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    Summary
    EudraCT Number:2014-002601-38
    Sponsor's Protocol Code Number:D5010C00009
    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:2015-01-02
    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 number2014-002601-38
    A.3Full title of the trial
    A 24-Month, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Efficacy, Safety, Tolerability, Biomarker and Pharmacokinetics Study of AZD3293 in Early Alzheimer´s Disease (The AMARANTH Study)
    Estudio multicéntrico, aleatorizado, en doble ciego, controlado con placebo y de grupos paralelos, de 24 meses de duración, sobre la eficacia, seguridad, tolerabilidad, biomarcadores y farmacocinética de AZD3293 en la enfermedad de Alzheimer en fase inicial (Estudio AMARANTH)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to assess the effect of AZD3293 in early Alzheimer's Disease
    Estudio para valorar el efecto de AZD3293 en la enfermedad de Alzheimer en fase inicial
    A.3.2Name or abbreviated title of the trial where available
    The AMARANTH Study
    Estudio AMARANTH
    A.4.1Sponsor's protocol code numberD5010C00009
    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 SponsorAstraZeneca AB
    B.1.3.4CountrySweden
    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 supportAstraZeneca
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca
    B.5.2Functional name of contact pointInformation Desk
    B.5.3 Address:
    B.5.3.1Street AddressForskaregatan 18
    B.5.3.2Town/ citySodertalje
    B.5.3.3Post codeSE-151 85
    B.5.3.4CountrySweden
    B.5.4Telephone number+34913913443
    B.5.6E-mailInformation.center@astrazeneca.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 nameAZD3293 20mg
    D.3.2Product code AZD3293
    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 INNNot yet available
    D.3.9.1CAS number 1522418-41-2
    D.3.9.2Current sponsor codeAZD3293 camsylate
    D.3.9.3Other descriptive nameBicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S,4R)-, compound with (1?,1'R,4ß)-4-methoxy-5''-methyl-6'-[5-(1-propyn-1-yl)-3-pyridinyl]dispiro[cyclohexane-1,2'-[2H]indene-1'(3'H),2''-[2H]imidazol]-4''-amine (1:1)
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 nameAZD3293 50mg
    D.3.2Product code AZD3293
    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 INNNot yet available
    D.3.9.1CAS number 1522418-41-2
    D.3.9.2Current sponsor codeAZD3293 camsylate
    D.3.9.3Other descriptive nameBicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S,4R)-, compound with (1?,1'R,4ß)-4-methoxy-5''-methyl-6'-[5-(1-propyn-1-yl)-3-pyridinyl]dispiro[cyclohexane-1,2'-[2H]indene-1'(3'(1:1)
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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
    Early Alzheimer´s Disease (mild cognitive impairment due to AD (ie, prodromal AD) and mild dementia of the Alzheimer´s type)
    enfermedad de Alzheimer en fase inicial (deterioro cognitivo leve debido a EA (es decir, EA prodrómica) y demencia leve de tipo Alzheimer)
    E.1.1.1Medical condition in easily understood language
    Early Alzheimer´s Disease
    enfermedad de Alzheimer en fase inicial
    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 17.1
    E.1.2Level PT
    E.1.2Classification code 10012271
    E.1.2Term Dementia Alzheimer's type
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of AZD3293 on cognitive and functional outcomes in patients with early Alzheimer´s disease (AD) as measured by the Clinical Dementia Rating - Sum of Boxes score.
    To evaluate the safety and tolerability of AZD3293 in patients with early AD.
    Evaluar la eficacia del AZD3293 sobre variables cognitivas y funcionales en pacientes con enfermedad de Alzheimer (EA) en fase inicial en su determinación mediante la puntuación de la escala de valoración clínica de la demencia - suma de las casillas (CDR-SB, Clinical Dementia Rating - Sum of Boxes).
    Evaluar la seguridad y la tolerabilidad del AZD3293 en pacientes con EA en fase inicial.
