Estetrol for the Treatment of Moderate to Severe Vasomotor Symptoms in Postmenopausal Women

Study Overview
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Brief Summary
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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 (Safety Study Part).

Detailed Description
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This is a two-part study: The first part is the Efficacy Study mainly designed to evaluate the frequency and severity of vasomotor symptoms [VMS] in both hysterectomized and non hysterectomized postmenopausal participants after treatment with two doses of E4 (15 mg or 20 mg) or placebo for 12 consecutive weeks. Thereafter, treatment will proceed for a total duration of up to 53 weeks, to continue the evaluation of secondary efficacy, safety and the effect on the endometrium. For endometrial protection, all non-hysterectomized subjects will receive treatment with 200 mg progesterone (P4) once daily for 14 consecutive days, after completion of the E4/placebo treatment. The second part is the Safety Study designed to evaluate the general safety, secondary efficacy (lipid and glucose metabolism, health-related quality of life [HRQoL] and treatment satisfaction [TS]) after treatment with E4 20 mg for up to 53 weeks in hysterectomized and non hysterectomized postmenopausal participants. For endometrial protection, all non-hysterectomized subjects will receive treatment with 200 mg progesterone (P4) once daily for 14 consecutive days, after completion of the E4 treatment.

Official Title
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A Randomized Double-blind Placebo Controlled Phase 3 Trial to Evaluate the Efficacy and Safety of Estetrol for the Treatment of Moderate to Severe Vasomotor Symptoms in Postmenopausal Women (E4Comfort Study II)

Conditions
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Vasomotor Symptoms, Menopausal Symptoms

Intervention / Treatment
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* Drug: Estetrol oral tablet
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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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/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 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 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 <20 pg/mL (value obtained after washout of estrogen/progestin containing drugs, see exclusion criteria 18 and 20); or at least 6 weeks postsurgical bilateral oophorectomy; For hysterectomized subjects: serum FSH >40 mIU/mL and E2 <20 pg/mL (values obtained after washout of estrogen/progestin containing drug, see exclusion criteria 18 and 20); or at least 6 weeks post-surgical bilateral oophorectomy; 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 to Visit 1; Able to understand and comply with the protocol requirements, instructions, and protocol-stated restrictions; Able and willing to complete trial daily diaries 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 squamous intraepithelial lesion [LSIL], atypical squamous cells- cannot exclude high-grade squamous 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: History or presence of uterine cancer, endometrial hyperplasia, or disordered proliferative endometrium; Presence of endometrial polyp; Undiagnosed vaginal bleeding or undiagnosed abnormal uterine bleeding; Endometrial ablation; Any uterine/endometrial abnormality that in the judgment of the investigator contraindicates the use of estrogen and/or progestin therapy. This includes presence or history of adenomyosis or significant myoma; 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 of congenital coagulopathy or abnormal coagulation factors, including known thrombophilia's; Laboratory values of fasting glucose above 125 mg/dL and/or glycated hemoglobin above 7%; Dyslipoproteinaemia (LDL >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, 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; For non-hysterectomized subjects: history or presence of allergy to peanuts; 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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: There are 3 blinded arms in the Efficacy part and 1 open-labeled arm in the Safety part.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Estetrol 15 mg - Efficacy Part<br>Estetrol (E4) 15 mg will be administered orally once daily for up to 53 weeks. | Drug: Estetrol oral tablet<br>* Estetrol oral tablet will be administered orally once daily.<br>* Other names: E4 oral tablet;|
| Experimental: Estetrol 20 mg - Efficacy Part<br>Estetrol (E4) 20 mg will be administered orally once daily for up to 53 weeks. | Drug: Estetrol oral tablet<br>* Estetrol oral tablet will be administered orally once daily.<br>* Other names: E4 oral tablet;|
| Placebo Comparator: Placebo - Efficacy Part<br>Placebo will be administered orally once daily for up to 53 weeks. | Drug: Placebo oral tablet<br>* Placebo oral tablet will be administered orally once daily.<br>|
| Experimental: Estetrol 20 mg - Safety Part<br>Estetrol (E4) 20 mg will be administered orally once daily for up to 53 weeks. | Drug: Estetrol oral tablet<br>* Estetrol oral tablet will be administered orally once daily.<br>* Other names: E4 oral tablet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 4 (Efficacy part) | The weekly frequency of moderate to severe VMS at Baseline and Week 4 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 4. Mean change = mean weekly frequency at Week 4 - mean weekly frequency at Baseline | Baseline and Week 4 | 
| Mean change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 12 (Efficacy part) | The weekly frequency of moderate to severe VMS at Baseline and Week 12 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 12. Mean change = mean weekly frequency at Week 12 - mean weekly frequency at Baseline | Baseline and Week 12 | 
| Mean change in severity of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 4 (Efficacy part) | The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 4 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 4. Baseline severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS). Week 4 severity score = [(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of mild + moderate + severe VMS). Mean change = mean severity score at Week 4 - mean severity score at Baseline | Baseline and Week 4 | 
| Mean change in severity of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 12 (Efficacy part) | The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 12 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 12. Baseline severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS). Week 12 severity score = [(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of mild + moderate + severe VMS). Mean change = mean severity score at Week 12 - mean severity score at Baseline | Baseline and Week 12 | 
| Number of participants with treatment-emergent adverse events (TEAEs) (Safety part) | Treatment emergent adverse events (TEAEs) are those adverse events occurring from time point of first ingestion of investigational product until last visit or any event already present that worsens in either intensity or frequency following exposure to the treatment. | From Baseline to Follow-up visit (up to Week 56) | 
| Number of participants with changes in physical and gynecological examination results (Safety part) | Physical examination will include an examination of general appearance, head, eyes, ears, nose, throat, skin neck, lungs, breast, lymph nodes, abdomen, and the cardiovascular musculoskeletal and neurological systems. Gynecological examination will include a manual pelvic examination. | Screening and Week 53 | 
| Number of participants with changes in vital sign results (Safety part) | Vital signs will include height, body weight, body mass index, sitting systolic and diastolic blood pressures, and heart rate. | Screening and Week 53 | 
| Number of participants with changes in electrocardiogram (ECG) results (Safety part) | The ECG interpretation scheme will include the analysis of the morphology, rhythm, conduction, ST segment, PR, QRS, QT and corrected QT (QTc) intervals, T waves, U waves and the presence or absence of any pathological changes. | Screening and Week 53 | 
| Number of participants with changes in mammography results (Safety part) |  | Screening and Week 53 | 
| Number of participants with changes in breast examination results (Safety part) | Breast examination will include a manual breast examination. | Screening, Week 29 and Week 53 | 
| Number of participants with changes in routine clinical laboratory test (hematology and chemistry) results (Safety part) |  | Screening, Baseline and Week 53 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change from Baseline to Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 in the weekly frequency of moderate to severe vasomotor symptoms (VMS) (Efficacy part) | Weekly frequency of moderate to severe VMS at Baseline = total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization Weekly frequency of moderate to severe VMS at Week X = total number (sum) of all recorded moderate to severe VMS experienced during the week X Mean change = mean weekly frequency at Week X - mean weekly frequency at Baseline | Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 | 
| Mean change from Baseline to Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 in the severity of moderate to severe vasomotor symptoms (VMS) (Efficacy part) | The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. Mean severity score of VMS at Baseline = arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior to randomization Mean severity score of VMS at Week X = arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed during the week x. Baseline severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS). Week X severity score = [(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of mild + moderate + severe VMS). Mean change = mean severity score at Week X - mean severity score at Baseline | Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 | 
| Mean change from Baseline to Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 in the weekly frequency and severity of moderate and severe vasomotor symptoms (VMS) (Efficacy part) | This endpoint also called VMS weekly weighted score takes into account both the frequency and the severity of VMS. The weekly frequency and severity of moderate and severe VMS at Baseline and at Week X is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week X. The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The weekly weighted score will be computed as follows: Baseline weekly weighted score = (2 x number of moderate VMS) + (3 x number of severe VMS) Week X weekly weighted score = (2 x number of moderate VMS) + (3 x number of severe VMS) Mean change = mean weekly weighted score at Week X - mean weekly weighted score at Baseline | Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 | 
| Percentage of subjects with 50% reduction from Baseline in the weekly frequency of moderate to severe vasomotor symptoms (VMS) at Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 (Efficacy part) | The weekly frequency of moderate to severe VMS at Baseline and Week X is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization (Baseline) and from day [(X-1)*7+1] to day X*7 (Week X). | Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 | 
| Percentage of subjects with 75% reduction from Baseline in the weekly frequency of moderate to severe vasomotor symptoms (VMS) at Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 (Efficacy part) | The weekly frequency of moderate to severe VMS at Baseline and Week X is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization (Baseline) and from day [(X-1)*7+1] to day X*7 (Week X). | Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 | 
| Percentage of subjects with 50% reduction from Baseline in the weekly frequency of mild, moderate, and severe VMS at Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 (Efficacy part) | The weekly frequency of moderate to severe VMS at Baseline and Week X is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization (Baseline) and from day [(X-1)*7+1] to day X*7 (Week X). | Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 | 
| Percentage of subjects with 75% reduction from Baseline in the weekly frequency of mild, moderate, and severe VMS at Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 (Efficacy part) | The weekly frequency of moderate to severe VMS at Baseline and Week X is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization (Baseline) and from day [(X-1)*7+1] to day X*7 (Week X). | Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 | 
| Percentage of subjects with a clinically important difference (CID) compared to Baseline in the weekly frequency of moderate to severe VMS after Week 4 and Week 12 using the Clinical Global Impression (CGI) questionnaire (Efficacy part) | The CGI score is a seven point scale in which subjects were asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse. Results for the top two responses - Very Much Improved and Much Improved, and No Change or Worsening (Minimally worse, Much worse, Very much worse) - were combined for each Estetrol treatment groups compared to placebo. | Baseline, Week 4, Week 12 | 
| Plasma concentration of Prothrombin fragment 1+2 (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Endogenous thrombin potential (ETP)-based activated Protein C sensitivity ratio (APCsr ETP) (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Activated partial thromboplastin time (aPTT) based activated Protein C resistance (APCr) (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Plasma concentration of anti-thrombin III (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Plasma concentration of Protein-C (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Plasma concentration of free Protein-S (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Plasma concentration of factor VIII (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Serum concentration of angiotensinogen (Efficacy part) |  | Baseline, Week 13 and Week 53 | 
