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

Vasomotor Symptoms Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04209543
• Other study ID #: MIT-Do001-C301
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: December 30, 2019
• Est. completion date: February 2024

Study information

• Verified date: December 2023
• Source: Estetra
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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)

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1570
• Est. completion date: February 2024
• Est. primary completion date: February 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 40 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Menopausal Symptoms
• Vasomotor Symptoms

Intervention

Drug:
• Estetrol oral tablet
Estetrol oral tablet will be administered orally once daily
• Placebo oral tablet
Placebo oral tablet will be administered orally once daily
• Progesterone oral tablet
Progesterone oral tablet will be administered orally once daily

Locations

Country	Name	City	State
Argentina	IDIM - Instituto de Investigaciones Metabolicas	Buenos Aires
Argentina	Centro Medico Dra Laura Maffei Investigacion Clinica Aplicada	Caba
Argentina	Fundacion Respirar (Centro Medico Dra. De Salvo) - Instituto Argentino de Investigaciones Clinicas (IAIC) S.R.L	Ciudad Autonoma de Buenos Aires
Argentina	Glenny Corp. S. A. / Bioclinica Argentina	Ciudad Autonoma de Buenos Aires
Argentina	Mautalen Salud e Investigacion	Ciudad Autonoma de Buenos Aires
Argentina	Centro de Investigacion Medico Lanus-CIMEL	Lanús
Argentina	Centro De Investigaciones Medicas Mar Del Plata	Mar Del Plata
Argentina	Instituto de Investigaciones Clinicas Mar del Plata	Mar Del Plata
Argentina	Instituto Medico de la Fundacion Estudios Clinicos	Rosario
Brazil	Centro De Medicina Reprodutiva Ltda - Clinica Origen	Belo Horizonte
Brazil	Faculdade de Medicina de Botucatu - UNESP	Botucatu
Brazil	Centro De Pesquisa Clinica Do Brasil	Brasília
Brazil	IPCC-Instituto de Pesquisa Clinica de Campinas	Campinas
Brazil	University of Campinas Medical School	Campinas
Brazil	Centro de Oncologia de Santa Catarina Ltda / Supera Oncologia	Chapeco
Brazil	Instituto Tropical de Medicina Reprodutiva - Clinica INTRO	Cuiabá
Brazil	CEPEME / CERHFAC Centro De Estudos E Pesquisas Em Reproducao Humana E Fertilizacao Assistida De Curitiba Ltda	Curitiba
Brazil	Federal University Of Ceara	Fortaleza
Brazil	Universidade Federal Do Rio Grande Do Norte/ Maternidade Escola Januario Cicco	Natal
Brazil	Hospital Sao Vicente de Paulo, Associacao Hospitalar Beneficente Sao Vicente de Paulo	Passo Fundo
Brazil	Hospital de Clinicas de Porto Alegre (HCPA)	Porto Alegre
Brazil	Hospital Sao Lucas da PUC	Porto Alegre
Brazil	Nucleo de Pesquisa Clinica do Rio Grande do Sul Ltda	Porto Alegre
Brazil	Unidade de Pesquisa Clínica - Centro de Medicina Reprodutiva	Porto Alegre
Brazil	lnstituto Brasil De Pesquisa Clinica S.A (IBPCLIN)	Rio De Janeiro
Brazil	CEMEC - Faculdade de Medicina do ABC	São Bernardo Do Campo
Brazil	CPQuali Pesquisa Clinica LTDA	Sao Paulo
Brazil	CEPIC - Centro Paulista de Investigacao Clinica e Servicos Medicos Ltda	São Paulo
Brazil	College - Centro De Pesquisa Clinica E Servicos Medicos Ltda College - Centro De Pesquisa Clinica (Baby Center Medicina Reprodutiva)	São Paulo
Brazil	CPClin- Centro de Pesquisas Clinicas Ltda./Clinica Dr. Freddy Goldberg Eliaschewitz	São Paulo
Brazil	Hospital Perola Byington/ Centro de Referencia da Saude da Mulher	São Paulo
Brazil	Universidade Federal De Sao Paulo (Unifesp) - Hospital Sao Paulo (Hsp)	São Paulo
Brazil	CEDOES - Centro de Diagnostico e Pesquisa da Osteoporose do Espirito Santo	Vitória
Brazil	Santa Casa De Votuporanga-Philanthropic hospital	Votuporanga
Canada	Aggarwal and Associates Limited	Brampton
Canada	Clinique Rsf Inc.	Quebec
Canada	Alpha Recherche Clinique	Québec
Canada	Estetra Study Site	Québec
Canada	Estetra Study Site	Québec
Canada	Alpha Recherche Clinique	Quebec City
Canada	DIEX Research Quebec	Quebec City
Canada	Estetra Study Site	Sarnia
Canada	Diex Research Sherbrooke Inc.	Sherbrooke
Canada	Diex Recherche	Victoriaville
Canada	Fadia El Boreky Medicine Professional Corporation	Waterloo
Czechia	Dr. Vladimir Dvorak MD, Office Of	Brno
Czechia	Gynekologie Meda Brno	Brno
Czechia	Dr. Jiri Tiser MD, Office of	Ceske Budejovice
Czechia	GYN-Mika s.r.o.	Ceské Budejovice
Czechia	MUDr. Petr Sak	Ceské Budejovice
Czechia	Gynekologie Cheb s.r.o.	Cheb
Czechia	MUDr. Martin Stepan s.r.o.	Hradec Králové
Czechia	Gynekologie Jihlava	Jihlava
Czechia	MUDr. Jan Kestranek - gynekologicka ambulance	Nachod
Czechia	Estetra Study Site	Olomouc
Czechia	G-CENTRUM Olomouc, s.r.o.	Olomouc
Czechia	NEUMED gynekologicka ambulance s.r.o.	Olomouc
Czechia	Dr. Karel Buchta MD, Office of	Ostrava
Czechia	Dr. Martina Maresova Rosenbergova MD, Office of	Plzen
Czechia	Gynekologicka ambulance Gyncare MUDr. Michael Svec s.r.o.	Plzen
Czechia	Mediva s.r.o	Praha 5
Czechia	Gynekologicko-porodnicka klinika	Praha 8
Czechia	Dr. Lubomir Mikulasek, MD office Of	Praha 9
Czechia	Vestra Clinics	Rychnov nad Kneznou
Czechia	Dr. Tereza Smrhova-Kovacs MD, Office of	Tábor
Czechia	Dr. Ivana Salamonova MD, Office of	Vysoke
Hungary	Szent Anna Privat Surgery-Szent Anna Maganrendelo	Debrecen
Hungary	Pecsi Tudomanyegyetem (PTE) Altalanos Orvostudomanyi Kar (AOK) - Klinikai Kozpont Szuleszeti es Nogyogyaszati Klinika	Pécs
Hungary	Univ. of Szeged Faculty of General Medicine Albert Szent-Gyaergyi	Szeged
Hungary	Csongrad Megyei Dr. Bugyi Istvan Korhaz	Szentes
Italy	Ginecologia e Fisiopatologia della Riproduzione Umana,UO Ostetricia e Ginecologia,Policlinico S.Orsola-Malpighi	Bologna
Italy	Ospedale Pugliese	Calabria
Italy	Universita degli Studi di Firenze - Azienda Ospedaliero Universitaria Careggi, DAI Materno Infantile, SOD Ginecologia e Ostetricia	Firenze
Italy	Azienda Ospedaliero - Universitaria Policlinico di Modena	Modena
Italy	Universita degli Studi di Perugia - Policlinico Monteluce - Centro di Medicina Perinatale e della Riproduzione	Perugia
Italy	Azienda Ospedaliero Universitaria Pisana	Pisa
Italy	Policlinico Univ. Agostino Gemelli	Roma
Italy	Universita degli Studi di Roma La Sapienza - Umberto I Policlinico di Roma	Roma
Lithuania	Saules Family Medicine Centre	Kaunas
Lithuania	UAB VAKK - Dr. Kildos Klinika	Kaunas
Lithuania	Klaipedos Miesto Poliklinika	Klaipeda
Lithuania	JSC Kardiolita	Vilnius
Lithuania	JSC Maxmeda	Vilnius
Lithuania	Public Institution Centro Poliklinika	Vilnius
Lithuania	UAB Seimos gydytojas	Vilnius
Lithuania	Vilnius University Hospital Santaros klinikos	Vilnius
Poland	Centrum Ginekologii Endokrynologii i Medycyny Rozrodu Artemida	Bialystok
Poland	Prywatna Klinika Polozniczo - Ginekologiczna Sp. Z O.O.	Bialystok
Poland	Osrodek Badan Klinicznych IN-VIVO	Bydgoszcz
Poland	Przychodnia Srodmiescie Sp. z o.o.	Bydgoszcz
Poland	Mital Site Badania Kliniczne	Elblag
Poland	Copernicus Podmiot Leczniczy - Szpital sw. Wojciecha	Gdansk
Poland	Centrum Medyczne Angelius Provita	Katowice
Poland	Centrum Medyczne Mikolowska Dr Adam Sipinski	Katowice
Poland	Clinical Medical Research sp. z o.o.	Katowice
Poland	Gyncentrum Sp. z o.o.	Katowice
Poland	NZOZ Sanas	Katowice
Poland	NZOZ Vita Longa Sp. z o.o.	Katowice
Poland	Pro Familia Altera Sp. z o.o.	Katowice
Poland	Grazyna Bogutyn Medico Praktyka Lekarska	Kraków
Poland	Pratia MCM Krakow	Kraków
Poland	NZOZ Medican	Lodz
Poland	Salve Medica-Przychodnia	Lódz
Poland	Centrum Medyczne Chodzki	Lublin
Poland	KO-MED Centra Kliniczne Sp. z o.o., Osrodek Badan Klinicznych w Lublinie II	Lublin
Poland	Niepubliczny Zak¿ad Opieki Zdrowotnej PROFI-MED	Lublin
Poland	ETYKA Osrodek Badan Klinicznych	Olsztyn
Poland	Centrum Innowacyjnych Terapii Sp. z o.o.	Piaseczno
Poland	IRMED Osrodek Badan Klinicznych	Piotrków Trybunalski
Poland	Clinical Research Center Spolka z ograniczona odpowiedzialnoscia Medic-R Spolka Komandytowa	Poznan
Poland	Estetra Study Site	Skorzewo
Poland	Twoja Przychodnia - Szczecinskie Centrum Medyczne	Szczecin
Poland	Nzoz Zieniewicz Medical	Warsaw
Poland	Centrum Badawcze Wspolczesnej Terapii Prywatny Gabinet Lekarski Dr Anna Bochenek-Mularczyk	Warszawa
Poland	ETG Warszawa	Warszawa
Poland	Medical Concierge Centrum Medyczne	Warszawa
Poland	Marek Elias Gabinety Ginekologiczne	Wroclaw
Poland	ETG Zamosc	Zamosc
Romania	Centrul Medical de Diagnostic si Tratament Ambulatoriu Neomed SRL	Brasov
Romania	Centrul Medical Unirea Policlinica Brasov	Brasov
Romania	Spitalul Clinic Nicolae Malaxa	Bucharest
Romania	Centrul Medical Euromed	Bucuresti
Romania	Centrul Medical Unirea - Spitalul Baneasa	Bucuresti
Romania	Sana Monitoring	Bucuresti
Romania	SC Centrul Medical Unirea SRL	Bucuresti
Romania	SC Quantum Medical Center SRL	Bucuresti
Romania	Spitalul Municipal Caracal	Caracal
Romania	Centrul Medical Unirea	Constanta
Romania	Vitaplus Medclin SRL	Craiova
Romania	SC Centrul Medical Unirea SRL	Târgu-Mures
Romania	Spitalul De Urgenta Targu Mures-Emergency University County Hospital	Târgu-Mures
Russian Federation	Scientific Center for Family Health Problems and Human Reproduction	Irkutsk
Russian Federation	Krasnoyarsk State Medical University named after Prof. V.F. VoinoYasenetsky	Krasnoyarsk
Russian Federation	LLC Olla-Med	Moscow
Russian Federation	Scientific Centre Of Obsterics, Gynecology And Perinatology n.a.academican V.I.Kulakov of Federal Agency of High Tech Medical Care	Moscow
Russian Federation	JCS Avicenna	Novosibirsk
Russian Federation	Clinical diagnostic center Zdorovye	Rostov-on-Don
Russian Federation	Astarta Clinic	Saint Petersburg
Russian Federation	Saint-Petersburg State Healthcare Institution Maternity hospital	Saint Petersburg
Russian Federation	The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott - Center Menopause and Women's Health	Saint Petersburg
Russian Federation	Woman's consulting center #22	Saint Petersburg
Russian Federation	Closed Joint Stock Company Medical Company Idk	Samara
Slovakia	MCM GYNPED, s.r.o.	Dubnica nad Váhom
Slovakia	BrenCare, s. r. o.	Poprad
Spain	Diatros S.L.P	Gavà
Spain	Hospital Clinico San Carlos	Madrid
Spain	Instituto Palacios, Salud y Medicina de la Mujer	Madrid
Spain	Hospital Universitario Virgen del Rocio, Hospital de la Mujer	Sevilla
United Kingdom	Accellacare - (MeDiNova Limited) - Northamptonshire	Corby
United Kingdom	Accellacare (Previously MeDiNova) Warwickshire Quality Research Site	Coventry
United Kingdom	CPS Research	Glasgow
United Kingdom	Egin Research Ltd	High Wycombe
United Kingdom	Queen Charlotte's and Chelsea Hospital - Imperial College Healthcare NHS Trust	London
United Kingdom	Accellacare - (MeDiNova Limited) - North London	Northwood
United Kingdom	Accellacare - South London	Orpington
United Kingdom	Estetra Study Site	Orpington
United Kingdom	Accellacare - (MeDiNova Limited) - East London	Romford
United Kingdom	Accellacare - (MeDiNova Limited) - Yorkshire	Shipley
United Kingdom	Accellacare - (MeDiNova Limited) - West London	Wokingham
United States	Bosque Women's Care	Albuquerque	New Mexico
United States	Estetra Study Site	Altamonte Springs	Florida
United States	Estetra Study Site	Atlanta	Georgia
United States	Northwest Clinical Research Center	Bellevue	Washington
United States	Hassman Research Institute	Berlin	New Jersey
United States	Estetra Study Site	Birmingham	Alabama
United States	Hope Clinical Research, LLC	Canoga Park	California
United States	PMG Research of Charlotte, LLC	Charlotte	North Carolina
United States	Estetra Study Site	Chattanooga	Tennessee
United States	Estetra Study Site	Coconut Creek	Florida
United States	Estetra Study Site	Columbus	Ohio
United States	Cedar Health Research, LLC	Dallas	Texas
United States	Velocity Clinical Research	Denver	Colorado
United States	Estetra Study Site	Durham	North Carolina
United States	Estetra Study Site	Englewood	Ohio
United States	Signature Gyn Services	Fort Worth	Texas
United States	Estetra Study Site	Hialeah	Florida
United States	Biopharma Informatic, Inc. Research Center	Houston	Texas
United States	Estetra Study Site	Houston	Texas
United States	Estetra Study Site	Houston	Texas
United States	Clinical Research Prime	Idaho Falls	Idaho
United States	Cedar Health Research LLC	Irving	Texas
United States	Clinical Neuroscience Solutions, Inc.	Jacksonville	Florida
United States	Altus Research	Lake Worth	Florida
United States	Excel Clinical Research	Las Vegas	Nevada
United States	Jubilee Clinical Research, Inc	Las Vegas	Nevada
United States	Praetorian Pharmaceutical Research	Marrero	Louisiana
United States	Estetra Study Site	Mesa	Arizona
United States	Estetra Study Site	Miami	Florida
United States	Genoma Research Group, Inc.	Miami	Florida
United States	Medical Research Center of Miami II	Miami	Florida
United States	Miami Clinical Research	Miami	Florida
United States	San Marcus Research Clinic, Inc.	Miami Lakes	Florida
United States	IMA Clinical Research	Morgantown	West Virginia
United States	Infinite Clinical Trials	Morrow	Georgia
United States	Magnolia Ob/Gyn Research Center	Myrtle Beach	South Carolina
United States	Estetra Study Site	New Port Richey	Florida
United States	Estetra Study Site	Norfolk	Virginia
United States	Meridian Clinical Research	Norfolk	Nebraska
United States	Estetra Study Site	North Miami	Florida
United States	Estetra Study Site	Ocoee	Florida
United States	Clinical Neurosciecne Solutions, Inc. dba CNS Healthcare	Orlando	Florida
United States	Estetra Study Site	Ormond Beach	Florida
United States	Estetra Study Site	Palm Harbor	Florida
United States	Estetra Study Site	Pembroke Pines	Florida
United States	Estetra Study Site	Philadelphia	Pennsylvania
United States	Estetra Study Site	Phoenix	Arizona
United States	Precision Trials AZ, LLC	Phoenix	Arizona
United States	Estetra Study Site	Pinellas Park	Florida
United States	Estetra Study Site	Plano	Texas
United States	Estetra Study Site	Pleasant Grove	Utah
United States	Estetra Study Site	Pomona	California
United States	Estetra Study Site	Port Saint Lucie	Florida
United States	Clinical Trials Research	Sacramento	California
United States	Estetra Study Site	Sacramento	California
United States	Estetra Study Site	San Antonio	Texas
United States	Estetra Study Site	San Antonio	Texas
United States	Estetra Study Site	San Antonio	Texas
United States	Physician Care Clinical Research, LLC	Sarasota	Florida
United States	Fellows Research Alliance, Inc.	Savannah	Georgia
United States	Estetra Study Site	Tampa	Florida
United States	Estetra Study Site	Thousand Oaks	California
United States	Noble Clinical Research	Tucson	Arizona
United States	Tidewater Clinical Research Inc	Virginia Beach	Virginia
United States	Estetra Study Site	West Covina	California

Sponsors (2)

Lead Sponsor	Collaborator
Estetra	ICON Clinical Research

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Canada,  Czechia,  Hungary,  Italy,  Lithuania,  Poland,  Romania,  Russian Federation,  Slovakia,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 4 (Efficacy Study 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
Primary	Mean change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 12 (Efficacy Study 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
Primary	Mean change in severity of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 4 (Efficacy Study 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 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
Primary	Mean change in severity of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 12 (Efficacy Study 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 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
Primary	Incidence of endometrial hyperplasia with up to 12 months of treatment based on endometrial biopsies (Endometrial and General Safety Study Part)	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	Mean change from Baseline to Week 1 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part)	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
Secondary	Mean change from Baseline to Week 2 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part)	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
Secondary	Mean change from Baseline to Week 3 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) ((Efficacy Study Part)	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
Secondary	Mean change from Baseline to Week 4 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (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; 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
Secondary	Mean change from Baseline to Week 5 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part)	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
Secondary	Mean change from Baseline to Week 6 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part)	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
Secondary	Mean change from Baseline to Week 7 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part)	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
Secondary	Mean change from Baseline to Week 8 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part)	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
Secondary	Mean change from Baseline to Week 9 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part)	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
Secondary	Mean change from Baseline to Week 10 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part)	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
Secondary	Mean change from Baseline to Week 11 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part)	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
Secondary	Mean change from Baseline to Week 12 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study 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; 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
Secondary	Mean change from Baseline to Week 1 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study 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 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
Secondary	Mean change from Baseline to Week 2 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study 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 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
Secondary	Mean change from Baseline to Week 3 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study 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 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
Secondary	Mean change from Baseline to Week 4 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study 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 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
Secondary	Mean change from Baseline to Week 5 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study 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 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
Secondary	Mean change from Baseline to Week 6 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study 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 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
Secondary	Mean change from Baseline to Week 7 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study 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 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
Secondary	Mean change from Baseline to Week 8 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study 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 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
Secondary	Mean change from Baseline to Week 9 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study 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 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
Secondary	Mean change from Baseline to Week 10 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study 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 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
Secondary	Mean change from Baseline to Week 11 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study 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 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
Secondary	Mean change from Baseline to Week 12 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study 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 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
Secondary	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)	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 X*7 (Week X).	Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12
Secondary	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)	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 X*7 (Week X).	Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12
Secondary	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)	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 X*7 (Week X).	Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12
Secondary	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)	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 X*7 (Week X).	Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12
Secondary	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)	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
Secondary	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)	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
Secondary	Change from Baseline to Week 12 in vulvovaginal atrophy (VVA) symptoms (Efficacy Study Part)	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
Secondary	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)	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
Secondary	Change from Baseline to Week 12 in plasma concentration of triglycerides (Efficacy Study Part)		Baseline and Week 12
Secondary	Change from Baseline to Week 12 in plasma concentration of low-density lipoprotein (LDL)-cholesterol (Efficacy Study Part)		Baseline and Week 12
Secondary	Change from Baseline to Week 12 in plasma concentration of total cholesterol (Efficacy Study Part)		Baseline and Week 12
Secondary	Change from Baseline to Week 12 in the total cholesterol/high density cholesterol (HDL) cholesterol ratio (Efficacy Study Part)		Baseline and Week 12
Secondary	Change from Baseline to Week 12 in the HDL-cholesterol ratio (Efficacy Study Part)		Baseline and Week 12
Secondary	Change from Baseline to Week 12 in plasma concentration of lipoprotein (a) (Efficacy Study Part)		Baseline and Week 12
Secondary	Change from Baseline to Week 12 in fasting glycaemia (Efficacy Study part)		Baseline and Week 12
Secondary	Change from Baseline to Week 12 in plasma concentration of insulin (Efficacy Study Part)		Baseline and Week 12
Secondary	Change from Baseline to Week 12 in plasma concentration of glycated hemoglobin (Efficacy Study Part)		Baseline and Week 12
Secondary	Change from Baseline to Week 12 in Homeostasis model-assessment-estimated insulin resistance (HOMA-IR) (Efficacy Study Part)		Baseline and Week 12
Secondary	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)	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
Secondary	Total score in treatment satisfaction using the Clinical Global Impression (CGI) questionnaire (Efficacy Study Part)	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
Secondary	Number of participants with treatment-emergent adverse events (TEAEs) (Efficacy Study Part)	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)
Secondary	Number of participants with changes in physical and gynecological examination results (Efficacy Study 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 13
Secondary	Number of participants with changes in vital sign results (Efficacy Study Part)	Vital signs will include height, body weight, body mass index, sitting systolic and diastolic blood pressures, and heart rate.	From screening to Week 13
Secondary	Number of participants with changes in electrocardiogram (ECG) results (Efficacy Study 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 13
Secondary	Number of participants with changes in breast examination results (Efficacy Study Part)		Screening and Week 13
Secondary	Number of participants with changes in routine clinical laboratory test results (Efficacy Study Part)	Routine laboratory tests include hematology and chemistry.	Screening, Baseline and Week 13
Secondary	Change from baseline to each measured time point in endometrial thickness (Efficacy Study Part)	Endometrial thickness will be assessed by transvaginal ultrasound (TVUS).; Baseline: data will be recorded at Screening.	Screening, Week 13, Week 16
Secondary	Frequency of subjects in the different endometrial categories according to Blaustein's pathology (Efficacy Study Part)	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
Secondary	Number of participants with vaginal bleeding and/or spotting during each 28-day cycle of treatment with E4 (Efficacy Study Part)	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)
Secondary	Number of days with bleeding and/or spotting during each 28-day cycle of treatment (Efficacy Study Part)	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)
Secondary	Number of participants with amenorrhea (absence of any bleeding or spotting) during each 28-day cycle of treatment with E4 (Efficacy Study Part)	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)
Secondary	Cumulative rates of amenorrhea (Efficacy Study Part)	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)
Secondary	Number of participants with treatment-emergent adverse events (TEAEs) (Endometrial and General Safety Part)	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
Secondary	Number of participants with changes in physical and gynecological examination results (Endometrial and General 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
Secondary	Number of participants with changes in vital sign results (Endometrial and General Safety 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
Secondary	Number of participants with changes in breast examination results (Endometrial and General Safety 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
Secondary	Number of participants with changes in electrocardiogram (ECG) results (Endometrial and General 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
Secondary	Number of participants with changes in mammography results (Endometrial and General Safety Part)		Screening and Week 53
Secondary	Number of participants with changes in routine clinical laboratory test results (Endometrial and General Safety Part)	Routine laboratory tests include hematology and chemistry.	Screening, Baseline and Week 13
Secondary	Number of women with vaginal bleeding and/or spotting during each 28-day cycle of treatment with E4 (Endometrial and General Safety Part)	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
Secondary	Number of days with bleeding and/or spotting during each 28-day cycle of treatment (Endometrial and General Safety Part)	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
Secondary	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)	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
Secondary	Cumulative rates of amenorrhea (Endometrial and General Safety Part)	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
Secondary	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)	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
Secondary	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)	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
Secondary	Change from Baseline to Weeks 12 and 52 in plasma concentration of triglycerides (Endometrial and General Safety Part)		Baseline and Weeks 12 and 52
Secondary	Change from Baseline to Weeks 12 and 52 in plasma concentration of high-density lipoprotein (HDL)-cholesterol (Endometrial and General Safety Part)		Baseline and Weeks 12 and 52
Secondary	Change from Baseline to Weeks 12 and 52 in plasma concentration of low-density lipoprotein (LDL)-cholesterol (Endometrial and General Safety Part)		Baseline and Weeks 12 and 52
Secondary	Change from Baseline to Weeks 12 and 52 in plasma concentration of total cholesterol (Endometrial and General Safety Part)		Baseline and Weeks 12 and 52
Secondary	Change from Baseline to Weeks 12 and 52 in the total cholesterol/high density cholesterol (HDL) cholesterol ratio (Endometrial and General Safety Part)		Baseline and Weeks 12 and 52
Secondary	Change from Baseline to Weeks 12 and 52 in plasma concentration of lipoprotein (a) (Endometrial and General Safety Part)		Baseline and Weeks 12 and 52
Secondary	Change from Baseline to Weeks 12 and 52 in fasting glycaemia (Endometrial and General Safety Part)		Baseline and Weeks 12 and 52
Secondary	Change from Baseline to Weeks 12 and 52 in plasma concentration of insulin (Endometrial and General Safety Part)		Baseline and Weeks 12 and 52
Secondary	Change from Baseline to Weeks 12 and 52 in plasma concentration of glycated hemoglobin (Endometrial and General Safety Part)		Baseline and Weeks 12 and 52
Secondary	Change from Baseline to Weeks 12 and 52 in Homeostasis model-assessment-estimated insulin resistance (HOMA-IR) (Endometrial and General Safety Part)		Baseline and Weeks 12 and 52
Secondary	Change from Baseline to each measured time point in endometrial thickness (Endometrial and General Safety Study Part)	Endometrial thickness will be assessed by transvaginal ultrasound (TVUS).	Screening, Baseline, Weeks 13, 29, and 53
Secondary	Frequency of subjects in the different endometrial categories according to Blaustein's pathology (Endometrial and General Safety Study Part)	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