Clinical Trial Page

Summary
EudraCT Number:2019-004934-40
Sponsor's Protocol Code Number:20072651
National Competent Authority:Denmark - DHMA
Clinical Trial Type:EEA CTA
Trial Status:Ongoing
Date on which this record was first entered in the EudraCT database:2020-04-24
Trial 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
A. Protocol Information
A.1Member State ConcernedDenmark - DHMA
A.2EudraCT number2019-004934-40
A.3Full title of the trial
Endocrine, cardiovascular, pharmacologic and physiologic aspects of sex hormone treatment in Turner syndrome - project part B
Endokrinologiske, kardiovaskulære, farmakologiske og fysiologiske aspekter ved kønshormonbehandling ved Turner syndrom - projekt del B
A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
Hormonal, cardiovascular, medical, muscle- and fitness aspects of sex hormone treatment in patients with Turner syndrome - project part B
Hormonel, hjertekar, medicinsk, muskel- og konditionsmæssige aspekter ved kønshormonbehandling hos patienter med Turner syndrom - projekt del B
A.3.2Name or abbreviated title of the trial where available
Aspects of sex hormone treatment in Turner syndrome
Aspekter af kønshormonbehandling ved Turner syndrom
A.4.1Sponsor's protocol code number20072651
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 SponsorDepartment of Endocrinology and Internal Medicine, Aarhus University Hospital
B.1.3.4CountryDenmark
B.3.1 and B.3.2Status of the sponsorNon-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1Name of organisation providing supportAarhus Universityhospital
B.4.2CountryDenmark
B.4.1Name of organisation providing supportAarhus University
B.4.2CountryDenmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1Name of organisationDiabetes and Hormone Diseases, Aarhus Universityhospital
B.5.2Functional name of contact pointMedical Research Lab
B.5.3 Address:
B.5.3.1Street AddressPalle Juul-Jensens Boulevard 165
B.5.3.2Town/ cityAarhus N
B.5.3.3Post code8200
B.5.3.4CountryDenmark
B.5.4Telephone number004578455470
B.5.6E-mailauh.doh.klinik@rm.dk
D. IMP Identification
D.IMP: 1
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 Estrofem
D.2.1.1.2Name of the Marketing Authorisation holderDanish Medicines Agency
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 Film-coated tablet
D.3.4.1Specific paediatric formulation No
D.3.7Routes of administration for this IMPOral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNEstradiol
D.3.9.3Other descriptive nameESTRADIOL
D.3.9.4EV Substance CodeSUB07242MIG
D.3.10 Strength
D.3.10.1Concentration unit mg milligram(s)
D.3.10.2Concentration typeequal
D.3.10.3Concentration number2
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 Divigel
D.2.1.1.2Name of the Marketing Authorisation holderDanish Medicines Agency
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.3.1Product nameDivigel
D.3.2Product code 9688
D.3.4Pharmaceutical form Gel
D.3.4.1Specific paediatric formulation No
D.3.7Routes of administration for this IMPCutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNEstradiol
D.3.9.3Other descriptive nameESTRADIOL
D.3.9.4EV Substance CodeSUB07242MIG
D.3.10 Strength
D.3.10.1Concentration unit mg milligram(s)
D.3.10.2Concentration typeequal
D.3.10.3Concentration number1
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
E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1Medical condition(s) being investigated
Ovarian dysgenesis and related hypogonadism causes by Turner syndrome
Ovariedysfunktion og relateret hypogonadisme forårsaget af Turner syndrom
E.1.1.1Medical condition in easily understood language
Failure of the ovaries and related decreased production of female sex hormone, estrogen, caused by the congenital Turner syndrome
Manglede funktion af æggestokkene og dermed relateret nedsat produktion af kvindelig kønshormon, østrogen, forårsaget af det medfødte Turner syndrom
E.1.1.2Therapeutic area Diseases [C] - Hormonal diseases [C19]
MedDRA Classification
E.1.2 Medical condition or disease under investigation
E.1.2Version 20.0
E.1.2Level PT
E.1.2Classification code 10045181
E.1.2Term Turner's syndrome
E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
E.1.3Condition being studied is a rare disease Yes
E.2 Objective of the trial
E.2.1Main objective of the trial
1. Find the equipotency for different estradiol regimens, oral versus transdermal (TD) route of administration, using different estradiol-dependent surrogate markers.
2. Clarify the endocrine, metabolic, cardiovascular, physiologic and thromboembolic risk factors in Turner syndrome (TS) after a wash out period off estrogen.
3. To compare the effect of two different estradiol (E2) regimens, oral versus TD route, in terms of equipotency by using different estradiol-dependent surrogate markers.
4. To examine long term effects of E2 by the two administration routes on endocrine, metabolic, cardiovascular, physiologic and thromboembolic risk endpoints.
1. Finde ækvipotens for forskellige østradiolregimer, oral versus transdermal (TD) administrationsvej, ved hjælp af forskellige østradiol-afhængige surrogatmarkører.
2. Klarlægge endokrine, metaboliske, kardiovaskulære og tromboemboliske risikofaktorer ved TS efter en periode med udvaskning af østrogen.
3. Sammenligne effekten af to forskellige E2 regimer, oral versus TD administrationsvej, med hensyn til ækvipotens ved hjælp af forskellige østradiol-afhængige surrogatmarkører.
4. Undersøge langtidseffekterne af E2 ved de to forskellige administrationsveje på endokrine, fysiologiske, metaboliske, kardiovaskulære og koagulatoriske effektmål.
E.2.2Secondary objectives of the trial
Not applicable
Ikke anvendelig
E.2.3Trial contains a sub-study No
E.3Principal inclusion criteria
For participants with TS:
- Diagnosis of TS regardless of karyotype
- Age 18-40 years
- Receives estrogen treatment in advance

