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    Summary
    EudraCT Number:2018-004739-58
    Sponsor's Protocol Code Number:BAN2401-G000-301
    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:2019-06-11
    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 number2018-004739-58
    A.3Full title of the trial
    A Placebo-Controlled, Double-Blind, Parallel-Group, 18-Month Study With an Open-Label Extension Phase to Confirm Safety and Efficacy of BAN2401 in Subjects With Early Alzheimer’s Disease
    Estudio doble ciego, de grupos paralelos, controlado con placebo, de 18 meses de duración, con una Fase de Extensión abierta, para confirmar la seguridad y eficacia de BAN2401 en sujetos con enfermedad de Alzheimer en etapa inicial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 clinical study to investigate the effects of BAN2401 in patients with Early Alzheimer's Disease
    Un estudio clínico de fase 3 para investigar los efectos de BAN2401 en pacientes con enfermedad de Alzheimer temprana
    A.4.1Sponsor's protocol code numberBAN2401-G000-301
    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 SponsorEisai Limited
    B.1.3.4CountryUnited Kingdom
    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 supportEisai Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEisai Limited
    B.5.2Functional name of contact pointMedical Information
    B.5.3 Address:
    B.5.3.1Street AddressMosquito Way
    B.5.3.2Town/ cityHatfield
    B.5.3.3Post codeAL10 9SN
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number4408456761400
    B.5.5Fax number4408456761486
    B.5.6E-mailLMedInfo@eisai.net
    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 nameBAN2401
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBAN2401
    D.3.9.1CAS number 1260393-98-3
    D.3.9.2Current sponsor codeBAN2401
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    D.3.11.13.1Other medicinal product typeMonoclonal Antibody
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia
    Deterioro cognitivo leve debido a la enfermedad de Alzheimer o demencia leve por enfermedad de Alzheimer
    E.1.1.1Medical condition in easily understood language
    Mild cognitive impairment or mild dementia caused by Alzheimer's disease which results in progressive memory loss, reasoning, language and other mental abilities.
    Deterioro cognitivo leve o demencia leve causada por la enfermedad de Alzheimer que resulta en pérdida progresiva de memoria, razonamiento, lenguaje y otras capacidades mentales.
    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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10001896
    E.1.2Term Alzheimer's disease
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10074616
    E.1.2Term Prodromal Alzheimer's disease
    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
    Core study: To evaluate the efficacy of BAN2401 in subjects with EAD by determining the superiority of BAN2401 compared with placebo on the change from baseline in the CDR-SB at 18 months of treatment.

    Extension phase:
    -To evaluate the long-term safety and tolerability of BAN2401 in subjects with EAD in the Extension Phase
    -To evaluate whether the long-term effects of BAN2401 as measured by the CDR-SB at the end of the Core Study is maintained over time in the Extension Phase
    Core: Evaluar la eficacia de BAN2401 en sujetos con enfermedad de Alzheimer en fase inicial (early Alzheimer’s disease, EAD), mediante determinación de la superioridad de BAN2401 sobre el placebo en cuanto al cambio frente al Baseline en la Clinical Dementia Rating–Sum of Boxes (CDR-SB) (Suma de cajas del índice clínico de demencia) a los 18 meses de tratamiento

    Extension Phase:
    Objetivos principales
    • Evaluar la seguridad y la tolerabilidad a largo plazo de BAN2401 en sujetos con EAD en la Extension Phase
    • Evaluar si los efectos a largo plazo de BAN2401, en su medición mediante la CDR-SB, al final del Core Study se mantienen a lo largo del tiempo en la Extension Phase
    E.2.2Secondary objectives of the trial
    Key Secondary Objectives:
    -To determine that BAN2401 is superior to placebo in reducing brain amyloid levels as measured by amyloid PET at 18 months of treatment in subjects with EAD
    -To evaluate the efficacy of BAN2401 in subjects with EAD by determining the superiority of BAN2401 compared with placebo on the change from baseline in the ADCOMS at 18 months of treatment
    -To evaluate the efficacy of BAN2401 in subjects with EAD by determining the superiority of BAN2401 compared with placebo on the change from baseline in the ADAS-cog14 at 18 months of treatment

    For all other objectives see protocol.
