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

Inclusion Criteria:

• Signed and dated written informed consent form and any required privacyauthorization prior to the initiation of any trial procedure, after the nature ofthe 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 6weeks 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 mmon TVUS;

• For non-hysterectomized subjects: an evaluable endometrial biopsy taken duringscreening that reveals no abnormal results, i.e., presence of hyperplasia (simple orcomplex, with or without atypia), presence of carcinoma, and presence of disorderedproliferative endometrium findings. The screening biopsy should have sufficientendometrial tissue for diagnosis;

• Seeking treatment for relief of VMS associated with menopause;

1. For the Efficacy Study part: at least 7 moderate to severe bothersome VMS perday or at least 50 moderate to severe bothersome VMS per week in the last 7consecutive days during the Screening period;

2. For the Endometrial and General Safety Study part: at least 1 moderate tosevere VMS per week;

• 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 orwithin 9 months prior to the start of screening ;

• Post-menopausal status defined as any of the following:

• For non-hysterectomized subjects:

1. at least 12 months of spontaneous amenorrhea with serum follicle stimulatinghormone (FSH) >40 milli-International unit (mIU)/mL (value obtained afterwashout of estrogen/progestin containing drugs, see exclusion criteria 18 and 20);

2. or at least 6 months of spontaneous amenorrhea with serum FSH >40 mIU/mL and E2 <20 pg/mL (<73.4 pmol/L,value obtained after washout of estrogen/progestincontaining drugs, see exclusion criteria 18 and 20);

3. or at least 6 weeks postsurgical bilateral oophorectomy;

• For hysterectomized subjects:

1. serum FSH >40 mIU/mL and E2 <20 pg/mL (<73.4 pmol/L, values obtained afterwashout of estrogen/progestin containing drug see exclusion criteria 18 and 20);

2. or at least 6 weeks post-surgical bilateral oophorectomy.

• Good physical and mental health, in the judgement of the Investigator as based onmedical history, physical and gynecological examination and clinical assessmentsperformed prior Visit 1;

• Able to understand and comply with the protocol requirements, instructions, andprotocol-stated restrictions;

• Able and willing to complete trial daily paper diaries (if applicable) andquestionnaires.

Exclusion Criteria:

• History of malignancy with the exception of basal cell or squamous cell carcinoma ofthe skin if diagnosed more than 1 year prior to the Screening visit;

• Any clinically significant findings found by the Investigator at the breastexamination and/or on mammography suspicious of breast malignancy that would requireadditional clinical testing to rule out breast cancer (however, simple cystsconfirmed by ultrasound are allowed);

• Papanicolaou (PAP) test with atypical squamous cells undetermined significance (ASC-US) or higher (low-grade intraepithelial lesion [LSIL], atypical squamouscells- cannot exclude high-grade intraepithelial lesion [HSIL] [ASC-H], HSIL,dysplastic or malignant cells) in sub-totally hysterectomized andnon-hysterectomized subjects . Note: ASC-US is allowed if a reflex human papillomavirus (HPV) testing is performed and is negative for high risk oncogene HPV subtypes 16 and 18;

• For non-hysterectomized subjects:

1. History or presence of uterine cancer, endometrial hyperplasia, or disorderedproliferative endometrium;

2. Presence of endometrial polyps;

3. Undiagnosed vaginal bleeding or undiagnosed abnormal uterine bleeding;

4. Endometrial ablation;

5. Any uterine/endometrial abnormality that in the judgment of the investigatorcontraindicates the use of estrogen and/or progestin therapy. This includespresence or history of adenomyosis or significant myoma;

• Systolic blood pressure (BP) higher than 130 mmHg, diastolic BP higher than 80 mmHgduring screening;

• History of venous or arterial thromboembolic disease (e.g., superficial or deep veinthrombosis, 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 coagulationfactors, including known thrombophilia's;

• Laboratory values of fasting glucose above 125 mg/dL (>6.94 mmol/L) and/or glycatedhemoglobin 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 beenperformed;

• Systemic lupus erythematosus;

• Any malabsorption disorders including gastric by-pass surgery;

• History of acute liver disease in the preceding 12 months before the start ofscreening or presence or history of chronic or severe liver disease [alaninetransaminase (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 <60ml/min);

• Porphyria;

• Diagnosis or treatment of major psychiatric disorder (e.g., schizophrenia, bipolardisorder, etc.), in the judgement of the Investigator;

• Use of estrogen/progestin containing drug(s) up to:

1. 1 week before screening start for vaginal non systemic hormonal products (rings, creams, gels);

2. 4 weeks before screening start for vaginal or transdermal estrogen orestrogen/progestin products;

3. 8 weeks before screening start for oral estrogen and/or progestin productsand/or selective estrogen receptor modulator therapy;

4. 8 weeks before screening start for intrauterine progestin therapy;

5. 3 months before screening start for progestin implants or estrogen aloneinjectable drug therapy;

6. 6 months before screening start for estrogen pellet therapy or progestininjectable drug therapy;

• Use of androgen/dehydroepiandrosterone (DHEA) containing drugs:

1. 8 weeks before screening start for oral, topical, vaginal or transdermalandrogen;

2. 6 months before screening start for implantable or injectable androgen therapy;

• Use of phytoestrogens or black cohosh for the treatment of VMS up to 2 weeks beforethe start of screening;

• For the women participating in the Efficacy Study part: use of prescription orover-the-counter products used for the treatment of VMS, e.g., anti-depressants:paroxetine, escitalopram, methyldopa, opioid and clonidine up to 4 weeks before thestart of screening, and venlafaxine and desvenlafaxine up to 3 months before thestart of screening , and not willing to stop these during their participation in thetrial;

• Not willing to stop any hormonal products as described in exclusion criteria 18, 19and 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 normalrange;

• History or presence of allergy/intolerance to the investigational product or drugsof this class or any component of it, or history of drug or other allergy that, inthe 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 determinedby the Investigator, based on reported observations;

• Sponsor or contract research organization (CRO) employees or employees under thedirect supervision of the Investigator and/or involved directly in the trial;

• Subjects with known or suspected history of a clinically significant systemicdisease, unstable medical disorders, life-threatening disease or currentmalignancies that would pose a risk to the subject in the opinion of theInvestigator;

• Participation in another investigational drug clinical trial within 1 month (30days) 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 orpresence of allergy to peanuts.