Hot FlushesPhase 2NCT02834312
E4Relief (Response to Estetrol in Life Improvement for MEnopausal-associated Hot Flushes)
A Phase 2 study testing Estetrol in people with Hot Flushes, run by Donesta Bioscience at 1 site in Belgium.
Trial 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. Read more about this study
- Who is it for?
- Ages 40 to 65 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Hot Flushes
- What is being tested?
- Estetrol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 260 participants
- Where
- 1 siteBelgium
- Study dates
- May 2016to 22 Jan 2018
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 65 years
- Women only
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 23Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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
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.
Read the 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.
- Conditions
- Hot Flushes
- Being tested
- Estetrol, Placebo
- Keywords
- Estetrol, Vasomotor symptoms, Menopause
- Medical subject headings
- Hot Flashes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EstetrolDrug
Also called E4
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.
PlaceboDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 2.5 mg estetrol | Experimental | Not described Receives: Drug: Estetrol |
| 5 mg estetrol | Experimental | Not described Receives: Drug: Estetrol |
| 10 mg estetrol | Experimental | Not described Receives: Drug: Estetrol |
| 15 mg estetrol | Experimental | Not described Receives: Drug: Estetrol |
| placebo | Placebo comparator | Not described Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in weekly frequency of moderate to severe VMS from baseline to week 4.
Measured: From baseline to week 4
Change in weekly frequency of moderate to severe VMS from baseline to week 12.
Measured: 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.
Measured: 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.
Measured: From baseline to week 12
Secondary outcomes (29)
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).
Measured: From baseline to week 12
Change in the Menopause Rating Scale (MRS) from baseline to week 5.
Measured: From baseline to week 5
Change in the Menopause Rating Scale (MRS) from baseline to week 12.
Measured: From baseline to week 12
Change from baseline to week 12 in Vaginal pH.
Measured: From baseline to week 12
Change from baseline to week 12 in Vaginal Maturation Index (MI) (parabasal and superficial cells)
Measured: From baseline to week 12
Serum concentration of triglycerides.
Measured: From baseline to week 12
Serum concentration of low density lipoprotein (LDL)-cholesterol.
Measured: Baseline and Week 12
Serum concentration of high density lipoprotein (HLD)-cholesterol.
Measured: Baseline and Week 12
Serum concentration of total cholesterol.
Measured: Baseline and Week 12
Fasting glycemia.
Measured: Baseline and Week 12
Serum concentration of glycated hemoglobin.
Measured: Baseline and Week 12
Homeostasis model assessment-estimated insulin resistance [HOMA-IR]
Measured: Baseline and Week 12
Serum concentration of prothrombin fragment 1 + 2.
Measured: Baseline and Week 12
Activated protein C sensitivity ratio (APCsr) (Endogenous Thrombin Potential [ETP]-Based).
Measured: Baseline and Week 12
Serum concentration of D-dimers.
Measured: Baseline and Week 12
Serum concentration of sex-hormone binding globulin (SHBG).
Measured: Baseline and Week 12
Serum concentration of antithrombin.
Measured: Baseline and Week 12
Serum concentration of protein-C.
Measured: Baseline and Week 12
Serum concentration of free protein-S.
Measured: Baseline and Week 12
Serum concentration of factor VIII.
Measured: Baseline and Week 12
Serum concentration of free tissue factor pathway inhibitor [TFPI].
Measured: Baseline and Week 12
Serum concentration of osteocalcin.
Measured: Baseline and Week 12
Serum concentration of C-terminal telopeptide [CTX-1]
Measured: Baseline and Week 12
Percentage of subjects who had a change in endometrial thickness at each study visit.
Measured: From baseline to week 16
Percentage of subjects with adverse events as a measure of safety and tolerability.
Measured: Up to week 16
Maximum concentration (Cmax) of E4 in plasma.
Measured: Up to 90 days
Time to Cmax (Tmax) of E4 in plasma.
Measured: Up to 90 days
Terminal half-life (T1/2) of E4 in plasma.
Measured: Up to 90 days
Area under the plasma concentration-time curve from baseline to the last quantifiable concentration following dosing (AUCtau) of E4.
Measured: Up to 90 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Jul 2016 (estimated)
- Study startMay 2016
- Primary completion22 Jan 2018
- Study completion22 Jan 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Hot FlushesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 260 participants (actual)
Sponsor and investigators
- Lead sponsor
- Donesta Bioscience
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- SynteractHCR
- Responsible party
- Sponsor
- Investigators
- Donesta Bioscience, Study director, Donesta Bioscience BV
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02834312
- Sponsor's protocol ID
- MIT-Do0001-C201
- Other IDs
- 2015-004018-44, 2015
- Status last verified
- Nov 2024
- First submitted
- 7 Jul 2016
- Last updated
- 18 Nov 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Gaspard U, Taziaux M, Jost M, Coelingh Bennink HJT, Utian WH, Lobo RA, Foidart JM. A multicenter, randomized, placebo-controlled study to select the minimum effective dose of estetrol in postmenopausal participants (E4Relief): part 2-vaginal cytology, genitourinary syndrome of menopause, and health-related quality of life. Menopause. 2023 May 1;30(5):480-489. doi: 10.1097/GME.0000000000002167. Epub 2023 Feb 20.