| Serum concentration Sex Hormone Binding Globulin (SHBG) (Efficacy part) |  | Baseline, Week 13 and Week 53 | 
| Serum concentration of triglycerides (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Serum concentration of high-density lipoprotein (HDL)-cholesterol (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Serum concentration of low-density lipoprotein (LDL)-cholesterol (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Serum concentration of lipoprotein(a) (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Total cholesterol/HDL-cholesterol ratio (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Serum concentration of total cholesterol (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Plasma concentration of fasting glucose (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Serum concentration of insulin (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Glycated hemoglobin (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Homeostasis model assessment-estimated insulin resistance (HOMA-IR) (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Serum concentration of procollagen I N-propeptide (PINP) (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Serum concentration of C-terminal telopeptide type 1 (CTX-1) (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Serum concentration of calcium (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Serum concentration of Vitamine D (Efficacy part) |  | Baseline, Weeks 13 and 53 | 
| Health-related quality of life assessment using the Menopause-specific Quality of Life (MENQOL) questionnaire (Efficacy part) | The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Vasomotor domain score is mean of = Q1,Q2, Q3, with 1 being not at all bothered and 8 being extremely bothered. | Baseline, Weeks 13 and 53 | 
| Total score in treatment satisfaction using the Clinical Global Impression (CGI) questionnaire (Efficacy part) | The CGI score is a seven point scale in which subjects were asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse. Results for the top two responses - Very Much Improved and Much Improved, and No Change or Worsening (Minimally worse, Much worse, Very much worse) - were combined for each estetrol treatment groups compare to placebo. | Weeks 4, 12 and 52 | 
| Number of participants with treatment-emergent adverse events (TEAEs) (Efficacy part) | Treatment emergent AEs (TEAEs) are those adverse events occurring from time point of first ingestion of investigational product until last visit or any event already present that worsens in either intensity or frequency following exposure to the treatment. | From baseline to Follow-up visit (up to Week 56) | 
| Number of participants with changes in physical and gynecological examination results (Efficacy part) | Physical examination will include an examination of general appearance, head, eyes, ears, nose, throat, skin neck, lungs, breast, lymph nodes, abdomen, and the cardiovascular musculoskeletal and neurological systems. Gynecological examination will include a manual pelvic examination. | Screening and Week 53 | 
| Number of participants with changes in vital sign results (Efficacy part) | Vital signs will include height, body weight, body mass index, sitting systolic and diastolic blood pressures, and heart rate. | From screening to Week 53 | 
| Number of participants with changes in electrocardiogram (ECG) results (Efficacy part) | The ECG interpretation scheme will include the analysis of the morphology, rhythm, conduction, ST segment, PR, QRS, QT and QTc intervals, T waves, U waves and the presence or absence of any pathological changes. | Screening and Week 53 | 
| Number of participants with changes in mammography results (Efficacy part) |  | Screening and Week 53 | 
| Number of participants with changes in breast examination results (Efficacy part) |  | Screening, Week 29 and Week 53 | 
| Number of participants with changes in routine clinical laboratory test results (Efficacy part) | Routine laboratory tests include hematology and chemistry. | Screening, Baseline and Week 53 | 
| Mean endometrial thickness (Efficacy part) | Endometrial thickness will be assessed by transvaginal ultrasound (TVUS). | Screening, Weeks 13, 29, 41, 53, and Follow-up (Week 55/56) | 
| Endometrial biopsy histology at Screening and Week 53 (Efficacy part) | Endometrial biopsies will be centrally evaluated by 3 independent expert pathologists from different institutions. If there is no agreement among the three pathologists, the most severe pathologic diagnosis will be used as the final diagnosis. Endometrial biopsy will be classified using criteria described in Blaustein's Pathology text into 1 of following 11 categories: Cat.0: No tissue; Cat.1: Tissue insufficient for diagnosis; Cat.2: Atrophic; Cat 3: Inactive; Cat 4: Proliferative; Cat 5: Secretory; Cat 6: Menstrual type; Cat 7: Simple hyperplasia without atypia; Cat 8: Simple hyperplasia with atypia; Cat 9: Complex hyperplasia without atypia; Cat 10: Complex hyperplasia with atypia; and Cat 11: Carcinoma. | Screening and Week 53 | 
