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About
This is a two-part study designed to evaluate the effect of Estetrol (E4) 15 or 20 mg, or placebo on the severity and frequency of vasomotor symptoms (VMS) (Efficacy Study Part) and the safety of E4 20 mg (Endometrial and General Safety Study Part)
Full description
This is a two-part study:
The Efficacy Study Part is designed to evaluate the frequency and severity of vasomotor symptoms [VMS] in both hysterectomized and non-hysterectomized postmenopausal participants after treatment with E4 15 mg or 20 mg or placebo for up to 13 consecutive weeks. For endometrial protection, all non-hysterectomized participants will be treated with 200 mg progesterone (P4) once daily for 14 consecutive days, after completion of the E4/placebo treatment. The Endometrial and General Safety Study Part (Safety Part) is designed to evaluate the general safety, endometrial safety, secondary efficacy (lipid, glucose metabolism, health-related quality of life [HRQoL] and treatment satisfaction) of E4 in non-hysterectomized participants. All participants will receive E4 20 mg in combination with 100 mg P4 continuously for up to 53 weeks.
Enrollment
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Inclusion criteria
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;
Females, ≥ 40 up to ≤ 65 years of age at randomization;
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);
For non-hysterectomized subjects: uterus with bi-layer endometrial thickness ≤ 4 mm on TVUS;
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;
Seeking treatment for relief of VMS associated with menopause;
Body mass index ≥ 18.0 kg/m^2 to ≤ 38.0 kg/m^2;
A mammogram that shows no sign of significant disease performed during screening or within 9 months prior to the start of screening ;
Post-menopausal status defined as any of the following:
For non-hysterectomized subjects:
For hysterectomized subjects:
Good physical and mental health, in the judgement of the Investigator as based on medical history, physical and gynecological examination and clinical assessments performed prior Visit 1;
Able to understand and comply with the protocol requirements, instructions, and protocol-stated restrictions;
Able and willing to complete trial daily paper diaries (if applicable) and questionnaires.
Exclusion criteria
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;
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);
Papanicolaou (PAP) test with atypical squamous cells undetermined significance (ASC-US) or higher (low-grade intraepithelial lesion [LSIL], atypical squamous cells- cannot exclude high-grade 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;
For non-hysterectomized subjects:
Systolic blood pressure (BP) higher than 130 mmHg, diastolic BP higher than 80 mmHg during screening;
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 venous thromboembolism (VTE);
History of known acquired or congenital coagulopathy or abnormal coagulation factors, including known thrombophilia's;
Laboratory values of fasting glucose above 125 mg/dL (>6.94 mmol/L) and/or glycated hemoglobin above 7%18;
Dyslipoproteinemia (LDL >190 mg/dL [>4.91 mmol/L] and/or triglycerides >300 mg/dL [>3.39 mmol/L])19;
Subjects smoking >15 cigarettes per day;
Presence or history of gallbladder disease, unless cholecystectomy has been performed;
Systemic lupus erythematosus;
Any malabsorption disorders including gastric by-pass surgery;
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;
Chronic or current acute renal impairment (estimated glomerular filtration rate <60 ml/min);
Porphyria;
Diagnosis or treatment of major psychiatric disorder (e.g., schizophrenia, bipolar disorder, etc.), in the judgement of the Investigator;
Use of estrogen/progestin containing drug(s) up to:
Use of androgen/dehydroepiandrosterone (DHEA) containing drugs:
Use of phytoestrogens or black cohosh for the treatment of VMS up to 2 weeks before the start of screening;
For the women participating in the Efficacy Study part: use of prescription or over-the-counter products used for the treatment of VMS, e.g., anti-depressants: paroxetine, escitalopram, methyldopa, opioid and clonidine up to 4 weeks before the start of screening, and venlafaxine and desvenlafaxine up to 3 months before the start of screening , and not willing to stop these during their participation in the trial;
Not willing to stop any hormonal products as described in exclusion criteria 18, 19 and 20, during their participation in the trial;
Inadequately treated hyperthyroidism with abnormal TSH and free T4 at screening. Subjects with low or high TSH are allowed if free T4 at screening is within normal range;
History or presence of allergy/intolerance to the investigational product or drugs of this class or any component of it, or history of drug or other allergy that, in the opinion of the Investigator contraindicates subject participation;
History of alcohol or substance abuse (including marijuana, even if legally allowed) or dependence in the previous 12 months before the start of screening as determined by the Investigator, based on reported observations;
Sponsor or contract research organization (CRO) employees or employees under the direct supervision of the Investigator and/or involved directly in the trial;
Subjects with known or suspected history of a clinically significant systemic disease, unstable medical disorders, life-threatening disease or current malignancies that would pose a risk to the subject in the opinion of the Investigator;
Participation in another investigational drug clinical trial within 1 month (30 days) or having received an investigational drug within the last month (30 days) before the start of screening;
Is judged by the Investigator to be unsuitable for any reason;
For non-hysterectomized subjects to be included in the USA and Canada: history or presence of allergy to peanuts.
Primary purpose
Allocation
Interventional model
Masking
1,570 participants in 4 patient groups, including a placebo group
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Central trial contact
Estetra; Estetra
Data sourced from clinicaltrials.gov
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