| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10014778 |
| E.1.2 | Term | Endometriosis |
| E.1.2 | System Organ Class | 10038604 - Reproductive system and breast disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate long-term efficacy of relugolix 40 mg once daily co administered with low-dose estradiol and norethindrone acetate for up to 52 and 104 weeks, among patients who previously completed a 24-week treatment period in one of the parent studies (MVT-601-3101 or MVT 601-3102), on endometriosis-associated pain. |
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| E.2.2 | Secondary objectives of the trial |
To evaluate long-term efficacy of relugolix 40 mg once daily co-administered with low-dose estradiol and norethindrone acetate at week 52 and week 104, among patients who previously completed a 24-week treatment period in one of the parent studies MVT-601-3101 or MVT 601-3102, on the following:
- Function, as measured by the EHP-30 Pain Domain;
- Dysmenorrhea, as measured by the NRS for dysmenorrhea;
- PGIC for dysmenorrhea;
- NMPP, as measured by the NRS for NMPP;
-Overall pelvic pain, as measured by the NRS
-Analgesic use
- PGIC for NMPP;
- Dyspareunia, measured by the NRS;
- PGIC for dyspareunia;
- Dyspareunia-related functional effects (sB&B);
- To determine the benefit of relugolix 40 mg once daily co-administered with 24 weeks of low-dose estradiol and norethindrone acetate compared with placebo on function measured by the EHP-30 Pain Domain
- PGA for pain;
- PGA for function;
- Endometriosis-associated quality of life, as measured by the EHP-30
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Completed 24 weeks of study drug treatment and study participation in either MVT-601-3101 or MVT-601-3102;
2. Has voluntarily signed and dated the informed consent form prior to initiation of any study-specific procedures for MVT-601-3103;
Note: Procedures conducted as part of the parent study that also serve as baseline procedures for this study will be done under the informed consent for the parent study.
3. Is not expected to undergo gynecological surgery or other surgical procedures for treatment of endometriosis (including ablation, shaving, or excision) during the study, including during the Follow-Up Period, and the patient does not desire such treatment during this time frame;
4. Has a negative urine pregnancy test at the Week 24/Baseline visit;
5. Has agreed to continue to use only study-specified analgesic medications during the study and is not known to be intolerant to these;
6. Agrees to continue to use acceptable nonhormonal contraceptive methods as described in Section 4.6 consistently during the Open-Label Treatment Period and for at least 30 days after the last dose of study drug. However, the patient is not required to use the specified nonhormonal contraceptive methods if she:
a. Has a sexual partner(s) who was vasectomized at least 6 months prior to the Week 24/Baseline visit;
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as Essure™), at least 6 months prior to the Week 24/Baseline visit (patients with Essure must have prior confirmation of tubal occlusion by hysterosalpingogram) and there must be no evidence of post-Essure syndrome;
c. Has a nonhormonal intrauterine device (eg, Paragard®) placed in the uterus;
d. Is not sexually active with men; periodic sexual relationship(s) with men requires the use of nonhormonal contraception as noted above;
e. Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic abstinence is not acceptable. |
|
| E.4 | Principal exclusion criteria |
Exclusion Criteria: None of the following criteria may be true for a patient to be eligible for enrollment into this study.
1. Has had a surgical procedure for treatment of endometriosis at any time during the parent study (MVT-601-3101 or MVT-601-3102);
2. Has any chronic pain or frequently recurring pain condition, other than endometriosis, that is treated with opioids or requires analgesics for ≥ 7 days per month;
3. Has a weight that exceeds the weight limit of the DXA scanner or has a condition that precludes an adequate DXA measurement at the lumbar spine and proximal femur (eg, bilateral hip replacement, spinal hardware in the lumbar spine);
4. Has a Z-score < -2.0 or has a ≥ 7% decrease in BMD from the parent study Baseline at lumbar spine, total hip, or femoral neck based on the parent study Week 24 DXA assessment of BMD;
5. Anticipated to use any prohibited medications as detailed in Section 5.10.1;
6. Has any contraindication to treatment with low-dose estradiol and norethindrone acetate, including:
a. Known, suspected, or history of breast cancer;
b. Known or suspected estrogen-dependent neoplasia;
c. Active deep vein thrombosis or pulmonary embolism, or history of these conditions prior to the Week 24/Baseline visit;
d. History of or active arterial thromboembolic disease, including stroke and myocardial infarction;
e. Known anaphylactic reaction or angioedema or hypersensitivity to estradiol or norethindrone acetate;
f. Known protein C, protein S, or antithrombin deficiency, or other known thrombophilia disorders, including Factor V Leiden;
g. Migraine with aura;
h. History of porphyria;
7. Has current active liver disease from any cause;
8. Has a systemic autoimmune disease (eg, systemic lupus erythematosus, Sjogren’s syndrome, rheumatoid arthritis, polymyositis, systemic sclerosis, psoriasis, psoriatic arthritis, vasculitic syndromes, etc); psoriasis not requiring or anticipated to require systemic therapy is permitted;
9. Had any of the following clinical laboratory abnormalities at the parent study Week 20 visit or, if available, any subsequent visit in one of the parent studies (MVT-601-3101 or MVT-601-3102):
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.0 times the upper limit of normal (ULN); or
b. Bilirubin (total bilirubin) > 1.5 x ULN (or > 2.0 x ULN if secondary to Gilbert syndrome or pattern consistent with Gilbert syndrome);
10. Is currently pregnant or lactating, or intends to become pregnant during the study period or within 1 month after the last dose of study drug, or plans to donate ova during the study period or within 2 months after the last dose of study drug;
11. The presenting visual acuity score has decreased by 10 or more points at the Week 24/Baseline visit relative to the parent study Baseline visit;
Note: Visual acuity score must have been obtained with corrective lenses, if applicable.
