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    Summary
    EudraCT Number:2011-005529-34
    Sponsor's Protocol Code Number:TRx-237-007
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-04-01
    Trial results View 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 number2011-005529-34
    A.3Full title of the trial
    A Double-Blind, Placebo-Controlled, Randomized, Parallel Group, 12-Month Safety and Efficacy Trial of Leuco-methylthioninium bis(hydromethanesulfonate) in Subjects with Behavioral Variant Frontotemporal Dementia (bvFTD)
    Estudio doble ciego, controlado con placebo, aleatorizado, de grupos paralelos y de 12 meses de duración, sobre la seguridad y la eficacia de bis(hidrometanosulfonato) de leuco-metiltioninio en sujetos con demencia frontotemporal, variante conductual (DFTvc)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A comparison study of LMTM and placebo in patients with behavioral variant frontotemporal dementia
    Un estudio comparativo de LMTM y placebo en pacientes con demencia frontotemporal, variante conductual
    A.3.2Name or abbreviated title of the trial where available
    TRx-237-007
    A.4.1Sponsor's protocol code numberTRx-237-007
    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 SponsorTauRx Therapeutics Ltd
    B.1.3.4CountrySingapore
    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 supportTauRx Therapeutics Ltd
    B.4.2CountrySingapore
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTauRx Therapeutics Ltd
    B.5.2Functional name of contact pointInformation Desk
    B.5.3 Address:
    B.5.3.1Street AddressLiberty Building, University of Aberdeen, Foresterhill Road
    B.5.3.2Town/ cityAberdeen, Scotland
    B.5.3.3Post codeAB25 2ZP
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+441224 555191
    B.5.5Fax number+441224 555173
    B.5.6E-mailinfo@taurx.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/10/805
    D.3 Description of the IMP
    D.3.1Product nameLeuco-methylthioninium bis(hydromethanesulfonate)
    D.3.2Product code LMTM/TRx0237
    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 INNN/A
    D.3.9.1CAS number 1236208-20-0
    D.3.9.2Current sponsor codeTRx0237
    D.3.9.3Other descriptive nameN,N,N?,N?-tetramethyl-10H-phenothiazine-3,7-diaminium bis(methanesulfonate)
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    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
    behavioral variant Frontotemporal Dementia (bvFTD)
    demencia frontotemporal, variante conductual (DFTvc)
    E.1.1.1Medical condition in easily understood language
    Frontotemporal Dementia
    demencia frontotemporal
    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 16.1
    E.1.2Level PT
    E.1.2Classification code 10068968
    E.1.2Term Frontotemporal dementia
    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
    To demonstrate the efficacy of LMTM as assessed by the change from Baseline on:
    ? Addenbrooke?s Cognitive Examination Scale Revised (ACE-R)
    ? Modified Alzheimer?s Disease Cooperative Study ? Clinical Global Impression of Change (Modified ADCS-CGIC) - independently rated
    1. Demostrar la eficacia del LMTM evaluada mediante el cambio respecto al valor basal de:
    ? Escala ACE-R (Addenbrooke?s Cognitive Examination-Revised)
    ? Escala ADCS-CGIC modificada (Modified Alzheimer?s Disease Cooperative Study ? Clinical Global Impression of Change) ? con valoración independiente
    E.2.2Secondary objectives of the trial
    To evaluate the safety and tolerability of LMTM
    To evaluate the effect of LMTM as measured by the following additional disease severity, self-care, and motor impairment scales:
    ? Frontotemporal Dementia Rating Scale (FRS)
    ? Functional Activities Questionnaire (FAQ)
    ? Unified Parkinson?s Disease Rating Scale (UPDRS Parts II and III)
    2. Evaluar la seguridad y la tolerabilidad del LMTM
    3. Evaluar el efecto del LMTM determinado mediante las siguientes escalas de intensidad de la enfermedad, cuidados personales y afectación motora:
    ? Escala FRS (Frontotemporal Dementia Rating Scale)
    ? Escala FAQ (Functional Activities Questionnaire)
    ? Partes II y III de la escala UPDRS (Unified Parkinson?s Disease Rating Scale)
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    MT plasma concentrations: Provided the site has a refrigerated centrifuge and adequate capability to reliably freeze samples, blood will be collected at Baseline (Visit 2; pre-dose and approximately 3.5 hours post-dose) and, to the extent possible, at each subsequent on-treatment visit through Week 52 for purposes of population pharmacokinetic (PK) analysis of MT concentrations; samples may also be analyzed for other analytes, such as metabolites, depending on method availability. The time of the prior dose and the time of the blood sample will be recorded. All samples will be tested in accordance with the terms of the subjects? consent.
