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    Summary
    EudraCT Number:2017-000142-22
    Sponsor's Protocol Code Number:148-2016
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-04-13
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2017-000142-22
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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)
    A.3.2Name or abbreviated title of the trial where available
    Therapeutical equivalence of estradiol vaginal tablets in postmenopausal women with vaginal atrophy
    A.4.1Sponsor's protocol code number148-2016
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorHelm AG
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportHelm AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHelm AG
    B.5.2Functional name of contact pointClinical Trials
    B.5.3 Address:
    B.5.3.1Street AddressNordkanalstrasse 28
    B.5.3.2Town/ cityHamburg
    B.5.3.3Post code20097
    B.5.3.4CountryGermany
    B.5.4Telephone number+494023750
    B.5.5Fax number+494023751845
    B.5.6E-mailRudolf.Theodor@helmag.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameEstradiol 10 μg vaginal tablets
    D.3.4Pharmaceutical form Vaginal tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPVaginal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNESTRADIOL HEMIHYDRATE
    D.3.9.1CAS number 35380-71-3
    D.3.9.4EV Substance CodeSUB11941MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10 (estradiol)
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Vagifem® 10 μg vaginal tablets
    D.2.1.1.2Name of the Marketing Authorisation holderNovo Nordisk A/S
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Vaginal tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPVaginal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNESTRADIOL HEMIHYDRATE
    D.3.9.1CAS number 35380-71-3
    D.3.9.4EV Substance CodeSUB11941MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10 (estradiol)
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboVaginal tablet
    D.8.4Route of administration of the placeboVaginal use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboVaginal tablet
    D.8.4Route of administration of the placeboVaginal use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Investigation of efficacy, safety and tolerability of estradiol vaginal tablets in postmenopausal women with vaginal atrophy
    E.1.1.1Medical condition in easily understood language
    Investigation of efficacy, safety and tolerability of estradiol vaginal tablets in postmenopausal women with vaginal atrophy
    E.1.1.2Therapeutic 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.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10047782
    E.1.2Term Vulvovaginal atrophy
    E.1.2System Organ Class 100000004872
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal 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
    E.4Principal 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
    E.5 End points
    E.5.1Primary 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

    E.5.1.1Timepoint(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

    E.5.2Secondary 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
    E.5.2.1Timepoint(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
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other 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
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    double-dummy
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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
    E.8.7Trial 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
    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.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months8
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 75
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 45
    F.4.2.2In the whole clinical trial 50
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    No treatment is planned at the end of the trial. However, patients will be informed, that their original therapy can be continued or they should visit the family doctor to decide upon treatment. In case that, due to participation in the trial health problems occur, which did not exist before participation, the site will conduct a detailed consultation with the patient about therapeutic measures and potential of recovery, observe and take first measures or initiate
    further treatments.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-05-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-05-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-01-17
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