    E.2.2Secondary objectives of the trial
    To evaluate the efficacy of AZD3293 on:
    - cognitive outcomes as measured by the ADAS-Cog-13 score
    - functional outcome as measured by the FAQ score and the ADCS-ADL
    instrumental items score
    - neuropsychiatric symptoms as assessed by NPI score
    To evaluate the efficacy of AZD3293 to prolong time in the current disease state as measured by the CDR global score
    To evaluate the effect of AZD3293 on underlying pathology as measured by brain volumes using MRI
    To assess the population pharmacokinetics (PK) of AZD3293 and metabolite AZ13569724
    Evaluar la eficacia del AZD3293 sobre:
    - variables cognitivas determadas mediante la puntuación de la escala de valoración ADAS-Cog-13
    -variables funcionales determinadas mediante la puntuación del cuestionario de actividades funcionales (FAQ, Functional Activities Questionnaire)
    -sobre síntomas neuropsiquiátricos evaluados mediante la puntuación del inventario neuropsiquiátrico
    Evaluar la eficacia del AZD3293 para prolongar el tiempo en el estado actual de la enfermedad en su determinación mediante la puntuación global de la escala de valoración clínica de la demencia (CDR, Clinical Dementia Rating)
    Evaluar el efecto del AZD3293 sobre la enfermedad subyacente en su determinación mediante volúmenes cerebrales con resonancia magnética nuclear (RMN)
    Evaluar la farmacocinética poblacional del AZD3293 y del metabolito AZ13569724
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    PET sub-study
    To evaluate the effect of AZD3293 on:
    - brain amyloid burden using PET
    - brain metabolic rates using fluorodeoxyglucose (FDG) PET

    CSF sub-study
    To evaluate the effect of AZD3293 on:
    -central markers of pharmacodynamics by assessing Aß 1-42 and Aß 1-40 concentrations
    -central markers of neurodegeneration by assessing CSF total tau and phosphorylated tau concentrations
    subestudio de PET
    Para evaluar el efecto de AZD3293 sobre:
    - la carga de amiloide cerebral mediante tomografía de emisión de positrones (PET)
    - los índices metabólicos cerebrales mediante PET con fluorodesoxiglucosa (FDG)

    Subestudio CSF
    Para evaluar el efecto del AZD3293 sobre:
    - marcadores centrales de farmacodinámica mediante evaluación de las concentraciones de Aß1-42 y Aß1-40
    - marcadores centrales de neurodegeneración mediante evaluación de las concentraciones de tau total y tau fosforilada en LCR
    E.3Principal inclusion criteria
    -Gradual and progressive change in the patient´s memory function over more than 6 months
    -Male or female, aged 55 to 85 years inclusive
    -MMSE score of 21 to 28 inclusive
    -Score of <80 on the Delayed Memory Index of the Repeatable Battery for the assessment of Neuropsychological Status
    -FAQ score of >/=2
    -Rosen Modified Hachinski Ischemic score </=4
    -For a diagnosis of mild AD, patient (1) meets the National Institute on Aging (NIA) and the Alzheimer´s Association (AA) (NIA-AA) criteria for probable AD and (2) has a CDR global score of 0.5 or 1, with the memory box score >/= 0.5
    -For a diagnosis of MCI due to AD, patient (1) meets NIA-AA criteria for MCI due to AD and (2) had CDR global score of 0.5, with the memory box score >/= 0.5
    -Screening MRI shows no evidence of significant abnormality that would suggest another potential etiology for MCI or dementia.
    -Laboratory tests show no evidence of other etiologies for MCI or dementia
    -PET visual reading positive for presence of amyloid according to the binary image-reading guidelines of florbetapir F 18 injection (AmyvidTM), or CSF Aß1-42 concentration below the prespecified threshold by Innotest enzyme-linked immunosorbent assay (ELISA)
    -Contraception: Women must be postmenopausal or surgically sterile. Men must abstain or use barrier contraception from the first day of dosing until 3 months after the last dose.
    -Concomitant medication: The dose of any concomitant medication must be stable for at least 30 days before screening, and between screening and randomization. For cholinesterase inhibitors (a) the dose regimen must be stable for at least 90 days prior to baseline, (b) the patient must be free from any clinically important side effects attributable to the drug, and (c) patient and study partner agree that, barring unforeseen circumstances, the dosage regimen will remain stable for the study duration. Treatment with memantine must be discontinued at least 3 weeks before randomization.
    -Agreement to undergo ApoE genotyping
    -The patient must have a reliable study partner with whom he/she cohabits or has regular contact.
