Study of Relugolix With Estradiol and Norethindrone Acetate in Women With Heavy Menstrual Bleeding Associated With Uterine Fibroids

Study Overview
=================
Brief Summary
-----------------
The objectives of this randomized withdrawal study are to evaluate the long-term efficacy and safety of the combination of relugolix, estradiol (E2) and norethindrone acetate (NETA), once daily, for up to 104 weeks in patients with uterine fibroids who have completed a total of 52 weeks of treatment, including a 24-week treatment period in a parent study (study MVT-601-3001 or MVT-601-3002) and a 28-week treatment period in the open-label extension study (MVT-601-3003), and who meet the definition of responder, defined as a patient who demonstrates a menstrual blood loss of < 80 mL and at least a 50% reduction from parent study baseline menstrual blood loss volume on the alkaline hematin analysis of the feminine products returned at Week 48 in the extension study.

Detailed Description
-----------------
This randomized withdrawal study is an international phase 3 double-blind, placebo-controlled study that will enroll eligible patients with uterine fibroids who have completed the 24-week treatment period in a parent study (MVT-601-3001 or MVT-601-3002) and the 28-week treatment period of the open-label extension study (MVT-601-3003). When including treatment during the parent study and the extension study, patients completing this randomized withdrawal study will have received up to a total of 104 weeks of treatment with relugolix. Approximately 360 women with heavy menstrual bleeding associated with uterine fibroids completing the extension study with a response to treatment will be eligible to participate in this study. A responder is defined as a patient who demonstrates a menstrual blood loss of < 80 mL and at least a 50% reduction from parent study baseline menstrual blood loss volume on the alkaline hematin analysis of the feminine products returned at Week 48 in the extension study. Screening procedures will be done on the same day as the Week 52 visit for the extension study. This visit will be referred to as the Week 52/Baseline visit. When the Week 52/Baseline procedures in the extension study have been completed, the investigator will assess patient eligibility for participation in this study. The eligibility assessment will be based on data available at the Week 52/Baseline visit. Patients will be asked to provide feminine products for alkaline hematin analysis at each visit until the analysis confirms the return of heavy menstrual bleeding. The patients will then be offered retreatment with open-label relugolix with E2/NETA with the onset of the next menses. They will resume collection of feminine products for alkaline hematin analysis until two consecutive analyses confirm resolution of heavy menstrual bleeding (menstrual blood loss of < 80 mL). Safety will be assessed throughout the study by monitoring adverse events, vital signs, physical examinations, clinical laboratory tests, and assessments of bone mineral density.

Official Title
-----------------
An International Phase 3 Double-Blind, Placebo-Controlled, Randomized Withdrawal Study of Relugolix With Estradiol and Norethindrone Acetate in Women With Heavy Menstrual Bleeding Associated With Uterine Fibroids

Conditions
-----------------
Uterine Leiomyoma, Uterine Fibroids

Intervention / Treatment
-----------------
* Drug: Relugolix
* Drug: Estradiol/norethindrone acetate
* Drug: Placebo for relugolix
* Drug: Placebo for E2/NETA


