Efficacy and Safety Study of Elagolix in Women With Endometriosis

Study Overview
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Brief Summary
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The purpose of this study is to evaluate elagolix (NBI-56418) compared to placebo for its effects on endometriosis related pelvic pain and its safety.

Detailed Description
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Participants were randomized (1:1) to 150 mg elagolix once daily or placebo once daily for the first 8 weeks of the study. Following 8 weeks of dosing, participants continued in the study for an additional 16 weeks in an open-label phase where all participants still enrolled in the study received 150 mg elagolix once daily. There was no pre-specified primary efficacy end point for this study as there is no single key efficacy outcome measure in this exploratory Phase 2 study. However, the efficacy measures of primary interest included the daily assessment of dysmenorrhea, non-menstrual pelvic pain and dyspareunia on a 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe) using an e-Diary.

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of NBI-56418 Sodium in Subjects With Endometriosis

Conditions
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Endometriosis, Pain

Intervention / Treatment
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* Drug: Placebo
* Drug: Elagolix


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be female, aged 18 to 49 years, inclusive. Have moderate to severe pelvic pain due to endometriosis. Have a history of regular menstrual cycles. Have been surgically (laparoscopy or laparotomy) diagnosed with endometriosis within 8 years of the start of screening. Have a Body Mass Index (BMI) of 18 to 36 kg/m², inclusive. Agree to use two forms of non-hormonal contraception during the study. Exclusion Criteria: Are currently receiving gonadotropin-releasing hormone (GnRH) agonist, a GnRH antagonist other than NBI-56418, or danazol or have received any of these agents within 6 months of the start of screening. Are currently receiving subcutaneous medroxyprogesterone acetate (DMPA-SC) or intramuscular medroxyprogesterone acetate (DMPA-IM) or have received any 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. Have had a hysterectomy or bilateral oophorectomy. Are using systemic steroids on a chronic or regular basis within 3 months. Have uterine fibroids ≥ 3 cm in diameter. Have pelvic pain that is not caused by endometriosis. Have unstable medical condition or chronic disease. Have been pregnant within the last six months. Currently breast feeding.

Ages Eligible for Study
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Minimum Age: 18 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: Elagolix 150 mg<br>Participants received 150 mg elagolix orally once a day for 8 weeks during the double-blind treatment period and continued to receive 150 mg elagolix for 16 additional weeks during the open-label treatment period. | Drug: Elagolix<br>* Immediate release (IR) tablets taken orally once a day<br>* Other names: Orilissa™;|
| Placebo Comparator: Placebo<br>Participants received placebo orally once a day for 8 weeks during the double-blind treatment period and switched to receive 150 mg elagolix for 16 weeks during the open-label treatment period. | Drug: Placebo<br>* Matching placebo tablets taken orally once a day<br>Drug: Elagolix<br>* Immediate release (IR) tablets taken orally once a day<br>* Other names: Orilissa™;|

