Alzheimer Disease
Conditions
Brief summary
This early phase 1 study explored the brain uptake, retention, and safety of flortaucipir and obtained preliminary information regarding dosimetry of flortaucipir.
Interventions
DRUGFlortaucipir F18
IV injection, 370 MBq (10 mCi), single dose
PROCEDUREBrain PET Scan
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).
PROCEDUREWhole body PET scan
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
DRUGFlorbetapir F 18
IV injection, 370 MBq (10 mCi), single dose
PROCEDUREBrain MRI
Volume-based T1-weighted Magnetic Resonance Imaging (MRI) of the brain
Sponsors
Avid Radiopharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brain Flortaucipir Uptake | 80-100 minutes postdose | 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. |
| Flortaucipir Whole Body Effective Dose | injection to 6 hours postdose | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Flortaucipir PET Correlations With Cognitive Assessments (Mini-mental State Exam) | at baseline | 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. |
| Flortaucipir PET Correlations With Cognitive Assessments Cognitive Assessments (Digit Symbol Substitution Test) | at baseline | 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. |
| Flortaucipir PET Correlations With Cognitive Assessments Cognitive Assessments (Alzheimer's Disease Assessment Scale) | at baseline | 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. |
Countries
United States
Participant flow
Recruitment details
Enrollment occurred between Aug and Dec 2013. Subjects in the MRI and Amyloid Extension cohort received flortaucipir brain PET scans in Study T807000 (NCT01733355)
Pre-assignment details
Subjects enrolled in the MRI/amyloid extension cohort were to be combined with the Brain PET subgroups for analysis per protocol. MRI allows previously-obtained flortaucipir scan and cognitive data to be combined with the PET scan results from the Brain PET subgroups for analysis.
Participants by arm
| Arm | Count |
|---|---|
| Brain PET Scan (AD Subjects) AD subjects receiving a flortaucipir and florbetapir PET scan | 4 |
| Brain PET (MCI Subjects) Mild cognitive impairment (MCI) subjects receiving a florbetapir and a flortaucipir PET scan | 3 |
| Brain PET (YCN Subjects) Young cognitively normal (YCN) subjects receiving florbetapir and a flortaucipir PET scan | 4 |
| Brain PET (OCN Subjects) Older cognitively normal (OCN) subjects receiving a florbetapir and a flortaucipir PET scan | 4 |
| Whole Body PET Scan Subjects receiving a whole body PET scan after flortaucipir administration | 9 |
| MRI and Amyloid Extension Cohort Magnetic resonance imaging (MRI) scans and amyloid scans for subjects previously participating in Study T807000. \[n=3 AD, n=2 MCI, n=1 OCN\] | 4 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Other | 0 | 0 | 0 | 0 | 3 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Brain PET Scan (AD Subjects) | Brain PET (MCI Subjects) | Brain PET (YCN Subjects) | Brain PET (OCN Subjects) | Whole Body PET Scan | MRI and Amyloid Extension Cohort |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 60.1 years STANDARD_DEVIATION 16.52 | 68.0 years STANDARD_DEVIATION 7.87 | 78.7 years STANDARD_DEVIATION 2.89 | 27.5 years STANDARD_DEVIATION 2.08 | 66.3 years STANDARD_DEVIATION 0.5 | 56.3 years STANDARD_DEVIATION 4.42 | 73.0 years STANDARD_DEVIATION 13.09 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 0 Participants | 0 Participants | 4 Participants | 1 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 18 Participants | 4 Participants | 3 Participants | 0 Participants | 3 Participants | 5 Participants | 3 Participants |
| Region of Enrollment United States | 28 Participants | 4 Participants | 3 Participants | 4 Participants | 4 Participants | 9 Participants | 4 Participants |
| Sex/Gender, Customized Female | 11 Participants | 2 Participants | 1 Participants | 1 Participants | 3 Participants | 3 Participants | 1 Participants |
| Sex/Gender, Customized Male | 16 Participants | 2 Participants | 2 Participants | 3 Participants | 1 Participants | 6 Participants | 2 Participants |
| Sex/Gender, Customized Unknown | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 3 | 0 / 4 | 0 / 4 | 0 / 9 | 0 / 4 |
| other Total, other adverse events | 0 / 4 | 0 / 3 | 1 / 4 | 0 / 4 | 3 / 9 | 0 / 4 |
| serious Total, serious adverse events | 0 / 4 | 0 / 3 | 0 / 4 | 0 / 4 | 0 / 9 | 0 / 4 |
Outcome results
Primary
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.
