Assessment of therapeutical equivalence of a newly developed vaginal tablet containing 10 µg of estradiol in comparison with a marketed reference product (Vagifem®)–a double-blind, double-dummy, multiple dose, parallel-group, placebo- and active-controlled trial with additional characterisation of systemic exposure in postmenopausal female volunteers (women for whom vaginal bleeding has stopped) suffering from vaginal atrophy (thinning and shrinking of vaginal tissues with decreased lubrication)

• Register: EUCTR
• Last refreshed on: 30 April 2019
• Main ID: EUCTR2017-000142-22-DE
• Date of registration: 13/04/2017
• Prospective Registration: Yes
• Primary sponsor: Helm AG
• Public title: Assessment of therapeutical equivalence of a newly developed vaginal tablet containing 10 µg of estradiol in comparison with a marketed reference product (Vagifem®)–a double-blind, double-dummy, multiple dose, parallel-group, placebo- and active-controlled trial with additional characterisation of systemic exposure in postmenopausal female volunteers (women for whom vaginal bleeding has stopped) suffering from vaginal atrophy (thinning and shrinking of vaginal tissues with decreased lubrication)
• Scientific title: Assessment of therapeutical equivalence of a newly developed vaginal tablet containing 10 µg of estradiol in comparison with a marketed reference product (Vagifem®) – a double-blind, double-dummy, multiple dose, parallel-group, placebo- and active-controlled trial with additional characterisation of systemic exposure in postmenopausal female volunteers suffering from vaginal atrophy - Therapeutical equivalence of estradiol vaginal tablets in postmenopausal women with vaginal atrophy
• Date of first enrolment: 24/05/2017
• Target sample size: 50
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-000142-22
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: yes; Other trial design description: double-dummy; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: yes; Other: no; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Bulgaria, Germany, Moldova, Republic of

Contacts

• Name: Clinical Trials
• Affiliation: Helm AG

• Name: Clinical Trials
• Affiliation: Helm AG

Key inclusion & exclusion criteria

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
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 75
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 25

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 pharm

Age minimum:
Age maximum:
Gender:
Female: yes
Male: no

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]

Investigation of efficacy, safety and tolerability of estradiol vaginal tablets in postmenopausal women with vaginal atrophy
MedDRA version: 20.0 Level: LLT Classification code 10047782 Term: Vulvovaginal atrophy System Organ Class: 100000004872

Intervention(s)

Product Name: Estradiol 10 µg vaginal tablets
Pharmaceutical Form: Vaginal tablet
INN or Proposed INN: ESTRADIOL HEMIHYDRATE
CAS Number: 35380-71-3
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 10 (estradiol)-
Pharmaceutical form of the placebo: Vaginal tablet
Route of administration of the placebo: Vaginal use

Trade Name: Vagifem® 10 µg vaginal tablets
Pharmaceutical Form: Vaginal tablet
INN or Proposed INN: ESTRADIOL HEMIHYDRATE
CAS Number: 35380-71-3
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 10 (estradiol)-
Pharmaceutical form of the placebo: Vaginal tablet
Route of administration of the placebo: Vaginal use

Primary Outcome(s)

Secondary Objective: Not applicable

Main Objective: 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.

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

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

Secondary Outcome(s)

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

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

Secondary ID(s)

148-2016

Source(s) of Monetary Support

Helm AG

Ethics review

Status: Approved
Approval date:
Contact: