Clinical trial NCT02488720: Longitudinal Evaluation of Amyloid Risk and Neurodegeneration - the LEARN Study
Official title: Longitudinal Evaluation of Amyloid Risk and Neurodegeneration - the LEARN Study. A Companion Observational Study to Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Trial
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Cognition Disorders
Keywords: amyloid imaging
biomarkers
cognition
longitudinal
cognitive decline
observational
Lead sponsor: University of Southern California
Sponsor class: OTHER
Collaborators: name: Alzheimer's Association
name: National Institute on Aging (NIA)
name: Alzheimer's Therapeutic Research Institute
First posted: 2015-07-02
Enrollment: 538
Sex: ALL
Minimum age (years): 65
Maximum age (years): 85
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: 500 subjects without evidence of elevated ABeta on screening PET scan. Subjects will have consented to participate in the A4 trial and previously met demographic, cognitive and clinical criteria and have an A4 screening PET scan results that fallows below the ABeta threshold levels required for randomization into the treatment arms for the A4 trials.

Brief summary: The LEARN study a multicenter, observational study will that will evaluate the rate of cognitive change in approximately 500 clinically normal older individuals who "screen-fail" for the A4 trial on the basis of their screening PET imaging not demonstrating evidence of elevated amyloid accumulation (Aβ negative) but meet all other A4 study eligibility criteria. This study will leverage the A4 infrastructure and maximize the data acquired in screening a large number of well-characterized older adults for the A4 trial.

The LEARN observational cohort will provide a critical comparison group for the A4 placebo arm, and future trials in preclinical AD. Although accumulating longitudinal data suggest that older individuals with elevated Aβ burden are at increased risk of cognitive decline, it is important to demonstrate a differential rate of clinical decline between Aβe ("Aβ elevated") and Aβne ("Aβ not elevated") individuals on a standardized set of clinical outcomes. Over 2000 well-characterized, highly motivated older volunteers will "screen fail" for the A4 trial. The LEARN study will follow 500 of these individuals, matched as closely as possible to the two treatment arms, in this observation cohort. The LEARN study may selectively recruit from a specific range of SUVr that fall below the threshold for "elevated amyloid" in order to support analyses of the relationship of baseline SUVr to subsequent cognitive change and amyloid accumulation. The observational cohort will be followed for 384 weeks with identical clinical/cognitive testing performed every 24 weeks, running parallel to the A4 treatment study and open label extension.


Eligibility criteria: Inclusion Criteria:

1. Consented to participate in the A4 study and previously met A4 demographic, cognitive and clinical criteria (e.g., Mini-Mental State Examination (MMSE); Clinical Dementia Ratin (CDR); Logical Memory test, part IIa (LMIIa); medications; medical history).
2. Has a florbetapir PET scan that falls below the Aβ threshold levels required for randomization into the treatment arms of the A4 trial.
3. In general, permitted medications should be stable for 8 weeks prior to LEARN Visit 1. Changes to medications that, in the opinion of the investigator, are not likely to impact LEARN Visit 1 assessments are permissible.
4. Has a study partner that is willing to participate as a source of information and has at least weekly contact with the subject (contact can be in-person, via telephone or electronic communication). The study partner must have sufficient contact such that the investigator feels the study partner can provide meaningful information about the subject's daily function.
5. In the investigator's opinion, is both willing and able to participate in all required procedures for the duration of the study (at least 240 weeks), including adequate literacy in English or Spanish and adequate vision and hearing to complete the required psychometric tests.

Exclusion Criteria:

1. Is receiving a prescription acetylcholinesterase inhibitor (AChEI) and/or memantine at LEARN Visit 1
2. 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.
3. Has any contraindications for MRI studies, including claustrophobia, the presence of metal (ferromagnetic) implants, or a cardiac pacemaker that is not compatible with MRI.
4. Has a LEARN Visit 1 MRI scan with results showing \>4 hemosiderin deposits (definite microhemorrhages or areas of superficial siderosis); or any amyloid-related imaging abnormalities - edema/effusions (ARIA-E).
5. Has received any exclusionary medication, including those with significant central nervous system (CNS) anticholinergic effects, within 3 months prior to LEARN Visit 1 or initiated at any point after screen. A full list of exclusionary medication will be provided in the relevant procedures manual.
6. Is currently enrolled in a clinical trial involving an investigational product or non-approved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. Participation in observational studies may be permitted upon review of the observational study protocol and approval by the Project Director or one of the ADCS Medical Monitors.

   For subjects participating in the optional Lumbar Puncture (LP, all of the above, plus:
7. Current use of anticoagulants, such as warfarin or dabigatran.

Primary outcomes:
measure: Change from Baseline of the ADCS Preclinical Alzheimer Cognitive Composite (ADCS-PACC) to Week 240
timeFrame: 4.5 years
Secondary outcomes:
measure: Change from Baseline in Cognitive Function Index (CFI) to Week 240
timeFrame: 4.5 years
measure: Change from Baseline in Mean Composite Summary Uptake Value Ratio (SUVr) to Week 240
timeFrame: 4.5 years
measure: Change from Baseline in Cerebral Spinal Fluid (CSF) Tau Biomarkers to Week 240
timeFrame: 4.5 years
measure: Change from Baseline of Cerebrospinal Fluid (CSF) Concentrations of Amyloid Beta (Abeta) to Week 240
timeFrame: 4.5 years
measure: Change from Baseline of Volumetric Magnetic Resonance Imaging (vMRI) to Week 240
timeFrame: 4.5 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama, Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Banner Alzheimer's Institute
state: Arizona
city: Sun City
country: United States
facility: Banner Sun Health Research Institute
state: Arizona
city: Irvine
country: United States
facility: University of California, Irvine
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: Palo Alto
country: United States
facility: VA Palo Alto HSC / Stanford School of Medicine
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Washington
country: United States
facility: Howard University
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic, Jacksonville
state: Florida
city: Miami Beach
country: United States
facility: Wien Center for Clinical Research
state: Florida
city: Orlando
country: United States
facility: Synexus Clinical Research
state: Florida
city: Tampa
country: United States
facility: University of South Florida - Health Byrd Alzheimer Institute
state: Florida
city: The Villages
country: United States
facility: Synexus Clinical Research - The Villages
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Fairway
country: United States
facility: University of Kansas
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston University
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan, Ann Arbor
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic, Rochester
state: Minnesota
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Las Vegas
country: United States
facility: Cleveland Clinic Lou Ruvo Center for Brain Health
state: Nevada
city: Amherst
country: United States
facility: Dent Neurologic Institute
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Beachwood
country: United States
facility: Case Western Reserve University
state: Ohio
city: Tulsa
country: United States
facility: Central States Research
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Providence
country: United States
facility: Butler Hospital Memory and Aging Program
state: Rhode Island
city: Charleston
country: United States
facility: Roper St. Francis Healthcare
state: South Carolina
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
Study officials:
affiliation: Center for Alzheimer Research and Treatment Brigham and Women's Hospital
name: Reisa Sperling, MD
role: STUDY_DIRECTOR
References:
citation: Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):280-92. doi: 10.1016/j.jalz.2011.03.003. Epub 2011 Apr 21.
citation: Vos SJ, Xiong C, Visser PJ, Jasielec MS, Hassenstab J, Grant EA, Cairns NJ, Morris JC, Holtzman DM, Fagan AM. Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study. Lancet Neurol. 2013 Oct;12(10):957-65. doi: 10.1016/S1474-4422(13)70194-7. Epub 2013 Sep 4.
citation: Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010 Jan;9(1):119-28. doi: 10.1016/S1474-4422(09)70299-6.
citation: Mormino EC, Betensky RA, Hedden T, Schultz AP, Amariglio RE, Rentz DM, Johnson KA, Sperling RA. Synergistic effect of beta-amyloid and neurodegeneration on cognitive decline in clinically normal individuals. JAMA Neurol. 2014 Nov;71(11):1379-85. doi: 10.1001/jamaneurol.2014.2031.
citation: Knopman DS, Jack CR Jr, Wiste HJ, Weigand SD, Vemuri P, Lowe V, Kantarci K, Gunter JL, Senjem ML, Ivnik RJ, Roberts RO, Boeve BF, Petersen RC. Short-term clinical outcomes for stages of NIA-AA preclinical Alzheimer disease. Neurology. 2012 May 15;78(20):1576-82. doi: 10.1212/WNL.0b013e3182563bbe. Epub 2012 May 2.
citation: Lim YY, Pietrzak RH, Ellis KA, Jaeger J, Harrington K, Ashwood T, Szoeke C, Martins RN, Bush AI, Masters CL, Rowe CC, Villemagne VL, Ames D, Darby D, Maruff P. Rapid decline in episodic memory in healthy older adults with high amyloid-beta. J Alzheimers Dis. 2013;33(3):675-9. doi: 10.3233/JAD-2012-121516.