Menopausal Symptoms, Vasomotor Symptoms
Conditions
Keywords
Estetrol, Hot Flushes, Vasomotor Symptoms
Brief 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)
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.
Interventions
DRUGEstetrol
Estetrol oral tablet: administered orally once daily
DRUGPlacebo
Placebo oral tablet: administered orally once daily
DRUGProgesterone
Progesterone oral tablet: administered orally once daily
Sponsors
ICON Clinical Research
Estetra
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This study consists of 3 blinded arms (efficacy part) and 1 open-label arm (safety part).
Intervention model description
This study consists of 3 blinded arms (efficacy part) and 1 open-label arm (safety part).
Eligibility
Sex/Gender
FEMALE
Age
40 Years to 65 Years
Healthy volunteers
Yes
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; * 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; 1. 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; 2. 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: 1. 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); 2. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 4 (Efficacy Study Part) | Baseline and Week 4 | 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 |
| Mean change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 12 (Efficacy Study Part) | Baseline and Week 12 | 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 |
| Mean change in severity of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 4 (Efficacy Study Part) | Baseline and Week 4 | 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 |
| Mean change in severity of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 12 (Efficacy Study Part) | Baseline and Week 12 | 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 |
| Incidence of endometrial hyperplasia with up to 12 months of treatment based on endometrial biopsies (Endometrial and General Safety Study Part) | Screening and Week 53 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean change from Baseline to Week 6 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 6 | 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 |
| Mean change from Baseline to Week 7 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 7 | 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 |
| Mean change from Baseline to Week 8 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 8 | 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 |
| Mean change from Baseline to Week 9 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 9 | 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 |
| Mean change from Baseline to Week 10 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 10 | 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 |
| Mean change from Baseline to Week 11 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 11 | 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 |
| Mean change from Baseline to Week 12 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 12 | 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 |
| Mean change from Baseline to Week 1 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 1 | 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 |
| Mean change from Baseline to Week 2 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 2 | 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 |
| Mean change from Baseline to Week 3 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 3 | 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 |
| Mean change from Baseline to Week 4 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 4 | 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 |
| Mean change from Baseline to Week 5 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 5 | 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 |
| Mean change from Baseline to Week 6 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 6 | 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 |
| Mean change from Baseline to Week 7 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 7 | 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 |
| Mean change from Baseline to Week 8 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 8 | 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 |
| Mean change from Baseline to Week 9 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 9 | 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 |
| Mean change from Baseline to Week 10 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 10 | 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 |
| Mean change from Baseline to Week 11 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 11 | 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 |
| Mean change from Baseline to Week 12 in the weekly frequency and severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 12 | 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 |
| 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) | Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 | 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). |
| 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) | Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 | 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). |
| 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) | Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 | 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). |
| 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) | Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 | 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). |
| 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) | Week 4 | 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. |
| 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) | Week 12 | 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. |
| Change from Baseline to Week 12 in vulvovaginal atrophy (VVA) symptoms (Efficacy Study Part) | Baseline and Week 12 | 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. |
| Frequency of subjects in the different endometrial categories according to Blaustein's pathology (Efficacy Study Part) | Screening and Week 13 | 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. |
| 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) | Baseline and Week 12 | 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. |
| Change from Baseline to Week 12 in plasma concentration of triglycerides (Efficacy Study Part) | Baseline and Week 12 | — |
| Change from Baseline to Week 12 in plasma concentration of low-density lipoprotein (LDL)-cholesterol (Efficacy Study Part) | Baseline and Week 12 | — |
| Change from Baseline to Week 12 in plasma concentration of total cholesterol (Efficacy Study Part) | Baseline and Week 12 | — |
| Change from Baseline to Week 12 in the total cholesterol/high density cholesterol (HDL) cholesterol ratio (Efficacy Study Part) | Baseline and Week 12 | — |
| Change from Baseline to Week 12 in the HDL-cholesterol ratio (Efficacy Study Part) | Baseline and Week 12 | — |
| Change from Baseline to Week 12 in plasma concentration of lipoprotein (a) (Efficacy Study Part) | Baseline and Week 12 | — |
| Change from Baseline to Week 12 in fasting glycaemia (Efficacy Study part) | Baseline and Week 12 | — |
| Change from Baseline to Week 12 in plasma concentration of insulin (Efficacy Study Part) | Baseline and Week 12 | — |
| Change from Baseline to Week 12 in plasma concentration of glycated hemoglobin (Efficacy Study Part) | Baseline and Week 12 | — |
| Change from Baseline to Week 12 in Homeostasis model-assessment-estimated insulin resistance (HOMA-IR) (Efficacy Study Part) | Baseline and Week 12 | — |
| 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) | Baseline and Week 12 | 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. |
| Total score in treatment satisfaction using the Clinical Global Impression (CGI) questionnaire (Efficacy Study Part) | Weeks 4 and 12 | 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. |
