E4Relief (Response to Estetrol in Life Improvement for MEnopausal-associated Hot Flushes)

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

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.

Study Overview

• Status: Completed
• Conditions: Hot Flushes
• Intervention / Treatment: Drug: Estetrol; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 260
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Liège, Belgium, 4000
    • Donesta Bioscience BV

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo	Drug: Placebo; 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.
Experimental: 2.5 mg estetrol	Drug: Estetrol; 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.; Other Names: E4
Experimental: 5 mg estetrol	Drug: Estetrol; 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.; Other Names: E4
Experimental: 10 mg estetrol	Drug: Estetrol; 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.; Other Names: E4
Experimental: 15 mg estetrol	Drug: Estetrol; 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.; Other Names: E4

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in weekly frequency of moderate to severe VMS from baseline to week 4.		From baseline to week 4
Change in weekly frequency of moderate to severe VMS from baseline to week 12.		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.	From baseline to week 4
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.	From baseline to week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	From baseline to week 12
Change in the Menopause Rating Scale (MRS) from baseline to week 5.		From baseline to week 5
Change in the Menopause Rating Scale (MRS) from baseline to week 12.		From baseline to week 12
Change from baseline to week 12 in Vaginal pH.		From baseline to week 12
Change from baseline to week 12 in Vaginal Maturation Index (MI) (parabasal and superficial cells)		From baseline to week 12
Serum concentration of triglycerides.		From baseline to week 12
Serum concentration of low density lipoprotein (LDL)-cholesterol.		Baseline and Week 12
Serum concentration of high density lipoprotein (HLD)-cholesterol.		Baseline and Week 12
Serum concentration of total cholesterol.		Baseline and Week 12
Fasting glycemia.		Baseline and Week 12
Serum concentration of glycated hemoglobin.		Baseline and Week 12
Homeostasis model assessment-estimated insulin resistance [HOMA-IR]		Baseline and Week 12
Serum concentration of prothrombin fragment 1 + 2.		Baseline and Week 12
Activated protein C sensitivity ratio (APCsr) (Endogenous Thrombin Potential [ETP]-Based).		Baseline and Week 12
Serum concentration of D-dimers.		Baseline and Week 12
Serum concentration of sex-hormone binding globulin (SHBG).		Baseline and Week 12
Serum concentration of antithrombin.		Baseline and Week 12
Serum concentration of protein-C.		Baseline and Week 12
Serum concentration of free protein-S.		Baseline and Week 12
Serum concentration of factor VIII.		Baseline and Week 12
Serum concentration of free tissue factor pathway inhibitor [TFPI].		Baseline and Week 12
Serum concentration of osteocalcin.		Baseline and Week 12
Serum concentration of C-terminal telopeptide [CTX-1]		Baseline and Week 12
Percentage of subjects who had a change in endometrial thickness at each study visit.		From baseline to week 16
Percentage of subjects with adverse events as a measure of safety and tolerability.		Up to week 16
Maximum concentration (Cmax) of E4 in plasma.		Up to 90 days
Time to Cmax (Tmax) of E4 in plasma.		Up to 90 days
Terminal half-life (T1/2) of E4 in plasma.		Up to 90 days
Area under the plasma concentration-time curve from baseline to the last quantifiable concentration following dosing (AUCtau) of E4.		Up to 90 days

Collaborators and Investigators

• Sponsor: Donesta Bioscience
• Collaborators: SynteractHCR
• Investigators: Study Director: Donesta Bioscience, Donesta Bioscience BV

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2016
• Primary Completion (Actual): January 22, 2018
• Study Completion (Actual): January 22, 2018

Study Registration Dates

• First Submitted: July 7, 2016
• First Submitted That Met QC Criteria: July 12, 2016
• First Posted (Estimate): July 15, 2016

Study Record Updates

• Last Update Posted (Actual): January 26, 2018
• Last Update Submitted That Met QC Criteria: January 25, 2018
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Menopause; Estetrol; Vasomotor symptoms
• Additional Relevant MeSH Terms: Hot Flashes
• Other Study ID Numbers: MIT-Do0001-C201; 2015-004018-44 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No