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    Summary
    EudraCT Number:2014-002601-38
    Sponsor's Protocol Code Number:D5010C00009
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-12-30
    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 ConcernedGermany - BfArM
    A.2EudraCT number2014-002601-38
    A.3Full title of the trial
    A 24-Month, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Efficacy, Safety, Tolerability, Biomarker and Pharmacokinetics Study of AZD3293 in Early Alzheimer’s Disease (The AMARANTH Study)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to assess the effect of AZD3293 in early Alzheimer's Disease
    A.3.2Name or abbreviated title of the trial where available
    The AMARANTH Study
    A.4.1Sponsor's protocol code numberD5010C00009
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorEli Lilly and Company
    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 supportEli Lilly and Company
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEli Lilly
    B.5.2Functional name of contact pointClinical Trial Registry Office
    B.5.3 Address:
    B.5.3.1Street AddressLilly Corporate Center, DC 1526
    B.5.3.2Town/ cityIndianapolis
    B.5.3.3Post code46285
    B.5.3.4CountryUnited States
    B.5.6E-mailEU_Lilly_Clinical_Trials@lilly.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAZD3293 20mg
    D.3.2Product code AZD3293
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot yet available
    D.3.9.1CAS number 1522418-41-2
    D.3.9.2Current sponsor codeAZD3293
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAZD3293 50mg
    D.3.2Product code AZD3293
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot yet available
    D.3.9.1CAS number 1522418-41-2
    D.3.9.2Current sponsor codeAZD3293
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Early Alzheimer’s Disease (mild cognitive impairment due to AD (ie, prodromal AD) and mild dementia of the Alzheimer’s type)
    E.1.1.1Medical condition in easily understood language
    Early Alzheimer’s Disease
    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 test the hypothesis that AZD3293, administered orally at doses of 20 and 50 mg daily for 104 weeks, will slow the decline of AD as compared with placebo in patients with early AD dementia as measured by ADAS-Cog13
    E.2.2Secondary objectives of the trial
    •To evaluate the efficacy of AZD3293 on functional, clinical, and cognitive outcomes at the end of the Double-Blind Treatment period (Week 104)
    •To evaluate the relationship between treatment effect of AZD3293 and time
    •To test the hypothesis that AZD3293 will slow the rate of cognitive and functional decline associated with AD, compared with placebo
    •To evaluate the efficacy of AZD3293 to prolong time in the current disease state
    •To evaluate the clinical worsening and need for symptomatic treatments
    •To evaluate the effect of AZD3293 on brain atrophy as measured by brain volumes using MRI
    •To assess the population pharmacokinetics of AZD3293 and metabolite AZ13569724
    •To evaluate the safety and tolerability of AZD3293
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    •To evaluate the effect of AZD3293 on brain amyloid burden using positron emission tomography (PET) in the longitudinal PET sub-study (included in the main protocol).

    •To evaluate the effect of AZD3293 on brain metabolic rates using fluorodeoxyglucose (FDG) PET


    CSF longitudinal sub-study (included in main protocol):
    To evaluate the effect of AZD3293 on CSF amyloid beta peptide pharmacodynamics markers and markers of neurodegeneration (total tau and phosphorylated tau)
    E.3Principal inclusion criteria
    •Gradual and progressive change in the patient’s memory function over more than 6 months
    •Male or female, aged 55 to 85 years inclusive
    •MMSE score of 20 to 30 inclusive
    •Score of ≤ 85 on the Delayed Memory Index of the Repeatable Battery for the assessment of Neuropsychological Status (RBANS)
    •For a diagnosis of mild AD, patient (1) meets the National Institute on Aging (NIA) and the Alzheimer’s Association (AA) (NIA-AA) criteria for probable AD and (2) has a CDR global score of 0.5 or 1, with the memory box score ≥0.5
    •For a diagnosis of MCI due to AD, patient (1) meets NIA-AA criteria for MCI due to AD and (2) has a CDR global score of 0.5, with the memory box score ≥0.5
    •Laboratory tests show no evidence of other etiologies for MCI or dementia
    •PET visual reading or CSF Ab1-42 concentration positive for presence of amyloid
    •Contraception: Women must be postmenopausal, surgically sterile or infertile due to congenital abnormality. Men must abstain or use barrier contraception from the first day of dosing until 3 months after the last dose and abstain for 24 hours after amyloid PET scans
    •All medication dosing should be stable for at least 30 days before screening, and between screening and randomization (does not apply to medications discontinued during screening, medications taken as needed, and/ or medications not expected to substantially influence safety or efficacy assessments, in the opinion of the investigator, at baseline).
    •Treatment with memantine must be discontinued at least 3 weeks before randomization
    •Agreement to undergo ApoE genotyping
    •The patient must have a reliable study partner with whom he/she cohabits or has regular contact

    E.4Principal exclusion criteria
    •Prior or ongoing participation in another clinical trial or medical research judged not to be scientifically or medically compatible
    •Significant and/or current neurological disease affecting the CNS, other than AD, that may affect cognition or ability to complete the study
    •History of clinically evident stroke or multiple strokes based on history or imaging results
    •History of clinically important carotid or vertebrobasilar stenosis or plaque
    •History of multiple concussions or a concussion with sustained cognitive complaints or objective change in neuropsychological function in the last 5 years
    •Patients with a current DSM-V diagnosis of Major Depressive Disorder or any current primary psychiatric diagnosis other than AD if, the psychiatric disorder or symptom is likely to confound interpretation of drug effect, affect cognitive assessment, or affect the patient’s ability to complete the study, history of schizophrenia or other chronic psychosis
    •History of alcohol, drug abuse or dependence (except nicotine dependence) within the last 2 years
    •Within 1 year before the screening visit or between screening and baseline: myocardial infarction; moderate or severe congestive heart failure, NYHA class III or IV; hospitalization for, or symptoms of, unstable angina; syncope due to orthostatic hypotension or unexplained syncope; known significant structural heart disease; hospitalization for arrhythmia
    •Congenital QT prolongation
    •Intermittent second- or third-degree AV heart block or AV dissociation or history of ventricular tachycardia
    •History of cancer within the last 5 years, with the exception of non-metastatic basal and/or squamous cell carcinoma of the skin, in situ cervical, or non-progressive prostate cancer or cancers with low risk of recurrence or spread
    •Current serious or unstable clinically important systemic illness likely to affect cognitive assessment, deteriorate, or affect the patient’s safety or ability to complete the study , including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic, or hematologic disorders
    •History of vitiligo and/or current evidence of post-inflammatory hypopigmentation or exposure to depigmenting agents in the 6 months prior to screening
    •History of 2 or more clinically important drug allergies, eg, severe drug-induced rash or anaphylaxis
    •Screening MRI shows evidence of significant abnormality that would suggest
    another potential etiology for MCI or dementia
    •Uncontrolled hypertension
    •A corrected QT (QTcF) interval measurement >470 msec
    •Positive serologic findings for HIV antibodies
    •Positive hepatitis B surface antigen or hepatitis C virus antibodies
    •Urine drug screen positive for inappropriate drug use
    •Any clinically important abnormality at screening
    •Calculated creatinine clearance <30 mL/min
    •ALT ≥2 × the upper limit of normal (ULN) of the performing laboratory, AST
    ≥2 × ULN, total bilirubin ≥1.5 × ULN or ALP ≥1.5 x ULN
    •Use of medications that would interfer with cognitive testing
    •Use of strong inhibitors of CYP3A4 within 14 days or 5 half-lives, whichever is
    longer, or strong inducers of CYP3A4 within 30 days before randomisation
    •Use of strong inhibitors of Pgp or BCRP within 14 days or 5 half-lives, whichever is longer, before randomisation or inducers of Pgp within 30 days before baseline
    •For patients undergoing lumbar puncture, use of medications known to significantly influence coagulation, such as warfarin or heparin
    •Treatment with any investigational drug or device within 60 days or 5 half-lives prior to screening (whichever is longer) or between screening and randomisation
    •Prior treatment with an AD vaccine
    •Presence of any of the following MRI contraindications: pacemaker; cardiac
    defibrillator; spinal cord or vagus nerve stimulator; aneurysm clip; artificial heart valve; coronary or carotid stent; ear implant; CSF shunt; other implanted medical device; metal fragments or foreign objects in the eyes, skin or body; severe claustrophobia
    CSF sub-study:
    •Any spinal malformations or other aspects/clinical findings that may complicate or contraindicate lumbar puncture
    •Current blood-clotting or bleeding disorder, including clinically significant abnormal findings in laboratory assessments of coagulation or hematology
    PET sub-studies:
    •Present or planned participation in any other research and/or medical protocol involving PET ligands or radioactive agents
    •Exposure to ionizing radiation that, in combination with the planned administration of study amyloid PET ligand, would result in a cumulative exposure exceeding local recommended exposure limits
    •Hypersensitivity to the active substance or any of the excipients of AMYVID
    •Inclusion in both FDG PET and tau sub-studies
    E.5 End points
    E.5.1Primary end point(s)
    Alzheimer’s Disease Assessment Scale – Cognitive subscale (ADASCog13)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline up to 104 Weeks
    E.5.2Secondary end point(s)
    Efficacy
    •Change from baseline to Week 104 in the FAQ score, ADCS-iADL instrumental items score, Integrated Alzheimer’s Disease Rating Scale (iADRS) score, Sum of Boxes (CDR-SB) score, CDR-Global Score, NPI total score and Mini-Mental State Examination (MMSE)
    •Changes from baseline in the CDR-SB, ADAS-Cog-13, FAQ, ADCS-iADL instrumental items, and iADRS score across time
    •AD symptomatic treatments time of initiation

    Biomarker
    •Changes from screening in volumetric MRI measures
    CSF sub-study:
    •Changes from screening in CSF Aβ1-40 and Aβ1-42
    •Changes from screening in CSF biomarkers total tau and phosphorylated tau
    PET sub-study:
    •Change from screening in brain amyloid as measured by amyloid PET
    •Change from baseline in brain metabolism as measured by FDG PET

    Safety:
    •Frequencies of clinically significant changes in physical examination findings, including results of neurological, skin, and eye examinations
    •Frequencies of spontaneously reported adverse events (AEs)
    •Changes in vital signs and body weight
    •Changes in ECG and serial MRI findings
    •Changes in clinical laboratory test results
    •Changes in Columbia - Suicide Severity Rating Scale (C-SSRS) scores

    Pharmacokinetic
    •Apparent Oral Clearance of AZD3293
    •Central Volume of Distribution of AZD3293

    E.5.2.1Timepoint(s) of evaluation of this end point
    All safety endpoints will be evaluated at all time points from screening.
    Time points for the primary and secondary efficacy endpoints that will be tested through a step-down approach.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned24
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA91
    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
    Australia
    Canada
    Japan
    Korea, Republic of
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    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 months2
    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 months7
    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: 136
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 768
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state132
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 904
    F.4.2.2In the whole clinical trial 2202
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    It is anticipated the first subject ending treatment will be in 2017. Completers will be offered participation in a separate long term extension trial if they so wish and the CTA application for this trial is approved.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-01-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-01-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-10-04
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