For the healthy controls:
- Woman
- Age 18-40 years
- Formerly healthy and healthy
- Does not receive medication
- Does not use any contraceptive pills
- Have no mental or psychiatric disorders
For deltagerne med TS:
- Diagnose med TS uanset karyotype
- Alderen 18-40 år
- Modtager behandling med østrogen i forvejen

For de raske kontroller:
- Kvinde
- Alderen 18-40 år
- Tidligere sund og rask
- Modtager ikke medicin
- Bruger ikke nogen former for præventions-piller
- Har ingen psykiske eller psykiatriske lidelser
E.4Principal exclusion criteria
- Active systemic chronic diseases
- Known with or with suspicion of breast cancer
- Known or suspected estradiol-dependent tumors (endometrial cancer or similar)
- Untreated endometrial hyperplasia
- Current or past venous thromboembolism
- Acute or previous liver disease, where liver enzymes are still elevated by at least a factor of 3
- Known hypersensitivity to active substances or excipients in any of the used medicines
- Pregnancy
- The menopause of the control group alone
- Aktive systemiske kroniske sygdomme
- Kendt med eller med mistanke om brystkræft
- Kendt med eller med mistanke om østradiolafhængige tumorer (endometriecancer eller lignende)
- Ubehandlet endometrie hyperplasi
- Nuværende eller tidligere venøs tromboembolisme
- Akut eller tidligere leversygdom, hvor leverenzymerne stadig er forhøjet med mindst en faktor på 3
- Kendt overfølsomhed overfor aktive stoffer eller hjælpestoffer i nogen af de anvendte lægemidler
- Graviditet
- Overgangsalderen for kontrolgruppen alene
E.5 End points
E.5.1Primary end point(s)
1. Sex hormone level after a wash out period:
The level of sex hormone imbalance after a wash out period without estrogen measured by the bloodsamples serum FSH and serum LH.

2. Blood test changes:
The change in the blood test values from baseline within the areas of metabolism, endocrine, cardiovascular and coagulation.

3. Bones:
Bone density measured by DEXA scan

4. Body composition:
Measured by bio impedance

5. Cardiovascular status:
24 hours blood pressure measurement and a sphygmocor scan

6. Hand strength test:
Maximal hand strength meassured in kg

7. Quadriceps strength test:
Maximal isometric muscle strength of both quadriceps meassured at once in nM.

8. Muscle quality:
MR scan of both quadriceps: to measure muscle cross-sectional area (CSA) and fat content in the muscle. Muscle quality = maximum quadriceps strength meassured in nM/muscle CSA.

9. Fitness:
Meassured with a bike test: fat oxidation test with increasing intensity - 5 min break - VO2max test with the value: ml/O2/kg

10. Jumping height:
maximal jumping height meassured in cm
1.Kønshormonniveau efter en udvaskningsperiode:
Niveauet af kønshormonubalance efter en udvaskningsperiode uden østrogen målt med blodprøverne serum FSH og serum LH.

2. Ændringer i blodprøverne:
Ændringen i blodprøveværdierne fra baseline inden for metabolismen, endokrinologi, kardiovaskularitet og koagulation.

3. Knogler:
Knogletæthed målt ved DEXA-scan

4. Kropssammensætning:
Målt med bioimpedans

5. Kardiovaskulær status:
24 timers blodtryksmåling og en sphygmocor-scanning

6.Hand styrke test:
Maksimal håndstyrke målt i kg

7. Quadriceps styrke test:
Maksimal isometrisk muskelstyrke af begge quadriceps målt på én gang i nM.

8. Muskelkvalitet:
MR-scanning af begge quadriceps: til måling af muskeltværsnit (CSA) og fedtindhold i musklen. Muskelkvalitet = maksimal quadriceps styrke målt i nM / muskel CSA.

