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

NCT04090957 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: MIT-Do001-C302
• Study Type: interventional
• Target: 1,015
• Locations: 2 countries
• Sites: 117

Brief Summary

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.

Conditions

Vasomotor Symptoms; Menopausal Symptoms

Keywords

Estetrol; Hot Flushes; Vasomotor symptoms

Outcome Measures

Primary Outcomes (2)

• Mean Change in Weekly Frequency of Moderate to Severe Vasomotor Symptoms (VMS) From Baseline to Week 4 and Week 12 -- (Efficacy Study Part)

  Weekly frequency of moderate to severe VMS at Baseline = total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization (Week 0). Weekly frequency of moderate to severe VMS at Week X = total number (sum) of all recorded moderate to severe VMS experienced during the week X.

  Week 0 (Baseline), Week 4, Week 12.

• Mean Change in Severity of Moderate to Severe Vasomotor Symptoms (VMS) From Baseline to Week 4 and Week 12 -- (Efficacy Study Part)

  Mean severity score of VMS at Baseline: arithmetic mean of daily severity score values of moderate and severe VMS during the last 7 days prior randomization (Week 0). Mean severity score of VMS at Week 4 or 12: arithmetic mean of daily severity score values of moderate and severe VMS during Week 4 or 12. Daily severity score of VMS at Baseline = \[(2 x number of moderate VMS) + (3 x number of severe VMS)\]/(total number of moderate + severe VMS)\], if at least one moderate to severe VMS was recorded during the day. If documented absence of moderate to severe VMS during the day, daily severity was set to zero. Daily severity score of VMS Post-Baseline = \[(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)\]/(total number of mild + moderate + severe VMS)\], if at least one mild to severe VMS was recorded during the day. If documented absence of VMS during the day, daily severity was set to zero. Severity score: mild=1, moderate=2, severe=3.

  Week 0 (Baseline), Week 4, Week 12.

Secondary Outcomes (48)

• Mean Change From Baseline to Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 in the Weekly Frequency of Moderate to Severe Vasomotor Symptoms (VMS) -- (Efficacy Study Part)

  Week 0 (Baseline), Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

• Mean Change in Severity of Moderate and Severe Vasomotor Symptoms (VMS) From Baseline to Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 -- (Efficacy Study Part)

  Week 0 (Baseline), Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

• Mean Change From Baseline to Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 in the Weekly Frequency of Mild to Severe Vasomotor Symptoms (VMS) -- (Efficacy Study Part)

  Week 0 (Baseline), Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

• Percentage of Subjects With ≥50% and ≥75% Reduction From Baseline in the Weekly Frequency of Moderate to Severe Vasomotor Symptoms (VMS) at Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 -- (Efficacy Study Part)

  Week 0 (Baseline), Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

• Percentage of Subjects With a Clinically Important Difference (CID) Compared With Baseline in the Weekly Frequency of Moderate to Severe VMS -- Week 4 and Week 12 -- Clinical Global Impression (CGI) Questionnaire -- (Efficacy Study Part)

  Week 4, Week 12.

Study Arms (4)

Estetrol 15 mg - Efficacy Study Part

EXPERIMENTAL

Estetrol (E4) 15 mg, administered orally once daily for up to 53 weeks.

Drug: Estetrol oral tablet

Estetrol 20 mg - Efficacy Study Part

EXPERIMENTAL

Estetrol (E4) 20 mg, administered orally once daily for up to 53 weeks.

Drug: Estetrol oral tablet

Placebo - Efficacy Study Part

PLACEBO COMPARATOR

Placebo, administered orally once daily for up to 53 weeks.

Drug: Placebo oral tablet

Estetrol 20 mg - Safety Study Part

EXPERIMENTAL

Estetrol (E4) 20 mg, administered orally once daily for up to 53 weeks.

Drug: Estetrol oral tablet

Interventions

Estetrol oral tablet DRUG

Estetrol oral tablet, administered orally once daily.

Also known as: E4 oral tablet

Estetrol 15 mg - Efficacy Study Part; Estetrol 20 mg - Efficacy Study Part; Estetrol 20 mg - Safety Study Part

Placebo oral tablet DRUG

Placebo oral tablet, administered orally once daily.

Placebo - Efficacy Study Part

Eligibility Criteria

• Age: 40 Years - 65 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

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:

You may not qualify if:

• or at least 6 weeks postsurgical bilateral oophorectomy;
• For hysterectomized subjects:
• 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.
• 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;

Sponsors & Collaborators

• Estetra: lead
• ICON Clinical Research: collaborator

Study Sites (117)

Estetra Study Site

Birmingham, Alabama, 35205, United States

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Birmingham, Alabama, 35218, United States

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Birmingham, Alabama, 35235, United States

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Dothan, Alabama, 36303-1928, United States

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Phoenix, Arizona, 85018, United States

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Phoenix, Arizona, 85032, United States

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Tempe, Arizona, 85281, United States

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Tucson, Arizona, 85704, United States

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Tucson, Arizona, 85712, United States

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Tucson, Arizona, 85715, United States

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Tucson, Arizona, 85745, United States

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Little Rock, Arkansas, 72204, United States

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Bellflower, California, 90706, United States

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Canoga Park, California, 91303, United States

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Chula Vista, California, 91911, United States

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Huntington Beach, California, 92647, United States

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La Mesa, California, 91942, United States

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Lincoln, California, 95648, United States

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Los Angeles, California, 90057, United States

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Pomona, California, 91767, United States

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Sacramento, California, 95821, United States

