Study to Evaluate the Long-Term Safety and Efficacy of Elagolix in Adults With Moderate to Severe Endometriosis-Associated Pain

Study Overview
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Brief Summary
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A randomized study evaluating the continued safety and efficacy of elagolix in the management of moderate to severe endometriosis-associated pain in pre-menopausal women.

Detailed Description
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This is a Phase 3 multicenter, double blind randomized study to assess the continued safety and efficacy of the 150 mg once daily (QD) and 200 mg twice daily (BID) doses of elagolix in premenopausal women with moderate to severe endometriosis-associated pain who completed the 6 month treatment period in the pivotal study M12-665 (NCT01620528). The study consists of 2 periods: a 6 month Treatment Period and a post treatment follow-up period of up to 12 months. Participants who received elagolix in the pivotal study who met all entry criteria continued to receive the same dose, either elagolix 150 mg QD or elagolix 200 mg BID for up to an additional 6 months in this extension study; participants who received placebo in the pivotal study were randomized in a 1:1 ratio to receive either elagolix 150 mg QD or elagolix 200 mg BID for up to 6 months. An electronic diary will be used to collect endometriosis-associated pain, uterine bleeding, and analgesic medication use for endometriosis associated pain on a daily basis. All participants who prematurely discontinued treatment (unless pregnant or elected surgery for endometriosis) or completed the 6-month Treatment Period in this extension study were to enter the Post-treatment Follow-up (PTFU) Period within this study for up to 12 months.

Official Title
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Extension Study to Evaluate the Long-Term Safety and Efficacy of Elagolix in Subjects With Moderate to Severe Endometriosis-Associated Pain

Conditions
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Endometriosis

Intervention / Treatment
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* Drug: Elagolix


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Completed the 6 month Treatment Period in pivotal study M12-665 (NCT01620528) Agrees to use required birth control methods during the study through Month 6 of the Post-treatment Follow-up period Exclusion Criteria: Clinically significant gynecological condition Bone mineral density (BMD) loss greater than or equal to 8 percent in the spine, femoral neck or total hip Plans to become pregnant in the next 18 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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 QD<br>Participants received elagolix 150 mg tablets once a day (QD) for 6 months. | Drug: Elagolix<br>* Elagolix tablets administered orally<br>* Other names: Orilissa™;|
| Experimental: Elagolix 200 mg BID<br>Participants received elagolix 200 mg tablets twice a day (BID) for 6 months. | Drug: Elagolix<br>* Elagolix tablets administered orally<br>* Other names: Orilissa™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Response for Dysmenorrhea at Month 6 Based on Daily Assessment | Response was defined as a reduction of -0.81 or more from baseline in dysmenorrhea (pain during menstruation) as well as no increase in rescue analgesic use for endometriosis-associated pain (defined as a < 15% increase in average rescue analgesic pill count and no additional analgesic). The response threshold represents a clinically meaningful response that was determined in pivotal Study M12-665. Participants recorded rescue analgesic use for endometriosis-associated pain daily and dysmenorrhea and its impact on daily activities each day of their period in an electronic diary (e-Diary). Dysmenorrhea was assessed 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. Analgesic use and pain scores were averaged over the 35 days prior to each visit. | Baseline (defined as baseline of Study M12-665 for participants who received elagolix in the pivotal study and baseline of the extension study M12-667 for participants who received placebo in the pivotal study) and Month 6 | 