    Si el centro cuenta con una centrífuga refrigerada y medios adecuados para congelar de manera fiable las muestras, también se obtendrán muestras de sangre en el momento basal (visita 2; antes de la dosis y aproximadamente 3.5 horas después de la dosis) y, en la medida de lo posible, en todas las visitas posteriores durante el tratamiento hasta la semana 52 (aproximadamente 20 min después del registro del ECG), para el análisis de farmacocinética poblacional de las concentraciones de MT. Se registrará la hora de la dosis previa y la hora de extracción de la muestra.
    Se obtendrá una sola muestra de sangre para genotipificación, exclusivamente de los sujetos que hayan aportado su consentimiento informado
    E.3Principal inclusion criteria
    1. Diagnosis of probable bvFTD according to the International Consensus Criteria for bvFTD
    2. Centrally rated frontotemporal atrophy score of 2 or greater, taken as the maximum of right or left frontal or anterior temporal lobes on brain MRI of sufficient quality obtained at Screening or within a maximum of 42 days before Baseline, irrespective of pre-existing structural or functional imaging evidence supporting a diagnosis of bvFTD
    3. MMSE ? 20 at the Screening visit
    4. Age <80 years at the Screening visit
    5. Modified Hachinski ischemic score of ? 4 at the Screening visit
    6. Females must meet one of the following:
    ?Surgically sterile (hysterectomy, bilateral salpingectomy / oophorectomy) for at least 6 months minimum
    ?Have undergone bilateral tubal occlusion / ligation at least 6 months prior
    ?Post-menopausal for at least 1 year
    ?Using adequate contraception (a barrier method [such as condom, diaphragm, or cervical/vault cap] with spermicidal foam, gel, film, cream, or suppository; intrauterine device [IUD] or system, or oral or long-acting injected or implanted hormonal contraceptives for at least 3 months prior to Baseline; or vasectomized partner [with the appropriate post-vasectomy documentation of the absence of spermatozoa in the ejaculate]), or true abstinence (when this is in line with the preferred and usual lifestyle of the subject); subjects must be competent to use adequate contraception and to agree to continue to maintain adequate contraception throughout participation in the study
    OR In Italy, accept to avoid a pregnancy for at least 3 months prior to Baseline and throughout participation in the study
    7. Subject and/or, in the case of reduced decision-making capacity, legally acceptable representative(s) consistent with national law is/are able to read, understand, and provide written informed consent in the designated language of the study site
    8. Has one or more identified adult caregivers who meets the following criteria:
    ?Either lives with the subject or sees the subject on average for ? 2 hours/day ? 3 days/week, or in the investigator's opinion, the extent of contact is sufficient to provide meaningful assessment of changes in subject behavior and function over time and provide information on safety and tolerability
    ?Is willing to provide written informed consent for his/her own participation
    ? Is able to read, understand, and speak the designated language at the study site
    ? Agrees to accompany the subject to each study visit
    ?Is able to verify daily compliance with study drug
    9. If currently taking an AChEI (i.e., donepezil, galantamine, or rivastigmine) and/or memantine, at the time of Screening:
    ?The subject must have been taking such medication(s) for ?3 months
    ?The current dosage regimen and dosage form must be within the locally approved dose range and must have remained stable for ? 6 weeks
    ?It must be planned that the dosage regimen will remain stable throughout participation in the study
    Subjects not being treated with an AChEI or memantine (for ? 6 weeks before Screening) may also be enrolled if initiation of an AChEI or memantine is not planned for the time period during which the subject will be participating in this study
    10. Able to comply with the study procedures in the view of the investigator
    1. Diagnóstico de DFTvc probable según los Criterios de consenso internacional para la DFTvc (Rascovsky et al., 2007; sección 24.1)
    2. Puntuación de atrofia frontotemporal igual o superior a 2, según una valoración centralizada, entendida como el máximo de los lóbulos frontales o temporales anteriores derechos o izquierdos (Kipps et al., 2007) en una RM cerebral de calidad suficiente obtenida en la selección o en un plazo de hasta 42 días antes del momento basal, con independencia de los signos estructurales o funcionales ya existentes en pruebas de diagnóstico por imagen que respalden el diagnóstico de DFTvc
    3. Escala MMSE ?20 la visita de selección
    4. Edad <80 años en la visita de selección
    5. Puntuación de la escala de isquemia de Hachinski modificada ?4 en la visita de selección
    6. Las mujeres deben cumplir una de las siguientes condiciones:
    ? Esterilizadas quirúrgicamente (histerectomía, salpingectomía/ooforectomía bilateral) como mínimo 6 meses antes
    ? Sometidas a ligadura/oclusión de trompas bilateral como mínimo 6 meses antes
    ? En posmenopausia desde hace por lo menos un año
    ? Que utilicen un método anticonceptivo adecuado (un método de barrera [por ejemplo, preservativo, diafragma o capuchón cervical] con espermicida en espuma, gel, película, crema u óvulo vaginal; sistema o dispositivo intrauterino [DIU], o anticonceptivos hormonales orales o inyectables o implantados de acción prolongada desde por lo menos 3 meses antes del momento basal; o pareja vasectomizada [con la documentación adecuada de ausencia de espermatozoides en el semen después de la vasectomía]), o abstinencia completa (siempre que se corresponda con el estilo de vida preferido y habitual de la sujeto; las sujetoslas pacientes deben ser capaces de utilizar métodos anticonceptivos adecuados y estar de acuerdo en mantenerlos durante toda su participación en el estudio
    O BIEN
    En Italia, las pacientes deben comprometerse a evitar el embarazo durante por lo menos 3 meses antes del momento basal y a lo largo de su participación en el estudio
    7. El sujeto (y/o, en caso de una merma de la capacidad para tomar decisiones, uno o varios representantes legales en conformidad con la legislación nacional) sabe y puede leer, entender y otorgar su consentimiento informado por escrito en el idioma establecido en el centro de estudio
    8. Tiene uno o más cuidadores adultos identificados que cumplen los criterios siguientes:
    ? Vive con el sujeto o ve al sujeto un promedio de ?2 horas/día ?3 días/semana, o en opinión del investigador el grado de contacto es suficiente para permitir una evaluación significativa de los cambios de la conducta y el desempeño funcional del sujeto a lo largo del tiempo y ofrecer información sobre la seguridad y la tolerabilidad
    ? Está dispuesto a otorgar su consentimiento informado por escrito para su propia participación
    ? Sabe y puede leer, entiende y habla el idioma correspondiente al centro de estudio
    ? Está de acuerdo en acompañar al sujeto en todas las visitas del estudio
    ? Puede verificar el cumplimiento diario del medicamento del estudio
    9. Si está tomando actualmente un inhibidor de la acetilcolinesterasa (IAChE, por ejemplo, donepezilo, galantamina o rivastigmina) y/o memantina, en el momento de la selección:
    ? El sujeto debe haber estado tomando dichos medicamentos durante ?3 meses
    ? La pauta posológica y la forma farmacéutica actuales deben encontrarse dentro del intervalo de dosis autorizado localmente y deben haberse mantenido estables durante ?6 semanas
    ? Debe estar previsto que la pauta posológica vaya a permanecer estable durante toda la participación en el estudio
    También se podrá incluir a sujetos que no reciban tratamiento con un IAChE o con memantina (durante ?6 semanas antes de la selección) si no está previsto iniciar un IAChE o memantina durante el tiempo de participación del sujeto en este estudio
    10. Puede cumplir los procedimientos del estudio a juicio del investigador
    E.4Principal exclusion criteria
    1.Significant CNS disorder other than bvFTD
    2.Other significant intracranial pathology seen on brain MRI scan that would lead to a diagnosis other than probable bvFTD or that puts the subject at risk of Amyloid Related Imaging Abnormalities including:large confluent white matter hyperintense lesions, other focal brain lesion(s),a single area of superficial siderosis, >4 cerebral microhemorrhages,evidence of a prior macrohemorrhage.
    3.Biomarker evidence of underlying AD pathology as etiology of dementia
    4.Expressive language deficits such that the subject is too severely impaired to allow testing at Baseline
    5.Meets research criteria for Amyotrophic Lateral Sclerosis or motor; evidence of mild motor neuron disease on examination is allowed if not expected to interfere with subject's completion of study but prominent bulbar symptoms would be exclusionary
    6.Meets diagnostic criteria for probable bvFTD but has a proven mutation producing non-tau, non-TDP-43 pathology
    7.Clinical evidence or history of:
    ?Cerebrovascular accident (2 years)
    ?Transient ischemic attack (6 months)
    ?Significant head injury with associated loss of consciousness, skull fracture or persisting cognitive impairment (2 years)
    ?Other unexplained or recurrent loss of consciousness ?15 minutes (2 years)
    8.Epilepsy(a single prior seizure is considered acceptable)
    9.Rapid eye movement sleep behavior disorder
    10.DSM IV-TR criteria met for the following (within specified period):
    ?Major depressive disorder(current)
    ?Schizophrenia (lifetime)
    ?Other psychotic disorders, bipolar disorder (within the past 5 years), or substance related disorders (within the past 2 years)
    11.Metal implants in the head (except dental),pacemaker, any other non-removable items that are contraindications to MR imaging;any device proven to be MR compatible will be allowed
    12.Resides in hospital or moderate to high dependency continuous care facility
    13.History of swallowing difficulties
    14.Pregnant or breastfeeding
    15.G6PD deficiency
    16.History of significant hematological abnormality or current acute or chronic clinically significant abnormality, including:
    ?Hereditary or acquired methemoglobinemia or Baseline measurement of MetHb >2.0%
    ?Hemoglobinopathy, myelodysplastic syndrome, hemolytic anemia, or splenectomy
    ?Screening hemoglobin value below lower limit of the normal range
    17.Abnormal serum chemistry laboratory value at Screening clinically relevant. In addition, subjects with the following abnormalities must be excluded:
    ?Creatinine clearance <50 mL/min at Screening
    ?Thyroid stimulating hormone above laboratory normal range
    18.Clinically significant cardiovascular disease or abnormal assessments such as:
    ?Hospitalization for acute coronary syndrome or symptoms consistent with angina pectoris, within the 12 months preceding Baseline
    ?Signs or symptoms of clinical heart failure within the 12 months preceding Baseline
    ?Evidence of uncontrolled atrial fibrillation on Screening ECG or history of atrial fibrillation that is not currently controlled or where the QT interval cannot be assessed by triplicate ECGs
    ?QTcF at Screening >460 msec in males or >470 msec in females,or low or flat T waves making measurement of QT interval unreliable
    ?Recent history of poorly controlled hypertension
    ?Hypotension
    ?Heart rate <48 bpm or >96 bpm by measurement of vital signs or by ECG at Screening
    19.Preexisting or current signs or symptoms of respiratory failure. Subjects with previously diagnosed moderate to severe sleep apnea not adequately controlled should be excluded
    20.Concurrent acute or chronic clinically significant immunologic, hepatic,or endocrine disease and/or other unstable or major disease other than bvFTD.
    ?Subjects with hepatitis or primary biliary cirrhosis should be excluded
    ?HTLV-III, LAV (incl.any mutants/derivatives),any condition associated with Acquired Immunodeficiency Syndrome
    21.Diagnosis of cancer within the past 2 years prior to Baseline (other than basal cell or squamous cell skin cancer or Stage 1 prostate cancer) unless treatment has resulted in complete freedom from disease for at least 2 years
    22.Prior intolerance or hypersensitivity to MT-containing drug, similar organic dyes, or any of the excipients
    23.Treatment currently or within 3 months before Baseline with the following medications:
    ?Tacrine
    ?Amphetamine or dexamphetamine
    ?Antipsychotics:clozapine, olanzapine (other antipsychotics are allowable if they have not been initiated within 3 months before Baseline and are used in a stable dose and regimen)
    ?Carbamazepine, primidone
    ?Other mood stabilizers
    ?Drugs associated with methemoglobinemia
    24.Current or prior participation in a clinical trial:
    ?Clinical trial of a product for cognition with last dose received within 90 days prior to Screening (unless randomized to placebo)
    ?Clinical trial of a drug, biologic,device, or medical food with last dose received within 28 days prior to Baseline
    1.Trastorno importante del SNC distinto de la DFTvc, por ejemplo, enfermedad de Alzheimer, demencia con cuerpos de Lewy, enfermedad de Parkinson, esclerosis múltiple, parálisis supranuclear progresiva, hidrocefalia, enfermedad de Huntington, cualquier trastorno causado directa o indirectamente por encefalopatía espongiforme trasmisible (EET), enfermedad de Creutzfeldt-Jakob (ECJ), variante de la enfermedad de Creutzfeldt-Jakob (vECJ) o nueva variante de la enfermedad de Creutzfeldt-Jakob (nvECJ)
    2.Otra patología intracraneal importante observada mediante RM cerebral que llevaría a un diagnóstico distinto del de DFTvc probable o que le supone al sujeto un riesgo de anomalías amiloides en los estudios por imagen (conocidas por sus siglas en inglés, ARIA, Amyloid Related Imaging Abnormalities)
    3.Biomarcadores que demuestran una enfermedad de Alzheimer subyacente como causa de la demencia
    4.Trastornos del lenguaje expresivo tan intensos que no permiten realizar al sujeto los exámenes basales
    5.Cumple los criterios de investigación (El Escorial) de esclerosis lateral amiotrófica o enfermedad de la motoneurona (sección 24.2); se permite la presencia de signos a la exploración de enfermedad de la motoneurona leve si, a juicio del investigador, no es de esperar que obstaculicen la realización del estudio por el sujeto; unos síntomas bulbares marcados, indicativos de alto riesgo de afectación respiratoria, serían motivo de exclusión
    6.Cumple los criterios diagnósticos de DFTvc probable pero presenta una mutación productora de patología no-tau, no-TDP-43 (por ejemplo, FUS CHMP2B) demostrada
    7.Signos clínicos o antecedentes de cualquiera de los trastornos siguientes en el periodo especificado
    8.Epilepsia (una única crisis con anterioridad se considera aceptable)
    9.Trastorno conductual del sueño REM
    10.Ha cumplido los criterios de cualquiera de los siguientes trastornos (en el periodo especificado) según el DSM IV-TR (y no se ha modificado el diagnóstico posteriormente)
    11.Implantes metálicos en la cabeza (excepto implantes dentales), marcapasos, implantes cocleares o cualquier otro objeto no extraíble que constituya una contraindicación al estudio por RM; se permitirá el uso de prótesis, clips, endoprótesis o cualquier otro dispositivo que haya demostrado ser compatible con la RM
    12.Reside en un hospital o un centro de cuidados continuos para dependencia moderada o alta (se permite la residencia en centros tutelados de bajo nivel de cuidados en los que haya suficiente autonomía para permitir una evaluación válida de las actividades en relación con la conducta y el funcionamiento general, siempre y cuando no sea forzado por orden judicial o administrativa)
    13.Antecedentes de dificultades para la deglución (nota: el medicamento del estudio debe tragarse entero, SIN romper, aplastar, masticar ni disolver en líquido antes de ingerirlo)
    14.Embarazo o lactancia
    15.Deficiencia de glucosa-6-fosfato deshidrogenasa (G6PD)
    16.Antecedentes de alteración hemática importante o presencia de una alteración aguda o crónica de importancia clínica
    17.Valor anómalo de la bioquímica sérica en la selección que el investigador considere clínicamente importante (es decir, se considera que puede aumentar el riesgo asociado a la participación en el estudio o a la administración del producto en investigación y que, a juicio del investigador, haría que el sujeto fuera inadecuado para entrar en este estudio). Además, se debe excluir a los sujetos con cualquiera de las siguientes alteraciones:
    ?Aclaramiento de creatinina <50 ml/min en la visita de selección, estimado por el laboratorio central de acuerdo con la ecuación de Cockcroft y Gault
    ?Tirotropina (TSH) por encima del intervalo normal del laboratorio (se puede tratar al sujeto y volver a realizarle las evaluaciones de la selección al cabo de 3 meses)
    18.Enfermedad cardiovascular o resultados anómalos clínicamente importantes (en opinión del investigador)
    19.Signos o síntomas pasados o actuales de insuficiencia respiratoria (por ejemplo, producida por enfermedad pulmonar obstructiva crónica, asma bronquial, fibrosis pulmonar u otra enfermedad)
    20.Enfermedades concurrentes agudas o crónicas clínicamente importantes (en opinión del investigador) y/o cualquier otra enfermedad inestable o importante distinta de la DFTvc
    21.Diagnóstico de cáncer en los 2 años anteriores a la visita basal (distinto de carcinoma cutáneo basocelular o espinocelular o cáncer de próstata en estadio 1) salvo que el tratamiento haya logrado la ausencia total de enfermedad durante al menos 2 años
    22.Antecedentes de intolerancia o hipersensibilidad a medicamentos con MT, colorantes orgánicos similares o cualquiera de los excipientes
    23.Tratamiento concomitante o en los 3 meses anteriores al momento basal con cualquiera de los siguientes medicamentos (salvo que se señale otro criterio; véase la sección 4.7.4)
    24.Participación actual o anterior en un ensayo clínico
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy endpoint:
    ?Change from Baseline to Week 52 in the ACE-R
    ? Modified ADCS-CGIC at Week 52.
