Clinical Trial of Solanezumab for Older Individuals Who May be at Risk for Memory Loss
- Registration Number
- NCT02008357
- Lead Sponsor
- Eli Lilly and Company
- 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 \[AD\]).
- Detailed 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 & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1169
- 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)
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo/Solanezumab Placebo 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). Solanezumab/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/Solanezumab 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).
- Primary Outcome Measures
Name Time Method Change From Baseline of the Preclinical Alzheimer Cognitive Composite (PACC) Score Baseline, Week 336 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.
- Secondary Outcome Measures
Name Time Method Change From Baseline in Alzheimer's Disease Cooperative Study-Activities Daily Living-Prevention Questionnaire (ADCS-ADL-Prevention Questionnaire) Score Baseline, Week 336 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.
Change From Baseline in Mean Composite Standardized Uptake Value Ratio (SUVr) Baseline, Week approximately 240 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
Change From Baseline in Cerebrospinal Fluid (CSF) Tau Biomarkers Baseline, Week approximately 240 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.
Change From Baseline on the Clinical Dementia Rating-Sum of Boxes Score (CDR-SB) Baseline, Week 336 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.
Change From Baseline of Cerebrospinal Fluid (CSF) Concentrations of Amyloid Beta (Aβ) Baseline, Week approximately 240 CSF biomarker concentrations were analyzed for Aβ 1-40 and Aβ 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.
Change From Baseline in Brain Volume as Measured by Volumetric Magnetic Resonance Imaging (vMRI) Baseline, Week approximately 240 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.
Change From Baseline in Cognitive Function Index (CFI) Baseline, Week 336 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.
Change From Baseline on the Computerized Cognitive Composite (C3) Baseline, Week 336 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.
Trial Locations
- Locations (65)
University of Pennsylvania Hospital
🇺🇸Philadelphia, Pennsylvania, United States
University of Kansas Hospital
🇺🇸Fairway, Kansas, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
Great Lakes Clinical Trials
🇺🇸Chicago, Illinois, United States
Banner Health Research Institute
🇺🇸Phoenix, Arizona, United States
Univ of California San Francisco
🇺🇸San Francisco, California, United States
Emory University
🇺🇸Atlanta, Georgia, United States
Indiana University School of Medicine
🇺🇸Indianapolis, Indiana, United States
Brigham and Womens Hospital
🇺🇸Boston, Massachusetts, United States
Boston University Medical Center
🇺🇸Boston, Massachusetts, United States
Cleveland Clinic of Las Vegas
🇺🇸Las Vegas, Nevada, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Baylor College of Medicine
🇺🇸Houston, Texas, United States
Houston Methodist
🇺🇸Houston, Texas, United States
University of Washington School of Medicine
🇺🇸Seattle, Washington, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Barrow Neurological Institute
🇺🇸Phoenix, Arizona, United States
Banner Sun Health Research Institute
🇺🇸Sun City, Arizona, United States
University of California - San Diego
🇺🇸La Jolla, California, United States
University of Southern California School of Medicine
🇺🇸Los Angeles, California, United States
Institute for Memory Impairment & Neurological Disorders
🇺🇸Irvine, California, United States
Veterans Affairs Medical Center Palo Alto
🇺🇸Palo Alto, California, United States
University of California - Los Angeles
🇺🇸Los Angeles, California, United States
Univ of California Irvine College of Medicine
🇺🇸Orange, California, United States
Syrentis Clinical Research
🇺🇸Santa Ana, California, United States
Georgetown University Hospital
🇺🇸Washington, District of Columbia, United States
University of California, Davis - Health Systems
🇺🇸Walnut Creek, California, United States
Howard University Hospital
🇺🇸Washington, District of Columbia, United States
Brain Matters Research
🇺🇸Delray Beach, Florida, United States
Mayo Clinic-Jacksonville
🇺🇸Jacksonville, Florida, United States
Wien Center for Clinical Research
🇺🇸Miami Beach, Florida, United States
Compass Research -The Villages
🇺🇸The Villages, Florida, United States
Premiere Research Institute at Palm Beach Neurology
🇺🇸West Palm Beach, Florida, United States
Rush Alzheimer's Disease Center
🇺🇸Chicago, Illinois, United States
University of Iowa
🇺🇸Iowa City, Iowa, United States
Pennington Biomedical Research Center
🇺🇸Baton Rouge, Louisiana, United States
Dent Neurological Institute
🇺🇸Amherst, New York, United States
New York University Medical Center
🇺🇸New York, New York, United States
Mount Sinai School of Medicine
🇺🇸New York, New York, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
Tulsa Clinical Research LLC
🇺🇸Tulsa, Oklahoma, United States
Drexel University College of Medicine at EPPI
🇺🇸Philadelphia, Pennsylvania, United States
University of Pittsburgh Medical Center
🇺🇸Pittsburgh, Pennsylvania, United States
Butler Hospital
🇺🇸Providence, Rhode Island, United States
University of Texas Southwestern Medical Center at Dallas
🇺🇸Dallas, Texas, United States
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, Canada
Sunnybrook Health Sciences Centre
🇨🇦Toronto, Canada
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, Japan
Johns Hopkins University School of Medicine
🇺🇸Baltimore, Maryland, United States
Case Western Reserve University
🇺🇸Beachwood, Ohio, United States
Weill Cornell Medical College
🇺🇸New York, New York, United States
Roper Hospital
🇺🇸Charleston, South Carolina, United States
Sutter Medical Group
🇺🇸Sacramento, California, United States
Wake Forest University School of Medicine
🇺🇸Winston-Salem, North Carolina, United States
Yale University School of Medicine
🇺🇸New Haven, Connecticut, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Compass Research - Orlando
🇺🇸Orlando, Florida, United States
University of South Florida
🇺🇸Tampa, Florida, United States
Univ of Nebraska Med Center
🇺🇸Omaha, Nebraska, United States
University of Kentucky
🇺🇸Lexington, Kentucky, United States
University of Rochester
🇺🇸Rochester, New York, United States
University of Wisconsin-Madison Hospital and Health Clinic
🇺🇸Madison, Wisconsin, United States
Rhode Island Hospital
🇺🇸Providence, Rhode Island, United States