Study to assess the effect of AZD3293 in early Alzheimer's Disease

Phase 1

• Conditions: Early Alzheimer´s Disease (mild cognitive impairment due to AD (ie, prodromal AD) and mild dementia of the Alzheimer´s type); MedDRA version: 17.1Level: PTClassification code 10012271Term: Dementia Alzheimer's typeSystem Organ Class: 10029205 - Nervous system disorders; Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

• Registration Number: EUCTR2014-002601-38-ES
• Lead Sponsor: AstraZeneca AB

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2015-01-02
• Study Completion: 2018-10-04
• Last Update Posted: 2 August 2021

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 2218

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 -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 (AmyvidTM), or CSF Aß1-42 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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 96
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 541

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 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 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 wit

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: 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. <br>To evaluate the safety and tolerability of AZD3293 in patients with early AD.;Secondary Objective: To evaluate the efficacy of AZD3293 on:<br> - cognitive outcomes as measured by the ADAS-Cog-13 score<br> - functional outcome as measured by the FAQ score and the ADCS-ADL <br>instrumental items score<br> - neuropsychiatric symptoms as assessed by NPI score<br>To evaluate the efficacy of AZD3293 to prolong time in the current disease state as measured by the CDR global score<br>To evaluate the effect of AZD3293 on underlying pathology as measured by brain volumes using MRI<br>To assess the population pharmacokinetics (PK) of AZD3293 and metabolite AZ13569724;Primary end point(s): Clinical Dementia Rating - Sum of Boxes (CDR-SB) score;Timepoint(s) of evaluation of this end point: Baseline up to 104 Weeks