| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| hormone sensitive benign tumor |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10046784 |
| E.1.2 | Term | Uterine fibroids |
| 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 efficacy of two doses of ESN364 versus placebo when administered for 12 weeks to reduce excessive uterine bleeding (assessed by Pictorial Blood Loss Assessment Chart [PBAC]). |
|
| E.2.2 | Secondary objectives of the trial |
at Week 4 and Week 8 (assessed by PBAC)
• To evaluate efficacy of two doses of ESN364 versus placebo when administered for 12 weeks to reduce total fibroid volume (assessed by Magnetic Resonance Imaging [MRI] and/or Transvaginal Ultrasound [TVU])
• To evaluate if two doses of ESN364 versus placebo will lead to amenorrhea in Week 4, Week 8, and Week 12 (assessed by PBAC)
• To evaluate efficacy of two doses of ESN364 versus placebo when administered for 12 weeks to decrease uterine volume (assessed by MRI and/or TVU)
• To evaluate efficacy of two doses of ESN364 versus placebo when administered for 12 weeks to improve pain and quality of life (assed by Visual Analogue Scale [VAS] for dysmenorrhea, pelvic pain, urinary symptoms, bloating, and abdominal pressure, by the Uterine Fibroid Symptom - Quality of Life [UFS-QoL] score, and by the Patients’ Global Impression of Change [PGIC] scale)
For further information on the objectives, please see protocol |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Has been diagnosed with uterine fibroids and has not received surgical treatment for a myoma within the last 5 years;
2) Is a pre-menopausal woman between 18 and 55 years inclusive at screening;
3) Has a clinical breast examination without clinically relevant findings at the screening visit;
4) Has a myomatous uterus with a size equivalent to a uterus of ≤16 weeks gestation and at least one measurable noncalcified fibroid ≥3 cm diameter but none ˃10 cm diameter as measured by TVU (the three largest myoma's are to be followed up);
5) Willing to undergo an endometrial biopsy at Visit 2 and at Week 12 (end-of-treatment);
6) Has been diagnosed with menorrhagia (PBAC >100 during the first 8 days of the menses); apart from menorrhagia has a regular menstrual cycle (21-36 days);
7) Body Mass Index (BMI) between 18 – 33 kg/m² inclusive;
8) Has a negative (normal or atypical squamous cell of uncertain significance) cervical smear (Papanikolaou test [PAP], cytobrush or equivalent) within 36 months prior to screening;
9) In good physical and mental health as determined on the basis of medical history and general physical examination performed at screening;
10) Hematology and chemistry parameters, heart rate (HR) and/or blood pressure, and electrocardiogram ECG within the reference range for the population studies, or showing no clinically relevant deviations, as judged by the investigator;
11) Negative urine test for selected drugs (amphetamines benzodiazepines, cannabinoids, cocaine, tetrahydrocannabinol, barbiturates or opiates) of abuse at screening and before first administration of study drug;
12) Has a negative pregnancy test at screening;
Note: pregnancy testing will consist of a serum pregnancy test at screening and urine pregnancy tests at other visits.
13) Females who are not breast-feeding;
14) Women of childbearing potential agrees not to get pregnant and willing to be abstinent or to use adequate highly effective contraception (failure rate less than 1% per year) during the trial and for at least 42 days after end of treatment;
The following non-hormonal contraceptive methods are defined as acceptable:
o Partner with a vasectomy performed at least 3 months prior to the study and with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate. (The vasectomized male partner should be the sole partner for that subject).
