Exploratory Evaluation of Flortaucipir Injection in Healthy Volunteers and Cognitively Impaired Subjects

Study Overview
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Brief Summary
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This early phase 1 study explored the brain uptake, retention, and safety of flortaucipir and obtained preliminary information regarding dosimetry of flortaucipir.

Official Title
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An Exploratory Evaluation of the Tau Protein Binding Properties, Whole-Body Biodistribution and Safety of 18F-AV-1451 Injection in Healthy Volunteers and Cognitively Impaired Subjects

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: Flortaucipir F18
* Procedure: Brain PET Scan
* Procedure: Whole body PET scan
* Drug: Florbetapir F 18
* Procedure: Brain MRI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy volunteers had an Mini-Mental State Examination (MMSE) score of ≥ 29; MCI due to Alzheimer's disease (AD) consistent with National Institute on Aging (NIA)-Alzheimer's Association working group's on diagnostic guidelines for AD (Alzheimer's Dementia 7:270-9, 2011) Possible or probable AD: Met clinical criteria for possible or probable AD based on the NIA-Alzheimer's Association working group's on diagnostic guidelines for AD (Alzheimer's Dementia 7:263-9, 2011) Exclusion Criteria: Current clinically significant psychiatric disease. Evidence of structural abnormalities such as major stroke or mass on MRI that would have made a diagnosis of impairment due to AD unlikely or was likely to interfere with interpretation of a PET scan on MRI. Claustrophobic or otherwise unable to tolerate the imaging procedure. Current clinically significant cardiovascular disease or clinically significant abnormalities on screening electrocardiogram (including, but not limited to, corrected QT interval >450 msec). Current clinically significant infectious disease, endocrine or metabolic disease, pulmonary, renal or hepatic impairment, or cancer History of alcohol abuse or substance abuse or dependence Female subjects of childbearing potential who were not surgically sterile, not refraining from sexual activity or not using reliable methods of contraception. Required medications with a narrow therapeutic window Received a non-study related radiopharmaceutical imaging or treatment procedure within 7 days prior to imaging session Receiving any investigational medications or had participated in a trial with investigational medications within the last 30 days

Ages Eligible for Study
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Minimum Age: 20 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brain flortaucipir PET scan<br>Subjects receiving a brain PET scan after flortaucipir administration | Drug: Flortaucipir F18<br>* IV injection, 370 MBq (10 mCi), single dose<br>* Other names: Tauvid;Procedure: Brain PET Scan<br>* positron emission tomography (PET) scan of the brain starting immediately after administration (60 minute dynamic imaging plus 4 frames x 5 minutes at approximately 80 minutes post-dose).<br>Drug: Florbetapir F 18<br>* IV injection, 370 MBq (10 mCi), single dose<br>* Other names: Amyvid;Procedure: Brain MRI<br>* Volume-based T1-weighted Magnetic Resonance Imaging (MRI) of the brain<br>|
| Experimental: Whole body flortaucipir PET scan<br>Subjects receiving a whole body PET scan after flortaucipir administration | Drug: Flortaucipir F18<br>* IV injection, 370 MBq (10 mCi), single dose<br>* Other names: Tauvid;Procedure: Whole body PET scan<br>* positron emission tomography (PET) scan of the body from the vertex of the head to the thighs starting immediately following injection and repeated over 6 hours<br>|
| Other: MRI and Amyloid Extension Cohort<br>Magnetic resonance imaging (MRI) scans and amyloid scans for subjects previously participating in Study T807000 (NCT01733355) | Procedure: Brain PET Scan<br>* positron emission tomography (PET) scan of the brain starting immediately after administration (60 minute dynamic imaging plus 4 frames x 5 minutes at approximately 80 minutes post-dose).<br>Drug: Florbetapir F 18<br>* IV injection, 370 MBq (10 mCi), single dose<br>* Other names: Amyvid;Procedure: Brain MRI<br>* Volume-based T1-weighted Magnetic Resonance Imaging (MRI) of the brain<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain Flortaucipir Uptake | Brain imaging of tau in healthy volunteers and subjects with cognitive impairment. Standard uptake value ratios (SUVr), normalized to the entire cerebellum. A global cortical average volume of interest (VOI) is the average SUVr of the occipital cortex, parietal cortex, and temporal cortex. For SUVr, a value of 1 signifies no flortaucipir activity above background, values greater than 1 signify increasing flortaucipir activity in the brain. | 80-100 minutes postdose | 
| Flortaucipir Whole Body Effective Dose | Radiation dose estimates measured in millisieverts per megabecquerel (mSv/MBq) for the whole body obtained from Organ Level Internal Dose Assessment/Exponential Modeling (OLINDA/EXM) radiation dosimetry code. Results calculated using 73.7-kg man model. | injection to 6 hours postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Flortaucipir PET Correlations With Cognitive Assessments (Mini-mental State Exam) | Spearman's correlations between flortaucipir SUVr and cognitive function as measured on the Mini-Mental State Examination (MMSE). MMSE is a 30-point questionnaire that is used to measure cognitive impairment. 0 is the lowest score and 30 is the highest score, indicating normal cognitive function. Lower MMSE scores indicate worsening cognitive function. For this analysis, negative correlation values indicate that higher flortaucipir uptake is associated with decreasing cognitive function and positive correlation values indicate that lower flortaucipir uptake is associated with better cognitive function. 95% confidence interval uses a Fisher's z transformation. | at baseline | 
| Flortaucipir PET Correlations With Cognitive Assessments Cognitive Assessments (Digit Symbol Substitution Test) | Spearman's correlations between flortaucipir SUVr and cognitive function as measured on Digit Symbol Substitution Test (DSST). The DSST is sensitive to the presence of cognitive dysfunction as well as to change in cognitive function. Scores range from 0 to 133. Lower DSST scores indicate worsening cognitive function. For this analysis, negative correlation values indicate that higher flortaucipir uptake is associated with decreasing cognitive function and positive correlation values indicate that lower flortaucipir uptake is associated with better cognitive function. 95% confidence interval uses a Fisher's z transformation. | at baseline | 
| Flortaucipir PET Correlations With Cognitive Assessments Cognitive Assessments (Alzheimer's Disease Assessment Scale) | Spearman's correlations between flortaucipir SUVr and cognitive function as measured on a Modified Alzheimer's Disease Assessment Scale (ADAS)-Cognitive subscale (including orientation, verbal memory, language, and praxis, minus the spoken language assessment). Scores on the modified scale can range from 0 to 65. Higher scores indicate worsening cognitive function. For this analysis, positive correlation values indicate that higher flortaucipir uptake is associated with decreasing cognitive function and negative correlation values indicate that lower flortaucipir uptake is associated with better cognitive function. 95% confidence interval uses a Fisher's z transformation. | at baseline |