| Percentage of Participants With a Response for Non-menstrual Pelvic Pain at Month 6 Based on Daily Assessment | Response was defined as a reduction of -0.36 or greater from baseline for non-menstrual pelvic pain as well as no increase in rescue analgesic use for endometriosis-associated pain (defined as a < 15% increase in average pill count of rescue analgesics and no additional analgesics). The response threshold represents a clinically meaningful response that was determined in pivotal Study M12-665. Participants recorded rescue analgesic medication for endometriosis-associated pain and assessed non-menstrual pelvic pain and its impact on their daily activities each day 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. Pain scores and analgesic use were averaged over the 35 days prior to each visit. | Baseline (defined as baseline of Study M12-665 for participants who received elagolix in the pivotal study and baseline of the extension study M12-667 for participants who received placebo in the pivotal study) and Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Response for Dysmenorrhea at Each Month Based on Daily Assessment | Response was defined as a reduction of -0.81 or more from baseline in dysmenorrhea as well as no increase in rescue analgesic use for endometriosis-associated pain (defined as a < 15% increase in average pill count of rescue analgesics and no additional analgesic). The response threshold represents a clinically meaningful response that was determined in pivotal Study M12-665. Participants recorded rescue analgesic medication for endometriosis-associated pain daily and dysmenorrhea (pain during menstruation) and its impact on their daily activities each day of their period in an e-Diary. Dysmenorrhea was assessed 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. Analgesic use and pain scores were averaged over the 35 days prior to each visit. | Baseline (defined as baseline of Study M12-665 for participants who received elagolix in the pivotal study and baseline of the extension study M12-667 for participants who received placebo in the pivotal study) and months 1, 2, 3, 4, and 5 | 
| Percentage of Participants With a Response for Non-menstrual Pelvic Pain at Each Month Based on Daily Assessment | Response was defined as a reduction of -0.36 or greater from baseline for non-menstrual pelvic pain as well as no increase in rescue analgesic use for endometriosis-associated pain (defined as a < 15% increase in average pill count of rescue analgesics and no additional analgesics). The response threshold represents a clinically meaningful response that was determined in pivotal Study M12-665. Participants recorded rescue analgesic medication for endometriosis-associated pain and assessed non-menstrual pelvic pain and its impact on their daily activities each day 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. Pain scores and analgesic use were averaged over the 35 days prior to each visit. | Baseline (defined as baseline of Study M12-665 for participants who received elagolix in the pivotal study and baseline of the extension study M12-667 for participants who received placebo in the pivotal study) and months 1, 2, 3, 4, and 5 | 
| Percentage of Participants With a Response for Dyspareunia at Each Month Based on Daily Assessment | Response was defined as a reduction of -0.36 or more from baseline in dyspareunia (pain during sexual intercourse) as well as no increase in rescue analgesic use for endometriosis-associated pain (defined as a < 15% increase in average rescue analgesic pill count and no additional analgesics). Participants recorded rescue analgesic medication for endometriosis-associated pain and assessed dyspareunia each day in an e-Diary. Dyspareunia was assessed according to the following: 0: None; No discomfort during sexual intercourse 1: Mild; Able to tolerate the discomfort during sexual intercourse 2: Moderate; Intercourse was interrupted due to pain 3: Severe; Avoided intercourse because of pain Not applicable; I was not sexually active for reasons other than endometriosis or did not have sexual intercourse. Pain scores and analgesic use were averaged over the 35 days prior to each visit. Responses of Not Applicable were excluded. | Baseline (defined as baseline of Study M12-665 for participants who received elagolix in the pivotal study and baseline of the extension study M12-667 for participants who received placebo in the pivotal study) and months 1, 2, 3, 4, 5, and 6 | 
| Percent Change From Baseline in Dysmenorrhea Based on Daily Assessment | Participants assessed dysmenorrhea (pain during menstruation) and its impact on their daily activities 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. Pain scores were averaged over the 35 days prior to each visit. | Baseline (defined as baseline of Study M12-665 for participants who received elagolix in the pivotal study and baseline of the extension study M12-667 for participants who received placebo in the pivotal study) and months 1, 2, 3, 4, 5, and 6 | 
