Safety and Efficacy of Elagolix in Pre-Menopausal Women With Heavy Uterine Bleeding and Uterine Fibroids

Study Overview
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Brief Summary
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The purpose of this proof-of-concept study is to assess the safety and effectiveness of elagolix versus placebo to reduce uterine bleeding associated with uterine fibroids, and to reduce fibroid volume and uterine volume in premenopausal women 20 to 49 years of age with heavy uterine bleeding.

Official Title
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Phase 2a Proof Of Concept Study to Evaluate the Safety and Efficacy of Elagolix in Pre-Menopausal Women With Heavy Uterine Bleeding and Uterine Fibroids

Conditions
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Heavy Uterine Bleeding, Uterine Fibroids

Intervention / Treatment
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* Drug: Elagolix
* Drug: Placebo
* Drug: Estradiol/Norethindrone acetate (E2/NETA)
* Drug: Estradiol
* Drug: Progesterone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is a pre-menopausal female 20 to 49 years of age. Subject has a diagnosis of uterine fibroids documented by a pelvic ultrasound assessed by a central reader and verification that a fibroid present met the following criteria: At least 1 fibroid with diameter ≥ 2 cm (longest diameter), or multiple small fibroids with a total uterine volume of ≥ 200 cm³ to ≤ 2,500 cm³ (approximately 22 weeks' gestation) as documented by a centrally read ultrasound. Only intramural, submucosal non-pedunculated, and subserosal fibroids qualified subjects for enrollment (intracavitary pedunculated fibroids were exclusionary). Ultrasound procedures were performed during the Screening Period, and subjects were not randomized until the investigator reviewed the central reader results verifying the inclusion requirements. Subject has a history of regular menstrual cycles between 24 to 35 days. Subject has heavy uterine bleeding associated with uterine fibroids as evidenced by blood loss > 80 mL during 2 screening menstrual cycles, measured by the alkaline hematin method. Exclusion Criteria: Subject has had a myomectomy, uterine artery embolization, or high intensity focused ultrasound for fibroid destruction within 1 year prior to randomization or any history of endometrial ablation. 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), or neurologic diseases or any uncontrolled medical illness such as uncontrolled type 2 diabetes. Subject has a history of clinically significant condition(s) including but not limited to: Endometriosis Epilepsy or seizures Type 1 diabetes Any cancer (except 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: 20 Years
Maximum Age: 49 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 |
| --- | --- |
| Experimental: Cohort 4 Elagolix 400 mg QD<br>Participants received elagolix 400 mg once a day (QD) for 3 months. | Drug: Elagolix<br>* Elagolix tablets<br>* Other names: ABT-620;|
| Experimental: Cohort 4 Elagolix 100 mg BID<br>Participants received elagolix 100 mg twice a day (BID) for 3 months. | Drug: Elagolix<br>* Elagolix tablets<br>* Other names: ABT-620;|
| Placebo Comparator: Cohort 4 Placebo<br>Participants received placebo to elagolix BID for 3 months. | Drug: Placebo<br>* Matching placebo tablets<br>|
| Experimental: Cohort 1 Elagolix 200 mg BID<br>Participants received elagolix 200 mg twice a day for 3 months. | Drug: Elagolix<br>* Elagolix tablets<br>* Other names: ABT-620;|
| Placebo Comparator: Cohort 1 Placebo<br>Participants received placebo to elagolix twice a day for 3 months. | Drug: Placebo<br>* Matching placebo tablets<br>|
| Placebo Comparator: Cohort 3 Elagolix 200 mg BID + LD E2/NETA<br>Participants received elagolix 200 mg twice a day plus continuous low-dose (LD) estradiol (E2) 0.5 mg/norethindrone acetate 0.1 mg (NETA) once a day for 3 months. | Drug: Elagolix<br>* Elagolix tablets<br>* Other names: ABT-620;Drug: Estradiol/Norethindrone acetate (E2/NETA)<br>* A continuous once-daily oral tablet containing estrogen and progestin; the low-dose strength contains estradiol 0.5 mg and norethindrone acetate 0.1 mg.<br>* Other names: Activella®;|
| Experimental: Cohort 5 Elagolix 600 mg QD<br>Participants received elagolix 600 mg once a day for 3 months. | Drug: Elagolix<br>* Elagolix tablets<br>* Other names: ABT-620;|
| Experimental: Cohort 2 Elagolix 300 mg BID<br>Participants received elagolix 300 mg twice a day for 3 months. | Drug: Elagolix<br>* Elagolix tablets<br>* Other names: ABT-620;|
| Experimental: Cohort 2 Placebo<br>Participants received placebo to elagolix BID for 3 months. | Drug: Placebo<br>* Matching placebo tablets<br>|
| Experimental: Cohort 6 Elagolix 300 mg BID + CEP<br>Participants received elagolix 300 mg twice a day plus cyclical estrogen/progesterone (CEP, consisting of estradiol 1 mg a day and progesterone 200 mg on days 17 to 28 of each 30-day treatment cycle) for 3 months. | Drug: Elagolix<br>* Elagolix tablets<br>* Other names: ABT-620;Drug: Estradiol<br>* 1.0 mg micronized estradiol tablets administered once a day<br>* Other names: Estrace®;Drug: Progesterone<br>* Progesterone 200 mg administered during the last 12 days of the 28-day menstrual cycle<br>* Other names: Prometrium®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline to the Last 28 Days of Treatment in Menstrual Blood Loss (MBL) | The alkaline hematin method was used for the assessment of MBL. Sanitary products were collected at screening and for any spotting or bleeding episodes that occurred during treatment. Participants with missing MBL volume for the last treatment period and no bleeding indicated in the electronic daily bleeding diary (eDiary) in the last treatment period, and participants with no post-baseline MBL data were assigned an MBL value of zero. | Baseline (last menstrual cycle during the screening period) and the last 28 days of treatment (approximately days 61 to 90) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to the Last 28 Days of Treatment in Menstrual Blood Loss (MBL) | The alkaline hematin method was used for the assessment of MBL. Sanitary products were collected at screening and for any spotting or bleeding episodes that occurred during treatment. Participants with missing MBL volume for the last treatment period and no bleeding indicated in the electronic daily bleeding diary (eDiary) in the last treatment period, and participants with no post-baseline MBL data were assigned an MBL value of zero. | Baseline (last menstrual cycle during the screening period) and the last 28 days of treatment (approximately days 61 to 90) | 
| Percentage of Participants With MBL < 80 mL and With a ≥ 50% Reduction From Baseline in MBL During the Last 28 Days of Treatment | The alkaline hematin method was used for the assessment of MBL. Sanitary products were collected at screening and for any spotting or bleeding episodes that occurred during treatment. Participants with missing MBL volume for the last treatment period and no bleeding indicated in the electronic daily bleeding diary (eDiary) in the last treatment period, and participants with no post-baseline MBL data were assigned an MBL value of zero. | Baseline (last menstrual cycle during the screening period) and the last 28 days of treatment (approximately days 61 to 90) | 
| Percentage of Participants With MBL < 80 mL During the Last 28 Days of Treatment | The alkaline hematin method was used for the assessment of MBL. Sanitary products were collected at screening and for any spotting or bleeding episodes that occurred during treatment. Participants with missing MBL volume for the last treatment period and no bleeding indicated in the electronic daily bleeding diary (eDiary) in the last treatment period, and participants with no post-baseline MBL data were assigned an MBL value of zero. | The last 28 days of treatment (approximately days 61 to 90) | 
| Percentage of Participants With a ≥ 50% Reduction From Baseline in MBL During the Last 28 Days of Treatment | The alkaline hematin method was used for the assessment of MBL. Sanitary products were collected at screening and for any spotting or bleeding episodes that occurred during treatment. Participants with missing MBL volume for the last treatment period and no bleeding indicated in the electronic daily bleeding diary (eDiary) in the last treatment period, and participants with no post-baseline MBL data were assigned an MBL value of zero. | Baseline (last menstrual cycle during the screening period) and the last 28 days of treatment (approximately days 61 to 90) | 
| Percentage of Participants With No Change, Decrease From Baseline, or Increase From Baseline in Hemoglobin at Month 3 | The percentage of subjects with changes in hemoglobin concentration from Baseline to Month 3 in each of the following categories: No change from baseline in hemoglobin Decrease from baseline in hemoglobin ≥ -0.5 g/dL Decrease from baseline in hemoglobin ≥ -1.0 g/dL Increase from baseline in hemoglobin ≥ 0.5 g/dL Increase from baseline in hemoglobin ≥ 1.0 g/dL The above categories are not all mutually exclusive or exhaustive. | Baseline and Month 3 | 
