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

Completed · Phase 3 · Has a placebo group

Conditions studied: Vasomotor Symptoms, Menopausal Symptoms

In brief

A two-part study designed to evaluate the effect of Estetrol (E4) 15 mg, 20 mg, or placebo on the severity and frequency of vasomotor symptoms (VMS) in the Efficacy Study Part and the safety of E4 20 mg in the Safety Study Part.

Key facts

Study ID: NCT04090957
Run by: Estetra
People needed: 1015
Starts: 2019-09-27
Expected to finish: 2022-08-18
Last updated by the study team: 2025-12-26

Who can join

Age: 40 and older, up to 65. Sex: female. Healthy volunteers: accepted.

You may qualify if…

Signed and dated written informed consent form and any required privacy authorization prior to the initiation of any trial procedure, after the nature of the trial has been explained according to local regulatory requirements;
Females ≥ 40 up to ≤ 65 years of age at randomization/treatment allocation;
For hysterectomized subjects: documented hysterectomy must have occurred at least 6 weeks prior to the start of screening. Hysterectomy can be total or subtotal (i.e., cervix was not removed).
For non-hysterectomized subjects: uterus with bi-layer endometrial thickness ≤ 4 mm on transvaginal ultrasound (TVUS)
For non-hysterectomized subjects: endometrial biopsy taken during screening that reveals no abnormal result, i.e., presence of hyperplasia (simple or complex, with or without atypia), presence of carcinoma, and presence of disordered proliferative endometrium findings. The screening biopsy should have sufficient endometrial tissue for diagnosis. Biopsies without tissue or with insufficient tissue may be repeated once;
Seeking treatment for relief of VMS associated with menopause;
For the Efficacy Study part: at least 7 moderate to severe bothersome VMS per day or at least 50 moderate to severe bothersome VMS per week in the last 7 consecutive days during the Screening period;
For the Safety Study part: at least 1 moderate to severe VMS per week;
Body mass index ≥ 18.0 kg/m² up to ≤ 38.0 kg/m²;
A mammogram that shows no sign of significant disease performed during screening or within 9 months prior to the start of screening;
Post-menopausal status defined as any of the following:
For non-hysterectomized subjects:
At least 12 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) >40 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 (value obtained after washout of estrogen/progestin containing drugs, see exclusion criteria 18 and 20);
or at least 6 weeks postsurgical bilateral oophorectomy;
For hysterectomized subjects:
serum FSH >40 mIU/mL and E2 <20 pg/mL (values obtained after washout of estrogen/progestin containing drug, see exclusion criteria 18 and 20);
or at least 6 weeks post-surgical bilateral oophorectomy;
Good physical and mental health, in the judgement of the Investigator as based on medical history, physical and gynecological examination, and clinical assessments performed prior to Visit 1;
Able to understand and comply with the protocol requirements, instructions, and protocol-stated restrictions;
Able and willing to complete trial daily diaries and questionnaires.

You may not qualify if…

History of malignancy, with the exception of basal cell or squamous cell carcinoma of the skin if diagnosed more than 1 year prior to the Screening visit;
Any clinically significant findings found by the Investigator at the breast examination and/or on mammography suspicious of breast malignancy that would require additional clinical testing to rule out breast cancer (however, simple cysts confirmed by ultrasound are allowed);
Papanicolaou (PAP) test with atypical squamous cells undetermined significance (ASC-US) or higher (low-grade squamous intraepithelial lesion [LSIL], atypical squamous cells- cannot exclude high-grade squamous intraepithelial lesion [HSIL] [ASC-H], HSIL dysplastic or malignant cells) in sub-totally hysterectomized and non-hysterectomized subjects. Note: ASC-US is allowed if a reflex human papilloma virus (HPV) testing is performed and is negative for high risk oncogene HPV subtypes 16 and 18;
For non-hysterectomized subjects:
History or presence of uterine cancer, endometrial hyperplasia, or disordered proliferative endometrium;
Presence of endometrial polyp;
Undiagnosed vaginal bleeding or undiagnosed abnormal uterine bleeding;
Endometrial ablation;
Any uterine/endometrial abnormality that in the judgment of the investigator contraindicates the use of estrogen and/or progestin therapy. This includes presence or history of adenomyosis or significant myoma;
Systolic blood pressure (BP) higher than 130 mmHg, diastolic BP higher than 80 mmHg during screening;
History of venous or arterial thromboembolic disease (e.g., superficial or deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, angina pectoris, etc.), or first-degree family history of venous thromboembolism (VTE);
History of known acquired of congenital coagulopathy or abnormal coagulation factors, including known thrombophilia's;
Laboratory values of fasting glucose above 125 mg/dL and/or glycated hemoglobin above 7%;
Dyslipoproteinaemia (LDL >190 mg/dL and/or triglycerides >300 mg/dL);
Subjects smoking >15 cigarettes per day;
Presence or history of gallbladder disease, unless cholecystectomy has been performed;
Systemic lupus erythematosus;
Any malabsorption disorders including gastric bypass surgery;
History of acute liver disease in the preceding 12 months before the start of screening or presence or history of chronic or severe liver disease [alanine transaminase (ALT) or aspartate transaminase (AST) >2 x upper limit of normal (ULN), bilirubin >1.5 ULN], or liver tumors;
Chronic or current acute renal impairment (estimated glomerular filtration rate <60 ml/min);
Porphyria;
Diagnosis or treatment of major psychiatric disorder (e.g., schizophrenia, bipolar disorder, etc.) in the judgement of the Investigator;
Use of estrogen/progestin containing drug(s) up to:
1 week before screening start for vaginal non-systemic hormonal products (rings, creams, gels);
4 weeks before screening start for vaginal or transdermal estrogen or estrogen/progestin products;

Where it is running

Estetra Study Site — Birmingham, Alabama, United States
Estetra Study Site — Birmingham, Alabama, United States
Estetra Study Site — Dothan, Alabama, United States
Estetra Study Site — Phoenix, Arizona, United States
Estetra Study Site — Phoenix, Arizona, United States
Estetra Study Site — Tempe, Arizona, United States
Estetra Study Site — Tucson, Arizona, United States
Estetra Study Site — Tucson, Arizona, United States
Estetra Study Site — Tucson, Arizona, United States
Estetra Study Site — Tucson, Arizona, United States
Estetra Study Site — Little Rock, Arkansas, United States
Estetra Study Site — Bellflower, California, United States
Estetra Study Site — Canoga Park, California, United States
Estetra Study Site — Chula Vista, California, United States
Estetra Study Site — Huntington Beach, California, United States
Estetra Study Site — La Mesa, California, United States
Estetra Study Site — Lincoln, California, United States
Estetra Study Site — Los Angeles, California, United States
Estetra Study Site — Pomona, California, United States
Estetra Study Site — Sacramento, California, United States
Estetra Study Site — San Diego, California, United States
Estetra Study Site — San Diego, California, United States
Estetra Study Site — Santa Ana, California, United States
Estetra Study Site — Thousand Oaks, California, United States
Estetra Study Site — Birmingham, Alabama, United States

Full record on ClinicalTrials.gov

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