Alzheimer's Disease
Conditions
Brief summary
This study is designed to test the relationship between ante-mortem flortaucipir Positron Emission Tomography (PET) imaging and tau neurofibrillary pathology associated with Alzheimer's disease (AD), as measured at autopsy.
Interventions
DRUGFlortaucipir F18
370 megabecquerel (MBq) IV single-dose
PROCEDUREPET Scan
positron emission tomography (PET) scan
Sponsors
Avid Radiopharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have a projected life expectancy of ≤ 6 months * Can tolerate a 20 minute PET scan * Give informed consent or have a legally authorized representative to consent for study procedures and brain donation consistent with the legal requirements of the State in which they die
Exclusion criteria
* Aggressively being treated with life sustaining measures * Known to have a structural brain lesion that would interfere either with PET imaging or pathological assessment * Clinically significant infectious disease * Currently receiving any investigational medications except with permission from the study sponsor * Participated in an experimental study with an amyloid or tau targeting agent * Suspected encephalopathy due to alcoholism or end-stage liver disease * Females of childbearing potential * History of risk factors for Torsades de Pointes or are currently taking medication known to cause QT prolongation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Outcome 1: Diagnostic Performance of Individual Readers (NFT Score) | at autopsy within 9 months of baseline scan | Sensitivity and specificity of 5 independent readers' interpretations of ante-mortem flortaucipir PET imaging for detection of a pattern of flortaucipir neocortical uptake that corresponds to neurofibrillary tangles (NFT) Score of B3 (Hyman et al., 2012; Montine et al., 2012). NFT B scores range from B0 (Braak Stage 0; no NFTs in the brain) to B3 (Braak Stage V/VI; widespread NFTs in the brain). Sensitivity and specificity are percentages that can range from 0 to 100%. The hypothesis tested was that, of the 5 independent imaging physicians, at least 3 will have the lower bounds of 2-sided 95% CIs ≥50%, for both sensitivity and specificity. |
| Primary Outcome 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis) | at autopsy within 9 months of baseline scan | Sensitivity and specificity of 5 independent readers' interpretations of ante-mortem flortaucipir imaging for detection of a pattern of flortaucipir neocortical uptake that corresponds to high levels of Alzheimer's disease neuropathologic change (High ADNC) as defined by National Institute on Aging-Alzheimer's Association (NIA-AA) criteria. ADNC categories are None, Low, Intermediate and High, with High indicating the most severe level of AD-related pathology changes in the brain (Hyman et al., Alzheimers Dement. 2012 Jan;8(1):1-13). The hypothesis tested was that, of the 5 independent imaging physicians, at least 3 will have the lower bounds of 2-sided 95% CIs ≥50%, for both sensitivity and specificity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Flortaucipir Diagnostic Performance (NFT Score) | at autopsy within 9 months of baseline scan | Sensitivity and specificity of majority interpretation of AD pattern tau PET scan corresponding to NFT Score of B3. The 95% confidence intervals (CI) provided for specificity and sensitivity were based on the Wilson score method. The hypothesis tested was that majority read results had the lower bound of the 2-sided 95% CI greater than or equal to 55% for both sensitivity and specificity. |
| Flortaucipir Diagnostic Performance (NIA-AA Autopsy Diagnosis) | at autopsy within 9 months of baseline scan | Sensitivity and specificity of majority interpretation of of AD pattern tau PET scan corresponding to NIA-AA autopsy diagnosis. The 95% CIs provided for specificity and sensitivity were based on the Wilson score method. The hypothesis tested was that majority read results had the lower bound of the 2-sided 95% CI greater than or equal to 55% for both sensitivity and specificity. |
| Inter-Reader Agreement | baseline scan | Fleiss' Kappa statistics were used to assess inter-reader agreement for the diagnostic decisions associated with primary outcome 1. Fleiss' kappa is a statistical measure for assessing the reliability of agreement between a fixed number of raters when assigning categorical ratings to a number of items or classifying items. Fleiss' kappa can range from 0 to 1 with 1 indicating perfect agreement between the readers. Results are reported as overall agreement, calculated as proportion of scans where reader pairs agreed, divided by the total number of scans read by each reader pair. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Diagnostic Performance of Individual Readers (NFT Score B2-B3 as Truth Positive) | at autopsy within 9 months of baseline scan | Sensitivity and specificity of 5 independent readers' interpretations of ante-mortem flortaucipir PET imaging for detection of a pattern of flortaucipir neocortical uptake that corresponds to neurofibrillary tangles (NFT) Score of B3 (Hyman et al., 2012; Montine et al., 2012). NFT B scores range from B0 (no NFTs in the brain) to B3 (widespread NFTs in the brain). Sensitivity and specificity are percentages that can range from 0 to 100%. For this analysis, B scores of B2-B3 were considered truth positive, and B scores of B0-B1 were considered truth negative. |
Countries
Australia, United States
Participant flow
Recruitment details
Enrollment occurred between October 2015 and June 2018. Enrolled end-of-life subjects (life expectancy less than 6 months) at hospice centers in the US and Australia consented to a flortaucipir PET scan and to brain donation at autopsy.
