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 | 19.1 |
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 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 |
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E.2.2 | Secondary 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 |
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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 |
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
To evaluate the effect of AZD3293 on brain aggregated tau levels
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) |
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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 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) 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.
•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 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 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; or hospitalization for arrhythmia
•Congenital QT prolongation
•Intermittent second- or third-degree heart block or AV dissociation or history of ventricular tachycardia
•History of cancer within the last 5 years, with the exception of nonmetastatic 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 druginduced 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 randomization 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; 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
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/TAU 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 exceeding local recommended limits
•Hypersensitivity to AMYVID or 18F-AV-1451 or any of the excipients
•Inclusion in both the FDG PET and tau sub-studies
•History of risk factors for Torsades de Pointes or medication known to produce clinically relevant QT prolongation that cannot be discontinued or held for 5 half-lives prior to 18F-AV-1451 administration |
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E.5 End points |
E.5.1 | Primary end point(s) |
Alzheimer’s Disease Assessment Scale – Cognitive subscale (ADASCog13) |
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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 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 score and Mini-Mental State Examination (MMSE)
•Changes from baseline in the CDR-SB, ADAS-Cog-13, FAQ, ADCS-ADL 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 Aβ 1-40 and Aβ 1-42
•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
•Change from baseline in brain aggregated tau levels as measured by
18F-AV-1451 PET
Safety
•Frequencies of clinically significant changes in physical examination findings, including results of neurological, skin, and eye examinations
•Frequencies of spontaneously reportedadverse 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 |
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E.5.2.1 | Timepoint(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. |
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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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 91 |
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 |
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 | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |