group 
and placebo, and odds ratio with corresponding 90% confidence interval and 
P value will be presented.
8.4
Secondary Efficacy Analyses
The key secondary endpoint is change from baseline in the area under the luteinizing 
hormone (LH) serum concentration-time curve over the 4 hours (area under the curve 
[AUC]) at Day 7. Serial blood samples for LH assay will be collected at Baseline and 
Weeks 1, 4, and 16 according to the following schedule: 0 hour, 0.5, 1, 1.5, 5, 2.5, 3, 3.5, 
and 4 hours.  The AUC over the 4 hours will be calculated based on the linear trapezoidal 
rule. 
The analysis for the key secondary endpoint will be based on a mixed-effects model with 
repeated measures (MMRM). If appropriate, the natural logarithmic transformation or 
other transformation may be employed for LH AUC. The MMRM analysis will include 
the fixed categorical effects of treatment, visit, treatment-by-visit interaction, baseline FG 
score (< 8, ≥ 8), and baseline normal/obese status (BMI < 30, ≥ 30), subject as a random 
effect, and the continuous fixed covariate of baseline LH AUC. Each elagolix dose group 
will be compared to the placebo group; the LS mean of treatment difference and 
associated 90% CI and p-value will be reported. 
8.5
Additional Efficacy Analyses
8.5.1
Proportion of Complete Menstrual Cycle Responders
A subject is considered as a complete menstrual cycle responder if she has normal 
menstrual cycles by the beginning of Month 3 and maintained thereafter each month 
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Month 6 during the Treatment Period will be considered as non-responders. A normal 
menstrual cycle has been defined in Section 8.3.1.
The pairwise comparisons for the difference in proportion of complete menstrual cycle 
responders between each elagolix group and placebo will be analyzed using the Cochran-
Mantel-Haenszel test (CMH) adjusted for FG score (< 8, ≥ 8) and normal/obese status 
(BMI < 30, ≥ 30) at Baseline. Additionally, the CMH-based 90% confidence interval for 
the difference in proportion of complete menstrual cycle responders within each FG score 
(< 8, ≥ 8) and normal/obese status (BMI < 30, ≥ 30) at Baseline will be calculated based 
on normal approximation.
Same analysis will be conducted excluding subjects who premature discontinue during the 
Treatment Period.
8.5.2
LH, FSH, testosterone and other hormones 
The changes from baseline to each scheduled assessment of the hormone parameters will 
be analyzed using a mixed-effects model with repeated measures (MMRM). If 
appropriate, the natural logarithmic transformation or other transformation may be 
employed for the hormone parameters. The MMRM analysis will include the fixed 
categorical effects of treatment, visit, treatment-by-visit interaction, baseline FG score 
(< 8, ≥ 8), and baseline normal/obese status (BMI < 30, ≥ 30), subject as a random effect. 
and the continuous fixed covariate of baseline hormone value. 
8.5.3
Number of Menstrual Bleeding Episodes 
Number of menstrual bleeding episodes during the Treatment Period will be analyzed 
using one-way ANCOVA with treatment group as the main effect, and baseline FG score 
(< 8, ≥ 8) and normal/obese status (BMI < 30, ≥ 30) as the covariates. Subjects who 
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In addition, number of menstrual bleeding episodes per months of treatment will be 
analyzed using one-way ANCOVA with treatment group as the main effect, and baseline 
FG score (< 8, ≥ 8) and normal/obese status (BMI < 30, ≥ 30) as the covariates.
8.5.4
Ovulations
Determination of ovulation will be based on weekly serum progesterone level; a 
progesterone level ≥ 3 ng/mL will be used to indicate ovulation. One ovulation is defined 
as one weekly or more than one consecutive weekly serum progesterone level ≥ 3 ng/mL 
with the prior weekly serum progesterone level < 3 ng/mL or missing and the following 
weekly serum progesterone level < 3 ng/mL or missing.
Number of ovulations during the Treatment Period will be analyzed using one-way 
ANCOVA with treatment group as the main effect, and baseline FG score (< 8, ≥ 8) and 
normal/obese status (BMI < 30, ≥ 30) as the covariates. In addition, the proportion of 
subjects with at least 2 ovulations during the Treatment Period will be analyzed using the 
Cochran-Mantel-Haenszel test (CMH) adjusted for FG score (< 8, ≥ 8) and normal/obese 
status (BMI < 30, ≥ 30) at Baseline. Subjects who premature discontinue during the 
Treatment Period will be excluded from both analyses. 
