Moderate to Severe Vasomotor Symptoms (VMS) in Postmenopausal Women MedDRA version: 21.0 Level: LLT Classification code 10020407 Term: Hot flashes System Organ Class: 10047065 - Vascular disorders
Conditions
Interventions
Product Name: Estetrol (E4)
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Estetrol monohydrate
CAS Number: 2055649-81-3
Current Sponsor code: E4
Concentration unit: mg milligram(s)
Con
Sponsors
Estetra SRL
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Signed and dated written informed consent form and any required privacy authorization prior to the initiation of any trial procedure, after the nature of the trial has been explained according to local regulatory requirements; 2. Females, = 40 up to = 65 years of age at randomization/treatment allocation; 3. For hysterectomized subjects: documented hysterectomy must have occurred at least 6 weeks prior to the start of screening. Hysterectomy can be total or subtotal (i.e., cervix was not removed). 4. For non-hysterectomized subjects: uterus with bi-layer endometrial thickness = 4 mm on transvaginal ultrasound (TVUS) (Amendment 1, November 28, 2019); 5. For non-hysterectomized subjects: an evaluable endometrial biopsy taken during screening that reveals no abnormal results, i.e., presence of hyperplasia (simple or complex, with or without atypia), presence of carcinoma and presence of disordered proliferative endometrium findings. The screening biopsy should have sufficient endometrial tissue for diagnosis; 6. Seeking treatment for relief of VMS associated with menopause; a) For the Efficacy Study part: at least 7 moderate to severe bothersome VMS per day or at least 50 moderate to severe bothersome VMS per week in the last 7 consecutive days during the Screening period; b) For the Endometrial and General Safety Study part: at least 1 moderate to severe VMS per week; 7. Body mass index = 18.0 kg/m² to = 38.0 kg/m²; 8. A mammogram that shows no sign of significant disease performed during screening or within 9 months prior to the start of screening; 9. Post-menopausal status defined as any of the following: a) For non-hysterectomized subjects: - at least 12 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) >40 mIU/mL (value obtained after washout of estrogen/progestin containing drugs, see exclusion criteria 18 and 20); - or at least 6 months of spontaneous amenorrhea with serum FSH >40 mIU/mL and E2 40 mIU/mL and E2 =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. History of malignancy with the exception of basal cell or squamous cell carcinoma of the skin if diagnosed more than 1 year prior to the Screening visit; 2. Any clinically significant findings found by the Investigator at the breast examination and/or on mammography suspicious of breast malignancy that would require additional clinical testing to rule out breast cancer (however, simple cysts confirmed by ultrasound are allowed); 3. PAP test with atypical squamous cells undetermined significance (ASC-US) or higher (low-grade squamous intraepithelial lesion [LSIL], atypical squamous cells- cannot exclude high-grade squamous intraepithelial lesion [HSIL] [ASC-H], HSIL, dysplastic or malignant cells) in sub-totally hysterectomized and non-hysterectomized subjects. Note: ASC-US is allowed if a reflex human papilloma virus (HPV) testing is performed and is negative for high risk oncogene HPV subtypes 16 and 18; 4. For non-hysterectomized subjects: a) History or presence of uterine cancer, endometrial hyperplasia, or disordered proliferative endometrium b) Presence of endometrial polyps; c) Undiagnosed vaginal bleeding or undiagnosed abnormal uterine bleeding; d) Endometrial ablation; e) Any uterine/endometrial abnormality that in the judgment of the investigator contraindicates the use of estrogen and/or progestin therapy. This includes presence or history of adenomyosis or significant myoma (Amendment 2, February 24, 2020); 5. Systolic blood pressure (BP) higher than 130 mmHg, diastolic BP higher than 80 mmHg during screening; 6. History of venous or arterial thromboembolic disease (e.g., superficial or deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, angina pectoris, etc.), or first degree family history of VTE; 7. History of known acquired or congenital coagulopathy or abnormal coagulation factors, including known thrombophilia’s; 8. laboratory values of fasting glucose ranges above 125 mg/dL (>6.94 mmol/L) and/or glycated hemoglobin above 7% (Amendment 2, February 24, 2020); 9. Dyslipoproteinaemia (LDL >190 mg/dL [>4.91 mmol/L] and/or triglycerides >300 mg/dL [>3.39 mmol/L]) (Amendment 1, November 28, 2019 and Amendment 2, February 24, 2020); 10. Subjects smoking >15 cigarettes per day (amendment 1, November 28, 2019) 11. Presence or history of gallbladder disease, unless cholecystectomy has been performed; 12. Systemic lupus erythematosus; 13. Any malabsorption disorders including gastric bypass surgery; 