A Clinical Study to Evaluate the Safety and Efficacy of Elagolix in Participants With Moderate to Severe Endometriosis-Associated Pain

Study Overview
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Brief Summary
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The objective of this study is to evaluate safety and efficacy of elagolix in the management of moderate to severe endometriosis-associated pain in adult premenopausal female participants including the safety and efficacy of elagolix in combination with concomitant hormonal add-back therapy.

Official Title
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A Phase 3 Study to Evaluate the Safety and Efficacy of Elagolix in Combination With Estradiol/Norethindrone Acetate in Subjects With Moderate to Severe Endometriosis-Associated Pain

Conditions
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Endometriosis

Intervention / Treatment
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* Drug: Estradiol/Norethindrone Acetate
* Drug: Placebo for Elagolix
* Drug: Elagolix
* Drug: Placebo for E2/NETA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is a premenopausal female 18 to 49 years of age (inclusive) at the time of Screening. Participant has a documented surgical diagnosis (e.g., laparoscopy or laparotomy) of endometriosis established by visualization within 10 years prior to entry into Washout or Screening. Participant must agree to use only protocol specified rescue analgesics during the Screening and Treatment Periods for endometriosis-associated pain. Participant must have the following documented in the e-Diary during the last 35 days prior to Study Day 1: At least 2 days of moderate or severe dysmenorrhea (DYS) AND either At least 2 days of moderate or severe non-menstrual pelvic pain (NMPP) and an average NMPP score of at least 1.0, OR At least 4 days of moderate or severe NMPP and an average NMPP score of at least 0.5. Exclusion Criteria: Participant has chronic pelvic pain that is not caused by endometriosis, that requires chronic analgesic therapy, which would interfere with the assessment of endometriosis-related pain. Participant is using any systemic corticosteroids for over 14 days within 3 months prior to Screening or is likely to require treatment with systemic corticosteroids during the course of the study. Over-the-counter and prescription topical, inhaled or intranasal corticosteroids are allowed. Participant has a history of any major depression or post-traumatic stress disorder (PTSD) within 2 years of the screening visit or other major psychiatric disorder at any time. Participant has a history of suicide attempts or answered yes to questions 4 or 5 on the suicidal ideation portion of the Columbia-Suicide Severity Rating Scale (C-SSRS) within the last 1 year at Screening or prior to randomization on Day 1. Participant has any history of osteoporosis or other metabolic bone disease or any condition that would interfere with obtaining adequate dual energy x-ray absorptiometry (DXA) measurements Screening DXA results of the lumbar spine (L1-L4), femoral neck or total hip bone mineral density (BMD) corresponding to less than 2.0 or more standard deviations below normal. Participant has either: a newly diagnosed, clinically significant medical condition that requires therapeutic intervention (e.g., new onset hypertension), that has not been stabilized 30 days prior to randomization on Day 1 OR a clinically significant medical condition that is anticipated to require intervention during the course of study participation (e.g., anticipated major elective surgery) OR an unstable medical condition that makes the subject an unsuitable candidate for the study in the opinion of the Investigator, (including, but not limited to, uncontrolled diabetes mellitus, uncontrolled hypertension, epilepsy requiring anti-epileptic medication, unstable angina, confirmed inflammatory bowel disease, hyperprolactinemia, clinically significant infection or injury). Participant has any conditions contraindicated with use of E2/NETA.

