Back to resultsE4Relief (Response to Estetrol in Life Improvement for MEnopausal-associated Hot Flushes)
Primary Purpose
Hot Flushes
Status
Completed
Phase
Phase 2
Locations
Belgium
Study Type
Interventional
Intervention
Estetrol
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Hot Flushes focused on measuring Estetrol, Vasomotor symptoms, Menopause
Eligibility Criteria
Inclusion Criteria:
- Women presenting at least 7 moderate to severe hot flushes/day or at least 50 moderate to severe hot flushes/week in the week preceding randomization.
- Body Mass Index (BMI) between 18.0 and 35.0 kg/m², inclusive.
- Post-menopausal status.
- Intact uterus.
- Negative pregnancy test.
- Good physical and mental health.
- Subject has provided signed and dated written informed consent before admission to the study.
- Subject is able to understand and comply with the protocol requirements, instructions, and protocol-stated restrictions.
Exclusion Criteria:
- Uterine disease or any medical conditions associated with an increase in endometrial thickness.
- Any history of malignancy with the exception of basal cell (excluded if within the prior 2 years) or squamous cell (excluded if within the prior one year) carcinoma of the skin. Any clinically significant findings at the breast examination and/or on mammography suspicious of breast malignancy that would require additional clinical testing to rule out breast cancer.
- Abnormal cervical Pap smear.
- Systolic blood pressure (BP) outside the range 90 to 140 mmHg, diastolic BP outside the range 60 to 90 mmHg, and/or heart rate outside the range 40 to 100 bpm.
- Any clinically significant abnormality identified on the screening 12-lead ECG.
- History of venous or arterial thromboembolic disease, history of known coagulopathy or abnormal coagulation factors.
- Diabetes mellitus with poor glycaemic control.
- Dyslipoproteinaemia at screening.
- Smoking >10 cigarettes/day.
- Presence or history of gallbladder disease, unless cholecystectomy has been performed.
- Systemic lupus erythematosus.
- Multiple sclerosis.
- Acute or chronic liver disease.
- Acute or chronic renal impairment.
- Uncontrolled thyroid disorders.
- Use of oestrogen or progestin containing drug(s).
- Use of non-hormonal treatments to reduce hot flushes.
- History or presence of allergy or intolerance to any component of the investigational product.
- History of alcohol or substance abuse or dependence in the 12 months before screening as determined by the Investigator.
- Sponsor, CRO or Investigator's site personnel or their relatives directly affiliated with this study.
- Subjects with known or suspected history of a clinically significant systemic diseases, 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 study within 1 month (30 days) or have received an investigational drug within the last 3 months (90 days) prior to study entry.
- Is judged by the Investigator to be unsuitable for any reason.
Sites / Locations
- Donesta Bioscience BV
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm Type
Experimental
Experimental
Experimental
Experimental
Placebo Comparator
Arm Label
2.5 mg estetrol
5 mg estetrol
10 mg estetrol
15 mg estetrol
placebo
Arm Description
Outcomes
Primary Outcome Measures
Change in weekly frequency of moderate to severe VMS from baseline to week 4.
Change in weekly frequency of moderate to severe VMS from baseline to week 12.
Change in severity of moderate to severe VMS from baseline to week 4.
The Severity Scoring System of VMS will be documented by the subjects by using the following scores:
None (0) = No VMS symptoms; Mild (1) = Sensation of heat without sweating; Moderate (2) = Sensation of heat with sweating. Able to continue activity; Severe (3) = Sensation of heat with sweating. Causes cessation of activity.
Change in severity of moderate to severe VMS from baseline to week 12.
The Severity Scoring System of VMS will be documented by the subjects by using the following scores:
None (0) = No VMS symptoms; Mild (1) = Sensation of heat without sweating; Moderate (2) = Sensation of heat with sweating. Able to continue activity; Severe (3) = Sensation of heat with sweating. Causes cessation of activity.
Secondary Outcome Measures
Change from baseline to week 12 in genitourinary symptoms (GSM) of menopause
The following GSM symptoms will be evaluated:
Vaginal dryness (none, mild, moderate or severe)
Vaginal and/or vulvar irritation/itching (none, mild, moderate or severe)
Dysuria (none, mild, moderate or severe)
Vaginal pain associated with sexual activity (none, mild, moderate or severe)
Vaginal bleeding associated with sexual activity (presence vs. absence).
Change in the Menopause Rating Scale (MRS) from baseline to week 5.
Change in the Menopause Rating Scale (MRS) from baseline to week 12.
Change from baseline to week 12 in Vaginal pH.
Change from baseline to week 12 in Vaginal Maturation Index (MI) (parabasal and superficial cells)
Serum concentration of triglycerides.
Serum concentration of low density lipoprotein (LDL)-cholesterol.
Serum concentration of high density lipoprotein (HLD)-cholesterol.
Serum concentration of total cholesterol.
Fasting glycemia.
Serum concentration of glycated hemoglobin.
Homeostasis model assessment-estimated insulin resistance [HOMA-IR]
Serum concentration of prothrombin fragment 1 + 2.
Activated protein C sensitivity ratio (APCsr) (Endogenous Thrombin Potential [ETP]-Based).
Serum concentration of D-dimers.
Serum concentration of sex-hormone binding globulin (SHBG).
Serum concentration of antithrombin.
Serum concentration of protein-C.
Serum concentration of free protein-S.
Serum concentration of factor VIII.
Serum concentration of free tissue factor pathway inhibitor [TFPI].
Serum concentration of osteocalcin.
Serum concentration of C-terminal telopeptide [CTX-1]
Percentage of subjects who had a change in endometrial thickness at each study visit.
Percentage of subjects with adverse events as a measure of safety and tolerability.
Maximum concentration (Cmax) of E4 in plasma.
Time to Cmax (Tmax) of E4 in plasma.
Terminal half-life (T1/2) of E4 in plasma.
Area under the plasma concentration-time curve from baseline to the last quantifiable concentration following dosing (AUCtau) of E4.
Full Information
NCT ID
NCT02834312
First Posted
July 7, 2016
Last Updated
January 25, 2018
Sponsor
Donesta Bioscience
Collaborators
SynteractHCR
1. Study Identification
Unique Protocol Identification Number
NCT02834312
Brief Title
E4Relief (Response to Estetrol in Life Improvement for MEnopausal-associated Hot Flushes)
Official Title
A Multicentre Dose-Finding, Randomised, Double-Blind, Placebo-Controlled Study to Select the Daily Oral Dose of Estetrol (E4) for the Treatment of Vasomotor Symptoms in Post-Menopausal Women
Study Type
Interventional
2. Study Status
Record Verification Date
October 2017
Overall Recruitment Status
Completed
Study Start Date
May 2016 (Actual)
Primary Completion Date
January 22, 2018 (Actual)
Study Completion Date
January 22, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Donesta Bioscience
Collaborators
SynteractHCR
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
This dose-finding study is being conducted to select the daily oral dose of estetrol (E4) for the treatment of vasomotor symptoms (VMS) in post-menopausal women.
Detailed Description
Oestrogen therapy is the most consistently effective treatment used in the US and Europe for menopausal VMS. Following the safety issues reported in the primary Women's Health Initiative publications and with continued subject requests for treatment, a challenge to clinicians has been to identify the lowest effective dose of oestrogen for alleviating menopausal symptoms. In addition, it is a challenge to develop a safer oestrogen than those currently used.
For this purpose, the minimum effective dose (MED) of E4 has to be defined for the treatment of menopausal symptoms. The present study is intended to evaluate changes in frequency and in severity of moderate to severe VMS in order to define the MED.
Subjects will be randomly allocated to either treatment group (2.5 mg E4, 5 mg E4, 10 mg E4, 15 mg E4, or placebo) in a 1:1:1:1:1 ratio. All treatments (E4 or Placebo) will be administered once daily (QD) per os for at least 12 consecutive weeks until the last biological assessments (Day 90 maximum) have been performed.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hot Flushes
Keywords
Estetrol, Vasomotor symptoms, Menopause
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
260 (Actual)
8. Arms, Groups, and Interventions
Arm Title
2.5 mg estetrol
Arm Type
Experimental
Arm Title
5 mg estetrol
Arm Type
Experimental
Arm Title
10 mg estetrol
Arm Type
Experimental
Arm Title
15 mg estetrol
Arm Type
Experimental
Arm Title
placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Estetrol
Other Intervention Name(s)
E4
Intervention Description
All treatments (E4 [2.5 mg, 5 mg, 10 mg, 15 mg] capsule) will be administered once daily (QD) per os for at least 12 consecutive weeks until the last biological assessments (Day 90 maximum) have been performed.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
1 capsule will be administered QD per os for at least 12 consecutive weeks until the last biological assessments (Day 90 maximum) have been performed.
Primary Outcome Measure Information:
Title
Change in weekly frequency of moderate to severe VMS from baseline to week 4.
Time Frame
From baseline to week 4
Title
Change in weekly frequency of moderate to severe VMS from baseline to week 12.
Time Frame
From baseline to week 12
Title
Change in severity of moderate to severe VMS from baseline to week 4.
Description
The Severity Scoring System of VMS will be documented by the subjects by using the following scores:
None (0) = No VMS symptoms; Mild (1) = Sensation of heat without sweating; Moderate (2) = Sensation of heat with sweating. Able to continue activity; Severe (3) = Sensation of heat with sweating. Causes cessation of activity.
Time Frame
From baseline to week 4
Title
Change in severity of moderate to severe VMS from baseline to week 12.
Description
The Severity Scoring System of VMS will be documented by the subjects by using the following scores:
None (0) = No VMS symptoms; Mild (1) = Sensation of heat without sweating; Moderate (2) = Sensation of heat with sweating. Able to continue activity; Severe (3) = Sensation of heat with sweating. Causes cessation of activity.
Time Frame
From baseline to week 12
Secondary Outcome Measure Information:
Title
Change from baseline to week 12 in genitourinary symptoms (GSM) of menopause
Description
The following GSM symptoms will be evaluated:
Vaginal dryness (none, mild, moderate or severe)
Vaginal and/or vulvar irritation/itching (none, mild, moderate or severe)
Dysuria (none, mild, moderate or severe)
Vaginal pain associated with sexual activity (none, mild, moderate or severe)
Vaginal bleeding associated with sexual activity (presence vs. absence).
Time Frame
From baseline to week 12
Title
Change in the Menopause Rating Scale (MRS) from baseline to week 5.
Time Frame
From baseline to week 5
Title
Change in the Menopause Rating Scale (MRS) from baseline to week 12.
Time Frame
From baseline to week 12
Title
Change from baseline to week 12 in Vaginal pH.
Time Frame
From baseline to week 12
Title
Change from baseline to week 12 in Vaginal Maturation Index (MI) (parabasal and superficial cells)
Time Frame
From baseline to week 12
Title
Serum concentration of triglycerides.
Time Frame
From baseline to week 12
Title
Serum concentration of low density lipoprotein (LDL)-cholesterol.
Time Frame
Baseline and Week 12
Title
Serum concentration of high density lipoprotein (HLD)-cholesterol.
Time Frame
Baseline and Week 12
Title
Serum concentration of total cholesterol.
Time Frame
Baseline and Week 12
Title
Fasting glycemia.
Time Frame
Baseline and Week 12
Title
Serum concentration of glycated hemoglobin.
Time Frame
Baseline and Week 12
Title
Homeostasis model assessment-estimated insulin resistance [HOMA-IR]
Time Frame
Baseline and Week 12
Title
Serum concentration of prothrombin fragment 1 + 2.
Time Frame
Baseline and Week 12
Title
Activated protein C sensitivity ratio (APCsr) (Endogenous Thrombin Potential [ETP]-Based).
Time Frame
Baseline and Week 12
Title
Serum concentration of D-dimers.
Time Frame
Baseline and Week 12
Title
Serum concentration of sex-hormone binding globulin (SHBG).
