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    Summary
    EudraCT Number:2019-002873-80
    Sponsor's Protocol Code Number:AMILCA-DIFLU
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-11-11
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2019-002873-80
    A.3Full title of the trial
    Unicentre, open, uncontrolled clinical trial to assess the morphological, biochemical and functional effects of Diflunisal treatment in patients with transthyretin cardiac amyloidosis
    Ensayo clínico unicéntrico, abierto, no controlado, para evaluar las repercusiones morfológicas, bioquímicas y funcionales del tratamiento con Diflunisal en pacientes con amiloidosis cardiaca por Transtiretina
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Diflunisal effect in cardiac function in patients with transthyretin cardiac amyloidosis
    Efecto del diflunisal sobre la función cardiaca de pacientes con amiloidosis cardiaca por transtirretina
    A.4.1Sponsor's protocol code numberAMILCA-DIFLU
    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 SponsorFUNDACION JIMENEZ DIAZ HEALTH RESEARCH INSTITUTE
    B.1.3.4CountrySpain
    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 supportINSTITUTO DE SALUD CARLOS III
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFUNDACION JIMENEZ DIAZ HEALTH RESEARCH INSTITUTE
    B.5.2Functional name of contact pointUNIDAD DE INVESTIGACION CLINICA
    B.5.3 Address:
    B.5.3.1Street AddressAVDA REYES CATOLICOS N2
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28040
    B.5.3.4CountrySpain
    B.5.4Telephone number+349155048003214
    B.5.6E-mailmireia.arcas@fjd.es
    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 DILFLUNISAL
    D.2.1.1.2Name of the Marketing Authorisation holderPHARMA INTERNATIONAL
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 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 INNDIFLUNISAL
    D.3.9.1CAS number 22494-42-4
    D.3.9.4EV Substance CodeSUB07130MIG
    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) 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
    transthyretin cardiac amyloidosis
    Amiloidosis cardiaca por transtirretina
    E.1.1.1Medical condition in easily understood language
    transthyretin cardiac amyloidosis
    Amiloidosis cardiaca por transtirretina
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the morphological, biochemical and functional repercussions of Diflunisal treatment in patients with transthyretin cardiac amyloidosis.
    Evaluar las repercusiones morfológicas, bioquímicas y funcionales del tratamiento con Diflunisal en pacientes con amiloidosis cardíaca por transtiretina.
    E.2.2Secondary objectives of the trial
    To assess the safety and tolerability of Dflunisal 250mg / 12 hours for 1 year.
    Evaluar la seguridad y la tolerabilidad de Dflunisal 250 mg / 12 horas durante 1 año.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients over 18 years old
    2. Diagnosed of cardiac amyloidosis by TTR by cardiac uptake grade 2 or 3 in a scintigraphy performed with Tc-DPD in the absence of monoclonal scintigraphy or by myocardial biopsy with positive immunofixation in the case of presenting peripheral blood gamma pathia.
    3. Acceptance and signing of consent for the study after receiving the appropriate information.
    1. Pacientes mayores de 18 años.
    2. Diagnóstico de amiloidosis cardíaca por TTR por captación cardíaca de grado 2 o 3 en una gammagrafía realizada con Tc-DPD en ausencia de gammagrafía monoclonal o por biopsia de miocardio con inmunofijación positiva en el caso de presentar gammapatía en sangre periférica.
    3. Aceptación y firma del consentimiento para el estudio después de recibir la información apropiada.
    E.4Principal exclusion criteria
    1. Known allergy or hypersensitivity to diflunisal or any of its components, or to drugs from the group of non-steroidal anti-inflammatory drugs.
