Alzheimer's Disease Neuroimaging Initiative 3 (ADNI3) Protocol

Sponsor

University of Southern California (Other)

Overall Status

Recruiting

CT.gov ID

NCT02854033

Collaborator

Northern California Institute of Research and Education (Other), National Institute on Aging (NIA) (NIH), Alzheimer's Therapeutic Research Institute (Other)

2,000

Enrollment

Locations

Duration (Months)

33.9

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Since its launch in 2004, the overarching aim of the Alzheimer's Disease Neuroimaging Initiative (ADNI) has been realized in informing the design of therapeutic trials in AD. ADNI3 continues the previously funded ADNI-1, ADNI-GO, and ADNI-2 studies that have been combined public/private collaborations between academia and industry to determine the relationships between the clinical, cognitive, imaging, genetic and biochemical biomarker characteristics of the entire spectrum of Alzheimer's disease (AD). The overall goal of the study is to continue to discover, optimize, standardize, and validate clinical trial measures and biomarkers used in AD research.

Condition or Disease	Intervention/Treatment	Phase
Mild Cognitive Impairment (MCI) Alzheimer's Disease (AD)

Detailed Description

The overall goal of ADNI3 is to determine the relationships among the clinical, cognitive, imaging, genetic and biochemical biomarker characteristics of the entire spectrum of Alzheimer's disease (AD), as the pathology evolves from normal aging through very mild symptoms, to mild cognitive impairment (MCI), to dementia. ADNI3 continues the previously funded AD Neuroimaging Initiative (ADNI1, ADNI-GO, and ADNI-2), and remains a public/private collaboration between academia and industry to study biomarkers of AD. ADNI will continue to inform the neuroscience of AD, identify diagnostic and prognostic markers, identify outcome measures that can be used in clinical trials, and help develop the most effective clinical trial scenarios.

This is multi-center, a non-randomized, natural history, non-treatment study. 1,070-2,000 total participants will be enrolled across three cohorts: cognitively normal* (CN), mild cognitive impairment (MCI) and mild Alzheimer's Disease (AD) dementia. Participants between the ages of 55-90 (inclusive) will be enrolled at 59 sites in the United States and Canada. Approximately, 700 - 800 will be rollover participants from previous ADNI studies, and 370 - 1200 will be newly enrolled. Clinical/cognitive, imaging, biomarker, and genetic characteristics will be assessed across the three cohorts.

Participants will undergo longitudinal clinical and cognitive assessments, computerized cognitive batteries, biomarker and genetic tests, PET (FDG, amyloid and tau) and MRI scans and cerebral spinal fluid (CSF) collection for up to 5 years.

*currently recruiting non-Caucasian participants only for the cognitively normal cohort.

Study Design

Study Type:

Observational

Anticipated Enrollment :

2000 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Alzheimer's Disease Neuroimaging Initiative 3 (ADNI3) Protocol

Study Start Date :

Oct 1, 2016

Anticipated Primary Completion Date :

Jul 1, 2022

Anticipated Study Completion Date :

Jul 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Cognitively Normal (CN) 135-500 newly enrolled participants with no apparent memory problems, and 295-300 cognitively normal participants followed from the ADNI2 study. Currently recruiting non-Caucasian participants only for the normal cognition group.
Mild Cognitive Impairment (MCI) 150 - 515 newly enrolled participants with mild cognitive impairment (MCI), and 275-320 MCI participants followed from the ADNI2 study.
Mild Alzheimer's Disease (AD) dementia 85 - 185 newly enrolled participants with mild Alzheimer's disease (AD) dementia, and 130 - 150 mild AD participants followed from the ADNI2 study.

Outcome Measures

Primary Outcome Measures

Rate of change in cognition as measured by the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog13) [5 years]
The ADAS-Cog is an in-person examiner-administered, structured scale that evaluates memory (word recall, word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational praxis (placing letter in envelope) and constructional praxis (copying geometric designs). Ratings of spoken language, language comprehension, word finding difficulty, and ability to remember test instructions are also obtained.
Rate of change in cognition as measured by the Logical Memory Test I and II [5 years]
Rate of change in cognition as measured by the Mini-Mental State Examinations (MMSE) [5 years]
The MMSE scale evaluates orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy two overlapping pentagons.