o True abstinence: When this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptom-thermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)
o The subject is homosexual/has no intercourse with the opposite sex
o Partner is using condoms in combination with spermicidal cream or gel Women of childbearing potential are defined as any female who has experienced menarche and are not post-menopausal or permanently sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy);
15) Informed Consent Form (ICF) signed voluntarily before any study-related procedure is performed, indicating that the subject understands the purpose of and procedures required for the study and is willing to participate in the study. |
|
| E.4 | Principal exclusion criteria |
1. Has a hemoglobin value <8 g/dL at screening;
2. Has a follicle stimulating hormone (FSH) value >30 mIU/mL at screening;
3. Has a history of or currently ongoing hemoglobinopathy (i.e. Sickle Cell anemia and Thalassemia) or coagulopathies;
4. Has a known history of severe hypersensitivity or severe allergy to sanitary goods;
5. Has a recent history (<5 years) of uterine surgery (except Caesarean section or cervical conization) or bilateral oophorectomy;
6. Has a history of a previous endometrial ablation or uterine artery embolization;
7. Judged by investigator to have marked abnormal uterine bleeding; or non-diagnosable abnormal genital bleeding; or anovulatory bleeding;
8. Has regular abdominal discomfort or pain due to gastro-intestinal, urological or gynecological conditions other than UF;
9. Has a recent history (<5 years) of or currently ongoing pelvic inflammatory disease;
10. Has a history of or currently ongoing malignant tumor (except for basal cell carcinoma of the skin that has been treated with no evidence or recurrence);
11. Has been treated within 3 months of screening with any of the following drugs: gonadotrophin releasing hormone (GnRH) agonist/antagonist, selective estrogen receptor modulator (SERM), selective progesterone receptor modulator (SPRM), danazol, aromatase inhibitors, anticoagulant drugs, antiplatelet drugs, glucocorticoids, mineralocorticoids, androgens, depot contraceptive preparations or vitamin K;
12. Treatment with hormonal contraceptives (oral, transdermal, coated intrauterine device) and/or tranexamic acid should be stopped 1 month prior to screening;
13. Has a known severe allergy, hypersensitivity, or intolerance to any drug, including the study drug and any of its excipients;
14. Judged by investigator to be inappropriate to participate in this study based on findings observed during the general physical/gynecological examination (including endometrial hyperplasia on the biopsy of visit 2); or clinically relevant findings on the 12-lead ECG;
15. Has a copper intrauterine device
16. Has a contraindication for undergoing an MRI scan (e.g., unsuitable body weight, claustrophobia, pacemaker, …);
17. Has active liver disease or jaundice, or values of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >1.3 times the upper limit of normal (ULN); or total bilirubin >1.3 times the ULN; or creatinine >1.25 times the ULN at screening;
18. Has a medical condition or chronic disease (including neurological [including cognitive], hepatic, renal, cardiovascular, gastrointestinal, pulmonary, or endocrine disease), or malignancy that could confound interpretation of the study outcome as judged by the investigator;
19. Has any psychological disorder according to criteria indicated in the Diagnostics and Statistical Manual of Mental Disorders, 4th edition within one year before screening. Such disorders include, but are not limited to, alcohol (more than 3 glasses of wine, beer, or equivalent/day) and substance abuse/dependence within 2 years prior to the initial study medication administration;
20. Has a history of poor compliance in clinical research studies;
21. Has a positive hepatitis panel (including hepatitis B surface antigen [HBsAg] or anti-hepatitis C virus [HCV] antibodies) or positive human immunodeficiency virus (HIV) antibody at screening;
22. Presence or sequelae of gastrointestinal, liver, kidney or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs as judged by the investigator;
23. Concurrent participation or participation within 3 months prior to screening in a drug/device or biologic investigational research study;
Laboratory/ECG values outside the normal range will be flagged and their clinical relevance will be assessed by the investigator. Subjects presenting with out-of-range values that are judged by the investigator to be of no clinical relevance can be included at his discretion. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Decrease in uterine bleeding as change from baseline to Week 12. Blood loss will be assessed using the PBAC |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Decrease in uterine bleeding as change from baseline to Week 4 and Week 8 assessed by PBAC
• Percentage of subjects in amenorrhea at Week 4, Week 8, and Week 12 (end-of-treatment) assessed by PBAC
• Change in total fibroid volume of the three largest fibroids assessed by MRI from baseline to end-of-treatment visit (Week 12)
• Change in total fibroid volume assessed by TVU from baseline to end-of-treatment visit (Week 12)
• Change in total uterine volume assessed by MRI and/or TVU from baseline to end-of-treatment visit (Week 12)
• Change from baseline in symptoms related to uterine fibroids (measurement of discomfort due to uterine fibroids using VAS scales, the UFS-QoL, and the PGIC scale) at Week 4, Week 8, and Week 12 (end-of-treatment)
• Change in hemoglobin and hematocrit levels from baseline to end-of-treatment visit (Week 12) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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.8.3 |
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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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