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    Summary
    EudraCT Number:2017-002702-12
    Sponsor's Protocol Code Number:BN40031
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-05-21
    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 number2017-002702-12
    A.3Full title of the trial
    A MULTICENTER, OPEN-LABEL, LONG-TERM EXTENSION OF PHASE III STUDIES (BN29552/BN29553) OF CRENEZUMAB IN PATIENTS WITH ALZHEIMER’S DISEASE
    ESTUDIO MULTICÉNTRICO ABIERTO DE EXTENSIÓN A LARGO PLAZO DE LOS ESTUDIOS DE FASE III (BN29552/BN29553) DE CRENEZUMAB EN PACIENTES CON ENFERMEDAD DE ALZHEIMER
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    CREAD Open Label Extension: A Study of Crenezumab to Evaluate the Efficacy and Safety in Participants With Prodromal to Mild Alzheimer's Disease (AD)
    Extensión de fase Abierta de CREAD: Estudio de Crenezumab para evaluar eficacia y seguridad en Pacientes con Enfermedad de Alzheimer ( EA) de prodrómica a leve
    A.4.1Sponsor's protocol code numberBN40031
    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 SponsorRoche Farma S.A.(Soc. Unipersonal)que realiza el ensayo en España y que actúa como representante F.Hodmann-La Roche LTD
    B.1.3.4CountrySwitzerland
    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 supportF. Hoffmann-La Roche Ltd.
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF.Hoffmann-La Roche Ltd.
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+3491325 37 00
    B.5.6E-mailspain.start_up_unit@roche.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 namecrenezumab
    D.3.2Product code Ro 549-0245/F05
    D.3.4Pharmaceutical form Concentrate for 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 INNcrenezumab
    D.3.9.1CAS number 1095207-05-8
    D.3.9.2Current sponsor codeRO5490245
    D.3.9.3Other descriptive nameCrenezumab, Anti Abeta, MABT5102A
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number180
    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 Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Alzheimer’s Disease
    Enfermedad de Alzheimer (EA)
    E.1.1.1Medical condition in easily understood language
    Alzheimer's disease is a chronic neurodegenerative disease that results in memory loss and impairments in other important mental functions
    La enfermedad de alzheimer es una enfermedad crónica degenerativa que da como resultado perdida de memoria y deficiencias en otras funciones mentales importantes
    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 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the long-term safety and tolerability of crenezumab (60 mg/kg IV Q4W) in eligible patients with AD who participated in Study BN29552 or BN29553 and completed the Week 105 study visit.
    Evaluar la seguridad y la tolerabilidad a largo plazo del crenezumab (60 mg/kg IV cada 4 semanas) en pacientes elegibles con EA que hayan participado en los estudios BN29552 o BN29553 y que hayan completado la visita del estudio de la semana 105
    E.2.2Secondary objectives of the trial
    For exploratory efficacy objectives, the study aims to evaluate the long-term effect of crenezumab on global outcomes of disease progression, cognition, disease severity, patient dependence, patient function, patient behaviour and neuropsychological symptoms, health-related quality of life, and effect on caregiver burden.
    For exploratory pharmacokinetic objectives, the study aims to evaluate PK characteristics of crenezumab and to explore exposure-response relationships in patients with prodromal to mild Alzheimer’s disease.
    For exploratory biomarker objectives, the study aims to evaluate the effect of crenezumab on biomarkers.
    ·Para objetivos exploratorios de eficacia, los objetivos del estudio son:

    -Evaluar el efecto a largo plazo del crenezumab en las variables globales de progresión de la enfermedad, función cognitiva, gravedad de la enfermedad, dependencia del paciente, en el funcionamiento del paciente, en el comportamiento y síntomas neuropsicológicos, en la calidad de vida y en la carga para los cuidadores.
    ·Objetivos farmacocinéticos exploratorios, los objetivos del estudio son:
    -Evaluar las características farmacocinéticas del crenezumab y Investigar las relaciones exposición-respuesta en pacientes con EA de prodrómica a leve.
