E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Investigation of efficacy, safety and tolerability of estradiol vaginal tablets in postmenopausal women with vaginal atrophy |
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E.1.1.1 | Medical condition in easily understood language |
Investigation of efficacy, safety and tolerability of estradiol vaginal tablets in postmenopausal women with vaginal atrophy |
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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 | 10047782 |
E.1.2 | Term | Vulvovaginal atrophy |
E.1.2 | System Organ Class | 100000004872 |
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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 |
Aims of this clinical trial are:
- Characterisation and comparison of efficacy of Test vs. Reference with regard to pharmacodynamic (PD) surrogate parameters (primary endpoints: change from baseline of vaginal maturation value after 2 weeks of treatment and change from baseline of vaginal pH after 6 weeks of treatment)
- Assessment of superiority of Test vs. Placebo with regard to PD primary endpoints
- Assessment of therapeutic equivalence of Test vs. Reference with regard to PD primary endpoints
- Characterisation of systemic exposure by means of AUC- and Cmax–values of Test and Reference vaginal tablets containing 10 μg estradiol on Day 14 after multiple dose vaginal application (PK group)
- Descriptive characterisation of safety and tolerability of the Test and Reference treatments. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age: 18 years or older 2. Good state of health commensurate with age 3. Postmenopausal state defined as follows: - last spontaneous menstruation at least 1 year prior to the study and FSH (plasma) >= 40 IU/l, estradiol (serum) <= 20 pg/ml, or - bilateral ovariectomy with or without hysterectomy at least 3 months prior to individual enrolment 4. Maturation value ≤ 50 % 5. Vaginal pH > 5.0 6. Investigator’s assessment of vaginal health: visually assessed signs of vaginal atrophy (a thinned vaginal mucosa or a mucosa with flattening of folds; a dry, fragile, or pale vaginal mucosa; the presence of petechiae or any other alteration that the investigator considers indicative of vaginal atrophy) 7. At least one urogenital symptom self-assessed by the subjects (vaginal dryness, vaginal and/or vulvar irritation/itching, vaginal soreness, dysuria, dyspareunia, vaginal bleeding associated with sexual activity, recurrent vaginal infections, hyperactive bladder with urge incontinence or stress incontinence 8. Non-smoker or ex-smoker for at least 6 months 9. Written informed consent, after having been informed about benefits and potential risks of the clinical trial, as well as details of the insurance taken out to cover the subjects participating in this clinical trial |
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E.4 | Principal exclusion criteria |
Safety concerns 1. Existing cardiac and/or haematological diseases or pathological findings, which might interfere with the safety or tolerability of the active ingredient 2. Existing hepatic and/or renal diseases or pathological findings, which might interfere with the safety or tolerability, and/or pharmacokinetics of the active ingredient 3. History of relevant CNS and/or psychiatric disorders and/or currently treated CNS and/or psychiatric disorders 4. Known allergic reactions/hypersensitivity to the active ingredient used or to constituents of the pharmaceutical preparations 5. Subjects with severe allergies or multiple drug allergies unless it is judged as not relevant for the clinical trial by the investigator 6. Systolic blood pressure > 145 mmHg 7. Diastolic blood pressure >90 mmHg 8. Pulse rate < 50 bpm or > 100 bpm 9. Any laboratory value outside of normal and judged by investigator as relevant for participation under safety considerations 10. Any further contraindication to estrogen therapy - Known, past or suspected breast cancer - Known, past or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer) - Genital bleeding - Untreated endometrial hyperplasia - Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism) - Known thrombophilic disorders - Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction) - Porphyria 11. If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment - Leiomyoma (uterine fibroids) or endometriosis - Risk factors for thromboembolic disorders - Risk factors for oestrogen-dependent tumours, e.g. 1st degree heredity for breast cancer - Untreated or uncontrolled hypertension - Liver disorders (e.g. liver adenoma) - Diabetes mellitus with or without vascular involvement - Cholelithiasis - Migraine or (severe) headache - Systemic lupus erythematosus - A history of endometrial hyperplasia - Epilepsy - Asthma - Otosclerosis 12. Diagnosis of a cervical smear: findings classified in a group higher than IIa according to the Munich III nomenclature (or corresponding findings according to the Bethesda system) 13. For females with an intact uterus: no confirmation of an inactive endometrial lingering and/or endometrial thickness of ≥5 mm 14. Vaginal infection requiring further treatment 15. Hormone replacement therapy, therapy with phytoestrogens, local vaginal hormonal therapy or other drugs acting on the estrogen receptor within 3 months prior to first IMP administration (e.g. diethylstilbestrol, tibolone, SERM) 16. Use of systemic or intravaginal corticosteroids within 8 weeks prior to first IMP administration
Lack of suitability for the clinical trial 17. Acute or chronic diseases which may interfere with the pharmacokinetics of the IMP or the aims of the clinical trial 18. History of or current drug or alcohol dependence 19. Administration of any investigational medicinal product during the last 2 months prior to individual enrolment of the subject 20. Use of any type of vaginal or vulvar preparations within seven days prior to first IMP administration
Administrative reasons 21. Subjects suspected or known not to follow instructions 22. Subjects who are unable to understand the written and verbal instructions, in particular regarding the risks and inconveniences they will be exposed to during their participation in the clinical trial 23. Subject who is a family member or work associate (secretary, nurse, technician, etc.) of the investigator 24. Subject who has forfeited his freedom by administrative or legal award, or who is under guardianship.
For subjects of the PK group only: 25. Positive anti-HIV-test (if positive to be verified by western blot), HBs-AG-test (if positive to be verified by test for HBc-IgM) or anti-HCV-test 26. Regular intake of alcoholic food or beverages of ≥ 20 g pure ethanol per day 27. Regular intake of caffeine containing food or beverages of ≥ 500 mg caffeine per day 28. Blood donation or other blood loss of more than 400 ml within the last 2 months prior to individual enrolment of the subject |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy: - Change from baseline of vaginal maturation value (MV) after 2 weeks of treatment - Change from baseline of vaginal pH after 6 weeks of treatment
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy: - Change in vaginal maturation value (MV) after 2 weeks of treatment - Change in vaginal pH after 6 weeks of treatment
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E.5.2 | Secondary end point(s) |
Efficacy: - Investigator’s assessment of vaginal health (signs of vaginal atrophy) - Self-assessment by the subjects (symptoms of vaginal atrophy)
Safety - AEs, local tolerability, systemic exposure to estradiol |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Assessment of signs and symptoms of vaginal atrophy after 2 and 6 weeks of treatment
Safety - AEs, local tolerability after 2 and 6 weeks of treatment - systemic exposure to estradiol after 2 weeks of treatment |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
- Assessment of superiority of Test vs. Placebo with regard to PD primary endpoints - Assessment of therapeutic equivalence of Test vs. Reference with regard to PD primary endpoints |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Bulgaria |
Germany |
Moldova, Republic of |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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End of the clinical trial is defined as the day of shipment of the last Case Report Form (CRF) to the company responsible for data management and clinical biometrics. |
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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 | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 8 |