| 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 uterine fibroids |
|
| 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 | 19.1 |
| 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 | 19.1 |
| 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 determine the benefit of relugolix 40 mg once daily co-administered with low dose estradiol and norethindrone acetate compared with placebo for 24 weeks on heavy menstrual bleeding associated with uterine fibroids. |
|
| E.2.2 | Secondary objectives of the trial |
•To determine the benefit of relugolix 40 mg once daily for 12 weeks followed by 12 weeks of relugolix 40 mg once daily co-administered with low dose estradiol and norethindrone acetate compared with placebo for 24 weeks on heavy menstrual bleeding associated with uterine fibroids;
•To determine the benefit of 24 weeks of relugolix 40 mg once daily co-administered with either 12 or 24 weeks of low dose estradiol and norethindrone acetate compared with placebo for 24 weeks on the following:
oChange in hemoglobin;
oImpact of heavy menstrual bleeding on social, leisure, and physical activities;
oPain associated with uterine fibroids;
oUterine volume; and
oUterine fibroid volume.
•To determine the safety of 24 weeks of relugolix 40 mg once daily co-administered with either 12 or 24 weeks of low dose estradiol and norethindrone acetate in women with heavy menstrual bleeding associated with uterine fibroids compared with placebo for 24 weeks;
Please see all objectives in the protocol |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| optional pharmacogenomics testing |
|
| E.3 | Principal inclusion criteria |
1. Has voluntarily signed and dated the informed consent form prior to initiation of any screening or study-specific procedures;
2. Is a premenopausal female aged 18 to 50 years old (inclusive) on the day of signing and dating the informed consent form;
3. Has regularly-occurring menstrual periods of ≤ 14 days duration with a cycle of 21 to 38 days from the start of one menstrual period until the start of the next, by patient history for at least 3 months prior to the Screening 1 visit;
4. Has a diagnosis of uterine fibroids that is confirmed by a transvaginal ultrasound performed during the screening period; at least one uterine fibroid must be verified by a central reader to meet at least one of the following criteria:
a. Subserosal, intramural, or < 50% intracavitary submucosal fibroid with a diameter ≥ 2 cm (longest diameter), or
b. Multiple small fibroids with a total uterine volume of ≥ 130 cm3
Note 1: Once the transvaginal ultrasound is done, a transabdominal ultrasound may also be done if the uterus cannot be adequately imaged on transvaginal ultrasound; for example, due to enlarged size.
Note 2: Saline or gel contrast is not required, but may be performed to demonstrate fibroids that meet the criterion for inclusion if these are not adequately visualized with transvaginal ultrasound alone.
5. Has heavy menstrual bleeding associated with uterine fibroids as evidenced by a menstrual blood loss of ≥ 160 mL during 1 cycle or ≥ 80 mL per cycle for 2 menstrual cycles as measured by the alkaline hematin method during the screening period;
6. Patient not expected to undergo gynecological surgery or ablation procedures for uterine fibroids within the 6 months following enrollment;
7. Has a negative urine pregnancy test at the Screening 1, Screening 3, and Baseline Day 1 visits;
8. Agrees to use two forms of non-hormonal contraception (dual contraception, as described in Section 4.7) consistently, the screening period, and the randomized treatment period. However, the patient is not required to use dual contraception if she:
a. Has a sexual partner(s) who was vasectomized at least 6 months prior to the screening period;
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as Essure™), at least 4 months prior to the first screening visit (patients with Essure must have prior confirmation of tubal occlusion by hysterosalpingogram and no evidence of “post-Essure syndrome” in the investigator’s opinion;
c. Is not sexually active with men; periodic sexual relationship(s) with men requires the use of dual non-hormonal contraception as noted above; or
d. Practices total abstinence from sexual intercourse as her preferred lifestyle; periodic abstinence is not acceptable;
9. Has an adequate endometrial (aspiration) biopsy performed during the screening period, with results showing no clinically significant endometrial pathology (hyperplasia, polyp, or endometrial cancer). Note: polyps < 2.0 cm by ultrasound are not excluded;
10. If ≥ 39 years of age at the time of the Baseline Day 1 visit, has a normal mammogram (Breast Imaging Reporting and Data System category 1 or 2 or equivalent) during the screening period or within 6 months prior to the screening period. |
|
| E.4 | Principal exclusion criteria |
1. Has transvaginal and/or transabdominal ultrasound during the screening period demonstrating pathology other than uterine fibroids that could be responsible for or contributing to the patient’s heavy menstrual bleeding, such as uterine or cervical polyps ≥ 2.0 cm, large simple ovarian cyst > 4.0 cm, endometrioma(s) > 4.0 cm, or any other clinically significant gynecological disorder determined by the investigator to require further evaluation and/or treatment during the study;
Note: Saline or gel contrast is not routinely required. Use of such contrast is required only when the endometrium cannot be evaluated or when there are ambiguous and potentially exclusionary findings on the transvaginal or transabdominal ultrasound (eg, suspected intrauterine masses, equivocal endometrial findings, etc.);
Please see protocol for remaining exclusion criteria
2. Has known rapidly enlarging uterine fibroids in the opinion of the investigator;
3. 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, as well as endometrial ablation for abnormal uterine bleeding within 6 months prior to the Screening 1 visit;
4. Has a weight that exceeds the weight limit of the DXA scanner;
5. Has a baseline bone mineral density z-score < -2.0 at spine, total hip, or femoral neck;
6. Has a history of or currently has osteoporosis, or other metabolic bone disease, hyperparathyroidism, hyperprolactinemia, hyperthyroidism, anorexia nervosa, or low traumatic (from the standing position) or atraumatic fracture (toe, finger, skull, face and ankle fractures are allowed). A history of successfully treated hyperparathyroidism, hyperprolactinemia, or hyperthyroidism is allowed if the patient’s bone mineral density is within normal limits;
7. Has a history of the use of bisphosphonates, calcitonin, calcitriol, ipriflavone, teriparatide, denosumab, or any medication other than calcium and vitamin D preparations to treat bone mineral density loss;
8. Anticipated use of systemic glucocorticoids at an oral prednisone-equivalent dose of more than 5 mg every other day during the study. Note: topical, inhaled, intranasal, otic, ophthalmic, intraarticular, or intralesional subcutaneous are permitted without restriction;
9. Gastrointestinal disorder affecting absorption or gastrointestinal motility;
10. 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 Baseline Day 1 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;
11. Has jaundice or known current active liver disease from any cause, including hepatitis A (HAV IgM), hepatitis B (HBsAg), or hepatitis C (HCV Ab positive, confirmed by HCV RNA);
12. Has any of the following cervical pathology: high grade cervical neoplasia, atypical glandular cells, atypical endocervical cells, atypical squamous cells favoring high grade. Of note, patients with atypical squamous cells of undetermined significance and low-grade cervical neoplasia may be included in the study if high risk human papilloma virus testing is negative or if DNA testing for human papilloma virus 16 and 18 is negative;
13. Has any of the following clinical laboratory abnormalities at any screening visit:
a. Hemoglobin < 8.0 g/dL (patients with initial screening hemoglobin results < 8 g/dL may be prescribed iron supplements and have their hemoglobin levels retested prior to the Baseline Day 1 visit);
b. Alanine aminotransferase or aspartate aminotransferase > 2.0 times the upper limit of normal (ULN), or bilirubin (total bilirubin) > 1.5 x ULN on clinical laboratory testing at either the Screening 1 or Screening 2 visit (or > 2.0 x ULN if secondary to Gilbert syndrome or pattern consistent with Gilbert syndrome);
c. Estimated glomerular filtration rate < 60 mL/min/m2 using the Modification of Diet in Renal Disease method |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of women in the relugolix Group A versus the placebo Group C who achieve a menstrual blood loss volume of < 80 mL AND at least a 50% reduction from baseline menstrual blood loss volume, as measured by the alkaline hematin method. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| over the last 35days of treatment |
|
| E.5.2 | Secondary end point(s) |
•Proportion of women in the relugolix Group B versus the placebo Group C who achieve a menstrual blood loss volume of < 80 mL AND at least a 50% reduction from baseline menstrual blood loss volume, as measured by the alkaline hematin method.
The following secondary endpoints will be assessed comparing each relugolix treatment group to placebo inferentially and relugolix Group A to Group B descriptively:
•Time to achieving a menstrual blood loss volume of < 80 mL AND at least a 50% reduction from baseline menstrual blood loss volume as measured by the alkaline hematin method;
•Change from Baseline to Week 24 in menstrual blood loss;
•Proportion of women who achieve amenorrhea over the last 35 days of treatment as measured by the alkaline hematin method;
•Time to amenorrhea as measured by the by the alkaline hematin method;
•Proportion of women with a hemoglobin below the lower limit of normal at Baseline who achieve an increase of ≥ 1 g/dL from Baseline at Week 24;
•Change from Baseline to Week 24 in the Menorrhagia Impact Questionnaire Score for physical activities;
•Change from Baseline to Week 24 in the Menorrhagia Impact Questionnaire Score for social and leisure activities;
•Proportion of women who achieve a mean Numerical Rating Scale score for uterine fibroid-associated pain over the last 35 days of treatment that is at least a 30% reduction from Baseline in the subset of women with a maximum pain score ≥ 4 during the 35 days prior to randomization;
•Change from Baseline to Week 24 in uterine volume; and
•Change from Baseline to Week 24 in uterine fibroid volume.
•Treatment-emergent adverse events, change in vital signs (including weight), clinical laboratory tests, and electrocardiograms;
•Percent change from Baseline to Weeks 12 and 24 in bone mineral density at the spine (average of L1-L4), total hip, and femoral neck as assessed by DXA;
•Incidence of vasomotor symptoms.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| over the last 35 days of treatment |
|
| 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 | Yes |
| 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 | Yes |
| 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 | Yes |
| 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 | 3 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| 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 | Yes |
| 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 |
| Poland |
| South Africa |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 18 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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