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

December 8, 2023 updated by: Estetra

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 I)

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)

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Actual)

1570

Phase

Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Name: Estetra

Study Locations

Argentina
- - Buenos Aires, Argentina, 1012
    - IDIM - Instituto de Investigaciones Metabolicas
  - Caba, Argentina, 1425
    - Centro Medico Dra Laura Maffei Investigacion Clinica Aplicada
  - Ciudad Autonoma de Buenos Aires, Argentina, C1128AAF
    - Mautalen Salud e Investigación
  - Ciudad Autonoma de Buenos Aires, Argentina, C1426ABP
    - Fundacion Respirar (Centro Medico Dra. De Salvo) - Instituto Argentino de Investigaciones Clinicas (IAIC) S.R.L
  - Ciudad Autonoma de Buenos Aires, Argentina, C1430CKE
    - Glenny Corp. S. A. / Bioclinica Argentina
  - Lanús, Argentina, B1824KAJ
    - Centro de Investigacion Medico Lanus-CIMEL
  - Mar Del Plata, Argentina, B7600FYK
    - Centro de Investigaciones Médicas Mar del Plata
  - Mar Del Plata, Argentina, B7600FZO
    - Instituto de Investigaciones Clinicas Mar del Plata
  - Rosario, Argentina, 2000
    - Instituto Médico de la Fundación Estudios Clínicos
Brazil
- - Belo Horizonte, Brazil, 30110-051
    - Centro De Medicina Reprodutiva Ltda - Clinica Origen
  - Botucatu, Brazil, 18618-686
    - Faculdade de Medicina de Botucatu - UNESP
  - Brasília, Brazil, 71625-175
    - Centro de Pesquisa Clinica do Brasil
  - Campinas, Brazil, 13060-080
    - IPCC-Instituto de Pesquisa Clinica de Campinas
  - Campinas, Brazil, 13083-888
    - University of Campinas Medical School
  - Chapeco, Brazil, 89801-355
    - Centro de Oncologia de Santa Catarina Ltda / Supera Oncologia
  - Cuiabá, Brazil, 78043-306
    - Instituto Tropical de Medicina Reprodutiva - Clinica INTRO
  - Curitiba, Brazil, 80030-220
    - CEPEME / CERHFAC Centro De Estudos E Pesquisas Em Reproducao Humana E Fertilizacao Assistida De Curitiba Ltda
  - Fortaleza, Brazil, 60430-270
    - Federal University Of Ceara
  - Natal, Brazil, 59012-310
    - Universidade Federal Do Rio Grande Do Norte/ Maternidade Escola Januario Cicco
  - Passo Fundo, Brazil, 99010-080
    - Hospital Sao Vicente de Paulo, Associacao Hospitalar Beneficente Sao Vicente de Paulo
  - Porto Alegre, Brazil, 90035-903
    - Hospital de Clinicas de Porto Alegre (HCPA)
  - Porto Alegre, Brazil, 90430-001
    - Nucleo de Pesquisa Clinica do Rio Grande do Sul Ltda
  - Porto Alegre, Brazil, 90510-040
    - Unidade de Pesquisa Clínica - Centro de Medicina Reprodutiva
  - Porto Alegre, Brazil, 90610-000
    - Hospital São Lucas da PUC
  - Rio De Janeiro, Brazil, 20241-180
    - lnstituto Brasil De Pesquisa Clinica S.A (IBPCLIN)
  - Sao Paulo, Brazil, 01228-000
    - Cpquali Pesquisa Clinica Ltda
  - São Bernardo Do Campo, Brazil, 09715-090
    - CEMEC - Faculdade de Medicina do ABC
  - São Paulo, Brazil, 01228-200
    - CPClin- Centro de Pesquisas Clinicas Ltda./Clinica Dr. Freddy Goldberg Eliaschewitz
  - São Paulo, Brazil, 01317-000
    - Hospital Perola Byington/ Centro de Referencia da Saude da Mulher
  - São Paulo, Brazil, 04039-001
    - Universidade Federal De Sao Paulo (Unifesp) - Hospital Sao Paulo (Hsp)
  - São Paulo, Brazil, 04266-010
    - CEPIC - Centro Paulista de Investigacao Clinica e Servicos Medicos Ltda
  - São Paulo, Brazil, 04534-002
    - College - Centro De Pesquisa Clinica E Servicos Medicos Ltda College - Centro De Pesquisa Clinica (Baby Center Medicina Reprodutiva)
  - Vitória, Brazil, 29055-450
    - CEDOES - Centro de Diagnostico e Pesquisa da Osteoporose do Espirito Santo
  - Votuporanga, Brazil, 15500-003
    - Santa Casa De Votuporanga-Philanthropic hospital
Canada
- - Brampton, Canada, L6T 0G1
    - Aggarwal and Associates Limited
  - Quebec, Canada, G1S 2L6
    - Clinique RSF Inc.
  - Quebec City, Canada, G1N 4V3
    - DIEX Research Quebec
  - Quebec City, Canada, G3K 2P8
    - Alpha Recherche Clinique
  - Québec, Canada, G1W4R4
    - Estetra Study Site
  - Québec, Canada, G2J0C4
    - Alpha Recherche Clinique
  - Québec, Canada, H1M1B1
    - Estetra Study Site
  - Sarnia, Canada, N7T4X3
    - Estetra Study Site
  - Sherbrooke, Canada, J1L 0H8
    - Diex Research Sherbrooke Inc.
  - Victoriaville, Canada, G6P 6P6
    - Diex Recherche
  - Waterloo, Canada, N2J 1C4
    - Fadia El Boreky Medicine Professional Corporation
Czechia
- - Brno, Czechia, 602 00
    - Dr. Vladimir Dvorak MD, Office Of
  - Brno, Czechia, 60200
    - Gynekologie Meda Brno
  - Ceske Budejovice, Czechia, 37001
    - Dr. Jiri Tiser MD, Office of
  - Cheb, Czechia, 350 02
    - GYNEKOLOGIE CHEB s.r.o.
  - Hradec Králové, Czechia, 50002
    - MUDr. Martin Stepan s.r.o.
  - Jihlava, Czechia, 586 01
    - Gynekologie Jihlava
  - Nachod, Czechia, 54701
    - MUDr. Jan Kestranek - gynekologicka ambulance
  - Olomouc, Czechia, 77130
    - Estetra Study Site
  - Olomouc, Czechia, 772 00
    - G-CENTRUM Olomouc, s.r.o.
  - Olomouc, Czechia, 77900
    - NEUMED gynekologicka ambulance s.r.o.
  - Ostrava, Czechia, 702 00
    - Dr. Karel Buchta MD, Office of
  - Plzen, Czechia, 301 00
    - Dr. Martina Maresova Rosenbergova MD, Office of
  - Plzen, Czechia, 30100
    - Gynekologicka ambulance Gyncare MUDr. Michael Svec s.r.o.
  - Praha 5, Czechia, 155 00
    - Mediva s.r.o
  - Praha 8, Czechia, 18081
    - Gynekologicko-porodnicka klinika
  - Praha 9, Czechia, 190 16
    - Dr. Lubomir Mikulasek, MD office Of
  - Rychnov nad Kneznou, Czechia, 51601
    - Vestra Clinics
  - Tábor, Czechia, 39003
    - Dr. Tereza Smrhova-Kovacs MD, Office of
  - Vysoke, Czechia, 566 01
    - Dr. Ivana Salamonova MD, Office of
  - České Budějovice, Czechia, 370 01
    - MUDr. Petr Sak
  - České Budějovice, Czechia, 37001
    - GYN-MIKA s.r.o.
Hungary
- - Debrecen, Hungary, 4024
    - Szent Anna Privat Surgery-Szent Anna Maganrendelo
  - Pécs, Hungary, 7624
    - Pecsi Tudomanyegyetem (PTE) Altalanos Orvostudomanyi Kar (AOK) - Klinikai Kozpont Szuleszeti es Nogyogyaszati Klinika
  - Szeged, Hungary, 6725
    - Univ. of Szeged Faculty of General Medicine Albert Szent-Gyaergyi
  - Szentes, Hungary, 6600
    - Csongrád Megyei Dr. Bugyi István Kórház
Italy
- - Bologna, Italy, 40138
    - Ginecologia e Fisiopatologia della Riproduzione Umana,UO Ostetricia e Ginecologia,Policlinico S.Orsola-Malpighi
  - Calabria, Italy, 88100
    - Ospedale Pugliese
  - Firenze, Italy, 50134
    - Universita degli Studi di Firenze - Azienda Ospedaliero Universitaria Careggi, DAI Materno Infantile, SOD Ginecologia e Ostetricia
  - Modena, Italy, 41124
    - Azienda Ospedaliero - Universitaria Policlinico di Modena
  - Perugia, Italy, 06129
    - Universita degli Studi di Perugia - Policlinico Monteluce - Centro di Medicina Perinatale e della Riproduzione
  - Pisa, Italy, 56126
    - Azienda Ospedaliero Universitaria Pisana
  - Roma, Italy, 00168
    - Policlinico Univ. Agostino Gemelli
  - Roma, Italy, 00161
    - Universita degli Studi di Roma La Sapienza - Umberto I Policlinico di Roma
Lithuania
- - Kaunas, Lithuania, LT-49449
    - Saules Family Medicine Centre
  - Kaunas, Lithuania, LT-50128
    - UAB VAKK - Dr. Kildos Klinika
  - Klaipėda, Lithuania, LT-93200
    - Klaipedos Miesto Poliklinika
  - Vilnius, Lithuania, LT-08661
    - Vilnius University Hospital Santaros Klinikos
  - Vilnius, Lithuania, LT-01117
    - Public Institution Centro Poliklinika
  - Vilnius, Lithuania, LT-01118
    - UAB Seimos gydytojas
  - Vilnius, Lithuania, LT-03225
    - JSC Maxmeda
  - Vilnius, Lithuania, LT-05263
    - JSC Kardiolita
Poland
- - Białystok, Poland, 15-224
    - Prywatna Klinika Polozniczo - Ginekologiczna Sp. Z O.O.
  - Białystok, Poland, 15-464
    - Centrum Ginekologii Endokrynologii i Medycyny Rozrodu Artemida
  - Bydgoszcz, Poland, 85-080
    - Przychodnia Srodmiescie Sp. z o.o.
  - Bydgoszcz, Poland, 85-048
    - Osrodek Badan Klinicznych IN-VIVO
  - Elbląg, Poland, 82-300
    - Mital Site Badania Kliniczne
  - Gdańsk, Poland, 80-462
    - Copernicus Podmiot Leczniczy - Szpital sw. Wojciecha
  - Katowice, Poland, 40-648
    - Pro Familia Altera Sp. Z O.O.
  - Katowice, Poland, 40-851
    - Gyncentrum Sp. z o.o.
  - Katowice, Poland, 40-748
    - NZOZ Vita Longa Sp. z o.o.
  - Katowice, Poland, 40-611
    - Centrum Medyczne Angelius Provita
  - Katowice, Poland, 40-156
    - Clinical Medical Research Sp. z o.o.
  - Katowice, Poland, 40-065
    - Centrum Medyczne Mikolowska Dr Adam Sipinski
  - Katowice, Poland, 40-301
    - NZOZ Sanas
  - Kraków, Poland, 30-510
    - Pratia MCM Krakow
  - Kraków, Poland, 31-315
    - Grazyna Bogutyn Medico Praktyka Lekarska
  - Lodz, Poland, 93-312
    - NZOZ Medican
  - Lublin, Poland, 20-093
    - Centrum Medyczne Chodzki
  - Lublin, Poland, 20-362
    - KO-MED Centra Kliniczne Sp. z o.o., Osrodek Badan Klinicznych w Lublinie II
  - Lublin, Poland, 20-880
    - Niepubliczny Zak¿ad Opieki Zdrowotnej PROFI-MED
  - Olsztyn, Poland, 10-117
    - Etyka Osrodek Badan Klinicznych
  - Piaseczno, Poland, 05-500
    - Centrum Innowacyjnych Terapii Sp. z o.o.
  - Piotrków Trybunalski, Poland, 97300
    - IRMED Osrodek Badan Klinicznych
  - Poznań, Poland, 60-848
    - Clinical Research Center Spolka z ograniczona odpowiedzialnoscia MEDIC-R Spolka Komandytowa
  - Skorzewo, Poland, 60-185
    - Estetra Study Site
  - Szczecin, Poland, 71-434
    - Twoja Przychodnia - Szczecinskie Centrum Medyczne
  - Warsaw, Poland, 02-201
    - Nzoz Zieniewicz Medical
  - Warszawa, Poland, 02-798
    - Medical Concierge Centrum Medyczne
  - Warszawa, Poland, 02-793
    - Etg Warszawa
  - Warszawa, Poland, 02-679
    - Centrum Badawcze Wspolczesnej Terapii Prywatny Gabinet Lekarski Dr Anna Bochenek-Mularczyk
  - Wroclaw, Poland, 50-547
    - Marek Elias Gabinety Ginekologiczne
  - Zamość, Poland, 22-400
    - ETG Zamość
  - Łódź, Poland, 91-211
    - Salve Medica-Przychodnia
Romania
- - Braşov, Romania, 500283
    - Centrul Medical de Diagnostic si Tratament Ambulatoriu Neomed SRL
  - Braşov, Romania, 500091
    - Centrul Medical Unirea Policlinica Brasov
  - Bucharest, Romania, 020762
    - Spitalul Clinic Nicolae Malaxa
  - Bucuresti, Romania, 011858
    - SC Centrul Medical Unirea SRL
  - Bucuresti, Romania, 012071
    - SC Quantum Medical Center SRL
  - Bucuresti, Romania, 020762
    - Centrul Medical Euromed
  - Bucuresti, Romania, 11025
    - Sana Monitoring
  - Bucuresti, Romania, 13766
    - Centrul Medical Unirea - Spitalul Baneasa
  - Caracal, Romania, 235200
    - Spitalul Municipal Caracal
  - Constanta, Romania, 900001
    - Centrul Medical Unirea
  - Craiova, Romania, 200541
    - Vitaplus Medclin SRL
  - Târgu-Mureş, Romania, 540136
    - Spitalul De Urgenta Targu Mures-Emergency University County Hospital
  - Târgu-Mureş, Romania, 540139
    - SC Centrul Medical Unirea SRL
Russian Federation
- - Irkutsk, Russian Federation, 664003
    - Scientific Center for Family Health Problems and Human Reproduction
  - Krasnoyarsk, Russian Federation, 660022
    - Krasnoyarsk State Medical University named after Prof. V.F. VoinoYasenetsky
  - Moscow, Russian Federation, 105554
    - LLC Olla-Med
  - Moscow, Russian Federation, 117997
    - Scientific Centre Of Obsterics, Gynecology And Perinatology n.a.academican V.I.Kulakov of Federal Agency of High Tech Medical Care
  - Novosibirsk, Russian Federation, 630099
    - JCS Avicenna
  - Rostov-on-Don, Russian Federation, 344011
    - Clinical diagnostic center Zdorovye
  - Saint Petersburg, Russian Federation, 192174
    - Saint-Petersburg State Healthcare Institution Maternity hospital
  - Saint Petersburg, Russian Federation, 199034
    - The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott - Center Menopause and Women's Health
  - Saint Petersburg, Russian Federation, 199226
    - Astarta Clinic
  - Saint Petersburg, Russian Federation
    - Woman's consulting center #22
  - Samara, Russian Federation, 443067
    - Closed Joint Stock Company Medical Company Idk
Slovakia
- - Dubnica nad Váhom, Slovakia, 018 41
    - MCM GYNPED, s.r.o.
  - Poprad, Slovakia, 058 01
    - BrenCare, s. r. o.
Spain
- - Gavà, Spain, 08850
    - Diatros S.L.P
  - Madrid, Spain, 28040
    - Hospital Clinico San Carlos
  - Madrid, Spain, 28009
    - Instituto Palacios, Salud y Medicina de la Mujer
  - Sevilla, Spain, 41013
    - Hospital Universitario Virgen del Rocio, Hospital de la Mujer
United Kingdom
- - Corby, United Kingdom, NN18 9EZ
    - Accellacare - (MeDiNova Limited) - Northamptonshire
  - Coventry, United Kingdom, CV3 4FJ
    - Accellacare (Previously MeDiNova) Warwickshire Quality Research Site
  - Glasgow, United Kingdom, G20 0XA
    - CPS Research
  - High Wycombe, United Kingdom, HP11 2QW
    - Egin Research Ltd
  - London, United Kingdom, W12 0NN
    - Queen Charlotte's and Chelsea Hospital - Imperial College Healthcare NHS Trust
  - Northwood, United Kingdom, HA6 2RN
    - Accellacare - (MeDiNova Limited) - North London
  - Orpington, United Kingdom, BR5 3QG
    - Accellacare - South London
  - Orpington, United Kingdom, BR5 3QG
    - Estetra Study Site
  - Romford, United Kingdom, RM1 3PJ
    - Accellacare - (MeDiNova Limited) - East London
  - Shipley, United Kingdom, BD18 3SA
    - Accellacare - (MeDiNova Limited) - Yorkshire
  - Wokingham, United Kingdom, RG40 1XS
    - Accellacare - (MeDiNova Limited) - West London
United States
- Alabama
  - Birmingham, Alabama, United States, 35218
    - Estetra Study Site
- Arizona
  - Mesa, Arizona, United States, 85206
    - Estetra Study Site
  - Phoenix, Arizona, United States, 85032
    - Precision Trials AZ, LLC
  - Phoenix, Arizona, United States, 85018
    - Estetra Study Site
  - Tucson, Arizona, United States, 85704
    - Noble Clinical Research
- California
  - Canoga Park, California, United States, 91303
    - Hope Clinical Research, LLC
  - Pomona, California, United States, 91767
    - Estetra Study Site
  - Sacramento, California, United States, 95821
    - Clinical Trials Research
  - Sacramento, California, United States, 95821
    - Estetra Study Site
  - Thousand Oaks, California, United States, 91360
    - Estetra Study Site
  - West Covina, California, United States, 91790
    - Estetra Study Site
- Colorado
  - Denver, Colorado, United States, 80209
    - Velocity Clinical Research
- Florida
  - Altamonte Springs, Florida, United States, 32701
    - Estetra Study Site
  - Coconut Creek, Florida, United States, 33073
    - Estetra Study Site
  - Hialeah, Florida, United States, 33016
    - Estetra Study Site
  - Jacksonville, Florida, United States, 32256
    - Clinical Neuroscience Solutions, Inc.
  - Lake Worth, Florida, United States, 33461
    - Altus Research
  - Miami, Florida, United States, 33155
    - Miami Clinical Research
  - Miami, Florida, United States, 33134
    - Medical Research Center of Miami II
  - Miami, Florida, United States, 33165
    - Genoma Research Group, Inc.
  - Miami, Florida, United States, 33186
    - Estetra Study Site
  - Miami Lakes, Florida, United States, 33014
    - San Marcus Research Clinic, Inc.
  - New Port Richey, Florida, United States, 34653
    - Estetra Study Site
  - North Miami, Florida, United States, 33161
    - Estetra Study Site
  - Ocoee, Florida, United States, 34761
    - Estetra Study Site
  - Orlando, Florida, United States, 32801
    - Clinical Neurosciecne Solutions, Inc. dba CNS Healthcare
  - Ormond Beach, Florida, United States, 32174
    - Estetra Study Site
  - Palm Harbor, Florida, United States, 34684
    - Estetra Study Site
  - Pembroke Pines, Florida, United States, 33027
    - Estetra Study Site
  - Pinellas Park, Florida, United States, 33782
    - Estetra Study Site
  - Port Saint Lucie, Florida, United States, 34952
    - Estetra Study Site
  - Sarasota, Florida, United States, 34239
    - Physician Care Clinical Research, LLC
  - Tampa, Florida, United States, 33609
    - Estetra Study Site
- Georgia
  - Atlanta, Georgia, United States, 30342
    - Estetra Study Site
  - Morrow, Georgia, United States, 30260
    - Infinite Clinical Trials
  - Savannah, Georgia, United States, 31406
    - Fellows Research Alliance, Inc.
- Idaho
  - Idaho Falls, Idaho, United States, 83404
    - Clinical Research Prime
- Louisiana
  - Marrero, Louisiana, United States, 70072
    - Praetorian Pharmaceutical Research
- Nebraska
  - Norfolk, Nebraska, United States, 68701
    - Meridian Clinical Research
- Nevada
  - Las Vegas, Nevada, United States, 89109
    - Excel Clinical Research
  - Las Vegas, Nevada, United States, 89106
    - Jubilee Clinical Research, Inc
- New Jersey
  - Berlin, New Jersey, United States, 08009
    - Hassman Research Institute
- New Mexico
  - Albuquerque, New Mexico, United States, 87109-4640
    - Bosque Women's Care
- North Carolina
  - Charlotte, North Carolina, United States, 28209
    - PMG Research of Charlotte, LLC
  - Durham, North Carolina, United States, 27713
    - Estetra Study Site
- Ohio
  - Columbus, Ohio, United States, 43231
    - Estetra Study Site
  - Englewood, Ohio, United States, 45322
    - Estetra Study Site
- Pennsylvania
  - Philadelphia, Pennsylvania, United States, 19114
    - Estetra Study Site
- South Carolina
  - Myrtle Beach, South Carolina, United States, 29572
    - Magnolia Ob/Gyn Research Center
- Tennessee
  - Chattanooga, Tennessee, United States, 37404
    - Estetra Study Site
- Texas
  - Dallas, Texas, United States, 75251
    - Cedar Health Research, LLC
  - Fort Worth, Texas, United States, 76140
    - Signature Gyn Services
  - Houston, Texas, United States, 77084
    - Biopharma Informatic, Inc. Research Center
  - Houston, Texas, United States, 77054
    - Estetra Study Site
  - Houston, Texas, United States, 77084
    - Estetra Study Site
  - Irving, Texas, United States, 75062
    - Cedar Health Research LLC
  - Plano, Texas, United States, 75093
    - Estetra Study Site
  - San Antonio, Texas, United States, 78258
    - Estetra Study Site
  - San Antonio, Texas, United States, 78229
    - Estetra Study Site
  - San Antonio, Texas, United States, 78233
    - Estetra Study Site
- Utah
  - Pleasant Grove, Utah, United States, 84062
    - Estetra Study Site
- Virginia
  - Norfolk, Virginia, United States, 23507
    - Estetra Study Site
  - Virginia Beach, Virginia, United States, 23456
    - Tidewater Clinical Research Inc
- Washington
  - Bellevue, Washington, United States, 98007
    - Northwest Clinical Research Center
- West Virginia
  - Morgantown, West Virginia, United States, 26505
    - IMA Clinical Research

