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    Summary
    EudraCT Number:2013-003740-23
    Sponsor's Protocol Code Number:AB13004
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2013-12-05
    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 number2013-003740-23
    A.3Full title of the trial
    A prospective, multicentre, randomised, double-blind, placebo-controlled, parallel groups, phase 2b/3 study to compare the efficacy and safety of masitinib versus placebo in the treatment of patients suffering from Progressive Supranuclear Palsy (PSP)
    Estudio prospectivo, Fase IIb/III, multicéntrico, randomizado, doble ciego, controlado con placebo, de grupos paralelos para comparar la eficacia y seguridad de masitinib frente a placebo en el tratamiento de pacientes con parálisis supranuclear progresiva (PSP)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Evaluation of masitinib in the treatment of Progressive Supranuclear Palsy
    A.4.1Sponsor's protocol code numberAB13004
    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 SponsorAB Science
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAB Science
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAlpha Bioresearch, S.L.
    B.5.2Functional name of contact pointConsuelo Pozo
    B.5.3 Address:
    B.5.3.1Street AddressPº de la Castellana no. 163, 2ª planta
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28046
    B.5.3.4CountrySpain
    B.5.4Telephone number+34917452520
    B.5.5Fax number+34917450653
    B.5.6E-mailconsuelo.pozo@alphabioresearch.com
    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 No
    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 namemasitinib 100mg
    D.3.2Product code AB1010
    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 INNMasitinib mesylate
    D.3.9.1CAS number 790-299-79-5
    D.3.9.2Current sponsor codeAB1010
    D.3.9.3Other descriptive nameMASITINIB MESYLATE
    D.3.9.4EV Substance CodeSUB126308
    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.IMP: 2
    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 No
    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 namemasitinib 200mg
    D.3.2Product code AB1010
    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 INNMasitinib mesylate
    D.3.9.1CAS number 790-299-79-5
    D.3.9.2Current sponsor codeAB1010
    D.3.9.3Other descriptive nameMASITINIB MESYLATE
    D.3.9.4EV Substance CodeSUB126308
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    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
    Progressive Supranuclear Palsy
    Parálisis Supracraneal Progresiva
    E.1.1.1Medical condition in easily understood language
    Brain degenerescence disease
    Enfermedad neurodegenerativa
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10036813
    E.1.2Term Progressive supranuclear palsy
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Assess efficacy of masitinib in the treatment of PSP definied by the evolution of Progressive Supranuclear Palsy Rating Scale (PSPRS) score from week 12 to week 48.
    Puntuación de la escala de evaluación de parálisis supranuclear progresiva (PSPRS) desde la semana 12 hasta la semana 48.
    E.2.2Secondary objectives of the trial
    Disease progression:
    ? Brain volume changes, as measured by ventricular volumes, brain stem atrophy and frontal lobe volume
    ? Serum and cerebrospinal fluid Tau protein levels
    Disability level / severity of illness:
    ? Schwab and England Activities of Daily Living Scale (SEADL) scores from week 12 to week 48
    ? Clinical Global Impression of Change (CGI-C) scores from week 12 to week 48Clinical Global Impression of Disease Severity (CGI-ds) scores from week 12 to week 48
    Cognitive function:
    ? MMSE scores from week 12 to week 48
    ? RBANS scores from week 12 to week 48
    Psychiatric symptoms:
    ? Geriatric Depression Scale scores from week 12 to week 48
    ? Apathy Evaluation Scale scores from week 12 to week 48
    Quality of life:
    ? PSP-QoL scale score from week 12 to week 48
    Pharmacokinetics data: Biodisponibility of masitinib at W12 visit, prior to dose increase, compared to W24
    Safety: Occurrence of Adverse Events (AE)
    Progresión de la enfermedad:
    Cambios del volumen cerebral, según medición de volúmenes ventriculares, atrofia troncoencefálica y volumen del lóbulo frontal medido por RMN cerebral volumétrica en la semana 48.
    Niveles de la proteína tau en líquido cefalorraquídeo y en suero en la semana 48.
    Nivel de discapacidad/gravedad de la enfermedad:
    Puntuaciones de la Escala de actividades de la vida diaria de Schwab y England (SEADL) desde la semana 12 hasta la semana 48.
