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    Summary
    EudraCT Number:2011-000991-33
    Sponsor's Protocol Code Number:PI10/02877
    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:2012-03-28
    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 number2011-000991-33
    A.3Full title of the trial
    Impact of melatonin in the pretreatment of organ donor and the influence in the evolution of liver transplant: a prospective, randomised double-blind study.
    Impacto de la melatonina en el pretratamiento del donante de órganos y su influencia en la evolución del trasplante hepático: estudio prospectivo, aleatorizado, doble ciego.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Impact of melatonin in the pretreatment of organ donor and the influence in the evolution of liver transplant: a prospective, randomised double-blind study.
    Impacto de la melatonina en el pretratamiento del donante de órganos y su influencia en la evolución del trasplante hepático: estudio prospectivo, aleatorizado, doble ciego.
    A.4.1Sponsor's protocol code numberPI10/02877
    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 SponsorInstituto Aragonés de Ciencias de la Salud
    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 organisationInstituto Aragonés de Ciencias de la Salud
    B.5.2Functional name of contact pointEva López Hernández
    B.5.3 Address:
    B.5.3.1Street AddressAvda. San Juan Bosco 13, Planta 1ª
    B.5.3.2Town/ cityZaragoza
    B.5.3.3Post code50009
    B.5.3.4CountrySpain
    B.5.4Telephone number+34976716582
    B.5.5Fax number+34976715554
    B.5.6E-mailemlopezh.iacs@aragon.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 Circadin 2 mg comprimidos de liberación prolongada, blister de 21 comprimidos
    D.2.1.1.2Name of the Marketing Authorisation holderNeurim Pharmaceuticals
    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 Prolonged-release tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPNasogastric use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMELATONINA
    D.3.9.1CAS number 73-31-4
    D.3.9.3Other descriptive nameMELATONIN
    D.3.9.4EV Substance CodeSUB14496MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboNasogastric use (Noncurrent)
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Organ Transplant
    Trasplante de órganos sólidos
    E.1.1.1Medical condition in easily understood language
    Organ Transplant
    Trasplante de órganos sólidos
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04]
    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
    General objective: To establish the efficacy of melatonin administered in the encephalic-death organ donor (EDD) and its influence on the evolution of liver transplant (LT).

    Primary specific objective: To compare liver graft function between the control and the melatonin group.
    Objetivo General. Establecer la eficacia de la melatonina administrada en el donante en muerte encefálica (DME) y su influencia en la evolución del trasplante hepático (TH).

    Objetivo concreto Primario: Comparar la funcionalidad del injerto hepático entre el grupo control y el grupo melatonina.
    E.2.2Secondary objectives of the trial
    To evaluate the influence of donor pretreatment with melatonin on:
    - Postoperative evolution of AST, ALT, bilirubin and INR.
    - Oxidative stress in the encephalic-death organ donor (EDD) and in the graft.
    - Circulating levels of pro- and anti-inflammatory cytokines in the EDD.
    - Plasma biomarkers of cardiac and renal function in the EDD and in the liver transplant (LT) recipient.
    - Dynamic response of acute phase proteins as markers of the intensity of the inflammatory reaction in the EDD and in the recipient.
    - General plasma endocrine response in the EDD and response of the renin-angiotensin-aldosterone system in the recipient.
    - Damage and tissue/vascular proliferation markers in hepatic tissue
    - Histological parameters of ischemia-reperfusion in the liver graft
    Evaluar la influencia del pretratamiento con melatonina en el donante sobre:
    - Evolución postoperatoria de AST, ALT, bilirrubina e INR.
    - Estrés oxidativo en el DME y en el injerto.
    - Niveles circulantes de citoquinas pro y antiinflamatorias den el DME.
    - Biomarcadores plasmáticos de función cardíaca y renal en el DME y en el receptor TH.
    - Respuesta dinámica de las proteínas de fase aguda como marcadores de la intensidad de la reacción inflamatoria en el DME y en el receptor.
    - Respuesta general endocrina plasmática en el DME y respuesta del sistema renina-angiotensina-aldosterona en el receptor
    - Marcadores de daño y proliferación tisular/vascular en el tejido hepático
    - Parámetros histológicos de isquemia-reperfusión en el injerto hepático
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    A) Donors
    1. Encephalic-death (ED) organ donor who is situated in the ICUs of accredited hospitals in Zaragoza and meets each and every one of the following criteria.
    2. Being 16 years old or older.
    3. Informed consent for the donation signed by the immediate family.
    4. Informed consent for inclusion of the donor in the study .
    5. Receive intensive treatment and standard maintenance of the donor in ED, in accordance with universally accepted protocols of the Organizacion Nacional de Trasplantes (ONT), of the Aragon Autonomous Transplant Coordination, and of the ICUs and the participating hospitals in the study.
    B) Liver transplant recipients
    1. Being 18 years old or older and being less than 68 years of age.
    2. Informed consent for the procedure of LT signed.
    3. Informed consent for patient inclusion in the study, signed the same day that consent to the LT.
    A) Donantes
    1. Donante de órganos en muerte encefálica (ME) que se encuentre en las UCIs de los hospitales acreditados de Zaragoza y que cumplan todos y cada uno de los criterios siguientes.
    2. Edad igual o superior a 16 años.
    3. Consentimiento informado para la donación firmado por los familiares más próximos.
    4. Consentimiento informado para inclusión del donante en el estudio.
    5. Recibir el tratamiento intensivo y mantenimiento estándar del donante en ME, de acuerdo con los protocolos universalmente aceptados, de la Organización Nacional de Trasplantes (ONT), de la Coordinación Autonómica de Trasplantes de Aragón y de las UCIS de los hospitales participantes en el estudio.
    B) Receptores de trasplante hepático
    1. Edad igual o superior a 18 años e inferior a 68 años.
    2. Consentimiento informado para el procedimiento del TH firmado.
    3. Consentimiento informado para inclusión del paciente en el estudio, firmado el mismo día que el consentimiento para el TH.
    E.4Principal exclusion criteria
    A) Donors
    A potential encephalic-death organ donor will not be included in the study if either of the following criteria:
    1. Absence of either signed informed consent: for organ donation or for inclusion in the study.
    2. No standard concomitant treatment and management of donor in ED.
    B) Liver transplant recipients
    1. Absence of either signed informed consent: for liver transplantation or for inclusion in the study.
    2. Split, domino or multiorgan transplantation.
    3. Grafts removed by other surgical teams.
    4. Pregnant women or fertile not using contraceptive measures highly effective.
    A) Donantes
    Un potencial donante en ME no será incluido en el estudio si se da cualquiera de los siguientes criterios:
    1. Ausencia de cualquiera de los dos consentimientos informados firmados, bien sea para la donación de órganos o para la inclusión en el estudio.
    2. Ausencia del tratamiento y manejo estándar concomitantes del donante en ME.
    B) Receptores de trasplante hepático
    1. Ausencia de cualquiera de los dos consentimientos informados firmados, para el trasplante hepático o para el estudio
    2. Trasplante split, trasplante dominó y trasplante multiorgánico.
    3. Injertos extraídos por otros equipos quirúrgicos.
    4. Mujeres embarazadas o fértiles que no utilicen medidas anticonceptivas altamente eficaces.
    E.5 End points
    E.5.1Primary end point(s)
    AST, ALT, bilirubin and prothrombin levels
    Niveles de AST, ALT, bilirrubina y actividad de protrombina
    E.5.1.1Timepoint(s) of evaluation of this end point
    Between days 1 and 10 postoperatively
    Días del 1 al 10 del postoperatorio
    E.5.2Secondary end point(s)
    1) Post-reperfusion syndrome
    2) No primary function and primary graft dysfunction
    3) Survival of the graft
    4) Patient Survival
    5) Donor and recipient serological parameters
    6) Morphological and functional qualityof the liver graft evaluated by histological parameters of ischemia-reperfusion and tissue biochemical markers
    1) Síndrome post-reperfusión
    2) No función primaria y disfunción primaria del injerto
    3) Superviviencia del injerto
    4) Supervivencia del paciente
    5) Parámetros serológicos del donante y receptor
    6) Calidad morfológica y funcional del injerto hepático evaluadas por parámetros histológicos de isquemia-reperfusión y por marcadores bioquímicos tisulares
    E.5.2.1Timepoint(s) of evaluation of this end point
    Evaluation according to the protocol description
    Evaluación según descripción del protocolo
    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 No
    E.6.4Safety No
    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 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.8.2.4Number of treatment arms in the trial2
    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
    Last follow-up visit of the last patient included in the study
    Última visita de seguimiento del último paciente incluido en el estudio
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months30
    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: 60
    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 Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Donantes de órganos en muerte encefálica que se encuentren en las UCIs de los hospitales acreditados en Zaragoza. También se reclutan los receptores de trasplante hepático del Hospital Clínico Universitario Lozano Blesa.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state60
    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 6 months of follow-up study, patients will continue to receive standard clinical practice.
    Transcurridos los 6 meses de seguimiento del estudio, los pacientes se seguirán como por práctica clínica habitual
    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 Decision2012-07-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-03-21
    P. End of Trial
    P.End of Trial StatusOngoing
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