| Change in Hemoglobin Concentration From Baseline to Month 3 |  | Baseline and Month 3 | 
| Change From Baseline to Month 3 in Uterine Bleeding Score | Participants recorded the previous days' presence and severity of bleeding every morning in an electronic diary (eDiary) according to the Mansfield-Voda-Jorgenson Menstrual Bleeding Scale: 1 (Spotting): A drop or 2 of blood, not even requiring sanitary protection. 2 (Very light): Needing to change the least absorbent tampon or pad 1 to 2 times per day. 3 (Light): Needing to change a low or regular absorbency tampon or pad 2 or 3 times per day. 4 (Moderate): Needing to change a regular absorbency tampon or pad every 3 to 4 hours. 5 (Heavy): Needing to change a high absorbency tampon or pad every 3 to 4 hours. 6 (Very heavy/gushing): Very heavy bleeding, protection hardly works at all; needing to change the highest absorbency tampon or pad every hour or 2. | Baseline (average bleeding score over the 30 days prior to first dose) and month 3 (average bleeding score over days 61 to 90) | 
| Change From Baseline to Month 3 in Percentage of Days With Any Uterine Bleeding | Participants recorded the previous days' presence and severity of bleeding every morning in an electronic diary (eDiary) according to the Mansfield-Voda-Jorgenson Menstrual Bleeding Scale: 1 (Spotting): A drop or 2 of blood, not even requiring sanitary protection. 2 (Very light): Needing to change the least absorbent tampon or pad 1 to 2 times per day. 3 (Light): Needing to change a low or regular absorbency tampon or pad 2 or 3 times per day. 4 (Moderate): Needing to change a regular absorbency tampon or pad every 3 to 4 hours. 5 (Heavy): Needing to change a high absorbency tampon or pad every 3 to 4 hours. 6 (Very heavy/gushing): Very heavy bleeding, protection hardly works at all; needing to change the highest absorbency tampon or pad every hour or 2. A day with any uterine bleeding is defined as a days with a bleeding score ≥ 1. | Baseline (average bleeding score over the 30 days prior to first dose) and month 3 (average bleeding score over days 61 to 90) | 
| Change From Baseline to Month 3 in Percentage of Days With Moderate to Very Heavy Bleeding | Participants recorded the previous days' presence and severity of bleeding every morning in an electronic diary (eDiary) according to the Mansfield-Voda-Jorgenson Menstrual Bleeding Scale: 1 (Spotting): A drop or 2 of blood, not even requiring sanitary protection. 2 (Very light): Needing to change the least absorbent tampon or pad 1 to 2 times per day. 3 (Light): Needing to change a low or regular absorbency tampon or pad 2 or 3 times per day. 4 (Moderate): Needing to change a regular absorbency tampon or pad every 3 to 4 hours. 5 (Heavy): Needing to change a high absorbency tampon or pad every 3 to 4 hours. 6 (Very heavy/gushing): Very heavy bleeding, protection hardly works at all; needing to change the highest absorbency tampon or pad every hour or 2. A day with moderate to very heavy bleeding is defined as a days with a bleeding score ≥ 3. | Baseline (average bleeding score over the 30 days prior to first dose) and month 3 (average bleeding score over days 61 to 90) | 
| Percentage of Participants With Any Uterine Bleeding or Moderate to Very Heavy Uterine Bleeding at Month 3 | Participants recorded the previous days' presence and severity of bleeding every morning in an eDiary according to the Mansfield-Voda-Jorgenson Menstrual Bleeding Scale: 1 (Spotting): A drop or 2 of blood, not even requiring sanitary protection. 2 (Very light): Needing to change the least absorbent tampon or pad 1 to 2 times per day. 3 (Light): Needing to change a low or regular absorbency tampon or pad 2 or 3 times per day. 4 (Moderate): Needing to change a regular absorbency tampon or pad every 3 to 4 hours. 5 (Heavy): Needing to change a high absorbency tampon or pad every 3 to 4 hours. 6 (Very heavy/gushing): Very heavy bleeding, protection hardly works at all; needing to change the highest absorbency tampon or pad every hour or 2. Any bleeding is defined as a score ≥ 1 and moderate to very heavy bleeding is defined as a score ≥ 3. | Month 3 (average bleeding score over days 61 to 90) | 
| Percentage of Participants With Suppression of Bleeding (Spotting Allowed) or Amenorrhea During the Last 56 Days of Treatment | Suppression of bleeding is defined as no record of bleeding (spotting allowed) in the e-diary and no record of bleeding Indicated in the alkaline hematin data during the last 56 days of treatment. Amenorrhea is defined as no record of bleeding or spotting indicated in the e-diary and no record of bleeding or spotting Indicated in the alkaline hematin data during the last 56 days of treatment. | The last 56 days of treatment (approximately days 33 to 90) | 
