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

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.

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.

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.

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.

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.

Serum concentration of total cholesterol (Efficacy study part).

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

Serum concentration of total cholesterol (Safety study part).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Serum concentration of triglycerides (Efficacy study part).

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

Serum concentration of triglycerides (Safety study part).

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

Hemoglobin A1c (Efficacy study part).

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

Hemoglobin A1c = Glycated hemoglobin

Hemoglobin A1c (Safety study part).

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

Hemoglobin A1c = Glycated hemoglobin

Concentration of fasting glucose in plasma.

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

Concentration of fasting glucose in plasma.

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

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.

Serum concentration of insulin (Efficacy study part).

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

Serum concentration of insulin (Safety study part).

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

Angiotensinogen (Efficacy study part).

Change from Baseline to Week 12 and Week 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.

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.

Prothrombin fragment 1 + 2 (Efficacy study part).

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

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.

Protein-C (Efficacy study part).

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

Free Protein-S (Efficacy study part).

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

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

Change from Baseline to Week 12 and Week 52.

Calcium (Efficacy study part).

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

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

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

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

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

25-Hydroxyvitamin D (Efficacy study part).

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

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.

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

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

Endometrial thickness was assessed by transvaginal ultrasound (TVUS).

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.

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.

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.

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.

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).

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).