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Completed

NCT Number: NCT04090957

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

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.

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Key information

Conditions

Vasomotor Symptoms Hot Flashes Menopausal Symptoms Pathological Conditions, Signs and Symptoms Signs and Symptoms

Age range

40 year–65 year

Sex eligibility

Female

Study type

Interventional

Phase

Phase 3

Primary location

Estetra Study Site, Red Deer, Alberta, Canada

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About this study

This is a two-part study:

Arm 1, 2, and 3: randomized, double blind

  • 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 two doses of E4 (15 mg or 20 mg) or placebo for 12 consecutive weeks. Thereafter, treatment proceeded for a total duration of up to 53 weeks, to continue the evaluation of secondary efficacy (effect on hemostasis, lipid and glucose metabolism, bone turnover, health-related quality of life [HRQoL] and treatment satisfaction [TS]), safety and the effect on the endometrium. For endometrial protection, all non-hysterectomized subjects received 200 mg progesterone (P4) once daily for 14 consecutive days, after completion of the E4/placebo treatment.

Arm 4: open label

  • Safety Study Part: designed to evaluate the general safety, secondary efficacy (lipid and glucose metabolism, HRQoL and TS) after treatment with E4 20 mg for up to 53 weeks in hysterectomized and non hysterectomized postmenopausal participants. For endometrial protection, all non-hysterectomized subjects received 200 mg progesterone (P4) once daily for 14 consecutive days, after completion of the E4 treatment.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Signed and dated written informed consent form and any required privacy authorization prior to the initiation of any trial procedure, after the nature of the trial has been explained according to local regulatory requirements;
  • Females ≥ 40 up to ≤ 65 years of age at randomization/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.

Exclusion criteria

  • History of malignancy, with the exception of basal cell or squamous cell carcinoma of the skin if diagnosed more than 1 year prior to the Screening visit;
  • Any clinically significant findings found by the Investigator at the breast examination and/or on mammography suspicious of breast malignancy that would require additional clinical testing to rule out breast cancer (however, simple cysts confirmed by ultrasound are allowed);
  • Papanicolaou (PAP) test with atypical squamous cells undetermined significance (ASC-US) or higher (low-grade 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;
  • 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 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 thyroid stimulating hormone (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;
  • For non-hysterectomized subjects: history or presence of allergy to peanuts;
  • 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.

Treatment and study plan

Estetrol oral tablet

Drug

Estetrol oral tablet, administered orally once daily.

Other names: E4 oral tablet

Placebo oral tablet

Drug

Placebo oral tablet, administered orally once daily.

Primary outcomes

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

    Time frame: Week 0 (Baseline), Week 4, Week 12.

    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.

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

    Time frame: Week 0 (Baseline), Week 4, Week 12.

    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.

Secondary outcomes

  1. 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)

    Time frame: 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 moderate to severe vasomotor symptoms (VMS) (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.

  2. 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)

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

    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 X (post-baseline): arithmetic mean of daily severity score values of moderate and severe VMS during Week X.

    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.

  3. 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)

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

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

    Weekly frequency of mild to severe VMS at Week X = total number (sum) of all recorded mild to severe VMS experienced during the week X.

  4. 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)

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

    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

    Percentages of participants are based on the number of subjects with a non-missing percent change from Baseline result in each treatment arm by visit in the ITT Set.

  5. 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)

    Time frame: Week 4, Week 12.

    Percentage of subjects with a clinically important difference (CID) compared with baseline in the weekly frequency of moderate to severe VMS after Week 4 and Week 12, using the Clinical Global Impression (CGI) questionnaire (Efficacy Study Part).

    CGI questionnaire: questionnaire in which subjects were to answer the question "Rate the total improvement, whether or not in your judgement it is due entirely to drug treatment. Compared to your condition at administration to the study, how much has it changed?". The options were: very much improved, much improved, minimally improved, no change, minimally worse, much worse, and very much worse.

    CID (=Clinically Important Difference) = much improved + very much improved; MCID (=Minimally Clinically Important Difference) = minimally improved.

  6. Total Cholesterol -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Serum concentration of total cholesterol (Efficacy study part).

    Lipid Metabolism: Change from Baseline to Week 12 and Week 52.

  7. Total Cholesterol -- (Safety Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Serum concentration of total cholesterol (Safety study part).

    Lipid Metabolism: Change from Baseline to Week 12 and Week 52.

  8. Cholesterol/High-density Lipoprotein (HDL) Ratio -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Cholesterol/High-density lipoprotein (HDL) Ratio (Efficacy study part).

    Lipid Metabolism: Change from Baseline to Week 12 and Week 52.

  9. Cholesterol/High-density Lipoprotein (HDL) Ratio -- (Safety Study Part).

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Cholesterol/High-density lipoprotein (HDL) Ratio (Safety study part).

    Lipid Metabolism: Change from Baseline to Week 12 and Week 52.

  10. High-density Lipoprotein (HDL)-Cholesterol -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Serum concentration of high-density lipoprotein (HDL)-cholesterol (Efficacy study part).

    Lipid Metabolism: Change from Baseline to Week 12 and Week 52.

  11. High-density Lipoprotein (HDL)-Cholesterol -- (Safety Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Serum concentration of total HDL cholesterol (Safety study part).

    Lipid Metabolism: Change from Baseline to Week 12 and Week 52.

  12. Low-density Lipoprotein (LDL)-Cholesterol -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52

    Serum concentration of low-density lipoprotein (LDL)-cholesterol (Efficacy study part)

    Lipid Metabolism: Change from Baseline to Week 12 and Week 52.

  13. Low-density Lipoprotein (LDL)-Cholesterol -- (Safety Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Serum Concentration of LDL-cholesterol (Safety study part).

    Lipid Metabolism: Change from Baseline to Week 12 and Week 52.

  14. Lipoprotein(a) -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Serum concentration of lipoprotein(a) (Efficacy study part).

    Lipid Metabolism: Change from Baseline to Week 12 and Week 52.

  15. Lipoprotein(a) -- (Safety Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Serum Concentration of Lipoprotein(a) (Safety study part).

    Lipid Metabolism: Change from Baseline to Week 12 and Week 52.

  16. Triglycerides -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Serum concentration of triglycerides (Efficacy study part).

    Lipid Metabolism: Change from Baseline to Week 12 and Week 52.

  17. Triglycerides -- (Safety Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Serum concentration of triglycerides (Safety study part).

    Lipid Metabolism: Change from Baseline to Week 12 and Week 52.

  18. Hemoglobin A1c -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Hemoglobin A1c (Efficacy study part).

    Glucose metabolism parameters: Change from Baseline to Week 12 and Week 52.

    Hemoglobin A1c = Glycated hemoglobin

  19. Hemoglobin A1c -- (Safety Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Hemoglobin A1c (Safety study part).

    Glucose metabolism parameters: Change from Baseline to Week 12 and Week 52.

    Hemoglobin A1c = Glycated hemoglobin

  20. Fasting Glucose -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Concentration of fasting glucose in plasma.

    Glucose metabolism parameters: Change from Baseline to Week 12 and Week 52.

  21. Fasting Glucose -- (Safety Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Concentration of fasting glucose in plasma.

    Glucose metabolism parameters: Change from Baseline to Week 12 and Week 52.

  22. Insulin Resistance (HOMA-IR) -- Homeostasis Model Assessment -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Insulin resistance (HOMA-IR) -- Homeostasis model assessment (Efficacy study part).

    Glucose Metabolism parameters: Change from Baseline to Week 12 and Week 52.

    HOMA-IR is a mathematical homeostasis model assessment (HOMA) that evaluates systemic insulin resistance (IR).

    The HOMA-IR score is calculated as the product of fasting insulin and fasting glucose values divided by a constant. Low HOMA-IR means that a small amount of the hormone insulin is sufficient to keep blood sugars in good balance.

    HOMA-IR values less than 1.0 mean insulin-sensitivity which is optimal. Values ≥1.9 are indicative of early insulin resistance, and ≥2.9 indicate significant insulin resistance.

  23. Insulin Resistance (HOMA-IR) -- Homeostasis Model Assessment -- (Safety Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Insulin resistance (HOMA-IR) -- Homeostasis model assessment (Safety study part).

    Glucose Metabolism parameters: Change from Baseline to Week 12 and Week 52.

    HOMA-IR is a mathematical homeostasis model assessment (HOMA) that evaluates systemic insulin resistance (IR).

    The HOMA-IR score is calculated as the product of fasting insulin and fasting glucose values divided by a constant. Low HOMA-IR means that a small amount of the hormone insulin is sufficient to keep blood sugars in good balance.

    HOMA-IR values less than 1.0 mean insulin-sensitivity which is optimal. Values ≥1.9 are indicative of early insulin resistance, and ≥2.9 indicate significant insulin resistance.