    Objetivos secundarios clave:
    -Determinar que BAN2401 es superior al placebo en cuanto a reducir los niveles cerebrales de amiloide en su medición mediante tomografía de emisión de positrones (positron emission tomography, PET)- amiloide a los 18 meses de tratamiento en sujetos con EAD
    -Evaluar la eficacia de BAN2401 en sujetos con EAD mediante determinación de la superioridad de BAN2401 sobre el placebo en cuanto al cambio frente al Baseline en la ADCOMS a los 18 meses de tratamiento
    -Evaluar la eficacia de BAN2401 en sujetos con EAD mediante determinación de la superioridad de BAN2401 sobre el placebo en cuanto al cambio frente al Baseline en la AD Assessment Scale–Cognitive Subscale14 (ADAS-cog14) a los 18 meses de tratamiento

    Para todos los demás objetivos consultar el protocolo
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    A longitudinal amyloid PET will be conducted at 3, 6, 12, and 18 months of treatment in a subgroup of consenting subjects imaging substudy) from any participating country to demonstrate target engagement and to assess amyloid clearance for BAN2401. Longitudinal CSF assessments will be collected at 12 and 18 months of treatment for soluble biomarker analysis (eg, Aβ[1-42], neurogranin, NFL, t-tau, and p-tau) in consenting subjects in any participating country to assess effects on indicators of disease pathology.
    Se efectuarán estudios longitudinales con PET-amiloide a los 3, 6, 12 y 18 meses de tratamiento en los pacientes que otorguen su consentimiento de los países participantes para demostrar la validez de la diana y para evaluar la eliminación del amiloide por BAN2401. Se efectuarán estudios longitudinales de líquido cefalorraquídeo a los 12 y 18 meses de tratamiento para análisis de biomarcadores solubles (por ejemplo, Aβ[1-42], neurogranin, NFL, t-tau y p-tau) en los sujetos que otorguen su consentimiento en los países participantes, para evaluar los efectos sobre indicadores de la patología de la enfermedad
    E.3Principal inclusion criteria
    Diagnosis
    MCI due to AD–intermediate likelihood:
    1. Meet the NIA-AA core clinical criteria for MCI due to AD–intermediate likelihood.
    2. Have a global CDR score of 0.5 and a CDR Memory Box score of 0.5 or greater at Screening and Baseline.
    3. Report a history of subjective memory decline with gradual onset and slow progression over the last 1 year before Screening; must be corroborated by an informant.
    4. Meet the NIA-AA core clinical criteria for probable AD dementia.
    5. Have a global CDR score of 0.5 to 1.0 and a CDR Memory Box score of 0.5 or greater at Screening and Baseline.
    Key Inclusion Criteria that must be met by all subjects:
    6. Objective impairment in episodic memory as indicated by at least 1 standard deviation below age-adjusted mean in the Wechsler Memory Scale IV-Logical Memory (subscale)II (WMS-IV LMII), as follows:
    a. ≤15 for age 50 to 64 years
    b. ≤12 for age 65 to 69 years
    c. ≤11 for age 70 to 74 years
    d. ≤9 for age 75 to 79 years
    e. ≤7 for age 80 to 90 years
    7. Positive biomarker for brain amyloid pathology as indicated by at least 1 of the following:
    a. PET assessment of imaging agent uptake into brain. Note: amyloid PET screens will be performed according to local regulatory guidelines and thus may be restricted for those subjects who are not suitable for lumbar puncture (LP) to obtain CSF for testing of eligibility.
    b. CSF assessment of t-tau/Aβ[1-42]
    8. Male or female subjects aged ≥50 and ≤90 years, at the time of informed consent.
    9. MMSE score greater than or equal to 22 at Screening and Baseline and less than or equal to 30 at Screening and Baseline.