Secondary Outcome Measures

Rate of change in cognition as measured by the Cogstate Brief Battery (CBB) [5 years]
The Cogstate Brief battery (CBB) is a brief (10-15 minute) computerized cognitive battery developed by Cogstate (Cogstate Ltd. New Haven, CT, USA) that measures attention, speed of information processing, working memory and learning.
Rate of change in cognition as measured by the American National Adult Reading Test (ANART) [5 years]
The ANART estimates premorbid verbal intelligence (VIQ) in patients with dementia.
Rate of change in cognition as measured by the Montreal Cognitive Assessment (MoCA) [5 years]
The Montreal Cognitive Assessment test (MoCA) is a cognitive assessment designed to detect participants at the MCI stage of cognitive dysfunction.
Rate of change in cognition as measured by the Rey Auditory Verbal Learning Test [5 years]
The AVLT is a list-learning task, which assesses multiple cognitive parameters associated with learning and memory.
Rate of change in cognition as measured by the Trail Making Test: A and B [5 years]
Change in tau deposition as measured by 18F-AV-1451 [5 years]
Change in amyloid deposition as measured by Florbetapir [5 years]
Change in amyloid deposition as measured by Florbetaben [5 years]
Rate of conversion to MCI or dementia due to AD [5 years]
Rates of change of glucose metabolism (FDG-PET) [5 years]
Change in Cerebral Spinal Fluid (CSF) Tau Biomarkers [5 years]
Change in brain structure using magnetic resonance imaging (MRI) [5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

55 Years to 90 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria (all CN participants):

Participant with or without subjective memory complaints, verified by a study partner, beyond what one would expect for age
Normal memory function documented by scoring above education adjusted cutoffs on the Logical Memory II subscale (Delayed Paragraph Recall, Paragraph A only) from the

Wechsler Memory Scale -Revised (the maximum score is 25):

9 for 16 or more years of education
5 for 8-15 years of education
3 for 0-7 years of education
Mini-Mental State Exam score between 24 and 30 inclusive (Exceptions may be made for participants with less than 8 years of education at the discretion of the Project Director)
Clinical Dementia Rating = 0. Memory Box score must be 0
Cognitively normal, based on an absence of significant impairment in cognitive functions or activities of daily living
Stability of Permitted Medications for at least 4 weeks:
Stable doses of antidepressants lacking significant anticholinergic side effects (if they are currently adequately treated for depressive symptoms and do not have a history of major depression within the past 1 years)
Estrogen replacement therapy is permissible
Gingko biloba is permissible, but discouraged
Washout from psychoactive medication (e.g., excluded antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.) for at least 4 weeks prior to screening.

Inclusion Criteria (all MCI participants):

Participant must express a subjective memory concern as reported by participant, or recalled by study partner or clinician.
Abnormal memory function documented by scoring below education adjusted cutoffs on the Logical Memory II subscale (Delayed Paragraph Recall, Paragraph A only) from the

Wechsler Memory Scale -Revised (the maximum score is 25):

< 11 for 16 or more years of education b. ≤ 9 for 8-15 years of education c. ≤ 6 for 0-7 years of education

Mini-Mental State Exam score between 24 and 30 inclusive (Exceptions may be made for participants with less than 8 years of education at the discretion of the Project Director)
Clinical Dementia Rating = 0.5. Memory Box score must be at least 0.5
General cognition and functional performance sufficiently preserved such that a diagnosis of Alzheimer's disease cannot be made by the site physician at the time of the Screening Visit
Stability of Permitted Medications for at least 4 weeks:
Stable doses of antidepressants lacking significant anticholinergic side effects (if they are currently adequately treated for depressive symptoms and do not have a history of major depression within the past 1 years)
Cholinesterase inhibitors and memantine are allowable if stable for 12 weeks prior to Screening Visit
Estrogen replacement therapy is permissible
Gingko biloba is permissible, but discouraged
Washout from psychoactive medication (e.g., excluded antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.) for at least 4 weeks prior to screening.

Inclusion Criteria (all AD participants):

Participant must express a subjective memory concern as reported by participant, or recalled by study partner or clinician.n.
Abnormal memory function documented by scoring below education adjusted cutoffs on the Logical Memory II subscale (Delayed Paragraph Recall, Paragraph A only) from the

Wechsler Memory Scale -Revised (the maximum score is 25):

≤ 8 for 16 or more years of education
≤ 4 for 8-15 years of education
≤ 2 for 0-7 years of education
Mini-Mental State Exam score between 20 and 26 inclusive (Exceptions may be made for participants with less than 8 years of education at the discretion of the Project Director)
Clinical Dementia Rating = 0.5 or 1.0
NINCDS (National Institute of Neurological and Communicative Disorders and Stroke) -ADRDA (Alzheimer's Disease and Related Disorders Association) criteria for probable AD
Stability of Permitted Medications for at least 4 weeks:
Stable doses of antidepressants lacking significant anticholinergic side effects (if they are currently adequately treated for depressive symptoms and do not have a history of major depression within the past 1 years)
Cholinesterase inhibitors and memantine are allowable if stable for 12 weeks prior to Screening Visit
Estrogen replacement therapy is permissible
Gingko biloba is permissible, but discouraged
Washout from psychoactive medication (e.g., excluded antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.) for at least 4 weeks prior to screening.

Inclusion Criteria Specific to Newly Enrolled Participants

Geriatric Depression Scale score less than 6.
Age between 55-90 years (inclusive).
Study partner who has frequent contact with the participant (i.e., minimum average of 10 hours per week) and is available to accompany the participant to all clinic visits for the duration of the protocol.
Visual and auditory acuity adequate for neuropsychological testing.
Good general health with no diseases expected to interfere with the study.
Participant is not pregnant, lactating, or of childbearing potential (i.e. women must be two years post-menopausal or surgically sterile).
Willing and able to participate in a longitudinal imaging study.
Modified Hachinski Ischemic Score less than or equal to 4.
Completed six grades of education or has a good work history (sufficient to exclude mental retardation).
Must speak English or Spanish fluently.
Willing to undergo repeated MRIs (3Tesla) and at least two PET scans
Agrees to collection of blood for genomic analysis (including GWAS (genome-wide association study) sequencing and other analysis), APOE (Apolipoprotein E) testing and biospecimen banking.
Agrees to collection of blood for biomarker testing.
Agrees to at least one lumbar puncture for the collection of CSF.
Agrees to share genomic data and biomarker samples. Inclusion Criteria Specific to Rollover Participants"

The following additional inclusion criteria apply to all diagnostic categories for rollover participants only:

Must have been enrolled and followed in ADNI-1, ADNI-GO, or ADNI-2 for at least one year.
Willing and able to continue to participate in an ongoing longitudinal study. A reduced battery of tests is allowable if the participant is not able/willing to complete the full battery.

Exclusion Criteria (all CN participants):

Any significant neurologic disease, such as Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic deficits or known structural brain abnormalities

Exclusion Criteria (all MCI participants):

Any significant neurologic disease other than suspected incipient Alzheimer's disease, such as Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic deficits or known structural brain abnormalities.

Exclusion Criteria (all AD participants):

Any significant neurologic disease other than Alzheimer's disease, such as Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic deficits or known structural brain abnormalities.

Exclusion Criteria (all participants):

The following additional exclusion criteria apply to all diagnostic categories:

Screening/Baseline MRI brain scan with evidence of infection, infarction, or other focal lesions or multiple lacunes or lacunes in a critical memory structure
Subjects that have any contraindications for MRI studies, including the presence of cardiac pacemakers, or metal fragments or foreign objects in the eyes, skin or body.
Major depression, bipolar disorder as described in DSM-IV within the past 1 year. Psychotic features, agitation or behavioral problems within the last 3 months that could lead to difficulty complying with the protocol.
Currently treated with medication for obsessive-compulsive disorder or attention deficit disorder.
History of schizophrenia (DSM IV criteria).
History of alcohol or substance abuse or dependence within the past 2 years (DSM IV criteria).
Any significant systemic illness or unstable medical condition, which could lead to difficulty complying with the protocol.
Clinically significant abnormalities in B12 or thyroid function tests (TFTs) that might interfere with the study. A low B12 is exclusionary, unless follow-up labs (homocysteine (HC) and methylmalonic acid (MMA)) indicate that it is not physiologically significant.
Residence in a skilled nursing facility.
Current use of specific psychoactive medications (e.g., certain antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics). Current use of warfarin or other anticoagulants such as dabigatran, rivaroxaban and apixaban (exclusionary for lumbar puncture).
Current use of any other exclusionary medications
Investigational agents are prohibited one month prior to entry and for the duration of the trial.
Participation in clinical studies involving neuropsychological measures being collected more than one time per year.