    - Variación gradual y progresiva de la función de la memoria del paciente a lo largo de más de 6 meses
    - Hombre o mujer de 55 a 85 años de edad, ambos extremos incluidos
    - Puntuación del MMSE de 21 a 28, ambos extremos incluidos
    - Puntuación <80 del índice de memoria diferida (Delayed Memory Index) de la RBANS (Repeatable Battery for the Assessment of Neuropsychological Status)
    - Puntuación FAQ >/= 2
    - Puntuación de la escala de isquemia de Hachinski modificada por Rosen </= 4
    - Para el diagnóstico de EA leve, el paciente (1) cumple los criterios de EA probable del National Institute on Aging (NIA) y la Alzheimer´s Association (AA) de Estados Unidos (NIA-AA) y (2) presenta una puntuación global de la CDR de 0,5 o 1, con una puntuación de la casilla de memoria >/= 0,5 en la visita de selección
    - Para el diagnóstico de DCL debido a EA, el paciente (1) cumple los criterios de DCL debido a EA del NIA-AA y (2) presenta una puntuación global de la CDR de 0,5, con una puntuación de la casilla de memoria >/= 0,5
    - La RMN de la selección no muestra signos de anomalías importantes que indiquen otra posible causa del DCL o la demencia.
    - Los análisis clínicos no muestran signos de otras causas del DCL o demencia
    - Lectura visual de la PET positiva para la presencia de amiloide con arreglo a las directrices de lectura de imágenes binarias tras la inyección de florbetapir F 18 (AmyvidTM), o bien una concentración de Aß1-42 en LCR por debajo del umbral preespecificado en el método de ELISA
    -Anticoncepción: Las mujeres deben ser posmenopáusicas o haber sido esterilizadas quirúrgicamente. Los hombres deben mantener abstinencia sexual o estar dispuestos a utilizar un método anticonceptivo de barrera desde el primer día de tratamiento hasta 3 meses después de la última administración del tratamiento del estudio.

    - Medicación concomitante: la dosis deberá mantenerse estable desde un mínimo de 30 días antes de la selección, y entre la selección y la aleatorización. Si el paciente recibe inhibidores de la colinesterasa, deberán cumplirse también las siguientes condiciones: (a) el paciente se ha mantenido con una pauta de dosis estable desde un mínimo de 90 días antes del momento basal , (b) el paciente no presenta efectos secundarios de importancia clínica atribuibles al fármaco, y (c) el paciente y su compañero de estudio acceden a mantener estable la pauta posológica durante todo el estudio, salvo en circunstancias imprevisibles. El tratamiento con memantina deberá suspenderse como mínimo 3 semanas antes de la aleatorización.
    - El paciente accede a que se le realice el genotipado de ApoE
    - El paciente debe contar con un compañero de estudio fiable con el que conviva o tenga un contacto habitual
    E.4Principal exclusion criteria
    -Prior or ongoing participation in any AZD3293 study or other BACE inhibitor
    study or participation in any other interventional AD study during the proposed study
    -Significant neurological disease affecting the CNS, other than AD, that may affect cognition or ability to complete the study.
    -History of clinically evident stroke, or multiple strokes based on history or imaging results.
    -History of clinically important carotid or vertebrobasilar stenosis or plaque.
    -History of multiple concussions or a concussion with sustained cognitive complaints or objective change in neuropsychological function in the last 5 years
    -Patients with a current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of Major Depressive Disorder or any current primary psychiatric diagnosis other than AD if, the psychiatric disorder or symptom is likely to confound interpretation of drug effect, affect cognitive assessment, or affect the patient´s ability to complete the study
    -History of alcohol or drug abuse or dependence (except nicotine dependence) within the last 2 years
    -Within 1 year before the screening visit or between screening and baseline, any of the following: myocardial infarction; moderate or severe congestive heart failure, NYHA class III or IV; hospitalization for, or symptoms of, unstable angina; syncope due to orthostatic hypotension or unexplained syncope; known significant structural heart disease; or hospitalization for arrhythmia
    -Congenital QT prolongation
    -Intermittent second- or third-degree atrioventricular (AV) heart block or AV dissociation or history of ventricular tachycardia
    -History or presence of diabetes, unless well controlled and actively managed
    -History of cancer within the last 5 years, with the exception of non-metastatic basal and/or squamous cell carcinoma of the skin, in situ cervical, or non-progressive prostate cancer
    -Current serious or unstable clinically important systemic illness likely to affect cognitive assessment, deteriorate, or affect the patient´s safety or ability to complete the study , including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic, or hematologic disorders
    -History of vitiligo and/or current evidence of post-inflammatory hypopigmentation
    -History of 2 or more clinically important drug allergies, eg, severe drug-induced rash or anaphylaxis
    -Screening MRI shows evidence of significant abnormality that would suggest
    another potential etiology for MCI or dementia
    -Uncontrolled hypertension
    -A corrected QT (QTcF) interval measurement >450 msec
    -Known positive serologic findings for HIV antibodies
    -Positive hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies
    -Urine drug screen positive for amphetamine, cocaine, phencyclidine, or barbiturate.
