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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Flortaucipir PET Scan | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Flortaucipir F18 | Drug | 370 megabecquerel (MBq) IV single-dose |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | at autopsy within 9 months of baseline scan |
| 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. | at autopsy within 9 months of baseline scan |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Chief Medical Officer | Avid Radiopharmaceuticals, Inc. | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Banner Alzheimer's Institute | Phoenix | Arizona | 85006 | United States | ||
| St. Joseph's Hospital and Medical Center |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22265587 | Background | Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Thies B, Trojanowski JQ, Vinters HV, Montine TJ. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement. 2012 Jan;8(1):1-13. doi: 10.1016/j.jalz.2011.10.007. | |
| 22101365 |
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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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | All Enrolled Cohort | End-of-life subjects consenting to brain donation at autopsy from the flortaucipir PET scan arm |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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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 | Dec 18, 2017 | Jun 27, 2020 |
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| PET Scan | Procedure | positron emission tomography (PET) scan |
|
| at autopsy within 9 months of baseline scan |
| 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. | at autopsy within 9 months of baseline scan |
| 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. | baseline scan |
| at autopsy within 9 months of baseline scan |
| Phoenix |
| Arizona |
| 85013 |
| United States |
| Cherlin Research | Los Gatos | California | 95032 | United States |
| Hoag Memorial Hospital Presbyterian | Newport Beach | California | 92658 | United States |
| California Research Foundation | San Diego | California | 92103 | United States |
| Pacific Research Network | San Diego | California | 92103 | United States |
| Ray Dolby Brain Health Center | San Francisco | California | 94114 | United States |
| Syrentis Clinical Research | Santa Ana | California | 92705 | United States |
| Neuropsychiatric Research Center of Southwest Florida | Fort Myers | Florida | 33912 | United States |
| Galiz Research | Hialeah | Florida | 33016 | United States |
| Merritt Island Medical Research | Merritt Island | Florida | 32952 | United States |
| Miami Jewish Health Systems | Miami | Florida | 33137 | United States |
| D de la Vega MD Research Group | Miami | Florida | 33185 | United States |
| Bioclinica | Orlando | Florida | 32806 | United States |
| Emory University Brain Health Center | Atlanta | Georgia | 30329 | United States |
| Alzheimer's Disease Center | Quincy | Massachusetts | 02169 | United States |
| Steinberg Diagnostics | Henderson | Nevada | 89052 | United States |
| Adirondack Medical Research Center | Glens Falls | New York | 12801 | United States |
| Clarity Clinical Research, LLC | Syracuse | New York | 13210 | United States |
| Duke University Medical Center | Durham | North Carolina | 27710 | United States |
| Wake Forest School of Medicine | Winston-Salem | North Carolina | 27157 | United States |
| Valley Medical Primary Care | Centerville | Ohio | 45459 | United States |
| Hospice of the Western Reserve | Cleveland | Ohio | 44119 | United States |
| American Clinical Trials, LLC (Site 1216) | Oklahoma City | Oklahoma | 73112 | United States |
| Oklahoma Behavioral Health | Oklahoma City | Oklahoma | 73112 | United States |
| Rhode Island Hospital | Providence | Rhode Island | 02903 | United States |
| Houston Methodist Research Institute | Houston | Texas | 77030 | United States |
| Sante Clinical Research | Kerrville | Texas | 78028 | United States |
| Overlake Internal Medicine Associates, PS | Bellevue | Washington | 98004 | United States |
| University of Washington Medicine | Seattle | Washington | 98104 | United States |
| University of Melbourne | Parkville | Victoria | 3010 | Australia |
| Background |
| Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Trojanowski JQ, Vinters HV, Hyman BT; National Institute on Aging; Alzheimer's Association. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach. Acta Neuropathol. 2012 Jan;123(1):1-11. doi: 10.1007/s00401-011-0910-3. Epub 2011 Nov 20. |
| 32338734 | Result | Fleisher AS, Pontecorvo MJ, Devous MD Sr, Lu M, Arora AK, Truocchio SP, Aldea P, Flitter M, Locascio T, Devine M, Siderowf A, Beach TG, Montine TJ, Serrano GE, Curtis C, Perrin A, Salloway S, Daniel M, Wellman C, Joshi AD, Irwin DJ, Lowe VJ, Seeley WW, Ikonomovic MD, Masdeu JC, Kennedy I, Harris T, Navitsky M, Southekal S, Mintun MA; A16 Study Investigators. Positron Emission Tomography Imaging With [18F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes. JAMA Neurol. 2020 Jul 1;77(7):829-839. doi: 10.1001/jamaneurol.2020.0528. |
| 32542468 | Derived | Pontecorvo MJ, Keene CD, Beach TG, Montine TJ, Arora AK, Devous MD Sr, Navitsky M, Kennedy I, Joshi AD, Lu M, Serrano GE, Sue LI, Intorcia AJ, Rose SE, Wilson A, Hellstern L, Coleman N, Flitter M, Aldea P, Fleisher AS, Mintun MA, Siderowf A. Comparison of regional flortaucipir PET with quantitative tau immunohistochemistry in three subjects with Alzheimer's disease pathology: a clinicopathological study. EJNMMI Res. 2020 Jun 15;10(1):65. doi: 10.1186/s13550-020-00653-x. |
| Died While on Study |
|
| Valid Autopsy Results and PET Scan |
|
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | All Enrolled Cohort | All subjects consenting to flortaucipir PET and brain donation at autopsy |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| ||||||||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| |||||||||||||||||||||||