    Objetivos primarios de eficacia:

    Cambio respecto al valor basal en la Semana 52 de la Escala ACE-R

    Escala ADCS-CGIC modificada ? con valoración independiente en la Semana 52
    E.5.1.1Timepoint(s) of evaluation of this end point
    Efficacy will be evaluated at baseline and after 4 months (16 weeks), 8 months (32 weeks), and 12 months (52 weeks)
    La eficacia será evaluada en la visita basal y después de 4 meses (16 semanas), 8 meses (32 semanas) y 12 meses (52 semanas)
    E.5.2Secondary end point(s)
    Secondary endpoints are change from Baseline to Week 52 for the following parameters:
    ? FRS
    ? FAQ
    ? UPDRS Parts II and III

    Several exploratory analyses are pre-specified (additional post hoc analyses may be performed):
    ? Change from Baseline to Week 52 in the ACE-III
    ? Early effect on Modified ADCS-CGIC (after 4 and 10 weeks of treatment)
    ? Effect on MMSE at Week 52
    ? Change in whole brain volume assessed by brain MRI
    ? Effect of LMTM in subjects with known genetic mutations associated with bvFTD (in subjects by or for whom legally acceptable informed consent is provided)
    Los objetivos secundarios son el cambio desde la visita basal a la semana 52 para los siguientes parámetros:
    FRS
    FAQ
    UPDRS Partes II y III
    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety assessment will performed during screening, then at Baseline (and during the 4-hour post-dose observation), and 2, 4, 10, 16, 24, 32, 42, and 52 weeks after Baseline
    Blood will be collected at Baseline and as possible at each subsequent on-treatment visit through Week 52 for purposes of population pharmacokinetic (PK) analysis of MT concentrations.
    A single blood sample for genotyping may be collected any time after eligibility for randomization and participation in the study has been confirmed at Baseline (Visit 2).
    Se realizarán evaluaciones de la seguridad durante la selección con objeto de valorar la elegibilidad del sujeto para su inclusión en el estudio. A los sujetos incluidos se les realizarán evaluaciones de la seguridad en el momento basal (antes y después de la dosis durante el periodo de observación de 4 horas), 4, 8, 16, 24, 32, 42 y 52 semanas después del momento basal y aproximadamente 4 semanas después de la última dosis del medicamento del estudio (si procede). Se obtendrán muestras de sangre en el momento basal y, en la medida de lo posible, en todas las visitas posteriores durante el tratamiento hasta la semana 52, para el análisis de farmacocinética poblacional de las concentraciones de MT. Se obtendrá una sola muestra de sangre para genotipificación
    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 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 Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    Tolerabilidad
    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 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 concerned3
    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 Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    Australia
    Singapore
    United States
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months18
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months24
    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: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    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 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Either Subject or Subject?s legally acceptable representative is able to read, understand, and provide written informed consent in the designated language of the study site.
    O el paciente o su representante legal es capaz de leer, entender y otorgar por escrito el consentimiento informado en el lenguaje del centro
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 180
    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)
    Subjects who complete the treatment period may be offered an opportunity to subsequently receive treatment with LMTM in a separate open-label extension study. Otherwise, a follow-up visit will occur approximately 28 days after the last dose of study drug for those subjects discontinuing early or not entering the open-label extension.
    A los sujetos que completen el periodo de tratamiento se les podrá ofrecer la oportunidad de recibir tratamiento con LMTM posteriormente en un estudio abierto de extensión aparte. De no ser así, los sujetos que abandonen prematuramente o que no entren en la extensión abierta realizarán una visita de seguimiento aproximadamente 28 días después de la última dosis del medicamento del estudio
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation DeNDRoN
    G.4.3.4Network Country United Kingdom
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation SDCRN
    G.4.3.4Network Country United Kingdom
    G.4 Investigator Network to be involved in the Trial: 3
    G.4.1Name of Organisation Konsortium zur Erforschung der frontotemporalen Lobärdegeneration
    G.4.3.4Network Country Germany
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-05-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-04-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-02-10
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