    -Any clinically important abnormality at screening
    -Calculated creatinine clearance <40 mL/min
    -ALT >/=1.5 × the upper limit of normal (ULN) of the performing laboratory, AST
    >/=2 × ULN, or total bilirubin >/=1.5 × ULN
    -Regular use (eg, taken >3 days/week) of narcotic medications within 30 days before baseline
    -Use of strong inhibitors of CYP3A4 within 14 days or 5 half-lives, whichever is
    longer, or strong inducers of CYP3A4 within 30 days before baseline
    -Use of strong inhibitors of Pgp or BCRP within 14 days or 5 half-lives, whichever is longer, or inducers of Pgp within 30 days before baseline.
    -Use of drugs known to significantly prolong the QT interval within 14 days or 5 half-lives, whichever is longer, prior to baseline
    -Use of medications known to significantly influence coagulation, such as warfarin or heparin.
    -Treatment with any investigational drug or device within 60 days or 5 half-lives prior to screening (whichever is longer) or between screening and baseline
    -Prior treatment with an AD vaccine.
    -Presence of any of the following MRI contraindications: pacemaker; cardiac
    defibrillator; spinal cord or vagus nerve stimulator; aneurysm clip; artificial heart valve; recent coronary or carotid stent; ear implant; CSF shunt; other implanted medical device; metal fragments or foreign objects in the eyes, skin, or body; severe claustrophobia that would contraindicate a brain MRI scan

    CSF sub-study:
    -Any spinal malformations or other aspects or other clinical findings that may complicate or contraindicate lumbar puncture
    -Current blood-clotting or bleeding disorder, including clinically significant abnormal findings in laboratory assessments of coagulation or hematology

    PET sub-study:
    -Present or planned participation in any other research and/or medical protocol involving PET ligands or radioactive agents
    -Exposure to ionizing radiation that, in combination with the planned administration of study amyloid PET ligand, would result in a cumulative exposure that exceeds local recommended exposure limits
    -Hypersensitivity to the active substance or any of the excipients of AMYVID
    Participación previa/actual en cualquier estudio de AZD3293 u otro inhibidor de la BACE o en ningún otro estudio intervencionista de EA durante su participación en el presente estudio.
    Enfermedad neurológica con afectación del SNC, distinta de la EA, que pueda alterar la cognición o la capacidad para completar el estudio.
    Antecedentes de ictus sintomático o ictus múltiples según la anamnesis o los resultados de neuroimagen.
    Antecedentes de estenosis o placa carotídea o vertebrobasilar de importancia clínica.
    Antecedentes de conmociones cerebrales repetidas o conmoción cerebral con problemas cognitivos prolongados o con variación objetiva de la función neuropsicológica en los últimos 5 años.
    Diagnóstico actual de trastorno depresivo mayor según el Manual diagnóstico y estadístico de trastornos mentales, 5ª Edición o con cualquier diagnóstico psiquiátrico primario actual distinto de la EA si, el
    trastorno o síntoma psiquiátrico es probable que suponga un factor de confusión para la interpretación del efecto del fármaco, altere la evaluación cognitiva o la capacidad del paciente para finalizar el estudio.
    Antecedentes de alcoholismo, drogadicción o farmacodependencia(excepto nicotina) en los 2 años anteriores a la selección.
    Presentar en 1 año antes de la visita de selección o entre la selección y el momento basal cualquiera de lo siguiente:infarto de miocardio;insuficiencia cardiaca congestiva moderada o severa, de clase III o IV de la NYHA; angina inestable; síncope por hipotensión ortostática o no filiado;diagnóstico de cardiopatía estructural importante, u hospitalización por arritmia.
    Prolongación congénita del QT.
    Bloqueo cardiaco AV de segundo o tercer grado intermitente o disociación AV o antecedentes de taquicardia ventricular
    Antecedentes o presencia de diabetes, salvo que bien controlada y en tratamiento activo.
    Antecedentes de cáncer en los últimos 5 años, excepto carcinoma cutáneo basocelular y/o espinocelular no metastásico, carcinoma de cuello uterino in situ o cáncer de próstata no progresivo.
    Enfermedad sistémica actual, grave o inestable, clínicamente importante, que es probable altere la evaluación cognitiva, deteriore o afecte la seguridad del paciente o su capacidad para finalizar el estudio, incluyendo trastornos hepáticos, renales, gastroentéricos, respiratorios,cardiovasculares, endocrinos, inmunitarios o hematológicos.
    Antecedentes de vitíligo y/o signos actuales de hipopigmentación postinflamatoria.
    Antecedentes de 2 o más alergias medicamentosas.
    Signos de anomalía en la RMN de la selección que sugieran otra posible causa del DCL o la demencia.
    Hipertensión no controlada.
    Intervalo QT corregido >450 ms.
    Serología positiva para anticuerpos VIH.
    Positividad para el antígeno de superficie de hepatitis B o para anticuerpos de hepatitis C.
    Detección en orina positiva para anfetaminas, cocaína o barbitúricos.
    Alteración clínicamente importante.
    Aclaramiento de creatinina calculado <40 ml/min ALT >/= 1,5 × límite superior de la normalidad (LSN) del laboratorio que
    realiza la prueba, AST >/=2 × LSN, o bilirrubina total >/= 1,5 × LSN.
    Uso habitualde opiáceos en 30 días antes del momento basal
    Uso de inhibidores potentes de CYP3A4 durante 14 días o 5 semividas, o de inductores potentes de CYP3A4 en 30 días antes del momento basal
    Uso de inhibidores potentes de Pgp o BCRP en 14 días o 5 semividas, o de inductores potentes de Pgp en 30 días antes del momento basal
    Uso de fármacos con efecto de prolongación del intervalo QT en 14 días o 5 semividas antes del momento basal
    Uso de fármacos con efecto sobre la coagulación.
    Tratamiento con un medicamento o producto sanitario en investigación durante 60 días o 5 semividas antes de la selección o entre la selección y el momento basal.
    Tratamiento previo con una vacuna contra la EA.
    Presencia de cualquiera de las estas contraindicaciones para la RMN:marcapasos; desfibrilador cardiaco; estimulador de la médula espinal o del nervio vago; clip de aneurisma; válvula cardiaca artificial; stent coronario o carotídeo reciente; implante auditivo; derivación de LCR;otro producto sanitario implantado; fragmentos de metal u objetos extraños en los ojos, la piel u otra parte del cuerpo; claustrofobia intensa que contraindique una RMN cerebral.
    Subestudios:
    Malformaciones vertebrales u otros hallazgos clínicos que pudieran complicar la punción lumbar.
    Trastorno de la coagulación o hemorrágico actual, incluidas las alteraciones analíticas clínicamente importantes en el estudio de coagulación o el hemograma.
    Participación actual o prevista en un protocolo de investigación y/o médico con productos radioactivos o ligandos para PET.
    Radiaciones ionizantes que, en combinación con la administración prevista del ligando de amiloide para las PET del estudio, provocaría una exposición acumulada por encima de los límites recomendados.
    Hipersensibilidad al principio activo o a alguno de los excipientes de AMYVID.
    E.5 End points
    E.5.1Primary end point(s)
    Clinical Dementia Rating - Sum of Boxes (CDR-SB) score
    Escala de valoración clínica de la demencia - Suma de las casillas
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline up to 104 Weeks
    Momento basal hasta semana 104
    E.5.2Secondary end point(s)
    Efficacy
    -Change from baseline to Week 104 in the ADAS-Cog-13 score
    -Change from baseline to Week 104 in the FAQ score
    -Change from baseline to Week 104 in the ADCS-ADL instrumental items score
    -Time to loss of 1 global stage on the CDR global score through Week 104
    -Change from baseline to Week 104 in the NPI total score
    -Changes from baseline to Weeks 26, 52, and 78 in the CDR-SB, ADAS-Cog-13, FAQ, ADCS-ADL instrumental items, and NPI total scores, as well as changes from baseline to Week 13 in ADAS-Cog-13 score

    Biomarker
    -Changes from screening to Week 104 in volumetric MRI measures, including whole brain volume, ventricular volume, entorhinal cortex volume, hippocampal volume, and temporal lobe volume
    CSF sub-study:
    -Changes from screening to Week 97 in CSF CSF Aß 1-40 and CSF Aß 1-42
    -Changes from screening to Week 97 in CSF biomarkers total tau and
    phosphorylated tau
    PET sub-study:
    -Change from screening to Week 104 in brain amyloid as measured by amyloid PET
    -Change from baseline to Week 104 in brain metabolism as measured by FDG PET

    Safety
    -Frequencies of clinically significant changes in physical examination findings, including results of neurological, skin, and eye examinations
    -Frequencies of non-serious adverse events (AEs) and serious AEs (SAEs)
    -Changes in vital signs
    -Changes in ECG findings
    -Changes in clinical laboratory test results
    -Frequency and severity of amyloid-related imaging abnormalities (ARIA)
    -Worsening in cognition, as measured by the ADAS-Cog-13
    -Changes in Columbia - Suicide Severity Rating Scale (C-SSRS) scores

    Pharmacokinetic
    -Plasma AZD3293 and metabolite AZ13569724 concentrations
    -Evaluation of covariates that may contribute to AZD3293 and AZ13569724 PK variability.
