Vasomotor Symptoms in Post-Menopausal Women MedDRA version: 20.0 Level: LLT Classification code 10036268 Term: Post-menopausal bleeding System Organ Class: 100000004872
Conditions
Interventions
Product Name: Estetrol (E4) (2.5mg)
Pharmaceutical Form: Capsule
INN or Proposed INN: Estetrol monohydrate
CAS Number: 15183-37-6
Concen
Sponsors
Donesta Bioscience BV
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Women aged 40 to 65 years, inclusive, presenting at least 7 moderate to severe hot flushes/day or at least 50 moderate to severe hot flushes/week in the week preceding randomization. 2. Body Mass Index (BMI) between 18.0 and 35.0 kg/m², inclusive. 3. Post-menopausal status defined as levels of follicle stimulating hormone (FSH) >40 IU/L and: - amenorrhoea for at least 12 consecutive months or, - amenorrhoea for at least 6 months with estradiol (E2) =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1.For non-hysterectomised women: uterine disease or medical condition including : a. Bi-layer endometrial thickness >5mm as determined by TVUS; b. Presence of fibroid(s) that obscure(s) evaluation of endometrium by TVUS; c. History or presence of uterine cancer; d. Presence of endometrial hyperplasia; e. Presence of an endometrial polyp with hyperplastic or malignant epithelium. 2.Undiagnosed vaginal bleeding in the last 12 months. 3.Any history of malignancy with the exception of basal cell or squamous cell carcinoma of the skin. Any clinically significant findings at the breast examination and/or on mammography suspicious of breast malignancy that would require additional clinical testing to rule out breast cancer. Note: A screening mammogram is required unless the subject has a written documentation of a mammogram performed within the last 9 months 4.Abnormal cervical Pap smear in non-hysterectomised subjects with evidence of cervical dysplasia greater than low grade squamous intraepithelial lesion.Women with a diagnosis of ASCUS may be enrolled 5.Systolic BP outside the range 90 to 140 mmHg, diastolic BP outside the range 60 to 90 mmHg, and/or heart rate outside the range 40 to 100bpm. Subjects with mild to moderate hypertension who are controlled on a stable antihypertension regimen may be enrolled if they meet the inclusion/exclusion criteria. 6.Any clinically significant abnormality identified on the screening 12-lead ECG. 7.History of venous or arterial thromboembolic disease (e.g., deep vein thrombosis, pulmonary embolism, stroke,myocardial infarction, angina pectoris, etc.),history of known coagulopathy or abnormal coagulation factors. 8.Diabetes mellitus with poor glycaemic control in the last 6 months assessed by laboratory values of glucose outside the normal ranges and glycated haemoglobin above7%. 9.Dyslipoproteinaemia predisposes the subject to ASCVD. If a subject has a 10 years ASCVD score = 5% as calculated using the ASCVD risk estimator, she may not be included in the trial. In all cases, LDL cholesterol level = 190 mg/dL or triglycerides plasma level > 400 mg/dL is exclusionary. If a subject is receiving a lipid-lowering therapy, her treatment has to be on a stable dose for at least 1 month before screening and the same eligibility criteria has to be used. 11.Presence or history of gallbladder disease, unless cholecystectomy has been performed 12.Systemic lupus erythematosus. 13.Multiple sclerosis. 14.Acute or chronic liver disease. 15.Acute or chronic renal impairment, including severe renal impairment. 16.Uncontrolled thyroid disorders. 17.Subject has a history of major depression or PTSD within 2 years, OR a history of other major psychiatric disorder at any time. 18.Use of oestrogen or progestin containing drug(s). A washout period is required before the Run-in Period in case of use of: a.Vaginal hormonal products:washout of at least 4 weeks, b.Transdermal oestrogen or oestrogen/progestin:washout of at least 4 weeks, c.Oral oestrogen and/or progestin : washout of at least 4 weeks,
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To define the minimum effective dose (MED) of the oral dose of E4 by evaluating changes in frequency and in severity of moderate to severe vasomotor symptoms (VMS).; Secondary Objective: To evaluate effects of different doses of E4 on genitourinary syndrome of menopause (GSM) also called vulvovaginal atrophy (VVA), on vaginal maturation index (MI), on vaginal pH, on change in the Menopause Rating Scale (MRS), on lipid and glucose metabolism, on haemostatic and bone laboratory variables, and E4 concentrations at baseline and steady state. Safety objectives: To evaluate safety in non-hysterectomised subjects by monitoring transvaginal ultrasonography (TVUS) change of endometrial thickness at each study visit during the E4/placebo treatment period and by daily diary entry for bleeding pattern. To evaluate safety in both hysterectomised and non-hysterectomised subjects by (serious) adverse event ([S]AE) monitoring, physical and gynaecological examination (including vital signs and breast examination), electrocardiogram (ECG), routine clinical laboratory tests (e.g. haematology and chemistry) ; Primary end point(s): 1. Change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from baseline to week 4. 2. Change in weekly frequency of moderate to severe VMS from baseline to week 12. 3. Change in severity of moderate to severe VMS from baseline to week 4. 4. Change in severity of moderate to severe VMS from baseline to week 12. ; Timepoint(s) of evaluation of this end point: Endpoints 1 and 3 at week 4 and endpoints 2 and 4 at week 12 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Vaginal dryness (none, mild, moderate or severe), 2. Vaginal and/or vulvar irritation/itching (none, mild, moderate or severe), 3. Dysuria (none, mild, moderate or severe), 4. Vaginal pain associated with sexual activity (none, mild, moderate or severe), 5. Vaginal bleeding associated with sexual activity (presence vs. absence). ; Timepoint(s) of evaluation of this end point: From baseline to week 13 | — |
Countries
Belgium, Czech Republic, Ireland, Netherlands, Poland, United Kingdom
Contacts
Public ContactFrançoise Bruyère
Donesta Bioscience BV
Outcome results
None listed