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Completed the open-label extension study (MVT-601-3003). Is a responder: Has a menstrual blood loss of < 80 mL AND at least a 50% reduction from the parent study Baseline based on the results of the alkaline hematin testing performed on the feminine products returned at the Week 48 visit of the extension study. Is not expected to undergo gynecological surgery or ablation procedures for uterine fibroids within the study period Exclusion Criteria: Has undergone myomectomy, ultrasound-guided laparoscopic radiofrequency ablation, or any other surgical procedure for fibroids, uterine artery embolization, magnetic resonance guided focused ultrasound for fibroids, or endometrial ablation for abnormal uterine bleeding at any time during the Parent study or extension study. Has a weight that exceeds the weight limit of the DXA scanner Has developed any contraindication to treatment with estradiol or norethindrone acetate Is currently pregnant or lactating, or intends to become pregnant during the study period Met a withdrawal criterion in the OLE study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 51 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized withdrawal following an open-label extension to a randomized controlled parent study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Relugolix plus E2/NETA<br>Relugolix 40 mg co-administered with estradiol (1.0 mg) and norethindrone acetate (0.5 mg) for up to 52 weeks. | Drug: Relugolix<br>* Relugolix 40 mg tablet administered orally once daily<br>* Other names: TAK-385;Drug: Estradiol/norethindrone acetate<br>* Capsule containing co-formulated tablet of estradiol 1.0 mg and norethindrone acetate 0.5 mg administered orally once daily<br>* Other names: Low-dose hormonal add-back;|
| Placebo Comparator: Placebo tablets and capsules<br>Placebo for relugolix co-administered with placebo for E2/NETA for up to 52 weeks or until heavy menstrual bleeding returns. Retreatment with open-label relugolix with E2/NETA will be offered if heavy menstrual bleeding returns. | Drug: Placebo for relugolix<br>* Placebo tablet administered orally once daily and manufactured to match the relugolix tablet in size, shape, color, and odor<br>Drug: Placebo for E2/NETA<br>* Placebo capsule administered orally once daily and designed to match the E2/NETA capsule in size, shape, color, and odor<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of women who maintain a menstrual blood loss (MBL) volume of < 80 mL | MBL volume is measured using the alkaline hematin method. | at Week 24 (Week 72 relative to the parent study baseline) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of women who maintain a MBL volume of < 80 mL | MBL volume is measured using the alkaline hematin method. | at Week 52 (Week 104 relative to the parent study baseline) | 
| Change in MBL volume | MBL volume is measured using the alkaline hematin method. | from Baseline up to Week 52 (Week 104 relative to the parent study baseline) | 
| Proportion of women who responded (MBL volume < 80 mL) to retreatment during retreatment period | MBL volume is measured using the alkaline hematin method. | at Week 52 (Week 104 relative to the parent study baseline) | 
| Proportion of women with heavy menstrual bleeding | Defined as the proportion of women with MBL volume of ≥ 80 mL at any time. MBL volume is measured using the alkaline hematin method. | at Week 24 and 52 (Week 72 and Week 104 relative to the parent study baseline) | 
| Time to resumption of heavy menstrual bleeding | Defined as time to MBL volume of ≥ 80 mL. MBL volume is measured using the alkaline hematin method. | up to Week 52 (Week 104 relative to the parent study baseline) | 
| Proportion of women with suppression of bleeding | Will be assessed using patient daily diary and MBL volume measured using the alkaline hematin method. | at Week 24 and 52 (Week 72 and Week 104 relative to the parent study baseline) | 
| Time to resumption of menses in women who are amenorrhoeic | Will be assessed using patient daily diary. | up to Week 52 (Week 104 relative to the parent study baseline) | 
| Change in hemoglobin concentration | Blood samples will be collected from participants for hemoglobin measurements. | from Baseline up to Week 52 (Week 104 relative to the parent study baseline) | 
| Change in impact on quality of life: UFS-QOL | Assessed using the Uterine Fibroid Symptom Health-Related Quality of Life Questionnaire (UFS-QOL) | from Baseline up to Week 52 (Week 104 relative to the parent study baseline) | 
| Change in Patient Global Assessment (PGA) for symptoms | The PGA for symptoms is a 1-item questionnaire designed to assess participants impression of the severity of their symptoms related to uterine fibroids. | from Baseline up to Week 52 (Week 104 relative to the parent study baseline) | 
| Change in PGA for function | The PGA for function is a 1-item questionnaire designed to assess participants impression of how their symptoms related to uterine fibroids affected their usual activities. | from Baseline up to Week 52 (Week 104 relative to the parent study baseline) | 
| Bone Mineral Density (BMD) | Assessed by dual-energy X-ray absorptiometry (DXA) scan. | from parent study Baseline up to Week 104 | 
| Percentage of participants with adverse events (AEs) as a measure of safety and tolerability | Assessed by percentage of participants with AEs and serious AEs. | up to 52 weeks | 
| Serum estradiol concentrations | Blood samples will be collected from participants for estradiol measurements. | up to 52 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Heavy menstrual bleeding, Menorrhagia, Uterine Fibroids, Uterine Leiomyoma