In addition, number of ovulations per months of treatment will be analyzed using one-way 
ANCOVA with treatment group as the main effect, and baseline FG score (< 8, ≥ 8) and 
normal/obese status (BMI < 30, ≥ 30) as the covariates.
8.5.5
Change from baseline for other clinical efficacy endpoints
Change from baseline to each scheduled assessment for the following endpoints will be 
analyzed: acne measured with total lesion count and investigator global assessment of 
acne, hirsutism measured with Ferriman–Gallwey (FG) score, metabolic features (Hb 
A1c, fasting insulin/glucose, body mass index (BMI), lipids [LDL cholesterol, HDL 
cholesterol, total cholesterol, triglycerides], waist circumference), ovarian volume, and 
endpoints related to subject's quality of life (PCOSQ [emotions, body hair, weight, 
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one-way ANCOVA with treatment group as the main effect, and baseline FG score (< 8, 
≥8), baseline normal/obese status (BMI < 30, ≥ 30), and baseline value of the 
corresponding endpoint being analyzed as the covariates.
8.5.6
Patient Global Impression (PGI) for Acne and Hirsutism
For patient global impression for acne and hirsutism (PGIA and PGIH), the number and 
percentage of subjects in each response category will be summarized at each scheduled 
assessment during the Treatment Period. No statistical test will be performed.
For PGIA and PGIH, the response categories of "Much better" and "A little better" will be 
combined together. The remaining four categories will be combined and labeled 
"Otherwise." The number and percentage of subjects with response of (a) "Much better" 
or "A little better," and (b) "Otherwise" will be summarized at each scheduled assessment 
during the Treatment Period. Comparisons between each elagolix group and placebo will 
be made using a logistic regression model with (a) "Much better" or "A little better"/(b) 
"Otherwise" as the dependent variable, treatment as the main effect, and baseline FG 
score (< 8, ≥ 8) and baseline normal/obese status (BMI < 30, ≥ 30) as the covariates.
9.0
Safety Analyses
9.1
General Considerations
Safety analyses will be carried out using Safety Analysis Set. All safety analyses will be 
based on observed data. Unless otherwise specified, missing data will not be imputed.
For continuous variables, when the analyses of change and/or percent change from 
Baseline to post-baseline visit(s) are performed, the within-group change from Baseline to 
each relevant visit will be summarized by treatment group with the mean, SE, and 95% 
CIs. The between-group differences will be summarized with the mean, SE, 95% CIs, 
and P value when applicable. P value will be compared to an alpha level of 0.05. At each 
post-baseline visit, the Baseline mean and post-baseline visit mean will be calculated for 
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Categorical data will be summarized by number and percentage of subjects by treatment 
group.
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. 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 Preferred Term.  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 AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any treatment-emergent AE
●
Any treatment-emergent AE related to study drug according to the investigator
●
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Any serious treatment-emergent AE
●
Any treatment-emergent AE leading to discontinuation of study drug
●
Any treatment-emergent AE of special interest as specified in Appendix A
●
Any treatment-emergent AE leading to death
●
All deaths
9.2.3
Treatment-Emergent Adverse Events by SOC and PT
Treatment-emergent adverse events will be summarized by SOC and PT; by maximum 
relationship to study drug as assessed by the investigator (e.g., reasonable possibility or no 
reasonable possibility) and SOC and PT; by maximum severity and SOC and PT; and by 
subject number and SOC and PT.  Specific adverse events will be counted once for each 
subject for calculating percentages, unless stated otherwise.  In addition, if the same 
adverse event occurs multiple times within a subject, the highest severity and level of 
relationship to investigational product will be reported.
In addition, treatment-emergent adverse events will be summarized by PT and sorted by 
decreasing frequency for the total active group.
9.2.4
Deaths, Other Serious Adverse Events, and Adverse Events 
Leading to Study Drug Discontinuation
The number and percentage of subjects experiencing the following categories will be 
tabulated according to the primary MedDRA SOC and PT. In addition, listing of subjects 
experiencing the following categories will be generated.
