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This study will evaluate the performance of physician readers trained to read flortaucipir-PET (positron emission tomography) scans.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Flortaucipir PET Scan | Experimental | Scans previously acquired from Study A16 (NCT02516046) and A05 (NCT02016560) will be read by independent, blinded readers. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| flortaucipir F 18 | Drug | No study drug will be administered. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Primary Objective 1 Analysis 1: Diagnostic Performance of Individual Readers (NFT Score) | Sensitivity and specificity of 5 independent readers' interpretations of ante-mortem 18F-AV-1451 PET imaging for detection of a pattern of 18F-AV-1451 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%. 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. | baseline scan |
| Primary Objective 1 Analysis 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis) | Sensitivity and specificity of 5 independent readers' interpretations of ante-mortem 18F-AV-1451 PET imaging for detection of a pattern of 18F-AV-1451 neocortical uptake that corresponds to high levels of AD neuropathologic change (High ADNC) as defined by National Institute on Aging-Alzheimer's Association (NIA-AA) criteria (see Hyman et al. 2012). ADNC categories are None, Low, Intermediate and High, with High indicating the most severe level of AD-related pathology changes in the brain. 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. | baseline scan |
| Primary Objective 2: Inter-reader Reliability of Reader Interpretation of Flortaucipir-PET Imaging | As measured by Fleiss' Kappa across all scans read. 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. Scan results binarized as positive AD pattern versus negative AD pattern. Results are displayed as percentage of agreement for individual reader pairs, computed as follows: number of images for which reader had the same interpretation divided by the total number of images evaluated, multiplied by 100%. |
| Measure | Description | Time Frame |
|---|---|---|
| Secondary Objective 1 Analysis 1: Diagnostic Performance of Ï„AD++ Flortaucipir PET Images to Detect B3 NFTs | Flortaucipir F 18 PET imaging will be classified by each reader as either neocortical uptake not consistent with AD (Ï„AD-), neocortical uptake consistent with AD (Ï„AD+), or neocortical uptake consistent with AD with uptake beyond the temporal/occipital regions (Ï„AD++). NFT scoring is according to Hyman, et al 2012. Truth positive is a NFT B3 score. Truth negative is NFT \ |
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Scan Reader Criteria (5 total):
Scan Criteria:
- Previous enrollment in Study A05 confirmatory cohort (NCT02016560), or A16 (NCT02516046)
Scan Study Population Criteria for FR01 (A05 confirmatory cohort):
Scan Study Population Criteria for FR01 (Study A16):
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| Name | Affiliation | Role |
|---|---|---|
| Study Director | Avid Radiopharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| American College of Radiology | Philadelphia | Pennsylvania | 19103 | United States |
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Subjects were not recruited for this study. Study scans were selected from 2 previously completed imaging studies. Scans previously acquired from Study A16 (NCT02516046) and A05 (NCT02016560) were read by 5 independent, blinded to other study information.
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| ID | Title | Description |
|---|---|---|
| FG000 | All Autopsy Cases | Cases that had a valid scan and came to autopsy in in study A16 and the A16 supplemental cohort |
| FG001 | Non-Autopsy Cases | Mild cognitive impairment (MCI) and AD cases from the A05 confirmatory cohort |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | All Cases | All eligible subject scans from contributing studies |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Baseline analysis includes Study A16 autopsy cases (n=83) and Study A05 Non-autopsy cases (n=159). |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Primary Objective 1 Analysis 1: Diagnostic Performance of Individual Readers (NFT Score) | Sensitivity and specificity of 5 independent readers' interpretations of ante-mortem 18F-AV-1451 PET imaging for detection of a pattern of 18F-AV-1451 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%. 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. | Analysis included all autopsy subjects with an evaluable flortaucipir PET scan interpretation (n=82). One autopsy subject scan was rated as unevaluable. n=47 were truth positive for NFTs. n=35 were truth negative for NFTs. | Posted | Number | 95% Confidence Interval | percentage of cases correctly identified | baseline scan |
|
Not applicable. Adverse events were not assessed during this study.
Adverse events were not assessed during this study.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | All Cases | No study drug will be administered. Scans previously acquired from Study A16 (NCT02516046) and A05 (NCT02016560) will be read by independent, blinded readers. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Medical Director | Avid Radiopharmaceuticals, Inc. | 215-298-0700 | clinicaloperations@avidrp.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Mar 21, 2019 | Jun 27, 2020 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 30, 2019 | Jun 27, 2020 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D000544 | Alzheimer Disease |
| ID | Term |
|---|---|
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| C000591008 | 7-(6-fluoropyridin-3-yl)-5H-pyrido(4,3-b)indole |
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Physician PET scan readers are participants, blinded to demographic and clinical data from the source PET scans.
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PET scans were obtained in an open-label fashion.
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| baseline scan |
| baseline scan |
| Secondary Objective 1 Analysis 2: Diagnostic Performance of Ï„AD++ Flortaucipir PET Images to Detect High ADNC | Sensitivity and specificity of 5 independent readers' interpretations of ante-mortem 18F-AV-1451 PET imaging for detection of a pattern of 18F-AV-1451 neocortical uptake that corresponds to high levels of AD neuropathologic change (High ADNC) as defined by National Institute on Aging-Alzheimer's Association (NIA-AA) criteria (Hyman et al. 2012). Truth positive is a High ADNC score. Truth negative is No/Low/Intermediate ADNC score. | baseline scan |
| Secondary Objective 2: Inter-reader Reliability of Reader Interpretation of Ï„AD++ Flortaucipir PET Images | Overall reader agreement as measured by Fleiss' Kappa statistic. Scan results binarized as Ï„AD++ versus Ï„AD+/Ï„AD-. Results are displayed as percentage of agreement for individual reader pairs, computed as follows: number of images for which reader had the same interpretation divided by the total number of images evaluated, multiplied by 100%. | baseline scan |
| Secondary Objective 3: Inter-reader Reliability of Flortaucipir PET Scan Interpretation in the Population of Intended Use | Reader agreement measured by Fleiss' Kappa across scans from non-autopsy cases from Study A05. Scan results binarized as positive for AD pattern versus negative for AD pattern. Results are displayed as percentage of agreement for individual reader pairs, computed as follows: number of images for which reader had the same interpretation divided by the total number of images evaluated, multiplied by 100%. | baseline scan |
| Secondary Objective 4: Intra-reader Reliability of Reader Interpretation of Flortaucipir-PET Imaging | Cohen's Kappa will be calculated for each of 5 readers to assess the intra-reader reliability of flortaucipir F 18 PET scan visual interpretation. The statistic takes into account the possibility of the agreement occurring by chance. Cohen's kappa values range from 0 to 1 with 1 representing perfect agreement. Results are displayed as percentage of agreement within a reader, computed as follows: number of images for which reader had the same interpretation at initial and second read divided by the total number of images evaluated twice by a reader, multiplied by 100%. | baseline scan |
| Mean |
| Standard Deviation |
| years |
|
| Sex: Female, Male | Baseline analysis includes Study A16 autopsy cases (n=83) and Study A05 Non-autopsy cases (n=159). | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Measure Analysis Population Description: Baseline analysis includes Study A16 autopsy cases (n=83) and Study A05 Non-autopsy cases (n=159). | Count of Participants | Participants |
|
| Race (NIH/OMB) | Measure Analysis Population Description: Baseline analysis includes Study A16 autopsy cases (n=83) and Study A05 Non-autopsy cases (n=159). | Count of Participants | Participants |
|
| Sensitivity of Flortaucipir vs Autopsy NFT Score |
Subjects with a positive autopsy NFT score truth standard (NFT B3) |
| OG001 | Specificity of Flortaucipir vs Autopsy NFT Score | Subjects with a negative autopsy NFT score truth standard (NFT B2 or lower) |
|
|
| Primary | Primary Objective 1 Analysis 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis) | Sensitivity and specificity of 5 independent readers' interpretations of ante-mortem 18F-AV-1451 PET imaging for detection of a pattern of 18F-AV-1451 neocortical uptake that corresponds to high levels of AD neuropathologic change (High ADNC) as defined by National Institute on Aging-Alzheimer's Association (NIA-AA) criteria (see Hyman et al. 2012). ADNC categories are None, Low, Intermediate and High, with High indicating the most severe level of AD-related pathology changes in the brain. 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. | Analysis included all autopsy subjects with an evaluable flortaucipir PET scan interpretation (n=82). One autopsy subject scan was rated as unevaluable. n=41 were truth positive. n=41 were truth negative. | Posted | Number | 95% Confidence Interval | percentage of cases correctly identified | baseline scan |
|
|
|
| Primary | Primary Objective 2: Inter-reader Reliability of Reader Interpretation of Flortaucipir-PET Imaging | As measured by Fleiss' Kappa across all scans read. 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. Scan results binarized as positive AD pattern versus negative AD pattern. Results are displayed as percentage of agreement for individual reader pairs, computed as follows: number of images for which reader had the same interpretation divided by the total number of images evaluated, multiplied by 100%. | Analysis included all subjects who had a valid flortaucipir PET scan in the autopsy and non-autopsy groups (n=241) | Posted | Number | percentage agreement of cases | baseline scan |
|
|
|
|
| Secondary | Secondary Objective 1 Analysis 1: Diagnostic Performance of Ï„AD++ Flortaucipir PET Images to Detect B3 NFTs | Flortaucipir F 18 PET imaging will be classified by each reader as either neocortical uptake not consistent with AD (Ï„AD-), neocortical uptake consistent with AD (Ï„AD+), or neocortical uptake consistent with AD with uptake beyond the temporal/occipital regions (Ï„AD++). NFT scoring is according to Hyman, et al 2012. Truth positive is a NFT B3 score. Truth negative is NFT \ | Analysis included all autopsy subjects with an evaluable flortaucipir PET scan interpretation (n=82). One autopsy subject scan was rated as unevaluable. n=47 were truth positive for NFTs. n=35 were truth negative for NFTs. | Posted | Number | 95% Confidence Interval | percentage cases correctly identified | baseline scan |
|
|
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| Secondary | Secondary Objective 1 Analysis 2: Diagnostic Performance of Ï„AD++ Flortaucipir PET Images to Detect High ADNC | Sensitivity and specificity of 5 independent readers' interpretations of ante-mortem 18F-AV-1451 PET imaging for detection of a pattern of 18F-AV-1451 neocortical uptake that corresponds to high levels of AD neuropathologic change (High ADNC) as defined by National Institute on Aging-Alzheimer's Association (NIA-AA) criteria (Hyman et al. 2012). Truth positive is a High ADNC score. Truth negative is No/Low/Intermediate ADNC score. | Analysis included all autopsy subjects with an evaluable flortaucipir PET scan interpretation (n=82). One autopsy subject scan was rated as unevaluable. n=41 were truth positive. n=41 were truth negative. | Posted | Number | 95% Confidence Interval | percentage of cases correctly identified | baseline scan |
|
|
|
| Secondary | Secondary Objective 2: Inter-reader Reliability of Reader Interpretation of Ï„AD++ Flortaucipir PET Images | Overall reader agreement as measured by Fleiss' Kappa statistic. Scan results binarized as Ï„AD++ versus Ï„AD+/Ï„AD-. Results are displayed as percentage of agreement for individual reader pairs, computed as follows: number of images for which reader had the same interpretation divided by the total number of images evaluated, multiplied by 100%. | Analysis included all subjects who had a valid flortaucipir PET scan in the autopsy and non-autopsy groups (n=241) | Posted | Number | percentage agreement of cases | baseline scan |
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|
|
|
| Secondary | Secondary Objective 3: Inter-reader Reliability of Flortaucipir PET Scan Interpretation in the Population of Intended Use | Reader agreement measured by Fleiss' Kappa across scans from non-autopsy cases from Study A05. Scan results binarized as positive for AD pattern versus negative for AD pattern. Results are displayed as percentage of agreement for individual reader pairs, computed as follows: number of images for which reader had the same interpretation divided by the total number of images evaluated, multiplied by 100%. | Non-autopsy cases from Study A05 | Posted | Number | percentage agreement of cases | baseline scan |
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| Secondary | Secondary Objective 4: Intra-reader Reliability of Reader Interpretation of Flortaucipir-PET Imaging | Cohen's Kappa will be calculated for each of 5 readers to assess the intra-reader reliability of flortaucipir F 18 PET scan visual interpretation. The statistic takes into account the possibility of the agreement occurring by chance. Cohen's kappa values range from 0 to 1 with 1 representing perfect agreement. Results are displayed as percentage of agreement within a reader, computed as follows: number of images for which reader had the same interpretation at initial and second read divided by the total number of images evaluated twice by a reader, multiplied by 100%. | 20 scans read twice to assess the intra-reader reliability | Posted | Number | percentage agreement of cases | baseline scan |
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| D024801 |
| Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Title | Measurements |
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| Reader 3 v Reader 4 |
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| Reader 4 |
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| Reader 5 |
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| Title | Measurements |
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| Reader 1 v Reader 5 |
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| Reader 2 v Reader 3 |
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| Reader 2 v Reader 4 |
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| Reader 2 v Reader 5 |
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| Reader 3 v Reader 4 |
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| Reader 3 v Reader 5 |
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| Reader 4 v Reader 5 |
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| Title | Measurements |
|---|---|
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| Reader 1 v Reader 5 |
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| Reader 2 v Reader 3 |
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| Reader 2 v Reader 4 |
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| Reader 2 v Reader 5 |
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| Reader 3 v Reader 4 |
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| Reader 3 v Reader 5 |
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| Reader 4 v Reader 5 |
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| Title | Measurements |
|---|---|
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| Reader 4 |
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| Reader 5 |
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| Cohen's kappa |
| 0.71 |
| 2-Sided |
| 95 |
| 0.41 |
| 1.00 |
| Other |
| Cohen's kappa statistic for Reader 3 | Cohen's kappa | 0.60 | 2-Sided | 95 | 0.24 | 0.95 | Other |
| Cohen's kappa statistic for Reader 4 | Cohen's kappa | 0.89 | 2-Sided | 95 | 0.67 | 1.00 | Other |
| Cohen's kappa statistic for Reader 5 | Cohen's kappa | 0.79 | 2-Sided | 95 | 0.52 | 1.00 | Other |