AzTrials
AzTrials

Vasomotor SymptomsPhase 3NCT04209543

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

A Phase 3 study testing Estetrol and Progesterone in people with Vasomotor Symptoms and Menopausal Symptoms, run by Estetra at 224 sites in 14 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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) Read more about this study

Who is it for?
Ages 40 to 65 years, women onlyHealthy volunteers can take part
Conditions the study is for
Vasomotor Symptoms, Menopausal Symptoms
What is being tested?
Estetrol and Progesterone
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
1,570 participants
Where
224 sitesin 14 countries
Study dates
30 Dec 2019to 8 Feb 2024
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 40 to 65 years
  • Women only
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • 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;
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  • For the Efficacy Study part: at least 7 moderate to severe bothersome VMS per day or at least 50 moderate to severe bothersome VMS per week in the last 7 consecutive days during the Screening period;
  • For the 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:
  • at least 12 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) >40 milli-International unit (mIU)/mL (value obtained after washout of estrogen/progestin containing drugs, see exclusion criteria 18 and 20);
  • or at least 6 months of spontaneous amenorrhea with serum FSH >40 mIU/mL and E2 <20 pg/mL (<73.4 pmol/L,value obtained after washout of estrogen/progestin containing drugs, see exclusion criteria 18 and 20);
  • or at least 6 weeks postsurgical bilateral oophorectomy;
  • For hysterectomized subjects:
  • serum FSH >40 mIU/mL and E2 <20 pg/mL (<73.4 pmol/L, values obtained after washout of estrogen/progestin containing drug see exclusion criteria 18 and 20);
  • or at least 6 weeks post-surgical bilateral oophorectomy.
  • Good physical and mental health, in the judgement of the Investigator as based on medical history, physical and gynecological examination and clinical assessments performed prior 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.

Who cannot join

  • 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:
  • History or presence of uterine cancer, endometrial hyperplasia, or disordered proliferative endometrium;
  • Presence of endometrial polyps;
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  • Undiagnosed vaginal bleeding or undiagnosed abnormal uterine bleeding;
  • Endometrial ablation;
  • Any uterine/endometrial abnormality that in the judgment of the investigator contraindicates the use of estrogen and/or progestin therapy. This includes presence or history of adenomyosis or significant myoma;
  • Systolic blood pressure (BP) higher than 130 mmHg, diastolic BP higher than 80 mmHg during screening;
  • History of venous or arterial thromboembolic disease (e.g., superficial or deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, angina pectoris, etc.), or first degree family history of venous thromboembolism (VTE);
  • History of known acquired 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 week before screening start for vaginal non systemic hormonal products (rings, creams, gels);
  • 4 weeks before screening start for vaginal or transdermal estrogen or estrogen/progestin products;
  • 8 weeks before screening start for oral estrogen and/or progestin products and/or selective estrogen receptor modulator therapy;
  • 8 weeks before screening start for intrauterine progestin therapy;
  • 3 months before screening start for progestin implants or estrogen alone injectable drug therapy;
  • 6 months before screening start for estrogen pellet therapy or progestin injectable drug therapy;
  • Use of androgen/dehydroepiandrosterone (DHEA) containing drugs:
  • 8 weeks before screening start for oral, topical, vaginal or transdermal androgen;
  • 6 months before screening start for implantable or injectable androgen therapy;
  • Use of phytoestrogens or black cohosh for 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.

Trial locations and contacts

224 sites in 14 countries.

