Efficacy and Safety Study of Elagolix Versus Placebo or Leuprorelin Acetate in Endometriosis

Study Overview
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Brief Summary
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This study is designed to evaluate the safety and beneficial effects of elagolix (NBI-56418) compared to placebo and leuprorelin (an approved endometriosis therapy) over a three month period followed by an additional three months of treatment on elagolix.

Detailed Description
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The study followed a parallel-group design in which participants were randomized (1:1:1:1) to one of the following treatment groups for the first 12 weeks of dosing: 150 mg elagolix once daily (q.d.); 250 mg elagolix q.d.; placebo; or leuprorelin acetate depot injection 3.75 mg (monthly). Blinding was achieved using a double-dummy design. Following 12 weeks of dosing, participants continued in the study for an additional 12 weeks; participants randomized to elagolix continued to receive their assigned dose and participants randomized to placebo or leuprorelin acetate were re-randomized to receive one of the two doses of elagolix (150 mg q.d. or 250 mg q.d.) for 12 weeks in a double-blind fashion. Six weeks after the last dose of the study drug at the end of Week 24, a follow-up visit was performed (end of Week 30). There was no pre-specified primary efficacy end point as there was no single key efficacy outcome measure in this exploratory Phase 2 study. For purposes of results reported here, Change From Baseline in the Monthly Mean Numerical Rating Score (NRS) for Endometriosis Pain is designated as the primary outcome measure.

Official Title
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A Phase II, Randomized, Double-Blind, Placebo- and Active-Controlled Study to Assess the Efficacy and Safety of NBI-56418 in Subjects With Endometriosis

Conditions
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Endometriosis

Intervention / Treatment
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* Drug: Leuprorelin Acetate Depot
* Drug: Elagolix
* Drug: Placebo to Elagolix
* Drug: Placebo to Leuprorelin Acetate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Female, aged 18 to 45 years, inclusive Have moderate to severe pelvic pain due to endometriosis Have been surgically (laparoscopy) diagnosed with endometriosis within the last 5 years and have recurrent or persistent endometriosis symptoms Have regular menstrual cycle (23-33 day) Agree to use two forms of non-hormonal contraception during the study Exclusion Criteria: Received a Gonadotropin-releasing hormone (GnRH) agonist, GnRH antagonist, danazol, or have received any of these agents within 6 months of the start of screening. Received subcutaneous medroxyprogesterone acetate (DMPA-SC) or intramuscular (i.m.) medroxyprogesterone acetate (DMPA-IM), or have received either of these agents within 3 months of the start of screening. Are currently using hormonal contraception or other forms of hormonal therapy or received such treatment within the last month Have had surgery for endometriosis within the last month Are using systemic steroids on a chronic or regular basis within 3 months Have uterine fibroids or other pelvic lesions ≥ 3 cm in diameter Have had a hysterectomy or oophorectomy Have pelvic pain that is not caused by endometriosis Have unstable medical condition or chronic disease Have been pregnant within the last 6 months and is currently breast feeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Placebo<br>Participants received placebo tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks. | Drug: Placebo to Elagolix<br>* Placebo tablet administered orally<br>Drug: Placebo to Leuprorelin Acetate<br>* Saline solution administered as an intramuscular injection<br>|
| Experimental: Elagolix 150 mg<br>Participants received elagolix 150 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg for an additional 12 weeks. | Drug: Elagolix<br>* Elagolix tablets administered orally<br>* Other names: Orilissa™;Drug: Placebo to Leuprorelin Acetate<br>* Saline solution administered as an intramuscular injection<br>|
| Experimental: Elagolix 250 mg<br>Participants received elagolix 250 mg tablets once a day and placebo intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks. | Drug: Elagolix<br>* Elagolix tablets administered orally<br>* Other names: Orilissa™;Drug: Placebo to Leuprorelin Acetate<br>* Saline solution administered as an intramuscular injection<br>|