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
| |||||||||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| |||||||||||||||||||||||
| Region of Enrollment | Number | participants |
|
| 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 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. | Autopsy cohort N=64. n=39 were truth positive for NFTs. n=25 were truth negative for NFTs. | Posted | Number | 95% Confidence Interval | percentage of cases correctly identified | at autopsy within 9 months of baseline scan |
|
|
| |||||||||||||||||||||||||||||||||||
| 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. | Autopsy cohort N=64. n=38 were truth positive for NFTs. n=26 were truth negative for NFTs. | Posted | Number | 95% Confidence Interval | percentage of cases correctly identified | at autopsy within 9 months of baseline scan |
| |||||||||||||||||||||||||||||||||||||
| 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. | Autopsy cohort N=64. n=39 were truth positive for NFTs. n=25 were truth negative for NFTs. | Posted | Number | 95% Confidence Interval | percentage of cases correctly identified | at autopsy within 9 months of baseline scan |
|
| ||||||||||||||||||||||||||||||||||||
| 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. | Autopsy cohort N=64. n=38 were truth positive for NFTs. n=26 were truth negative for NFTs. | Posted | Number | 95% Confidence Interval | percentage of cases correctly identified | at autopsy within 9 months of baseline scan |
|
| ||||||||||||||||||||||||||||||||||||
| 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. | Posted | Number | proportion of agreed cases | baseline scan |
|
| ||||||||||||||||||||||||||||||||||||||
| 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. | Autopsy cohort N=64. n=56 were truth positive for NFTs. n=8 were truth negative for NFTs. | Posted | Number | 95% Confidence Interval | percentage of cases correctly identified | at autopsy within 9 months of baseline scan |
|
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9 months after flortaucipir scan, up to a total of 18 months if a subject was re-scanned per protocol
Adverse events (AEs) were collected at scan visits, regardless of attribution to study drug. End of study for AE reporting was 48 hours after the last study drug administration. AEs occurring after study drug administration, but outside that window were not recorded, unless considered attributable to study drug.
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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 | Safety Analysis Population | All enrolled subjects from the flortaucipir PET scan arm who received one dose of flortaucipir | 73 | 156 | 3 | 156 | 14 | 156 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| acute kidney injury | Renal and urinary disorders | 18.1 | Systematic Assessment |
| |
| malignant neoplasm | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 18.1 | Systematic Assessment |
| |
| myocardial infarction | Cardiac disorders | 18.1 | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| myocardial infarction | Cardiac disorders | 18.1 | Systematic Assessment |
| |
| vertigo | Ear and labyrinth disorders | 18.1 | Systematic Assessment |
| |
| diarrhoea | Gastrointestinal disorders | 18.1 | Systematic Assessment |
| |
| nausea | Gastrointestinal disorders | 18.1 | Systematic Assessment |
| |
| injection site bruising | General disorders | 18.1 | Systematic Assessment |
| |
| fall | Injury, poisoning and procedural complications | 18.1 | Systematic Assessment |
| |
| procedural vomiting | Injury, poisoning and procedural complications | 18.1 | Systematic Assessment |
| |
| hypomagnesaemia | Metabolism and nutrition disorders | 18.1 | Systematic Assessment |
| |
| myopathy | Musculoskeletal and connective tissue disorders | 18.1 | Systematic Assessment |
| |
| headache | Nervous system disorders | 18.1 | Systematic Assessment |
| |
| dizziness postural | Nervous system disorders | 18.1 | Systematic Assessment |
| |
| hypoxic-ischaemic encephalopathy | Nervous system disorders | 18.1 | Systematic Assessment |
| |
| tremor | Nervous system disorders | 18.1 | Systematic Assessment |
| |
| agitation | Psychiatric disorders | 18.1 | Systematic Assessment |
| |
| mental disorder | Psychiatric disorders | 18.1 | Systematic Assessment |
| |
| restlessness | Psychiatric disorders | 18.1 | Systematic Assessment |
| |
| Cardiac failure congestive | Cardiac disorders | 18.1 | Systematic Assessment |
|
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Medical Director | Avid Radiopharmaceuticals, Inc. | 215-298-0700 | clinicaloperations@avidrp.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Aug 15, 2018 | Jun 27, 2020 | SAP_001.pdf |
| ID | Term |
|---|---|
| D000544 | Alzheimer Disease |
| ID | Term |
|---|---|
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D024801 | Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
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Not provided
| ID | Term |
|---|---|
| C000591008 | 7-(6-fluoropyridin-3-yl)-5H-pyrido(4,3-b)indole |
| D009682 | Magnetic Resonance Spectroscopy |
| ID | Term |
|---|---|
| D013057 | Spectrum Analysis |
| D002623 | Chemistry Techniques, Analytical |
| D008919 | Investigative Techniques |
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| Unknown or Not Reported |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
| Reader 3 |
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| Reader 4 |
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| Reader 5 |
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| Units | Counts |
|---|---|
| Participants |
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| Participants |
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