  24. Insulin -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Serum concentration of insulin (Efficacy study part).

    Glucose metabolism parameters: Change from Baseline to Week 12 and Week 52.

  25. Insulin -- (Safety Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Serum concentration of insulin (Safety study part).

    Glucose metabolism parameters: Change from Baseline to Week 12 and Week 52.

  26. Angiotensinogen -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Angiotensinogen (Efficacy study part).

    Change from Baseline to Week 12 and Week 52.

  27. Antithrombin Activity (AT III) -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Antithrombin Activity (AT III) -- (Efficacy study part)

    Hemostasis parameters: Change from Baseline to Week 12 and Week 52.

    Antithrombin Activity (AT III) is a key biomarker that measures how effectively antithrombin, a natural anticoagulant protein, functions in the blood.

    The functional AT III assay is based on the principle of inhibition of Factor Xa by antithrombin in the presence of heparin.

    Antithrombin Activity results are expressed as a percentage, with normal levels ranging between 80% and 120%. Lower than normal levels may indicate an increased risk of blood clotting disorders, while elevated levels can occur during inflammation or certain physiological conditions.

  28. Activated Partial Thromboplastin Time (aPTT) Based Activated Protein-C Resistance (APCr) (APCR-V Ratio) -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Activated partial thromboplastin time (aPTT) based activated Protein-C resistance (APCr) (APCR-V ratio) (Efficacy study part).

    Hemostasis parameters: Change from Baseline to Week 12 and Week 52.

  29. Prothrombin Fragment 1 + 2 -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Prothrombin fragment 1 + 2 (Efficacy study part).

    Hemostasis parameters: Change from Baseline to Week 12 and Week 52.

  30. Factor VIII -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Factor VIII (Efficacy study part).

    Hemostasis parameters: Change from Baseline to Week 12 and Week 52.

    This test measures the activity of Factor VIII which is an essential protein for effective formation of a blood clot.

    Factor VIII activity results are expressed as a percentage, with normal levels ranging from 50% to 150%. Lower than normal levels can indicate bleeding disorders such as hemophilia A or acquired Factor VIII deficiency.

  31. Endogenous Thrombin Potential (ETP)-Based Activated Protein-C Sensitivity Ratio (APCsr ETP) -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Endogenous thrombin potential (ETP)-based activated Protein-C sensitivity ratio (APCsr ETP) (Efficacy study part).

    Hemostasis parameters: Change from Baseline to Week 12 and Week 52.

  32. Protein-C -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Protein-C (Efficacy study part).

    Hemostasis parameters: Change from Baseline to Week 12 and Week 52.

  33. Free Protein-S -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Free Protein-S (Efficacy study part).

    Hemostasis parameters: Change from Baseline to Week 12 and Week 52.

  34. Sex Hormone Binding Globulin (SHBG) -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Sex Hormone Binding Globulin (SHBG) (Efficacy study part).

    Change from Baseline to Week 12 and Week 52.

  35. Calcium -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Calcium (Efficacy study part).

    Bone turnover markers: Change from Baseline to Week 12 and Week 52.

  36. C-Terminal Telopeptide Type 1 (CTX-1) -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    C-terminal telopeptide type 1 (CTX-1) (Efficacy study part).

    Bone turnover markers: Change from Baseline to Week 12 and Week 52.

  37. Procollagen I N-Terminal Propeptide (PINP) -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    Procollagen I N-Terminal Propeptide (PINP) (Efficacy study part).

    Bone turnover markers: Change from Baseline to Week 12 and Week 52.

  38. 25-Hydroxyvitamin D -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Weeks 12 and 52.

    25-Hydroxyvitamin D (Efficacy study part).

    Bone turnover markers: Change from Baseline to Week 12 and Week 52.

  39. Health-related Quality of Life (HRQoL) Assessment, Change From Baseline -- Menopause-specific Quality of Life (MENQOL) Questionnaire -- (Efficacy Study Part)

    Time frame: Day 1 (Baseline), Week 12, and 52.

    Change from Baseline to W12 and W52 in HRQoL using the MENQOL questionnaire. MENQOL questionnaire=29-item assessment of QoL to capture self-reported information on the presence and bother of symptoms and feelings in the domains of vasomotor, psychosocial, physical and sexual functioning, among midlife women in the immediate post-menopause time.