    Puntuación de la Impresión clínica global del cambio (CGI-C) desde la semana 12 hasta la semana 48 y puntuación de la Impresión global clínica de la gravedad de la enfermedad (CGI-ds) desde la semana 12 hasta la semana 48.
    Función cognitiva:
    Puntuación del MMSE desde la semana 12 hasta la semana 48.
    Puntuación del RBANS desde la semana 12 hasta la semana 48.
    Síntomas psiquiátricos:
    Puntuación de la Escala de depresión geriátrica desde la semana 12 hasta la semana 48.
    Puntuación de la Escala de evaluación de ...
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Female or male patient aged between 40 and 80 years old, weighing more than 50 kg and with a Body Mass Index (BMI) between 18 and 35 kg/m².
    2. Probable PSP (clinical signs of PSP) with PSP stage ? II defined as:
    ? at least a 12-month history of postural instability or falls during the first 3 years that symptoms are present; and
    ? PSPRS score ? 29; and
    ? an akinetic-rigid syndrome with prominent axial rigidity
    3. MAPT H1 positive haplotype
    4. Modified Hachinski score ? 3. This modified Hachinski will not include the focal neurological signs, symptoms or pseudobulbar affect questions, given the prominence of all 3 in PSP.
    5. Score ? 25 on the mini-mental state examination (MMSE).
    6. Patient judged by investigator to be able to comply with neuropsychological evaluation at baseline and throughout the study.
    7. Patient must have reliable caregiver accompany him to all study visits. Caregiver and patient must read, understand, and speak local language fluently to ensure comprehension of informed consent form and informant-based assessments of patient. Caregiver must also have frequent contact with patient (at least 3 hours per week at one time or at different times) and be willing to monitor study medication compliance and the patient's health and concomitant medications throughout the study. Patient / caregiver able to understand the patient card and to follow the patient card procedures in case of signs or symptoms of severe neutropenia or severe cutaneous toxicity, during the study.
    8. Male or female patient of child bearing potential (entering the study after a menstrual period and who have a negative pregnancy test) must agree to use two methods (one for the patient and one for the partner) of medically acceptable forms of contraception during the study and for 3 months after the last treatment intake
    9. Patient residing outside a skilled nursing facility or dementia care facility at the time of screening, and admission to such a facility is not planned. Residence in an assisted living facility is allowed.
    10. If the patient is receiving levodopa/carbidopa, levodopa/benserazide, a dopamine agonist, catechol-o-methyltransferase (COMT) inhibitor, or other Parkinson's medication, with the exception of Azilect(rasagiline), the dose must have been stable for at least 60 days prior to the screening visit and must remain stable for the duration of the study. No such medication can be initiated during the study. Subjects receiving rasagiline or CoQ10 must be on a stable dose for at least 90 days prior to the screening visit.
    11. Patient able to tolerate the MRI scan during screening with either no sedation or low dose benzodiazepines
    12. Patient able to ambulate independently or with assistance defined as the ability to walk at least 30 meters with the assistance of another person who can only have contact with one upper extremity.
    13. Patient with life expectancy ? 6 months
    14. Patient with adequate organ function at screening and baseline:
    ? Absolute Neutrophils Count (ANC) ? 2 x 109/L
    ? Hemoglobin ? 10 g/dL
    ? Platelets (PTL) ? 100 x 109/L
    ? AST/ALT ? 2.5 ULN
    ? Bilirubin ? 1.5 ULN
    ? Albuminemia ? 1 x LLN
    ? Urea ? 1.5 x ULN
    ? Creatinine clearance > 50 mL/min (Cockcroft and Gault formula)
    ? Proteinuria < 30 mg/dL on dipstick; in case of the proteinuria ? 30 mg/dL, 24 hours proteinuria < 1.5g/24 hours
    15. Man or woman of child bearing potential, (entering the study after a menstrual period and who have a negative pregnancy test) who agree to use two methods (one for the patient and one for the partner) of medically acceptable forms of contraception during the study and for three months after the last treatment intake
    16. Patient able and willing to comply with study procedures as per protocol
    17. Patient able to understand, and willing to sign, and date the written informed consent form at screening visit prior to any protocol-specific procedures
    1. Pacientes, hombres o mujeres, entre 40 y 80 años, con un peso superior a los 50 kg y un índice de masa corporal (IMC) entre 18 kg/m2 y 35 kg/m2.
    2. PSP probable (signos clínicos de PSP) en estadio menor igual que II definido como:
    ? un mínimo de 12 meses de antecedentes de inestabilidad postural o caídas durante los 3 primeros años con sintomatología;
    ? una puntuación de PSPRS < 29; y
    ? síndrome rígido-acinético con notable rigidez axial.
    3. Haplotipo MAPT H1 positivo.
    4. Puntuación de la Escala modificada de Hachinski menor igual que 3. Esta escala no incluirá preguntas que afecten a los signos o síntomas neurológicos focales o seudobulbares, dada la importancia de los 3 en la PSP.
    5. Puntuación mayor igual que 25 en Minimental (MMSE).
    6. Pacientes capaces, a criterio del investigador, de realizar la evaluación neuropsicológica en la visita basal y a lo largo del estudio.
    7. Pacientes que tengan un cuidador responsable que les acompañe en todas las visitas del estudio. El cuidador y el paciente deberán poder leer, entender y hablar con fluidez el idioma local para garantizar la comprensión del impreso de consentimiento informado y las evaluaciones del paciente basadas en los datos proporcionados por el informador. El cuidador deberá tener contacto frecuente con el paciente (un mínimo de 3 horas por semana de una vez o en distintos momentos) y estar dispuesto a supervisar el cumplimiento terapéutico con la medicación en estudio, la salud del paciente y las medicaciones concomitantes a lo largo del estudio. Pacientes o cuidadores capaces de entender y dispuestos a seguir los procedimientos mencionados en la tarjeta del paciente en caso de observar signos o síntomas de neutropenia grave o toxicidad cutánea grave, durante el estudio.
    8. Hombres o mujeres en edad fértil (que entren en el estudio tras la menstruación y con una prueba de embarazo negativo) deben aceptar utilizar 2 métodos anticonceptivos (uno para el paciente y otro para la pareja) médicamente aceptados durante el estudio y 3 meses después de la última toma del tratamiento.
    9. Pacientes que residan fuera de un centro especializado de asistencia sanitaria o de atención a la demencia en el momento de la visita de selección, y cuyo ingreso en uno de estos centros no esté previsto. Se permitirá la inclusión a pacientes que residan en un centro de residencia asistida.
    10. Si el paciente recibe tratamiento con levodopa/carbidopa, levodopa/benserazida, agonistas de la dopamina, inhibidor de la catecol-o-metiltransferasa (COMT) u otra medicación para el Parkinson, salvo Azilect (rasagilina), las dosis deberán haber permanecido estables durante al menos los 60 días anteriores a la visita de selección y seguir así a lo largo de todo el estudio. No se podrá iniciar esta medicación durante el estudio. Los pacientes tratados con rasagilina o CoQ10 deberán mantener una dosis estable durante al menos los 90 días anteriores a la visita de selección.
    11. Pacientes capaces de tolerar la RMN durante la visita de selección sin sedación o con pequeñas dosis de benzodiacepinas.
    12. Pacientes capaces de deambular de forma independiente o con ayuda definida como la capacidad de andar al menos 30 metros con la ayuda de otra persona agarrándole únicamente de un brazo.
    13. Pacientes con una esperanza de vida mayor igual que 6 meses.
    14. Pacientes con un funcionamiento orgánico adecuado en la visita de selección y en la visita basal:
    ? Recuento absoluto de neutrófilos (RAN) mayor igual que 2 x 109/l
    ? Hemoglobina mayor igual que 10 g/dl
    ? Plaquetas (Plaq.) mayor igual que 100 x 109/l
    ? AST/ALT menor igual que 2,5 x LSN
    ? Bilirrubina menor igual que 1,5 x LSN
    ? Albuminemia mayor igual que 1 x LIN
    ? Urea menor igual que 1,5 x LSN
    ? Aclaramiento de creatinina > 50 ml/min. (fórmula de Cockcroft y Gault).
    ? Proteinuria < 30 mg/dl en tira reactiva; en caso de proteinuria mayor igual que 30 mg/dl, proteinuria de 24 horas < 1,5 g/24 horas.
    15. Los pacientes, hombres y mujeres, en edad fértil (que participen en el estudio una vez pasado el periodo menstrual y con una prueba de embarazo negativa) deben acceder a utilizar dos métodos anticonceptivos aceptados clínicamente (uno para el paciente y el otro para la pareja) durante el estudio y en los tres meses posteriores a la última toma del tratamiento.
    16. Pacientes capaces y dispuestos a seguir los procedimientos del estudio según el protocolo.
    17. Pacientes capaces de entender y dispuestos a firmar y fechar el impreso de consentimiento informado en la visita de selección antes de llevar a cabo cualquier procedimiento específico del protocolo.
    E.4Principal exclusion criteria
    1. Patient with history of cardiac, hematologic, hepatic, respiratory that is clinically significant for his/her participation in the study
    2. Insufficient fluency in local language to complete neuropsychological and functional assessments
    3. Diagnosis of Amyotrophic Lateral Sclerosis or other motor neuron disease or other diagnosis of taupathies (such as corticobasal degeneration, frontotemporal lobe dementia, multiple system athrophy)
    4. Any of the following condition:
    ? Abrupt onset of symptoms defined in inclusion criteria 2 associated with ictal events,
    ? Head trauma related to onset of symptoms defined in inclusion criteria 2,
    ? Severe amnesia within 6 months of the symptoms defined in inclusion criteria 2,
    ? Cerebellar ataxia,
    ? Choreoathetosis,
    ? Early, symptomatic autonomic dysfunction; or
    ? Tremor while at rest.
    5. Presence of other significant neurological or psychiatric disorders including (but not limited to) Alzheimer's disease; dementia with Lewy bodies; prion disease; Parkinson's disease (which has not subsequently been revised to PSP); any psychotic disorder; severe bipolar disorder; seizure disorder; tumor or other space-occupying lesion; or history of stroke or head injury with loss of consciousness for at least 15 minutes within the past 20 years.
    6. Within 4 weeks of screening or during the course of the study, concurrent treatment with memantine; acetylcholinesterase inhibitors; antipsychotic agents (other than quetiapine) or mood stabilizers (e.g., valproate, lithium); treatment with any investigational drugs or device or participation in an investigational drug study within 90 days of screening; or benzodiazepines (except as below):
    ? Low dose benzodiazepines (not more than 2 mg) may be used for sedation prior to MRI scans for those subjects requiring sedation. Neuropsychological testing may not be performed after benzodiazepines administration.
    ? Subjects who take short acting benzodiazepines (only temazepam or zolpidem are allowed) for sleep may continue to do so if they have been on a stable dose for 30 days prior to screening.
    ? Clonazepam may be used for treatment of dystonia or painful rigidity associated with PSP if the dose has been stable for 90 days prior to screening and is not expected to change during the course of the study.
    7. Treatment with lithium, methylene blue, tramiprosate, ketone bodies, latrepirdine, or any putative disease-modifying agent directed at tau within 90 days of screening.
    8. History of alcohol or substance abuse within 1 year prior to screening and deemed to be clinically significant by the site investigator.
    9. History of deep brain stimulator (DBS) surgery.
    10. History of early, prominent rapid eye movement (REM) sleep behaviour disorder.
    11. Contraindication to MRI examination for any reason (e.g., severe claustrophobia, ferromagnetic metal in body).
    12. Structural abnormality on MRI that precludes diagnosis of PSP, such as cortical infarct in brain region that might account for subject's symptoms.
    13. Patient with a diagnosis of malignant cancer or evidence of continued disease within five years before starting study treatment
    14. Patient with significant sensory abnormalities, dementia, other neurologic diseases, uncompensated medical illness, substance abuse and psychiatric illness
    15. Patient who have participated in a clinical trial within 3 months prior to screening
    16. Pregnant, or nursing female patient
    17. Patient having cardiac disorders defined by at least one of the following conditions:
    ? Patient with recent cardiac history (within 6 months) of:
    - Acute coronary syndrome
    - Acute heart failure (class III or IV of the NYHA classification)
    - Significant ventricular arrhythmia (persistent ventricular tachycardia, ventricular fibrillation, resuscitated sudden death)
    ? Patient with cardiac failure class III or IV of the NYHA classification
    ? Patient with severe conduction disorders which are not prevented by permanent pacing (atrio-ventricular block 2 and 3, sino-atrial block)
    ? Syncope without known aetiology within 3 months
    ? Uncontrolled severe hypertension, according to the judgment of the investigator, or symptomatic hypertension
    18. Patient with history of poor compliance or history of drug/alcohol abuse, or excessive alcohol beverage consumption that would interfere with the ability to comply with the study protocol, or current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent
    (Pending criteria 19-22)
    1. Pacientes con antecedentes cardíacos, hematológicos, hepáticos, respiratorios que son clínicamente significativos para su participación en el estudio.
    2. Fluidez insuficiente en el idioma local para realizar las evaluaciones neuropsicológicas y funcionales.
    3. Diagnóstico de esclerosis lateral amiotrófica u otra enfermedad de las motoneuronas u otro diagnóstico de taupatías (como degeneración corticobasal, demencia del lóbulo frontotemporal, atrofía multisistémica).
    4. Cualquiera de las siguientes afecciones:
    ? Aparición súbita de los síntomas definidos en el criterio de inclusión 2, asociados a episodios ictales;
    ? Traumatismo craneoencefálico relacionado con la aparición de los síntomas definidos en el criterio de inclusión 2;
    ? Amnesia grave en los 6 meses posteriores a la aparición de los síntomas definidos en el criterio de inclusión 2;
    ? Ataxia cerebelosa;
    ? Coreoatetosis;
    ? Distonía neurovegetativa sintomática temprana; o
    ? Temblor en reposo.
    5. Presencia de otros trastornos psiquiátricos o neurológicos significativos que incluyen, entre otros, la enfermedad de Alzheimer, demencia con cuerpos de Lewy, enfermedades priónicas, Parkinson (cuyo diagnóstico no pase a ser PSP), cualquier trastorno psicótico, trastorno bipolar grave, trastornos epilépticos, tumor u otra lesión expansiva, o antecedentes de ictus o lesión craneoencefálica con pérdida de conocimiento durante al menos 15 minutos en los 20 años anteriores.
    6. Tratamiento simultáneo con memantina, inhibidores de la acetilcolinesterasa, antipsicóticos (distintos a la quetiapina) o estabilizadores del estado de ánimo (p.ej., valproato, litio) durante las 4 semanas posteriores a la visita de selección o a lo largo del estudio; tratamiento con fármacos o dispositivos en fase de investigación o participación en un estudio de investigación en los 90 días posteriores a la visita de selección; o tratamiento con benzodiacepinas (salvo en los casos siguientes):
    ? Pueden usarse dosis bajas (inferiores a 2 mg) de benzodiacepinas como sedación antes de realizar una RMN en aquellos pacientes que lo requieran. No se realizarán pruebas neuropsicológicas tras la administración de benzodiacepinas;
    ? Los pacientes que toman benzodiacepinas de acción rápida (solo se permite temazepam o zolpidem) para conciliar el sueño pueden continuar con el tratamiento si han mantenido un dosis estable durante los 30 días anteriores a la visita de selección.
    ? Se permite el tratamiento con clonazepam para la distonía o la rigidez dolorosa asociada a la PSP si se ha mantenido una dosis estable durante los 90 días anteriores a la visita de selección y no está previsto modificarla en el transcurso del estudio.
    7. Tratamiento con litio, azul de metileno, tramiprosato, cuerpos cetónicos, latrepirdina o cualquier presunto fármaco modificador de la enfermedad dirigido a la proteína tau en los 90 días posteriores a la visita de selección.
    8. Antecedentes de alcoholismo o drogadicción en el año anterior a la visita de selección, considerados clínicamente significativos a juicio del investigador del centro.
    9. Antecedentes de cirugía de estimulación cerebral profunda (ECP).
    10. Antecedentes de trastorno de conducta del sueño REM (movimientos oculares rápidos), notable y precoz.
    11. Contraindicación para RMN por cualquier motivo (p.ej., fuerte claustrofobia, metal ferromagnético en el cuerpo).
    12. Anomalías estructurales en la RMN que descartan el diagnóstico de PSP, como infarto cortical en una región del cerebro que puede explicar los síntomas del paciente.
    13. Pacientes con diagnóstico de neoplasia maligna o indicios de una enfermedad continua en los cinco años anteriores al inicio del tratamiento en estudio.
    14. Pacientes con alteraciones sensitivas significativas, demencia, otras enfermedades neurológicas, enfermedad médica descompensada, drogadicción y enfermedades psiquiátricas.
    15. Pacientes que han participado en un ensayo clínico en los 3 meses anteriores a la visita de selección.
    16. Pacientes embarazadas o en periodo de lactancia.
    17. Pacientes con afecciones cardíacas definidas por al menos uno de los siguientes trastornos:
    ? Pacientes con antecedentes cardíacos recientes (en los 6 meses previos) de:
    - síndrome coronario agudo,
    - insuficiencia cardíaca aguda (clase III o IV según la clasificación de la NYHA),
    - arritmia ventricular importante (taquicardia ventricular persistente, fibrilación ventricular, muerte súbita reanimada).
    ? Pacientes con insuficiencia cardíaca de clase III o IV según la clasificación de la NYHA
    ? Pacientes con trastornos graves de la conducción cardíaca no evitables mediante electroestimulación cardíaca permanente (bloqueo auriculoventricular 2 y 3, bloqueo sinoauricular)
    ? Síncope de etiología desconocida en los 3 meses previos
    ? Hipertensión grave no controlada, a juicio del investigador, o hipertensión sintomática.
    Faltan criterios 18-22 (no cabe texto, ver protocolo)
    E.5 End points
    E.5.1Primary end point(s)
    Progressive Supranuclear Palsy Rating Scale (PSPRS) score
    Puntuación de la escala de evaluación de parálisis supranuclear progresiva (PSPRS) desde la semana 12 hasta la semana 48.
    E.5.1.1Timepoint(s) of evaluation of this end point
    from week 12 to week 48
    de semana 12 a semana 48
    E.5.2Secondary end point(s)
    Disease progression:
    ? Brain volume changes, as measured by ventricular volumes, brain stem atrophy and frontal lobe volume measured by volumetric brain MRI week 48.
    ? Serum and cerebrospinal fluid Tau protein levels (CSF samples are optional and will be realised only for voluntary patients) week 48.
    Disability level / severity of illness:
    ? Schwab and England Activities of Daily Living Scale (SEADL) scores from week 12 to week 48
    ? Clinical Global Impression of Change (CGI-C) scores from week 12 to week 48Clinical Global Impression of Disease Severity (CGI-ds) scores from week 12 to week 48
    Cognitive function:
    ? MMSE scores from week 12 to week 48
    ? RBANS scores from week 12 to week 48

    Psychiatric symptoms:
    ? Geriatric Depression Scale scores from week 12 to week 48
    ? Apathy Evaluation Scale scores from week 12 to week 48
    Quality of life:
    ? PSP-QoL scale score from week 12 to week 48
    Pharmacokinetics data:
    ? Biodisponibility of masitinib at W12 visit, prior to dose increase, compared to W24
    Safety:
    ? Occurrence of Adverse Events (AE), changes on clinical examination including vital signs (blood pressure, pulse rate) and weight, ECG and laboratory exams (biochemistry, hematology and urinalysis)
    ver punto E.2.2
    E.5.2.1Timepoint(s) of evaluation of this end point
    Disease progression:
    ? Brain volume changes week 48.
    ? Serum and cerebrospinal fluid Tau protein levels week 48.
    Disability level / severity of illness:
    ? Schwab and England Activities of Daily Living Scale (SEADL) scores from week 12 to week 48
    ? CGI-C scores from week 12 to week 48
    CGI-ds scores from week 12 to week 48
    Cognitive function:
    ? MMSE scores from week 12 to week 48
    ? RBANS scores from week 12 to week 48
    Psychiatric symptoms:
    ? Geriatric Depression Scale scores from week 12 to week 48
    ? Apathy Evaluation Scale scores from week 12 to week 48
    Quality of life:
    ? PSP-QoL scale score from week 12 to week 48
    Pharmacokinetics data:
    ? Biodisponibility of masitinib at W12 visit, prior to dose increase, compared to W24
    Safety:
    ? Occurrence of Adverse Events
    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 Yes
    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 trial3
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    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 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    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: 25
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 65
    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 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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 90
    F.4.2.2In the whole clinical trial 90
    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
    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 Decision2015-02-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-01-16
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2017-04-27
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