A Longitudinal Evaluation of a Radiotracer for Use in Tau Tracking

Study Overview
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Brief Summary
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This is a longitudinal, observational study evaluating the imaging characteristics of the tau PET radioligand [18F]MK-6240 in Alzheimer's disease (AD), Mild Cognitive Impairment (MCI) and Healthy Volunteer (HV) subjects. Up to 42 subjects, including approximately 28 MCI/mild AD subjects, up to 5 moderate AD subjects, and 9 similarly aged HV subjects will be consented and screened. Imaging procedures include [11C]PiB to evaluate amyloid deposition, [18F]MK-6240 PET, and structural MRI. All subjects complete an evaluable baseline [18F]MK-6240 PET scan, as well as scans at 6, 12 and 24 months post-baseline. If unable to complete the 6 month, 12 month, or 24 month visit, an 18 month and/or 30 month visit may instead be scheduled, totaling a maximum of four time points.

Official Title
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Longitudinal Evaluation of [18-F]MK-6240 as a Novel Tau PET Radiotracer in Patients With Alzheimer's Disease Dementia or Mild Cognitive Impairment Compared to Healthy Volunteers

Conditions
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Alzheimer Disease, Mild Cognitive Impairment

Intervention / Treatment
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* Drug: All Subjects


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for all subjects: Signed and dated written informed consent must be obtained from the subject to enter the study and before any assessment is performed. Pregnancy: Participant is not pregnant at the time of the PET and MRI imaging exams. Urine pregnancy tests will be conducted as needed with pre-menopausal women who are of child-bearing potential. Willing and able to undergo study procedures and study schedule Availability of a study partner who has frequent and sufficient contact with the subject and is able to provide accurate information regarding the subject's cognitive and functional abilities for the CDR, agrees to accompany the subject and provide information at visits or is available by phone. The study partner must have sufficient cognitive capacity, in the judgment of the investigator, to accurately report upon the subject's behavior and cognitive and functional abilities. Healthy with no clinically relevant finding on physical examination at screening and upon reporting for the Baseline [18F]MK-6240 imaging visit. Inclusion Criteria for Healthy Volunteers Normal Cognition based on cognitive results at screening. Healthy with no clinically relevant finding on physical examination at screening and upon reporting for the Baseline [18F]MK-6240 imaging visit. CDR global score =0 Inclusion Criteria for Subjects with a Diagnosis of MCI or Dementia Due to AD Have screening [11C]PiB PET imaging demonstrating amyloid binding based on qualitative read or DVR index value >1.20. MMSE score 26-30 (inclusive), CDR global score 0.5 for subjects with MCI MMSE score 22-26 (inclusive), CDR global score 0.5 or 1 for subjects with mild dementia due to AD MMSE score 16-21 (inclusive), CDR global score 1-2 for subjects with moderate dementia due to AD Subjects with MCI must meet 2018 research criteria for MCI (Jack et al., 2018). Subjects with dementia must meet 2018 research criteria for dementia (Jack et al., 2018). A structural brain MRI with no evidence of non-AD disease to account for dementia or MRI exclusion criteria. Exclusion Criteria for all subjects Lack of capacity to provide informed consent at study entry. Subject has received an investigational drug or device within 30 days of screening. Other experimental PET radiotracer drugs are not excluded. For women, pregnant, lactating or breastfeeding or intention to become pregnant. Evidence of unstable or untreated clinically significant gastrointestinal, cardiovascular, hepatic, renal, hematological, neoplastic, endocrine, alternative neurological, immunodeficiency, pulmonary, or other disorder or disease. Stable, treated chronic medical conditions like hypertension, hypercholesterolemia, diabetes mellitus, non-metastatic dermatologic or prostatic cancer, etc. are acceptable as long as they do not, in the study investigator's opinion, contribute to cognitive dysfunction or limit participation in study procedures. Any illness or other consideration that makes it unlikely that the subject will be able to complete the 26-month study. Current or prior history (within past 5 years) of significant alcohol or substance abuse as determined by the investigator. Psychiatric disorders that may interfere with the study including current major Axis I DSM-V disorders including but not limited to severe Major depression, current or history of bipolar I disorder, or schizophrenia. Non-English speakers or subjects who are unable to comprehend study materials are excluded at entry MRI exclusion criteria include: Findings that may be responsible for neurologic status of the subject such as significant evidence of cerebrovascular disease with multiple infarcts, infectious disease, space-occupying lesion, normal pressure hydrocephalus, CNS trauma, or any other structural abnormality that may impact cognition or image analysis, as judged by the investigator. MRI-incompatible implants or devices such as certain cardiac pacemakers or defibrillators, insulin pumps, cochlear implants, metallic ocular foreign body, implanted neural stimulators, CNS aneurysm clips and other medical implants that have not been certified for MRI, or history of claustrophobia in MRI that prevents completion of MRI protocol. Treatment with any therapeutic molecule that targets Aβ or tau within 12 months prior to screening.