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

• Register: EUCTR
• Last refreshed on: 30 April 2019
• Main ID: EUCTR2014-002601-38-DE
• Date of registration: 30/12/2014
• Prospective Registration: Yes
• Primary sponsor: Eli Lilly and Company
• Public title: Study to assess the effect of AZD3293 in early Alzheimer's Disease
• Scientific title: 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) - The AMARANTH Study
• Date of first enrolment: 15/01/2015
• Target sample size: 2202
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-002601-38
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Belgium, Canada, France, Germany, Hungary, Japan, Korea, Republic of, Spain, United Kingdom, United States

Contacts

• Name: Clinical Trial Registry Office
• Affiliation: Eli Lilly

• Name: Clinical Trial Registry Office
• Affiliation: Eli Lilly

Key inclusion & exclusion criteria

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


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 136
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 768

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 st

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Early Alzheimer’s Disease (mild cognitive impairment due to AD (ie, prodromal AD) and mild dementia of the Alzheimer’s type)
MedDRA version: 20.0 Level: PT Classification code 10012271 Term: Dementia Alzheimer's type System Organ Class: 10029205 - Nervous system disorders

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Product Name: AZD3293 20mg
Product Code: AZD3293
Pharmaceutical Form: Tablet
INN or Proposed INN: Not yet available
CAS Number: 1522418-41-2
Current Sponsor code: AZD3293
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Name: AZD3293 50mg
Product Code: AZD3293
Pharmaceutical Form: Tablet
INN or Proposed INN: Not yet available
CAS Number: 1522418-41-2
Current Sponsor code: AZD3293
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: 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

Secondary Objective: •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

Primary end point(s): Alzheimer’s Disease Assessment Scale – Cognitive subscale (ADASCog13)

Timepoint(s) of evaluation of this end point: Baseline up to 104 Weeks

Secondary Outcome(s)

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.

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 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 Aß1-40 and Aß1-42
•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

Secondary ID(s)

2014-002601-38-GB

D5010C00009

Source(s) of Monetary Support

Eli Lilly and Company

Ethics review

Status: Approved
Approval date:
Contact:

Results

• Results available: Yes
• Date Posted: 27/06/2019
• Date Completed: 04/10/2018
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002601-38/results