| Percent Change From Baseline to Month 3 in Uterine Volume | Uterine volume was determined using transabdominal ultrasound. The images were analyzed by a central imaging center. | Baseline and month 3 | 
| Percentage of Participants With ≥ 25% Reduction in Uterine Volume at Month 3 / Final Visit | Uterine volume was determined using transabdominal ultrasound. The images were analyzed by a central imaging center. | Baseline and month 3 or the final visit during the treatment period for participants who prematurely discontinued. | 
| Percent Change From Baseline to Month 3 in Volume of the Largest Fibroid | The volume of the largest fibroid was determined using transabdominal ultrasound. The images were analyzed by a central imaging center. | Baseline and month 3 | 
| Percentage of Participants With ≥ 25% Reduction in Volume of Largest Fibroid at Month 3 / Final Visit | The volume of the largest fibroid was determined using transabdominal ultrasound. The images were analyzed by a central imaging center. | Baseline and month 3 or the final visit during the treatment period for participants who prematurely discontinued. | 
| Change From Baseline to Month 3 in the Uterine Fibroid Symptom Quality of Life Questionnaire (UFS-QoL) | The UFS-QoL is a disease-specific, self-administered, validated questionnaire developed to evaluate the symptoms associated with uterine fibroids and their impact on health-related quality of life (HRQL) in women with symptomatic uterine fibroids. The questionnaire consists of 37 questions, divided into 2 parts: 1) an 8-item symptom severity scale and 2) a 29-item HRQL subscale comprising 6 domains (concern, activities, energy/mood, control, self-consiousness, and sexual function), with a 4-week recall. All items are scored on a 5-point scale, ranging from not at all to a very great deal for symptom severity items and none of the time to all of the time for the HRQL items. Symptom severity and HRQL subscale scores were summed and transformed into a 0 to 100 point scale to provide a total score for each of the 2 components. Lower symptom severity scores indicate better quality of life and higher total HRQL scores indicate better quality of life. | Baseline and month 3 | 
| Change From Baseline to Month 3 in the Uterine Fibroids Daily Symptom Scale Scores | The uterine fibroid daily symptom scale is self-administered questionnaire, with a scale that ranges from 0 to 10 for the symptoms of pelvic pain, fatigue, and cramping and the impact of uterine fibroids on the subject's daily life, with 0 being the absence of the symptom and 10 being the worst severity of the symptoms or completely preventing the subjects from performing daily activities. Participants self-reported values daily in the e-Diary. | Baseline (average score over the 30 days prior to first dose) and month 3 (average score over days 61 to 90) | 
| Change From Baseline to Month 3 in the Subject Surgery Intention Questionnaire (SSIQ) Version 2.0 | The Subject Intention Questionnaire (SSIQ) is a non-validated, exploratory questionnaires intended to evaluate the subject's intent to undergo surgical procedures if current endometriosis-associated symptoms continued. The scoring scale ranged from 0 (not at all likely to consider surgery) to 10 (very likely to consider surgery). SSIQ included the 2 following questions: How likely are you to consider having myomectomy surgery to treat your uterine fibroid if your symptoms continue as they are now? How likely are you to consider hysterectomy surgery if your uterine fibroid symptoms continue as they are now? | Baseline and month 3 | 
| Change From Baseline to Month 3 in the Physician Surgery Intention Questionnaire (PSIQ) Version 2.0 | The Physician Intention Questionnaire (PSIQ) is a non-validated, exploratory questionnaire intended to evaluate the investigator's intent to recommend surgical procedures if current endometriosis-associated symptoms continued. The scoring scale ranged from 0 (not at all likely to recommend surgery) to 10 (very likely to recommend surgery). The PSIQ included the 2 following questions: How likely are you to recommend myomectomy to treat this patient's uterine fibroid if her symptoms continue as they are now? How likely are you to recommend definitive surgery hysterectomy for this patient if her uterine fibroid symptoms continue as they are now? | Baseline and month 3 | 

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