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All Subjects<br>All subjects will complete PET imaging sessions evaluating the tau PET radioligand [18F]MK-6240 at baseline, as well as at 6, 12 and 24 months post-baseline. If unable to complete the 6 month, 12 month, or 24 month visit, an 18 month and/or 30 month visit may instead be scheduled, totaling a maximum of four time points. | Drug: All Subjects<br>* All subjects will be given the experimental tau PET radioligand [18F]MK-6240<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in [18F]MK-6240 Standard Uptake Value Ratio (SUVR) Uptake | Composite mean SUVR across standard regions including: numerator was the entorhinal, amygdala, fusiform, inferior temporal, middle temporal cortex; denominator was the inferior cerebellum cortex. The SUVR is a ratio and has a theoretic interpretable minimum of 1.0. This primary outcome is reported by the three primary groups: Healthy Volunteers, Mild Cognitive Impairment, and Dementia. | Baseline to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Correlation Between the Change in [18F]MK-6240 Uptake and the Change in the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) Using Items 1-11 | This outcome is correlational and therefore the arms/groups are collapsed to All Subjects so that we can assess the overall pattern of relationship between cognition and tau signal across the entire continuum of Alzheimer's disease. The ADAS-cog is one of the most frequently used tests to measure cognition in clinical trials in AD. The first 11 items of the ADAS-cog were used for this outcome. The ADAS was developed as a two-part scale: one that measured cognitive functions and one that measured non-cognitive functions such as mood and behavior. Most current research, including this study, uses the ADAS-Cog, which is the sub-scale that measures cognitive ability. The ADAS-cog score is based on incorrect items or errors and has a range of 0-50, where lower scores indicate better cognitive functioning. | Baseline to 12 months | 
| Correlate the Changes in [18F]MK-6240 Uptake and Changes in Clinical Cognitive Assessments by Clinical Dementia Rating Scale (CDR). | This outcome is correlational and therefore the arms/groups are collapsed to All Subjects so that we can assess the overall pattern of relationship between cognition and tau signal across the entire continuum of Alzheimer's disease. The CDR was developed primarily for use in persons with dementia of the Alzheimer type. The six domains of CDR are: Memory, Orientation, Judgment and Problem-solving, Community Affairs, Home and Hobbies, and Personal Care. Each domain is rated on a 5-point scale of functioning: 0 no impairment; 0.5 questionable impairment; 1 mild impairment; 2 moderate impairment; and 3 severe impairment. The Sum of Boxes is the score used which is simply the sum of the 6 Domain Box Scores. The range is 0-18 with lower scores indicating better cognitive function. | Baseline to 12 months | 
| Correlate the Changes in [18F]MK-6240 Uptake and Changes in Clinical Cognitive Assessments by Mini-Mental Status Exam (MMSE) | This outcome is correlational and therefore the arms/groups are collapsed to All Subjects so that we can assess the overall pattern of relationship between cognition and tau signal across the entire continuum of Alzheimer's disease. The MMSE is a sensitive, valid and reliable 30-point questionnaire that is used extensively in clinical and research settings to measure cognitive impairment. It is commonly used as screening tool for dementia. It is also used to estimate the severity and progression of cognitive impairment and to follow the course of cognitive changes in an individual over time; thus, making it an effective way to document an individual's response to treatment. The range is 0-30 with higher scores indicating better cognitive functioning. | Baseline to 12 months | 
| Change in [18F]MK-6240 Standard Uptake Value Ratio (SUVR) Uptake | Composite mean SUVR across standard regions including: numerator was the entorhinal, amygdala, fusiform, inferior temporal, middle temporal cortex; denominator was the inferior cerebellum cortex. The SUVR is a ratio and has a theoretic interpretable minimum of 1.0. This primary outcome is reported by the three primary groups: Healthy Volunteers, Mild Cognitive Impairment, and Dementia. | Baseline to 24 months | 
| Change in [18F]MK-6240 Standard Uptake Value Ratio (SUVR) Uptake | Composite mean SUVR across standard regions including: numerator was the entorhinal, amygdala, fusiform, inferior temporal, middle temporal cortex; denominator was the inferior cerebellum cortex. The SUVR is a ratio and has a theoretic interpretable minimum of 1.0. This primary outcome is reported by the three primary groups: Healthy Volunteers, Mild Cognitive Impairment, and Dementia. | Baseline to 6 months |