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    Summary
    EudraCT Number:2006-001066-16
    Sponsor's Protocol Code Number:H23750
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2010-06-18
    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 ConcernedUK - MHRA
    A.2EudraCT number2006-001066-16
    A.3Full title of the trial
    A randomized, double-blind, placebo-controlled, international multi-center trial of
    diflunisal on neurologic disease progression in 200 familial amyloid subjects
    A.3.2Name or abbreviated title of the trial where available
    The effect of diflunisal on familial amyloidosis
    A.4.1Sponsor's protocol code numberH23750
    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
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsor
    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 AuthorisationUnited Kingdom
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    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 No
    D.3.11.8Extractive medicinal product No
    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
    Hereditary neuropathic amyloidosis
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 11.
    E.1.2Level LLT
    E.1.2Classification code 10019889
    E.1.2Term Hereditary neuropathic amyloidosis
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The principal objective of this study is to determine whether diflunisal inhibits disease progression in patients with familial amyloid polyneuropathy (FAP). Peripheral neuropathy (temperature/vibratory or light touch sensory loss, parasthesias), the most common feature of familial amyloidosis ,is the primary end point of this study. Worsening peripheral neuropathy indicates disease progression. Neurologic Impairment Score (NIS), a highly quantitative assessment of peripheral neurologic function employed in studies of diabetic neuropathy, will be the primary outcome measure.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are as follows:

    -Kumamoto Neurologic Scale to assess autonomic dysfunction, sensori-motor peripheral neuropathy, and visceral organ involvement of FAP using a qualitative, office-based measure.
    -Echocardiographic readings to determine the rate of heart change in FAP in the presence and absence of the study drug.
    -Medical Outcomes Study 36-item Short Form General Health Survey (SF-36) - a quality of life measure validated in patients with systemic amyloidosis.
    -Amyloid Content in Aspirated Fat Tissue - a rough measure of total body amyloid burden.
    -modified Body Mass Index - validated as an outcome predictor in a post-liver transplant FAP cohort; we will correlate serial measures to neurologic disease course in this patient population
    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 peripheral or autonomic neuropathy -- detectable by a
    neurologist (performance status ≤ 3)
    4. Age ≥ 18 and ≤ 75 years
    5. Negative βHCG testing and contraception for sexually active women of child-bearing potential
    E.4Principal exclusion criteria
    1. Use of non-study NSAIDs after enrollment (low dose aspirin allowed)
    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)
    The primary outcome measure is the NIS+7 composite neurologic scoring system.
    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) Information not present in EudraCT
    E.7.1.1First administration to humans Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    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) Information not present in EudraCT
    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 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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA4
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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 study will be defined as last patient last visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    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 No
    F.3.3.1Women of childbearing potential not using contraception Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women Information not present in EudraCT
    F.3.3.4Nursing women Information not present in EudraCT
    F.3.3.5Emergency situation Information not present in EudraCT
    F.3.3.6Subjects incapable of giving consent personally Information not present in EudraCT
    F.3.3.7Others Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 85
    F.4.2.2In the whole clinical trial 140
    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)
    Investigators will help subjects acquire additional courses of diflunisal beyond the treatment defined in this protocol. Once the participant has been discontinued from the study, the participant's doctor will continue to manage them according to the routine standard of care.
    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 Decision2010-06-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-08-25
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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