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San Diego, California, 92111, United States

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San Diego, California, 92120, United States

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Santa Ana, California, 92705, United States

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Thousand Oaks, California, 91360, United States

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West Covina, California, 91790, United States

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Colorado Springs, Colorado, 80918, United States

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Denver, Colorado, 80209, United States

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Crystal River, Florida, 34429, United States

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Jacksonville, Florida, 32207, United States

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Jacksonville, Florida, 32256, United States

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Miami, Florida, 33134, United States

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Miami, Florida, 33155, United States

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Miami, Florida, 33173, United States

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Miami Lakes, Florida, 33014, United States

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New Port Richey, Florida, 34653, United States

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Ocoee, Florida, 34761, United States

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Orlando, Florida, 32801, United States

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Sarasota, Florida, 34239-3132, United States

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West Palm Beach, Florida, 33409, United States

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Atlanta, Georgia, 30342, United States

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Morrow, Georgia, 30260, United States

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Sandy Springs, Georgia, 30328, United States

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Savannah, Georgia, 31406, United States

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Idaho Falls, Idaho, 83404, United States

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Meridian, Idaho, 83642, United States

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Evansville, Indiana, 47714, United States

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Marrero, Louisiana, 70072, United States

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Saginaw, Michigan, 48602, United States

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Saginaw, Michigan, 48604, United States

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Rochester, Minnesota, 55905, United States

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St Louis, Missouri, 63141, United States

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Lincoln, Nebraska, 68510, United States

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Norfolk, Nebraska, 68701, United States

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Las Vegas, Nevada, 89106, United States

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Las Vegas, Nevada, 89128, United States

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Albuquerque, New Mexico, 87102, United States

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Albuquerque, New Mexico, 87109-4640, United States

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New York, New York, 10032, United States

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Charlotte, North Carolina, 28209, United States

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Charlotte, North Carolina, 28277, United States

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Columbus, North Carolina, 28412, United States

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Fayetteville, North Carolina, 28304, United States

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Hickory, North Carolina, 28601, United States

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New Bern, North Carolina, 28562, United States

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Raleigh, North Carolina, 27609, United States

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Raleigh, North Carolina, 27612, United States

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Rocky Mount, North Carolina, 27804, United States

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Cincinnati, Ohio, 45212, United States

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Cincinnati, Ohio, 45267, United States

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Cleveland, Ohio, 44122, United States

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Columbus, Ohio, 43213, United States

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Columbus, Ohio, 43231, United States

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Fairfield, Ohio, 45014, United States

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Erie, Pennsylvania, 16507, United States

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Philadelphia, Pennsylvania, 19114, United States

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Bluffton, South Carolina, 29910, United States

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Columbia, South Carolina, 29201, United States

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Mt. Pleasant, South Carolina, 29464, United States

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Myrtle Beach, South Carolina, 29572, United States

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North Charleston, South Carolina, 29405, United States

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Chattanooga, Tennessee, 37404, United States

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Jefferson City, Tennessee, 37760, United States

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Knoxville, Tennessee, 37912, United States

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Knoxville, Tennessee, 37938, United States

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Memphis, Tennessee, 38119, United States

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Memphis, Tennessee, 38120, United States

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Dallas, Texas, 75251, United States

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Fort Worth, Texas, 76104, United States

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Fort Worth, Texas, 76140, United States

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Georgetown, Texas, 78626, United States

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Houston, Texas, 77023, United States

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Houston, Texas, 77024, United States

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Houston, Texas, 77054, United States

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Houston, Texas, 77081, United States

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Houston, Texas, 77084, United States

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Houston, Texas, 77099, United States

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McAllen, Texas, 78503, United States

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McAllen, Texas, 78504, United States

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Pearland, Texas, 77581, United States

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Plano, Texas, 75093, United States

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San Antonio, Texas, 78258, United States

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Draper, Utah, 84020, United States

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Pleasant Grove, Utah, 84062, United States

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West Jordan, Utah, 84088, United States

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Charlottesville, Virginia, 22911, United States

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Norfolk, Virginia, 23507, United States

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Virginia Beach, Virginia, 23456, United States

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Bellevue, Washington, 98007, United States

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Seattle, Washington, 98105, United States

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Morgantown, West Virginia, 26505, United States

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Red Deer, Alberta, T4P 1K4, Canada

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Montreal, Quebec, H4P 2S4, Canada

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Brampton, L6T 0G1, Canada

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Québec, G1N 4V3, Canada

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Québec, G1S 2L6, Canada

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Waterloo, N2J 1C4, Canada

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Related Publications (1)

• 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.

  PMID: 41289787 DERIVED

MeSH Terms

Conditions

Hot Flashes

Interventions

Estetrol

Condition Hierarchy (Ancestors)

Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Estriol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Results Point of Contact

• Title: Clinical Study Leader
• Organization: Estetra SRL

clinical.trials@estetra.com

+3243254451

Study Officials

• Estetra

  Estetra

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: There are 3 blinded arms in the Efficacy part and 1 open-labeled arm in the Safety part.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: For the Efficacy study part, there are 3 blinded arms (randomized) and for the Safety study part, there is 1 open-label (non-randomized) arm.

Study Record Dates

• First Submitted: September 13, 2019
• First Posted: September 16, 2019
• Study Start: September 27, 2019
• Primary Completion: August 18, 2022
• Study Completion: August 18, 2022
• Last Updated: December 26, 2025
• Results First Posted: December 26, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

CA (6); US (111)