    10. Body mass index (BMI) greater than 17 and less than 35 at Screening.
    11. If receiving an approved AD treatment, such as AChEIs, or memantine, or both for AD, must be on a stable dose for at least 12 weeks prior to Baseline. Treatment-naïve subjects for AD can be entered into the study. Unless otherwise stated, subjects must have been on stable doses of all other (ie, non-AD-related) permitted concomitant medications for at least 4 weeks prior to Baseline.
    12. Have an identified study partner (defined as a person able to support the subject for the duration of the study and who spends at least 8 hours per week with the subject). The study partner must provide separate written informed consent. In addition, this person must be willing and able to provide follow-up information on the subject throughout the course of the study. This person must, in the opinion of the investigator, spend sufficient time with the subject on a regular basis such that the study partner can reliably fulfill the study requirements. A permanent study partner need not be living in the same residence with the subject. For such a study partner not residing with the subject, the investigator has to be satisfied that the subject can contact the study partner readily during the times when the study partner is not with the subject. If in doubt about whether a subject's care arrangements are suitable for inclusion, the investigator should discuss this with the medical monitor. Study partners need to participate in person for visits where clinical assessment of CDR (global and CDR-SB), EQ-5D-5L, QOL-AD, ADCS MCI-ADL and Zarit Burden Interview take place.
    13. Provide written informed consent. If a subject lacks capacity to consent in the
    investigator's opinion, the subject's assent should be obtained, if required in accordance with local laws, regulations and customs, plus the written informed consent of a legal representative should be obtained (capacity to consent and definition of legal representative should be determined in accordance with applicable local laws and regulations). In countries where local laws, regulations, and customs do not permit subjects who lack capacity to consent to participate in this study, they will not be enrolled.
    14. Willing and able to comply with all aspects of the protocol.
    Diagnóstico
    MCI debido a probabilidad intermedia de AD:
    1. Cumplir los criterios clínicos core de la NIA-AA para MCI por probabilidad intermedia de AD.
    2. Presentar una puntuación global de la CDR de 0,5 y una puntucación de la CDR Memory Box de 0,5 o mayor en el Screening y en Baseline.
    3. Tener historia de pérdida subjetiva de la memoria de comienzo gradual y progresión lenta a lo largo del último 1 año antes del Screening, lo que deberá ser corroborado por un informante.
    4. Cumplir los criterios clínicos core de la NIA-AA para demencia probable por AD.
    5. Presentar una puntuación global de la CDR de 0,5 a 1,0 y una puntuación de la CDR Memory Box de 0,5 o mayor en el Screening y en Baseline.
    Criterios clave de inclusión que deben cumplir todos los sujetos:
    6. Afectación objetiva de la memoria episódica indicada por como mínimo 1 desviación estándar por debajo de la media ajustada por edad en la Wechsler Memory Scale IV-Logical Memory (subscala) II (WMS-IV LMII), de la siguiente manera:
    a. ≤15 para la edad de 50 a 64 años
    b. ≤12 para la edad de 65 a 69 años
    c. ≤11 para la edad de 70 a 74 años
    d. ≤9 para la edad de 75 a 79 años
    e. ≤7 para la edad de 80 a 90 años
    7. Biomarcador positivo para la patología de amiloide cerebral, indicada por como mínimo 1 de los siguientes:
    a. Examen PET con captación cerebral del agente de imagen. Nota: Los exámenes de PET-amiloide se practicarán de acuerdo a las directrices reguladoras locales, por lo que podrán estar restringidos a aquellos sujetos que no sean adecuados para punción lumbar (LP) para obtener muestras de líquido cefalorraquídeo para determinar su elegibilidad.
    b. Determinación de t-tau/Aβ[1-42] en líquido cefalorraquídeo
    8. Hombres o mujeres de edad ≥50 y ≤90 en el momento de otorgar el consentimiento informado.
    9. MMSE con una puntuación mínima > 22 y una puntuación máxima < 30 en el Screening y en el Baseline.
    10. Índice de masa corporal (body mass index, BMI) mayor de 17 y menor de 35 en el Screening.
