| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Vasomotor Symptoms in Post-Menopausal Women |
|
| E.1.1.1 | Medical condition in easily understood language |
| Vasomotor Symptoms in Post-Menopausal Women |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036268 |
| E.1.2 | Term | Post-menopausal bleeding |
| E.1.2 | System Organ Class | 100000004872 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To define the minimum effective dose (MED) of the oral dose of E4 by evaluating changes in frequency and in severity of moderate to severe vasomotor symptoms (VMS). |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate effects of different doses of E4 on genitourinary syndrome of menopause (GSM) also called vulvovaginal atrophy (VVA), on vaginal maturation index (MI), on vaginal pH, on change in the Menopause Rating Scale (MRS), on lipid and glucose metabolism, on haemostatic and bone laboratory variables, and E4 concentrations at baseline and steady state.
Safety objectives: To evaluate safety in non-hysterectomised subjects by monitoring transvaginal ultrasonography (TVUS) change of endometrial thickness at each study visit during the E4/placebo treatment period and
by daily diary entry for bleeding pattern.
To evaluate safety in both hysterectomised and non-hysterectomised subjects by (serious) adverse event ([S]AE) monitoring, physical and gynaecological examination (including vital signs and breast examination), electrocardiogram (ECG), routine clinical laboratory tests
(e.g. haematology and chemistry) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Women aged 40 to 65 years, inclusive, 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.
2. Body Mass Index (BMI) between 18.0 and 35.0 kg/m², inclusive.
3. Post-menopausal status defined as levels of follicle stimulating hormone (FSH) >40 IU/L and:
- amenorrhoea for at least 12 consecutive months or,
- amenorrhoea for at least 6 months with estradiol (E2) < 20 pg/mL or,
- at least 6 weeks post-surgical bilateral oophorectomy with or without
hysterectomy with a copy of the pathology report or a statement on letterhead from the subject's physician documenting both ovaries were removed is required.
4. For non-hysterectomised women: intact uterus with bi-layer endometrial thickness ≤ 5 mm on TVUS
5. Negative pregnancy test.
6. Good physical and mental health, in the judgement of the Principal Investigator (PI), on the basis of medical, surgical and gynaecological history, physical examination, gynaecological examination, clinical laboratory, and vital signs.
7. Subject has provided signed and dated written informed consent before admission to the study.
8. Subject is able to understand and comply with the protocol requirements, instructions, and protocol-stated restrictions. |
|
| E.4 | Principal exclusion criteria |
1.For non-hysterectomised women: uterine disease or medical condition including :
a.Bi-layer endometrial thickness >5mm as determined by TVUS;
b.Presence of fibroid(s) that obscure(s) evaluation of endometrium by TVUS;
c.History or presence of uterine cancer;
d.Presence of endometrial hyperplasia;
e.Presence of an endometrial polyp with hyperplastic or malignant epithelium.
2.Undiagnosed vaginal bleeding in the last 12 months.
3.Any history of malignancy with the exception of basal cell or squamous
cell 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.
Note: A screening mammogram is required unless the subject has a written documentation of a mammogram performed within the last 9 months
4.Abnormal cervical Pap smear in non-hysterectomised subjects with evidence of cervical dysplasia greater than low grade squamous intraepithelial lesion.Women with a diagnosis of ASCUS may be enrolled
5.Systolic 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. Subjects with mild to moderate hypertension who are controlled on a stable antihypertension regimen may be enrolled if they meet the inclusion/exclusion criteria.
6.Any clinically significant abnormality identified on the screening 12-lead ECG.
7.History of venous or arterial thromboembolic disease (e.g., deep vein
thrombosis, pulmonary embolism, stroke,myocardial infarction, angina
pectoris, etc.),history of known coagulopathy or abnormal coagulation factors.
8.Diabetes mellitus with poor glycaemic control in the last 6 months assessed by laboratory values of glucose outside the normal ranges and glycated haemoglobin above7%.
9.Dyslipoproteinaemia predisposes the subject to ASCVD. If a subject has a 10 years ASCVD score ≥ 5% as calculated using the ASCVD risk estimator, she may not be included in the trial. In all cases, LDL
cholesterol level ≥ 190 mg/dL or triglycerides plasma level > 400 mg/dL is exclusionary.
If a subject is receiving a lipid-lowering therapy, her treatment has to be on a stable dose for at least 1 month before screening and the same eligibility criteria has to be used.
11.Presence or history of gallbladder disease, unless cholecystectomy has been performed
12.Systemic lupus erythematosus.
13.Multiple sclerosis.
14.Acute or chronic liver disease.
15.Acute or chronic renal impairment, including severe renal impairment.
16.Uncontrolled thyroid disorders.
17.Subject has a history of major depression or PTSD within 2 years, OR a history of other major psychiatric disorder at any time.
18.Use of oestrogen or progestin containing drug(s). A washout period is required before the Run-in Period in case of use of:
a.Vaginal hormonal products:washout of at least 4 weeks,
b.Transdermal oestrogen or oestrogen/ progestin:washout of at least 4 weeks,
c.Oral oestrogen and/or progestin:washout of at least 4 weeks,
d.Intrauterine progestin therapy:washout of at least 4 weeks,
Current users of progestin implants or oestrogen alone injectable drug therapy are not allowed to participate unless the treatment was stopped more than 3 months ago. Current users of oestrogen pellet therapy or progestin injectable drug therapy are not allowed to participate unless
the treatment was stopped more than 6 months ago.
19.Use of non-hormonal treatments to reduce hot flushes. A washout period of 1 week is required before the Run-in Period in the case of use of non-hormonal prescription and OTC treatments for hot flushes. Note
that if one of these treatments is concomitantly taken with an oestrogen
or progestin-containing drug, washout periods can be combined and must not be sequential.
20. Use of medication that may affect the outcome of the VMS endpoints within 28 days before the Run-in Period. This includes (but is not limited to): SSRIs, SNRIs, dopaminergic or antidopaminergic drugs, or
gabapentin
21.History or presence of allergy to the investigational product or drugs
of this class, or history of drug or other allergy that, in the opinion of the Investigator contraindicates subject participation.
22.History or presence of allergy or intolerance to any component of the
investigational product.
23.History of alcohol or substance abuse or dependence in the 12 months as determined by the Investigator, i.e. subject consumes
excessive alcohol, abuses drugs, or has a condition that could compromise the subject's ability to comply with study requirements in the Investigator's opinion.
25.Subjects with porphyria with known or suspected history of a clinically significant systemic diseases, unstable medical disorders, lifethreatening disease or current malignancies that would pose a risk to
the subject in the opinion of the Investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from baseline to week 4.
2. Change in weekly frequency of moderate to severe VMS from baseline to week 12.
3. Change in severity of moderate to severe VMS from baseline to week 4.
4. Change in severity of moderate to severe VMS from baseline to week 12. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Endpoints 1 and 3 at week 4 and endpoints 2 and 4 at week 12 |
|
| E.5.2 | Secondary end point(s) |
1. Vaginal dryness (none, mild, moderate or severe),
2. Vaginal and/or vulvar irritation/itching (none, mild, moderate or severe),
3. Dysuria (none, mild, moderate or severe),
4. Vaginal pain associated with sexual activity (none, mild, moderate or severe),
5. Vaginal bleeding associated with sexual activity (presence vs. absence).
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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