    Objetivos exploratorios de biomarcadores, el objetivo del estudio es evaluar el efecto del crenezumab en los biomarcadores
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Amyloid-PET Longitudinal Substudy & Tau-PET Longitudinal Substudy included in the main protocol V1 dated 18.Sept 2017
    Subestudio longitudinal de PET-amiloide y subestudio longitudinal de Tau-PET incluido en el protocolo principal V1 con fecha de 18.Sept. 2017
    E.3Principal inclusion criteria
    •Previous participation in Study BN29552 or BN29553 and completion of the Week 105 visit
    •Able to provide written consent signed by the patient or the patient’s authorized representative under applicable local law
    •A caregiver, defined as:
    –Has frequent and sufficient contact with the patient to be able to provide accurate information regarding the patient’s cognitive and functional abilities
    –Be in sufficiently good general health
    •Willingness and ability to complete all aspects of the study
    •Adequate visual and auditory acuity, in the investigator’s judgment, sufficient to perform the neuropsychological testing
    •For women of childbearing potential, must follow protocol specified acceptable methods of contraception
    •For men with female partners of childbearing potential, must follow protocol specified acceptable methods of contraception
    •Haber participado en los estudios BN29552 o BN29553 y haber completado la visita de la semana 105.
    •Capacidad para otorgar el consentimiento por escrito firmado por el paciente o por el representante legal del paciente conforme a la ley local aplicable.
    •Un cuidador, definido como:
    -Tener un contacto frecuente y suficiente con el paciente para poder proporcionar información precisa sobre su capacidad cognitiva y funcional
    -Tener un estado general de salud suficientemente bueno
    •Disposición y capacidad para completar todos los aspectos del estudio
    •Agudeza visual y auditiva suficiente para realizar las pruebas neuropsicológicas en opinión del investigador
    •En las mujeres con capacidad reproductiva: debe seguir los métodos de anticoncepción aceptados por el protocolo
    •Para hombres con parejas femeninas en edad fértil, deben seguir los métodos de anticoncepción aceptados por el protocolo
    E.4Principal exclusion criteria
    •Patients who discontinued treatment permanently in Study BN29552 or BN29553 for safety reasons
    •Evidence of more than 10 microbleeds and/or ARIA-H at the Study BN29552 or BN29553 Week 105 visit, as assessed by central review of MRI
    •Diagnosed with three recurrent, symptomatic ARIA-E events or exacerbations of previous events
    •Presence of intracranial lesion that could potentially increase the risk of CNS bleeding (e.g., intracranial aneurysm; arterio-venous malformation)
    •At risk of suicide in the opinion of the investigator
    •Alcohol and/or substance abuse or dependence (according to Diagnostic and Statistical Manual of Mental Disorders Version 5 criteria) within the past 2 years and during the study (nicotine use is allowed; marijuana use is not allowed within the past 2 years)
    •Inability to tolerate MRI procedures or contraindication to MRI
    •Pregnant or lactating, or intending to become pregnant during the study
    •Any other severe or unstable medical condition that, in the opinion of the investigator or Sponsor, could be expected to progress, recur, or change
    •Chronic use of anticoagulants or participation in any other investigational drug treatment trial
    •Pacientes que hayan discontinuado de forma permanente el tratamiento en los estudios BN29552 o BN29553 por motivos de seguridad.
    •Evidencia de más de 10 micro hemorragias y/o alteraciones en la imagen relacionadas con el amiloide por depósito de hemosiderina (ARIA-H) en los estudios BN29552 o BN29553 en la visita de la semana 105, conforme a una revisión central de RM.
    •Diagnóstico de tres episodios recurrentes de alteraciones en la imagen sintomáticas relacionadas con el amiloide por edema/derrame (ARIA-E) o exacerbaciones de episodios previos.
    •Presencia de lesión intracraneal que podría aumentar el riesgo de hemorragia en el SNC (por ejemplo, aneurisma intracraneal, malformación arteriovenosa).
    •Riesgo de suicidio en opinión del investigador.
    •Abuso o dependencia de alcohol o sustancias (según los criterios del Manual diagnóstico y estadístico de trastornos mentales, versión 5) en los 2 años anteriores y durante el estudio.(Se permite el consumo de nicotina,no se permite el uso de marihuana en los 2 años anteriores.)
    •Incapacidad de tolerar los procedimientos de RM o contraindicación de la RM
    •Mujer embarazada, en período de lactancia o con intención de quedarse embarazada durante el estudio
    •Cualquier otra enfermedad grave o inestable que, en opinión del investigador o el promotor, pueda progresar, reaparecer o cambiar en tal grado que suponga un riesgo especial para el paciente
    •Uso crónico de anticoagulantes o participación en cualquier otro ensayo de tratamiento con un fármaco en investigación.
    E.5 End points
    E.5.1Primary end point(s)
    •Nature, frequency, severity, and timing of adverse events, serious adverse events, and adverse events of special interest
    •Physical and neurologic examinations, vital signs, blood tests, ECGs, and C-SSRS
    •Incidence of ARIA E and ARIA H
    •The immunogenic potential of crenezumab
    •Naturaleza, frecuencia, intensidad y cronología de los acontecimientos adversos y acontecimientos adversos graves
    •Exploraciones físicas y neurológicas, constantes vitales, análisis de sangre, ECG y C-SSRS.