●
Treatment-emergent SAEs
●
Treatment-emergent AEs leading to discontinuation of study drug
●
Treatment-emergent AEs leading to death


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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 or CMQs), or based on 
adjudication results.  Adverse events of special interest are categorized as follows:
●
Elevated hepatic transaminases
●
BMD decrease/fractures
●
Mood and depression-related events
Detailed information about the search criteria are provided in Appendix A.
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.  Mean change from baseline to each applicable post-baseline 
visit will be summarized for selected laboratory variables, with the number of 
observations, baseline mean, and visit mean.  The change from baseline mean, standard 
error, and 95% confidence interval will be presented for the mean change from baseline 
within each treatment group and difference between each elagolix group and placebo. 
Selected laboratory variables are lipid variables, liver variables (alkaline phosphatase, 
ALT, AST, bilirubin), hemoglobin, hematocrit, platelet count, and red blood cell (RBC) 
count.
Changes in 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 


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laboratory used for each sample.  A shift table from baseline either to the worse value 
(based on NCI CTC criteria) during treatment or to minimum and maximum value (based 
on normal range), will be created.  A similar shift table will be provided to summarize 
shifts from baseline to the final post-baseline value. 
Laboratory abnormalities meeting CTCAE 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 relevant visit by treatment group in the Treatment Period:
●
Total cholesterol:  ≤ 300, > 300 – ≤ 400, > 400 – ≤ 500, and > 500 mg/dL
●
HDL-C:  < 40 and ≥ 40 mg/dL
●
LDL-C:  < 130, ≥ 130 – < 160, ≥ 160 – < 190, and ≥ 190 mg/dL
●
TG:  ≤ 150, > 150 – ≤ 300, > 300 – ≤ 500, > 500 – ≤ 1000, and > 1000 mg/dL
In addition, the number and percentage of subjects who have potentially clinically 
significant (PCS) lipid values meeting the following criteria any time during the 
Treatment Period will be summarized by treatment group: Listings will be provided to 
summarize subject-level laboratory data for subjects meeting PCS criteria.
●
Total cholesterol > 200 mg/dL
●
LDL-C > 130 mg/dL
●
LDL-C > 160 mg/dL
●
HDL-C < 40 mg/dL
●
TG > 150 mg/dL
The number and percentage of subjects in each treatment group with maximum on 
treatment laboratory values meeting the following criteria compared to the upper limit of 
normal (ULN) will be summarized by treatment group to assess potential hepatotoxicity.
●
ALT ≥ 3 × ULN and total bilirubin ≥ 2 × ULN
●
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ALT and AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN
●
ALT ≥ 3 × ULN and total bilirubin < 2 × ULN
●
AST ≥ 3 × ULN and total bilirubin < 2 × ULN
●
ALT and AST ≥ 3 × ULN and total bilirubin < 2 × ULN
●
ALT ≥ 3 × ULN and total bilirubin ≥1.5 × ULN
●
AST ≥ 3 × ULN and total bilirubin ≥ 1.5 × ULN
●
ALT and AST ≥ 3 × ULN and total bilirubin ≥ 1.5 × ULN
●
ALT ≥ 3 × ULN, ≥ 5 × ULN, ≥ 10 × ULN, ≥ 20 × ULN
●
AST ≥ 3 × ULN, ≥ 5 × ULN, ≥ 10 × ULN, ≥ 20 × ULN
●
Total bilirubin ≥ 1.5 × ULN, ≥ 2.0 × ULN
The maximum ratio relative to the ULN is used to determine if subjects met the criteria 
listed above.  The ALT, AST, and total bilirubin values do not need to be concurrent in 
order to meet the defined criteria.  For ALT, AST, and total bilirubin, a subject is counted 
if the post-baseline laboratory value during the Treatment Period meets the above criteria 
regardless of Baseline laboratory value (i.e., the post-baseline laboratory value does not 
need to be worse than Baseline laboratory value).
A listing of all ALT, AST, total bilirubin, and alkaline phosphatase values will be 
provided for each subject who met any of the criteria defined above.
The following plots will be generated:  peak AST vs. peak bilirubin; peak ALT vs. peak 
bilirubin.
9.4
Analysis of Vital Signs and Weight
Vital sign variables include sitting systolic blood pressure and sitting diastolic blood 
pressure.