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 Dysmenorrhea Score During the Double-blind Treatment Phase | 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 electronic diary (e-Diary) according to the following response options: 0 = No discomfort 1 = Mild discomfort but I was easily able to do the things I usually do 2 = Moderate discomfort or pain that made it difficult to do some of the things I usually do 3 = Severe pain that made it difficult to do the things I usually do. 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 and 8 | 
| Change From Baseline in the Monthly Mean Dysmenorrhea Score During the Open-label and Posttreatment Phases | 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 electronic diary (e-Diary) according to the following response options: 0 = No discomfort 1 = Mild discomfort but I was easily able to do the things I usually do 2 = Moderate discomfort or pain that made it difficult to do some of the things I usually do 3 = Severe pain that made it difficult to do the things I usually do. The monthly mean dysmenorrhea score is the average of the daily values reported during the 4 weeks prior to each visit, except for the week 30 value which is based on 6 weeks of data. | Baseline and Weeks 12, 16, 20, 24, and 30 (6 weeks posttreatment) | 
| Change From Baseline in the Monthly Mean Non-menstrual Pelvic Pain Score During the Double-Blind Treatment Phase | Participants assessed their pelvic pain not related to menses and its impact on their daily activities at approximately the same time each day they were not having their period in an e-Diary according to the following response options: 0 = No discomfort 1 = Mild discomfort but I was easily able to do the things I usually do 2 = Moderate discomfort or pain that made it difficult to do some of the things I usually do 3 = Severe pain that made it difficult to do the things I usually do. 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 and 8 | 
| Change From Baseline in the Monthly Mean Non-menstrual Pelvic Pain Score During the Open-label and Posttreatment Phases | Participants assessed their pelvic pain not related to menses and its impact on their daily activities at approximately the same time each day they were not having their period in an e-Diary according to the following response options: 0 = No discomfort 1 = Mild discomfort but I was easily able to do the things I usually do 2 = Moderate discomfort or pain that made it difficult to do some of the things I usually do 3 = Severe pain that made it difficult to do the things I usually do. The monthly mean non-menstrual pelvic pain score is the average of the daily values reported during the 4 weeks prior to each visit, except for the week 30 value which is based on 6 weeks of data. | Baseline and Weeks 12, 16, 20, 24, and 30 (6 weeks posttreatment) | 
| Change From Baseline in the Monthly Mean Cumulative Pain Score During the Double-Blind Treatment Phase | Participants assessed dysmenorrhea or non-menstrual pelvic pain at approximately the same time each day in an e-Diary according to the following: 0 = No discomfort 1 = Mild discomfort but I was easily able to do the things I usually do 2 = Moderate discomfort or pain that made it difficult to do some of the things I usually do 3 = Severe pain that made it difficult to do the things I usually do. The monthly mean cumulative pain score is the average of the daily values for all days (menstrual and non-menstrual) reported during the 4 weeks prior to each visit. | Baseline and weeks 4 and 8 | 
| Change From Baseline in the Monthly Mean Cumulative Pain Score During the Open-label and Posttreatment Phases | Participants assessed dysmenorrhea or non-menstrual pelvic pain at approximately the same time each day in an e-Diary according to the following: 0: No discomfort 1: Mild discomfort, I was easily able to do the things I usually do 2: Moderate discomfort or pain making it difficult to do some of the things I usually do 3: Severe pain making it difficult to do the things I usually do The monthly mean cumulative pain score is the average of the daily values for all days (menstrual and non-menstrual) reported during the 4 weeks prior to each visit, except for the week 30 value which is based on 6 weeks of data. | Baseline and Weeks 12, 16, 20, 24, and 30 (6 weeks posttreatment) | 
| Change From Baseline in the Monthly Mean Dyspareunia Score During the Double-Blind Treatment Phase | Participants assessed their dyspareunia (pain during sexual intercourse) at approximately the same time every day in an e-Diary according to the following response options: 0 = Absent; No discomfort during sexual intercourse 1 = Mild; I was able to tolerate the discomfort during sexual intercourse 2 = Moderate; Intercourse was interrupted due to pain 3 = Severe; I avoided intercourse because of pain Does not apply; I was not sexually active for reasons other than my endometriosis or did not have sexual intercourse The monthly mean dyspareunia score is the average of the daily values reported during the 4 weeks prior to each visit. Responses of does not apply were not included in the calculations. | Baseline and weeks 4 and 8 | 
| Change From Baseline in the Monthly Mean Dyspareunia Score During the Open-label and Posttreatment Phases | Participants assessed their dyspareunia (pain during sexual intercourse) at approximately the same time every day in an e-Diary according to the following response options: 0: Absent; No discomfort during sexual intercourse 1: Mild; I was able to tolerate the discomfort during sexual intercourse 2: Moderate; Intercourse was interrupted due to pain 3: Severe; I avoided intercourse because of pain Does not apply; I was not sexually active for reasons other than my endometriosis or did not have sexual intercourse The monthly mean dyspareunia score is the average of the daily values reported during the 4 weeks prior to each visit, except for week 30 which is based on 6 weeks of data. Responses of does not apply were not included in the calculations. | Baseline and Weeks 12, 16, 20, 24, and 30 (6 weeks posttreatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Response in Monthly Mean Dysmenorrhea Score at Week 8 | 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: 0: No discomfort 1: Mild discomfort but I was easily able to do the things I usually do 2: Moderate discomfort or pain that made it difficult to do some of the things I usually do 3: Severe pain that made it difficult to do the things I usually do. The monthly mean dysmenorrhea score is the average of the daily values reported during the 4 weeks prior to each time point. Response was defined as the percentage of participants with a percent decrease from baseline in the week 8 monthly mean score that was greater than or equal to each specified threshold value (10% through 90% in steps of 10%). | Baseline and Week 8 | 
| Percentage of Participants With a Response in Monthly Mean Non-menstrual Pelvic Pain Score at Week 8 | Participants assessed their pelvic pain not related to menses and its impact on their daily activities at approximately the same time each day they were not having their period in an e-Diary according to the following response options: 0 = No discomfort 1 = Mild discomfort but I was easily able to do the things I usually do 2 = Moderate discomfort or pain that made it difficult to do some of the things I usually do 3 = Severe pain that made it difficult to do the things I usually do. The monthly mean non-menstrual pelvic pain score is the average of the daily values reported during the 4 weeks prior to each time point. Response is defined as the percentage of participants with a percent decrease from baseline in the week 8 monthly mean score that was greater than or equal to each specified threshold value (10% through 90% in steps of 10%). | Baseline and Week 8 | 
| Percentage of Participants With a Response in Monthly Mean Cumulative Pain Score at Week 8 | Participants assessed dysmenorrhea or non-menstrual pelvic pain at approximately the same time every day in an e-Diary according to the following: 0 = No discomfort 1 = Mild discomfort 2 = Moderate discomfort or pain 3 = Severe pain The monthly mean cumulative pain score is the average of the daily values for all days (menstrual and non-menstrual) in the 4 weeks prior to each time point. Response is the percentage of participants with a percent decrease from baseline in the week 8 monthly mean score that was greater than or equal to each specified threshold value (10% through 90% in steps of 10%). | Baseline and Week 8 | 
| Percentage of Participants With a Response in Monthly Mean Dyspareunia Score at Week 8 | Participants assessed their dyspareunia (pain during sexual intercourse) at approximately the same time every day in an e-Diary according to the following response options: 0 = Absent; No discomfort during sexual intercourse 1 = Mild; I was able to tolerate the discomfort during sexual intercourse 2 = Moderate; Intercourse was interrupted due to pain 3 = Severe; I avoided intercourse because of pain Does not apply; I was not sexually active for reasons other than my endometriosis or did not have sexual intercourse The monthly mean dyspareunia score is the average of the daily values reported during the 4 weeks prior to each time point. Response is defined as the percentage of participants with a percent decrease from baseline in the week 8 monthly mean score that was greater than or equal to each specified threshold value (10% through 90% in steps of 10%). | Baseline and Week 8 | 
| Change From Baseline in the Percentage of Days of Any Analgesic Use During the Double-Blind Treatment Phase | 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 and Weeks 4 and 8 | 
| Change From Baseline in the Percentage of Days of Any Analgesic Use During the Open-Label and Posttreatment Phases | 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 (except for week 30 which is based on 6 weeks of data) 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 and Weeks 12, 16, 20, 24, and 30 (6 weeks posttreatment) | 
| Change From Baseline in the Percentage of Days of Prescription Analgesic Use During the Double-Blind Treatment Phase | 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 and Weeks 4 and 8 | 
| Change From Baseline in the Percentage of Days of Prescription Analgesic Use During the Open-Label and Posttreatment Phases | 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 (except for week 30 which is based on 6 weeks of data) 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 and Weeks 12, 16, 20, 24, and 30 (6 weeks posttreatment) | 
| Change From Baseline in the Percentage of Days of Narcotic Analgesic Use During the Double-Blind Treatment Phase | 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 and Weeks 4 and 8 | 
| Change From Baseline in the Percentage of Days of Narcotic Analgesic Use During the Open-Label and Posttreatment Phases | 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 (except for week 30 which is based on 6 weeks of data) 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 and Weeks 12, 16, 20, 24, and 30 (6 weeks posttreatment) | 
| Change From Baseline to the End of the Double-blind Treatment Phase in Composite Pelvic Signs and Symptoms Score (CPSSS) Total Score and Component Scores | The CPSSS consists of 5 components that address dysmenorrhea, dyspareunia, non-menstrual pelvic pain, pelvic tenderness, and pelvic induration. Each component was scored on a scale of 0 to 3 (0 = absent, 1 = mild, 2 = moderate, and 3 = severe). Dysmenorrhea, dyspareunia, and non-menstrual pelvic pain scores are based on the participant's assessment of symptoms during the past 28 days; pelvic tenderness and induration were assessed by the investigator based on findings associated with a pelvic examination. The total CPSSS has a maximum possible value of 15 (total score range: 0 to 15, where a lower score indicates less signs and symptoms of endometriosis or better functioning). Individual component scores range from 0 (absent) to 3 (severe). | Baseline and Week 8 | 
| Change From Baseline to the End of the Open-label Treatment Phase in Composite Pelvic Signs and Symptoms Score (CPSSS) Total Score and Component Scores | The CPSSS consists of 5 components that address dysmenorrhea, dyspareunia, non-menstrual pelvic pain, pelvic tenderness, and pelvic induration. Each component was scored on a scale of 0 to 3 (0 = absent, 1 = mild, 2 = moderate, and 3 = severe). Dysmenorrhea, dyspareunia, and non-menstrual pelvic pain scores are based on the participant's assessment of symptoms during the past 28 days; pelvic tenderness and induration were assessed by the investigator based on findings associated with a pelvic examination. The total CPSSS has a maximum possible value of 15 (total score range: 0 to 15, where a lower score indicates less signs and symptoms of endometriosis or better functioning). Individual component scores range from 0 (absent) to 3 (severe). | Baseline and week 24 | 
| Patient Global Impression of Change During the Double-blind Treatment Phase | 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 and 8 | 
| Patient Global Impression of Change During the Open-Label and Posttreatment Phases | 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 12, 16, 20, 24, and 30 (6 weeks posttreatment) | 
| Percentage of Participants With a PGIC Response of Much Improved or Very Much Improved During the Double-blind Treatment Phase | 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 and 8 | 
| Percentage of Participants With a PGIC Response of Much Improved or Very Much Improved During the Open-label Treatment Phase | 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 12, 16, 20, 24, and 30 (6 weeks posttreatment) | 
| Change From Baseline to the End of the Double-blind Treatment Phase in Endometriosis Health Profile-5 (EHP-5) | 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 impact of endometriosis in 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 impact of endometriosis on 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 8 | 
| Change From Baseline to the End of the Open-label Treatment Phase in Endometriosis Health Profile-5 (EHP-5) | 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 impact of endometriosis on 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 impact of endometriosis on 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 24 | 
| Percentage of Days With Uterine Bleeding During the Double- Blind Treatment Phase | 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 e-Diary report of vaginal bleeding in the phase. | Screening (8 weeks prior to day 1) and the double-blind treatment phase (Weeks 1-8) | 
| 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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Pelvic Pain,NBI-56418,Endometriosis