Pre-assignment details
To be considered eligible for the primary analysis, death had to occur within 9 months of flortaucipir scan and valid autopsy was required. The first 3 subjects to come to autopsy were considered front-runners. Front-runner scan and autopsy results were unblinded to the sponsor to optimize analysis.
Participants by arm
| Arm | Count |
|---|---|
| All Enrolled Cohort All subjects consenting to flortaucipir PET and brain donation at autopsy | 156 |
| Total | 156 |
Baseline characteristics
| Characteristic | All Enrolled Cohort |
|---|---|
| Age, Continuous | 80.2 years STANDARD_DEVIATION 12.51 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 136 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 143 Participants |
| Region of Enrollment Australia | 5 participants |
| Region of Enrollment United States | 151 participants |
| Sex: Female, Male Female | 86 Participants |
| Sex: Female, Male Male | 70 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 73 / 156 |
| other Total, other adverse events | 14 / 156 |
| serious Total, serious adverse events | 3 / 156 |
Outcome results
Primary
Primary Outcome 1: Diagnostic Performance of Individual Readers (NFT Score)
Sensitivity and specificity of 5 independent readers' interpretations of ante-mortem flortaucipir PET imaging for detection of a pattern of flortaucipir neocortical uptake that corresponds to neurofibrillary tangles (NFT) Score of B3 (Hyman et al., 2012; Montine et al., 2012). NFT B scores range from B0 (Braak Stage 0; no NFTs in the brain) to B3 (Braak Stage V/VI; widespread NFTs in the brain). Sensitivity and specificity are percentages that can range from 0 to 100%. The hypothesis tested was that, of the 5 independent imaging physicians, at least 3 will have the lower bounds of 2-sided 95% CIs ≥50%, for both sensitivity and specificity.
Time frame: at autopsy within 9 months of baseline scan
Population: Autopsy cohort N=64. n=39 were truth positive for NFTs. n=25 were truth negative for NFTs.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Primary Outcome 1: Diagnostic Performance of Individual Readers (NFT Score) | Reader 2 | 92.3 percentage of cases correctly identified |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Primary Outcome 1: Diagnostic Performance of Individual Readers (NFT Score) | Reader 4 | 92.3 percentage of cases correctly identified |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Primary Outcome 1: Diagnostic Performance of Individual Readers (NFT Score) | Reader 3 | 92.3 percentage of cases correctly identified |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Primary Outcome 1: Diagnostic Performance of Individual Readers (NFT Score) | Reader 5 | 100 percentage of cases correctly identified |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Primary Outcome 1: Diagnostic Performance of Individual Readers (NFT Score) | Reader 1 | 97.4 percentage of cases correctly identified |
| Specificity of Flortaucipir vs Autopsy NFT Score <B3 | Primary Outcome 1: Diagnostic Performance of Individual Readers (NFT Score) | Reader 5 | 52.0 percentage of cases correctly identified |
| Specificity of Flortaucipir vs Autopsy NFT Score <B3 | Primary Outcome 1: Diagnostic Performance of Individual Readers (NFT Score) | Reader 1 | 68.0 percentage of cases correctly identified |
| Specificity of Flortaucipir vs Autopsy NFT Score <B3 | Primary Outcome 1: Diagnostic Performance of Individual Readers (NFT Score) | Reader 2 | 92.0 percentage of cases correctly identified |
| Specificity of Flortaucipir vs Autopsy NFT Score <B3 | Primary Outcome 1: Diagnostic Performance of Individual Readers (NFT Score) | Reader 3 | 88.0 percentage of cases correctly identified |
| Specificity of Flortaucipir vs Autopsy NFT Score <B3 | Primary Outcome 1: Diagnostic Performance of Individual Readers (NFT Score) | Reader 4 | 76.0 percentage of cases correctly identified |
Primary
Primary Outcome 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis)
Sensitivity and specificity of 5 independent readers' interpretations of ante-mortem flortaucipir imaging for detection of a pattern of flortaucipir neocortical uptake that corresponds to high levels of Alzheimer's disease neuropathologic change (High ADNC) as defined by National Institute on Aging-Alzheimer's Association (NIA-AA) criteria. ADNC categories are None, Low, Intermediate and High, with High indicating the most severe level of AD-related pathology changes in the brain (Hyman et al., Alzheimers Dement. 2012 Jan;8(1):1-13). The hypothesis tested was that, of the 5 independent imaging physicians, at least 3 will have the lower bounds of 2-sided 95% CIs ≥50%, for both sensitivity and specificity.