224 sites in 14 countries

United States65 sites

  • Bosque Women's Care

    Albuquerque, New Mexico, 87109-4640

  • Estetra Study Site

    Altamonte Springs, Florida, 32701

  • Estetra Study Site

    Atlanta, Georgia, 30342

  • Northwest Clinical Research Center

    Bellevue, Washington, 98007

  • Hassman Research Institute

    Berlin, New Jersey, 08009

  • Estetra Study Site

    Birmingham, Alabama, 35218

  • Hope Clinical Research, LLC

    Canoga Park, California, 91303

  • PMG Research of Charlotte, LLC

    Charlotte, North Carolina, 28209

  • Estetra Study Site

    Chattanooga, Tennessee, 37404

  • Estetra Study Site

    Coconut Creek, Florida, 33073

  • Estetra Study Site

    Columbus, Ohio, 43231

  • Cedar Health Research, LLC

    Dallas, Texas, 75251

  • Velocity Clinical Research

    Denver, Colorado, 80209

  • Estetra Study Site

    Durham, North Carolina, 27713

  • Estetra Study Site

    Englewood, Ohio, 45322

  • Signature Gyn Services

    Fort Worth, Texas, 76140

  • Estetra Study Site

    Hialeah, Florida, 33016

  • Estetra Study Site

    Houston, Texas, 77054

  • Biopharma Informatic, Inc. Research Center

    Houston, Texas, 77084

  • Estetra Study Site

    Houston, Texas, 77084

  • Clinical Research Prime

    Idaho Falls, Idaho, 83404

  • Cedar Health Research LLC

    Irving, Texas, 75062

  • Clinical Neuroscience Solutions, Inc.

    Jacksonville, Florida, 32256

  • Altus Research

    Lake Worth, Florida, 33461

  • Jubilee Clinical Research, Inc

    Las Vegas, Nevada, 89106

  • Excel Clinical Research

    Las Vegas, Nevada, 89109

  • Praetorian Pharmaceutical Research

    Marrero, Louisiana, 70072

  • Estetra Study Site

    Mesa, Arizona, 85206

  • Medical Research Center of Miami II

    Miami, Florida, 33134

  • Miami Clinical Research

    Miami, Florida, 33155

  • Genoma Research Group, Inc.

    Miami, Florida, 33165

  • Estetra Study Site

    Miami, Florida, 33186

  • San Marcus Research Clinic, Inc.

    Miami Lakes, Florida, 33014

  • IMA Clinical Research

    Morgantown, West Virginia, 26505

  • Infinite Clinical Trials

    Morrow, Georgia, 30260

  • Magnolia Ob/Gyn Research Center

    Myrtle Beach, South Carolina, 29572

  • Estetra Study Site

    New Port Richey, Florida, 34653

  • Meridian Clinical Research

    Norfolk, Nebraska, 68701

  • Estetra Study Site

    Norfolk, Virginia, 23507

  • Estetra Study Site

    North Miami, Florida, 33161

  • Estetra Study Site

    Ocoee, Florida, 34761

  • Clinical Neurosciecne Solutions, Inc. dba CNS Healthcare

    Orlando, Florida, 32801

  • Estetra Study Site

    Ormond Beach, Florida, 32174

  • Estetra Study Site

    Palm Harbor, Florida, 34684

  • Estetra Study Site

    Pembroke Pines, Florida, 33027

  • Estetra Study Site

    Philadelphia, Pennsylvania, 19114

  • Estetra Study Site

    Phoenix, Arizona, 85018

  • Precision Trials AZ, LLC

    Phoenix, Arizona, 85032

  • Estetra Study Site

    Pinellas Park, Florida, 33782

  • Estetra Study Site

    Plano, Texas, 75093

  • Estetra Study Site

    Pleasant Grove, Utah, 84062

  • Estetra Study Site

    Pomona, California, 91767

  • Estetra Study Site

    Port Saint Lucie, Florida, 34952

  • Clinical Trials Research

    Sacramento, California, 95821

  • Estetra Study Site

    Sacramento, California, 95821

  • Estetra Study Site

    San Antonio, Texas, 78229

  • Estetra Study Site

    San Antonio, Texas, 78233

  • Estetra Study Site

    San Antonio, Texas, 78258

  • Physician Care Clinical Research, LLC

    Sarasota, Florida, 34239

  • Fellows Research Alliance, Inc.

    Savannah, Georgia, 31406

  • Estetra Study Site

    Tampa, Florida, 33609

  • Estetra Study Site

    Thousand Oaks, California, 91360

  • Noble Clinical Research

    Tucson, Arizona, 85704

  • Tidewater Clinical Research Inc

    Virginia Beach, Virginia, 23456

  • Estetra Study Site

    West Covina, California, 91790

Other trials in United States

Poland32 sites

  • Prywatna Klinika Polozniczo - Ginekologiczna Sp. Z O.O.

    Bialystok, 15-224

  • Centrum Ginekologii Endokrynologii i Medycyny Rozrodu Artemida

    Bialystok, 15-464

  • Osrodek Badan Klinicznych IN-VIVO

    Bydgoszcz, 85-048

  • Przychodnia Srodmiescie Sp. z o.o.

    Bydgoszcz, 85-080

  • Mital Site Badania Kliniczne

    Elblag, 82-300

  • Copernicus Podmiot Leczniczy - Szpital sw. Wojciecha

    Gdansk, 80-462

  • Centrum Medyczne Mikolowska Dr Adam Sipinski

    Katowice, 40-065

  • Clinical Medical Research sp. z o.o.

    Katowice, 40-156

  • NZOZ Sanas

    Katowice, 40-301

  • Centrum Medyczne Angelius Provita

    Katowice, 40-611

  • Pro Familia Altera Sp. z o.o.

    Katowice, 40-648

  • NZOZ Vita Longa Sp. z o.o.

    Katowice, 40-748

  • Gyncentrum Sp. z o.o.

    Katowice, 40-851

  • Pratia MCM Krakow

    Krakow, 30-510

  • Grazyna Bogutyn Medico Praktyka Lekarska

    Krakow, 31-315

  • Salve Medica-Przychodnia

    Lodz, 91-211

  • NZOZ Medican

    Lodz, 93-312

  • Centrum Medyczne Chodzki

    Lublin, 20-093

  • KO-MED Centra Kliniczne Sp. z o.o., Osrodek Badan Klinicznych w Lublinie II

    Lublin, 20-362

  • Niepubliczny Zak¿ad Opieki Zdrowotnej PROFI-MED

    Lublin, 20-880

  • ETYKA Osrodek Badan Klinicznych

    Olsztyn, 10-117

  • Centrum Innowacyjnych Terapii Sp. z o.o.

    Piaseczno, 05-500

  • IRMED Osrodek Badan Klinicznych

    Piotrkow Trybunalski, 97300

  • Clinical Research Center Spolka z ograniczona odpowiedzialnoscia Medic-R Spolka Komandytowa

    Poznan, 60-848

  • Estetra Study Site

    Skorzewo, 60-185

  • Twoja Przychodnia - Szczecinskie Centrum Medyczne

    Szczecin, 71-434

  • Nzoz Zieniewicz Medical

    Warsaw, 02-201

  • Centrum Badawcze Wspolczesnej Terapii Prywatny Gabinet Lekarski Dr Anna Bochenek-Mularczyk

    Warsaw, 02-679

  • ETG Warszawa

    Warsaw, 02-793

  • Medical Concierge Centrum Medyczne

    Warsaw, 02-798

  • Marek Elias Gabinety Ginekologiczne

    Wroclaw, 50-547

  • ETG Zamosc

    Zamość, 22-400

Other trials in Poland

Brazil25 sites

  • Centro De Medicina Reprodutiva Ltda - Clinica Origen

    Belo Horizonte, 30110-051

  • Faculdade de Medicina de Botucatu - UNESP

    Botucatu, 18618-686

  • Centro De Pesquisa Clinica Do Brasil

    Brasília, 71625-175

  • IPCC-Instituto de Pesquisa Clinica de Campinas

    Campinas, 13060-080

  • University of Campinas Medical School

    Campinas, 13083-888

  • Centro de Oncologia de Santa Catarina Ltda / Supera Oncologia

    Chapecó, 89801-355

  • Instituto Tropical de Medicina Reprodutiva - Clinica INTRO

    Cuiabá, 78043-306

  • CEPEME / CERHFAC Centro De Estudos E Pesquisas Em Reproducao Humana E Fertilizacao Assistida De Curitiba Ltda

    Curitiba, 80030-220

  • Federal University Of Ceara

    Fortaleza, 60430-270

  • Universidade Federal Do Rio Grande Do Norte/ Maternidade Escola Januario Cicco

    Natal, 59012-310

  • Hospital Sao Vicente de Paulo, Associacao Hospitalar Beneficente Sao Vicente de Paulo

    Passo Fundo, 99010-080

  • Hospital de Clinicas de Porto Alegre (HCPA)

    Porto Alegre, 90035-903

  • Nucleo de Pesquisa Clinica do Rio Grande do Sul Ltda

    Porto Alegre, 90430-001

  • Unidade de Pesquisa Clínica - Centro de Medicina Reprodutiva

    Porto Alegre, 90510-040

  • Hospital Sao Lucas da PUC

    Porto Alegre, 90610-000

  • lnstituto Brasil De Pesquisa Clinica S.A (IBPCLIN)

    Rio de Janeiro, 20241-180

  • CEMEC - Faculdade de Medicina do ABC

    São Bernardo do Campo, 09715-090

  • CPQuali Pesquisa Clinica LTDA

    São Paulo, 01228-000

  • CPClin- Centro de Pesquisas Clinicas Ltda./Clinica Dr. Freddy Goldberg Eliaschewitz