14. History of acute liver disease in the preceding 12 months before the start of screening or presence or history of chronic or severe liver disease [alanine transaminase (ALT) or aspartate transaminase (AST) >2x upper limit of normal (ULN), bilirubin >1.5 ULN], or liver tumors; 15. Chronic or current acute renal impairment (estimated glomerular filtration rate <60 ml/min); 16. Porphyria; 17. Diagnosis or treatment of major psychiatric disorder (e.g., schizophrenia, bipolar disorder, etc.), in the judgement of the Investigator; 18. Use of estrogen/progestin containing drug(s) up to: a) 1 week before screening start for vaginal non systemic hormonal products (rings, creams, gels); b) 4 weeks before screening start for vaginal or transdermal estrogen or estrogen/progestin products; c) 8 weeks before screening start for oral estrogen and/or progestin products and/or selective estrogen receptor modulator therapy; d) 8 weeks before screening start for intrauterine progestin therapy; e) 3 months before screening st
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Arms 1-3: To measure the effect of treatment with E4 15 mg or E4 20 mg compared to placebo on the frequency and severity of moderate to severe VMS in postmenopausal women at 4 and 12 weeks Arm 4: To evaluate the effect of treatment with E4 20 mg / P4 100 mg on the endometrium;Secondary Objective: Arms 1-3: Treatment with E4 15 mg or E4 20 mg: - To measure the effect of treatment compared to placebo on the frequency and severity of moderate to severe VMS in postmenopausal women weekly up to 12 weeks, on symptoms of vulvovaginal atrophy (VVA), lipid and glucose metabolism, health-related quality of life (HRQoL) and treatment satisfaction (TS), and on the endometrium and vaginal bleeding in non-hysterectomized subjects - To measure the clinical meaningfulness compared to placebo on the reduction of VMS at weeks 4 and 12 - To evaluate the general safety of treatment compared to placebo Arm 4: Treatment with E4 20 mg / P4 100 mg: - To evaluate the general safety of treatment - To evaluate the effect of treatment on vaginal bleeding, HRQoL and TS, lipid and glucose metabolism - To further evaluate the effects of treatment with E4 20 mg / P4 100 mg on the endometrium;Primary end point(s): Arm 1-3: Mean change in weekly frequency of moderate to severe VMS from baseline to week 4 and week 12 Mean change in severity of moderate to severe VMS from baseline to week 4 and week 12 Arm 4: - Incidence of endometrial hyperplasia with up to 12 months of treatment based on endometrial biopsies ;Timepoint(s) of evaluation of this end point: Arm 1-3: Week 4 and week 12 Arm 4: week 13, 29, 53 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Arm 1-3: For Objective 1 - Change from baseline to week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 in the weekly frequency of moderate to severe VMS, and in the severity of moderate to severe VMS - Change from baseline to weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 in the weekly frequency and severity of mild, moderate and severe VMS - Percentage of subjects with 50% and 75% reduction from baseline in the weekly frequency of mild, moderate and severe VMS at weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 For Objective 2 - Percentage of subjects with a clinically important difference (CID) compared to baseline in the weekly frequency of moderate to severe VMS after weeks 4 and 12 using the Clinical Global Impression (CGI) questionnaire For Objective 3 - Change from baseline to week 12 in VVA symptoms (subject self-assessment) using VVA questionnaire - Change from baseline to week 12 in the VVA symptoms (subject self-assessment) that is initially identified by the subject as being the most bothersome using the VVA questionnaire at baseline For Objective 4 - Change from baseline to week 12 in triglycerides, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, total cholesterol, lipoprotein(a), total cholesterol/HDL-cholesterol ratio, fasting glycemia, insulin, glycated hemoglobin and homeostasis model assessment estimated insulin resistance (HOMA-IR) For Objective 5 - Change from baseline to week 12 in HRQoL using the Menopause-specific Quality of Life (MENQOL) questionnaire - Total score in TS after 4 and 12 weeks of treatment using the Clinical Global Impression (CGI) questionnaire For Objective 6 - Frequency of treatment emergent adverse events (TEAE) (including treatment emergent serious adverse event [SAE] monitoring) - Frequency of changes in results in physical and gynecological examination, vital signs, electrocardiogram (ECG) and breast examination at each measured time point - Frequency of cha | — |
Countries
Argentina, Brazil, Canada, Czechia, Czech Republic, Hungary, Italy, Lithuania, Poland, Romania, Russian Federation, Slovakia, Spain, United Kingdom, United States
Contacts
Public ContactClinical Project Leader
Estetra SRL
Outcome results
None listed