Time frame: at autopsy within 9 months of baseline scan
Population: Autopsy cohort N=64. n=38 were truth positive for NFTs. n=26 were truth negative for NFTs.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Primary Outcome 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis) | Reader 2 | 95.0 percentage of cases correctly identified |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Primary Outcome 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis) | Reader 4 | 95.0 percentage of cases correctly identified |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Primary Outcome 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis) | Reader 3 | 95.0 percentage of cases correctly identified |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Primary Outcome 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis) | Reader 5 | 100 percentage of cases correctly identified |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Primary Outcome 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis) | Reader 1 | 97.5 percentage of cases correctly identified |
| Specificity of Flortaucipir vs Autopsy NFT Score <B3 | Primary Outcome 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis) | Reader 5 | 50.0 percentage of cases correctly identified |
| Specificity of Flortaucipir vs Autopsy NFT Score <B3 | Primary Outcome 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis) | Reader 1 | 65.4 percentage of cases correctly identified |
| Specificity of Flortaucipir vs Autopsy NFT Score <B3 | Primary Outcome 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis) | Reader 2 | 92.3 percentage of cases correctly identified |
| Specificity of Flortaucipir vs Autopsy NFT Score <B3 | Primary Outcome 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis) | Reader 3 | 88.5 percentage of cases correctly identified |
| Specificity of Flortaucipir vs Autopsy NFT Score <B3 | Primary Outcome 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis) | Reader 4 | 76.9 percentage of cases correctly identified |
Secondary
Flortaucipir Diagnostic Performance (NFT Score)
Sensitivity and specificity of majority interpretation of AD pattern tau PET scan corresponding to NFT Score of B3. The 95% confidence intervals (CI) provided for specificity and sensitivity were based on the Wilson score method. The hypothesis tested was that majority read results had the lower bound of the 2-sided 95% CI greater than or equal to 55% for both sensitivity and specificity.
Time frame: at autopsy within 9 months of baseline scan
Population: Autopsy cohort N=64. n=39 were truth positive for NFTs. n=25 were truth negative for NFTs.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Flortaucipir Diagnostic Performance (NFT Score) | 92.3 percentage of cases correctly identified |
| Specificity of Flortaucipir vs Autopsy NFT Score <B3 | Flortaucipir Diagnostic Performance (NFT Score) | 80.0 percentage of cases correctly identified |
Secondary
Flortaucipir Diagnostic Performance (NIA-AA Autopsy Diagnosis)
Sensitivity and specificity of majority interpretation of of AD pattern tau PET scan corresponding to NIA-AA autopsy diagnosis. The 95% CIs provided for specificity and sensitivity were based on the Wilson score method. The hypothesis tested was that majority read results had the lower bound of the 2-sided 95% CI greater than or equal to 55% for both sensitivity and specificity.
Time frame: at autopsy within 9 months of baseline scan
Population: Autopsy cohort N=64. n=38 were truth positive for NFTs. n=26 were truth negative for NFTs.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Flortaucipir Diagnostic Performance (NIA-AA Autopsy Diagnosis) | 94.7 percentage of cases correctly identified |
| Specificity of Flortaucipir vs Autopsy NFT Score <B3 | Flortaucipir Diagnostic Performance (NIA-AA Autopsy Diagnosis) | 80.8 percentage of cases correctly identified |
Secondary
Inter-Reader Agreement
Fleiss' Kappa statistics were used to assess inter-reader agreement for the diagnostic decisions associated with primary outcome 1. Fleiss' kappa is a statistical measure for assessing the reliability of agreement between a fixed number of raters when assigning categorical ratings to a number of items or classifying items. Fleiss' kappa can range from 0 to 1 with 1 indicating perfect agreement between the readers. Results are reported as overall agreement, calculated as proportion of scans where reader pairs agreed, divided by the total number of scans read by each reader pair.
Time frame: baseline scan
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Inter-Reader Agreement | Reader 1 v Reader 2 | 0.79 proportion of agreed cases |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Inter-Reader Agreement | Reader 1 v Reader 3 | 0.79 proportion of agreed cases |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Inter-Reader Agreement | Reader 1 v Reader 4 | 0.79 proportion of agreed cases |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Inter-Reader Agreement | Reader 1 v Reader 5 | 0.81 proportion of agreed cases |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Inter-Reader Agreement | Reader 2 v Reader 3 | 0.96 proportion of agreed cases |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Inter-Reader Agreement | Reader 2 v Reader 4 | 0.88 proportion of agreed cases |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Inter-Reader Agreement | Reader 2 v Reader 5 | 0.65 proportion of agreed cases |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Inter-Reader Agreement | Reader 3 v Reader 4 | 0.92 proportion of agreed cases |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Inter-Reader Agreement | Reader 3 v Reader 5 | 0.68 proportion of agreed cases |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Inter-Reader Agreement | Reader 4 v Reader 5 | 0.72 proportion of agreed cases |
Comparison: Inter-reader agreement analysis using Fleiss' kappa. The hypothesis tested was that the observed kappa values were ≥0.64 and the lower bound of the 2-sided 95% CIs were ≥0.55 for the inter-reader agreement among readers.95% CI: [0.74, 0.86]
Other Pre-specified
Diagnostic Performance of Individual Readers (NFT Score B2-B3 as Truth Positive)
Sensitivity and specificity of 5 independent readers' interpretations of ante-mortem flortaucipir PET imaging for detection of a pattern of flortaucipir neocortical uptake that corresponds to neurofibrillary tangles (NFT) Score of B3 (Hyman et al., 2012; Montine et al., 2012). NFT B scores range from B0 (no NFTs in the brain) to B3 (widespread NFTs in the brain). Sensitivity and specificity are percentages that can range from 0 to 100%. For this analysis, B scores of B2-B3 were considered truth positive, and B scores of B0-B1 were considered truth negative.
Time frame: at autopsy within 9 months of baseline scan
Population: Autopsy cohort N=64. n=56 were truth positive for NFTs. n=8 were truth negative for NFTs.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Diagnostic Performance of Individual Readers (NFT Score B2-B3 as Truth Positive) | Reader 2 | 67.9 percentage of cases correctly identified |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Diagnostic Performance of Individual Readers (NFT Score B2-B3 as Truth Positive) | Reader 4 | 73.2 percentage of cases correctly identified |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Diagnostic Performance of Individual Readers (NFT Score B2-B3 as Truth Positive) | Reader 3 | 67.9 percentage of cases correctly identified |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Diagnostic Performance of Individual Readers (NFT Score B2-B3 as Truth Positive) | Reader 5 | 85.7 percentage of cases correctly identified |
| Sensitivity of Flortaucipir vs Autopsy NFT Score B3 | Diagnostic Performance of Individual Readers (NFT Score B2-B3 as Truth Positive) | Reader 1 | 80.4 percentage of cases correctly identified |
| Specificity of Flortaucipir vs Autopsy NFT Score <B3 | Diagnostic Performance of Individual Readers (NFT Score B2-B3 as Truth Positive) | Reader 5 | 62.5 percentage of cases correctly identified |
| Specificity of Flortaucipir vs Autopsy NFT Score <B3 | Diagnostic Performance of Individual Readers (NFT Score B2-B3 as Truth Positive) | Reader 1 | 87.5 percentage of cases correctly identified |
| Specificity of Flortaucipir vs Autopsy NFT Score <B3 | Diagnostic Performance of Individual Readers (NFT Score B2-B3 as Truth Positive) | Reader 2 | 100.0 percentage of cases correctly identified |
| Specificity of Flortaucipir vs Autopsy NFT Score <B3 | Diagnostic Performance of Individual Readers (NFT Score B2-B3 as Truth Positive) | Reader 3 | 87.5 percentage of cases correctly identified |
| Specificity of Flortaucipir vs Autopsy NFT Score <B3 | Diagnostic Performance of Individual Readers (NFT Score B2-B3 as Truth Positive) | Reader 4 | 87.5 percentage of cases correctly identified |