M12-665 A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Elagolix in Subjects with Moderate to Severe Endometriosis-Associated Pain
Subjects will be randomized to one of three parallel dose groups in a 3:2:2 ratio to
receive daily doses of either placebo (n = 375), elagolix 150 mg QD (n = 250) or elagolix 200 mg BID (n = 250) for 6 months.
The study consists of 4 periods including: 1) a Washout Period (if applicable); 2) a Screening Period of up to 75 days prior to first dose; 3) a 6 month Treatment Period 4) a Post treatment Follow-up Period of up to 12 months (if applicable). Eligible subjects who have completed the 6 month Treatment Period and who have consented to participate may enter a separate continuous use extension study for 6 additional months of treatment with elagolix. Subjects, who prematurely discontinue from treatment, decline to participate in or do not qualify for the continuous use extension study will enter into the Post-treatment Follow-up Period within this study for up to 12 months. A month is defined as 28 days.
Subjects with a diagnosis of endometriosis who are interested in participating in this clinical trial and who are taking exclusionary hormonal contraceptives or hormonal therapy must sign the informed consent and meet the applicable inclusion/exclusion criteria prior to initiating the Washout Period.
Subjects will begin the use of non-hormonal dual contraception and receive counseling on the
importance of consistent use of appropriate and effective birth control. The requirements for washout must be completed prior to entering the Screening Period and undergoing any screening procedures.
Subjects who are not taking exclusionary medications that require washout will enter directly into the Screening Period and will provide written informed consent before any study-related procedures are performed. The subject will undergo screening procedures, an e-Diary will be dispensed and training provided to record endometriosis-associated pain, NRS, uterine bleeding, and analgesic medication use for endometriosis-associated pain on a daily basis. At least 45 days of daily e-Diary entries are required to be completed before a subject can enter into the Treatment Period. Subjects will begin the use of nonhormonal dual contraception and receive counseling on the importance of consistent use of appropriate and effective birth control during the Washout Period (if applicable), and this will continue throughout all periods of the study, including through Month 6 of the Post-treatment Follow-up Period. After Month 3 in the Post-treatment Follow-up Period, if preferable, subjects may begin the use of hormonal contraception in place of non-hormonal dual contraception. All subjects will undergo an endometrial biopsy during screening; this procedure should occur only after completing other less invasive screening procedures.
Once eligibility is confirmed, subjects will be enrolled into the Treatment Period of the study between days 1 through 4 of their menstrual cycle and randomized to a treatment through an Interactive Voice Response/Interactive Web-Based system (IXRS). The first dose of study drug will be administered at the study site on Day 1. Subjects will continue to maintain a daily e-Diary and record endometriosis-associated pain, NRS, uterine bleeding, analgesic use for endometriosis-associated pain and time of study medication dosing during the entire Treatment Period. Serum and/or urine pregnancy testing will be performed monthly and subjects will be counseled at each visit on appropriate and effective forms of dual non-hormonal contraception and the need for consistent use to promotepregnancy prevention. PK and PD of elagolix will be assessed during the Treatment Period of the study.
1. Subject has voluntarily signed and dated the informed consent form (ICF),
approved by an Institutional Review Board/Ethics Committee (IRB/EC), prior to
washout (if applicable), or initiation of any screening or study-specific procedures.
2. Subject is a premenopausal female, between 18 and 49 years of age, inclusive, at
the time of signing consent.
3. Subject has a clinical diagnosis of endometriosis established by means of documented
surgical visualization (laparoscopy or laparotomy) performed within 10 years of entry into
the Washout Period (if applicable) or Screening Period.
4. Subject must agree to the Washout Intervals for prohibited therapies, if applicable
5. Subject must agree to switch from her usual analgesic rescue medication to only
those permitted by the protocol during the Washout Period, Screening, Treatment
and Post-treatment Follow-up Period (through Month 6).
6. Subject must agree to use two forms of non-hormonal contraception (dual
contraception) consistently during the Washout Period (if applicable), Screening,
Treatment and the Post-treatment Follow-up Periods (through Month 6). After
Month 3 in the Post-treatment Follow-up Period, if preferable, subjects may begin
the use of hormonal contraception in place of non-hormonal dual contraception.
Subject must have a negative serum pregnancy test during the Screening Period
and a negative urine pregnancy test prior to randomization. Acceptable methods of
dual contraception include the following combinations:
* Condoms used with spermicide (cream, spray, foam, gel, suppository, or
* Diaphragm used with spermicide (condom may or may not be used)
* Cervical cap used with spermicide (condom may or may not be used)
* Vaginal sponge impregnated with spermicide; used with a condom
Subject is not required to use dual contraception methods if:
* Sexual partner(s) is (are) vasectomized, at least 6 months prior to Screening.
* Subject has had a bilateral tubal occlusion (including ligation and blockage
methods such as Essure(RegisteredTM)), at least 3 months prior to Screening.
* Subject is not sexually active with men; periodic sexual relationship(s) with
men requires the use of dual non-hormonal contraception as noted above.
* Hormonal contraception is started after completion of Month 3 in
Post-treatment Follow-up Period.
Inclusion Criteria for Screening Period (in addition to 1x6 above):
7. Subject must have had a menstrual cycle with an interval of 24 x 38 days prior to entering
the Screening Period.
8. Subject has a Composite Pelvic Signs and Symptoms Score (CPSSS) total score of
>= 6 at Screening with a score of at least 2 for DYS AND at least 2 for NMPP.
Inclusion Criteria for Treatment Period (in addition to 1x8 above):
9. Subject must have at least two menstrual cycles with an interval of 24 x 38 days within
the Screening Period, prior to Day 1.
10. Subject has at least 45 days of e-Diary entries during the Screening Period
11. Subject has at least 2 days of "moderate" or "severe" pain for DYS AND NMPP
during the last 35 calendar days of the Screening Period prior to Day 1.
12. Subject has an average daily e-Diary score of at least 0.5 for NMPP during the last
35 calendar days of the Screening Period.
13. Subject must meet at least one of the following using the e-Diary entries (in
addition to meeting criterion numbers 11 and 12 above):
* Average NMPP during screening of at least 1.0 during the last 35 calendar
days of the Screening Period OR
* At least 4 days of "moderate" or "severe" NMPP during the last 35 calendar
days of the Screening Period.
14. Subject has "moderate" or "severe" pain for DYS and NMPP using the Monthly
Assessment of Endometriosis Pain on Day 1 (reflecting subject recall of the
preceding menstrual month).
15. Subject has a Pap test collected during the Screening Period that contains adequate
endocervical cells and shows no evidence of malignancy or pre-malignant changes (as
defined in Study Procedures, Section 220.127.116.11). Subjects with low grade squamous
intraepithelial lesion (LSIL) on Pap results or those who have a known history of LSIL
may undergo colposcopic evaluation (unless one has been performed within the past year)
and may be enrolled if there is no evidence of high-grade disease.
16. Subject >= 40 years of age has a normal mammogram within 1 year of
randomization (subject with BI-RADS Classification 1 x 3 is eligible for