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    Summary
    EudraCT Number:2017-003940-19
    Sponsor's Protocol Code Number:331-14-213
    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:2018-05-21
    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 number2017-003940-19
    A.3Full title of the trial
    A Phase 3, 12-Week, Multicenter, Randomized, Double-blind, Placebo controlled, 2 Arm, Fixed-dose Trial to Evaluate the Efficacy, Safety, and Tolerability of Brexpiprazole (OPC-34712) in the Treatment of Subjects With Agitation Associated With Dementia of the Alzheimer’s Type
    Estudio en fase III, de 12 semanas de duración, multicéntrico, aleatorizado, doble ciego, controlado con placebo, de 2 grupos y dosis fija para evaluar la eficacia, seguridad y tolerabilidad de brexpiprazol (OPC-34712) en el tratamiento de sujetos con agitación asociada a la demencia de tipo Alzheimer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A 12-Week, Multicenter, Randomized, Double-blind, Placebo Trial to check how safe, effective and tolerable Brexpiprazole is in the Treatment of Subjects With Agitation Associated With Dementia of the Alzheimer’s Type
    Estudio de 12 semanas de duración, multicéntrico, aleatorizado, doble ciego, con placebo para evaluar la eficacia, seguridad y tolerabilidad de brexpiprazol en el tratamiento de sujetos con agitación asociada a la demencia de tipo Alzheimer
    A.4.1Sponsor's protocol code number331-14-213
    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 SponsorOtsuka Pharmaceutical Development & Commercialization, Inc.
    B.1.3.4CountryUnited States
    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 supportOtsuka Pharmaceutical Development & Commercialization, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOtsuka Pharmaceutical Development & Commercialization, Inc.
    B.5.2Functional name of contact pointJocelyn Ottinger
    B.5.3 Address:
    B.5.3.1Street Address2440 Research Boulevard
    B.5.3.2Town/ cityRockville, Maryland
    B.5.3.3Post code20850
    B.5.3.4CountryUnited States
    B.5.6E-mailjocelyn.ottinger@otsuka-us.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 Yes
    D.2.1.1.1Trade name REXULTI®
    D.2.1.1.2Name of the Marketing Authorisation holderOtsuka Pharmaceutical Development & Commercialization, Inc.
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameBrexpiprazole
    D.3.2Product code OPC-34712
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBrexpiprazole
    D.3.9.1CAS number 913611-97-9
    D.3.9.2Current sponsor codeOPC-34712
    D.3.9.3Other descriptive nameBREXPIPRAZOLE
    D.3.9.4EV Substance CodeSUB91646
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5
    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 Yes
    D.2.1.1.1Trade name REXULTI®
    D.2.1.1.2Name of the Marketing Authorisation holderOtsuka Pharmaceutical Development & Commercialization, Inc.
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameBrexpiprazole
    D.3.2Product code OPC-34712
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBrexpiprazole
    D.3.9.1CAS number 913611-97-9
    D.3.9.2Current sponsor codeOPC-34712
    D.3.9.3Other descriptive nameBREXPIPRAZOLE
    D.3.9.4EV Substance CodeSUB91646
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name REXULTI®
    D.2.1.1.2Name of the Marketing Authorisation holderOtsuka Pharmaceutical Development & Commercialization, Inc.
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameBrexpiprazole
    D.3.2Product code OPC-34712
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBrexpiprazole
    D.3.9.1CAS number 913611-97-9
    D.3.9.2Current sponsor codeOPC-34712
    D.3.9.3Other descriptive nameBREXPIPRAZOLE
    D.3.9.4EV Substance CodeSUB91646
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name REXULTI®
    D.2.1.1.2Name of the Marketing Authorisation holderOtsuka Pharmaceutical Development & Commercialization, Inc.
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameBrexpiprazole
    D.3.2Product code OPC-34712
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBrexpiprazole
    D.3.9.1CAS number 913611-97-9
    D.3.9.2Current sponsor codeOPC-34712
    D.3.9.3Other descriptive nameBREXPIPRAZOLE
    D.3.9.4EV Substance CodeSUB91646
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Agitation Associated With Dementia of the Alzheimer’s Type
    Agitación asociada con demencia de tipo Alzheimer
    E.1.1.1Medical condition in easily understood language
    Agitation in dementia due to Alzheimer's Disease
    Agitación en demencia debido a la enfermedad de Alzheimer
    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 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 confirm the efficacy of brexpiprazole compared with placebo in subjects with Agitation in Alzheimer’s dementia
    Confirmar la eficacia del brexpiprazol en comparación con placebo en sujetos con agitación en la demencia por Alzheimer.
    E.2.2Secondary objectives of the trial
    To evaluate the safety and tolerability of brexpiprazole compared with placebo in subjects with Agitation in Alzheimer’s dementia
    Evaluar la seguridad y la tolerabilidad de brexpiprazol en comparación con placebo en sujetos con agitación en la demencia por Alzheimer.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    An optional pharmacogenomic sample and an optional sample for Future Biospecimen Research will be collected if patients consent.
    Se recogerá una muestra opcional farmacogenómica y una muestra opcional para Investigación Biomédica Futura si los pacientes dan su consentimiento.
    E.3Principal inclusion criteria
    1.The investigator must assess the capacity of the subject to provide informed consent during the screening period and throughout the course of the trial.
    2.Male and female subjects between 55 and 90 years of age, inclusive, at the time of informed consent.
    3.Subjects with a diagnosis of probable Alzheimer’s disease according to the NINCDS-ADRDA criteria.
    4.Subjects with a diagnosis of agitation that meets the IPA provisional definition of agitation
    5.Subjects with a MMSE score of 5 to 22, inclusive, at the screening and baseline visits.
    6.Subjects with a previous MRI or CT scan of the brain, that was performed after the onset of the symptoms of dementia, with findings consistent with a diagnosis of Alzheimer’s disease. Note that for subjects in Germany only, the MRI/CT scan can only be performed if it is standard of care.
    7.Subjects who are residing at their current location for at least 28 days before screening and are expected to remain at the same location for the duration of the trial.
    8.Institutionalized subjects with an identified caregiver who has sufficient contact (minimum of 2 hours per day for 4 days per week) to describe the subject’s symptoms and has direct observation of the subject’s behavior. The identified caregiver can be a staff member of the institutionalized setting or another individual (eg, family member, family friend, hired professional caregiver) who meets the caregiver requirements.
    Non-institutionalized subjects may not be living alone and must have an identified caregiver who has sufficient contact (minimum of 2 hours per day for 4 days per week) to describe the subject’s symptoms and has direct observation of the subject’s behavior.
    9.Subjects with a total score (frequency × severity) of ≥ 4 on the agitation/aggression item of the NPI NH (for institutionalized subjects) or the NPI/NPI-NH (for non-institutionalized subjects) at the screening and baseline visits.
    10.Subjects with onset of symptoms of agitation at least 2 weeks prior to the screening visit.
    11.Subjects must meet additional predetermined blinded eligibility criteria according to the blinded addendum.
    12.Subjects who require pharmacotherapy for the treatment of agitation per the investigator’s judgment, after:
    •An evaluation for reversible factors (eg, pain, infection, or polypharmacy), and
    •A trial of nonpharmacological interventions (eg, redirecting behavior, group activities, music therapy).
    13.Subjects who are capable of self-locomotion or locomotion with an assistive device (eg, 4-point walker, wheelchair).
    14.Subjects willing and able to discontinue all prohibited concomitant medications to meet protocol required washouts prior to and during the trial period.
    15.Subjects able to satisfactorily comply with the protocol requirements.
    1. El investigador debe evaluar la capacidad del sujeto para proporcionar el consentimiento informado durante el periodo de selección y el transcurso del ensayo.