12. Is inappropriate for participation in this study because of conditions that may interfere with interpretation of study results or prevent the patient from complying with study requirements, as determined by the investigator, sub-investigator, or medical monitor;
13. Met a withdrawal criterion in the parent study (MVT-601-3101 or MVT-601-3102). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoints
- Proportion of women who respond or maintain response at Week 52 and 104/Early Termination, based on their dysmenorrhea NRS scores;
- Proportion of women who respond or maintain response at Week 52 and 104/Early Termination, based on their NMPP NRS scores.
-Percent change from the parent study Baseline in bone mineral density at the lumbar spine (L1-L4), total hip, and femoral neck as assessed by DXA |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 52 and 104 (week 28 considering the extension study alone)/Early Termination. |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints
-Change from the parent Baseline in the mean NRS score;
-Proportion of patients not using opioids
-Proportion of patients not using analgesics;
- Change from the parent study Baseline to Week 52 in the EHP-30 Pain Domain scores;
- Change from the parent study Baseline to Week 52/end of treatment (EOT) in the mean dysmenorrhea NRS score;
- Proportion of patients who are better or much better on the PGIC for dysmenorrhea at Week 52/EOT;
- Change from the parent study Baseline to Week 52/EOT in the mean NMPP NRS score;
- Proportion of patients who are better or much better on the PGIC for NMPP at Week 52/EOT;
- Change from the parent study Baseline to Week 52/EOT in the mean dyspareunia NRS scores;
- Proportion of patients who are better or much better on the PGIC for dyspareunia at Week 52/EOT;
- Change from the parent study Baseline to Week 52/EOT in the mean dyspareunia functional impairment on the sB&B scale;
- Change from the parent study Baseline to Week 52/EOT in severity scores on the PGA for pain;
- Proportion of responders at Week 52/EOT based on their EHP-30 Pain Domain score;
- Change from the parent study Baseline to Week 52/EOT in function impairment on the PGA for function;
- Change from the parent study Baseline to Week 52/EOT in each of the non-pain EHP-30 domains (Control and Powerlessness, Social Support, Emotional Well-Being, and Self-Image);
- Change from the parent study Baseline pain assessment period to Week 52/EOT in dysmenorrhea-related functional effects (sB&B);
- Change from the parent study Baseline pain assessment period to Week 52/EOT in NMPP-related functional effects (sB&B).
Safety Endpoints
- Incidence of adverse events;
- Percent change from the parent study Baseline to Week 52 in bone mineral density at the lumbar spine (L1-L4), femoral neck, and total hip as assessed by DXA.
Pharmacodynamic Endpoint:
- Change from parent study Baseline to Week 52 in pre-dose concentrations of serum estradiol.
Exploratory Endpoints
- Change from Baseline to Week 52/EOT in the EHP-30 scale total score;
- Change from Baseline to Week 52/EOT in the EHP Work Domain score;
- Change from parent study Baseline to Week 52/EOT in the EQ-5D-5L. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 52 and 104 (week 28 considering the extension study alone)/Early Termination. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 118 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Brazil |
| Chile |
| Georgia |
| New Zealand |
| South Africa |
| Ukraine |
| United States |
| Belgium |
| Bulgaria |
| Finland |
| Hungary |
| Italy |
| Poland |
| Portugal |
| Romania |
| Spain |
| United Kingdom |
| Czechia |
| Argentina |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 6 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 6 |
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