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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT02008357
Registration number
NCT02008357
Ethics application status
Date submitted
6/12/2013
Date registered
11/12/2013
Date last updated
28/12/2023
Titles & IDs
Public title
Clinical Trial of Solanezumab for Older Individuals Who May be at Risk for Memory Loss
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Scientific title
Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4 Study)
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Secondary ID [1]
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H8A-MC-LZAZ
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Secondary ID [2]
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15275
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Universal Trial Number (UTN)
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Trial acronym
A4
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Cognition Disorders
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Condition category
Condition code
Mental Health
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Other mental health disorders
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Mental Health
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Learning disabilities
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Neurological
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Dementias
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Placebo
Treatment: Drugs - Solanezumab
Experimental: Solanezumab/Solanezumab - Participants received 400 milligram (mg) solanezumab followed by 800 mg solanezumab and then 1600 milligram solanezumab administered intravenously (IV) every 4 weeks (Q4W) for approximately 240 weeks in double-blind placebo-controlled period.
Participants begin open label extension and received 1600 mg solanezumab Q4W for 204 weeks (from week 240 to week 444).
Placebo comparator: Placebo/Solanezumab - Participants received placebo administered IV Q4W for approximately 240 weeks in double-blind period.
Participants begin open label extension period and received 1600 mg solanezumab Q4W for 204 weeks (from week 240 to week 444).
Treatment: Drugs: Placebo
Administered IV
Treatment: Drugs: Solanezumab
Administered IV
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Change From Baseline of the Preclinical Alzheimer Cognitive Composite (PACC) Score
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Assessment method [1]
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PACC has 4 components: Free and Cued Selective Reminding Test (0 (worst)-96 (best recall); Delayed Paragraph Recall test (Range 0 (worst)-25 (best recall); Wechsler Adult Intelligence scale: Digit Symbol Substitution Test (DSST): (ranges 0 \[none\]-91 \[best performance\]) and Mini Mental State Examination (Range 0 \[worst\] - 30 \[best performance\]). Component scores are transformed using an established normalization method into z-scores. Each of 4 component change scores is divided by baseline sample standard deviation (SD) of that component. These z scores are summed to form the composite score. Thus, a change of 1 baseline standard deviation on each component would correspond to a 4-point change on the composite. A z-score of 0 is equal to the mean and implies how many SD higher or lower score as compared with baseline score, with increase signifying improvement.
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Timepoint [1]
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Baseline, Week approximately 240
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Primary outcome [2]
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Change From Baseline of the Preclinical Alzheimer Cognitive Composite (PACC) Score
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Assessment method [2]
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PACC has 4 components: Free and Cued Selective Reminding Test (0 (worst)-96 (best recall); Delayed Paragraph Recall test (Range 0 (worst)-25 (best recall); Wechsler Adult Intelligence scale: Digit Symbol Substitution Test (DSST): (ranges 0 \[none\]-91 \[best performance\]) and Mini Mental State Examination (Range 0 \[worst\] - 30 \[best performance\]). Component scores are transformed using an established normalization method into z-scores. Each of 4 component change scores is divided by baseline sample standard deviation (SD) of that component. These z scores are summed to form the composite score. Thus, a change of 1 baseline standard deviation on each component would correspond to a 4-point change on the composite. A z-score of 0 is equal to the mean and implies how many SD higher or lower score as compared with baseline score, with increase signifying improvement.
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Timepoint [2]
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Baseline, Week 336
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Secondary outcome [1]
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Change From Baseline in Cognitive Function Index (CFI)
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Assessment method [1]
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The CFI is a modified version of the Mail-in Cognitive Function Screening Instrument, a participant- and study partner/informant-reported outcome measure developed by the Alzheimer's Disease Cooperative Study (ADCS). This assessment includes 15 questions (14 of which contribute to the total score, and 1 additional unscored item) that assess the participant's perceived ability to perform high-level functional tasks in daily-life and sense of overall cognitive functional ability. Study participants and their informants independently rate the participant's abilities. A total score is calculated by combining participant-reported and an informant-reported scores, and ranges from 0 to 14 (yes=1; no=0; maybe=0.5 for each question) with higher scores indicating greater impairment. LS mean was derived using natural cubic spline models with factors for treatment, time, and covariates = age, baseline florbetapir cortical SUVr score, years of education, APOE4 carrier status (n).
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Timepoint [1]
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Baseline, Week approximately 240
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Secondary outcome [2]
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Change From Baseline in Cognitive Function Index (CFI)
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Assessment method [2]
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The CFI is a modified version of the Mail-in Cognitive Function Screening Instrument, a participant- and study partner/informant-reported outcome measure developed by the ADCS. This assessment includes 15 questions (14 of which contribute to the total score, and 1 additional unscored item) that assess the participant's perceived ability to perform high-level functional tasks in daily-life and sense of overall cognitive functional ability. Study participants and their informants independently rate the participant's abilities. A total score is calculated by combining participant-reported and an informant-reported scores, and ranges from 0 to 14 (yes=1; no=0; maybe=0.5 for each question) with higher scores indicating greater impairment.
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Timepoint [2]
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Baseline, Week 336
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Secondary outcome [3]
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Change From Baseline in Alzheimer's Disease Cooperative Study-Activities Daily Living-Prevention Questionnaire (ADCS-ADL-Prevention Questionnaire) Score
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Assessment method [3]
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The ADCS-ADL-prevention questionnaire is a functional measure composed of 18 items that includes 15 activities of daily living rated on a 4-point scale and 3 high level function items. Study participants and their informants independently rate the participant's level of ability (with no difficulty = 3, with some difficulty = 2, with a lot of difficulty = 1, did not do/don't know = 0). Informants are additionally asked to evaluate whether activities were completed less often, required more time to complete, and if any errors were made performing the task. High-level function items are rated as "yes" or "no". The total score is the sum of the scores of the 15 activities of daily living questions (range: 0-45) with higher scores indicating less impairment.
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Timepoint [3]
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Baseline, Week approximately 240
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Secondary outcome [4]
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Change From Baseline in Alzheimer's Disease Cooperative Study-Activities Daily Living-Prevention Questionnaire (ADCS-ADL-Prevention Questionnaire) Score
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Assessment method [4]
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The ADCS-ADL-prevention questionnaire is a functional measure composed of 18 items that includes 15 activities of daily living rated on a 4-point scale and 3 high level function items. Study participants and their informants independently rate the participant's level of ability (with no difficulty = 3, with some difficulty = 2, with a lot of difficulty = 1, did not do/don't know = 0). Informants are additionally asked to evaluate whether activities were completed less often, required more time to complete, and if any errors were made performing the task. High-level function items are rated as "yes" or "no". The scores range from 0 to 45 with higher scores indicating less impairment. The total score is the sum of the scores of the 15 activities of daily living questions (range: 0-45) with higher scores indicating less impairment.
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Timepoint [4]
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Baseline, Week 336
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Secondary outcome [5]
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Change From Baseline in Mean Composite Standardized Uptake Value Ratio (SUVr)
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Assessment method [5]
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Deposition of abnormal tau protein in the brain associated with AD was assessed by quantitative positron emission tomography (PET) scan using flortaucipir F-18. Flortaucipir is an F-18-labeled small molecule that binds with high affinity and selectivity to aggregated tau, and provides a measure of aggregated tau deposition in the brain, expressed as flortaucipir SUVr. LS Mean was calculated using an analysis of covariance (ANCOVA) model with fixed effects of baseline florbetapir result, treatment, APOE4 Carrier Status (yes/no), and age at baseline
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Timepoint [5]
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Baseline, Week approximately 240
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Secondary outcome [6]
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Change From Baseline in Cerebrospinal Fluid (CSF) Tau Biomarkers
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Assessment method [6]
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CSF concentrations of total tau and tau phosphorylated protein concentrations were analyzed using validated Immunoassay method. LS mean was derived using an analysis of covariance (ANCOVA) model with fixed effects of baseline CSF, treatment, APOE4 Carrier Status (yes/no) and age at baseline.
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Timepoint [6]
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Baseline, Week approximately 240
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Secondary outcome [7]
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Change From Baseline of Cerebrospinal Fluid (CSF) Concentrations of Amyloid Beta (Aß)
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Assessment method [7]
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CSF biomarker concentrations were analyzed for Aß 1-40 and Aß 1-42 using Innotest Enzyme-linked immunosorbent assays (ELISA) method. LS mean was derived using an ANCOVA model with fixed effects of baseline CSF, treatment, APOE4 Carrier Status (yes/no) and age at baseline.
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Timepoint [7]
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Baseline, Week approximately 240
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Secondary outcome [8]
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Change From Baseline in Brain Volume as Measured by Volumetric Magnetic Resonance Imaging (vMRI)
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Assessment method [8]
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Alzheimer's disease is also associated with pronounced brain atrophy, reflecting bulk neurodegenerative loss of gray and white matter. Progression of brain atrophy is assessed by vMRI, providing regional quantification of volume loss. Negative change from baseline indicates greater disease severity. Total hippocampal volume and Total Lateral Ventricular Volume were analyzed for vMRI parameters. LS mean was derived using an ANCOVA model with fixed effects of baseline vMRI value, treatment, age at baseline, education, APOE4 Carrier Status (yes/no), and baseline florbetapir cortical SUVr.
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Timepoint [8]
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Baseline, Week approximately 240
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Secondary outcome [9]
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Change From Baseline on the Clinical Dementia Rating-Sum of Boxes Score (CDR-SB)
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Assessment method [9]
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The CDR-SB is an interviewer administered scale and impairment is scored in each of categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment is scored on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2 and severe = 3. The 6 individual category ratings, or "box scores", were added together to give the CDR-Sum of Boxes which ranges from 0-18. Higher score indicates severe impairment.
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Timepoint [9]
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Baseline, Week 336
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Secondary outcome [10]
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Change From Baseline on the Computerized Cognitive Composite (C3)
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Assessment method [10]
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The C3 includes tasks from the CogState battery aimed at measuring processing speed, working memory, visual navigation, and executive function. The C3 also include 2 investigator-developed sensitive episodic memory probes of hippocampal function. A composite score is generated and CogState scores are measured on a linear scale (with no maximum score) and a reduction in scores compared to baseline indicates an improvement in cognitive functions.
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Timepoint [10]
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Baseline, Week 336
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Eligibility
Key inclusion criteria
* Has a Mini-Mental State Examination (MMSE) score at screening of 25 to 30
* Has a global Clinical Dementia Rating (CDR) scale score at screening of 0
* Has a Logical Memory II score at screening of 6 to 18
* Has a florbetapir positron emission tomography (PET) scan that shows evidence of brain amyloid pathology at screening
* Has a study partner that is willing to participate as a source of information and has at least weekly contact with the participant (contact can be in-person, via telephone or electronic communication)
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Minimum age
65
Years
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Maximum age
85
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
* Is receiving a prescription acetylcholinesterase inhibitor (AChEI) and/or memantine at screening or baseline
* Lacks good venous access, such that intravenous drug delivery or multiple blood draws would be precluded
* Has current serious or unstable illness including cardiovascular, hepatic, renal, gastroenterologic, respiratory, endocrinologic, neurologic, psychiatric, immunologic, or hematologic disease or other conditions that, in the investigator's opinion, could interfere with the analyses of safety and efficacy in this study
* Has had a history within the last 5 years of a serious infectious disease affecting the brain (including neurosyphilis, meningitis, or encephalitis) or head trauma resulting in protracted loss of consciousness
* Has had a history within the last 5 years of a primary or recurrent malignant disease with the exception of any in situ cancer that was appropriately treated and is being appropriately monitored, such as resected cutaneous squamous cell carcinoma in situ or in situ prostate cancer with normal prostate-specific antigen post-treatment
* Has a known history of human immunodeficiency virus (HIV), clinically significant multiple or severe drug allergies, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, or exfoliative dermatitis)
* Is clinically judged by the investigator to be at serious risk for suicide
* Has a history within the past 2 years of major depression or bipolar disorder as defined by the most current version of the Diagnostic and Statistical Manual of Mental Disorders (DSM)
* Has a history within the past 5 years of chronic alcohol or drug abuse/dependence as defined by the most current version of the DSM
Open-Label Inclusion Criteria:
* All participants who complete the placebo-controlled period will be allowed to continue into the open-label period
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
28/02/2014
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
8/06/2023
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Sample size
Target
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Accrual to date
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Final
1169
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
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For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. - Parkville
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Recruitment postcode(s) [1]
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3010 - Parkville
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Recruitment outside Australia
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United States of America
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Alabama
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Arizona
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California
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Connecticut
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United States of America
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District of Columbia
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United States of America
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Florida
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Georgia
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Illinois
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Indiana
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Iowa
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Kansas
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Kentucky
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Louisiana
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Maryland
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Massachusetts
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Michigan
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Missouri
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Nebraska
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Nevada
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New York
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North Carolina
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Ohio
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Oklahoma
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Oregon
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Pennsylvania
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Rhode Island
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South Carolina
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Texas
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Washington
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Wisconsin
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Canada
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London
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Canada
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Toronto
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Canada
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Vancouver
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Japan
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Bunkyo-ku
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
Eli Lilly and Company
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Address
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Other collaborator category [1]
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Other
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Name [1]
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Alzheimer's Therapeutic Research Institute
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Address [1]
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Ethics approval
Ethics application status
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Summary
Brief summary
The purpose of this study is to test whether an investigational drug called solanezumab can slow the progression of memory problems associated with brain amyloid (protein that forms plaques in the brains of people with Alzheimer Disease \[AD\]).
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Trial website
https://clinicaltrials.gov/study/NCT02008357
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Trial related presentations / publications
Lewis CK, Bernstein OM, Grill JD, Gillen DL, Sultzer DL. Anxiety and Depressive Symptoms and Cortical Amyloid-beta Burden in Cognitively Unimpaired Older Adults. J Prev Alzheimers Dis. 2022;9(2):286-296. doi: 10.14283/jpad.2022.13. Grober E, Lipton RB, Sperling RA, Papp KV, Johnson KA, Rentz DM, Veroff AE, Aisen PS, Ezzati A. Associations of Stages of Objective Memory Impairment With Amyloid PET and Structural MRI: The A4 Study. Neurology. 2022 Mar 29;98(13):e1327-e1336. doi: 10.1212/WNL.0000000000200046. Epub 2022 Feb 23.
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Public notes
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Contacts
Principal investigator
Name
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Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)
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Address
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Eli Lilly and Company
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Email
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Contact person for public queries
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Contact person for scientific queries
No information has been provided regarding IPD availability
What supporting documents are/will be available?
No Supporting Document Provided
Type
Other Details
Attachment
Study protocol
https://cdn.clinicaltrials.gov/large-docs/57/NCT02008357/Prot_000.pdf
Statistical analysis plan
https://cdn.clinicaltrials.gov/large-docs/57/NCT02008357/SAP_001.pdf
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results are available at
https://clinicaltrials.gov/study/NCT02008357
Download to PDF