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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02834312
Recruitment Status : Completed
First Posted : July 15, 2016
Last Update Posted : January 26, 2018
Sponsor:
Collaborator:
SynteractHCR
Information provided by (Responsible Party):
Donesta Bioscience

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.

Condition or disease Intervention/treatment Phase
Hot Flushes Drug: Estetrol Drug: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 260 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : May 2016
Actual Primary Completion Date : January 22, 2018
Actual Study Completion Date : January 22, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Menopause

Arm Intervention/treatment
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 Name: 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 Name: 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 Name: 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 Name: E4

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.




Primary Outcome Measures :
  1. Change in weekly frequency of moderate to severe VMS from baseline to week 4. [ Time Frame: From baseline to week 4 ]
  2. Change in weekly frequency of moderate to severe VMS from baseline to week 12. [ Time Frame: From baseline to week 12 ]
  3. Change in severity of moderate to severe VMS from baseline to week 4. [ Time Frame: 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.


  4. Change in severity of moderate to severe VMS from baseline to week 12. [ Time Frame: 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 :
  1. Change from baseline to week 12 in genitourinary symptoms (GSM) of menopause [ Time Frame: From baseline to week 12 ]

    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).

  2. Change in the Menopause Rating Scale (MRS) from baseline to week 5. [ Time Frame: From baseline to week 5 ]
  3. Change in the Menopause Rating Scale (MRS) from baseline to week 12. [ Time Frame: From baseline to week 12 ]
  4. Change from baseline to week 12 in Vaginal pH. [ Time Frame: From baseline to week 12 ]
  5. Change from baseline to week 12 in Vaginal Maturation Index (MI) (parabasal and superficial cells) [ Time Frame: From baseline to week 12 ]
  6. Serum concentration of triglycerides. [ Time Frame: From baseline to week 12 ]
  7. Serum concentration of low density lipoprotein (LDL)-cholesterol. [ Time Frame: Baseline and Week 12 ]
  8. Serum concentration of high density lipoprotein (HLD)-cholesterol. [ Time Frame: Baseline and Week 12 ]
  9. Serum concentration of total cholesterol. [ Time Frame: Baseline and Week 12 ]
  10. Fasting glycemia. [ Time Frame: Baseline and Week 12 ]
  11. Serum concentration of glycated hemoglobin. [ Time Frame: Baseline and Week 12 ]
  12. Homeostasis model assessment-estimated insulin resistance [HOMA-IR] [ Time Frame: Baseline and Week 12 ]
  13. Serum concentration of prothrombin fragment 1 + 2. [ Time Frame: Baseline and Week 12 ]
  14. Activated protein C sensitivity ratio (APCsr) (Endogenous Thrombin Potential [ETP]-Based). [ Time Frame: Baseline and Week 12 ]
  15. Serum concentration of D-dimers. [ Time Frame: Baseline and Week 12 ]
  16. Serum concentration of sex-hormone binding globulin (SHBG). [ Time Frame: Baseline and Week 12 ]
  17. Serum concentration of antithrombin. [ Time Frame: Baseline and Week 12 ]
  18. Serum concentration of protein-C. [ Time Frame: Baseline and Week 12 ]
  19. Serum concentration of free protein-S. [ Time Frame: Baseline and Week 12 ]
  20. Serum concentration of factor VIII. [ Time Frame: Baseline and Week 12 ]
  21. Serum concentration of free tissue factor pathway inhibitor [TFPI]. [ Time Frame: Baseline and Week 12 ]
  22. Serum concentration of osteocalcin. [ Time Frame: Baseline and Week 12 ]
  23. Serum concentration of C-terminal telopeptide [CTX-1] [ Time Frame: Baseline and Week 12 ]
  24. Percentage of subjects who had a change in endometrial thickness at each study visit. [ Time Frame: From baseline to week 16 ]
  25. Percentage of subjects with adverse events as a measure of safety and tolerability. [ Time Frame: Up to week 16 ]
  26. Maximum concentration (Cmax) of E4 in plasma. [ Time Frame: Up to 90 days ]
  27. Time to Cmax (Tmax) of E4 in plasma. [ Time Frame: Up to 90 days ]
  28. Terminal half-life (T1/2) of E4 in plasma. [ Time Frame: Up to 90 days ]
  29. 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 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   40 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02834312


Locations
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Belgium
Donesta Bioscience BV
Liège, Belgium, 4000
Sponsors and Collaborators
Donesta Bioscience
SynteractHCR
Investigators
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Study Director: Donesta Bioscience Donesta Bioscience BV
Additional Information:
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Responsible Party: Donesta Bioscience
ClinicalTrials.gov Identifier: NCT02834312    
Other Study ID Numbers: MIT-Do0001-C201
2015-004018-44 ( EudraCT Number )
First Posted: July 15, 2016    Key Record Dates
Last Update Posted: January 26, 2018
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Donesta Bioscience:
Estetrol
Vasomotor symptoms
Menopause
Additional relevant MeSH terms:
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Hot Flashes