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

40 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

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;
1. 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;
2. For the Endometrial and General Safety Study part: at least 1 moderate to severe 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 or within 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 stimulating hormone (FSH) >40 milli-International unit (mIU)/mL (value obtained after washout 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/progestin containing 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 after washout 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 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:
1. History or presence of uterine cancer, endometrial hyperplasia, or disordered proliferative 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 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 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:
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 or estrogen/progestin products;
3. 8 weeks before screening start for oral estrogen and/or progestin products and/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 alone injectable drug therapy;
6. 6 months before screening start for estrogen pellet therapy or progestin injectable drug therapy;
Use of androgen/dehydroepiandrosterone (DHEA) containing drugs:
1. 8 weeks before screening start for oral, topical, vaginal or transdermal androgen;
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 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Interventional Model: Parallel Assignment
Masking: Quadruple

Number of Arms

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Estetrol 15 mg -Efficacy Part Estetrol (E4) 15 mg will be administered orally once daily for a minimum of 12 weeks and not longer than 13 weeks	Drug: Estetrol oral tablet Estetrol oral tablet will be administered orally once daily
Experimental: Estetrol 20 mg -Efficacy Part Estetrol (E4) 20 mg will be administered orally once daily for a minimum of 12 weeks and not longer than 13 weeks	Drug: Estetrol oral tablet Estetrol oral tablet will be administered orally once daily
Placebo Comparator: Placebo - Efficacy Part Placebo will be administered orally once daily for a minimum of 12 weeks and not longer than 13 weeks	Drug: Placebo oral tablet Placebo oral tablet will be administered orally once daily
Experimental: Estetrol 20 mg + P4 100 mg - Safety Part Estetrol (E4) 20 mg and Progesterone (P4) 100 mg will be administered once daily for up to 53 weeks	Drug: Estetrol oral tablet Estetrol oral tablet will be administered orally once daily Drug: Progesterone oral tablet Progesterone oral tablet will be administered orally once daily

What is the study measuring?

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 Study Part) Time Frame: Baseline and Week 4	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 Study Part) Time Frame: Baseline and Week 12	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 Study Part) Time Frame: Baseline and Week 4	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 moderate and severe VMS observed at Week 4. Baseline and Week 4 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of 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 Study Part) Time Frame: Baseline and Week 12	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 moderate and severe VMS observed at Week 12. Baseline and Week 12 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 12 - mean severity score at Baseline	Baseline and Week 12
Incidence of endometrial hyperplasia with up to 12 months of treatment based on endometrial biopsies (Endometrial and General Safety Study Part) Time Frame: Screening and Week 53	Endometrial biopsies will be centrally evaluated by three independent expert pathologists from different institutions, blinded to treatment group and to each other's readings. The concurrence of two of the three pathologists will be accepted as the final diagnosis. If there is no agreement among the three pathologists, the most severe pathologic diagnosis, i.e., atypical hyperplasia >complex hyperplasia >simple hyperplasia >benign endometrium, will be used as the final diagnosis.	Screening and Week 53