9. Fitness:
Målt med en cykeltest: fedtoxidationstest med stigende intensitet - 5 min pause - VO2max test med værdien: ml / O2 / kg

10. Hoppehøjde:
Maksimal hoppehøjde målt i cm
E.5.1.1Timepoint(s) of evaluation of this end point
For all the endpoints evaluation after 1 month (the first wash out period), after 6 months (the first intervention period) and after further 7 months (the second wash period and second intervention period).
For alle slutpunkter evaluering efter 1 måned (den første udvaskningsperiode), efter 6 måneder (den første interventionsperiode) og efter yderligere 7 måneder (den anden vaskeperiode og anden interventionsperiode).
E.5.2Secondary end point(s)
11.Experienced health-related quality of life and functioning:
Self-reported quality of life questionnaires - SF-36. It consists of eight scaled scores. Each scale is transformed directly into a 0-100 scale. The lower the score the greater the difficulty.

12.Life quality:
Self-reported quality of life questionnaires - WHOQoL-Bref. Based on the participant's answer to the 26 questions in the questionnaire, an overall quality of life profile for the participant is formed, which consists of a quality of life score for each dimension of the questionnaire. These are physical health, mental health, social relationships and the participants' surroundings.
1. Erfaren sundhedsrelateret livskvalitet og funktionsevne:
Selvrapporterede spørgeskemaer om livskvalitet - SF-36. Det består af otte skalerede scoringer. Hver skala transformeres direkte til en 0-100 skala. Jo lavere score jo større er vanskeligheden.

12. Livskvalitet
Selvrapporterede spørgeskemaer om livskvalitet - WHOQoL-Bref. Baseret på deltagerens svar på de 26 spørgsmål i spørgeskemaet dannes en samlet livskvalitetsprofil for deltageren, der består af en livskvalitetsscore for hver dimension af spørgeskemaet. Dette er fysisk sundhed, mental sundhed, sociale forhold og deltagernes omgivelser.
E.5.2.1Timepoint(s) of evaluation of this end point
Evaluation after 1 month (the first wash out period), after 6 months (the first intervention period) and after further 7 months (the second wash period and second intervention period).
Evaluering efter 1 måned (den første udvaskningsperiode), efter 6 måneder (den første interventionsperiode) og efter yderligere 7 måneder (den anden vaskeperiode og anden interventionsperiode).
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 No
E.6.5Efficacy No
E.6.6Pharmacokinetic No
E.6.7Pharmacodynamic No
E.6.8Bioequivalence Yes
E.6.9Dose response No
E.6.10Pharmacogenetic No
E.6.11Pharmacogenomic No
E.6.12Pharmacoeconomic No
E.6.13Others No
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) No
E.7.4Therapeutic use (Phase IV) Yes
E.8 Design of the trial
E.8.1Controlled No
E.8.1.1Randomised Yes
E.8.1.2Open Yes
E.8.1.3Single blind No
E.8.1.4Double blind No
E.8.1.5Parallel group Yes
E.8.1.6Cross over Yes
E.8.1.7Other No
E.8.2 Comparator of controlled trial
E.8.2.1Other medicinal product(s) No
E.8.2.2Placebo No
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 No
E.8.6 Trial involving sites outside the EEA
E.8.6.1Trial being conducted both within and outside the EEA No
E.8.6.2Trial being conducted completely outside of the EEA No
E.8.7Trial 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
The trial will end when the last participants has gone through the last examination day (after the first wash period, the first intervention period, the second wash out period and the second intervention period).
Forsøget afsluttes, når den sidste deltager har gennemgået den sidste undersøgelsesdag (efter den første vaskeperiode, den første interventionsperiode, den anden udvaskningsperiode og den anden interventionsperiode).
E.8.9 Initial estimate of the duration of the trial
E.8.9.1In the Member State concerned years
E.8.9.1In the Member State concerned months
E.8.9.1In the Member State concerned days
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: 50
F.1.3Elderly (>=65 years) No
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 state50
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)
After completing the project, patients return to their usual medication. If, during the trial, there are indications that they are not receiving the correct dosage, their regular therapists are advised if patients so desire for dose optimization.
Efter endt projekt går patienter tilbage til deres vanlige medicin. Såfremt der under forsøget findes indikationer for de ikke får den korrekte dosering, underrettes der vanlige behandler såfremt patienterne ønsker dette med henblik på dosisoptimering.
G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
N. Review by the Competent Authority or Ethics Committee in the country concerned
N.Competent Authority Decision Authorised
N.Date of Competent Authority Decision2021-03-19
N.Ethics Committee Opinion of the trial applicationFavourable
N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
N.Date of Ethics Committee Opinion2020-06-08
P. End of Trial
P.End of Trial StatusOngoing

Sponsors and Collaborators

Medical Conditions

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