Study of the Safety and Contraceptive Efficacy of Relugolix Combination Therapy in Women With Uterine Fibroids or Endometriosis Who Are at Risk for Pregnancy

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the contraceptive efficacy of relugolix combination therapy.

Detailed Description
-----------------
This is a single-arm, open-label, phase 3 study to assess the contraceptive efficacy of relugolix combination therapy (relugolix 40 milligrams [mg], estradiol [E2] 1 mg, and norethindrone acetate [NETA] 0.5 mg).

Official Title
-----------------
A Phase 3, Single-Arm, Open-Label Study to Evaluate the Safety and Contraceptive Efficacy of Relugolix Combination Therapy in Women With Uterine Fibroids or Endometriosis Who Are 18 to 50 Years of Age and at Risk for Pregnancy

Conditions
-----------------
Contraception

Intervention / Treatment
-----------------
* Drug: Relugolix Combination Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Is a premenopausal woman, 18 to 50 years of age. Is at risk of pregnancy (that is, having heterosexual intercourse at least once per month) and is seeking contraception. Has normal, regular menstrual cycles that are between 21 and 35 days in duration. Has a diagnosis of uterine fibroids or endometriosis meeting either of the following criteria: Diagnosis of uterine fibroids by confirmation of ultrasound performed in the last 2 years and patient report of heavy menstrual bleeding affecting quality of life. Diagnosis of endometriosis and has had surgical or direct visualization (laparoscopy or laparotomy) and/or histopathologic confirmation of endometriosis, and the patient reports moderate, severe, or very severe pain during the most recent menses and/or during nonmenstrual portion of the cycle in the prior month Is willing to use the study intervention as the sole method of contraception for 13 consecutive 28-day treatment cycles and does not intend to use any other form of contraception (for example, condoms). Key Exclusion Criteria: Is pregnant, or breastfeeding, or has breastfed in the last year. Has a known history of infertility or sub-fertility. Has presence or history of a venous thromboembolic event (for example, deep vein thrombosis, pulmonary embolism), an arterial thrombotic or thromboembolic event (for example, myocardial infarction, stroke, or peripheral arterial), or a transient ischemic attack, angina pectoris, or claudication. Has a higher risk of arterial, venous thrombotic, or thromboembolic disorders. Has a history of migraine with aura or focal neurological symptoms. Has uncontrolled hypertension, diabetes with inadequate control, or multiple cardiovascular risk factors. Has a history of clinically significant ventricular arrhythmias. Has clinically significant liver disease, including active viral hepatitis or cirrhosis. Has a history of pancreatitis associated with severe hypertriglyceridemia. Has known human immunodeficiency virus (HIV) infection or high risk of contracting HIV. Has a hepatic hemangioma or has a history of cholestasis with prior estrogen use or during pregnancy. Has a serious contraindication to pregnancy (for example, a medical condition or use of chronic medication such as isotretinoin or thalidomide). History of suicidal ideation or behavior, or confirmed yes to any question (with exception of non-suicidal self-injurious behavior, unless deemed as an unacceptable risk by the investigator) on the C-SSRS. Has a bone mineral density Z-score ≤ -2.0 at lumbar spine, femoral neck, or total hip during the screening period. Has a history of or currently has osteoporosis, or other metabolic bone disease, collagen vascular disease, chronic kidney disease (CKD) stage 3 or greater with glomerular filtration rate (GFR) < 60 mL/min/m2 using Modification of Diet in Renal Disease (MDRD) method, hyperparathyroidism, hyperprolactinemia, known pituitary adenoma, hyperthyroidism, anorexia nervosa, abnormal bone mineral metabolism (eg, hypophosphatemia), or low traumatic (fragility) fracture. Has used chronic glucocorticoids that are oral, parenteral, inhaled (prednisone equivalents of ≥ 2.5 mg daily for ≥ 3 months) in 12 months prior to the study. Has known BRCA mutation or other mutation associated with increased risk of breast cancer.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Relugolix/E2/NETA<br>Participants will receive relugolix combination therapy for 1 year (13 consecutive 28-day treatment cycles). | Drug: Relugolix Combination Therapy<br>* Participants will receive orally 1 fixed-dose combination tablet (relugolix 40 mg/E2 1 mg/NETA 0.5 mg) once daily.<br>* Other names: Myfembree;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Contraceptive Efficacy of Relugolix Combination Therapy as Assessed by the At-Risk Pearl Index (PI) | The At-Risk PI is defined as the number of on treatment pregnancies per 100 women-years of treatment. The At-Risk PI will be calculated on the basis of cycles considered at-risk of pregnancy, that is, consecutive 28-day periods without use of any other contraceptive methods and with affirmed occurrence of vaginal intercourse. On-treatment pregnancies are pregnancies with an estimated conception date between the first day of study intervention intake up to and including 7 days after the last intake of study medication. | 13 consecutive 28-day treatment cycles | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Contraceptive Efficacy of Relugolix Combination Therapy as Assessed by the Modified At-Risk PI | The Modified At-Risk PI is based on the number of on-treatment pregnancies occurring during cycles without any other contraceptive methods, regardless of occurrence of vaginal intercourse. On-treatment pregnancies are pregnancies with an estimated conception date between the first day of study intervention intake up to and including 7 days after the last intake of study medication. | 13 consecutive 28-day treatment cycles | 
| Contraceptive Efficacy of Relugolix Combination Therapy as Assessed by the Gross PI | The typical use contraceptive efficacy will be assessed using the Gross PI, based on the number of on-treatment pregnancies occurring during all cycles regardless of the use of other contraceptive methods, confirmed vaginal intercourse, or protocol compliance. On-treatment pregnancies are pregnancies with an estimated conception date between the first day of study intervention intake up to and including 7 days after the last intake of study medication. | 13 consecutive 28-day treatment cycles | 
| Contraceptive Efficacy of Relugolix Combination Therapy as Assessed by the Method Failure PI | The perfect use contraceptive efficacy will be assessed using the Method Failure PI, based on the number of on-treatment pregnancies occurring during cycles that are at risk and without major protocol deviations. On-treatment pregnancies are pregnancies with an estimated conception date between the first day of study intervention intake up to and including 7 days after the last intake of study medication. | 13 consecutive 28-day treatment cycles | 
| Contraceptive Efficacy of Relugolix Combination Therapy as Assessed by the Cumulative 1-Year Pregnancy Rates |  | 13 consecutive 28-day treatment cycles | 
| Incidence of Treatment-Emergent Adverse Events |  | 54 Weeks | 
| Number of Participants Who Do Not Complete 13 Treatment Cycles |  | 13 consecutive 28-day treatment cycles | 
| Percent Change in Bone Mineral Density from Baseline to 6 and 12 Months On-Treatment | The percent change in bone mineral density will be measured from baseline to 6- and 12-months on treatment at the lumbar spine (L1-L4), total hip, and femoral neck. | 12 Months On-Treatment or EOT | 
| Percent Change in Bone Mineral Density from Baseline an 12 Months On-Treatment (or EOT) to 6 and 12 Months Post-Treatment | The percent change in bone mineral density will be measured from baseline and 12-months on-treatment (or End-of-Treatment) to 6- and 12-months post-treatment at the lumbar spine (L1-L4), total hip, and femoral neck. | 12 Months Post-Treatment Follow-Up | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Relugolix, Estradiol, Norethindrone acetate, Uterine Fibroids, Endometriosis