E.1 Medical condition or disease under investigation |
E.1.1 | Medical 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) |
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E.1.1.1 | Medical condition in easily understood language |
Early Alzheimer’s Disease |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012271 |
E.1.2 | Term | Dementia Alzheimer's type |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of AZD3293 on cognitive and functional outcomes in patients with early Alzheimer’s disease (AD) as measured by the Clinical Dementia Rating – Sum of Boxes score.
To evaluate the safety and tolerability of AZD3293 in patients with early AD. |
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E.2.2 | Secondary objectives of the trial |
•To evaluate the efficacy of AZD3293 on:
- cognitive outcomes as measured by the ADAS-Cog-13 score
- functional outcome as measured by the FAQ score and the ADCS-ADL
instrumental items score
- neuropsychiatric symptoms as assessed by NPI score
•To evaluate the efficacy of AZD3293 to prolong time in the current disease state as measured by the CDR global score
•To evaluate the effect of AZD3293 on underlying pathology as measured by brain volumes using MRI
•To assess the population pharmacokinetics (PK) of AZD3293 and metabolite AZ13569724
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PET sub-study
To evaluate the effect of AZD3293 on:
- brain amyloid burden using PET
- brain metabolic rates using fluorodeoxyglucose (FDG) PET
CSF sub-study
To evaluate the effect of AZD3293 on:
-central markers of pharmacodynamics by assessing Aβ 1-42 and Aβ 1-40 concentrations
-central markers of neurodegeneration by assessing CSF total tau and phosphorylated tau concentrations
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E.3 | Principal 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 21 to 28 inclusive
•Score of <80 on the Delayed Memory Index of the Repeatable Battery for the assessment of Neuropsychological Status
•FAQ score of ≥2
•Rosen Modified Hachinski Ischemic score ≤4
•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) had CDR global score of 0.5, with the memory box score ≥0.5
•Screening MRI shows no evidence of significant abnormality that would suggest another potential etiology for MCI or dementia.
•Laboratory tests show no evidence of other etiologies for MCI or dementia
•PET visual reading positive for presence of amyloid according to the binary image-reading guidelines of florbetapir F 18 injection (Amyvid™), or CSF Aβ1-42 concentration below the prespecified threshold by Innotest enzyme-linked immunosorbent assay (ELISA)
•Contraception: Women must be postmenopausal or surgically sterile. Men must abstain or use barrier contraception from the first day of dosing until 3 months after the last dose.
•Concomitant medication: The dose of any concomitant medication must be stable for at least 30 days before screening, and between screening and randomization. For cholinesterase inhibitors (a) the dose regimen must be stable for at least 90 days prior to baseline, (b) the patient must be free from any clinically important side effects attributable to the drug, and (c) patient and study partner agree that, barring unforeseen circumstances, the dosage regimen will remain stable for the study duration. 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.
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E.4 | Principal exclusion criteria |
•Prior or ongoing participation in any AZD3293 study or other BACE inhibitor
study or participation in any other interventional AD study during the proposed study
•Significant 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 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) diagnosis of Major Depressive Disorder (MDD) 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 alcohol or drug abuse or dependence (except nicotine dependence) within the last 2 years
•Within 1 year before the screening visit or between screening and baseline, any of the following: 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; or hospitalization for arrhythmia
•Congenital QT prolongation
•Intermittent second- or third-degree atrioventricular (AV) heart block or AV dissociation or history of ventricular tachycardia
•History or presence of diabetes, unless well controlled and actively managed
•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
•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
•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 >450 msec
•Known positive serologic findings for HIV antibodies
•Positive hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies
•Urine drug screen positive for amphetamine, cocaine, phencyclidine, or barbiturate
•Any clinically important abnormality at screening
•Calculated creatinine clearance <40 mL/min
•ALT ≥1.5 × the upper limit of normal (ULN) of the performing laboratory, AST ≥2 × ULN, or total bilirubin ≥1.5 × ULN
•Regular use (eg, taken >3 days/week) of narcotic medications within 30 days before baseline
•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 baseline
•Use of strong inhibitors of Pgp or BCRP within 14 days or 5 half-lives, whichever is longer, or inducers of Pgp within 30 days before baseline
•Use of drugs known to significantly prolong the QT interval within 14 days or 5 half-lives, whichever is longer, prior to baseline
•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 baseline
•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; recent 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 that would contraindicate a brain MRI scan
CSF sub-study:
•Any spinal malformations or other aspects or other 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-study:
•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 that exceeds local recommended exposure limits
•Hypersensitivity to the active substance or any of the excipients of MYVID
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E.5 End points |
E.5.1 | Primary end point(s) |
Clinical Dementia Rating - Sum of Boxes (CDR-SB) score |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Efficacy
•Change from baseline to Week 104 in the ADAS-Cog-13 score
•Change from baseline to Week 104 in the FAQ score
•Change from baseline to Week 104 in the ADCS-ADL instrumental items score
•Time to loss of 1 global stage on the CDR global score through Week 104
•Change from baseline to Week 104 in the NPI total score
•Changes from baseline to Weeks 26, 52, and 78 in the CDR-SB, ADAS-Cog-13, FAQ, ADCS-ADL instrumental items, and NPI total scores, as well as changes from baseline to Week 13 in ADAS-Cog-13 score
Biomarker
•Changes from screening to Week 104 in volumetric MRI measures, including whole brain volume, ventricular volume, entorhinal cortex volume, hippocampal volume, and temporal lobe volume
CSF sub-study:
•Changes from screening to Week 97 in CSF CSF Aβ 1-40 and CSF Aβ 1-42
•Changes from screening to Week 97 in CSF biomarkers total tau and
phosphorylated tau
PET sub-study:
•Change from screening to Week 104 in brain amyloid as measured by amyloid PET
•Change from baseline to Week 104 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 non-serious adverse events (AEs) and serious AEs (SAEs)
•Changes in vital signs
•Changes in ECG findings
•Changes in clinical laboratory test results
•Frequency and severity of amyloid-related imaging abnormalities (ARIA)
•Worsening in cognition, as measured by the ADAS-Cog-13
•Changes in Columbia - Suicide Severity Rating Scale (C-SSRS) scores
Pharmacokinetic
•Plasma AZD3293 and metabolite AZ13569724 concentrations
•Evaluation of covariates that may contribute to AZD3293 and AZ13569724 PK variability.
•CSF AZD3293 and AZ13569724 PK at Weeks 52 and 97 (CSF sub-study)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
All safety endpoints will be evaluated from baseline to Week 104. Efficacy endpoints as specified in E.5.2. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 78 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Belgium |
Canada |
Czech Republic |
France |
Germany |
Hungary |
Japan |
Korea, Republic of |
Poland |
Romania |
Spain |
United States |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |