Clinical trial NCT02843529: Evaluation of a Computerized Complex Instrumental Activities of Daily Living Marker (NMI)
Official title: Evaluation of a Computerized Complex Instrumental Activities of Daily Living Marker (NMI) as a Pre-Clinical or Pro-Dromal Alzheimers Diagnosis (Prognosis) for Optimum Outcomes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Alzheimer Disease
Mild Cognitive Impairment
Memory Disorders
Cognitive Impairment
Dementia
Presymptomatic Disease
Keywords: biomarkers
CSF
EEG
MRI
Digital biomarkers
Lead sponsor: Altoida
Sponsor class: INDUSTRY
Collaborators: name: Greek Alzheimer's Association and Related Disorders
name: University of Roma La Sapienza
name: IRCCS Centro San Giovanni di Dio Fatebenefratelli
name: Neuromed IRCCS
name: Scripps Health
name: Global Brain Health Institute (GBHI)
name: Takeda Pharmaceuticals International, Inc.
name: Research Center on Computational BioMarkers
name: Bioinformatics and Human Electrophysiology Laboratory
name: Fundacion Clinic per a la Recerca Biomédica
name: University of Dublin, Trinity College
name: University of Barcelona
name: EIT Health
name: Klinik Hirslanden, Zurich
name: The University of Texas at Dallas
First posted: 2016-07-26
Enrollment: 548
Sex: ALL
Minimum age (years): 55
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Adults at high risk of developing ALZ within 18-40 months (MCI) or cognitively normal for their age sex matching group. Risk factors include parents with a history of ALZ, and/or positive APOE4 alleles.
Primary purpose: DIAGNOSTIC

Brief summary: The proposed study is designed to evaluate the performance of the ALTOIDA™ System as a tool to assist physicians in diagnosing Alzheimer's Disease (AD) in real-world clinical settings. The design of this study is guided by two overriding factors: 1) to optimize the performance of the ALTOIDA™ Neuro Motor Index (NMI) prognosis classifiers, the subjects making up the training sets must be well characterized as to their clinical diagnosis, and 2) all ALTOIDA™ tests must be performed and reproduced in real-world clinical settings.

Although there is already a large body of peer-reviewed scientific literature demonstrating that certain digital biomarker patterns are associated with certain neurologic conditions, the utilization of such tools for the evaluation of neurologic disorders is still considered an emerging science and therefore in the investigational stage. Although this protocol will report on brain patterns of certain neurologic conditions such as cognitive impairment and Alzheimer's disease, based on patterns published in peer-reviewed journals, such findings are not considered stand alone or diagnostic per se and should always be considered by the primary physician in conjunction with the patient's clinical condition. These data should only be used as additional information to add to the primary physician's diagnostic impression.

Detailed description: The goal of the study is to determine relationships among the clinical, cognitive, imaging, genetic, and biochemical biomarker characteristics of the stage of the AD spectrum that precedes MCI, the mildest symptomatic phase of AD, referred to here as MCI. The ADNI-GO model posits that AD begins with amyloid β (Aβ) deposition in the cortex, which leads to synaptic dysfunction, neurodegeneration, and cognitive/ functional decline.

It may be possible to determine the future development of ALZ in a preclinical state in a cognitively normal but high risk individual at least 18-24 months before any symptoms develop of cognitive impairment. In addition a newly proposed research framework proposes to use biomarkers for amyloid, tau, and neurodegeneration (ATN) to classify MCI patients.

Some of the leading-edge technologies under study are brain-imaging techniques, such as positron emission tomography (PET), including FDG-PET (which measures glucose metabolism in the brain); PET using a radioactive compound (F-AV-45) that measures brain beta-amyloid; and structural MRI. Brain scans are showing scientists how the brain's structure and function change as AD starts and progresses. Biomarkers in cerebrospinal fluid are revealing other changes that could identify which patients with MCI will develop Alzheimer's. Scientists are looking at levels of beta-amyloid and tau in cerebrospinal fluid. (Abnormal amounts of the amyloid and tau proteins in the brain are hallmarks of Alzheimer's disease.)

The aim of the study is to evaluate the performance of the ALTOIDA™ System as as a tool to assist physicians in diagnosing Alzheimer's Disease (AD) in real-world clinical settings.

The study will be :

A. Multi-Center Study:

primary goal of this study will be to evaluate the ALTOIDA™ Platform across multiple study locations. This will demonstrate an ability to perform tests, collect data, and generate classifications irrespective of variations in testing locations and personnel.

12 international study sites will be selected with the US based sites being a recognized NIH Center of Excellence for Alzheimer's disease or other nationally recognized Alzheimer's disease research center. Each site will evaluate up to 60 community dwellers evenly divided between MCI patients and age-matched controls (while the prevalence of AD is approximately 12% in the general population, the ratio of AD to normal among those who visit a clinic for memory or cognitive related issues is between 50-60%).

Each site will follow the same testing protocols. Participants will be asked if they would like to participate in a protocol that monitors their prospective risk for developing ALZ short term, and whether certain of their prescribed medications may have a protective effect. Those who are accepting to be participants are then enrolled in the study.

Enrollees will be tested for risk factors for having pre-clinical ALZ. Individuals identified as being at risk at baseline are followed at 6 month intervals for a 48 month period using psychometric testing and functional neuroimaging. Their maintenance of cognitive stability or cognitive decline is monitored while under the care of their PMD and while taking medications of interest.

All test data will be uploaded to the online ALTOIDA™ database server.

B. The overall impact of this study will be increased knowledge concerning the sequence and timing of events leading to MCI and from MCI to AD, development of better clinical and Neuro Motor Index prognosis methods for early detection and for monitoring the progression of these conditions, and facilitation of clinical trials of treatments to slow disease progression, ultimately contributing to the prevention of AD.

Eligibility criteria: Inclusion Criteria:

* Between 55 and 90 years of age
* Study partner to accompany patient to all clinic visits for the duration of the protocol
* Memory complaint by patient and/or study partner
* Abnormal memory function score on Wechsler Memory Scale (adjusted for education)
* Mini-Mental State Exam score between 24 and 30 (inclusive)
* Clinical Dementia Rating = 0.5; Memory Box score 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 the following permitted medications for 4 weeks (unless stated otherwise):
* Antidepressants lacking significant anticholinergic side effects
* Estrogen replacement therapy
* 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
* Cholinesterase inhibitors and memantine if stable for 12 weeks prior to screening
* Geriatric Depression Scale less than 6
* Visual and auditory acuity adequate for neuropsychological testing
* Good general health with no diseases expected to interfere with the study
* Not pregnant, lactating, or of childbearing potential (i.e. women must be two years post-menopausal or surgically sterile)
* Hachinski less than or equal to 4
* Six grade education or has a good work history (sufficient to exclude mental retardation)
* Fluent in English or Spanish
* Agrees to at least one lumbar puncture for the collection of CSF
* Willing and able to complete all baseline assessments
* Willing to undergo repeated MRIs and at least two PET scans and willing to provide DNA and plasma samples as specified
* Willing and able to participate in a longitudinal imaging study

Exclusion Criteria:

* 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 defaults or known structural brain abnormalities
* Screening/baseline MRI scans with evidence of infection, infarction, or other focal lesions; multiple lacunes or lacunes in a critical memory structure
* Presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, 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 which could lead to difficulty complying with the protocol
* History of schizophrenia
* History of alcohol or substance abuse or dependence within the past 2 years
* Any significant systemic illness or unstable medical condition which could lead to difficulty complying with the protocol
* Clinically significant abnormalities in B12, or TFTs that might interfere with the study
* Residence in skilled nursing facility
* Current use of specific psychoactive medications (e.g.,certain antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.); current use of warfarin (exclusionary for lumbar puncture)
* Use of investigational agents one month prior to entry and for the duration of the trial
* Exclusion for amyloid imaging with 18F -AV-45: Current or recent participation in any procedures involving radioactive agents such that the total radiation dose exposure to the participant in any given year would exceed the limits of annual and total dose commitment set forth in the US Code of Federal Regulations (CFR) Title 21 Section 361.1
* Exceptions to these guidelines may be considered on a case-by-case basis at the discretion of the protocol director

Primary outcomes:
measure: Change in Diagnostic Area Under the Receiver Operating Characteristic Curve (ROC-AUC)
timeFrame: approximately 40 months follow up
Secondary outcomes:
measure: Change From Baseline in Clinical Measure 1
timeFrame: baseline, 6, 12, 24, 36 and 42 months of follow up
measure: Change From Baseline in Clinical Measure 2
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Change From Baseline in Clinical Measure 3
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Change From Baseline in Clinical Measure 4
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Change From Baseline in Clinical Measure 5
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Change From Baseline in Clinical Measure 6
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Change From Baseline in Clinical Measure 7
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Change From Baseline in Cognitive Measure
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Change From Baseline in Cognitive Measure
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Change From Baseline in Cognitive Measure
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Change From Baseline in Cognitive Measure
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Change From Baseline in Cognitive Measure
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Change From Baseline in Cognitive Measure
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Change From Baseline in Cognitive Measure
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Change From Baseline in Cognitive Measure
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Change From Baseline in Cognitive Measure
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Change From Baseline in Cognitive Measure
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Change From Baseline in Cognitive Measure
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Change From Baseline in Cognitive Measure
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Secondary Resting State EEG Endpoints
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Secondary Resting State Auditory Oddball ERP Endpoints
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Total Abeta 1-42 (Aβ42) Amyloid Deposition
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Change of Brain Amyloid Deposition
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Change of CSF Biomarkers Tau and ptau181 Values
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: MRI (Optional)
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Changes in Driving Breaking Force
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Changes in Driving Acceleration Velocity
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Changes in Driving Direction
timeFrame: baseline, 6, 12, 24, 36 and approximately 40 months follow up
measure: Changes in Driving Violations
timeFrame: Continuous measurement for approximately 12 months follow up
Other outcomes:
Locations:
Study officials:
affiliation: Scripps Clinic La Jolla Poole Building
name: Mark Wiederhold, PhD
role: STUDY_CHAIR
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