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    Summary
    EudraCT Number:2015-003670-32
    Sponsor's Protocol Code Number:REFLECT
    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:2016-04-07
    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 number2015-003670-32
    A.3Full title of the trial
    A dual-center prospective phase I/II trial to establish safety, tolerability and to obtain first data on efficacy of losartan in children with recessive dystrophic epidermolysis bullosa (RDEB)
    Eine bizentrische prospektive Phase I/II Studie zur Etablierung von Sicherheit, Verträglichkeit und zur Erfassung erster Daten zur Wirksamkeit von Losartan bei Kindern mit rezessiv dystropischer Epidermis bullosa
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase I/II trial to establish safety, tolerability and efficacy of losartan in children with epidermolysis bullosa
    Phase I/II Studie zur Etablierung von Sicherheit, Verträglichkeit und Wirksamkeit von Losartan bei Kindern mit Epidermolysis bullosa
    A.3.2Name or abbreviated title of the trial where available
    REFLECT
    A.4.1Sponsor's protocol code numberREFLECT
    A.5.4Other Identifiers
    Name:DRKSNumber:DRKS00009269
    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 SponsorMedical Center - University of Freiburg
    B.1.3.4CountryGermany
    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 supportDEBRA
    B.4.2CountryAustria
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedical Center - University of Freiburg
    B.5.2Functional name of contact pointCoordinating Investigator
    B.5.3 Address:
    B.5.3.1Street AddressHauptstrasse 7
    B.5.3.2Town/ cityFreiburg
    B.5.3.3Post code79104
    B.5.3.4CountryGermany
    B.5.4Telephone number+490761270-67100
    B.5.5Fax number+490761270-67200
    B.5.6E-maildimitra.kiritsi@uniklinik-freiburg.de
    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 Yes
    D.2.1.1.1Trade name Losartan HEXAL
    D.2.1.1.2Name of the Marketing Authorisation holderHexal AG
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 INNlosartan potassium
    D.3.9.3Other descriptive nameLOSARTAN POTASSIUM
    D.3.9.4EV Substance CodeSUB02974MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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
    Recessive dystrophic epidermolysis bullosa (RDEB)
    Rezessiv dystrophische Epidermolysis bullosa
    E.1.1.1Medical condition in easily understood language
    Epidermolysis bullosa
    Epidermolysis bullosa
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10014989
    E.1.2Term Epidermolysis bullosa
    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
    Establish tolerability and saftey of losartan in children with moderate to serve RDEB
    E.2.2Secondary objectives of the trial
    Obtain first information on the efficacy of losartan in improving the disease manifestations and quality of life, and reducing inflammation and fibrosis in moderate to severe RDEB over a period of 9 months
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written informed consent of parents or legal guardian obtained according to international guidelines and local laws;
    2. Patient’s assent (if applicable according to patient’s age and understanding);
    3. Male or female patients from 2 to 16 years (age of > 25 months);
    4. Molecularly confirmed diagnosis of moderate to severe RDEB. If the patient is completely collagen VII-deficient, as shown by negative collagen VII immunofluorescence staining of a skin biopsy, no genetic confirmation of the diagnosis will be required for inclusion in the study. In case of residual collagen VII expression, the COL7A1 gene will be analyzed for mutations, to confirm the diagnosis of RDEB;
    5. Ability of the patient (if applicable according to patient’s age and understanding), parents or legal guardian to understand the nature of the trial and trial-related procedures and to comply with them;
    6. Able to travel to trial site for all clinic visits;
    E.4Principal exclusion criteria
    1. Simultaneous or previous participation in any interventional trial within the past 3 months before entering this trial; participation in simultaneous registry and diagnostic trials during the trials is allowed;
    2. Anemia with hemoglobin < 8 g/dl;
    3. Hypotension (defined as age-related systolic blood pressure under the 5th percentile);
    4. Cardiologic contraindications, such as severe heart failure with ejection fraction < 35%;
    5. Patient requires any medications that are likely to cause interactions with losartan, e.g. rifampicin, ACE-inhibitors;
    6. Renal artery stenosis or renal insufficiency with creatinine clearance < 30 ml/min;
    7. Liver failure;
    8. Severe, untreated electrolyte disturbances;
    9. History of cancer or chronic viral infections (HBV, HCV, HIV);
    10. Hypersensitivity to losartan or any of the excipients;
    11. Current pregnancy or nursing period;
    12. For female patients of child-bearing age: unwillingness to use adequate contraception or to stay sexually abstinent during the course of the trial;
    13. Known or persistent abuse of medication, drugs or alcohol;
    14. Persons who are in a relationship of dependence/employment with the sponsor or the investigator.
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint is defined as occurrence of a serious safety concern, specified as one of the following side effects of losartan:
    1) clinically relevant severe hypotension i.e. the patient experiences continuous dizziness and headaches owing to the low blood pressure, leading to interruption of study medication;
    2) immediate hypersensitivity reactions to the drug
    (Serious) adverse events, evaluated by monitoring heart rate and function and blood pressure, using echocardiography, home blood pressure monitoring devices, and blood tests throughout the study
    3)clinical relevant severe hypo- und hyperkalemia
    E.5.1.1Timepoint(s) of evaluation of this end point
    the primary endpoint will be documented as SAE. All SAEs will be assessed from first intake of the IMP until 30 days after last intake of the IMP: day 1 until day 309 +/- 7 days)
    E.5.2Secondary end point(s)
    Efficacy will be assessed using validated scoring systems for the clinical manifestations of RDEB :
    • Physician Global Assessment (PGA)
    • Birmingham Epidermolysis Bullosa Severity
    Score (BEBS)
    • Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI)
    • Score of Colville and Terrill
    • Our own morphometric scoring instrument of pseudosyndactyly progression
    • Mayo Dysphagia Questionnaire-day 30 (MDQ-30)
    • Itch Assessment Scale for the Pediatric Burn Patients
    • Wong-Baker FACES Scale for Pain
    • Quality Of Life in EB (QOLEB) questionnaire
    • Children’s Dermatology Life Quality Index (CDLQI)
    E.5.2.1Timepoint(s) of evaluation of this end point
    PGA at visits 1 (day 1, visit 3 (day 57 +/-7days), visit 7 (day 281 +/- 7days) and EOS (end of study, day 399 +/- 7 days)
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    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.8.3 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 EEA1
    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 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 30
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 15
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 15
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    children (25 month - 16 years) will be included in the clinical trial
    In die Studie werden Kinder eingeschlossen (25 Monate bis 16 Jahre)
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 30
    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 the end of the trial, the patients will be treated according to the standards of care. In case the patient has a benefit under IMP administration, further treatment with losartan suspension after end of trial will be offered to the patients as off-label use (after informing the patient's parents)
    Nach dem Studienende werden die Patienten nach klinischer Routine behandelt. Falls die Patienten von der Behandlung mit Losartan profitieren, wird den Patienten eine weitere bahandlung mit Losartsan im off-lable Bereich angeboten (nach information der Eltern)
    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 Decision2016-08-15
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-02-12
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