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    Summary
    EudraCT Number:2016-003288-20
    Sponsor's Protocol Code Number:BN29553
    National Competent Authority:Estonia - SAM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2017-02-08
    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 ConcernedEstonia - SAM
    A.2EudraCT number2016-003288-20
    A.3Full title of the trial
    A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED, PARALLEL GROUP, EFFICACY AND SAFETY STUDY OF CRENEZUMAB IN PATIENTS WITH PRODROMAL TO MILD ALZHEIMER’S DISEASE
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Efficacy and Safety Study of Crenezumab in Patients with Prodromal to Mild Alzheimer’s Disease
    A.4.1Sponsor's protocol code numberBN29553
    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 SponsorF. Hoffmann-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+4161 688 1111
    B.5.6E-mailglobal.rochegenentechtrials@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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution 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
    Alzheimer’s Disease (AD)
    E.1.1.1Medical condition in easily understood language
    Alzheimer's disease (AD)
    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 evaluate the efficacy of crenezumab compared with placebo based on change from baseline to Week (W) 105 in global outcomes as assessed by Clinical Dementia Rating-Sum of Boxes (CDR-SB)
    E.2.2Secondary objectives of the trial
    • To evaluate the efficacy of crenezumab compared with placebo based on additional cognitive, functional, and behavioral outcomes
    •To evaluate the efficacy of crenezumab compared with placebo on caregiver and quality of life endpoints
    • To evaluate the safety of crenezumab compared with placebo
    • To characterize the crenezumab pharmacokinetic (PK) profile
    • To explore exposure-response relationships in patients with prodromal to mild AD
    • To evaluate the effect of crenezumab compared with placebo on biomarker changes
    •To explore exposure response relationships in patients with prodromal to mild AD based on CSF biomarkers, Plasma PD biomarkers, Imaging biomarkers, and Efficacy and safety outcomes
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    PET LONGITUDINAL SUBSTUDY ASSOCIATED WITH:
    A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, EFFICACY AND SAFETY STUDY OF CRENEZUMAB IN PATIENTS WITH PRODROMAL TO MILD ALZHEIMER’S DISEASE

    CSF LONGITUDINAL SUBSTUDY ASSOCIATED WITH:
    A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, EFFICACY AND SAFETY STUDY OF CRENEZUMAB IN PATIENTS WITH PRODROMAL TO MILD ALZHEIMER’S DISEASE

    RESEARCH SUBSTUDY ASSOCIATED WITH:
    A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, EFFICACY AND SAFETY STUDY OF CRENEZUMAB IN PATIENTS WITH PRODROMAL TO MILD ALZHEIMER’S DISEASE
    E.3Principal inclusion criteria
    - Aged between 50 and 85 years at screening, inclusive
    - Weight between 40 and 120 kg, inclusive
    - Availability of caregiver
    - Fluency in the language used at the study site
    - Willingness and ability to complete all aspects of the study (including magnetic resonance imaging [MRI], lumbar puncture [if applicable], clinical genotyping, and positron emission tomography (PET)imaging [if applicable]); the patient should be capable of completing assessments either alone or with the help of the caregiver
    - Adequate visual and auditory acuity, in the investigator’s judgment, sufficient to perform the neuropsychological testing (eye glasses and hearing aids are permitted)
    - For men and women Use appropriate contraceptive measures or agreement to refrain from heterosexual intercourse for at least 8 weeks after last dose of drug study
    - For men only: agreement to refrain from donating sperm during treatment for at least 8 weeks after last dose of drug study
    - Evidence of the AD pathological process, by a positive amyloid assessment either on cerebrospinal fluid (CSF) Aβ1−42 levels as measured on the Elecsys β-Amyloid(1-42) Test System OR amyloid PET scan by qualitative read by the core/central PET laboratory
    - Demonstrated abnormal memory function at early screening (up to 4 weeks before screening begins) or at screening
    - Evidence of retrospective decline confirmed by a diagnosis verification form
    - Mild symptomatology, as defined by a screening MMSE score of ≥ 22 points and Clinical Dementia Rating-Global Score (CDR-GS) of 0.5 or 1.0. MMSE may be performed at FCSRT/MMSE consent or main screening
    - Meets National Institute on Aging/Alzheimer’s Association core clinical criteria for probable AD dementia or prodromal Alzheimer’s disease
    - If the patient is receiving symptomatic AD medications, the dosing regimen must have been stable for 3 months prior to screening. If the patient is taking medical food supplements (e.g., Axona® or
    Souvenaid®), these must also have been stable for 3 months prior to screening.
    - Inclusion is subject to review of clinical criteria at screening
    - Patient must have completed at least 6 years of formal education after the age of 5 years
    - For enrollment into the China Extension Phase, patients must have residence in mainland China, Hong Kong, or Taiwan and be of Chinese ancestry
    E.4Principal exclusion criteria
    - Any evidence of a condition other than AD that may affect cognition
    - Seizure history that, in the opinion of the investigator, is likely to result in cognitive impairment
    - History of any condition that is clinically significant and may result in cognitive impairment including
    • Infections with neurological sequelae such as syphilis
    • Autoimmune disorders that cause progressive neurological disease associated with cognitive deficits
    • History of central nervous system trauma (e.g. cerebral contusion)
    • History of presence of intracranial tumour (e.g. glioma)
    - History or presence of clinically evident vascular disease that could potentially affect the brain and that in the opinion of the investigator has the potential to affect cognitive function
    - History or presence of any stroke with clinical symptoms within the past 2 years, or documented history within the last 6 months of an acute event consistent, in the opinion of the investigator, with a transient ischemic attack
    - Presence on MRI of any cortical stroke regardless of age
    - History of schizophrenia, schizoaffective disorder, major depression, or bipolar disorder
    - At risk of suicide in the opinion of the investigator
    - Alcohol and/or substance abuse or dependence
    - Inability to tolerate MRI procedures or contraindication to MRI
    - MRI evidence of a) > 2 lacunar infarcts, b) any territorial infarct > 1 cm3, or c) any white matter lesion that corresponds to an overall Fazekas score of 3 that requires at least 1 confluent hyperintense lesion on the fluid−attenuated inversion recovery sequence, which is >= 20 mm in any dimension
    - Evidence of more than 4 microbleeds and/or areas of leptomeningeal hemosiderosis (ARIA-H) as assessed by central review
    - Presence of significant cerebral vascular pathology as assessed by MRI review
    - Patients with cardiovascular disorders, hepatic/renal disorders, infections and immune disorders, metabolic/endocrine disorders as defined in protocol
    - History of cancer unless considered cured or unlikely to require treatment within 5 years
    - Screening folic acid or vitamin B12 levels that are sufficiently low that deficiency may be contributing to cognitive impairment
    - Screening hemoglobin A1c (HbA1C) > 8% (retesting is permitted if slightly elevated) or poorly controlled insulin-dependent diabetes (past including hypoglycemic episodes) are considered one example of poor control)
    - Pregnant or lactating, or intending to become pregnant during the study
    - Poor peripheral venous access
    - Other causes of intellectual disability that may account for cognitive deficits observed at screening
    - Clinically significant sleep apnea that may be contributing to cognitive impairment. Sleep apnea which in the clinical judgment of the investigator is adequately treated (e.g., continuous positive airway
    pressure adequate patient treatment compliance should be documented) is allowed
    - Significant respiratory diseases (e.g., severe COPD – Global Initiative for Obstructive Lung Disease criteria Stage IV)
    - Sleep apnea that requires treatment or other significant respiratory diseases likely to result in cognitive impairment
    - Clinically significantly abnormal blood or urine test results at screening and that remain abnormal at retest
    - Impaired coagulation
    - Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins
    - Any other severe or unstable medical condition that, could be expected to progress, recur, or change to such an extent that it could put the patient at special risk, bias the assessment of the clinical or mental status of the patient to a significant degree, interfere with the patient’s ability to complete the study assessments, or would require the equivalent of institutional or hospital care
    - Residence in a skilled nursing facility such as a convalescent home or long-term care facility: Patients who subsequently require residence in these facilities during the study may continue in the study and be followed for efficacy and safety provided that they have a caregiver who meets the minimum requirement
    E.5 End points
    E.5.1Primary end point(s)
    1. Change from baseline to Week 105 in global outcomes as assessed by CDR-SB
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Baseline (Week 1) to Week 105
    E.5.2Secondary end point(s)
    1. Change from baseline to Week 105 on cognition as measured by ADAS-Cog-13 and ADAS-Cog-11
    2. Change from baseline to Week 105 on severity of dementia, assessed by the CDR-GS and MMSE
    3. Change from baseline to Week 105 on function as assessed by the ADCS-ADL total score and its ADCS-iADL subscore and by the FAQ total score
    4. Change from baseline to Week 105 on a measure of dependence derived from the ADCS-ADL score
    5. Change from baseline to Week 105 on behavior assessed by the Neuropsychiatric Inventory Questionnaire total score
    6. Effect of crenezumab on HRQOL, assessed using the quality of life -AD scale
    7. Effect of crenezumab on caregiver burden, assessed using the Zarit Caregiver Interview for Alzheimer’s Disease scale
    8. Effect of crenezumab on health outcomes in patient and caregiver as measured by EQ-5D
    9. Incidence of adverse events, serious adverse events, adverse events of special interest, treatment discontinuations due to adverse events, and Amyloid−related imaging abnormalities and Amyloid−related imaging abnormalities-edema/effusion assessed by MRI
    10. Incidence of abnormal vital sign measurements, laboratory test results, ECG assessments, Physical and neurologic examination abnormalities
    11. Changes in Columbia Suicide Severity Rating Scale (CSSR-S) scores from baseline over time
    12. Incidence of immunogenicity as evidenced by antibodies to crenezumab or other components of drug product
    13. Serum concentration of crenezumab (administered at a dose of 60 mg/kg IV)
    14.CSF concentration of crenezumab (administered at a dose of 60 mg/kg IV) at specified timepoints in a subset of consenting patients in a substudy (BN29553-CSF longitudinal)
    15. Brain amyloid load over time measured by amyloid-PET in a substudy (BN29552/BN29553-Amyloid PET longitudinal)
    16. Brain tau load over time measured by tau-PET in a substudy (BN29552/BN29553-tau PET longitudinal) CSF markers of disease over time in a substudy (BN29553-CSF longitudinal)
    17. CSF biomarkers
    18. Plasma PD biomarkers
    19. Plasma Abeta concentrations
    20. Imaging biomarkers
    21. MRI-derived measurements over time such as volumetric changes in whole brain, ventricles, hippocampus, or other structures
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-5. Baseline to Week 105
    7-10. Up to Week 153
    11. Up to Week 105
    12. Up to Week 117
    13. Weeks 1, 5, 13, 25, 37, 53, 77, 105, and 117
    14-17. Screening (Weeks -8 to -1), Weeks 53 and 105
    18-19. Screening (Weeks -8 to -1), Weeks 1, 5, 25, 53, 77, 105, and 117
    20-21. Up to Week 105
    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 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 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 Yes
    E.8.2.3.1Comparator description
    florbetapir F18) & Florbetaben F 18 (Neuraceq ®)
    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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA78
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Belgium
    Brazil
    Canada
    Chile
    China
    Colombia
    Estonia
    France
    Germany
    Greece
    Guatemala
    Israel
    Italy
    Japan
    Korea, Democratic People's Republic of
    Mexico
    Netherlands
    Norway
    Peru
    Poland
    Portugal
    Russian Federation
    Serbia
    Slovakia
    South Africa
    Spain
    Taiwan
    Turkey
    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 (LPLV) occurs or the date at which the last data point required for safety analyses or safety follow up is received for the last patient, whichever occurs later. LPLV for the double blind treatment period is expected to occur 153 weeks after the last patient is enrolled (i.e., 52 weeks after the last dosing visit at week 101)
    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: 150
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 600
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 350
    F.4.2.2In the whole clinical trial 750
    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)
    1) Open Label Extension: All eligible patients will have the opportunity to enter an OLE (documented in a separate protocol).
    2) Post-Trial Access to Crenezumab: The Sponsor will offer post-trial access to the study drug (crenezumab) free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product,
    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 Decision2017-04-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-03-20
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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