| Other: Leuprorelin<br>Participants received placebo tablets once a day and leuprorelin acetate 1-month depot 3.75 mg intramuscular injection once a month for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) for 12 weeks. | Drug: Leuprorelin Acetate Depot<br>* Leuprorelin acetate depot injection 3.75 mg administered as an intramuscular injection<br>* Other names: Prostap SR;Drug: Placebo to Elagolix<br>* Placebo tablet administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Monthly Mean Numerical Rating Score (NRS) for Endometriosis Pain | The NRS is an 11-point scale used to measure endometriosis pain and was completed at approximately the same time each day using an electronic diary (e-Diary). Participants were instructed to select a single number between 0 (No pain) and 10 (Worst pain ever) that best described their endometriosis pain at its worst over the past day. The monthly mean NRS is the average of the daily values reported during the 4 weeks prior to each visit. | Baseline and Weeks 4, 8, and 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Monthly Peak Numerical Rating Score (NRS) for Endometriosis Pain | The NRS is an 11-point scale used to measure endometriosis pain and was completed at approximately the same time each day using an electronic diary (e-Diary). Participants were instructed to select a single number between 0 (No pain) and 10 (Worst pain ever) that best described their endometriosis pain at its worst over the past day. The monthly peak NRS is the maximum of the daily values reported during the 4 weeks prior to each visit. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline in the Monthly Mean Non-menstrual Pelvic Pain Score | Participants assessed their pelvic pain not related to menses and its impact on their daily activities at approximately the same time every day in an e-Diary according to the following response options: 0 = No pelvic pain 1 = Mild pelvic pain; subject could not do some of the things she usually does 2 = Moderate pelvic pain; subject could not do many of the things she usually does 3 = Severe pelvic pain; subject could not do most or all of the things she usually does. The monthly mean non-menstrual pelvic pain score is the average of the daily values reported during the 4 weeks prior to each visit. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline in the Monthly Mean Dysmenorrhea Score | Participants assessed dysmenorrhea (pain during menstruation) and its impact on their daily activities at approximately the same time each day of their period in an e-Diary according to the following response options: Subject is not having her period 0 = No pain related to period 1 = Mild pain related to period; subject could not do some of the things she usually does 2 = Moderate pain related to period; subject could not do many of the things she usually does 3 = Severe pain related to period; subject could not do most of or all of the things she usually does. The monthly mean dysmenorrhea score is the average of the daily values reported during the 4 weeks prior to each visit. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline in the Monthly Mean Sum of Dysmenorrhea and Non-menstrual Pelvic Pain Scores | Participants assessed dysmenorrhea and pelvic pain not related to menses and their impact on daily activities at approximately the same time every day on a 4-point scale (0 = none, 1 = mild, 2 = moderate, and 3 = severe) in an e-Diary. The dysmenorrhea scale included an option for participants who were not having their period. The sum of the dysmenorrhea and non-menstrual pelvic pain scores on each day were calculated to create a daily total score. On days the participant was not having her period, the dysmenorrhea score was not defined; hence, the total score was equal to the non-menstrual pelvic pain score (range 0 to 3). On days where the participant recorded menstruation the total score ranged from 0 to 6, where higher scores indicate more severe pain. The monthly mean sum of dysmenorrhea and non-menstrual pelvic pain scores is the average of the daily values reported during the 4 weeks prior to each visit. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline in the Percentage of Days of Any Analgesic Use | The daily use of endometriosis analgesics was reported by participants daily using the e-Diary. Participants reported whether the medication was over-the-counter (OTC) or prescription, and, if prescription, whether the medication was a narcotic. The percentage of days of any analgesic use is defined as the number of days in the 4 weeks prior to each study visit that the participant reported the use of an analgesic, divided by the number of study days in the interval that the participant provided an e-Diary report regarding the use of endometriosis analgesics (including a response of none). | Baseline, Weeks 4, 8 and 12 | 
