Estetrol for the Treatment of Moderate to Severe Vasomotor Symptoms in Postmenopausal Women (E4Comfort II)

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/treatment allocation;
• 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 transvaginal ultrasound (TVUS)
• For non-hysterectomized subjects: endometrial biopsy taken during screening that reveals no abnormal result, 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. Biopsies without tissue or with insufficient tissue may be repeated once;
• Seeking treatment for relief of VMS associated with menopause;
• 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;
• For the Safety Study part: at least 1 moderate to severe VMS per week;
• Body mass index ≥ 18.0 kg/m² up to ≤ 38.0 kg/m²;
• 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:
• At least 12 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) >40 milli-International unit (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 190 mg/dL and/or triglycerides >300 mg/dL);
• 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 bypass 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) >2 x 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:
• 1 week before screening start for vaginal non-systemic hormonal products (rings, creams, gels);
• 4 weeks before screening start for vaginal or transdermal estrogen or estrogen/progestin products;
• 8 weeks before screening start for oral estrogen and/or progestin products and/or selective estrogen receptor modulator therapy;
• 8 weeks before screening start for intrauterine progestin therapy;
• 3 months before screening start for progestin implants or estrogen alone injectable drug therapy;
• 6 months before screening start for estrogen pellet therapy or progestin injectable drug therapy;
• Use of androgen/dehydroepiandrosterone (DHEA) containing drugs:
• 8 weeks before screening start for oral, topical, vaginal or transdermal androgen;
• 6 months before screening start for implantable or injectable androgen therapy;
• Use of phytoestrogens or black cohosh for 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,