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    Summary
    EudraCT Number:2006-001066-16
    Sponsor's Protocol Code Number:H23750
    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:2006-11-09
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSweden - MPA
    A.2EudraCT number2006-001066-16
    A.3Full title of the trial
    The effect of diflunisal (IND 68092) on familial amyloidosis
    A.3.2Name or abbreviated title of the trial where available
    The Diflunisal Trial
    A.4.1Sponsor's protocol code numberH23750
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberNCT00294671
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorJohn L. Berk, M.D.
    B.1.3.4CountryUnited States
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 Dolobid
    D.2.1.1.2Name of the Marketing Authorisation holderMerck, Sharp & Dohme B.V. P.O. 581, 2003 PC Haarlem, The Netherlands
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    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 namediflunisal (dolobid)
    D.3.4Pharmaceutical form Capsule*
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNdiflunisal
    D.3.9.1CAS number 22494-42-4
    D.3.9.2Current sponsor codeIND 68092
    D.3.9.3Other descriptive name2',4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    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 Yes
    D.3.11.13.1Other medicinal product type2’,4’-difluorophenyl salicylate derivative (non-steroidal anti-inflammatory)
    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 placeboCapsule*
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Familial Amyloid Polyneuropathy (FAP)
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine whether diflunisal inhibits (peripheral and autonomic neuropathic) disease progression in patients with familial amyloid polyneuropathy (FAP).
    E.2.2Secondary objectives of the trial
    To examine TTR stability and amyloidogenicity in FAP subjects randomly assigned to the placebo and diflunisal treatment groups, correlating disease progression with TTR stability.

    To compare the detection of FAP neurologic disease progression by a highly quantitative composite testing instrument (NIS + 7) versus a clinical neurologic scoring system (Kumamoto Scale).

    To define the natural history of ATTR cardiomyopathy.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Biopsy proven amyloid deposition
    2. Genotyping of variant TTR
    3. Signs of mild to moderate peripheral or autonomic neuropathy -- detectable by a neurologist (performance status < 3)
    4. Age > 18 and < 75 years
    5. Negative bHCG testing and contraception for sexually active women of child-bearing potential
    E.4Principal exclusion criteria
    1. Use of non-study NSAIDs within 30 days of enrollment
    2. Other causes of sensorimotor polyneuropathy
    a. Vitamin B12 deficiency
    b. HIV patients on anti-retroviral drugs
    c. Diabetes mellitus (Hgb A1C > 6.2%)
    d. Chronic alcoholism (> 6 ounces hard liquor daily for 10 or greater years)
    3. Co-morbidities with anticipated survival <2 years or liver transplantation in <1 yr
    4. Liver transplantation
    5. End-stage neuropathic disease (performance status > 3, parenteral nutrition, bedsores)
    6. NYHA class IV (cardiac symptoms at rest & with minimal exertion)
    7. Pregnancy or unwillingness to use contraception by women of childbearing age
    8. Renal insufficiency (creatinine clearance < 30 ml/min)
    9. Active or recent non-hemorrhoidal GI bleeding (within past 18 months)
    10. Current anti-coagulation therapy, non-study NSAID or aspirin use
    11. AST, ALT or Total Bilirubin > twice the upper limit of normal lab value
    12. Non-steroidal or aspirin allergy/hypersensitivity
    13. Thrombocytopenia (< 100,000 platelets/mm3)
    14. Previous participation in this study
    15. Inability or unwillingness of subject or legal guardian/representative to give written informed consent
    E.5 End points
    E.5.1Primary end point(s)
    Neurologic Impairment Score (NIS+7), a highly quantitative assessment of peripheral neurologic function employed in studies of diabetic neuropathy, will be the primary outcome measure. NIS+7 is a composite score of neuropathic signs, 5 attributes of nerve conduction, quantitative sensation testing (vibration threshold), and autonomic function (heart rate variability).

    Longitudinal studies of diabetic peripheral neuropathy demonstrate that a 2 point increase in mean NIS + 7 composite score correlates with clinically detectable progression of disease. In the Rochester Diabetic Neuropathy Study cohort, patients with diabetic polyneuropathy displayed an annual 0.85 point NIS + 7 score worsening. Neurologists and amyloid experts agree that the natural progression of FAP neuropathy is far more rapid than diabetic peripheral neuropathy.
    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 Information not present in EudraCT
    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) 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 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 Yes
    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.8.5The trial involves multiple Member States Yes
    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 Information not present in EudraCT
    E.8.7Trial has a data monitoring committee Information not present in EudraCT
    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
    Drug administration will cease after 24 months of participation or if subjects:
    1. exhibit study drug intolerance (GI bleed, hemolytic anemia, thrombocytopenia, hepatitis, renal insufficiency, hypersentivity reactions)
    2. anticipate liver transplantation in <30 days
    3. become pregnant despite using contraceptive agents
    4. voluntarily withdraw.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 Information not present in EudraCT
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2006-11-09. Yes
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 90
    F.4.2.2In the whole clinical trial 200
    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)
    Diflunisal is commercially available in each of the European Union member states participating in this clinical trial. If proven effective, subjects could be prescribed the study drug, diflunisal, by their physicians.
    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 Decision2007-01-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-02-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-12-15
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