| Change From Baseline in the Percentage of Days of Prescription Analgesic Use | The daily use of endometriosis analgesics was reported by participants daily using the e-Diary. Participants reported whether the medication was over-the-counter (OTC) or prescription, and, if prescription, whether the medication was a narcotic. The percentage of days of prescription analgesic use is defined as the number of days in the 4 weeks prior to each study visit that the participant reported the use of a prescription analgesic, divided by the number of study days in the interval that the participant provided an e-Diary report regarding the use of endometriosis analgesics (including a response of none). | Baseline, Weeks 4, 8 and 12 | 
| Change From Baseline in the Percentage of Days of Narcotic Analgesic Use | The daily use of endometriosis analgesics was reported by participants daily using the e-Diary. Participants reported whether the medication was over-the-counter (OTC) or prescription, and, if prescription, whether the medication was a narcotic. The percentage of days of narcotic analgesic use is defined as the number of days in the 4 weeks prior to each study visit that the participant reported the use of a narcotic analgesic, divided by the number of study days in the interval that the participant provided an e-Diary report regarding the use of endometriosis analgesics (including a response of none). | Baseline, Weeks 4, 8 and 12 | 
| Change From Baseline in Dyspareunia Component of the Composite Pelvic Signs and Symptoms Score (CPSSS) | The CPSSS consists of 5 components that address dysmenorrhea, dyspareunia, non-menstrual pelvic pain, pelvic tenderness, and pelvic induration. To assess dyspareunia (painful intercourse) participants were asked to select the best description of pain during sexual intercourse over the past 28 days using the following response categories: 0 = Absent; No discomfort during sexual intercourse. 1 = Mild; I can tolerate the discomfort during sexual intercourse. 2 = Moderate; Intercourse is sometime interrupted due to pain. 3 = Severe; I prefer to avoid intercourse because of pain. Not applicable. I am not sexually active for reasons other than my endometriosis symptoms. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline in Dysmenorrhea Component of the CPSSS | The CPSSS consists of 5 components that address dysmenorrhea, dyspareunia, non-menstrual pelvic pain, pelvic tenderness, and pelvic induration. To assess dysmenorrhea (pain during menstruation), participants were asked to select the best description of painful menstruation over the past 28 days using the following response categories: 0 = Absent; Amenorrhea (no bleeding) or no discomfort. 1 = Mild; Some loss of work efficiency; occasional use of analgesics. 2 = Moderate; In bed part of one day, occasional loss of work; regular use of analgesics. 3 = Severe; In bed ≥ 1 day, incapacitation; requirement for strong analgesics. | Baseline and Week 12 | 
| Change From Baseline in Non-menstrual Pelvic Pain CPSSS Component | The CPSSS consists of 5 components that address dysmenorrhea, dyspareunia, non-menstrual pelvic pain, pelvic tenderness, and pelvic induration. To assess non-menstrual pelvic pain, participants were asked to select the best description of pelvic pain over the past 28 days using the following response categories: 0 = Absent; No discomfort. 1 = Mild; Occasional pelvic discomfort that can be treated with NSAIDs. 2 = Moderate; Noticeable discomfort or pain for most of cycle requiring regular use of NSAID or weak opiate. 3 = Severe; Pain persisting during the cycle or pain requiring strong analgesics. | Baseline and Week 12 | 
| Patient Global Impression of Change at Weeks 4, 8 and 12 | The Patient Global Impression of Change (PGIC) is a questionnaire-based assessment of the change in endometriosis pain since the initiation of study drug. The participant was asked to select from one of seven response categories: Very Much Improved Much Improved Minimally Improved Not Changed Minimally Worse Much Worse Very Much Worse | Weeks 4, 8 and 12 | 
| Percentage of Participants With a PGIC Response of Minimally Improved, Much Improved, or Very Much Improved | The PGIC is a questionnaire-based assessment of the change in endometriosis pain since the initiation of study drug. The participant was asked to select from one of seven response categories: Very Much Improved Much Improved Minimally Improved Not Changed Minimally Worse Much Worse Very Much Worse | Weeks 4, 8 and 12 | 
| Percentage of Participants With a PGIC Response of Much Improved or Very Much Improved | The PGIC is a questionnaire-based assessment of the change in endometriosis pain since the initiation of study drug. The participant was asked to select from one of seven response categories: Very Much Improved Much Improved Minimally Improved Not Changed Minimally Worse Much Worse Very Much Worse | Weeks 4, 8 and 12 | 
| Change From Baseline in Endometriosis Health Profile-5 (EHP-5) at Week 12 | The EHP-5 is an instrument to measure health-related quality of life in women with endometriosis. The EHP-5 consists of two parts: A core questionnaire consisting of five questions that measure the areas of pain, control and powerlessness, emotional well-being, social support, and self-image with five response categories for each item (Never, Rarely, Sometimes, Often, Always) A supplemental questionnaire consisting of six additional questions which assess the areas of work, relationship with children, sexual intercourse, feelings about the medical profession, treatment, and infertility with the same five response categories plus an additional response category of Not Relevant which was not scored. The scores associated with each possible outcome category are as follows: never (0), rarely (25), sometimes (50), often (75), and always (100). A negative change from baseline score indicates improvement in quality of life. | Baseline and week 12 | 
| Concentration of Serum Estradiol | The concentration of serum estradiol (E2) was quantified using liquid chromatography with tandem mass spectrophotometry (LC/MS/MS). Serum estradiol concentrations below the limit of quantification (BLQ) were set equal to the lower limit of quantification (2.5 pg/mL). | Baseline and Weeks 4, 8 and 12 | 
| Percent Change From Baseline in Bone Mineral Density of the Femur at Week 12 | Bone mineral density (BMD) of the femur (total hip) was measured by dual-energy X-ray absorptiometry (DXA). | Baseline and week 12 | 
| Percent Change From Baseline in Bone Mineral Density of the Spine at Week 12 | Bone mineral density (BMD) of the spine was measured by dual-energy X-ray absorptiometry (DXA). | Baseline and week 12 | 
| Percent Change From Baseline in Bone Mineral Density of the Femur at Week 24 | Bone mineral density (BMD) of the femur (total hip) was measured by dual-energy X-ray absorptiometry (DXA). | Baseline and Week 24 | 
| Percent Change From Baseline in Bone Mineral Density of the Spine at Week 24 | Bone mineral density (BMD) of the spine was measured by dual-energy X-ray absorptiometry (DXA). | Baseline and Week 24 | 
| Change From Baseline in Serum N-telopeptide Concentration at Week 12 | Blood samples to determine N-telopeptide concentrations were analyzed by a central laboratory using an enzyme-linked immunosorbent assay (ELISA). | Baseline and week 12 | 
| Average Number of Hot Flashes Per Day | Hot flashes, if any, were reported daily by participants during the study using the e-Diary. The average number of hot flashes per day was calculated for each participant as the total number of hot flashes divided by total days in the phase. | Screening (8 weeks prior to day 1), Treatment phase (weeks 1 to 12 for participants in the placebo and leuprorelin treatment groups and weeks 1 to 24 for participants in the elagolix treatment groups) | 
| Percentage of Days With Uterine Bleeding | Uterine bleeding was reported daily by participants during the study using the e-Diary. The percentage of days a participant reported any bleeding was calculated as the total number of days the participant reported any bleeding ( light, moderate, or heavy) divided by the total number of days the participant had a non-missing eDiary report of vaginal bleeding in the phase. | Screening (8 weeks prior to day 1), Treatment phase (weeks 1 to 12 for participants in the placebo and leuprorelin treatment groups and weeks 1 to 24 for participants in the elagolix treatment groups) | 
| Number of Days to First Posttreatment Menses | Defined as the number of days from the last dose of study drug until the start date of the first post-treatment menses. | From last day of study drug up to 6 weeks after the last dose. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bone mineral density,endometriosis,pelvic pain