    •Acontecimientos adversos evaluados mediante RM: ARIA-E y ARIA-H.
    •Capacidad inmunogénica del crenezumab
    E.5.1.1Timepoint(s) of evaluation of this end point
    Change from baseline at Week 105
    Cambio de basal a la semana 105
    E.5.2Secondary end point(s)
    For exploratory efficacy endpoints, change from baseline in the double-blind treatment period of BN29552 or BN29553 in BN40031 for CDR-SB, ADAS-Cog13, ADAS-Cog12, MMSE, CDR-GS, ADCS-ADL, FAQ, NPI-Qz, QoL-AD and ZCI-AD.
    For exploratory pharmacokinetic endpoints, serum concentrations of crenezumab, CSF concentrations of crenezumab, correlation between crenezumab concentration and biomarkers as well as safety and efficacy outcomes.
    For exploratory biomarker endpoints, brain amyloid load over time measured by PET, brain tau load and spread over time measured by PET, CSF markers of disease change over time, plasma pharmacodynamic markers of disease over time and MRI derived measurements over time
    Variable exploratoria de eficacia:
    -Variación desde el momento basal (es decir, momento basal del período de tratamiento doble ciego de los estudios BN29552 o BN29553) durante el estudio abierto de extensión BN40031 en la escala CDR-SB, ADAS-Cog13,ADAS-Cog12, MMSE, CDR-GS, ADCS-ADL, FAQ, cuestionario Inventario Neuropsiquiátrico, Calidad de vida de EA y escala Entrevista de Zarit para cuidadores para la EA.
    Variable exploratoria farmacocinética: Concentración sérica de crenezumab, Concentración de crenezumab en el LCR,Correlación entre la concentración de crenezumab y biomarcadores, así como la de los resultados de seguridad y eficacia.
    Variable exploratoria de biomarcadores: Carga cerebral de amiloide a lo largo del tiempo medida mediante PET de amiloide, Carga y diseminación cerebral de proteína tau a lo largo del tiempo medida mediante PET, Marcadores de enfermedad en el LCR a lo largo del tiempo, Marcadores farmacodinámicos de enfermedad en el plasma a lo largo del tiempo y Mediciones derivadas de la RM a lo largo del tiempo
    E.5.2.1Timepoint(s) of evaluation of this end point
    Weeks 25, 53, 77, 105 and every year thereafter, as well as at follow up 4 weeks after the last dose.
    Semanas 25, 53, 77, 105 y cada año desde entonces, también cada 4 semanas después de la última dosis
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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 No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 Yes
    E.8.2.3.1Comparator description
    PET Ligand (florbetapir F18)
    E.8.2.4Number of treatment arms in the trial1
    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 concerned34
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA184
    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
    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 OLE study will continue until crenezumab is commercially available in the patient’s country, as per local regulation, or should the Sponsor decide to terminate the program for prodromal to mild AD. The study will not exceed approx. 2 years after the last patient enters the OLE study.
    For UK only:The OLE study will not exceed approx. 2 years after the last patient enters the OLE study or until a decision to terminate the program for pAD to mAD is made by the Sponsor ( Protocol section 3.3)
    Estudio extensión fase abierta continuará hasta q la comercialización de crenezumab este disponible en país del paciente,según regulación local,o Promotor decida finalizar programa de AE de prodrómica a leve. Estudio no excederá aprox. 2 años después de último paciente entre a estudio OLE.
    Sólo para Reino Unido:Estudio OLE no excederá de aprox. 2 años después de el último paciente entre a estudio OLE o hasta que Promotor tome decisión de finalizar programa para pAD a mAD (Protocolo,sección 3.3)
    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 months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months9
    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: 750
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 375
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2018-05-21. Yes
    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
    decline in Alzheimer’s Disease
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state186
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 351
    F.4.2.2In the whole clinical trial 1125
    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)
    The Sponsor will offer post-trial access to the Roche IMP (crenezumab) free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product (see Protocol section 4.3.4)
    El promotor ofrecerá acceso continuado a la medicación del estudio (Crenezumab) de forma gratuita a los pacientes elegidos de acuerdo con la Politica Global de Roche de acceso continuado a Productos médicos de Investigación (Ver sección 4.3.4 del protocolo)
    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 Decision2018-07-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-07-05
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2019-05-31
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