    11. Si están recibiendo un tratamiento aprobado para la AD, como inhibidores de la acetilcolinesterasa (AChEI), memantina o ambos, deberán haber estado con una dosis estable durante como mínimo las 12 semanas anteriores al Baseline. En el estudio podrán entrar sujetos que no hayan recibido previamente tratamiento para la AD. Salvo que se señale otra cosa, los sujetos deberán haberse mantenido con dosis estables de todos los demás medicamentos concomitantes permitidos (decir, no relacionados con la AD) durante como mínimo 4 semanas antes del Baseline.
    12. Disponer de un acompañante identificado para el estudio (definido como una persona que puede ayudar al sujeto a lo largo del estudio y que pase como mínimo 8 horas a la semana con él). Dicho acompañante deberá otorgar también su consentimiento informado por separado. Además, esta persona deberá estar conforme en y ser capaz de otorgar información de seguimiento sobre el sujeto a lo largo del curso del estudio. En opinión del investigador, el acompañante deberá pasar un tiempo suficiente con el sujeto de forma regular para que esa persona pueda cumplir con fiabilidad los requisitos del estudio. Un acompañante de estudio permanente no tiene por qué vivir en la misma residencia que el sujeto. En caso de que el acompañante no resida con el sujeto, el investigador deberá percibir que el sujeto puede contactar con su acompañante con facilidad cuando este último no se encuentre con el sujeto. En caso de duda acerca de si las circunstancias de atención del sujeto son las adecuadas para su inclusión en el estudio, el investigador deberá discutir el caso con el monitor médico. Los acompañantes para el estudio deberán participar personalmente en aquellas visitas en las que se practiquen evaluaciones clínicas de la CDR (global y CDR-SB), EQ-5D-5L, QOL-AD, ADCS MCI-ADL y Zarit Burden Interview.
    13. Otorgar el consentimiento informado por escrito. Si, en opinión del investigador, un sujeto careciera de capacidad para otorgar su consentimiento, deberá obtenerse su asentimiento, si lo exigieran las leyes, normativas y costumbres locales, más el consentimiento informado por escrito del representante legal (la capacidad de otorgar el consentimiento y la definición de representante legal se determinarán en función de las leyes y normas locales pertinentes). En aquellos países en que las leyes, normas y costumbres no permitan la participación en este estudio de sujetos sin capacidad de otorgar su consentimiento, dichos sujetos no podrán participar en el estudio.
    14. Conformidad y capacidad de cumplir con todos los aspectos del protocolo.
    E.4Principal exclusion criteria
    1. Females who are breastfeeding or pregnant at Screening or Baseline
    2. Females of childbearing potential who:
    a. Within 28 days before study entry, did not use a highly effective method of contraception (see protocol for full details)
    b. Do not agree to use a highly effective method of contraception (as described in the protocol) throughout the entire study period and for 28 days after study drug discontinuation.
    3. Any neurological condition that may be contributing to cognitive impairment above and beyond that caused by the subject’s AD.
    4. History of transient ischemic attacks, stroke, or seizures within 12 months of Screening.
    5. Any psychiatric diagnosis or symptoms that could interfere with study procedures in the subject.
    6. GDS score greater than or equal to 8 at Screening.
    7. Contraindications to MRI scanning
    8. Evidence of other clinically significant lesions on brain MRI at Screening that could indicate a dementia diagnosis other than AD.
