| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| heavy menstrual bleeding associated with uterine fibroids |
|
| E.1.1.1 | Medical condition in easily understood language |
| heavy menstrual bleeding associated with fibroids in the uterus |
|
| 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 | LLT |
| E.1.2 | Classification code | 10027331 |
| E.1.2 | Term | Menstrual flow altered |
| E.1.2 | System Organ Class | 100000004872 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10046783 |
| E.1.2 | Term | Uterine fibroid |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 the long-term effect of relugolix 40 mg with estradiol 1.0 mg and norethindrone acetate 0.5 mg (relugolix with E2/NETA) once daily, compared with placebo on menstrual blood loss at Week 76 (24 weeks after randomization). |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the long-term effect of relugolix with E2/NETA once daily, compared with placebo on menstrual blood loss at 52-weeks after
randomization.
• To evaluate the effect of retreatment with relugolix with E2/NETA on menstrual blood loss in patients whose menstrual blood volume returned to
≥ 80 mL during the 52-week randomized period.
• To evaluate the long-term effect of relugolix with E2/NETA at 52 weeks after randomization on the following:
• Achievement of amenorrhea
• Resumption of menses
• Resumption of heavy menstrual bleeding (HMB)
• Hemoglobin
• Health-related quality of life as measured by the Short Form (36) (SF-36)
• Patient Global Assessment (PGA) for function and symptoms
• Work and productivity impact as measured by the Work Productivity
•Activity Impairment-Uterine Fibroids (WPAI-UF)
•Disease-specific quality of life as measured by the Uterine Fibroid Symptom and Health-Related Quality of Life (UFS-QoL). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A woman will be eligible for enrollment in this study only if all of the following
inclusion criteria are met at the time of the Week 52/Baseline visit:
1. Completed the OLE study;
2. Has voluntarily signed and dated the informed consent form prior to initiation of any screening or study-specific procedures for MVT-601-035;
Note: Procedures conducted as part of the OLE study that also serve as baseline procedures for
this study may be done under the informed consent for the OLE study;
3. Is not expected to undergo gynecological surgery or ablation procedures for uterine fibroids within the study period, including the Safety Follow-up period;
4. 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 OLE study. Results from Week 44 may be used if Week 48 data is unavailable;
5. Has a negative urine pregnancy test at the Week 52/Baseline visit;
6. Agrees to continue to use acceptable nonhormonal contraceptive methods as described in protocol consistently during the 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 24 weeks prior to the Week 52/Baseline visit;
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as Essure™), at least 16 weeks prior to the Week 52/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 (e.g., 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 |
None of the following criteria may be true for a patient to be eligible for enrollment into this study:
1. 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 OLE study;
2. 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 (e.g., bilateral hip replacement or spinal hardware in the lumbar spine);
3. Anticipates use of any prohibited medications as detailed in the protocol;
4. Has developed any contraindication to treatment with estradiol or norethindrone acetate including:
a. Known or suspected breast cancer;
b. Known or suspected estrogen-dependent neoplasia;
c. Active deep vein thrombosis or pulmonary embolism;
d. 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. Porphyria;
5. Has current active liver disease from any cause;
6. Has a new diagnosis of a systemic autoimmune disease (e.g., systemic lupus erythematosus, Sjogren’s syndrome, rheumatoid arthritis, polymyositis, systemic sclerosis, psoriasis, psoriaticarthritis, vasculitic syndromes, etc.). Psoriasis not requiring or anticipated to require systemic therapy is permitted;
7. Had any of the following clinical laboratory abnormalities at the OLE study Week 48 visit or any subsequent visit:
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);
c. Hemoglobin < 8 g/dL despite iron supplementation;
8. Is currently pregnant or lactating, or intends to become pregnant during the study period or within 4 weeks after the last dose of study drug, or plans to donate ova during the study period or within 8 weeks after the last dose of study drug;
9. 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;
10. Met a withdrawal criterion in the OLE study.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the study is the proportion of women who maintain a menstrual blood loss volume of < 80 mL at Week 76 (24 weeks of the randomized treatment period) as measured by the alkaline hematin method. The primary endpoint of responder rate will be evaluated using the mITT Population. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
•Proportion of women who maintain a menstrual blood loss volume of < 80 mL at Week 104 (52 weeks of the randomized treatment period) as measured by the alkaline hematin method;
• Change from Week 52/Baseline to Week 76/Week 104 in menstrual blood volume (during the randomized treatment period);
• Percentage change from Week 52/Baseline to Week 76 / Week 104 (during the randomized treatment period);
• Proportion of patients who responded (menstrual blood loss volume of < 80 mL) to retreatment with relugolix 40 mg and E2/NETA during the retreatment period among placebo patients whose menstrual blood volume had returned to ≥ 80 mL during the 52-week randomized treatment period;
• Proportion of women achieving or maintaining amenorrhea;
• Proportion of women whose menses has resumed (among those who were amenorrhoeic at Week 52/Baseline);
• Time to resumption of menses;
• Proportion of women with menstrual blood volume ≥ 80 mL at any time point during the 52-week randomized treatment period;
• Time to resumption of menstrual blood volume ≥ 80 mL;
• Change from Week 52/Baseline in hemoglobin;
• Change from Week 52/Baseline in SF-36 domain and summary component scores;
• Change from Week 52/Baseline in PGA for function and symptoms scores;
• Change from Week 52/Baseline in the WPAI-UF scores;
• Change from Week 52/Baseline in the UFS-QoL Symptom Severity scale and subscales as well as total scores. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| week 52; week 24 and week 52 |
|
| 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 | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 51 |
| 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 |
| Belgium |
| Brazil |
| Chile |
| Czech Republic |
| Hungary |
| Italy |
| Poland |
| South Africa |
| United Kingdom |
| United States |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 5 |
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