Time frame: 80-100 minutes postdose
Population: Includes quantitative flortaucipir PET scan results from subjects with a flortaucipir scan in the present study (n=15), plus subjects consented in the MRI/Amyloid extension cohort who provided valid flortaucipir PET scans (n=3 AD, n=2 MCI, n=1 OCN) and received MRI in the present study permitting quantitative analysis per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Brain PET Scan (AD Subjects) | Brain Flortaucipir Uptake | 1.780 standardized uptake value ratio (SUVr) | Standard Deviation 0.857 |
| Brain PET (MCI Subjects) | Brain Flortaucipir Uptake | 1.317 standardized uptake value ratio (SUVr) | Standard Deviation 0.161 |
| Brain PET (YCN Subjects) | Brain Flortaucipir Uptake | 1.128 standardized uptake value ratio (SUVr) | Standard Deviation 0.047 |
| Brain PET (OCN Subjects) | Brain Flortaucipir Uptake | 1.107 standardized uptake value ratio (SUVr) | Standard Deviation 0.175 |
Primary
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.
Time frame: injection to 6 hours postdose
Population: Includes only subjects from the whole body PET scan group (n=9)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Brain PET Scan (AD Subjects) | Flortaucipir Whole Body Effective Dose | 0.0241 mSv/MBq | Standard Deviation 0.0016 |
Secondary
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.
Time frame: at baseline
Population: Includes quantitative flortaucipir PET scan results from subjects with a flortaucipir scan in the present study (n=15), plus subjects consented in the MRI/Amyloid extension cohort who provided valid flortaucipir PET scans from a previous study (n=6) and received MRI in the present study permitting quantitation per protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brain PET Scan (AD Subjects) | Flortaucipir PET Correlations With Cognitive Assessments Cognitive Assessments (Alzheimer's Disease Assessment Scale) | 0.220 correlation coefficient |
Secondary
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.
Time frame: at baseline
Population: Includes quantitative flortaucipir PET scan results from subjects with a flortaucipir scan in the present study (n=15), plus subjects consented in the MRI/Amyloid extension cohort who provided valid flortaucipir PET scans from a previous study n=6) and received MRI in the present study permitting quantitation per protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brain PET Scan (AD Subjects) | Flortaucipir PET Correlations With Cognitive Assessments Cognitive Assessments (Digit Symbol Substitution Test) | -0.273 correlation coefficient |
Secondary
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.
Time frame: at baseline
Population: Includes quantitative flortaucipir brain PET scan results from subjects with a flortaucipir scan in the present study (n=15), plus subjects consented in the MRI/Amyloid extension cohort who provided valid flortaucipir PET scans from a previous study (n=6) and received MRI in the present study permitting quantitation per protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brain PET Scan (AD Subjects) | Flortaucipir PET Correlations With Cognitive Assessments (Mini-mental State Exam) | -0.404 correlation coefficient |
Post Hoc
Flortaucipir Whole Body Effective Dose With Urine Radioactivity
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 and accounting for total integrated radioactivity excreted in the urine collected in Study A15 (NCT02336360)
Time frame: injection to 6 hours postdose
Population: Includes only subjects from the whole body PET scan group (n=9)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Brain PET Scan (AD Subjects) | Flortaucipir Whole Body Effective Dose With Urine Radioactivity | 0.0235 mSv/MBq | Standard Deviation 0.0016 |