    9. Other significant pathological findings on brain MRI at Screening
    10. Hypersensitivity to BAN2401 or any of the excipients, or to any mAb treatment.
    11. Any immunological disease not adequately controlled/which requires treatment with biologic drugs during the study.
    12. Subjects with a bleeding disorder not under adequate control
    13. Have TSH above normal range.
    14. Abnormally low serum vitamin B12 levels for the testing laboratory
    15. HIV positive.
    16. Any other clinically significant abnormalities in physical examination, vital signs, laboratory tests, or ECG at Screening or Baseline which may require further investigation
    17. Subjects with malignant neoplasms within 3 years of Screening (see protocol for exceptions).
    18. Answer “yes” to C-SSRS suicidal ideation Type 4 or 5, or any suicidal behavior assessment within 6 months before Screening, at Screening, or at the Baseline Visit, or has been hospitalized or treated for suicidal behavior in the past 5 years before Screening.
    19. Known or suspected history of drug or alcohol abuse or dependence within 2 years before Screening or a positive urine drug test at Screening. Subjects who test positive for benzodiazepines or opioids in urine drug testing need not be excluded if in the clinical opinion of the investigator, this is due to the subject taking prior/concomitant medications containing benzodiazepines or opioids for a medical condition and not due to drug abuse.
    20. Any other medical conditions which are not stably and adequately controlled, or which in the opinion of the investigator(s) could affect the subject’s safety or interfere with the study assessments.
    21. Subjects who are taking prohibited medications.
    22. Participation in a clinical study involving any therapeutic monoclonal antibody, protein derived from a monoclonal antibody, immunoglobulin therapy, or vaccine within 6 months before Screening (anti-amyloid therapies within 1 year before screening), unless it can be documented that the subject was randomized to placebo.
    23. Subjects who have any known prior exposure to BAN2401.
    24. Subjects who were dosed in a clinical study involving any new chemical entities for AD within 6 months prior to Screening unless it can be documented that the subject was in a placebo treatment arm.
    25. Participated in any other investigational medication or device study in the 8 weeks or 5 half-lives (whichever is longer) of the medication before randomization unless it can be documented that the subject was in a placebo treatment arm.
    26. Planned surgery which requires general anesthesia that would take place during the study.
    27. Severe visual or hearing impairment that would prevent the subject from performing psychometric tests accurately.

    Extension phase:
    1. Discontinued Core Study treatment due to amyloid-related imaging abnormality edema/effusion(ARIA-E), amyloid-related imaging abnormality hemorrhage (ARIA-H), or other AEs considered related to study drug.
    1. Mujeres que estén amamantando o embarazadas en el Screening o en el Baseline
    2. Mujeres potencialmente fértiles que:
    a.En el plazo de los 28 días anteriores a la entrada en el estudio no han utilizado un método anticonceptivo altamente efectivo (Para todos los demás objetivos consultar el protocolo)
    b.No conformidad en utilizar un método anticonceptivo altamente efectivo (en la forma arriba descrita) a lo largo de todo el periodo del estudio y los 28 días siguientes al abandono del fármaco del studio
    3. Todo proceso neurológico que, además de la AD, pueda haber contribuído al deterioro cognitivo del sujeto.
    4. Antecedente de ataque isquémico transitorio, ictus o convulsiones en el plazo de los 12 meses anteriores al Screening.
    5. Cualquier diagnóstico o síntoma psiquiátrico que pueda interferir con los procedimientos del estudio a practicar en el sujeto.
    6. Puntuación de la GDS mayor de o igual a 8 en el Screening.
    7. Contraindicación para la resonancia magnética
    8. Evidencia de otras lesiones clínicamente importantes en la resonancia magnética cerebral del Screening que pudieran indicar un diagnóstico de demencia distinto de AD.
    9. Otros hallazgos patológicos importantes en la resonancia magnética cerebral del Screening
    10. Hipersensibilidad a BAN2401 o cualquiera de sus excipientes, o a cualquier tratamiento con anticuerpos monoclonales.
    11. Toda enfermedad inmunológica que no se encuentre controlada adecuadamente o que precise tratamiento con fármacos biológicos durante el estudio.