    For each item, women are asked if they experience that symptom or feeling, and if yes, to rate bother on a scale of 0-6 corresponding to "not at all bothered" to "extremely bothered". Non-endorsement of an item is scored a "1" and endorsement a "2", plus the number of the particular rating, so that the possible score on any item ranges from 1 (not experiencing symptom or feeling) to 8 (extremely bothered).

    Domain score=mean of the item scores in that domain. Total MENQOL=mean of the domain-specific scores. Administered at Day 1 (=day of randomization) for baseline, W12 and W52. It refers to the symptoms experienced over the past month.

  40. Health-related Quality of Life (HRQoL) Assessment, Change From Baseline -- Menopause-specific Quality of Life (MENQOL) Questionnaire -- (Safety Study Part)

    Time frame: Day 1 (Baseline), Week 12 and 52.

    Change from Baseline to W12 and W52 in HRQoL using the MENQOL questionnaire. MENQOL questionnaire=29-item assessment of QoL to capture self-reported information on the presence and bother of symptoms and feelings in the domains of vasomotor, psychosocial, physical and sexual functioning, among midlife women in the immediate post-menopause time.

    For each item, women are asked if they experience that symptom or feeling, and if yes, to rate bother on a scale of 0-6 corresponding to "not at all bothered" to "extremely bothered". Non-endorsement of an item is scored a "1" and endorsement a "2", plus the number of the particular rating, so that the possible score on any item ranges from 1 (not experiencing symptom or feeling) to 8 (extremely bothered).

    Domain score=mean of the item scores in that domain. Total MENQOL=mean of the domain-specific scores. Administered at Day 1 (=day of randomization) for baseline, W12 and W52. It refers to the symptoms experienced over the past month.

  41. Total Score in Treatment Satisfaction (TS) Using the Clinical Global Impression (CGI) Questionnaire -- (Efficacy Study Part, Safety Study Part)

    Time frame: Weeks 4, 12, and 52.

    Total score in treatment satisfaction (TS) using the Clinical Global Impression (CGI) questionnaire (Efficacy study part and Safety study part).

    CGI questionnaire: questionnaire in which subjects were to answer the question "Rate the total improvement, whether or not in your judgement it is due entirely to drug treatment. Compared to your condition at administration to the study, how much has it changed?". The options were: very much improved, much improved, minimally improved, no change, minimally worse, much worse, and very much worse.

    Results are shown as percentage of participants.

    TS=Treatment satisfaction

  42. Change From Baseline in Mean Endometrial Thickness -- (Efficacy Study Part, Safety Study Part)

    Time frame: Screening, Week 13, 29, 41, 53, Follow-up (Week 55/56), and early discontinuation (up to Week 53 for hysterectomized subjects and Week 55/56 for non-hysterectomized subjects)

    Change from baseline for non-hysterectomized subjects by visit (Efficacy Study Part and Safety Study Part).

    Endometrial thickness was assessed by transvaginal ultrasound (TVUS).

  43. Number of Subjects in the Different Endometrial Categories -- (Efficacy Study Part, Safety Study Part)

    Time frame: Screening and Week 53.

    A summary of the Final/Consensus diagnosis of endometrial biopsies across all post-baseline visits is provided. An endometrial biopsy was obtained during the Screening period and at the EOT/Early Discontinuation visit. An additional unscheduled biopsy could have been taken if a subject presented with endometrial thickness >10 mm on TVUS, or persistent and/or recurrent bleeding.

    Biopsies were read by 3 independent expert pathologists as per regulatory requirements. The Final/Consensus diagnosis was defined as the concurrence of at least 2 diagnoses from the 3 pathologists, and if there was no agreement among at least 2 pathologists, the most severe pathologic diagnosis was used.

    The World Health Organization (WHO) classification which separates endometrial diagnoses into 6 categories (benign endometrium, simple hyperplasia, complex hyperplasia, simple atypical hyperplasia, complex atypical hyperplasia, carcinoma) was applied for the assessment of the Final/Consensus diagnosis.

  44. Vaginal Bleeding and/or Spotting During Each 28-day Cycle of Treatment With E4 -- (Efficacy Study Part, Safety Study Part)

    Time frame: Cycle 1,2,3,4,5,6,7,8,9,10,11,12,13

    Frequency (percentage) of non-hysterectomized participants with vaginal bleeding and/or spotting during each 28-day cycle of treatment with E4, based on the subject diary (Efficacy study part and Safety study part).

    Vaginal bleeding was daily recorded by the participant in the diary. Absence or occurrence of vaginal bleeding/ spotting was 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.

  45. Number of Days With Bleeding or Spotting by Cycle for Non-Hysterectomized Subjects (Efficacy Study Part, Safety Study Part)

    Time frame: Cycle 1,2,3,4,5,6,7,8,9,10,11,12,13.

    Number of days with bleeding or spotting during each 28-day cycle of treatment for non-hysterectomized (NH) subjects (Efficacy study part, Safety study part). The Overall Number of Participants Analyzed corresponds to the total number of NH participants in each study arm in the SAF. For each cycle, the number analyzed corresponds to the number of NH subjects with corresponding bleeding/spotting information available in the diary for that cycle. Women with bleeding and spotting during a cycle are counted in both the Bleeding Days and Spotting Days categories for that cycle.

    Vaginal bleeding was recorded daily by the participants in the diary. Absence or occurrence of vaginal bleeding/spotting was 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.

  46. Cumulative Rate of Amenorrhea (Absence of Any Bleeding or Spotting) During Each 28-day Cycle of Treatment With E4 -- (Efficacy Study Part, Safety Study Part)

    Time frame: Cycle 1,2,3,4,5,6,7,8,9,10,11,12,13.

    Cumulative rates of amenorrhea defined as the percentage of women who reported consecutive cycles of amenorrhea (absence of any bleeding or spotting) for a given cycle of time (Efficacy study part and Safety study part).

    Percentages (%) are based on the number of non-hysterectomized subjects with amenorrhea diary data available through cycle 13 in the Safety Analysis Set in each treatment arm.

  47. Number of Participants With Serious Adverse Events (SAE) in SOC 'Reproductive System and Breast Disorders' or With PT 'Abdominal Pain' by Hysterectomy Status (Hysterectomized and Non-Hysterectomized) -- (Efficacy Study Part, Safety Study Part)

    Time frame: Day 1 (allocation to treatment) until Week 53 (hysterectomized participants) or Week 55/56 (non-hysterectomized participants).

    Number of participants with SAEs belonging to the system organ class (SOC) 'Reproductive system and breast disorders' or with preferred term (PT) 'Abdominal Pain', by hysterectomy status (hysterectomized and non-hysterectomized); Efficacy Study Part and Safety Study Part.

    Adverse events (AEs) are defined as occurring from time of first IMP intake until last visit or any event already present that worsens (in either intensity or frequency) after exposure to the treatment.

    AEs in SOC 'Reproductive System and Breast Disorders' or with PT 'Abdominal Pain' were reported separately for non-hysterectomized (NH) and hysterectomized women. For endometrial protection, NH women received commercially available P4 200 mg once daily for 14 consecutive days, after completing the E4/placebo treatment. All AEs were collected until the last visit, including the period of P4 intake, and reported grouped by arm (ESP: E4 15 mg/E4 20 mg/Placebo; SSP: E4 20 mg).

  48. Number of Participants With Non-serious Adverse Events (AEs) in SOC 'Reproductive System and Breast Disorders' or With PT 'Abdominal Pain' by Hysterectomy Status -- (Efficacy Study Part, Safety Study Part)

    Time frame: Day 1 (allocation to treatment) until Week 53 (hysterectomized participants) or Week 55/56 (non-hysterectomized participants).

    Number of participants with non-serious AEs at 2% threshold in any treatment group in the system organ class (SOC) 'Reproductive system and breast disorders' or with preferred term (PT) 'Abdominal Pain', during the Efficacy Study Part and the Safety Study Part.

    Adverse events (AEs) are defined as occurring from time of first IMP intake until last visit or any event already present that worsens (in either intensity or frequency) after exposure to the treatment.

    AEs in SOC 'Reproductive System and Breast Disorders' or with PT 'Abdominal Pain' were reported separately for non-hysterectomized (NH) and hysterectomized women. For endometrial protection, NH women received commercially available P4 200 mg once daily for 14 consecutive days, after completing the E4/placebo treatment. All AEs were collected until the last visit, including the period of P4 intake, and reported grouped by arm (ESP: E4 15 mg/E4 20 mg/Placebo; SSP: E4 20 mg).

Sponsors and collaborators

Lead sponsor

Estetra

Industry

Collaborators

  • ICON Clinical Research

Registry information

Official study 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 II)

Acronym: E4Comfort II

Important dates

Study start
2019
Primary completion
2022
Study completion
2022
First posted
Sep 16, 2019
Registry last updated
Dec 26, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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