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 |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo for elagolix administered twice daily (BID) plus placebo for estradiol/norethindrone acetate (E2/NETA) administered once daily (QD) for the 12-month placebo-controlled Treatment Period, followed by elagolix 200 mg BID plus E2/NETA 1 mg/0.5 mg QD for the remaining 36 months of the Treatment Period. | Drug: Placebo for Elagolix<br>* Tablet<br>Drug: Placebo for E2/NETA<br>* Tablets<br>|
| Experimental: Elagolix / Elagolix + E2/NETA<br>Elagolix 200 mg BID alone for the first 6 months of the 12-month placebo-controlled Treatment Period and elagolix 200 mg BID+E2/NETA 1 mg/0.5 mg QD for the second 6 months, followed by elagolix 200 mg BID+E2/NETA 1 mg/0.5 mg QD for the remaining 36 months of the Treatment Period. | Drug: Estradiol/Norethindrone Acetate<br>* Tablets<br>* Other names: E2/NETA;Drug: Elagolix<br>* Tablet<br>* Other names: ORILISSA;|
| Experimental: Elagolix + E2/NETA<br>Elagolix 200 mg BID + E2/NETA 1 mg/0.5 mg QD for the 12-month placebo-controlled Treatment Period, followed by elagolix 200 mg BID plus E2/NETA 1 mg/0.5 mg QD for the remaining 36 months of the Treatment Period. | Drug: Estradiol/Norethindrone Acetate<br>* Tablets<br>* Other names: E2/NETA;Drug: Elagolix<br>* Tablet<br>* Other names: ORILISSA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Co-Primary Endpoint: Percentage of Participants With a Response for Dysmenorrhea (DYS) at Months 6 and 12 Based on Daily Assessment | Participants recorded rescue analgesic use for endometriosis-associated pain daily and DYS (pain during menstruation ) and its impact on daily activities each day of their period in an electronic diary (e-Diary). DYS was measured by the 4-point Endometriosis Daily Pain Impact 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. Pain scores and analgesic use were averaged over 35 days prior to each visit. Response was defined as a reduction of -0.92 or more from baseline in DYS 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). | Month 6, Month 12 | 
| Co-Primary Endpoint: Percentage of Participants With a Response for Non-menstrual Pelvic Pain (NMPP) at Months 6 and 12 Based on Daily Assessment | Participants recorded rescue analgesic medication for endometriosis-associated pain and assessed NMPP and its impact on their daily activities each day in an e-Diary was measured by the 4-point Endometriosis Daily Pain Impact 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. Pain scores and analgesic use were averaged over the 35 days prior to each visit. Response was defined as a reduction of -0.55 or greater from baseline for NMPP 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). | Month 6, Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in DYS at Month 12 Based on Daily Assessment | Participants assessed DYS (pain during menstruation) and its impact on their daily activities each day of their period in an e-Diary. DYS was measured by the 4-point Endometriosis Daily Pain Impact 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. Pain scores were averaged over the 35 days prior to each visit. | Baseline, Month 12 | 
| Change From Baseline in DYS at Month 6 Based on Daily Assessment | Participants assessed DYS (pain during menstruation) and its impact on their daily activities each day of their period in an e-Diary. DYS was measured by the 4-point Endometriosis Daily Pain Impact Diary according to the following: 0: No discomfort Mild discomfort but I was easily able to do the things I usually do Moderate discomfort or pain that made it difficult to do some of the things I usually do 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, Month 6 | 
| Change From Baseline in DYS at Month 3 Based on Daily Assessment | Participants assessed DYS (pain during menstruation) and its impact on their daily activities each day of their period in an e-Diary. DYS was measured by the 4-point Endometriosis Daily Pain Impact Diary according to the following: 0: No discomfort Mild discomfort but I was easily able to do the things I usually do Moderate discomfort or pain that made it difficult to do some of the things I usually do 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, Month 3 | 
| Change From Baseline in Non-menstrual Pelvic Pain (NMPP) at Month 12 Based on Daily Assessment | Participants recorded rescue analgesic medication for endometriosis-associated pain and assessed NMPP and its impact on their daily activities each day in an e-Diary was measured by the 4-point Endometriosis Daily Pain Impact 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. Pain scores and analgesic use were averaged over the 35 days prior to each visit. | Baseline, Month 12 | 
| Change From Baseline in NMPP at Month 6 Based on Daily Assessment | Participants recorded rescue analgesic medication for endometriosis-associated pain and assessed NMPP and its impact on their daily activities each day in an e-Diary was measured by the 4-point Endometriosis Daily Pain Impact 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. Pain scores and analgesic use were averaged over the 35 days prior to each visit. | Baseline, Month 6 | 
| Change From Baseline in NMPP at Month 3 Based on Daily Assessment | Participants recorded rescue analgesic medication for endometriosis-associated pain and assessed NMPP and its impact on their daily activities each day in an e-Diary was measured by the 4-point Endometriosis Daily Pain Impact 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. Pain scores and analgesic use were averaged over the 35 days prior to each visit. | Baseline, Month 3 | 
| Change From Baseline to Month 6 in Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue Short Form 6a T-Score | The PROMIS Fatigue Short Form 6a is self-administered and composed of 6 questions to evaluate fatigue over the past 7 days. All questions employ the following five response options: 1 = Never, 2 = Rarely, 3 = Sometimes, 4 = Often, and 5 = Always. The PROMIS Fatigue 6a score is calculated as a T-score, which is a standardized score with a mean of 50 (based on the average for the United States general population) and a standard deviation (SD) of 10. Higher scores indicate higher levels of fatigue. A decrease in score (negative change from baseline) indicates improvement in fatigue. | Baseline, Month 6 | 
| Change From Baseline in Dyspareunia (DYSP) at Month 12 Based on Daily Assessment | Participants assessed DYSP 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, Month 12 | 
| Change From Baseline in DYSP at Month 6 Based on Daily Assessment | Participants assessed DYSP 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, Month 6 | 
| Change From Baseline in DYSP at Month 3 Based on Daily Assessment | Participants assessed DYSP 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, Month 3 | 
| Change From Baseline to Month 12 in Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue Short Form 6a T-Score | The PROMIS Fatigue Short Form 6a is self-administered and composed of 6 questions to evaluate fatigue over the past 7 days. All questions employ the following five response options: 1 = Never, 2 = Rarely, 3 = Sometimes, 4 = Often, and 5 = Always. The PROMIS Fatigue 6a score is calculated as a T-score, which is a standardized score with a mean of 50 (based on the average for the United States general population) and a standard deviation (SD) of 10. Higher scores indicate higher levels of fatigue. A decrease in score (negative change from baseline) indicates improvement in fatigue. | Baseline, Month 12 | 
| Change From Baseline in Endometriosis-Associated Pain Score at Month 12 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. Site staff administered the Overall Endometriosis-Associated Pain questionnaire assessing pain over a 7-day recall period, and recorded the participant's response electronically via a tablet at the time of visit. Pain scores were averaged over the 35 days prior to each visit. | Baseline, Month 12 | 
| Change From Baseline in Endometriosis-Associated Pain Score at Month 6 Assessed With 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. Site staff administered the Overall Endometriosis-Associated Pain questionnaire assessing pain over a 7-day recall period, and recorded the participant's response electronically via a tablet at the time of visit. Pain scores were averaged over the 35 days prior to each visit. | Baseline, Month 6 | 
| Change From Baseline in Endometriosis-Associated Pain Score at Month 3 Assessed With 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. Site staff administered the Overall Endometriosis-Associated Pain questionnaire assessing pain over a 7-day recall period, and recorded the participant's response electronically via a tablet at the time of visit. Pain scores were averaged over the 35 days prior to each visit. | Baseline, Month 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Elagolix, Endometriosis associated pain, Dysmenorrhea (DYS), Non-menstrual pelvic pain (NMPP), ORILISSA