Clinical Trial of Solanezumab for Older Individuals Who May be at Risk for Memory Loss

Cognition Disorders Clinical Trial

— A4  

Official title:

Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4 Study)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02008357
• Other study ID #: 15275
• Secondary ID: H8A-MC-LZAZ
• Status: Completed
• Phase: Phase 3
• Start date: February 28, 2014
• Est. completion date: June 8, 2023

Study information

• Verified date: December 2023
• Source: Eli Lilly and Company
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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]).

Description:

The A4 study is a clinical trial for older individuals who have evidence of amyloid plaque build-up in their brains who may be at risk for memory loss and cognitive decline due to Alzheimer's disease. The A4 study will test an anti-amyloid investigational drug in older individuals who do not yet show symptoms of Alzheimer's disease cognitive impairment or dementia with the aim of slowing memory and cognitive decline. The A4 study will also test whether anti-amyloid treatment can delay the progression of AD related brain injury on imaging and other biomarkers.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1169
• Est. completion date: June 8, 2023
• Est. primary completion date: December 27, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 65 Years to 85 Years

Eligibility

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)

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

Related Conditions & MeSH terms

• Cognition Disorders

Intervention

Drug:
• Placebo
Administered IV
• Solanezumab
Administered IV

Locations

Country	Name	City	State
Australia	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	Victoria
Canada	For additional information regarding investigative sites for this trial, contact 1-888-545-5972 Mon - Fri, 9 AM to 4 PM or 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri, 9 AM to 5 PM Eastern Time or speak with your personal physician.	London
Canada	For additional information regarding investigative sites for this trial, contact 1-888-545-5972 Mon - Fri, 9 AM to 4 PM or 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri, 9 AM to 5 PM Eastern Time or speak with your personal physician.	Toronto
Canada	Sunnybrook Health Sciences Centre	Toronto
Canada	For additional information regarding investigative sites for this trial, contact 1-888-545-5972 Mon - Fri, 9 AM to 4 PM or 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri, 9 AM to 5 PM Eastern Time or speak with your personal physician.	Vancouver
Japan	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.	Bunkyo-ku
United States	Dent Neurological Institute	Amherst	New York
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	Johns Hopkins University School of Medicine	Baltimore	Maryland
United States	Pennington Biomedical Research Center	Baton Rouge	Louisiana
United States	Case Western Reserve University	Beachwood	Ohio
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Boston University Medical Center	Boston	Massachusetts
United States	Brigham and Womens Hospital	Boston	Massachusetts
United States	Roper Hospital	Charleston	South Carolina
United States	Great Lakes Clinical Trials	Chicago	Illinois
United States	Northwestern University	Chicago	Illinois
United States	Rush Alzheimer's Disease Center	Chicago	Illinois
United States	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas
United States	Brain Matters Research	Delray Beach	Florida
United States	University of Kansas Hospital	Fairway	Kansas
United States	Baylor College of Medicine	Houston	Texas
United States	Houston Methodist	Houston	Texas
United States	Indiana University School of Medicine	Indianapolis	Indiana
United States	University of Iowa	Iowa City	Iowa
United States	Institute for Memory Impairment & Neurological Disorders	Irvine	California
United States	Mayo Clinic-Jacksonville	Jacksonville	Florida
United States	University of California - San Diego	La Jolla	California
United States	Cleveland Clinic of Las Vegas	Las Vegas	Nevada
United States	University of Kentucky	Lexington	Kentucky
United States	University of California - Los Angeles	Los Angeles	California
United States	University of Southern California School of Medicine	Los Angeles	California
United States	University of Wisconsin-Madison Hospital and Health Clinic	Madison	Wisconsin
United States	Wien Center for Clinical Research	Miami Beach	Florida
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Columbia University Medical Center	New York	New York
United States	Mount Sinai School of Medicine	New York	New York
United States	New York University Medical Center	New York	New York
United States	Weill Cornell Medical College	New York	New York
United States	Univ of Nebraska Med Center	Omaha	Nebraska
United States	Univ of California Irvine College of Medicine	Orange	California
United States	Compass Research - Orlando	Orlando	Florida
United States	Veterans Affairs Medical Center Palo Alto	Palo Alto	California
United States	Drexel University College of Medicine at EPPI	Philadelphia	Pennsylvania
United States	University of Pennsylvania Hospital	Philadelphia	Pennsylvania
United States	Banner Health Research Institute	Phoenix	Arizona
United States	Barrow Neurological Institute	Phoenix	Arizona
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Butler Hospital	Providence	Rhode Island
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Sutter Medical Group	Sacramento	California
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Univ of California San Francisco	San Francisco	California
United States	Syrentis Clinical Research	Santa Ana	California
United States	University of Washington School of Medicine	Seattle	Washington
United States	Banner Sun Health Research Institute	Sun City	Arizona
United States	University of South Florida	Tampa	Florida
United States	Compass Research -The Villages	The Villages	Florida
United States	Tulsa Clinical Research LLC	Tulsa	Oklahoma
United States	University of California, Davis - Health Systems	Walnut Creek	California
United States	Georgetown University Hospital	Washington	District of Columbia
United States	Howard University Hospital	Washington	District of Columbia
United States	Premiere Research Institute at Palm Beach Neurology	West Palm Beach	Florida
United States	Wake Forest University School of Medicine	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Eli Lilly and Company	Alzheimer's Therapeutic Research Institute

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline of the Preclinical Alzheimer Cognitive Composite (PACC) Score	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.	Baseline, Week approximately 240
Primary	Change From Baseline of the Preclinical Alzheimer Cognitive Composite (PACC) Score	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.	Baseline, Week 336
Secondary	Change From Baseline in Cognitive Function Index (CFI)	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).	Baseline, Week approximately 240
Secondary	Change From Baseline in Cognitive Function Index (CFI)	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.	Baseline, Week 336
Secondary	Change From Baseline in Alzheimer's Disease Cooperative Study-Activities Daily Living-Prevention Questionnaire (ADCS-ADL-Prevention Questionnaire) Score	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.	Baseline, Week approximately 240
Secondary	Change From Baseline in Alzheimer's Disease Cooperative Study-Activities Daily Living-Prevention Questionnaire (ADCS-ADL-Prevention Questionnaire) Score	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.	Baseline, Week 336
Secondary	Change From Baseline in Mean Composite Standardized Uptake Value Ratio (SUVr)	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	Baseline, Week approximately 240
Secondary	Change From Baseline in Cerebrospinal Fluid (CSF) Tau Biomarkers	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.	Baseline, Week approximately 240
Secondary	Change From Baseline of Cerebrospinal Fluid (CSF) Concentrations of Amyloid Beta (Aß)	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.	Baseline, Week approximately 240
Secondary	Change From Baseline in Brain Volume as Measured by Volumetric Magnetic Resonance Imaging (vMRI)	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.	Baseline, Week approximately 240
Secondary	Change From Baseline on the Clinical Dementia Rating-Sum of Boxes Score (CDR-SB)	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.	Baseline, Week 336
Secondary	Change From Baseline on the Computerized Cognitive Composite (C3)	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.	Baseline, Week 336

External Links

•   A Study of Solanezumab in Older Participants Who May be at Risk for Memory Loss (A4)