Exclusion Criteria Specific to AV-1451 PET:

The following criteria are exclusionary only for the AV-1451 scanning portion of the study:

History of risk factors for torsades de pointes (a cardiac dysrhythmia associated with sudden death) or taking medications known to prolong the QT interval. A list of restricted medications will be provided.
Have an ECG obtained prior to the AV-1451 PET scan that in the opinion of the investigator is clinically significant with regard to the subject's participation in the study. Bazett's corrected QT (QTcB) interval must be evaluated and must not exceed 458 msec in males, or 474 msec in females.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama, Birmingham	Birmingham	Alabama	United States	35294
2	Banner Alzheimer's Institute	Phoenix	Arizona	United States	85006
3	Barrow Neurological Institute	Phoenix	Arizona	United States	85013
4	Banner Sun Health Research Institute	Sun City	Arizona	United States	85351
5	University of California, Irvine	Irvine	California	United States	92697
6	University of California, San Diego	La Jolla	California	United States	920371707
7	Long Beach VA Neuropsychiatric Research Program	Long Beach	California	United States	90822
8	University of Southern California	Los Angeles	California	United States	900335310
9	University of California, Los Angeles	Los Angeles	California	United States	90095
10	VA Palo Alto HSC / Stanford School of Medicine	Palo Alto	California	United States	94304
11	University of California, San Francisco	San Francisco	California	United States	94158
12	University of California, Davis	Walnut Creek	California	United States	945985900
13	Yale University School of Medicine	New Haven	Connecticut	United States	65103330
14	Georgetown University	Washington	District of Columbia	United States	200072145
15	Howard University	Washington	District of Columbia	United States	200600001
16	Mayo Clinic, Jacksonville	Jacksonville	Florida	United States	32224
17	Wien Center for Clinical Research	Miami Beach	Florida	United States	331402877
18	University of South Florida - Health Byrd Alzheimer Institute	Tampa	Florida	United States	336134808
19	Emory University	Atlanta	Georgia	United States	30322
20	Northwestern University	Chicago	Illinois	United States	606113010
21	Rush University Medical Center	Chicago	Illinois	United States	606123806
22	Indiana University	Indianapolis	Indiana	United States	46202
23	University of Iowa	Iowa City	Iowa	United States	52242
24	University of Kansas	Fairway	Kansas	United States	66205
25	University of Kentucky	Lexington	Kentucky	United States	405042681
26	Johns Hopkins University	Baltimore	Maryland	United States	212242764
27	Brigham and Women's Hospital	Boston	Massachusetts	United States	21155804
28	Boston University School of Medicine	Boston	Massachusetts	United States	21182307
29	University of Michigan, Ann Arbor	Ann Arbor	Michigan	United States	481052967
30	Mayo Clinic, Rochester	Rochester	Minnesota	United States	559050001
31	Washington University, St. Louis	Saint Louis	Missouri	United States	631082215
32	Cleveland Clinic Lou Ruvo Center for Brain Health	Las Vegas	Nevada	United States	891060100
33	Albany Medical College	Albany	New York	United States	12208
34	Dent Neurologic Institute	Buffalo	New York	United States	142261727
35	New York University Medical Center	New York	New York	United States	100166055
36	Mount Sinai School of Medicine	New York	New York	United States	100296552
37	Columbia University	New York	New York	United States	10032
38	Nathan Kline Institute for Psychiatric Research	Orangeburg	New York	United States	109621159
39	University of Rochester	Rochester	New York	United States	14620
40	Duke University Medical Center	Durham	North Carolina	United States	27710
41	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
42	Case Western Reserve University	Beachwood	Ohio	United States	441224312
43	Ohio State University	Columbus	Ohio	United States	43210
44	Oregon Health & Science University	Portland	Oregon	United States	972393011
45	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
46	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
47	Rhode Island Hospital	Providence	Rhode Island	United States	02903
48	Butler Hospital Memory and Aging Program	Providence	Rhode Island	United States	02906
49	Roper St. Francis Hospital	Charleston	South Carolina	United States	29401
50	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37212
51	University of Texas, Southwestern MC at Dallas	Dallas	Texas	United States	75390
52	Baylor College of Medicine	Houston	Texas	United States	77030
53	Houston Methodist	Houston	Texas	United States	77030
54	University of Wisconsin	Madison	Wisconsin	United States	537920001
55	University of British Columbia, Clinic for AD & Related	Vancouver	British Columbia	Canada	V6T1Z3
56	Parkwood Institute	London	Ontario	Canada	N6C 0A7
57	St. Joseph's Health Center - Cognitive Neurology	London	Ontario	Canada	N6C 4R3
58	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N 3M5
59	Jewish General Hospital Memory Clinic	Montreal	Quebec	Canada	H3T 1E2

Sponsors and Collaborators

University of Southern California
Northern California Institute of Research and Education
National Institute on Aging (NIA)
Alzheimer's Therapeutic Research Institute

Investigators

Study Director: Michael W. Weiner, MD, University of California, San Francisco
Principal Investigator: Paul Aisen, MD, USC Alzheimer's Therapeutic Research Institute (ATRI)
Principal Investigator: Ronald Peterson, MD, PHD, Mayo Clinic