    12. Sujetos con trastorno hemorrágico que no está adecuadamente controlado
    13. Niveles de hormona tiro-estimulante por encima del rango normal.
    14. Niveles séricos de vitamina B12 anormalmente bajos según el laboratorio que los ha determinado
    15. Positividad conocida del HIV.
    16. Cualquier otra anomalía clínicamente importante de la exploración física, constantes vitales, determinaciones de laboratorio o ECG en el Screening o en el Baseline que requiera nuevos exámenes
    17. Sujetos con tumores malignos en el plazo de los 3 años anteriores al Screening (consultar el protocolo para excepciones)
    18. Respuesta “sí” a la ideación suicida de Tipo 4 o 5 de la C-SSRS, o cualquier diagnóstico de conducta suicida en el plazo de los 6 meses anteriores al Screening, en el Screening o en la visita Baseline, u hospitalización o tratamiento por conducta suicida en los 5 años anteriores al Screening.
    19. Conocimiento o sospecha de abuso o dependencia de drogas o alcohol en el plazo de los 2 años anteriores al Screening o un resultado positivo de drogas en orina en el Screening. Podrán participar los sujetos que den positivos para benzodiazepinas u opiáceos en orina si, en opinión del investigador, ello se debe a que estaban o están en tratamiento concomitante con medicamentos que contienen benzodiazepinas u opiáceos por un proceso médico y no se debe al uso indebido de drogas.
    20. Cualquier otro proceso médico que no se encuentre estable y adecuadamente controlado o que, en opinión del investigador(es), pueda afectar a la seguridad del sujeto o interferir con las evaluaciones del estudio.
    21. Sujetos en tratamiento con medicamentos prohibidos.
    22. Participación en un estudio clínico con cualquier anticuerpo monoclonal terapéutico, proteína derivada de un anticuerpo monoclonal, tratamiento con inmunoglobulinas o vacuna en el plazo de los 6 meses anteriores al Screening (en el caso de los tratamientos anti-amiloide, en el plazo de 1 año antes del Screening), salvo si pudiera documentarse que el sujeto fue aleatorizado al placebo.
    23. Sujetos con cualquier tipo de tratamiento previo con BAN2401.
    24. Sujetos que han recibido tratamiento en un estudio clínico con cualquier nueva entidad química para la AD en el plazo de 12 meses anteriores al Screening, salvo si pudiera documentarse que el sujeto fue aleatorizado al grupo de placebo.
    25. Participación en otro estudio con un medicamento o producto sanitario experimental en el plazo de 8 semanas o 5 semividas (eligiéndose el mayor de estos plazos) del producto en cuestión antes de la aleatorización, salvo si pudiera documentarse que el sujeto estuvo en el grupo de placebo.
    26. Cirugía programada que precise anestesia general que se llevaría a cabo durante el estudio.
    27. Problema visual o auditivo importantes que pudiera impedir que el sujeto pudiera someterse adecuadamente a las pruebas psicométricas.

    Extension phase
    1. Abandono del tratamiento del Core Study por imágenes anormales de edema/derrame relacionadas con el amiloide (ARIA-E), imágenes anormales de hemorragia relacionadas con el amiloide (ARIA-H) u otros acontecimientos adversos que se considere que están relacionados con el fármaco del estudio
    E.5 End points
    E.5.1Primary end point(s)
    Core study:
    -Change from baseline in the CDR-SB at 18 months .

    Extension Phase
    -Safety assessments will be based on medical review of AE reports and the results of vital sign measurements, ECG, physical examinations, clinical laboratory tests, ADA test results, and any relevant test of cognitive function to evaluate decline. Additionally, MRI assessments of microhemorrhage, vasogenic edema, and other clinically significant abnormalities will be evaluated.
    -Change from core study baseline in CDR-SB
    Core: Cambios frente al Baseline en la CDR-SB a los 18 meses

    Extension phase: Las evaluaciones de seguridad se basarán en el examen médico de los informes de acontecimientos adversos y los resultados de constantes vitales, ECG, exploraciones físicas, determinaciones de laboratorio, resultados del estudio de ADA y toda prueba relevante de la función cognitiva que permita evaluar su eventual disminución. También se evaluarán los estudios mediante RM de microhemorragia, edema vasogénico y otras anomalías clínicamente importantes.
    • Cambio frente a la situación Baseline del Core Study en CDR-SB
    E.5.1.1Timepoint(s) of evaluation of this end point
    Core
    • 18 months
    Core
    - 18 meses
    E.5.2Secondary end point(s)
    The key secondary endpoints for this study are:
    - Change from baseline in amyloid PET SUVR composite at 18 months for brain amyloid levels
    - Change from baseline in ADCOMS at 18 months
    - Change from baseline in ADAS-cog14 at 18 months

    OTHER SECONDARY ENDPOINTS
    The other secondary endpoints for this study are:
    - Rate of change over time (mean slope) based on CDR-SB score over 18 months
    - Correlation between changes in CDR-SB and changes in amyloid PET SUVR composite for brain amyloid levels
    - Time to worsening of global CDR scores at 18 months, eg, the worsening of global CDR score is defined as an increase from baseline by at least 0.5 points on the global CDR scale on 2 consecutive scheduled visits at which global CDR is undertaken
    - Change from baseline in MMSE at 18 months
    - Incidence of AEs and changes in vital signs, ECGs, laboratory safety tests, suicidality assessments, and MRI safety parameters
    - Population PK parameters of BAN2401 in serum, including but not limited, to AUC, Cav
    Criterios de valoración clave
    Cambios frente al Baseline en el resultado compuesto del cociente del valor de captación estándar (standard uptake value ratio, SUVR) de los niveles cerebrales de amiloide según PET-amiloide
    • Cambios frente al Baseline en ADCOMS a los 18 meses
    • Cambios frente al Baseline en ADAS-cog14 a los 18 meses

    Otros criterios de valoración secundarios
    • Tasa de cambio a lo largo del tiempo (pendiente media) en función de la puntuación de la CDR-SB a lo largo de 18 meses
    • Correlación entre los cambios en la CDR-SB y los cambios en el resultado compuesto del SUVR de los niveles cerebrales de amiloide según PET-amiloide
    • Tiempo hasta el deterioro de las puntuaciones globales de la CDR a los 18 meses: el deterioro de la puntuación global de la CDR se define como un aumento frente al Baseline de como mínimo 0,5 puntos en la escala global de la CDR en 2 visitas programadas consecutivas en las que se evalúe la CDR global
    • Cambios frente al Baseline en el MMSE a los 18 meses
    • Incidencia de acontecimientos adversos y cambios en constantes vitales, ECG, analítica a fines de seguridad, evaluación del riesgo de suicidio y parámetros de la RM para evaluación de la seguridad
    • Parámetros de farmacocinética poblacional de BAN2401 en suero, tales como, entre otros AUC y Cav
    E.5.2.1Timepoint(s) of evaluation of this end point
    Core
    • 18 months
    Core
    -18 meses
    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 No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned 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 EEA44
    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
    China
    France
    Germany
    Italy
    Japan
    Korea, Republic of
    Russian Federation
    Singapore
    Spain
    Sweden
    United Kingdom
    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
    Last patient, last visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months0
    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: 310
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1256
    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 state80
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 307
    F.4.2.2In the whole clinical trial 1566
    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 have completed Visit 42 (Week 79) have the option to participate in the Extension Phase. Those who choose not to participate in the Extension will complete the 3-month Follow-up Visits after their last dose of study drug in the study. Subjects who discontinue the study or study drug must comply with the Early Termination Visit (within 7 days after the last dose of study drug) and the Follow-up Visit (3 months after the last dose of study drug).
    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 Decision2019-09-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-09-13
    P. End of Trial
    P.End of Trial StatusOngoing
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