PubMed 36809193
Study at a glance
From the registry record, last updated by the sponsor on 18 Nov 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02834312
- Acronym / sponsor ID
- MIT-Do0001-C201
- Conditions
- Hot Flushes
- Keywords
- Estetrol, Vasomotor symptoms, Menopause
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 260 participants (actual)
- Lead sponsor
- Donesta BioscienceIndustry (pharma, biotech, devices)
- Collaborators
- SynteractHCR
- Study start
- May 2016 (actual)
- Primary completion
- 22 Jan 2018 (actual)
- Study completion
- 22 Jan 2018 (actual)
- First posted
- 15 Jul 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| 2.5 mg estetrol | Experimental | Drug: Estetrol |
| 5 mg estetrol | Experimental | Drug: Estetrol |
| 10 mg estetrol | Experimental | Drug: Estetrol |
| 15 mg estetrol | Experimental | Drug: Estetrol |
| placebo | Placebo comparator | Drug: Placebo |
Who may qualify
- Ages
- 40 to 65 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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.
Key exclusion criteria (23 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EstetrolAlso: E4All 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. | Drug | 10 mg estetrol, 15 mg estetrol, 2.5 mg estetrol, 5 mg estetrol |
| Placebo1 capsule will be administered QD per os for at least 12 consecutive weeks until the last biological assessments (Day 90 maximum) have been performed. | Drug | placebo |
Primary outcome
Change in weekly frequency of moderate to severe VMS from baseline to week 4.
Time frame: From baseline to week 4
Change in weekly frequency of moderate to severe VMS from baseline to week 12.
Time frame: From baseline to week 12
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.
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.
29 secondary outcomes
Change from baseline to week 12 in genitourinary symptoms (GSM) of menopause
Time frame: From baseline to week 12
Change in the Menopause Rating Scale (MRS) from baseline to week 5.
Time frame: From baseline to week 5
Change in the Menopause Rating Scale (MRS) from baseline to week 12.
Time frame: From baseline to week 12
Change from baseline to week 12 in Vaginal pH.
Time frame: From baseline to week 12
Change from baseline to week 12 in Vaginal Maturation Index (MI) (parabasal and superficial cells)
Time frame: From baseline to week 12
Serum concentration of triglycerides.
Time frame: From baseline to week 12
Serum concentration of low density lipoprotein (LDL)-cholesterol.
Time frame: Baseline and Week 12
Serum concentration of high density lipoprotein (HLD)-cholesterol.
Time frame: Baseline and Week 12
Serum concentration of total cholesterol.
Time frame: Baseline and Week 12
Fasting glycemia.
Time frame: Baseline and Week 12
Serum concentration of glycated hemoglobin.
Time frame: Baseline and Week 12
Homeostasis model assessment-estimated insulin resistance [HOMA-IR]
Time frame: Baseline and Week 12
Serum concentration of prothrombin fragment 1 + 2.
Time frame: Baseline and Week 12
Activated protein C sensitivity ratio (APCsr) (Endogenous Thrombin Potential [ETP]-Based).
Time frame: Baseline and Week 12
Serum concentration of D-dimers.
Time frame: Baseline and Week 12
Serum concentration of sex-hormone binding globulin (SHBG).
Time frame: Baseline and Week 12
Serum concentration of antithrombin.
Time frame: Baseline and Week 12
Serum concentration of protein-C.
Time frame: Baseline and Week 12
Serum concentration of free protein-S.
Time frame: Baseline and Week 12
Serum concentration of factor VIII.
Time frame: Baseline and Week 12
Serum concentration of free tissue factor pathway inhibitor [TFPI].
Time frame: Baseline and Week 12
Serum concentration of osteocalcin.
Time frame: Baseline and Week 12
Serum concentration of C-terminal telopeptide [CTX-1]
Time frame: Baseline and Week 12
Percentage of subjects who had a change in endometrial thickness at each study visit.
Time frame: From baseline to week 16
Percentage of subjects with adverse events as a measure of safety and tolerability.
Time frame: Up to week 16
Maximum concentration (Cmax) of E4 in plasma.
Time frame: Up to 90 days
Time to Cmax (Tmax) of E4 in plasma.
Time frame: Up to 90 days
Terminal half-life (T1/2) of E4 in plasma.
Time frame: Up to 90 days
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Nov 2024.
- Derived from this study: PubMed 36809193Gaspard U, Taziaux M, Jost M, Coelingh Bennink HJT, Utian WH, Lobo RA, Foidart JM. A multicenter, randomized, placebo-controlled study to select the minimum effective dose of estetrol in postmenopausal participants (E4Relief): part 2-vaginal cytology, genitourinary syndrome of menopause, and health-related quality of life. Menopause. 2023 May 1;30(5):480-489. doi: 10.1097/GME.0000000000002167. Epub 2023 Feb 20.
- Trial results were released to public view on the EudraCT (EudraCT Number: 2015-004018-44).Link provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Donesta Bioscience study director
Donesta Bioscience BV
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Estetrol in people with Hot Flushes, run by Donesta Bioscience at 1 site in Belgium.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Nov 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in weekly frequency of moderate to severe VMS from baseline to week 4. (time frame: From baseline to week 4). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02834312, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Nov 2024.