A 24-month, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Efficacy, Safety, Tolerability, Biomarker, and Pharmacokinetic Study of AZD3293 in Early Alzheimer's Disease (The AMARANTH Study)
Overview
- Phase
- Phase 2
- Intervention
- Lanabecestat
- Conditions
- Alzheimer´s Disease
- Sponsor
- AstraZeneca
- Enrollment
- 2218
- Locations
- 249
- Primary Endpoint
- Change From Baseline on the 13-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog13)
- Status
- Terminated
- Last Updated
- 6 years ago
Overview
Brief Summary
The purpose of this study is to assess the efficacy and safety of lanabecestat compared with placebo administered for 104 weeks in the treatment of early Alzheimer´s disease. The study will test the hypothesis that lanabecestat is a disease-modifying treatment for participants with early Alzheimer´s disease, defined as the continuum of participants with mild cognitive impairment (MCI) due to Alzheimer´s disease and participants diagnosed with mild dementia of the Alzheimer´s type, as measured by change from baseline on the 13-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog13) score at week 104 in each of the 2 lanabecestat treatment groups compared with placebo.
Detailed Description
Participants who meet other study entry requirements will be required to undergo either an amyloid positron emission tomography (PET) scan or a lumbar puncture for cerebrospinal fluid (CSF) sampling at screening to document presence of abnormal levels of brain and CSF amyloid for study inclusion. The study includes 2 sub-studies: the participants that undergo a PET scan at screening will be included in the PET-substudy, and participants who undergo a lumbar puncture at screening will be included in the CSF substudy until each of these substudies are completed.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Gradual and progressive change in the participant's memory function over more than 6 months, reported by participant and study partner
- •Mini-Mental State Examination score of 20-30 inclusive at screening
- •Objective impairment in memory as evaluated by memory test performed at screening
- •For a diagnosis of mild Alzheimer's Disease (AD), participant meets the National Institute on Aging and the Alzheimer's Association (NIA-AA) criteria for probable AD
- •For a diagnosis of MCI due to AD, participant meets NIA-AA criteria for MCI due to AD
Exclusion Criteria
- •Significant neurological disease affecting the central nervous system, other than AD, that may affect cognition or ability to complete the study, including but not limited to, other dementias, serious infection of the brain, Parkinson´s disease, or epilepsy or recurrent seizures
- •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 with sustained cognitive complaints or objective change in neuropsychological function in the last 5 years
- •Participants 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, in the judgment of the investigator, the psychiatric disorder or symptom is likely to confound interpretation of drug effect, affect cognitive assessments, or affect the participant´s ability to complete the study
- •History of alcohol or drug abuse or dependence (except nicotine dependence) within 2 years before the screening
- •Within 1 year before the screening or between screening and baseline, any of the following: myocardial infarction; moderate or severe congestive heart failure, New York Heart Association class III or IV; hospitalization for, or symptom of, unstable angina; syncope due to orthostatic hypotension or unexplained syncope; known significant structural heart disease (eg, significant valvular disease, hypertrophic cardiomyopathy), or hospitalization for arrhythmia
- •Congenital QT prolongation
- •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 cancer, non-progressive prostate cancer or other cancers with low-risk of recurrence or spread
- •Current serious or unstable clinically important systemic illness that, in the judgment of the investigator, is likely to affect cognitive assessment, deteriorate, or affect the participant's safety or ability to complete the study, including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic, or hematologic disorders
Arms & Interventions
Lanabecestat 20 milligrams (mg)
Lanabecestat 20 mg given orally once daily for 104 weeks.
Intervention: Lanabecestat
Lanabecestat 50 mg
Lanabecestat 50 mg given orally once daily for 104 weeks.
Intervention: Lanabecestat
Placebo
Placebo given orally once daily for 104 weeks.
Intervention: Placebo
Outcomes
Primary Outcomes
Change From Baseline on the 13-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog13)
Time Frame: Baseline, Week 104
ADAS-Cog13 (13-item version of ADAS-Cog) is a psychometric instrument that evaluates word recall, ability to follow commands, constructional praxis, naming, ideational praxis, orientation, word recognition, memory, comprehension of spoken language, word-finding, and language ability, with a measure of delayed word recall and concentration/ distractibility. The total score of the 13-item scale ranges from 0 to 85, with an increase in score indicating cognitive worsening. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, apolipoprotein E4 (APOE4) status, acetylcholinesterase inhibitor (AChEI) use at baseline, pooled country, and covariates for baseline ADAS-Cog13 total score, age at baseline, and baseline ADAS-Cog13 total score-by-visit interaction.
Secondary Outcomes
- Change From Baseline on the Alzheimer´s Disease Cooperative Study Activities of Daily Living Inventory Instrumental Items (ADCS-iADL)(Baseline, Week 104)
- Time to Progression as Measured by Loss of Clinical Dementia Rating (CDR) Global Score Stage(Baseline through Loss of 1 Global Stage or Week 104)
- Change From Baseline in Neuropsychiatric Inventory (NPI) Score(Baseline, Week 104)
- Change From Baseline on the Mini-Mental State Examination (MMSE)(Baseline, Week 104)
- Pharmacodynamics (PD): Percent Change From Baseline in Concentration of Cerebrospinal Fluid (CSF) Biomarker Amyloid Beta (Aβ)1-42(Baseline, Week 97)
- PD: Percent Change From Baseline in Concentration of CSF Biomarker Aβ1-40(Baseline, Week 97)
- Change From Baseline in CSF Total Tau(Baseline, Week 97)
- Change From Baseline in CSF Phosphorylated Tau(Baseline, Week 97)
- Change From Baseline on the Functional Activities Questionnaire (FAQ) Score(Baseline, Week 104)
- Change From Baseline on the Integrated Alzheimer's Disease Rating Scale (iADRS) Score(Baseline, Week 104)
- Change From Baseline on the Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score(Baseline, Week 104)
- Change From Baseline in Brain Amyloid Burden Using Florbetapir Amyloid Positron Emission Tomography (PET) Scan(Baseline, Week 104)
- Change From Baseline in Tau PET ((Flortaucipir F18)(Baseline, Week 104)
- Change From Baseline in Brain Metabolism Using Fluorodeoxyglucose (FDG)(Baseline, Week 104)
- Change From Baseline in Whole Brain Volume(Baseline, Week 104)
- Pharmacokinetics (PK): Plasma Concentration of Lanabecestat(Week 4, post dose prior to departure from the clinic)