    São Paulo, 01228-200

  • Hospital Perola Byington/ Centro de Referencia da Saude da Mulher

    São Paulo, 01317-000

  • Universidade Federal De Sao Paulo (Unifesp) - Hospital Sao Paulo (Hsp)

    São Paulo, 04039-001

  • CEPIC - Centro Paulista de Investigacao Clinica e Servicos Medicos Ltda

    São Paulo, 04266-010

  • College - Centro De Pesquisa Clinica E Servicos Medicos Ltda College - Centro De Pesquisa Clinica (Baby Center Medicina Reprodutiva)

    São Paulo, 04534-002

  • CEDOES - Centro de Diagnostico e Pesquisa da Osteoporose do Espirito Santo

    Vitória, 29055-450

  • Santa Casa De Votuporanga-Philanthropic hospital

    Votuporanga, 15500-003

Other trials in Brazil

Czechia21 sites

  • Dr. Vladimir Dvorak MD, Office Of

    Brno, 602 00

  • Gynekologie Meda Brno

    Brno, 60200

  • MUDr. Petr Sak

    České Budějovice, 370 01

  • Dr. Jiri Tiser MD, Office of

    České Budějovice, 37001

  • GYN-Mika s.r.o.

    České Budějovice, 37001

  • Gynekologie Cheb s.r.o.

    Cheb, 350 02

  • MUDr. Martin Stepan s.r.o.

    Hradec Králové, 50002

  • Gynekologie Jihlava

    Jihlava, 586 01

  • MUDr. Jan Kestranek - gynekologicka ambulance

    Náchod, 54701

  • Estetra Study Site

    Olomouc, 77130

  • G-CENTRUM Olomouc, s.r.o.

    Olomouc, 772 00

  • NEUMED gynekologicka ambulance s.r.o.

    Olomouc, 77900

  • Dr. Karel Buchta MD, Office of

    Ostrava, 702 00

  • Dr. Martina Maresova Rosenbergova MD, Office of

    Pilsen, 301 00

  • Gynekologicka ambulance Gyncare MUDr. Michael Svec s.r.o.

    Pilsen, 30100

  • Mediva s.r.o

    Prague, 155 00

  • Gynekologicko-porodnicka klinika

    Prague, 18081

  • Dr. Lubomir Mikulasek, MD office Of

    Prague, 190 16

  • Vestra Clinics

    Rychnov nad Kněžnou, 51601

  • Dr. Tereza Smrhova-Kovacs MD, Office of

    Tábor, 39003

  • Dr. Ivana Salamonova MD, Office of

    Vysoké, 566 01

Other trials in Czechia

Romania13 sites

  • Centrul Medical Unirea Policlinica Brasov

    Brasov, 500091

  • Centrul Medical de Diagnostic si Tratament Ambulatoriu Neomed SRL

    Brasov, 500283

  • SC Centrul Medical Unirea SRL

    Bucharest, 011858

  • SC Quantum Medical Center SRL

    Bucharest, 012071

  • Centrul Medical Euromed

    Bucharest, 020762

  • Spitalul Clinic Nicolae Malaxa

    Bucharest, 020762

  • Sana Monitoring

    Bucharest, 11025

  • Centrul Medical Unirea - Spitalul Baneasa

    Bucharest, 13766

  • Spitalul Municipal Caracal

    Caracal, 235200

  • Centrul Medical Unirea

    Constanța, 900001

  • Vitaplus Medclin SRL

    Craiova, 200541

  • Spitalul De Urgenta Targu Mures-Emergency University County Hospital

    Târgu Mureş, 540136

  • SC Centrul Medical Unirea SRL

    Târgu Mureş, 540139

Other trials in Romania

Canada11 sites

  • Aggarwal and Associates Limited

    Brampton, L6T 0G1

  • DIEX Research Quebec

    Québec, G1N 4V3

  • Clinique Rsf Inc.

    Québec, G1S 2L6

  • Estetra Study Site

    Québec, G1W4R4

  • Alpha Recherche Clinique

    Québec, G2J0C4

  • Alpha Recherche Clinique

    Québec, G3K 2P8

  • Estetra Study Site

    Québec, H1M1B1

  • Estetra Study Site

    Sarnia, N7T4X3

  • Diex Research Sherbrooke Inc.

    Sherbrooke, J1L 0H8

  • Diex Recherche

    Victoriaville, G6P 6P6

  • Fadia El Boreky Medicine Professional Corporation

    Waterloo, N2J 1C4

Other trials in Canada

Russia11 sites

  • Scientific Center for Family Health Problems and Human Reproduction

    Irkutsk, 664003

  • Krasnoyarsk State Medical University named after Prof. V.F. VoinoYasenetsky

    Krasnoyarsk, 660022

  • LLC Olla-Med

    Moscow, 105554

  • Scientific Centre Of Obsterics, Gynecology And Perinatology n.a.academican V.I.Kulakov of Federal Agency of High Tech Medical Care

    Moscow, 117997

  • JCS Avicenna

    Novosibirsk, 630099

  • Clinical diagnostic center Zdorovye

    Rostov-on-Don, 344011

  • Saint-Petersburg State Healthcare Institution Maternity hospital

    Saint Petersburg, 192174

  • The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott - Center Menopause and Women's Health

    Saint Petersburg, 199034

  • Astarta Clinic

    Saint Petersburg, 199226

  • Woman's consulting center #22

    Saint Petersburg

  • Closed Joint Stock Company Medical Company Idk

    Samara, 443067

Other trials in Russia

United Kingdom11 sites

  • Accellacare - (MeDiNova Limited) - Northamptonshire

    Corby, NN18 9EZ

  • Accellacare (Previously MeDiNova) Warwickshire Quality Research Site

    Coventry, CV3 4FJ

  • CPS Research

    Glasgow, G20 0XA

  • Egin Research Ltd

    High Wycombe, HP11 2QW

  • Queen Charlotte's and Chelsea Hospital - Imperial College Healthcare NHS Trust

    London, W12 0NN

  • Accellacare - (MeDiNova Limited) - North London

    Northwood, HA6 2RN

  • Accellacare - South London

    Orpington, BR5 3QG

  • Estetra Study Site

    Orpington, BR5 3QG

  • Accellacare - (MeDiNova Limited) - East London

    Romford, RM1 3PJ

  • Accellacare - (MeDiNova Limited) - Yorkshire

    Shipley, BD18 3SA

  • Accellacare - (MeDiNova Limited) - West London

    Wokingham, RG40 1XS

Other trials in United Kingdom

Argentina9 sites

  • IDIM - Instituto de Investigaciones Metabolicas

    Buenos Aires, 1012

  • Mautalen Salud e Investigacion

    Buenos Aires, C1128AAF

  • Fundacion Respirar (Centro Medico Dra. De Salvo) - Instituto Argentino de Investigaciones Clinicas (IAIC) S.R.L

    Buenos Aires, C1426ABP

  • Glenny Corp. S. A. / Bioclinica Argentina

    Buenos Aires, C1430CKE

  • Centro Medico Dra Laura Maffei Investigacion Clinica Aplicada

    Caba, 1425

  • Centro de Investigacion Medico Lanus-CIMEL

    Lanus, B1824KAJ

  • Centro De Investigaciones Medicas Mar Del Plata

    Mar del Plata, B7600FYK

  • Instituto de Investigaciones Clinicas Mar del Plata

    Mar del Plata, B7600FZO

  • Instituto Medico de la Fundacion Estudios Clinicos

    Rosario, 2000

Other trials in Argentina

Italy8 sites

  • Ginecologia e Fisiopatologia della Riproduzione Umana,UO Ostetricia e Ginecologia,Policlinico S.Orsola-Malpighi

    Bologna, 40138

  • Ospedale Pugliese

    Calabria, 88100

  • Universita degli Studi di Firenze - Azienda Ospedaliero Universitaria Careggi, DAI Materno Infantile, SOD Ginecologia e Ostetricia

    Florence, 50134

  • Azienda Ospedaliero - Universitaria Policlinico di Modena

    Modena, 41124

  • Universita degli Studi di Perugia - Policlinico Monteluce - Centro di Medicina Perinatale e della Riproduzione

    Perugia, 06129

  • Azienda Ospedaliero Universitaria Pisana

    Pisa, 56126

  • Universita degli Studi di Roma La Sapienza - Umberto I Policlinico di Roma

    Roma, 00161

  • Policlinico Univ. Agostino Gemelli

    Roma, 00168

Other trials in Italy

Lithuania8 sites

  • Saules Family Medicine Centre

    Kaunas, LT-49449

  • UAB VAKK - Dr. Kildos Klinika

    Kaunas, LT-50128

  • Klaipedos Miesto Poliklinika

    Klaipėda, LT-93200

  • Public Institution Centro Poliklinika

    Vilnius, LT-01117

  • UAB Seimos gydytojas

    Vilnius, LT-01118

  • JSC Maxmeda

    Vilnius, LT-03225

  • JSC Kardiolita

    Vilnius, LT-05263

  • Vilnius University Hospital Santaros klinikos

    Vilnius, LT-08661

Other trials in Lithuania

Hungary4 sites

  • Szent Anna Privat Surgery-Szent Anna Maganrendelo

    Debrecen, 4024

  • Pecsi Tudomanyegyetem (PTE) Altalanos Orvostudomanyi Kar (AOK) - Klinikai Kozpont Szuleszeti es Nogyogyaszati Klinika

    Pécs, 7624

  • Univ. of Szeged Faculty of General Medicine Albert Szent-Gyaergyi

    Szeged, 6725

  • Csongrad Megyei Dr. Bugyi Istvan Korhaz

    Szentes, 6600

Other trials in Hungary

Spain4 sites

  • Diatros S.L.P

    Gavà, 08850

  • Instituto Palacios, Salud y Medicina de la Mujer

    Madrid, 28009

  • Hospital Clinico San Carlos

    Madrid, 28040

  • Hospital Universitario Virgen del Rocio, Hospital de la Mujer

    Seville, 41013

Other trials in Spain

Slovakia2 sites

  • MCM GYNPED, s.r.o.

    Dubnica nad Váhom, 018 41

  • BrenCare, s. r. o.

    Poprad, 058 01

Other trials in Slovakia

About this study

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)

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)

Read the detailed description

This study consists of two-parts, performed with 2 separate groups of participants:

  • Efficacy Study Part: 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 were treated with 200 mg progesterone (P4) once daily for 14 consecutive days, after completion of the E4/placebo treatment. This part of the study consisted of 3 treatment groups.
  • Safety Study Part: The Endometrial and General Safety Study 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 received E4 20 mg in combination with 100 mg P4 continuously for up to 53 weeks.
Being tested
Estetrol, Placebo, Progesterone
Keywords
Estetrol, Hot Flushes, Vasomotor Symptoms
Medical subject headings
Hot Flashes

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EstetrolDrug

    Estetrol oral tablet: administered orally once daily

  • PlaceboDrug

    Placebo oral tablet: administered orally once daily

  • ProgesteroneDrug

    Progesterone oral tablet: administered orally once daily

Study groups in NCT04209543
Study groupRoleWhat they receive
Estetrol 15 mg - Efficacy PartExperimentalEstetrol (E4) 15 mg was administered orally once daily for a minimum of 12 weeks and not longer than 13 weeks.
Receives: Drug: Estetrol
Estetrol 20 mg - Efficacy PartExperimentalEstetrol (E4) 20 mg was administered orally once daily for a minimum of 12 weeks and not longer than 13 weeks.
Receives: Drug: Estetrol
Placebo - Efficacy PartPlacebo comparatorPlacebo was administered orally once daily for a minimum of 12 weeks and not longer than 13 weeks.
Receives: Drug: Placebo
Estetrol 20 mg + P4 100 mg - Safety PartExperimentalEstetrol (E4) 20 mg and Progesterone (P4) 100 mg was administered once daily for up to 53 weeks.
Receives: Drug: Estetrol; Drug: Progesterone

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: Baseline and Week 4

  2. 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

    Measured: Baseline and Week 12

  3. 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

    Measured: Baseline and Week 4

  4. 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

    Measured: Baseline and Week 12

  5. 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.

    Measured: Screening and Week 53

Secondary outcomes (81)

  1. 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

    Measured: Baseline and Week 1

  2. 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

    Measured: Baseline and Week 2

  3. 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

    Measured: Baseline and Week 3

  4. 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

    Measured: Baseline and Week 4

  5. 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

    Measured: Baseline and Week 5

  6. 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

    Measured: Baseline and Week 6

  7. 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

    Measured: Baseline and Week 7

  8. 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

    Measured: Baseline and Week 8

  9. 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

    Measured: Baseline and Week 9

  10. 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

    Measured: Baseline and Week 10

  11. 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

    Measured: Baseline and Week 11

  12. 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

    Measured: Baseline and Week 12

  13. 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

    Measured: Baseline and Week 1

  14. 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

    Measured: Baseline and Week 2

  15. 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

    Measured: Baseline and Week 3

  16. 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

    Measured: Baseline and Week 4

  17. 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

    Measured: Baseline and Week 5

  18. 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

    Measured: Baseline and Week 6

  19. 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

    Measured: Baseline and Week 7

  20. 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

    Measured: Baseline and Week 8

  21. 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

    Measured: Baseline and Week 9

  22. 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

    Measured: Baseline and Week 10

  23. 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

    Measured: Baseline and Week 11

  24. 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

    Measured: Baseline and Week 12

  25. 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).

    Measured: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12

  26. 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).

    Measured: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12

  27. 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).

    Measured: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12

  28. 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).

    Measured: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12

  29. 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.

    Measured: Week 4

  30. 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.

    Measured: Week 12

  31. 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.

    Measured: Baseline and Week 12

  32. 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.

    Measured: Baseline and Week 12

  33. Change from Baseline to Week 12 in plasma concentration of triglycerides (Efficacy Study Part)

    Measured: Baseline and Week 12

  34. Change from Baseline to Week 12 in plasma concentration of low-density lipoprotein (LDL)-cholesterol (Efficacy Study Part)

    Measured: Baseline and Week 12

  35. Change from Baseline to Week 12 in plasma concentration of total cholesterol (Efficacy Study Part)

    Measured: Baseline and Week 12

  36. Change from Baseline to Week 12 in the total cholesterol/high density cholesterol (HDL) cholesterol ratio (Efficacy Study Part)

    Measured: Baseline and Week 12

  37. Change from Baseline to Week 12 in the HDL-cholesterol ratio (Efficacy Study Part)

    Measured: Baseline and Week 12

  38. Change from Baseline to Week 12 in plasma concentration of lipoprotein (a) (Efficacy Study Part)

    Measured: Baseline and Week 12

  39. Change from Baseline to Week 12 in fasting glycaemia (Efficacy Study part)

    Measured: Baseline and Week 12

  40. Change from Baseline to Week 12 in plasma concentration of insulin (Efficacy Study Part)

    Measured: Baseline and Week 12

  41. Change from Baseline to Week 12 in plasma concentration of glycated hemoglobin (Efficacy Study Part)

    Measured: Baseline and Week 12

  42. Change from Baseline to Week 12 in Homeostasis model-assessment-estimated insulin resistance (HOMA-IR) (Efficacy Study Part)

    Measured: Baseline and Week 12

  43. 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".

    Measured: Baseline and Week 12

  44. 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.

    Measured: Weeks 4 and 12

  45. 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.

    Measured: From baseline to Follow-up visit (up to Week 16)

  46. 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.

    Measured: Screening and Week 13

  47. 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.

    Measured: From screening to Week 13

  48. 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.

    Measured: Screening and Week 13

  49. Number of participants with changes in breast examination results (Efficacy Study Part)

    Measured: Screening and Week 13

  50. Number of participants with changes in routine clinical laboratory test results (Efficacy Study Part)

    Routine laboratory tests include hematology and chemistry.

    Measured: Screening, Baseline and Week 13

  51. 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.

    Measured: Screening, Week 13, Week 16

  52. 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.

    Measured: Screening and Week 13

  53. 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.

    Measured: From Baseline up to Follow-up (Week 16)

  54. 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.

    Measured: From Baseline up to Follow-up (Week 16)

  55. 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.

    Measured: From Baseline up to Follow-up (Week 16)

  56. 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.

    Measured: From Baseline up to Follow-up (Week 16)

  57. 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.

    Measured: From baseline to Week 53

  58. 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.

    Measured: Screening and Week 53

  59. 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.

    Measured: From screening to Week 53

  60. 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.

    Measured: From screening to Week 53

  61. 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.

    Measured: Screening and Week 53

  62. Number of participants with changes in mammography results (Endometrial and General Safety Part)

    Measured: Screening and Week 53

  63. Number of participants with changes in routine clinical laboratory test results (Endometrial and General Safety Part)

    Routine laboratory tests include hematology and chemistry.

    Measured: Screening, Baseline and Week 13

  64. 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.

    Measured: From Baseline to Week 53

  65. 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.

    Measured: From Baseline to Week 53

  66. 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.

    Measured: From Baseline to Week 53

  67. 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.

    Measured: From Baseline to Week 53

  68. 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".

    Measured: Baseline and Weeks 12 and 52

  69. 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.

    Measured: Weeks 4, 12, and 52

  70. Change from Baseline to Weeks 12 and 52 in plasma concentration of triglycerides (Endometrial and General Safety Part)

    Measured: Baseline and Weeks 12 and 52

  71. Change from Baseline to Weeks 12 and 52 in plasma concentration of high-density lipoprotein (HDL)-cholesterol (Endometrial and General Safety Part)

    Measured: Baseline and Weeks 12 and 52

  72. Change from Baseline to Weeks 12 and 52 in plasma concentration of low-density lipoprotein (LDL)-cholesterol (Endometrial and General Safety Part)

    Measured: Baseline and Weeks 12 and 52

  73. Change from Baseline to Weeks 12 and 52 in plasma concentration of total cholesterol (Endometrial and General Safety Part)

    Measured: Baseline and Weeks 12 and 52

  74. Change from Baseline to Weeks 12 and 52 in the total cholesterol/high density cholesterol (HDL) cholesterol ratio (Endometrial and General Safety Part)

    Measured: Baseline and Weeks 12 and 52

  75. Change from Baseline to Weeks 12 and 52 in plasma concentration of lipoprotein (a) (Endometrial and General Safety Part)

    Measured: Baseline and Weeks 12 and 52

  76. Change from Baseline to Weeks 12 and 52 in fasting glycaemia (Endometrial and General Safety Part)

    Measured: Baseline and Weeks 12 and 52

  77. Change from Baseline to Weeks 12 and 52 in plasma concentration of insulin (Endometrial and General Safety Part)

    Measured: Baseline and Weeks 12 and 52

  78. Change from Baseline to Weeks 12 and 52 in plasma concentration of glycated hemoglobin (Endometrial and General Safety Part)

    Measured: Baseline and Weeks 12 and 52

  79. Change from Baseline to Weeks 12 and 52 in Homeostasis model-assessment-estimated insulin resistance (HOMA-IR) (Endometrial and General Safety Part)

    Measured: Baseline and Weeks 12 and 52

  80. 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).

    Measured: Screening, Baseline, Weeks 13, 29, and 53

  81. 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.

    Measured: Screening and Week 53

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Dec 2019
  2. Study start30 Dec 2019
  3. Primary completion8 Feb 2024
  4. Study completion8 Feb 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
This study consists of 3 blinded arms (efficacy part) and 1 open-label arm (safety part).
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
1,570 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04209543
Sponsor's protocol ID
MIT-Do001-C301
Status last verified
Oct 2024
First submitted
20 Dec 2019
Last updated
29 Jan 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Simoncini T, Bouchard C, Cloes M, Taziaux M, Palacios S, de Medeiros SF, Vrabii V, Archer DF, Panay N. Estetrol (E4) for the treatment of moderate to severe vasomotor symptoms in postmenopausal women - Efficacy and safety results from the phase 3 E4COMFORT I multicenter, placebo-controlled study. Maturitas. 2026 Jun;209:108965. doi: 10.1016/j.maturitas.2026.108965. Epub 2026 Apr 28.

    PubMed 42068869

  • Panay N, Simoncini T, Taziaux M, Bouchard C, Black A, Kapoor E, Utian W, Foidart JM, Lobo RA. Estetrol for the treatment of moderate to severe vasomotor symptoms in postmenopausal women: The design of the E4COMFORT I and II trials. Maturitas. 2026 Jan;204:108781. doi: 10.1016/j.maturitas.2025.108781. Epub 2025 Nov 17.

    PubMed 41289787

  • Gaspard U, Taziaux M, Jost M, Coelingh Bennink HJT, Utian WH, Lobo RA, Foidart JM. A multicenter, randomized, placebo-controlled study to select the minimum effective dose of estetrol in postmenopausal participants (E4Relief): part 2-vaginal cytology, genitourinary syndrome of menopause, and health-related quality of life. Menopause. 2023 May 1;30(5):480-489. doi: 10.1097/GME.0000000000002167. Epub 2023 Feb 20.

    PubMed 36809193

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Estetrol and Progesterone in people with Vasomotor Symptoms and Menopausal Symptoms, run by Estetra at 224 sites in 14 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 21 inclusion and 43 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 29 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 224 sites in United States, Poland, Brazil, Czechia, Romania and 9 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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 study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04209543, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Jan 2025.

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