| Percent Change From Baseline in Non-menstrual Pelvic Pain Based on Daily Assessment | Participants assessed non-menstrual pelvic pain and its impact on their daily activities each day 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. Pain scores were averaged over the 35 days prior to each visit. | Baseline (defined as baseline of Study M12-665 for participants who received elagolix in the pivotal study and baseline of the extension study M12-667 for participants who received placebo in the pivotal study) and months 1, 2, 3, 4, 5, and 6 | 
| Percent Change From Baseline in Dyspareunia Based on Daily Assessment | Participants assessed dyspareunia each day in an e-Diary according to the following response options: 0: None; No discomfort during sexual intercourse 1: Mild; Able to tolerate the discomfort during sexual intercourse 2: Moderate; Intercourse was interrupted due to pain 3: Severe; Avoided intercourse because of pain Not applicable; I was not sexually active for reasons other than endometriosis or did not have sexual intercourse. Pain scores were averaged over the 35 days prior to each visit. Responses of Not Applicable were excluded. | Baseline (defined as baseline of Study M12-665 for participants who received elagolix in the pivotal study and baseline of the extension study M12-667 for participants who received placebo in the pivotal study) and months 1, 2, 3, 4, 5, and 6 | 
| Change From Baseline in Any Rescue Analgesic Use | Permitted rescue analgesics varied by country and were limited to non-steroidal anti-inflammatory drugs (NSAID) (naproxen 500 mg), or opioid analgesics (hydrocodone 5 mg + acetaminophen 300 mg or 325 mg, and/or codeine 30 mg + acetaminophen 300 mg). Use of rescue analgesic medications taken for endometriosis-associated pain was recorded by the participant daily in the e-Diary as the total number of pills/tablets of each type taken within a 24-hour period. Any rescue analgesic use (NSAID and/or opioid) was calculated as the total number of pills divided by the number of days in the window (i.e. average daily pill count) over the 35-day window prior to and including the reference study day. | Baseline (defined as baseline of Study M12-665 for participants who received elagolix in the pivotal study and baseline of the extension study M12-667 for participants who received placebo in the pivotal study) and months 1, 2, 3, 4, 5, and 6 | 
| Change From Baseline in NSAID Rescue Analgesic Use | Permitted rescue analgesics varied by country and were limited to non-steroidal anti-inflammatory drugs (NSAID) (naproxen 500 mg), or opioid analgesics (hydrocodone 5 mg + acetaminophen 300 mg or 325 mg, and/or codeine 30 mg + acetaminophen 300 mg). Use of rescue analgesic medications taken for endometriosis-associated pain was recorded by the participant daily in the e-Diary as the total number of pills/tablets of each type taken within a 24-hour period. NSAID rescue analgesic use was calculated as the total number of NSAID pills divided by the number of days in the window (i.e. average daily pill count) over the 35-day window prior to and including the reference study day. | Baseline (defined as baseline of Study M12-665 for participants who received elagolix in the pivotal study and baseline of the extension study M12-667 for participants who received placebo in the pivotal study) and months 1, 2, 3, 4, 5, and 6 | 
| Change From Baseline in Opioid Rescue Analgesic Use | Permitted rescue analgesics varied by country and were limited to non-steroidal anti-inflammatory drugs (NSAID) (naproxen 500 mg), or opioid analgesics (hydrocodone 5 mg + acetaminophen 300 mg or 325 mg, and/or codeine 30 mg + acetaminophen 300 mg). Use of rescue analgesic medications taken for endometriosis-associated pain was recorded by the participant daily in the e-Diary as the total number of pills/tablets of each type taken within a 24-hour period. Opioid rescue analgesic use was calculated as the total number of opioid pills divided by the number of days in the window (i.e. average daily pill count) over the 35-day window prior to and including the reference study day. | Baseline (defined as baseline of Study M12-665 for participants who received elagolix in the pivotal study and baseline of the extension study M12-667 for participants who received placebo in the pivotal study) and months 1, 2, 3, 4, 5, and 6 | 
| Percent Change From Baseline in Endometriosis-Associated Pain Score Assessed With Numeric Rating Scale (NRS) | The NRS measured endometriosis-associated pain with and without menstruation on an 11-point scale from 0 = no pain to 10 = worst pain ever. Participants were asked to assess their endometriosis pain over the past 24 hours at it's worst at approximately the same time every day in the e-Diary. Pain scores were averaged over the 35 days prior to each visit. | Baseline (defined as baseline of Study M12-665 for participants who received elagolix in the pivotal study and baseline of the extension study M12-667 for participants who received placebo in the pivotal study) and months 1, 2, 3, 4, 5, and 6 | 
| Percentage of Participants With a PGIC Response of Much Improved or Very Much Improved | 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 | Months 1, 2, 3, 4, 5, and 6 | 
| Change From Baseline in Endometriosis Health Profile-30 (EHP-30) Pain Dimension | The EHP-30 is an instrument to measure health-related quality of life in women with endometriosis. The EHP-30 consists of two parts: a core questionnaire containing 5 scales that are applicable to all women with endometriosis and includes pain, control and powerlessness, emotional well-being, social support, and self-image, and a modular part containing 6 scales which do not necessarily apply to all women with endometriosis. Each question in the core questionnaire is scored on the following scale: 0 = Never, 1 = Rarely, 2 = Sometimes, 3 = Often, 4 = Always. The pain dimension consists of 11 questions. The dimension score ranges from 0 to 100, where 0 = best possible health status as measured by the questionnaire; 100 = worst possible health status. A negative change from baseline score indicates improvement in quality of life. | Baseline (defined as baseline of Study M12-665 for participants who received elagolix in the pivotal study and baseline of the extension study M12-667 for participants who received placebo in the pivotal study) and months 1, 3, and 6 | 
| Change From Baseline in Endometriosis Health Profile-30 (EHP-30) Sexual Intercourse Dimension | The EHP-30 is an instrument to measure health-related quality of life in women with endometriosis. The EHP-30 consists of two parts: a core questionnaire containing 5 scales that are applicable to all women with endometriosis and a modular part containing 6 scales which do not necessarily apply to all women with endometriosis; only 1 modular questionnaire (sexual intercourse [5 items]) was used in this study. The Sexual Intercourse dimension consists of 5 questions, each answered on the following scale: 0 = Never, 1 = Rarely, 2 = Sometimes, 3 = Often, 4 = Always, or Not Applicable (not scored). The dimension score ranges from 0 to 100, where 0 = best possible health status as measured by the questionnaire; 100 = worst possible health status. A negative change from baseline score indicates improvement in quality of life. | Baseline (defined as baseline of Study M12-665 for participants who received elagolix in the pivotal study and baseline of the extension study M12-667 for participants who received placebo in the pivotal study) and months 1, 3, and 6 | 
| Change From Baseline in Health-Related Productivity Questionnaire (HRPQ): Hours of Work Lost in Workplace and Household | The HRPQ consists of 9 questions measuring the impact of endometriosis-associated pain and its treatment on work productivity and daily activities in the home. Absenteeism: Number of hours of intended work lost due to illness or treatment. Presenteeism: Number of hours of work where output was impacted by illness or treatments. Total hours lost is the sum of hours missed due to absenteeism plus presenteeism. | Baseline (defined as baseline of Study M12-665 for participants who received elagolix in the pivotal study and baseline of the extension study M12-667 for participants who received placebo in the pivotal study) and month 6 | 
| Number of Participants With Non-study Health Visits During the Treatment Period | The Health Resource Use Questionnaire (HRUQ) was used to collect information on non-study-related health visits that participants had during the study. | 6 months | 
| Number of Days in Hospital During the Treatment Period | The Health Resource Use Questionnaire (HRUQ) was used to collect information on non-study-related health visits that participants had during the study, including physician visits, hospitalizations and types of procedures received. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endometriosis associated pain, Elagolix, Gonadotropin-Releasing Hormone Antagonist, Dysmenorrhea (DYS), Non-Menstrual Pelvic Pain (NMPP)