Safety and Efficacy in Premenopausal Women With Heavy Menstrual Bleeding (HMB) Associated With Uterine Fibroids (UF)

Study Overview
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Brief Summary
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This is a Phase 2b randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of elagolix alone and in combination with add-back therapy versus placebo on heavy menstrual bleeding in premenopausal women 18 to 51 years of age with uterine fibroids.

Official Title
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A Phase 2b Study to Evaluate the Safety and Efficacy of Elagolix in Premenopausal Women With Heavy Menstrual Bleeding Associated With Uterine Fibroids

Conditions
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Heavy Uterine Bleeding, Uterine Fibroids

Intervention / Treatment
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* Other: Elagolix placebo
* Drug: Elagolix
* Drug: 0.5 mg estradiol / 0.1 mg norethindrone acetate
* Drug: 1 mg estradiol / 0.5 mg norethindrone acetate
* Drug: E2/NETA placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is pre-menopausal female 18 to 51 years of age at Screening. Subject has diagnosis of uterine fibroids documented by a Pelvic Ultrasound. Subject has heavy uterine bleeding associated with uterine fibroids. Exclusion Criteria: Subject has had a myomectomy, uterine artery embolization or high intensity focused ultrasound for fibroid destruction within 6 months prior to Screening or endometrial ablation within 5 years prior to Screening. Subject has a history of osteoporosis or other metabolic bone disease. Subject shows evidence of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric (including depression, schizophrenia, bipolar disorder), or neurologic diseases or any uncontrolled medical illness such as uncontrolled type 2 diabetes. Subject has any history of attempted suicide. Subject has a history of clinically significant condition(s) including but not limited to: * Symptomatic Endometriosis * Epilepsy or seizures * Type 1 diabetes * Chronic kidney disease * Any cancer (except treated basal cell carcinoma of the skin), including breast or ovarian cancer or subject has taken any systemic cancer chemotherapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 51 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Cohort 1: Placebo<br>Placebo for elagolix and placebo for E2/NETA twice daily (BID) | Other: Elagolix placebo<br>* oral coated tablet<br>Drug: E2/NETA placebo<br>* oral hard capsule<br>|
| Experimental: Cohort 1: Elagolix 300 mg BID<br>Elagolix 300 mg BID alone | Drug: Elagolix<br>* oral coated tablet<br>* Other names: ABT-620;Drug: E2/NETA placebo<br>* oral hard capsule<br>|
| Experimental: Cohort 1: Elagolix 300 mg BID plus LD E2/NETA QD<br>Elagolix 300 mg BID plus low-dose (LD) E2/NETA once daily (QD) | Drug: Elagolix<br>* oral coated tablet<br>* Other names: ABT-620;Drug: 0.5 mg estradiol / 0.1 mg norethindrone acetate<br>* oral hard capsule<br>* Other names: Activelle, Activella, low dose (LD) E2/NETA;|
| Experimental: Cohort 1: Elagolix 300 mg BID plus SD E2/NETA QD<br>Elagolix 300 mg BID plus standard-dose (SD) E2/NETA QD | Drug: Elagolix<br>* oral coated tablet<br>* Other names: ABT-620;Drug: 1 mg estradiol / 0.5 mg norethindrone acetate<br>* oral hard capsule<br>* Other names: standard dose (SD) E2/NETA;|
| Placebo Comparator: Cohort 2: Placebo<br>Placebo for elagolix and E2/NETA QD | Other: Elagolix placebo<br>* oral coated tablet<br>Drug: E2/NETA placebo<br>* oral hard capsule<br>|
| Experimental: Cohort 2: Elagolix 600 mg QD<br>Elagolix 600 mg QD alone | Drug: Elagolix<br>* oral coated tablet<br>* Other names: ABT-620;Drug: E2/NETA placebo<br>* oral hard capsule<br>|
| Experimental: Cohort 2: Elagolix 600 mg QD plus LD E2/NETA QD<br>Elagolix 600 mg QD plus LD E2/NETA QD | Drug: Elagolix<br>* oral coated tablet<br>* Other names: ABT-620;Drug: 0.5 mg estradiol / 0.1 mg norethindrone acetate<br>* oral hard capsule<br>* Other names: Activelle, Activella, low dose (LD) E2/NETA;|
| Experimental: Cohort 2: Elagolix 600 mg QD plus SD E2/NETA QD<br>Elagolix 600 mg QD plus SD E2/NETA QD | Drug: Elagolix<br>* oral coated tablet<br>* Other names: ABT-620;Drug: 1 mg estradiol / 0.5 mg norethindrone acetate<br>* oral hard capsule<br>* Other names: standard dose (SD) E2/NETA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Menstrual Blood Loss (MBL) Volume of < 80 mL at the Final Month and a ≥ 50% Reduction in MBL Volume From Baseline to the Final Month | The percentage of participants meeting a composite endpoint consisting of these 2 bleeding assessments: a MBL Volume of < 80 mL at the Final Month and a ≥50% Reduction in MBL Volume from Baseline to the Final Month (last 28 days of treatment). Baseline is defined as the last qualified menstrual cycle during the screening period. | Baseline, Final Month (last 28 days of treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a MBL Volume < 80 mL and a ≥ 50% Reduction in MBL Volume From Baseline During the Last 56 to 29 Days of Treatment | The percentage of participants meeting a composite endpoint consisting of these 2 bleeding assessments: a MBL volume < 80 mL and a ≥ 50% reduction in MBL volume from baseline during the last 56 to 29 days of last treatment. Baseline is defined as the last qualified menstrual cycle during the screening period. | Baseline, second last 28 days of treatment (last 56 to 29 days of treatment) | 
| Percentage of Participants With a MBL Volume < 80 mL and a ≥ 50% Reduction in MBL Volume From Baseline During the Last 84 to 57 Days of Treatment | The percentage of participants meeting a composite endpoint consisting of these 2 bleeding assessments: a MBL volume < 80 mL and a ≥ 50% reduction in MBL volume from baseline during the last 84 to 57 days of last treatment. Baseline is defined as the last qualified menstrual cycle during the screening period. | Baseline, third last 28 days of treatment (last 84 to 57 days of treatment) | 
| Percentage of Participants Who Achieved an MBL Volume of < 80 mL at the Final Month | Percentage of participants who achieved an MBL volume of < 80 mL at the Final Month (last 28 days of treatment). Baseline is defined as the last qualified menstrual cycle during the screening period. | Final Month (last 28 days of treatment) | 
| Percentage of Participants With a ≥ 50% Reduction in MBL Volume From Baseline to the Final Month | Percentage of participants with a >= 50% reduction from baseline in MBL to the Final Month (last 28 days of treatment). Baseline is defined as the last qualified menstrual cycle during the screening period. | Baseline, Final Month (last 28 days of treatment) | 
| Percentage of Participants Who Achieved Amenorrhea During the Last 56 Days of Treatment | Amenorrhea is defined as having 0 days of bleeding or spotting based on observed validated and nonvalidated alkaline hematin data and having 0 days of bleeding or spotting, based on imputed electronic diary data during the last 56 days of treatment. Participants needed to have at least 66 days on treatment. | Last 56 days of treatment (after 10 days from first dose date) | 
| Percentage of Participants Who Achieved Suppression of Bleeding During the Last 56 Days of Treatment | Suppression of bleeding is defined as having 0 days of bleeding based on observed validated and nonvalidated alkaline hematin data and having 0 days of bleeding (spotting is allowed) based on imputed electronic diary data during the last 56 days of treatment. | Last 56 days of treatment (after 10 days from first dose date) | 
| Mean Change in the Number of Bleeding Days From Baseline to Month 6 | The number of days with any bleeding including spotting was calculated using data collected on daily bleeding diary. Baseline is defined as the last 28 days prior to the first dose day of study drug. | Baseline, Month 6 | 
| Mean Change in the Number of Heavy Bleeding Days From Baseline to Month 6 | The number of days with heavy bleeding (either heavy or very heavy/gushing bleeding) was calculated using data collected on daily bleeding diary. Baseline is defined as the last 28 days prior to the first dose day of study drug. | Baseline, Month 6 | 
| Change in Bleeding Severity Scores From Baseline at the Final Month | The average bleeding score was calculated for each 28-day interval starting on Day 29 using data collected on daily bleeding diary using the Mansfield-Voda-Jorgenson (MVJ) Menstrual Bleeding Scale (1=spotting, 2 = very light bleeding, 3 = light bleeding, 4 = moderate bleeding, 5 = heavy bleeding, 6 = very heavy/gushing bleeding). Baseline is defined as the last 28 days prior to the first day of study drug. | Baseline, Final Month (last 28 days of treatment) | 
| Mean Change in Hemoglobin Concentration From Baseline to Final Visit | Baseline is defined as the last measurement prior to the first dose of study drug. | Baseline, Final Visit during treatment period (Month 6 or early termination) | 
| Mean Percentage Change From Baseline in Total Fibroid Volume at Month 3, Month 6, and Final Visit | Volume of the total fibroid volume (3 largest fibroids), as measured by transvaginal ultrasound, or transabdominal ultrasound. | Baseline, Month 3, Month 6, and Final Visit during treatment period (Month 6 or early termination) | 
| Mean Percentage Change From Baseline in Primary Fibroid Volume at Month 3, Month 6, and Final Visit | Volume of the largest fibroid (primary fibroid), as measured by transvaginal ultrasound, or transabdominal ultrasound. | Baseline, Month 3, Month 6, and Final Visit during treatment period (Month 6 or early termination) | 
| Mean Percentage Change From Baseline in Uterine Volume at Month 3, Month 6, and Final Visit | Uterine volume, as measured by transvaginal ultrasound or transabdominal ultrasound. | Baseline, Month 3, Month 6, and Final Visit during treatment period (Month 6 or early termination) | 
| Percentage of Participants With ≥ 25% Reduction From Baseline in Total Fibroid Volume at Month 3, Month 6, and Final Visit | Total fibroid volume (3 largest fibroids) was measured by transvaginal ultrasound, or transabdominal ultrasound. | Baseline, Month 3, Month 6, and Final Visit during treatment period (Month 6 or early termination) | 
| Percentage of Participants With ≥ 25% Reduction From Baseline in Primary Fibroid Volume at Month 3, Month 6, and Final Visit | Volume of the largest fibroid (primary fibroid) was measured by transvaginal ultrasound or transabdominal ultrasound. | Baseline, Month 3, Month 6, and Final Visit during treatment period (Month 6 or early termination) | 
| Percentage of Participants With ≥ 25% Reduction From Baseline in Uterine Volume at Month 3, Month 6, and Final Visit | Uterine volume was measured by transvaginal ultrasound or transabdominal ultrasound. | Baseline, Month 3, Month 6, and Final Visit during treatment period (Month 6 or early termination) | 
| Change From Baseline to Each Month in Non-Bleeding Uterine Fibroids Symptom (NBUFSQ) Questionnaire | The NBUFSQ (8 items) is a brief patient-reported daily diary that assesses non-bleeding symptoms experienced by women with uterine fibroids. It includes 6 items, asking women to rate their symptoms (abdominal/pelvic pain, pressure, and cramping, back pain, bloating, and urinary problems) in the past 24 hours using an 11-point numeric response scale that ranges from 0 (i.e., no symptom) to 10 (i.e., worst possible symptom) and 2 items to address urinary frequency during the daytime and at night. Data presented in the sum of scores to the 6 symptom questions, ranging from 0 (no symptoms) to 60 (worst possible symptoms). Baseline is defined as the last 28 days prior to the first day of study drug. Final Month is defined as the last 28 days prior to and including the last dose date of study drug. | Baseline, Days 1-28, Days 29-56, Days 57-84, Days 85-112, Days 113-140, Days 141-168, Final Month of treatment, Post-treatment (PT) Days 1-28, PT Days 29-56, PT Days 57-84, PT Days 85-112, PT Days 113-140, PT Days 141-168 | 
| Percentage of Participants Who Successfully Avoided Surgical or Invasive Procedures for Uterine Fibroids | The percentage of participants who successfully avoided surgical or invasive procedures for Uterine Fibroids was assessed. | Month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ABT-620, Uterine Fibroids, Leiomyomata, Elagolix, Menorrhagia, Elagolix sodium, Heavy Uterine Bleeding