Vasomotor Symptoms in Post-Menopausal Women MedDRA version: 19.0 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
Concentration unit: mg milligram(s)
Concentration type: equal
Concentr
Sponsors
Donesta Bioscience BV
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Women aged 45 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 amenorrhoea for at least 12 consecutive months OR at least 6 weeks post-surgical bilateral oophorectomy without hysterectomy. Note: Although duration of amenorrhoea is initially determined by subject history at the time of the Screening visit, menopausal status must be confirmed by demonstrating levels of follicle stimulating hormone (FSH) >40 IU/L at entry. In addition, for women who are surgically menopausal, a copy of the pathology report or a statement on letterhead from the subject's physician documenting both ovaries were removed is required. 4. Intact uterus with bi-layer endometrial thickness =5 mm on TVUS. 5. Negative pregnancy test. 6. Good physical and mental health, in the judgement of the Principal Investigator (PI), on the basis of medical, surgical and gynaecological history, physical examination, gynaecological examination, clinical laboratory, and vital signs. 7. Subject has provided signed and dated written informed consent before admission to the study. 8. Subject is able to understand and comply with the protocol requirements, instructions, and protocol-stated restrictions. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 225 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1.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(excluded if within the prior 2 years)or squamous cell(excluded if within the prior one year)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 (however, simple cysts confirmed by ultrasound are allowed). Note: A screening mammogram is required unless the subject has had a mammogram performed within the last 9 months. 4.Abnormal cervical Pap smear with evidence of cervical dysplasia greater than low grade squamous intraepithelial lesion.Women with a diagnosis of atypical squamous cells of undetermined significance (ASCUS), or atypical glandular cells of undetermined significance may be enrolled. 5.Systolic blood pressure(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 100 bpm. 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. Subjects with QTc prolongation(QTcB and QTcF values >450msec)will be excluded. 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 at screening.If a subject is receiving a lipid-lowering therapy, then her dyslipoproteinaemia has to be corrected and her treatment has to be on a stable dose for at least 1 month before screening. 10.Smoking>10cigarettes/day. 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. 16.Uncontrolled thyroid disorders. 17.Subject has a history of major depression or post-traumatic stress disorder(PTSD)within 2 years of screening, OR a history of other major psychiatric disorder at any time(e.g.,schizophrenia, bipolar disorder,etc.). 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 (rings, creams, gels):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, d.Intrauterine progestin therapy:washout of at least 4 weeks, e.Progestin implants or oestrogen alone injectable drug therapy:washout of at least 3 months, f.Oestrogen pellet therapy or progestin injectable drug therapy:washout of at least 6 months. 19.Use of non-hormonal treatments to reduce hot flushes.A
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 by transvaginal ultrasonography (TVUS) change of endometrial thickness at each study visit during the E4/placebo treatment period, (S)AE monitoring, physical and gynaecological examination (including vital signs and breast examination), ECG, routine clinical laboratory tests and bleeding control. ;Primary end point(s): 1. Change in weekly frequency of moderate to severe vasomotor symptoms (VMS). 2. Change in weekly frequency of moderate to severe VMS. 3. Change in severity of moderate to severe VMS. 4. Change in severity of moderate to severe VMS.;Timepoint(s) of evaluation of this end point: 1, 2, 3, 4, 5, At week 4 to 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: 1, 2, 3, 4, 5, From baseline to week 12 | — |
Countries
Belgium, Czech Republic, Ireland, Netherlands, Poland, United Kingdom
Contacts
Public ContactFrançoise Bruyère
Donesta Bioscience BV
Outcome results
None listed