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    Summary
    EudraCT Number:2010-024119-15
    Sponsor's Protocol Code Number:rs4680-tolcapona
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Restarted
    Date on which this record was first entered in the EudraCT database:2014-04-04
    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 number2010-024119-15
    A.3Full title of the trial
    EVALUATION OF THE EFFICACY OF TOLCAPONE AS A GENOTYPE-BASED TARGETED COGNITIVE ENHANCER IN SCHIZOPHRENIA, BASED ON THE POLYMORPHISM RS4680
    EVALUACIÓN DE TOLCAPONA COMO POTENCIADOR COGNITIVO EN LA ESQUIZOFRENIA, EN FUNCIÓN DEL GENOTIPO PARA EL POLIMORFISMO RS4680.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    EVALUATION OF TOLCAPONE AS A COGNITIVE ENHANCER IN SCHIZOPHRENIA
    EVALUACIÓN DE TOLCAPONA COMO POTENCIADOR COGNITIVO EN LA ESQUIZOFRENIA
    A.4.1Sponsor's protocol code numberrs4680-tolcapona
    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 SponsorClínica Universidad de Navarra/Universidad de Navarra
    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 supportuniversidad de Navarra
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationClínica Universidad de Navarra
    B.5.2Functional name of contact pointUCICEC
    B.5.3 Address:
    B.5.3.1Street AddressAvd. Pio XII 36
    B.5.3.2Town/ cityPamplona
    B.5.3.3Post code31008
    B.5.3.4CountrySpain
    B.5.4Telephone number349482554001142
    B.5.5Fax number34948296667
    B.5.6E-mailucicec@unav.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 TASMAR 100 mg comprimidos recubiertos con película
    D.2.1.1.2Name of the Marketing Authorisation holderMEDA AB
    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 Film-coated 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 INNTOLCAPONA
    D.3.9.3Other descriptive nameTOLCAPONE
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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
    Esquizofrenia crónica controlada. (10 pacientes con el genotipo val/val y 10 pacientes con el genotipo met/met)
    Esquizofrenia crónica controlada.
    (10 pacientes con el genotipo val-val y 10 pacientes con el genotipo met-met)
    E.1.1.1Medical condition in easily understood language
    Chronic stabilized schizophrenia.
    Esquizofrenia crónica controlada.
    E.1.1.2Therapeutic area Psychiatry and Psychology [F] - Mental Disorders [F03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10009134
    E.1.2Term Chronic schizophrenia
    E.1.2System Organ Class 100000004873
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To assess the efficacy of tolcapone, as the first non-stimulant drug to improve cognition in schizophrenia, as a genotype-based targeted treatment of cognitive and negative symptoms of schizophrenia considering the polymorphism rs4680.
    1. Objetivar la eficacia de la tolcapona, en función del genotipo para el polimorfismo rs4680 del gen de la enzima COMT, para mejorar el deterioro cognitivo y los síntomas negativos en pacientes con esquizofrenia de larga evolución, en fase de compensación clínica.
    E.2.2Secondary objectives of the trial
    1. To study the performance of patients with schizophrenia in cognitive tasks dependent on prefrontal cortex, which require the functions of attention and context processing.
    2. To determine dysfunctional brain areas in patients with schizophrenia when conducting such cognitive tasks.
    3. To establish associations between the genotypes of the COMT enzyme polymorphism rs4680 and the cognitive performance in the administered tests, searching for genetic profiles that may be prognostic markers regarding cognitive performance and response to pharmacological treatment for schizophrenia.
    1. Estudiar el rendimiento de los pacientes con esquizofrenia en tareas cognitivas dependientes del córtex prefrontal, que requieran utilizar la función de la atención y el procesamiento de contexto.
    2. Determinar las áreas cerebrales disfuncionales en pacientes con esquizofrenia al realizar dichas tareas cognitivas.
    3. Establecer asociaciones entre los genotipos para el polimorfismo rs4680 del gen de la enzima COMT y los rendimientos cognitivos en las tareas administradas a los pacientes, buscando perfiles genéticos que puedan ser marcadores pronósticos en cuanto al funcionamiento cognitivo y a la respuesta al tratamiento farmacológico de la esquizofrenia.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Ability to give informed consent and express the wish to fulfill all the requirements of the protocol during the study period.
    2. The patient must be capable of fulfillment of all the requirements of the clinical trial, at the investigator?s discretion.
    3. Age between 18 and 65 years.
    4. Patients diagnosed with schizophrenia according toDSM-5. Only chronic patients will be recruited, and they must be clinically compensated in order to consent to participate. The determination of clinical compensation will be conducted according with these criteria: i) outpatients, with absence of hospitalization due to acute psychiatric decompensation in the previous year, and ii) maintained GAF score equal or higher than 60 during the previous month. The recruitment process will include a clinical interview to verify the diagnosis.
    5. Caucasic ethnicity.
    6. Negative pregnancy test for women of childbearing age.
    7. Due to the high prevalence of tobacco smoking habit among patients with schizophrenia, only patients who smoke 15-30 cigarettes per day will be recruited.
    1. Capacidad para otorgar consentimiento informado y expresar su deseo de cumplir todos los requisitos del protocolo durante el periodo de estudio.
    2. El/la paciente debe, en opinión del investigador, ser capaz de cumplir con todos los requerimientos del ensayo clínico.
    3. Edad comprendida entre 18-65 años.
    4. Pacientes diagnosticados de esquizofrenia según DSM-5. Sólo se reclutarán pacientes crónicos y, para poder obtener el consentimiento informado de la participación en este estudio, todos los pacientes deberán encontrarse en fase de compensación clínica en el momento de ser reclutados. La determinación de compensación clínica se realizará de acuerdo con estos criterios: i) pacientes que reciban tratamiento en régimen ambulatorio, con ausencia de hospitalización debida a descompensación psiquiátrica aguda durante el año anterior, y ii) puntuación en la Escala de Evaluación de la Actividad Global (GAF) mantenida igual o superior a 60 durante el último mes. El proceso de reclutamiento incluirá una entrevista clínica para verificar el diagnóstico.
    5. Origen caucásico
    6. En caso de mujer en edad fértil, test de embarazo negativo.
    7. Debido a la elevada prevalencia de hábito tabáquico en la población de pacientes con esquizofrenia crónica (70-80%), se incluirán únicamente pacientes fumadores, y con un consumo de tabaco comprendido entre 15 y 30 cigarrillos/día.
    E.4Principal exclusion criteria
    1. Severe infections or diseases or hepatic failure (or increased liver enzymes), renal failure or bone marrow failure that advise against participation in the study at the investigator?s discretion.
    2. Liver alterations (elevated liver enzymes above normal values) that advise against the patient participation in the study, at the investigator´s discretion
    3. Positive pregnancy test, or breastfeeding women.
    4. Carriers of pacemaker or any kind of metallic prosthesis incompatible with magnetic resonance imaging.
    5. History of hypersensitivity to Tasmar® (Tolcapona) or to any of its components.
    6. Active (in the last 12 mounths) substance abuse, or other disease that causes psychiatric symptoms.
    7. Cardiovascular disease and electrocardiogram alterations.
    8. Patients receiving treatment with monoamine oxidase inhibitors during the study or up to 15 days prior to the beginning of the study.
    9. Patients receiving treatment with a COMT inhibitor.
    10. Participation in another clinical trial in the previous 30 days.
    11. Other circumstances which involve Tasmar® (Tolcapona) contraindications: history of Neuroleptic Malignant Syndrome and/or non-traumatic Rhabdomyolysis or Hypertermia. Severe dyskinesia. Phaeochromocytoma. Hereditary galactose intolerance. Lapp lactase deficiency or glucose or galactose malabsortion.
    1. Infecciones o enfermedades graves o insuficiencia hepática (o aumento de las enzimas hepáticas), renal o medular que desaconsejen la participación del paciente en el estudio, según el criterio del investigador
    2. Alteraciones hepáticas (aumento de las enzimas hepáticas por encima de los valores normales) que desaconsejen la participación del paciente en el estudio, según el criterio del investigador
    3. Test de embarazo positivo, o mujeres en período de lactancia
    4. Ser portador de cualquier prótesis metálica o de marcapasos, debido la necesidad de realizar resonancia magnética nuclear.
    5. Antecedentes de hipersensibilidad a Tasmar® (Tolcapona) o a cualquier otro de sus componentes.
    6. Pacientes con antecedentes de abuso de sustancias excluyendo tabaco (alcoholismo o consumo de drogas) o que padezcan otra enfermedad que justifique la aparición de sintomatología psiquiátrica
    7. Enfermedad cardiovascular y alteración en el ECG
    8. Pacientes que durante el estudio o hasta 15 días antes de comenzar el estudio reciban o hayan recibido tratamiento con IMAO
    9. Pacientes en tratamiento con algún inhibidor de la COMT
    10. Participación en otro ensayo clínico en los 30 días anteriores.
    11. Otras situaciones que supongan contraindiaciones de Tasmar® (Tolcapona): Antecedentes de Síndrome neuroléptico maligno o de rabdomiolisis no traumática o hipertermia. Discinesia grave. Feocromocitoma. Intolerancia a la lactosa hereditaria o galactasa. Insuficiencia de lactasa de Lapp o malabsorción de glucosa o galactosa. Lactancia.
    E.5 End points
    E.5.1Primary end point(s)
    The primary end points are the performance in the cognitive test DPX (Modified MATRICS battery: number of errors and reaction times) and the elicited brain activation during functional neuroimaging (relative degree of activation of different brain regions). The DPX test has been selected for this study because of its capacity to discriminate the cognitive changes in clinical trials of cognitive enhancers in schizophrenia. The primary end point yielded by functional neuroimaging is the BOLD response, which reflects the relative degree of activation of different brain regions. The performance in the cognitive test will be measured in function of the number of errors and reaction times.
    La variable principal de valoración es el rendimiento en el test cognitivo DPX (Batería MATRICS) y la activación cerebral provocada por el mismo durante la RM funcional (RMf). Se ha seleccionado el test DPX por haber demostrado validez para discriminar los cambios cognitivos que se producen en ensayos clínicos de potenciadores cognitivos en esquizofrenia. La variable principal derivada de la RMf es la respuesta BOLD, que refleja el grado relativo de activación de distintas regiones cerebrales. El rendimiento en el test cognitivo se medirá en función del número de errores cometidos y los tiempos de respuesta.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The test during the functional neuroimaging will be conducted on Day 1 in the morning, prior to the first dose of Tolcapone, and on Day 8, after the morning dose.
    El test durante la RMf se realizará en el día 1 por la mañana, antes de la primera toma de Tolcapona, y en el día 8, después de la toma matutina.
    E.5.2Secondary end point(s)
    The secondary end points are the scores on the clinical scales (PANSS, BPRS, CGI and GAF) and the cognitive neuropsychological battery (MATRICS modified).
    Variables secundarias de valoración: Puntuaciones en las escalas clínicas (PANSS, BPRS, ICG, GAF) y batería neuropsicológica cognitiva (MATRICS modificada).
    E.5.2.1Timepoint(s) of evaluation of this end point
    The test during the functional neuroimaging will be conducted on Day 1 in the morning, prior to the first dose of Tolcapone, and on Day 8, after the morning dose. The clinical scales (PANSS, BPRS, CGI and GAF) will be conducted on Day 0 and on Day 8, after the neuroimaging.
    El test durante la RMf se realizará en el día 1 por la mañana, antes de la primera toma de Tolcapona, y en el día 8, después de la toma matutina. Las escalas clínicas (PANSS, BPRS, CGI y GAF) serán llevadas a cabo el día 0 y el día 8, después de la neuroimagen.
    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 No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial1
    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 Information not present in EudraCT
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    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 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.1.2.1Number of subjects for this age range: 20
    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 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 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)
    It will continue with the usual treatment for the condition
    Se continuará con el tratamiento habitual para la patología
    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 Decision2014-04-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-03-14
    P. End of Trial
    P.End of Trial StatusRestarted
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