    -CSF AZD3293 and AZ13569724 PK at Weeks 52 and 97 (CSF sub-study)
    Eficacia
    -Variación entre el momento basal y la semana 104 en la puntuación de la ADAS-Cog-13
    -Variación entre el momento basal y la semana 104 en la puntuación del FAQ
    -Variación entre el momento basal y la semana 104 en la puntuación de los ítems instrumentales del ADCS-ADL
    -Tiempo hasta la pérdida de un estadio global en la puntuación global de la CDR hasta la semana 104
    -Variación entre el momento basal y la semana 104 en la puntuación total del NPI
    - Variaciones entre el momento basal y las semanas 26, 52 y 78 en las puntuaciones de la CDR-SB, la ADAS-Cog-13, el FAQ, los ítems instrumentales del ADCS-ADL y total del NPI, así como variaciones entre el momento basal y la semana 13 en la puntuación de la ADAS-Cog-13
    Biomarcadores:
    -Variaciones entre la selección y la semana 104 en las medidas de RMN volumétrica, tales como volumen cerebral total, volumen ventricular, volumen de la corteza entorrinal, volumen del hipocampo y volumen del lóbulo temporal.
    Subestudio LCR:
    -Variaciones entre la selección y la semana 97 en los biomarcadores Aß1-40 y Aß1-42 en LCR
    -Variaciones entre la selección y la semana 97 en los biomarcadores tau total y tau fosforilada en LCR
    Subestudio PET:
    -Variación entre la selección y la semana 104 en el amiloide cerebral en su determinación mediante PET de amiloide
    -Variación entre el momento basal y la semana 104 en el metabolismo cerebral en su determinación mediante PET con FDG
    Seguridad:
    -Frecuencia de alteraciones clínicamente importantes halladas en la exploración física, incluidos los resultados de los exámenes neurológicos, cutáneos y oculares
    -Frecuencia de acontecimientos adversos (AE) no graves y AE graves (SAE)
    -Variaciones en las constantes vitales
    -Variaciones en los hallazgos del ECG
    -Variaciones en los resultados de los análisis clínicos.
    -Frecuencia y severidad de las anomalías amiloides en los estudios por imagen (ARIA)
    -Deterioro cognitivo en su determinación mediante la ADAS-Cog-13
    -Variaciones en las puntuaciones de la C-SSRS
    Farmacocinética
    -Concentraciones plasmáticas de AZD3293 y del metabolito AZ13569724
    -Evaluación de las covariables que puedan contribuir a la variabilidad farmacocinética del AZD3293 y del AZ13569724
    -Se evaluará la farmacocinética del AZD3293 y del AZ13569724 en las semanas 52 y 97 (subestudio de LCR)
    E.5.2.1Timepoint(s) of evaluation of this end point
    All safety endpoints will be evaluated from baseline to Week 104. Efficacy endpoints as specified in E.5.2.
    Todos las criterios de valoración de seguridad serán evaluados desde el momento basal a la semana 104. Los criterios de valoración de eficacia se especifican en la seccíon E.5.2
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) 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 concerned14
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA78
    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
    Argentina
    Australia
    Belgium
    Canada
    Czech Republic
    France
    Germany
    Hungary
    Japan
    Korea, Republic of
    Poland
    Romania
    Spain
    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
    Última Visita Último Paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial 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: 96
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 541
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state140
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 637
    F.4.2.2In the whole clinical trial 1551
    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 is anticipated the first subject ending treatment will be in 2017. At present , plans for the treatment or care after participation in the trial are under development. It is likely that the completers will be offered participation in a long term extension if they so wish.
    Se espera que el primer sujeto termine el tratamiento en 2017. Por el momento, los planes pare el tratamiento o cuidado después de la participación en el estudio están en desarrollo. Es probable que se ofrezca a los pacientes que completen el estudio la participación en una extensión a largo plazo si lo desean.
    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 Decision2015-01-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-01-14
    P. End of Trial
    P.End of Trial StatusOngoing
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