    2. Sujetos de ambos sexos de 55 a 90 años (inclusive), en el momento del consentimiento informado.
    3. Sujetos con un diagnóstico de probable Alzheimer según los criterios del Instituto Nacional de Trastornos Neurológicos y Comunicativos y Accidente Cerebrovascular y la Asociación de Alzheimer y Trastornos Relacionados (NINCDS-ADRDA)
    4. Sujetos con un diagnóstico de agitación que cumpla la definición de la Asociación Psicogeriátrica Internacional (IPA)
    5. Sujetos con una puntuación entre 5 y 22 (inclusive) en el Miniexamen mental del estado (Mini-Mental State Examination, MMSE) en la selección y en las visitas iniciales
    6. Sujetos con una exploración previa del cerebro por resonancia magnética (RM) o tomografía computarizada (TC), realizada después del inicio de los síntomas de demencia, con hallazgos coherentes con el diagnóstico de enfermedad de Alzheimer.
    7. Sujetos que vivan en su actual localización durante al menos los 28 días anteriores a la selección y esperan permanecer en la misma ubicación durante el ensayo
    en una residencia con asistencia o bien acompañados en una casa o apartamento
    8. Sujetos internos en una residencia (institucionalizados) con un cuidador identificado con el que tengan el contacto suficiente (un mínimo de 2 horas al día durante 4 días a la semana) para describir los síntomas del sujeto y que disponga de observación directa de la conducta del paciente. El cuidador identificado puede ser miembro de la plantilla de la residencia u otra persona (por ejemplo, familiar, amigo de la familia, cuidador profesional contratado) que cumpla con los requerimientos de cuidador.
    Los sujetos no-institucionalizados podrían no estar viviendo solos y deben tener un cuidador identificado con el que tengan el contacto suficiente (un mínimo de 2 horas al día durante 4 días a la semana) para describir los síntomas del sujeto y que disponga de observación directa de la conducta del paciente.
    9. Sujetos con una puntuación total (frecuencia x gravedad) de ≥ 4 en el factor de agitación/agresión del Inventario neuropsiquiátrico - Residencial para ancianos (Neuropsychiatric Inventory-Nursing Home, NPI-NH; internados en instituciones) o la Evaluación neuropsiquiátrica para pacientes que no viven en instituciones (Neuropsychiatric Assessment for Non-institutionalized Patients) en la selección y visitas iniciales
    10. Sujetos con aparición de síntomas de agitación al menos 2 semanas antes de la visita de selección
    11. Los sujetos deben cumplir con los criterios de elegibilidad ciegos predeterminados de acuerdo con la adenda ciega
    12. Sujetos que requieran farmacoterapia para el tratamiento de la agitación a criterio del investigador, después de:
    • Una evaluación de los factores reversible (por ejemplo, dolor, infección, o polifarmacia)
    • Un ensayo de internciones no farmacológicas (por ejemplo, reorientación de conducta, actividades de grupo, terapia musical)
    13. Sujetos que son capaces de moverse por sí mismo o con un dispositivo de apoyo (por ejemplo, andador, silla de ruedas)
    14. Sujetos dispuestos y capaces de suspender todas las medicaciones concomitantes prohibidas para cumplir con los periodos de lavado anteriores y durante el periodo del ensayo requeridos por el protocolo
    15. Sujetos capaces de cumplir satisfactoriamente con los requisitos del protocol
    E.4Principal exclusion criteria
    1) Subjects with dementia or other memory impairment not due to Alzheimer’s disease, such as mixed or vascular dementia, dementia with Lewy bodies, Parkinson’s disease dementia, frontotemporal dementia, substance-induced dementia, human immunodeficiency virus dementia, traumatic brain injury, normal pressure hydrocephalus, or any other specific non Alzheimer’s-type dementia; subjects with a diagnosis of Down syndrome.
    2) Subjects with a previous magnetic resonance imaging (MRI)/computed tomography (CT) scan of the brain, which was performed after the onset of the symptoms of dementia, with findings consistent with a clinically significant central nervous system disease other than Alzheimer’s disease, such as vascular changes (eg, cortical stroke, multiple infarcts), space-occupying lesion (eg, tumor), or other major structural brain disease. Note that for subjects in Germany only, the MRI/CT scan can only be performed if it is standard of care.
    3) Subjects with a history of stroke, well-documented transient ischemic attack, or pulmonary or cerebral embolism.
    4) Subjects with delirium or history of delirium within the 30 days prior to the screening visit.
    5) Subjects who have received high-dose antipsychotics exceeding the equivalent of ≥ 3 mg of risperidone (eg, ≥ 5 mg of haloperidol, ≥ 375 mg quetiapine, ≥ 10 mg olanzapine, or local equivalent) within 90 days prior to screening.
    6) Subjects who have received multiple antipsychotic medications simultaneously for a period of > 7 days within 90 days prior to screening.
    7) Subjects with evidence of serious risk of suicide based on the Sheehan Suicidality Tracking Scale (Sheehan-STS), ie, a score of 3 or 4 on any one question 2 through 6 or 11, or a score of 2 or higher on any one questions 1a, 7 through 10, or 12, or who, in the opinion of the investigator, present a serious risk of suicide.
    8) Subjects considered in poor general health based on the investigator’s judgment. Examples include subjects who have a recent clinically significant weight loss, chronic dehydration or hypovolemia, poor fluid or nutritional intake, or a recent clinically significant infection, as per the investigator’s judgment.
    1) Sujetos con demencia u otro trastorno de la memoria ajeno al Alzheimer, como demencia mixta o vascular, demencia de cuerpos de Lewy, demencia por enfermedad de Parkinson, demencia frontotemporal, demencia inducida por sustancias, demencia por virus de inmunodeficiencia, traumatismo craneoencefálico, hidrocefalia normotensiva o cualquier otro tipo de demencia específica que no sea de tipo Alzheimer, sujetos con un diagnóstico de síndrome de Down.
    2) Sujetos con una exploración previa del cerebro por resonancia magnética (RM) o tomografía computarizada (TC), realizada después del inicio de los síntomas de demencia, con hallazgos coherentes con una enfermedad clínicamente importante del sistema nervioso central diferente a la enfermedad de Alzheimer, como cambios vasculares (por ejemplo, accidente cerebrovascular cortical, infartos múltiples), lesión que ocupa espacio (por ejemplo, tumor) u otra enfermedad cerebral estructural grave. Tenga en cuenta que para los sujetos en Alemania únicamente, la exploración por RM/TC solo puede efectuarse si es parte de la atención habitual.
    3) Sujetos con antecedentes de accidente cerebrovascular, ataque isquémico transitorio bien documentado o embolia pulmonar o cerebral.
    4) Sujetos con delirio o antecedentes de delirio en los 30 días anteriores a la visita de selección.
    5) Sujetos que hayan recibido una dosis elevada de antipsicóticos que supere el equivalente de ≥3 mg de risperidona (p. ej., ≥5 mg de haloperidol, ≥375 mg de quetiapina, ≥10 mg de olanzapina o equivalente local) en los 90 días anteriores a la selección.
    6) Sujetos que hayan recibido múltiples antipsicóticos simultáneamente durante un período de >7 días en los 90 días anteriores a la selección.
    7) Sujetos con comprobación de riesgo grave de suicidio según la Escala de seguimiento de tendencias suicidas de Sheehan (Sheehan Suicidality Tracking Scale, Sheehan-STS), es decir, una puntuación de 3 o 4 en cualquiera de las preguntas 2 a 6 u 11, o una puntuación de 2 o más en cualquiera de las preguntas 1a, 7 a 10 o 12 o quien, a criterio del investigador, presente un riesgo grave de suicidio.
    8) Sujetos a quienes se considera con salud general deficiente según el criterio del investigador. Los ejemplos incluyen sujetos que presentan una pérdida de peso clínicamente importante, deshidratación o hipovolemia crónicas, ingesta líquida o nutricional deficiente o una infección reciente clínicamente importante, según el criterio del investigador.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the change from baseline to Week 12 in the CMAI total score.
    El principal criterio de valoración de eficacia es el cambio desde la visita inicial hasta la semana 12 en la puntuación total de CMAI.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Change from baseline to Week 12
    Cambio desde la visita inicial hasta la semana 12
    E.5.2Secondary end point(s)
    The key secondary efficacy endpoint is the change from baseline to Week 12 in the Clinical Global Impression Severity of Illness (CGI-S) score, as related to agitation.
    Secondary efficacy endpoints are as follows:
    • Change from baseline to Week 12 in CMAI subscale scores (aggressive behavior, physically nonaggressive behavior, verbally agitated behavior)
    • Change from baseline in CMAI total score for each trial visit during the double-blind treatment period
    • Change from baseline in CGI-S for each trial visit during the double-blind treatment period
    • Clinical Global Impression Improvement of Illness (CGI-I) score at each trial visit during the double-blind treatment period
    • CMAI-based responder analysis as described in the statistical analysis plan (SAP)
    • CGI-I responder analysis as described in the SAP
    El criterio de valoración secundario clave de eficacia es el cambio en la puntuación de CGI-S desde la visita inicial hasta la semana 12, en relación con la agitación.
    Criterios de valoración secundarios de eficacia:
    • Cambio desde la visita inicial hasta la semana 12 en las puntuaciones de las subescala de CMAI (conducta agresiva, conducta físicamente no agresiva, conducta con agitación verbal).
    • Cambio desde la visita inicial en la puntuación total de CMAI para cada visita del ensayo durante el periodo de tratamiento doble ciego.
    • Cambio desde la visita inicial en la puntuación de CGI-S para cada visita del ensayo durante el periodo de tratamiento doble ciego.
    • Puntuación de CGI-I para cada visita del ensayo durante el periodo de tratamiento doble ciego.
    • Análisis de pacientes que responden al tratamiento basado en CMAI, según se describe en el plan de análisis estadístico (PAS).
    • Análisis de pacientes que responden al tratamiento según CGI-I, como se describe en el PAS.
    E.5.2.1Timepoint(s) of evaluation of this end point
    • CGI-S: Change from baseline to Week 12
    • CMAI subscale scores : Change from baseline to Week 12
    • CMAI total score: Change from baseline for each trial visit during the double-blind treatment period
    • CGI-S: Change from baseline for each trial visit during the double-blind treatment period
    • Clinical Global Impression Improvement of Illness (CGI-I) score at each trial visit during the double-blind treatment period
    • CGI-S: cambio desde la visita inicial hasta la semana 12
    • Puntuaciones en la subescala CMAI: cambio desde la visita inicial hasta la semana 12
    • Puntuación total CMAI: cambio desde la visita inicial para cada visita del ensayo durante el period de tratamiento doble ciego
    • CGI-S: cambio desde la visita inicial para cada visita del ensayo durante el period de tratamiento doble ciego
    • Escala de Impresión clínica global de mejoría de la enfermedad(CGI-S) en cada visita del ensayo durante el period de tratamiento doble ciego
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic 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) 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 No
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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
    Bulgaria
    Spain
    Ukraine
    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
    The end of trial date is defined as the last date of contact or the date of final contact attempt from the post-treatment follow-up eSource page for the last subject completing or withdrawing from the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months2
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 205
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Due to the disease condition i.e. dementia due to Alzheimer's disease.
    Debido a la condición de la enfermeda, por ejemplo, demencia debido a la enfermedad de Alzheimer
    F.3.3.7Others Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Patients with dementia fall under vulnerable group
    Pacientes con demencia entran dentro del grupo vulnerable
    F.4 Planned number of subjects to be included
    F.4.1In the member state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 114
    F.4.2.2In the whole clinical trial 225
    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 12-week double-blind treatment period of Trial 331-14-213 may be eligible to enter a 12-week open-label extension trial.
    Sujetos que completen la 12 semanas del periodo de tratamiento doble ciego del ensayo 331-14-213 podrían ser elegibles para entrar en el ensayo abierto de extensión de 12 semanas
    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 Decision2018-07-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-28
    P. End of Trial
    P.End of Trial StatusOngoing
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