Time Frame
Baseline and Week 12
Title
Serum concentration of antithrombin.
Time Frame
Baseline and Week 12
Title
Serum concentration of protein-C.
Time Frame
Baseline and Week 12
Title
Serum concentration of free protein-S.
Time Frame
Baseline and Week 12
Title
Serum concentration of factor VIII.
Time Frame
Baseline and Week 12
Title
Serum concentration of free tissue factor pathway inhibitor [TFPI].
Time Frame
Baseline and Week 12
Title
Serum concentration of osteocalcin.
Time Frame
Baseline and Week 12
Title
Serum concentration of C-terminal telopeptide [CTX-1]
Time Frame
Baseline and Week 12
Title
Percentage of subjects who had a change in endometrial thickness at each study visit.
Time Frame
From baseline to week 16
Title
Percentage of subjects with adverse events as a measure of safety and tolerability.
Time Frame
Up to week 16
Title
Maximum concentration (Cmax) of E4 in plasma.
Time Frame
Up to 90 days
Title
Time to Cmax (Tmax) of E4 in plasma.
Time Frame
Up to 90 days
Title
Terminal half-life (T1/2) of E4 in plasma.
Time Frame
Up to 90 days
Title
Area under the plasma concentration-time curve from baseline to the last quantifiable concentration following dosing (AUCtau) of E4.
Time Frame
Up to 90 days
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Women presenting at least 7 moderate to severe hot flushes/day or at least 50 moderate to severe hot flushes/week in the week preceding randomization.
Body Mass Index (BMI) between 18.0 and 35.0 kg/m², inclusive.
Post-menopausal status.
Intact uterus.
Negative pregnancy test.
Good physical and mental health.
Subject has provided signed and dated written informed consent before admission to the study.
Subject is able to understand and comply with the protocol requirements, instructions, and protocol-stated restrictions.
Exclusion Criteria:
Uterine disease or any medical conditions associated with an increase in endometrial thickness.
Any history of malignancy with the exception of basal cell (excluded if within the prior 2 years) or squamous cell (excluded if within the prior one year) carcinoma of the skin. Any clinically significant findings at the breast examination and/or on mammography suspicious of breast malignancy that would require additional clinical testing to rule out breast cancer.
Abnormal cervical Pap smear.
Systolic blood pressure (BP) outside the range 90 to 140 mmHg, diastolic BP outside the range 60 to 90 mmHg, and/or heart rate outside the range 40 to 100 bpm.
Any clinically significant abnormality identified on the screening 12-lead ECG.
History of venous or arterial thromboembolic disease, history of known coagulopathy or abnormal coagulation factors.
Diabetes mellitus with poor glycaemic control.
Dyslipoproteinaemia at screening.
Smoking >10 cigarettes/day.
Presence or history of gallbladder disease, unless cholecystectomy has been performed.
Systemic lupus erythematosus.
Multiple sclerosis.
Acute or chronic liver disease.
Acute or chronic renal impairment.
Uncontrolled thyroid disorders.
Use of oestrogen or progestin containing drug(s).
Use of non-hormonal treatments to reduce hot flushes.
History or presence of allergy or intolerance to any component of the investigational product.
History of alcohol or substance abuse or dependence in the 12 months before screening as determined by the Investigator.
Sponsor, CRO or Investigator's site personnel or their relatives directly affiliated with this study.
Subjects with known or suspected history of a clinically significant systemic diseases, 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 study within 1 month (30 days) or have received an investigational drug within the last 3 months (90 days) prior to study entry.
Is judged by the Investigator to be unsuitable for any reason.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Donesta Bioscience
Organizational Affiliation
Donesta Bioscience BV
Official's Role
Study Director
Facility Information:
Facility Name
Donesta Bioscience BV
City
Liège
ZIP/Postal Code
4000
Country
Belgium
12. IPD Sharing Statement
Plan to Share IPD
No
Links:
URL
http://www.e4relief.com/
Description
Related Info
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E4Relief (Response to Estetrol in Life Improvement for MEnopausal-associated Hot Flushes)
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