    2. History of acute episodes of asthma, hives, rhinitis or angioedema in relation to ibuprofen, aspirin or other NSAIDs.
    3. History or active episode of gastrointestinal bleeding or perforation related to previous treatment with NSAIDs.
    4. Severe heart failure (NYHA functional class IV)
    5. Severe renal impairment: Glomerular filtration estimated <30mL / min / 1.73 m2 calculated by the CKD-EPI formula.
    6. Survival <1 year due to some known comorbidity
    7. Concomintant treatment with 2 antiplatelet agents associated with 1 anticoagulant
    8. Previous liver or heart transplantation
    9. Hepatic dysfunction (ALT / AST or BT above 3 times the upper limit of normal)
    10. Platelets <100,000 / mm3
    11. Potentially fertile women who are not willing to use a contraceptive method that is considered effective
    12. Pregnancy or breastfeeding
    13. Participants in another clinical trial with medication in the 28 days prior to the start of recruitment.
    14. At the discretion of the investigator, the patient's inability to understand or comply with the study procedures
    1. Alergia o hipersensibilidad conocidas a diflunisal o cualquiera de sus componentes, oa medicamentos del grupo de medicamentos antiinflamatorios no esteroideos.
    2. Antecedentes de episodios agudos de asma, urticaria, rinitis o angioedema en relación con ibuprofeno, aspirina u otros AINE.
    3. Historia o episodio activo de hemorragia o perforación gastrointestinal relacionada con el tratamiento previo con AINE.
    4. Insuficiencia cardíaca severa (clase funcional NYHA IV)
    5. Insuficiencia renal severa: filtración glomerular estimada <30 ml / min / 1.73 m2 calculada por la fórmula CKD-EPI.
    6. Supervivencia <1 año debido a alguna comorbilidad conocida
    7. Tratamiento concomitante con 2 agentes antiplaquetarios asociados con 1 anticoagulante.
    8. Trasplante previo de hígado o corazón
    9. Disfunción hepática (ALT / AST o BT por encima de 3 veces el límite superior de lo normal)
    10. Plaquetas <100,000 / mm3
    11. Mujeres potencialmente fértiles que no están dispuestas a usar un método anticonceptivo que se considera efectivo
    12. Embarazo o lactancia.
    13. Participantes en otro ensayo clínico con medicamentos en los 28 días anteriores al inicio del reclutamiento.
    14. A discreción del investigador, la incapacidad del paciente para comprender o cumplir con los procedimientos del studio.
    E.5 End points
    E.5.1Primary end point(s)
    The primary analysis of the study will be the change in extracellular volume (CVD) measured by magnetic resonance using a T1 mapping technique before and after contrast at baseline and at 12 months of treatment.
    El análisis primario del estudio será el cambio en el volumen extracelular (CVD) medido por resonancia magnética usando una técnica de mapeo T1 antes y después del contraste al inicio y a los 12 meses de tratamiento.
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 months
    12 meses
    E.5.2Secondary end point(s)
    o Ejection fraction.
    o Ventricular thicknesses.
    o Necrotic / fibrotic area, defined as late Gadolinium uptake (high intensity STIR signals).
    o Functional class determined by the 6-minute walk test.
    o Score of the Kansas City Cardiomyopathy Questionnaire NT-proBNP levels.
    o High sensitivity C-reactive protein levels
    o High sensitivity Troponin levels
    o Serum TTR concentration
    o Proportion and description of Adverse Events.
    o Proportion of adherence to treatment.
    o Incidence of heart failure, death, or any acute coronary syndrome (IAMCEST or Acute coronary syndrome without ST elevation).
    o Fracción de eyección.
    o Grosores ventriculares.
    o Área necrótica / fibrótica, definida como captación tardía de gadolinio (señales STIR de alta intensidad).
    o Clase funcional determinada por la prueba de caminata de 6 minutos.
    o Puntuación de los niveles de NT-proBNP del Cuestionario de Cardiomiopatía de Kansas City.
    o Niveles de proteína C reactiva de alta sensibilidad
    o Niveles de troponina de alta sensibilidad
    o concentración sérica de TTR
    o Proporción y descripción de eventos adversos.
    o Proporción de adherencia al tratamiento.
    o Incidencia de insuficiencia cardíaca, muerte o cualquier síndrome coronario agudo (IAMCEST o síndrome coronario agudo sin elevación del ST).
    E.5.2.1Timepoint(s) of evaluation of this end point
    3, 6 and 9 months
    3, 6 y 9 meses
    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) 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 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
    LVLS
    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 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: 15
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 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 state20
    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. AFTER THE END OF THE TRIAL, PATIENTS WILL BE MANAGED ACCORDING TO LOCAL 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 Decision2020-01-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-12-19
    P. End of Trial
    P.End of Trial StatusOngoing
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