| Number of participants with vaginal bleeding and/or spotting during each 28-day cycle of treatment with E4 (Efficacy part) | Vaginal bleeding will be daily recorded by the participant in the diary. Absence or occurrence of vaginal bleeding/ spotting will be assessed using the scale below: 0 = Absence of vaginal bleeding or spotting; 1 = Spotting: evidence of minimal blood loss requiring none or at most one pad, tampon or panty liner per day; 2 = Bleeding: evidence of blood loss requiring more than one pad, tampon or panty liner per day. | From Baseline up to Follow-up (Week 55/56) | 
| Number of women with amenorrhea (absence of any bleeding or spotting) during each 28-day cycle of treatment with E4 (Efficacy part) | Vaginal bleeding will be daily recorded by the participant in the diary. Absence or occurrence of vaginal bleeding/ spotting will be assessed using the scale below: 0 = Absence of vaginal bleeding or spotting; 1 = Spotting: evidence of minimal blood loss requiring none or at most one pad, tampon or panty liner per day; 2 = Bleeding: evidence of blood loss requiring more than one pad, tampon or panty liner per day. | From Baseline up to Follow-up (Week 55/56) | 
| Serum concentration of triglycerides (Safety part) |  | Baseline, Weeks 13 and 53 | 
| Serum concentration of HDL-cholesterol (Safety part) |  | Baseline, Weeks 13 and 53 | 
| Serum concentration of LDL-cholesterol (Safety part) |  | Baseline, Weeks 13 and 53 | 
| Serum concentration of total cholesterol (Safety part) |  | Baseline, Weeks 13 and 53 | 
| Serum concentration of lipoprotein(a) (Safety part) |  | Baseline, Weeks 13 and 53 | 
| Total cholesterol/HDL-cholesterol ratio (Safety part) |  | Baseline, Weeks 13 and 53 | 
| Plasma concentration of fasting glucose (Safety part) |  | Baseline, Weeks 13 and 53 | 
| Serum concentration of insulin (Safety part) |  | Baseline, Weeks 13 and 53 | 
| Glycated hemoglobin (Safety part) |  | Baseline, Weeks 13 and 53 | 
| Homeostasis model assessment-estimated insulin resistance (HOMA-IR) (Safety part) |  | Baseline, Weeks 13 and 53 | 
| Health-related quality of life assessment using the Menopause-specific Quality of Life (MENQOL) questionnaire (Safety part) | The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Vasomotor domain score is mean of = Q1,Q2, Q3, with 1 being not at all bothered and 8 being extremely bothered. | Baseline, Weeks 12 and 52 | 
| Total score in treatment satisfaction using the Clinical Global Impression (CGI) questionnaire (Safety part) | The CGI score is a seven point scale in which subjects were asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse. Results for the top two responses - Very Much Improved and Much Improved, and No Change or Worsening (Minimally worse, Much worse, Very much worse) - were combined for each estetrol treatment groups compare to placebo. | Weeks 4, 12 and 52 | 
| Mean endometrial thickness (Safety part) | Endometrial thickness will be assessed by transvaginal ultrasound (TVUS). | Screening, Weeks 13, 29, 41, 53, and Follow-up (Week 55/56) | 
| Endometrial biopsy histology at Screening and Week 53 (Safety part) |  | Screening and Week 53 | 
| Number of women with vaginal bleeding and/or spotting during each 28-day cycle of treatment with E4 (Safety part) | Vaginal bleeding will be daily recorded by the participant in the diary. Absence or occurrence of vaginal bleeding/ spotting will be assessed using the scale below: 0 = Absence of vaginal bleeding or spotting; 1 = Spotting: evidence of minimal blood loss requiring none or at most one pad, tampon or panty liner per day; 2 = Bleeding: evidence of blood loss requiring more than one pad, tampon or panty liner per day. | From Baseline up to Follow-up (Week 55/56) | 
| Number of women with amenorrhea (absence of any bleeding or spotting) during each 28-day cycle of treatment with E4 (Safety part) | Vaginal bleeding will be daily recorded by the participant in the diary. Absence or occurrence of vaginal bleeding/ spotting will be assessed using the scale below: 0 = Absence of vaginal bleeding or spotting; 1 = Spotting: evidence of minimal blood loss requiring none or at most one pad, tampon or panty liner per day; 2 = Bleeding: evidence of blood loss requiring more than one pad, tampon or panty liner per day. | From Baseline up to Follow-up (Week 55/56) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
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Estetrol, Hot Flushes, Vasomotor symptoms