| Number of participants with treatment-emergent adverse events (TEAEs) (Efficacy Study Part) | From baseline to Follow-up visit (up to Week 16) | 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. |
| Number of participants with changes in physical and gynecological examination results (Efficacy Study Part) | Screening and Week 13 | 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. |
| Number of participants with changes in vital sign results (Efficacy Study Part) | From screening to Week 13 | Vital signs will include height, body weight, body mass index, sitting systolic and diastolic blood pressures, and heart rate. |
| Number of participants with changes in electrocardiogram (ECG) results (Efficacy Study Part) | Screening and Week 13 | 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. |
| Number of participants with changes in breast examination results (Efficacy Study Part) | Screening and Week 13 | — |
| Number of participants with changes in routine clinical laboratory test results (Efficacy Study Part) | Screening, Baseline and Week 13 | Routine laboratory tests include hematology and chemistry. |
| Change from baseline to each measured time point in endometrial thickness (Efficacy Study Part) | Screening, Week 13, Week 16 | Endometrial thickness will be assessed by transvaginal ultrasound (TVUS). Baseline: data will be recorded at Screening. |
| Number of participants with vaginal bleeding and/or spotting during each 28-day cycle of treatment with E4 (Efficacy Study Part) | From Baseline up to Follow-up (Week 16) | 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. |
| Number of days with bleeding and/or spotting during each 28-day cycle of treatment (Efficacy Study Part) | From Baseline up to Follow-up (Week 16) | 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. |
| Number of participants with amenorrhea (absence of any bleeding or spotting) during each 28-day cycle of treatment with E4 (Efficacy Study Part) | From Baseline up to Follow-up (Week 16) | 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. |
| Cumulative rates of amenorrhea (Efficacy Study Part) | From Baseline up to Follow-up (Week 16) | The rate of amenorrhea is defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. |
| Number of participants with treatment-emergent adverse events (TEAEs) (Endometrial and General Safety Part) | From baseline to Week 53 | 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. |
| Number of participants with changes in physical and gynecological examination results (Endometrial and General Safety Part) | Screening and Week 53 | 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. |
| Number of participants with changes in vital sign results (Endometrial and General Safety Part) | From screening to Week 53 | Vital signs will include height, body weight, body mass index, sitting systolic and diastolic blood pressures, and heart rate. |
| Number of participants with changes in breast examination results (Endometrial and General Safety Part) | From screening to Week 53 | Vital signs will include height, body weight, body mass index, sitting systolic and diastolic blood pressures, and heart rate. |
| Number of participants with changes in electrocardiogram (ECG) results (Endometrial and General Safety Part) | Screening and Week 53 | 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. |
| Number of participants with changes in mammography results (Endometrial and General Safety Part) | Screening and Week 53 | — |
| Number of participants with changes in routine clinical laboratory test results (Endometrial and General Safety Part) | Screening, Baseline and Week 13 | Routine laboratory tests include hematology and chemistry. |
| Number of women with vaginal bleeding and/or spotting during each 28-day cycle of treatment with E4 (Endometrial and General Safety Part) | From Baseline to Week 53 | 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. |
| Number of days with bleeding and/or spotting during each 28-day cycle of treatment (Endometrial and General Safety Part) | From Baseline to Week 53 | 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. |
| 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) | From Baseline to Week 53 | 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. |
| Cumulative rates of amenorrhea (Endometrial and General Safety Part) | From Baseline to Week 53 | The rate of amenorrhea is defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. |
| 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) | Baseline and Weeks 12 and 52 | 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. |
| 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) | Weeks 4, 12, and 52 | 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. |
| Change from Baseline to Weeks 12 and 52 in plasma concentration of triglycerides (Endometrial and General Safety Part) | Baseline and Weeks 12 and 52 | — |
| Change from Baseline to Weeks 12 and 52 in plasma concentration of high-density lipoprotein (HDL)-cholesterol (Endometrial and General Safety Part) | Baseline and Weeks 12 and 52 | — |
| Change from Baseline to Weeks 12 and 52 in plasma concentration of low-density lipoprotein (LDL)-cholesterol (Endometrial and General Safety Part) | Baseline and Weeks 12 and 52 | — |
| Change from Baseline to Weeks 12 and 52 in plasma concentration of total cholesterol (Endometrial and General Safety Part) | Baseline and Weeks 12 and 52 | — |
| Change from Baseline to Weeks 12 and 52 in the total cholesterol/high density cholesterol (HDL) cholesterol ratio (Endometrial and General Safety Part) | Baseline and Weeks 12 and 52 | — |
| Change from Baseline to Weeks 12 and 52 in plasma concentration of lipoprotein (a) (Endometrial and General Safety Part) | Baseline and Weeks 12 and 52 | — |
| Mean change from Baseline to Week 1 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 1 | 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 |
| Change from Baseline to Weeks 12 and 52 in plasma concentration of insulin (Endometrial and General Safety Part) | Baseline and Weeks 12 and 52 | — |
| Change from Baseline to Weeks 12 and 52 in plasma concentration of glycated hemoglobin (Endometrial and General Safety Part) | Baseline and Weeks 12 and 52 | — |
| Change from Baseline to Weeks 12 and 52 in Homeostasis model-assessment-estimated insulin resistance (HOMA-IR) (Endometrial and General Safety Part) | Baseline and Weeks 12 and 52 | — |
| Change from Baseline to each measured time point in endometrial thickness (Endometrial and General Safety Study Part) | Screening, Baseline, Weeks 13, 29, and 53 | Endometrial thickness will be assessed by transvaginal ultrasound (TVUS). |
| Frequency of subjects in the different endometrial categories according to Blaustein's pathology (Endometrial and General Safety Study Part) | Screening and Week 53 | 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. |
| Change from Baseline to Weeks 12 and 52 in fasting glycaemia (Endometrial and General Safety Part) | Baseline and Weeks 12 and 52 | — |
| Mean change from Baseline to Week 2 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 2 | 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 |
| Mean change from Baseline to Week 3 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) ((Efficacy Study Part) | Baseline and Week 3 | 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 |
| Mean change from Baseline to Week 4 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy part) | Baseline and Week 4 | 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 |
| Mean change from Baseline to Week 5 in the weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) | Baseline and Week 5 | 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 |
Countries
Argentina, Brazil, Canada, Czechia, Hungary, Italy, Lithuania, Poland, Romania, Russia, Slovakia, Spain, United Kingdom, United States
Outcome results
None listed