Each vital sign variable and weight will be summarized for all time points (starting with 
Baseline) with the number of non-missing observations, mean and standard deviation, 
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baseline visit will be summarized for each vital sign variable, with the number of 
observations, baseline mean, and visit mean.  The change from baseline mean, standard 
error, and 95% confidence interval will be presented for the mean change from baseline 
within each treatment group and difference between each elagolix group and placebo.
The number and percentage of subjects who have potentially clinically significant (PCS) 
vital sign and weight values meeting the following criteria will be summarized by 
treatment group.  All increase/decrease is calculated from Baseline to a post-baseline visit 
in the Treatment Period.
●
Diastolic blood pressure
○
≤ 50 mmHg and ≥ 15 mmHg decrease
○
> 90 mmHg and ≥ 15 mmHg increase
○
≥ 100 mmHg
●
Systolic blood pressure
○
≤ 90 mmHg and ≥ 20 mmHg decrease
○
≥ 140 mmHg and ≥ 20 mmHg increase
○
≥ 160 mmHg
●
Weight
○
≥ 5% decrease
○
≥ 7% increase.
Listings will be provided to summarize subject-level vital sign and weight data for 
subjects meeting PCS criteria.
9.5
Other Safety Analyses
9.5.1
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS data will be summarized as observed by treatment group.
The C-SSRS – Baseline/Screening measured at Day 1 will be considered as Baseline 
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C-SSRS will only include subjects who have at least 1 post-baseline C-SSRS 
measurement, regardless of whether they had a baseline C-SSRS measurement.  The 
number of subjects with suicidal ideation, suicidal behavior, and self-injurious behavior 
without suicidal intent at each scheduled assessment during Treatment Period will be 
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.
The number of subjects with suicide-related treatment-emergent events based on the 
C-SSRS during Treatment Period will be summarized.  No statistical tests will be 
performed. 
A listing of subjects with suicidal ideation, suicidal behavior, or self-injurious behavior 
without suicidal intent based on the C-SSRS during treatment period will be provided.
9.5.2
Bone Mineral Density
All analyses and summaries of bone mineral density (BMD) will be performed for each 
segment, i.e., femoral neck, lumbar spine, and total hip.  For subjects who had a right-side 
scan performed (rare instances), their data for right femoral neck and right femoral total 
hip will be included in the analysis with the data for the left femoral neck and left total 
hip, respectively (available for the majority of subjects).  If more than one scan is reported 
for an anatomical segment within an analysis window, the worse (the lower value) of the 
multiple measurements will be used for analysis for each anatomical segment.  The 
analyses below will exclude subjects who switch machine manufacturer types between 
baseline and post-baseline.
A continuous summary of BMD at Baseline and Month 6 will be provided by treatment 
group.  This summary will include the mean, SD, median, minimum, and maximum.  
The analysis of percent change from baseline in BMD during the Treatment Period will be 
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corresponding parameter as a covariate. Each elagolix group will be compared to 
placebo. 
The number and percentage of subjects with percent change from Baseline to Month 6 
during the Treatment Period in mutually exclusive categories of BMD decrease:  ≤ 0%, 
> 0% – ≤ 1.5%, > 1.5% – ≤ 3%, > 3% – ≤ 5%, > 5% – < 8%, and ≥ 8% will be 
summarized by treatment group. The comparison between each elagolix group and 
placebo will be made using Fisher's exact test.
A listing of subjects with BMD decrease from baseline ≥ 8% will be provided.
9.5.3
Pregnancy Results
Pregnancy information will be summarized by treatment group.
10.0
Overall Type-I Error Control
This is a Phase 2 proof of concept study; therefore, there will be no control of Type I error
for primary, secondary, or exploratory analyses for this study.
11.0
Version History
Table 2.
SAP Version History Summary
Version
Date
Summary
1.0
29 Oct 2019
Original version
12.0
References


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Appendix A.
Definition of Adverse Events of Special Interest
Adverse Events of Special Interest (AESI) will be identified using the following search 
criteria:
Item of Safety Interest
Method of Surveillance
Bone Mineral Density Loss
Osteoporosis/Osteopenia SMQ
Bone Fractures
Osteoporosis/Osteopenia SMQ
Mood and Depression-related Events
Depression and Suicide/Self-Injury SMQ
Elevated Hepatic Transaminases
Hepatic Questionnaire and the Drug-related hepatic 
disorders – comprehensive SMQ