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    Summary
    EudraCT Number:2014-001957-17
    Sponsor's Protocol Code Number:DFNS02
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-07-06
    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 ConcernedSweden - MPA
    A.2EudraCT number2014-001957-17
    A.3Full title of the trial
    THE EFFECT OF DIFLUNISAL ON FAMILIAL TRANSTHYRETIN AMYLOIDOSIS:
    An open label phase III extension study of the diflunisal trials (IND 68092 and DFNS01), and an open label observational study on previously untreated patients with familial transthyretin amyloidosis complicated by cardiomyopathy.

    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    THE EFFECT OF DIFLUNISAL ON FAMILIAL TRANSTHYRETIN AMYLOIDOSIS (Buildup of abnormal deposits of a protein called amyloid (amyloidosis) in the body's organs and tissues).
    An open follow-up study of the diflunisal trials (IND 68092 and DFNS01), and an open label observational study on previously untreated patients with familial transthyretin amyloidosis complicated by cardiomyopathy (diseases of the heart muscle).

    A.3.2Name or abbreviated title of the trial where available
    DFNS02
    A.4.1Sponsor's protocol code numberDFNS02
    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 SponsorUmeå University Hospital
    B.1.3.4CountrySweden
    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 supportVästerbotten county counsil
    B.4.2CountrySweden
    B.4.1Name of organisation providing supportUmeå University
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUmeå University Hospital
    B.5.2Functional name of contact pointIntissar Anan
    B.5.3 Address:
    B.5.3.1Street AddressUmeå University Hospital
    B.5.3.2Town/ cityUmeå
    B.5.3.3Post code90185
    B.5.3.4CountrySweden
    B.5.4Telephone number469078550000
    B.5.6E-mailintissar.anan@umu.se
    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.2.5The 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.3.11 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
    Familial transthyretin amyloidosis complicated by cardiomyopathy
    E.1.1.1Medical condition in easily understood language
    Familial Amyloid Cardiomyopathy (FAC), results from the aggregation of mutant and/or wild-type transthyretin protein in the heart
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10019893
    E.1.2Term Hereditary neuropathic amyloidosis, Swedish type
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To follow the development of neurological, nutritional and cardiac manifestations of transthyretin amyloidosis in patients treated by Diflunisal 250 mg twice daily.
    Primary end-points
    1. changes in the Kumamoto scale
    2. cardiac impairment measured by echocardiographic assessment of global systolic strain
    E.2.2Secondary objectives of the trial
    Secondary end points
    1. changes in nutritional status measured by the modified body mass index (mBMI)
    2. changes in neurological impairment measured by the PND-score.
    3. cardiac impairment measured by echocardiographic measurement of septal thickness and blood pro-BNP concentration.
    4. Karnofsky performance scale
    5. drug safety
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Open to patients that have been participating in the DFNS01 study. All patients will have a biopsy and genetically proven systemic transthyretin amyloidosis caused by a TTR gene mutation. The amyloid shall be proven to be of transthyretin type, and the fibril composition settled.
    For patients not previously participating in the DFNS01 trial, the diagnosis shall be proven by biopsy and identification of a TTR-gene mutation. The amyloid shall be proven to be of transthyretin type, and the fibril composition settled. TTTR-amyloid cardiomyopathy shall be confirmed by DPD-scintigraphy, and an increased intra-ventricular septal thickness of > 12 mm and a pro-BNP blood concentration above the normal limit.
    2. Age ≥ 18 years.
    3. Negative pregnancy test for sexually active women of child bearing potential and willing to comply with effective contraception methods during the course of the trial. Acceptable methods are such as oral contraceptives, contraceptive patches, contraceptive implant, vaginal contraceptive, double-barrier methods (for example, condom and spermicide), intrauterine device (IUD), hormonal IUD.
    E.4Principal exclusion criteria
    1. Concomitant use of non-study NSAIDs
    2. Heart failure with symptoms at daily activities (NYHA class ≥III)
    3. Renal insufficiency (creatinine clearence < 30 ml calculated from the Cockcroft-Gault formula)
    4. Active non-haemorrhoidal bleeding within the last 18 month.
    5. Non-treated peptic ulcer disease.
    6. Anticoagulation therapy, low dose ASA permitted (≤160 mg).
    7. Non-steroidal or aspirin allergy/hypersensitivity
    8. Thrombocytopenia (< 100,000 platelets/mm3)
    9. Inability or unwillingness of subject to give written informed consent
    10. By the investigator regarded as unable to follow the study guidelines and scheduled controls.
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoints will be:
    1. changes in the Kumamoto scale
    2. cardiac impairment measured by echocardiographic assessment of global systolic strain
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary and secondary end-points will be evaluated at 12 months and the end of the 24 months study period by descriptive statistical methods.
    E.5.2Secondary end point(s)
    Secondary end points will be:
    1. changes in nutritional status measured by the modified body mass index (mBMI)
    2. changes in neurological impairment measured by the PND-score.
    3. cardiac impairment measured by echocardiographic measurement of septal thickness and blood pro-BNP concentration.
    4. Karnofsky performance scale
    5. drug safety
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints for effect parameters will be evaluated at 12 months and the end of the 24 months study period by descriptive statistical methods. Safety parameters will be measured at 1 month (± 1 week), 3 months (±2 weeks), 6 months (± 1 month), 9 months (±1 month), 12 months (±1 month) and thereafter every 6 months (± 1month).

    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    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
    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 months0
    E.8.9.1In the Member State concerned days0
    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: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 Yes
    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 Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Women of childbearing potential using adequate contraception
    F.4 Planned number of subjects to be included
    F.4.1In the member state40
    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)
    None.
    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 Decision2015-09-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-10-21
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-06-04
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