A Global Phase 3 Study to Evaluate the Safety and Efficacy of Elagolix in Subjects With Moderate to Severe Endometriosis-Associated Pain (ELARIS EM-II)

• ClinicalTrials.gov Identifier: NCT01931670
• Recruitment Status: Completed
• First Posted: August 29, 2013
• Results First Posted: September 7, 2018
• Last Update Posted: September 7, 2018
• Sponsor: AbbVie
• Information provided by (Responsible Party): AbbVie

Study Description

Brief Summary:

A randomized study evaluating the safety and efficacy of elagolix in the management of moderate to severe endometriosis-associated pain in adult premenopausal female subjects.

Condition or disease	Intervention/treatment	Phase
Endometriosis	Other: placebo; Drug: Elagolix	Phase 3

Detailed Description:

The study consists of 4 periods: 1) Washout Period (if applicable); 2) a Screening Period of up to 100 days prior to first dose; 3) a 6 month Treatment Period; and 4) a Post treatment Follow-up Period of up to 12 months (if applicable). An electronic diary will be dispensed and training provided to record endometriosis-associated pain, uterine bleeding, and analgesic medication use for endometriosis-associated pain on a daily basis. Pregnancy testing will be performed monthly throughout the study. Subjects will be required to use nonhormonal dual contraception during the study, and will be counseled on appropriate and effective forms of birth control to promote pregnancy prevention.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 815 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Elagolix in Subjects With Moderate to Severe Endometriosis-Associated Pain
• Actual Study Start Date: September 9, 2013
• Actual Primary Completion Date: January 6, 2016
• Actual Study Completion Date: December 19, 2016

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Placebo twice daily (BID) for the 6-month Treatment Period	Other: placebo
Experimental: Elagolix 150 mg QD; Elagolix 150 mg once daily (QD) for the 6-month Treatment Period	Drug: Elagolix; Other Names: ABT-620; elagolix sodium
Experimental: Elagolix 200 mg BID; Elagolix 200 mg BID for the 6-month Treatment Period	Drug: Elagolix; Other Names: ABT-620; elagolix sodium

Outcome Measures

Primary Outcome Measures :

1. Percentage of Responders at Month 3 Based on Daily Assessment of Dysmenorrhea (DYS) [ Time Frame: At Month 3 of the Treatment Period ]
   The DYS pain scale ranges from 0 (none) to 3 (severe) as recorded in a daily electronic diary. The criteria for defining a participant as a responder included a reduction of -0.85 or greater from Baseline in DYS pain as well as no increased rescue analgesic use for endometriosis-associated pain.
2. Percentage of Responders at Month 3 Based on Daily Assessment of Non-Menstrual Pelvic Pain (NMPP) [ Time Frame: At Month 3 of Treatment Period ]
   The NMPP pain scale ranges from 0 (none) to 3 (severe) as recorded in a daily electronic diary. The criteria for defining a participant as a responder included a reduction of -0.43 or greater from Baseline in NMPP as well as no increased rescue analgesic use for endometriosis-associated pain.

Secondary Outcome Measures :

