Elagolix (ABT-620) M12-817 Clinical Study Report R&D/17/0779 2.0 Synopsis AbbVie Inc. Individual Study Table Referring (For National Authority to Part of Dossier: Use Only) Name of Study Drug: Volume: Elagolix (ABT-620) Page: Name of Active Ingredient: Elagolix Title of Study: A Phase 3 Study to Evaluate the Efficacy and Safety of Elagolix in Combination with Estradiol/Norethindrone Acetate for the Management of Heavy Menstrual Bleeding Associated with Uterine Fibroids in Premenopausal Women Coordinating Investigator: Study Sites: 77 sites in the United States and Canada Publications: 1 published abstract Studied Period (Years): Phase of Development: 3 First Subject First Visit: 03 February 2016 Last Subject Last Visit: 23 January 2019 Objectives: 1) to assess the efficacy, safety, and tolerability of elagolix 300 mg twice a day (BID) in combination with estradiol 1 mg/norethindrone acetate 0.5 mg (E2/NETA) once a day (QD) versus placebo to reduce heavy menstrual bleeding (HMB) associated with uterine fibroids, 2) to characterize the impact of E2/NETA on the safety/tolerability (including bone mineral density [BMD] and other hypoestrogenic side effects) and efficacy of elagolix. Methodology: This Phase 3, randomized, double-blind, multicenter, placebo-controlled study was designed to evaluate the efficacy, safety, and tolerability of elagolix 300 mg BID in combination with E2/NETA QD in the management of HMB associated with uterine fibroids in premenopausal women 18 to 51 years of age, inclusive. The study consisted of 4 periods: 1) a Washout Period (if applicable), 2) a Screening Period of approximately 2.5 to 3.5 months prior to first dose of study drug, 3) a 6-month Treatment Period, and 4) a 12-month Post-Treatment Follow-Up (PTFU) Period for subjects who either prematurely discontinued from the Treatment Period or completed the Treatment Period but did not enroll in the extension study (Study M12-816). 1 Elagolix (ABT-620) M12-817 Clinical Study Report R&D/17/0779 Methodology (Continued): Potential subjects were required to meet eligibility criteria and provide informed consent before washout (if applicable), or initiation of any screening or study-specific procedures. Subjects were to visit the site for assessments and testing during the Washout Period (for subjects who were taking exclusionary medications such as hormonal medications or antifibrinolytics that required washout), during the Screening Period (Initial Screening Visit and Screening Product Collection Visits), and Treatment Period (Day 1 [Randomization] and monthly during Month 1 through Month 6). Eligible subjects were randomized in a 1:1:2 ratio to 1 of 3 treatment groups: placebo, elagolix 300 mg BID, or elagolix 300 mg BID+E2/NETA QD. Eligible subjects who completed the 6-month Treatment Period were allowed to participate in a 6-month extension study in which all subjects received active treatment with either elagolix 300 mg BID alone or elagolix 300 mg BID+E2/NETA. Subjects who did not enroll in the extension study were to enter a 12-month PTFU Period with phone or on-site visits every month. All subjects, except those who were exempted per protocol, were to use at least 2 forms of nonhormonal contraception (nonhormonal dual contraception) consistently throughout the Washout (if applicable), Screening, Treatment Period, and PTFU Period and receive counseling on the importance of consistent, appropriate, and effective use of birth control. Hormonal contraception was permitted after completion of the PTFU Month 2 Visit if menses had returned. Number of Subjects (Planned and Analyzed): 400 planned; 378 randomized; 378 analyzed. Placebo: 100 planned, 94 analyzed; elagolix 300 mg BID: 100 planned, 95 analyzed; elagolix 300 mg BID+E2/NETA: 200 planned, 189 analyzed. Diagnosis and Main Criteria for Inclusion: Premenopausal women, 18 to 51 years of age, inclusive, were eligible for enrollment if they had a diagnosis of uterine fibroids that was documented by a pelvic ultrasound acquired at Screening (specifically, an intramural, submucosal non-pedunculated fibroid with total diameter ≥ 2 cm [longest diameter]; a subserosal fibroid ≥ 4 cm; or multiple fibroids with a total uterine volume of ≥ 200 cm3 to ≤ 2,500 cm3), adequate endometrial biopsy with no clinically significant endometrial pathology, and HMB evidenced by menstrual blood loss (MBL) > 80 mL per menstrual cycle as calculated by the alkaline hematin method. Subjects were excluded if they had menstrual cycles that were > 38 days in length for the 3 months before Screening; a clinically significant gynecological disorder; a BMD T-score of the lumbar spine, femoral neck, or total hip ≤ –1.5 at Screening; a myomectomy, uterine artery embolization, or high-intensity focused ultrasound within 6 months before Screening; or endometrial ablation within 1 year before Screening. Subjects with coexisting adenomyosis were eligible for this study regardless of the type of adenomyosis (i.e., focal, diffuse dominant [> 50% of the myometrium], or diffuse nondominant) as long as they had a qualifying fibroid and HMB as required per protocol. Test Product, Dose/Strength/Concentration, Mode of Administration and Lot Number: Orally administered tablets of elagolix 300 mg BID (lot numbers 16-000707, 15-004747) and orally administered over-encapsulated tablets of E2/NETA (1 mg/0.5 mg) QD (lot numbers 15-006127,16-001698,16-002891, 17-001331). Duration of Treatment: 6 months of treatment with a 12-month follow-up period for subjects who did not enroll in the extension study (Study M12-816). 2 Elagolix (ABT-620) M12-817 Clinical Study Report R&D/17/0779 Reference Therapy, Dose/Strength/Concentration and Mode of Administration and Lot Number: Orally administered tablets of placebo for elagolix 300 mg BID (lot numbers 16-000708, 15-004564) and capsules of placebo for E2/NETA (1 mg/0.5 mg) QD (lot numbers 12-004118,16-003269) Criteria for Evaluation Efficacy: The primary endpoint was the percentage of responders, defined as subjects who met the following conditions: MBL volume < 80 mL during the Final Month (the last 28 days prior to and including the Reference Day), and ≥ 50% reduction in MBL volume from Baseline to the Final Month (the last 28 days prior to and including the Reference Day). A subject who prematurely discontinued study drug because of adverse events (AEs), "lack of efficacy," or "requires surgery or invasive intervention for treatment of uterine fibroids" was considered to be a nonresponder regardless of whether she met the aforementioned responder criteria or not. The ranked secondary efficacy endpoints were: 1. change from Baseline in MBL volume to the Final Month, 2. percentage of subjects with suppression of bleeding (no bleeding allowed, spotting allowed) at the Final Month, 3. change from Baseline in MBL volume to Month 6, 4. change from Baseline in MBL volume to Month 3, 5. percentage of subjects with baseline hemoglobin (Hgb) ≤ 10.5 g/dL who had an increase in Hgb > 2 g/dL at Month 6, and 6. change from Baseline in MBL volume to Month 1. Other efficacy endpoints during the Treatment Period included other analysis of MBL volume, amenorrhea, suppression of bleeding, control of bleeding, bleeding days, Hgb concentration, uterine and fibroid volume, and quality of life. Pharmacodynamic/Pharmacokinetic: Pharmacodynamic (PD) variables were serum concentrations of estradiol (E2), progesterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Pharmacokinetic (PK) variables were plasma exposures to elagolix and norethindrone. Safety: Safety evaluations were BMD changes, AEs (including AEs of special interest [AESI]), clinical laboratory parameters (including liver and lipid profiles), vital signs, electrocardiograms, endometrial assessment (endometrial thickness and biopsy), ovarian cysts, Columbia-Suicide Severity Rating Scale (C-SSRS), pregnancy, and product complaints. 3 Elagolix (ABT-620) M12-817 Clinical Study Report R&D/17/0779 Statistical Methods Efficacy: General Principles The full analysis set, which consists of all randomized subjects who received at least 1 dose of study drug, was used for efficacy analyses. The data from the full analysis set are presented by the treatment group assigned at the time of randomization, even if the subject did not receive the correct treatment or did not follow the protocol until completion. The full analysis set was used for all baseline and efficacy analyses. Primary Analysis of Primary Endpoint The primary endpoint was analyzed using a logistic regression model including treatment as the main effect and baseline MBL volume as a covariate. The missing Final Month MBL volume was imputed using multiple imputations for the primary analysis of the primary efficacy endpoint. Subset analyses of the primary endpoint were performed on the adenomyosis subsets, which consisted of subjects with coexisting adenomyosis, either at Baseline (N = 52) or at any time at Baseline or during the Treatment Period (N = 65). Analyses for Ranked Secondary and Other Efficacy Endpoints For the first ranked secondary efficacy endpoint, the change from Baseline to the Final Month in MBL volume obtained from the primary analysis after multiple imputation was summarized by treatment group and compared between each elagolix group and placebo, using 1-way analysis of covariance (ANCOVA) with treatment as the main effect and Baseline MBL volume as a covariate. For the third, fourth, and sixth ranked secondary endpoints, the comparison of change from Baseline in MBL volume to each month between each of the elagolix groups and placebo was performed on observed MBL volume using a MMRM model, with treatment, month, and an interaction between treatment and month as fixed-effect factors, and baseline MBL volume as a covariate. For other continuous efficacy variables, which include change and percent change from Baseline analyses, treatment group differences were analyzed using ANCOVA models with treatment group as the main effect and corresponding baseline value as a covariate. Categorical data were analyzed using Pearson's chi-square test, Fisher's exact test, or logistics regression, as appropriate.