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean change from Baseline to Week 1 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 1	The weekly frequency of moderate to severe VMS at Baseline and Week 1 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 1. Mean change = mean weekly frequency at Week 1 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 1 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 moderate and severe VMS observed at Week 1. Baseline and Week 1 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 1 - mean severity score at Baseline	Baseline and Week 1
Mean change from Baseline to Week 2 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 2	The weekly frequency of moderate to severe VMS at Baseline and Week 2 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 2. Mean change = mean weekly frequency at Week 2 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 2 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 moderate and severe VMS observed at Week 2. Baseline and Week 2 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 2 - mean severity score at Baseline	Baseline and Week 2
Mean change from Baseline to Week 3 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) ((Efficacy Study Part) Time Frame: Baseline and Week 3	The weekly frequency of moderate to severe VMS at Baseline and Week 3 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 3. Mean change = mean weekly frequency at Week 3 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 3 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 moderate and severe VMS observed at Week 3. Baseline and Week 3 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 3 - mean severity score at Baseline	Baseline and Week 3
Mean change from Baseline to Week 4 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy part) Time Frame: Baseline and Week 4	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 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 moderate and severe VMS observed at Week 4. Baseline and Week 4 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 4 - mean severity score at Baseline	Baseline and Week 4
Mean change from Baseline to Week 5 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 5	The weekly frequency of moderate to severe VMS at Baseline and Week 5 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 5. Mean change = mean weekly frequency at Week 5 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 5 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 moderate and severe VMS observed at Week 5. Baseline and Week 5 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 5 - mean severity score at Baseline	Baseline and Week 5
Mean change from Baseline to Week 6 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 6	The weekly frequency of moderate to severe VMS at Baseline and Week 6 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 6. Mean change = mean weekly frequency at Week 6 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 6 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 moderate and severe VMS observed at Week 6. Baseline and Week 6 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 6 - mean severity score at Baseline	Baseline and Week 6
Mean change from Baseline to Week 7 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 7	The weekly frequency of moderate to severe VMS at Baseline and Week 7 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 7. Mean change = mean weekly frequency at Week 7 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 7 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 moderate and severe VMS observed at Week 7. Baseline and Week 7 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 7 - mean severity score at Baseline	Baseline and Week 7
Mean change from Baseline to Week 8 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 8	The weekly frequency of moderate to severe VMS at Baseline and Week 8 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 8. Mean change = mean weekly frequency at Week 8 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 8 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 moderate and severe VMS observed at Week 8. Baseline and Week 8 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 8 - mean severity score at Baseline	Baseline and Week 8
Mean change from Baseline to Week 9 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 9	The weekly frequency of moderate to severe VMS at Baseline and Week 9 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 9. Mean change = mean weekly frequency at Week 9 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 9 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 moderate and severe VMS observed at Week 9. Baseline and Week 9 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 9 - mean severity score at Baseline	Baseline and Week 9
Mean change from Baseline to Week 10 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 10	The weekly frequency of moderate to severe VMS at Baseline and Week 10 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 10. Mean change = mean weekly frequency at Week 10 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 10 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 moderate and severe VMS observed at Week 10. Baseline and Week 10 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 10 - mean severity score at Baseline	Baseline and Week 10
Mean change from Baseline to Week 11 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 11	The weekly frequency of moderate to severe VMS at Baseline and Week 11 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 11. Mean change = mean weekly frequency at Week 11 - mean weekly frequency at Baseline The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 11 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 moderate and severe VMS observed at Week 11. Baseline and Week 11 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 11 - mean severity score at Baseline	Baseline and Week 11
Mean change from Baseline to Week 12 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 12	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 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 moderate and severe VMS observed at Week 12. Baseline and Week 12 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS). Mean change = mean severity score at Week 12 - mean severity score at Baseline	Baseline and Week 12
Mean change from Baseline to Week 1 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 1	The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 1 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 1. Baseline and Week 1 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 1 - mean severity score at Baseline	Baseline and Week 1
Mean change from Baseline to Week 2 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 2	The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 2 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 2. Baseline and Week 2 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 2 - mean severity score at Baseline	Baseline and Week 2
Mean change from Baseline to Week 3 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 3	The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 3 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 3. Baseline and Week 3 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 3 - mean severity score at Baseline	Baseline and Week 3
Mean change from Baseline to Week 4 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 4	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 mild, 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 and 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 from Baseline to Week 5 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 5	The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 5 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 5. Baseline and Week 5 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 5 - mean severity score at Baseline	Baseline and Week 5
Mean change from Baseline to Week 6 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 6	The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 6 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 6. Baseline and Week 6 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 6 - mean severity score at Baseline	Baseline and Week 6
Mean change from Baseline to Week 7 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 7	The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 7 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 7. Baseline and Week 7 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 7 - mean severity score at Baseline	Baseline and Week 7
Mean change from Baseline to Week 8 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 8	The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 8 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 8. Baseline and Week 8 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 8 - mean severity score at Baseline	Baseline and Week 8
Mean change from Baseline to Week 9 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 9	The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 9 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 9. Baseline and Week 9 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 9 - mean severity score at Baseline	Baseline and Week 9
Mean change from Baseline to Week 10 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 10	The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 10 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 10. Baseline and Week 10 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 10 - mean severity score at Baseline	Baseline and Week 10
Mean change from Baseline to Week 11 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 11	The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at Baseline and Week 11 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 11. Baseline and Week 11 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 11 - mean severity score at Baseline	Baseline and Week 11
Mean change from Baseline to Week 12 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) Time Frame: Baseline and Week 12	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 mild, 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 and 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
Percentage of participants 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 Study Part) Time Frame: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12	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 day [(X-1)7+1] to day X7 (Week X).	Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12
Percentage of participants with 50% reduction from Baseline in the weekly frequency of mild, moderate, and severe vasomotor symptoms (VMS) at Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 (Efficacy Study Part) Time Frame: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12	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 day [(X-1)7+1] to day X7 (Week X).	Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12
Percentage of participants with 75% reduction from Baseline in the weekly frequency of moderate to severe VMS at Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 (Efficacy Study Part) Time Frame: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12	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 day [(X-1)7+1] to day X7 (Week X).	Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12
Percentage of participants 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 Study Part) Time Frame: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12	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 day [(X-1)7+1] to day X7 (Week X).	Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12
Percentage of participants with a clinically important difference (CID) compared to Baseline in the weekly frequency of moderate to severe VMS at Week 4 using the Clinical Global Impression (CGI) questionnaire (Efficacy Study Part) Time Frame: Week 4	The CGI score is a seven point scale in which subjects will be 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.	Week 4
Percentage of participants with a clinically important difference (CID) compared to baseline in the weekly frequency of moderate to severe VMS at Week 12 using the Clinical Global Impression (CGI) questionnaire (Efficacy Study Part) Time Frame: Week 12	The CGI score is a seven point scale in which subjects will be 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.	Week 12
Change from Baseline to Week 12 in vulvovaginal atrophy (VVA) symptoms (Efficacy Study Part) Time Frame: Baseline and Week 12	Genitourinary syndrome of menopause (GSM) will be assessed by the subjects using the vulvovaginal atrophy (VVA) self assessment questionnaire. The following GSM symptoms will be assessed: Vaginal dryness Vaginal and/or vulvar irritation/itching Dysuria Vaginal pain associated with sexual activity Vaginal bleeding associated with sexual activity All GSM symptoms except vaginal bleeding associated with sexual activity will be graded by the participants using the following scale: [0] none, [1] mild, [2] moderate, or [3] severe. Vaginal bleeding associated with sexual activity is documented using 2 categories: [0] absent or [1] present. A negative change from baseline score indicates improvement in symptoms.	Baseline and Week 12
Change from Baseline to Week 12 in the vulvovaginal atrophy (VVA) symptom that is initially identified by the participant as being the most bothersome using the VVA questionnaire at baseline (Efficacy Study Part) Time Frame: Baseline and Week 12	Genitourinary syndrome of menopause (GSM) will be assessed by the subjects using the vulvovaginal atrophy (VVA) self assessment questionnaire. The following GSM symptoms will be assessed: Vaginal dryness Vaginal and/or vulvar irritation/itching Dysuria Vaginal pain associated with sexual activity Vaginal bleeding associated with sexual activity All GSM symptoms except vaginal bleeding associated with sexual activity were graded by the participants using the following scale: [0] none, [1] mild, [2] moderate, or [3] severe. Vaginal bleeding associated with sexual activity was documented using 2 categories: [0] absent or [1] present. A negative change from baseline score indicates improvement in symptoms. At baseline the participant will be asked which of the above mentioned symptoms she identifies as being the most bothersome.	Baseline and Week 12
Change from Baseline to Week 12 in plasma concentration of triglycerides (Efficacy Study Part) Time Frame: Baseline and Week 12		Baseline and Week 12
Change from Baseline to Week 12 in plasma concentration of low-density lipoprotein (LDL)-cholesterol (Efficacy Study Part) Time Frame: Baseline and Week 12		Baseline and Week 12
Change from Baseline to Week 12 in plasma concentration of total cholesterol (Efficacy Study Part) Time Frame: Baseline and Week 12		Baseline and Week 12
Change from Baseline to Week 12 in the total cholesterol/high density cholesterol (HDL) cholesterol ratio (Efficacy Study Part) Time Frame: Baseline and Week 12		Baseline and Week 12
Change from Baseline to Week 12 in the HDL-cholesterol ratio (Efficacy Study Part) Time Frame: Baseline and Week 12		Baseline and Week 12
Change from Baseline to Week 12 in plasma concentration of lipoprotein (a) (Efficacy Study Part) Time Frame: Baseline and Week 12		Baseline and Week 12
Change from Baseline to Week 12 in fasting glycaemia (Efficacy Study part) Time Frame: Baseline and Week 12		Baseline and Week 12
Change from Baseline to Week 12 in plasma concentration of insulin (Efficacy Study Part) Time Frame: Baseline and Week 12		Baseline and Week 12
Change from Baseline to Week 12 in plasma concentration of glycated hemoglobin (Efficacy Study Part) Time Frame: Baseline and Week 12		Baseline and Week 12
Change from Baseline to Week 12 in Homeostasis model-assessment-estimated insulin resistance (HOMA-IR) (Efficacy Study Part) Time Frame: Baseline and Week 12		Baseline and Week 12
Change from baseline to Week 12 in health-related quality of life assessment (HRQoL) using the menopause-specific Quality of Life (MENQOL) questionnaire (Efficacy Study Part) Time Frame: Baseline and Week 12	The MENQOL is self-administered questionnaire which will assess 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 will be 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 and Week 12
Total score in treatment satisfaction using the Clinical Global Impression (CGI) questionnaire (Efficacy Study Part) Time Frame: Weeks 4 and 12	The CGI score is a seven point scale in which subjects will be 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.	Weeks 4 and 12
Number of participants with treatment-emergent adverse events (TEAEs) (Efficacy Study Part) Time Frame: From baseline to Follow-up visit (up to Week 16)	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 16)
Number of participants with changes in physical and gynecological examination results (Efficacy Study Part) Time Frame: Screening and Week 13	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 13
Number of participants with changes in vital sign results (Efficacy Study Part) Time Frame: From screening to Week 13	Vital signs will include height, body weight, body mass index, sitting systolic and diastolic blood pressures, and heart rate.	From screening to Week 13
Number of participants with changes in electrocardiogram (ECG) results (Efficacy Study Part) Time Frame: Screening and Week 13	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 13
Number of participants with changes in breast examination results (Efficacy Study Part) Time Frame: Screening and Week 13		Screening and Week 13
Number of participants with changes in routine clinical laboratory test results (Efficacy Study Part) Time Frame: Screening, Baseline and Week 13	Routine laboratory tests include hematology and chemistry.	Screening, Baseline and Week 13
Change from baseline to each measured time point in endometrial thickness (Efficacy Study Part) Time Frame: Screening, Week 13, Week 16	Endometrial thickness will be assessed by transvaginal ultrasound (TVUS). Baseline: data will be recorded at Screening.	Screening, Week 13, Week 16
Frequency of subjects in the different endometrial categories according to Blaustein's pathology (Efficacy Study Part) Time Frame: Screening and Week 13	Endometrial biopsies will be centrally evaluated by three independent expert pathologists from different institutions, blinded to treatment group and to each other's readings. The concurrence of two of the three pathologists will be accepted as the final diagnosis. If there is no agreement among the three pathologists, the most severe pathologic diagnosis, i.e., atypical hyperplasia >complex hyperplasia >simple hyperplasia >benign endometrium, will be used as the final diagnosis.	Screening and Week 13
Number of participants with vaginal bleeding and/or spotting during each 28-day cycle of treatment with E4 (Efficacy Study Part) Time Frame: From Baseline up to Follow-up (Week 16)	Vaginal bleeding will be daily recorded by the participant on 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 16)
Number of days with bleeding and/or spotting during each 28-day cycle of treatment (Efficacy Study Part) Time Frame: From Baseline up to Follow-up (Week 16)	Vaginal bleeding will be daily recorded by the participant on 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 16)
Number of participants with amenorrhea (absence of any bleeding or spotting) during each 28-day cycle of treatment with E4 (Efficacy Study Part) Time Frame: From Baseline up to Follow-up (Week 16)	Vaginal bleeding will be daily recorded by the participant on 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 16)
Cumulative rates of amenorrhea (Efficacy Study Part) Time Frame: From Baseline up to Follow-up (Week 16)	The rate of amenorrhea is defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time.	From Baseline up to Follow-up (Week 16)
Number of participants with treatment-emergent adverse events (TEAEs) (Endometrial and General Safety Part) Time Frame: From baseline to Week 53	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 Week 53
Number of participants with changes in physical and gynecological examination results (Endometrial and General Safety Part) Time Frame: Screening and Week 53	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 (Endometrial and General Safety Part) Time Frame: From screening to Week 53	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 breast examination results (Endometrial and General Safety Part) Time Frame: From screening to Week 53	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 (Endometrial and General Safety Part) Time Frame: Screening and Week 53	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 (Endometrial and General Safety Part) Time Frame: Screening and Week 53		Screening and Week 53
Number of participants with changes in routine clinical laboratory test results (Endometrial and General Safety Part) Time Frame: Screening, Baseline and Week 13	Routine laboratory tests include hematology and chemistry.	Screening, Baseline and Week 13
Number of women with vaginal bleeding and/or spotting during each 28-day cycle of treatment with E4 (Endometrial and General Safety Part) Time Frame: From Baseline to Week 53	Vaginal bleeding will be daily recorded by the participant on 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 to Week 53
Number of days with bleeding and/or spotting during each 28-day cycle of treatment (Endometrial and General Safety Part) Time Frame: From Baseline to Week 53	Vaginal bleeding will be daily recorded by the participant on 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 to Week 53
Number of participants with amenorrhea (absence of any bleeding or spotting) during each 28-day cycle of treatment with E4 (Endometrial and General Safety Part) Time Frame: From Baseline to Week 53	Vaginal bleeding will be daily recorded by the participant on 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 to Week 53
Cumulative rates of amenorrhea (Endometrial and General Safety Part) Time Frame: From Baseline to Week 53	The rate of amenorrhea is defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time.	From Baseline to Week 53
Change from Baseline to Weeks 12 and 52 in health-related quality of life assessment (HRQoL) using the menopause-specific Quality of Life (MENQOL) questionnaire (Endometrial and General Safety Part) Time Frame: Baseline and Weeks 12 and 52	The MENQOL is self-administered questionnaire which will assess 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 and Weeks 12 and 52
Total score in treatment satisfaction assessed after 4, 12 and 52 weeks of treatment using the Clinical Global Impression (CGI) questionnaire (Endometrial and General Safety Part) Time Frame: Weeks 4, 12, and 52	The CGI score is a seven point scale in which subjects will be 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.	Weeks 4, 12, and 52
Change from Baseline to Weeks 12 and 52 in plasma concentration of triglycerides (Endometrial and General Safety Part) Time Frame: Baseline and Weeks 12 and 52		Baseline and Weeks 12 and 52
Change from Baseline to Weeks 12 and 52 in plasma concentration of high-density lipoprotein (HDL)-cholesterol (Endometrial and General Safety Part) Time Frame: Baseline and Weeks 12 and 52		Baseline and Weeks 12 and 52
Change from Baseline to Weeks 12 and 52 in plasma concentration of low-density lipoprotein (LDL)-cholesterol (Endometrial and General Safety Part) Time Frame: Baseline and Weeks 12 and 52		Baseline and Weeks 12 and 52
Change from Baseline to Weeks 12 and 52 in plasma concentration of total cholesterol (Endometrial and General Safety Part) Time Frame: Baseline and Weeks 12 and 52		Baseline and Weeks 12 and 52
Change from Baseline to Weeks 12 and 52 in the total cholesterol/high density cholesterol (HDL) cholesterol ratio (Endometrial and General Safety Part) Time Frame: Baseline and Weeks 12 and 52		Baseline and Weeks 12 and 52
Change from Baseline to Weeks 12 and 52 in plasma concentration of lipoprotein (a) (Endometrial and General Safety Part) Time Frame: Baseline and Weeks 12 and 52		Baseline and Weeks 12 and 52
Change from Baseline to Weeks 12 and 52 in fasting glycaemia (Endometrial and General Safety Part) Time Frame: Baseline and Weeks 12 and 52		Baseline and Weeks 12 and 52
Change from Baseline to Weeks 12 and 52 in plasma concentration of insulin (Endometrial and General Safety Part) Time Frame: Baseline and Weeks 12 and 52		Baseline and Weeks 12 and 52
Change from Baseline to Weeks 12 and 52 in plasma concentration of glycated hemoglobin (Endometrial and General Safety Part) Time Frame: Baseline and Weeks 12 and 52		Baseline and Weeks 12 and 52
Change from Baseline to Weeks 12 and 52 in Homeostasis model-assessment-estimated insulin resistance (HOMA-IR) (Endometrial and General Safety Part) Time Frame: Baseline and Weeks 12 and 52		Baseline and Weeks 12 and 52
Change from Baseline to each measured time point in endometrial thickness (Endometrial and General Safety Study Part) Time Frame: Screening, Baseline, Weeks 13, 29, and 53	Endometrial thickness will be assessed by transvaginal ultrasound (TVUS).	Screening, Baseline, Weeks 13, 29, and 53
Frequency of subjects in the different endometrial categories according to Blaustein's pathology (Endometrial and General Safety Study Part) Time Frame: Screening and Week 53	Endometrial biopsies will be centrally evaluated by three independent expert pathologists from different institutions, blinded to treatment group and to each other's readings. The concurrence of two of the three pathologists will be accepted as the final diagnosis. If there is no agreement among the three pathologists, the most severe pathologic diagnosis, i.e., atypical hyperplasia >complex hyperplasia >simple hyperplasia >benign endometrium, will be used as the final diagnosis.	Screening and Week 53

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Estetra

Collaborators

ICON Clinical Research

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 30, 2019

Primary Completion (Estimated)

February 1, 2024

Study Completion (Estimated)

February 1, 2024

Study Registration Dates

First Submitted

December 20, 2019

First Submitted That Met QC Criteria

December 20, 2019

First Posted (Actual)

December 24, 2019

Study Record Updates

Last Update Posted (Estimated)

December 11, 2023

Last Update Submitted That Met QC Criteria

December 8, 2023

Last Verified

December 1, 2023

More Information

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Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

MIT-Do001-C301

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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

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 I)

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More Information

Terms related to this study

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Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Studies a U.S. FDA-regulated device product

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