1. Change From Baseline to Month 3 in Numeric Rating Scale (NRS) Scores [ Time Frame: Baseline, Month 3 of the Treatment Period ]
   The NRS for overall endometriosis-associated pain ranges 0 (none) to 10 (worst pain ever).
2. Change From Baseline to Month 6 in DYS [ Time Frame: Baseline, Month 6 of Treatment Period ]
   The DYS pain scale ranges from 0 (none) to 3 (severe).
3. Change From Baseline to Month 6 in NMPP [ Time Frame: Baseline, Month 6 of Treatment Period ]
   The NMPP pain scale ranges from 0 (none) to 3 (severe).
4. Change From Baseline to Month 3 in Analgesic Use Across Both Classes of Rescue Analgesics [ Time Frame: Baseline, Month 3 of Treatment Period ]
   Permitted rescue medications included the nonsteroidal anti-inflammatory drug naproxen (500 or 550 mg), and one country-specific narcotic analgesic (5 mg hydrocodone + 300 or 325 mg acetaminophen, or 30 mg codeine + 500 mg acetaminophen, or 30 mg codeine, or 37.5 mg tramadol + 325 mg acetaminophen). Assessment was based on average pill counts.
5. Change From Baseline to Month 6 in Analgesic Use Across Both Classes of Rescue Analgesics [ Time Frame: Baseline, Month 6 of Treatment Period ]
   Permitted rescue medications included the nonsteroidal anti-inflammatory drug naproxen (500 or 550 mg), and one country-specific narcotic analgesic (5 mg hydrocodone + 300 or 325 mg acetaminophen, or 30 mg codeine + 500 mg acetaminophen, or 30 mg codeine, or 37.5 mg tramadol + 325 mg acetaminophen). Assessment was based on average pill counts.
6. Change From Baseline to Month 3 in Dyspareunia (DYSP) [ Time Frame: Baseline, Month 3 of Treatment Period ]
   The DYSP pain scale ranges from 0 (absent) to 3 (severe).
7. Change From Baseline to Month 3 in Use of Narcotic Class of Medication (Opioids) [ Time Frame: Baseline, Month 3 of Treatment Period ]
   Permitted country-specific rescue narcotic analgesics included 5 mg hydrocodone + 300 or 325 mg acetaminophen, or 30 mg codeine + 500 mg acetaminophen, or 30 mg codeine, or 37.5 mg tramadol + 325 mg acetaminophen. Assessment was based on average pill counts.
8. Percentage of Responders for Each Month, Except Month 3, in DYS [ Time Frame: Months 1, 2, 4, 5, 6 of the Treatment Period ]
   The DYS pain scale ranges from 0 (none) to 3 (severe) as recorded in a daily electronic diary. The criteria for defining a participant as a responder included a reduction of -0.85 or greater from Baseline in DYS pain as well as no increased rescue analgesic use for endometriosis-associated pain.
9. Percentage of Responders for Each Month, Except Month 3, in NMPP [ Time Frame: Months 1, 2, 4, 5, 6 of the Treatment Period ]
   The NMPP pain scale ranges from 0 (none) to 3 (severe) as recorded in a daily electronic diary. The criteria for defining a participant as a responder included a reduction of -0.43 or greater from Baseline in NMPP as well as no increased rescue analgesic use for endometriosis-associated pain.
10. Percentage of Responders at Each Month for DYSP [ Time Frame: Months 1, 2, 3, 4, 5, 6 of Treatment Period ]
    The DYSP pain scale ranged from 0 (absent) to 3 (severe) as recorded in a daily electronic diary. The criteria for defining a participant as a responder included a reduction of -0.29 or greater from Baseline in DYSP as well as no increased rescue analgesic use for endometriosis-associated pain.
11. Change From Baseline to Each Month, Except Month 6, in Mean Pain Score for DYS [ Time Frame: Baseline (Prior to administering study drug), Months 1, 2, 3, 4, 5 of Treatment Period ]
    The DYS pain scale ranges from 0 (none) to 3 (severe).
12. Percent Change From Baseline to Each Month in Mean Pain Score for DYS [ Time Frame: Baseline, Months 1, 2, 3, 4, 5, 6 of Treatment Period ]
    The DYS pain scale ranges from 0 (none) to 3 (severe).
13. Change From Baseline to Each Month, Except Month 6, in Mean Pain Score for NMPP [ Time Frame: Baseline, Months 1, 2, 3, 4, 5 of Treatment Period ]
    The NMPP pain scale ranges from 0 (none) to 3 (severe).
14. Percent Change From Baseline to Each Month in the Mean Pain Score for NMPP [ Time Frame: Baseline, Months 1, 2, 3, 4, 5, 6 of Treatment Period ]
    The NMPP pain scale ranges from 0 (none) to 3 (severe).
15. Change From Baseline to Each Month, Except Month 3, in the Mean Pain Score of DYSP [ Time Frame: Baseline, Months 1, 2, 4, 5, 6 of Treatment Period ]
    The DYSP pain scale ranged from 0 (absent) to 3 (severe).
16. Change From Baseline to Each Month, Except Months 3 and 6, in Analgesic Use Across Both Classes of Rescue Analgesics [ Time Frame: Baseline, Months 1, 2, 4, 5 ]
    Permitted rescue medications included the nonsteroidal anti-inflammatory drug naproxen (500 or 550 mg), and one country-specific narcotic analgesic (5 mg hydrocodone + 300 or 325 mg acetaminophen, or 30 mg codeine + 500 mg acetaminophen, or 30 mg codeine, or 37.5 mg tramadol + 325 mg acetaminophen). Assessment was based on average pill counts.
17. Patient Global Impression of Change (PGIC) Questionnaire [ Time Frame: Months 1, 2, 3, 4, 5, 6 of Treatment Period ]
    The PGIC questionnaire is a self-reported 7-point scale rating a participant's overall impression of change from 1 = very much improved to 7 = very much worse. Participants evaluated the change in their endometriosis-associated pain since initiation of study drug.
18. Change From Baseline to Each Month, Except Month 3, in NRS Scores [ Time Frame: Baseline, Months 1, 2, 4, 5, 6 of Treatment Period ]
    The NRS for overall endometriosis-associated pain ranges 0 (none) to 10 (worst pain ever).
19. Change From Baseline to Each Scheduled Assessment in the Pain Domain of Endometriosis Health Profile-30 (EHP-30) Questionnaire Scores [ Time Frame: Baseline, Months 1, 3, 6 of Treatment Period ]
    The EHP-30 is a disease-specific self-administered questionnaire used to measure health-related quality of life in women with endometriosis. Each domain is calculated on a scale from 0 = best possible health status to 100 = worst possible health status.
20. Change From Baseline to Each Scheduled Assessment in the Sexual Intercourse Domain of EHP-30 Questionnaire Scores [ Time Frame: Baseline, Months 1, 3, 6 of Treatment Period ]
    The EHP-30 is a disease-specific self-administered questionnaire used to measure health-related quality of life in women with endometriosis. Each domain is calculated on a scale from 0 = best possible health status to 100 = worst possible health status.
21. Change From Baseline to Each Month in Health Related Productivity Questionnaire (HRPQ): Number of Hours of Work Lost From Workplace Due to Absenteeism [ Time Frame: Baseline, Months 1, 2, 3, 4, 5, 6 of Treatment Period ]
    The HRPQ consists of questions measuring the impact of endometriosis-associated pain and its treatment on work productivity (number of work hours lost from the workplace due to absenteeism) in the 7 days prior to survey administration.
22. Change From Baseline to Each Month in HRPQ: Number of Hours of Work Lost From Household Due to Absenteeism [ Time Frame: Baseline, Months 1, 2, 3, 4, 5, 6 of Treatment Period ]
    The HRPQ consists of questions measuring the impact of endometriosis-associated pain and its treatment on work productivity (number of work hours lost from the household due to absenteeism) in the 7 days prior to survey administration.
23. Change From Baseline to Each Month in HRPQ: Number of Hours of Work Lost From Workplace Due to Presenteeism [ Time Frame: Baseline, Months 1, 2, 3, 4, 5, 6 of Treatment Period ]
    The HRPQ consists of questions measuring the impact of endometriosis-associated pain and its treatment on work productivity (number of work hours lost from the workplace due to presenteeism [working while sick]) in the 7 days prior to survey administration.
24. Change From Baseline to Each Month in HRPQ: Number of Hours of Work Lost From Household Due to Presenteeism [ Time Frame: Baseline, Months 1, 2, 3, 4, 5, 6 of Treatment Period ]
    The HRPQ consists of questions measuring the impact of endometriosis-associated pain and its treatment on work productivity (number of work hours lost from the household due to presenteeism [working while sick]) in the 7 days prior to survey administration.
25. Change From Baseline to Each Month in HRPQ: Total (Absenteeism and Presenteeism) Number of Hours of Work Lost From Workplace [ Time Frame: Baseline, Months 1, 2, 3, 4, 5, 6 of Treatment Period ]
    The HRPQ consists of questions measuring the impact of endometriosis-associated pain and its treatment on work productivity (number of work hours lost from the workplace due to absenteeism and presenteeism) in the 7 days prior to survey administration.
26. Change From Baseline to Each Month in HRPQ: Total (Absenteeism and Presenteeism) Number of Hours of Work Lost From Household [ Time Frame: Baseline, Months 1, 2, 3, 4, 5, 6 of Treatment Period ]
    The HRPQ consists of questions measuring the impact of endometriosis-associated pain and its treatment on work productivity (number of work hours lost from the household due to absenteeism and presenteeism) in the 7 days prior to survey administration.
27. Number of Participants With Endometriosis-Related Non-Study Health Visits During the Treatment Period [ Time Frame: Months 1, 2, 3, 4, 5, 6 of Treatment Period ]
    This is assessed using Health Resource Utilization Questionnaire (HRUQ).
28. Number of Days of Hospitalization [ Time Frame: Up to Month 6 of Treatment Period ]
    This is assessed using HRUQ.
29. Number of Participants With Emergency Room/Outpatient Procedures During the Treatment Period, by Type [ Time Frame: Up to Month 6 of Treatment Period ]
    This is assessed using HRUQ.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 49 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Premenopausal female, between 18 and 49 years of age, inclusive, at the time of signing consent.
2. Clinical diagnosis of endometriosis (laparoscopy or laparotomy) performed within 10 years of entry into the Washout Period.
3. Agrees to use required birth control methods during the entire length of participation in the study.
4. Subject has a Composite Pelvic Signs and Symptoms Score total score of 6 or greater at Screening with a score of at least 2 for dysmenorrhea AND at least 2 for non-menstrual pelvic pain.
5. Subjects must have at least two regular menstrual cycles with an interval of 24-38 days within the Screening Period, prior to Day 1.

Exclusion Criteria:

1. Subject is pregnant or breast feeding or is planning a pregnancy within the next 24 months or is less than 6 months postpartum, post-abortion, or post-pregnancy at the time of entry into the Screening Period.
2. Subject has a history of previous non-response to gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, Depot medroxyprogesterone acetate, or aromatase inhibitors as assessed by subject report of no improvement in dysmenorrhea or non-menstrual pelvic pain.
3. Subject has chronic pelvic pain that is not caused by endometriosis that requires chronic analgesic or other chronic therapy, or that would interfere with the assessment of endometriosis related pain.
4. Clinically significant gynecologic condition identified on Screening transvaginal ultrasound or endometrial biopsy.
5. Subject has a history of osteoporosis or other metabolic bone disease.
6. Subject has a current history of undiagnosed abnormal uterine bleeding.

Contacts and Locations

Sponsors and Collaborators

AbbVie

Investigators

• Study Director: AbbVie Inc.; AbbVie

More Information

Publications of Results:

Taylor HS, Giudice LC, Lessey BA, Abrao MS, Kotarski J, Archer DF, Diamond MP, Surrey E, Johnson NP, Watts NB, Gallagher JC, Simon JA, Carr BR, Dmowski WP, Leyland N, Rowan JP, Duan WR, Ng J, Schwefel B, Thomas JW, Jain RI, Chwalisz K. Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist. N Engl J Med. 2017 Jul 6;377(1):28-40. doi: 10.1056/NEJMoa1700089. Epub 2017 May 19.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Beck D, Winzenborg I, Liu M, Degner J, Mostafa NM, Noertersheuser P, Shebley M. Population Pharmacokinetics of Elagolix in Combination with Low-Dose Estradiol/Norethindrone Acetate in Women with Uterine Fibroids. Clin Pharmacokinet. 2022 Apr;61(4):577-587. doi: 10.1007/s40262-021-01096-w. Epub 2021 Dec 8.

Abrao MS, Surrey E, Gordon K, Snabes MC, Wang H, Ijacu H, Taylor HS. Reductions in endometriosis-associated pain among women treated with elagolix are consistent across a range of baseline characteristics reflective of real-world patients. BMC Womens Health. 2021 Jun 16;21(1):246. doi: 10.1186/s12905-021-01385-3.

Stodtmann S, Nader A, Polepally AR, Suleiman AA, Winzenborg I, Noertersheuser P, Ng J, Mostafa NM, Shebley M. Validation of a quantitative systems pharmacology model of calcium homeostasis using elagolix Phase 3 clinical trial data in women with endometriosis. Clin Transl Sci. 2021 Jul;14(4):1611-1619. doi: 10.1111/cts.13040. Epub 2021 May 7.

Beck D, Winzenborg I, Gao W, Mostafa NM, Noertersheuser P, Chiuve SE, Owens C, Shebley M. Integrating real-world data and modeling to project changes in femoral neck bone mineral density and fracture risk in premenopausal women. Clin Transl Sci. 2021 Jul;14(4):1452-1463. doi: 10.1111/cts.13006. Epub 2021 Apr 8. Erratum In: Clin Transl Sci. 2022 Mar;15(3):799.

Agarwal SK, Singh SS, Archer DF, Mai Y, Chwalisz K, Gordon K, Surrey E. Endometriosis-Related Pain Reduction During Bleeding and Nonbleeding Days in Women Treated with Elagolix. J Pain Res. 2021 Feb 2;14:263-271. doi: 10.2147/JPR.S284703. eCollection 2021.

Pokrzywinski RM, Soliman AM, Snabes MC, Chen J, Taylor HS, Coyne KS. Responsiveness and thresholds for clinically meaningful changes in worst pain numerical rating scale for dysmenorrhea and nonmenstrual pelvic pain in women with moderate to severe endometriosis. Fertil Steril. 2021 Feb;115(2):423-430. doi: 10.1016/j.fertnstert.2020.07.013. Epub 2020 Oct 14.

Abbas Suleiman A, Nader A, Winzenborg I, Beck D, Polepally AR, Ng J, Noertersheuser P, Mostafa NM. Exposure-Safety Analyses Identify Predictors of Change in Bone Mineral Density and Support Elagolix Labeling for Endometriosis-Associated Pain. CPT Pharmacometrics Syst Pharmacol. 2020 Nov;9(11):639-648. doi: 10.1002/psp4.12560. Epub 2020 Oct 8.

Taylor HS, Soliman AM, Johns B, Pokrzywinski RM, Snabes M, Coyne KS. Health-Related Quality of Life Improvements in Patients With Endometriosis Treated With Elagolix. Obstet Gynecol. 2020 Sep;136(3):501-509. doi: 10.1097/AOG.0000000000003917.

Winzenborg I, Polepally AR, Nader A, Mostafa NM, Noertersheuser P, Ng J. Effect of Elagolix Exposure on Clinical Efficacy End Points in Phase III Trials in Women With Endometriosis-Associated Pain: An Application of Markov Model. CPT Pharmacometrics Syst Pharmacol. 2020 Aug;9(8):466-475. doi: 10.1002/psp4.12545. Epub 2020 Jul 31.

Surrey ES, Soliman AM, Palac HL, Agarwal SK. Impact of Elagolix on Workplace and Household Productivity Among Women with Moderate to Severe Pain Associated with Endometriosis: A Pooled Analysis of Two Phase III Trials. Patient. 2019 Dec;12(6):651-660. doi: 10.1007/s40271-019-00394-7.

Pokrzywinski RM, Soliman AM, Chen J, Snabes M, Diamond MP, Surrey E, Coyne KS. Impact of elagolix on work loss due to endometriosis-associated pain: estimates based on the results of two phase III clinical trials. Fertil Steril. 2019 Sep;112(3):545-551. doi: 10.1016/j.fertnstert.2019.04.031. Epub 2019 Jun 18. Erratum In: Fertil Steril. 2020 Jan;113(1):237.

Rolla E. Endometriosis: advances and controversies in classification, pathogenesis, diagnosis, and treatment. F1000Res. 2019 Apr 23;8:F1000 Faculty Rev-529. doi: 10.12688/f1000research.14817.1. eCollection 2019.

Wang ST, Johnson SJ, Mitchell D, Soliman AM, Vora JB, Agarwal SK. Cost-effectiveness of elagolix versus leuprolide acetate for treating moderate-to-severe endometriosis pain in the USA. J Comp Eff Res. 2019 Apr;8(5):337-355. doi: 10.2217/cer-2018-0124. Epub 2019 Feb 6.

Winzenborg I, Nader A, Polepally AR, Liu M, Degner J, Klein CE, Mostafa NM, Noertersheuser P, Ng J. Population Pharmacokinetics of Elagolix in Healthy Women and Women with Endometriosis. Clin Pharmacokinet. 2018 Oct;57(10):1295-1306. doi: 10.1007/s40262-018-0629-6.

• Responsible Party: AbbVie
• ClinicalTrials.gov Identifier: NCT01931670
• Other Study ID Numbers: M12-671; 2011-004295-11 ( EudraCT Number )
• First Posted: August 29, 2013
• Results First Posted: September 7, 2018
• Last Update Posted: September 7, 2018
• Last Verified: March 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by AbbVie:

Non-Menstrual Pelvic Pain (NMPP); Dysmenorrhea (DYS); Elagolix; Endometriosis Associated Pain; Gonadotropin-Releasing Hormone Antagonist

Additional relevant MeSH terms:

Endometriosis; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases