Trial Outcomes & Findings for 18F-AV-1451 Autopsy Study (NCT NCT02516046)
NCT ID: NCT02516046
Last Updated: 2020-09-07
Results Overview
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.
COMPLETED
PHASE3
156 participants
at autopsy within 9 months of baseline scan
2020-09-07
Participant Flow
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.
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.
Participant milestones
| Measure |
All Enrolled Cohort
End-of-life subjects consenting to brain donation at autopsy from the flortaucipir PET scan arm
|
|---|---|
|
Overall Study
STARTED
|
156
|
|
Overall Study
Died While on Study
|
73
|
|
Overall Study
Valid Autopsy Results and PET Scan
|
67
|
|
Overall Study
COMPLETED
|
64
|
|
Overall Study
NOT COMPLETED
|
92
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
18F-AV-1451 Autopsy Study
Baseline characteristics by cohort
| Measure |
All Enrolled Cohort
n=156 Participants
All subjects consenting to flortaucipir PET and brain donation at autopsy
|
|---|---|
|
Age, Continuous
|
80.2 years
STANDARD_DEVIATION 12.51 • n=99 Participants
|
|
Sex: Female, Male
Female
|
86 Participants
n=99 Participants
|
|
Sex: Female, Male
Male
|
70 Participants
n=99 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
20 Participants
n=99 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
136 Participants
n=99 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=99 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=99 Participants
|
|
Race (NIH/OMB)
Asian
|
2 Participants
n=99 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=99 Participants
|
|
Race (NIH/OMB)
Black or African American
|
11 Participants
n=99 Participants
|
|
Race (NIH/OMB)
White
|
143 Participants
n=99 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=99 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=99 Participants
|
|
Region of Enrollment
United States
|
151 participants
n=99 Participants
|
|
Region of Enrollment
Australia
|
5 participants
n=99 Participants
|
PRIMARY outcome
Timeframe: at autopsy within 9 months of baseline scanPopulation: Autopsy cohort N=64. n=39 were truth positive for NFTs. n=25 were truth negative for NFTs.
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.
Outcome measures
| Measure |
Sensitivity of Flortaucipir vs Autopsy NFT Score B3
n=39 Participants
Subjects with a positive autopsy NFT score truth standard (NFT B3)
|
Specificity of Flortaucipir vs Autopsy NFT Score <B3
n=25 Participants
Subjects with a negative autopsy NFT score truth standard (NFT B2 or lower)
|
|---|---|---|
|
Primary Outcome 1: Diagnostic Performance of Individual Readers (NFT Score)
Reader 2
|
92.3 percentage of cases correctly identified
Interval 79.7 to 97.3
|
92.0 percentage of cases correctly identified
Interval 75.0 to 97.8
|
|
Primary Outcome 1: Diagnostic Performance of Individual Readers (NFT Score)
Reader 5
|
100 percentage of cases correctly identified
Interval 91.0 to 100.0
|
52.0 percentage of cases correctly identified
Interval 33.5 to 70.0
|
|
Primary Outcome 1: Diagnostic Performance of Individual Readers (NFT Score)
Reader 1
|
97.4 percentage of cases correctly identified
Interval 86.8 to 99.5
|
68.0 percentage of cases correctly identified
Interval 48.4 to 82.8
|
|
Primary Outcome 1: Diagnostic Performance of Individual Readers (NFT Score)
Reader 3
|
92.3 percentage of cases correctly identified
Interval 79.7 to 97.3
|
88.0 percentage of cases correctly identified
Interval 70.0 to 95.8
|
|
Primary Outcome 1: Diagnostic Performance of Individual Readers (NFT Score)
Reader 4
|
92.3 percentage of cases correctly identified
Interval 79.7 to 97.3
|
76.0 percentage of cases correctly identified
Interval 56.6 to 88.5
|
PRIMARY outcome
Timeframe: at autopsy within 9 months of baseline scanPopulation: Autopsy cohort N=64. n=38 were truth positive for NFTs. n=26 were truth negative for NFTs.
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.
Outcome measures
| Measure |
Sensitivity of Flortaucipir vs Autopsy NFT Score B3
n=38 Participants
Subjects with a positive autopsy NFT score truth standard (NFT B3)
|
Specificity of Flortaucipir vs Autopsy NFT Score <B3
n=26 Participants
Subjects with a negative autopsy NFT score truth standard (NFT B2 or lower)
|
|---|---|---|
|
Primary Outcome 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis)
Reader 2
|
95.0 percentage of cases correctly identified
Interval 83.5 to 98.6
|
92.3 percentage of cases correctly identified
Interval 75.9 to 97.9
|
|
Primary Outcome 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis)
Reader 3
|
95.0 percentage of cases correctly identified
Interval 83.5 to 98.6
|
88.5 percentage of cases correctly identified
Interval 71.0 to 96.0
|
|
Primary Outcome 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis)
Reader 1
|
97.5 percentage of cases correctly identified
Interval 87.1 to 99.6
|
65.4 percentage of cases correctly identified
Interval 46.2 to 80.6
|
|
Primary Outcome 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis)
Reader 4
|
95.0 percentage of cases correctly identified
Interval 83.5 to 98.6
|
76.9 percentage of cases correctly identified
Interval 57.9 to 89.0
|
|
Primary Outcome 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis)
Reader 5
|
100 percentage of cases correctly identified
Interval 91.2 to 100.0
|
50.0 percentage of cases correctly identified
Interval 32.1 to 67.9
|
SECONDARY outcome
Timeframe: at autopsy within 9 months of baseline scanPopulation: Autopsy cohort N=64. n=39 were truth positive for NFTs. n=25 were truth negative for NFTs.
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.
Outcome measures
| Measure |
Sensitivity of Flortaucipir vs Autopsy NFT Score B3
n=39 Participants
Subjects with a positive autopsy NFT score truth standard (NFT B3)
|
Specificity of Flortaucipir vs Autopsy NFT Score <B3
n=25 Participants
Subjects with a negative autopsy NFT score truth standard (NFT B2 or lower)
|
|---|---|---|
|
Flortaucipir Diagnostic Performance (NFT Score)
|
92.3 percentage of cases correctly identified
Interval 79.7 to 97.3
|
80.0 percentage of cases correctly identified
Interval 60.9 to 91.1
|
SECONDARY outcome
Timeframe: at autopsy within 9 months of baseline scanPopulation: Autopsy cohort N=64. n=38 were truth positive for NFTs. n=26 were truth negative for NFTs.
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.
Outcome measures
| Measure |
Sensitivity of Flortaucipir vs Autopsy NFT Score B3
n=38 Participants
Subjects with a positive autopsy NFT score truth standard (NFT B3)
|
Specificity of Flortaucipir vs Autopsy NFT Score <B3
n=26 Participants
Subjects with a negative autopsy NFT score truth standard (NFT B2 or lower)
|
|---|---|---|
|
Flortaucipir Diagnostic Performance (NIA-AA Autopsy Diagnosis)
|
94.7 percentage of cases correctly identified
Interval 82.7 to 98.5
|
80.8 percentage of cases correctly identified
Interval 62.1 to 91.5
|
SECONDARY outcome
Timeframe: baseline scanFleiss' 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.
Outcome measures
| Measure |
Sensitivity of Flortaucipir vs Autopsy NFT Score B3
n=105 Participants
Subjects with a positive autopsy NFT score truth standard (NFT B3)
|
Specificity of Flortaucipir vs Autopsy NFT Score <B3
Subjects with a negative autopsy NFT score truth standard (NFT B2 or lower)
|
|---|---|---|
|
Inter-Reader Agreement
Reader 2 v Reader 3
|
0.96 proportion of agreed cases
|
—
|
|
Inter-Reader Agreement
Reader 3 v Reader 5
|
0.68 proportion of agreed cases
|
—
|
|
Inter-Reader Agreement
Reader 1 v Reader 3
|
0.79 proportion of agreed cases
|
—
|
|
Inter-Reader Agreement
Reader 1 v Reader 4
|
0.79 proportion of agreed cases
|
—
|
|
Inter-Reader Agreement
Reader 1 v Reader 5
|
0.81 proportion of agreed cases
|
—
|
|
Inter-Reader Agreement
Reader 2 v Reader 4
|
0.88 proportion of agreed cases
|
—
|
|
Inter-Reader Agreement
Reader 2 v Reader 5
|
0.65 proportion of agreed cases
|
—
|
|
Inter-Reader Agreement
Reader 3 v Reader 4
|
0.92 proportion of agreed cases
|
—
|
|
Inter-Reader Agreement
Reader 4 v Reader 5
|
0.72 proportion of agreed cases
|
—
|
|
Inter-Reader Agreement
Reader 1 v Reader 2
|
0.79 proportion of agreed cases
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: at autopsy within 9 months of baseline scanPopulation: Autopsy cohort N=64. n=56 were truth positive for NFTs. n=8 were truth negative for NFTs.
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.
Outcome measures
| Measure |
Sensitivity of Flortaucipir vs Autopsy NFT Score B3
n=56 Participants
Subjects with a positive autopsy NFT score truth standard (NFT B3)
|
Specificity of Flortaucipir vs Autopsy NFT Score <B3
n=8 Participants
Subjects with a negative autopsy NFT score truth standard (NFT B2 or lower)
|
|---|---|---|
|
Diagnostic Performance of Individual Readers (NFT Score B2-B3 as Truth Positive)
Reader 3
|
67.9 percentage of cases correctly identified
Interval 54.8 to 78.6
|
87.5 percentage of cases correctly identified
Interval 52.9 to 97.8
|
|
Diagnostic Performance of Individual Readers (NFT Score B2-B3 as Truth Positive)
Reader 1
|
80.4 percentage of cases correctly identified
Interval 68.2 to 88.7
|
87.5 percentage of cases correctly identified
Interval 52.9 to 97.8
|
|
Diagnostic Performance of Individual Readers (NFT Score B2-B3 as Truth Positive)
Reader 2
|
67.9 percentage of cases correctly identified
Interval 54.8 to 78.6
|
100.0 percentage of cases correctly identified
Interval 67.6 to 100.0
|
|
Diagnostic Performance of Individual Readers (NFT Score B2-B3 as Truth Positive)
Reader 4
|
73.2 percentage of cases correctly identified
Interval 60.4 to 83.0
|
87.5 percentage of cases correctly identified
Interval 52.9 to 97.8
|
|
Diagnostic Performance of Individual Readers (NFT Score B2-B3 as Truth Positive)
Reader 5
|
85.7 percentage of cases correctly identified
Interval 74.3 to 92.6
|
62.5 percentage of cases correctly identified
Interval 30.6 to 86.3
|
Adverse Events
Safety Analysis Population
Serious adverse events
| Measure |
Safety Analysis Population
n=156 participants at risk
All enrolled subjects from the flortaucipir PET scan arm who received one dose of flortaucipir
|
|---|---|
|
Renal and urinary disorders
acute kidney injury
|
0.64%
1/156 • Number of events 1 • 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.
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
malignant neoplasm
|
0.64%
1/156 • Number of events 1 • 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.
|
|
Cardiac disorders
myocardial infarction
|
0.64%
1/156 • Number of events 1 • 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.
|
Other adverse events
| Measure |
Safety Analysis Population
n=156 participants at risk
All enrolled subjects from the flortaucipir PET scan arm who received one dose of flortaucipir
|
|---|---|
|
Cardiac disorders
myocardial infarction
|
0.64%
1/156 • Number of events 1 • 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.
|
|
Ear and labyrinth disorders
vertigo
|
0.64%
1/156 • Number of events 1 • 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.
|
|
Gastrointestinal disorders
diarrhoea
|
0.64%
1/156 • Number of events 1 • 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.
|
|
Gastrointestinal disorders
nausea
|
0.64%
1/156 • Number of events 1 • 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.
|
|
General disorders
injection site bruising
|
0.64%
1/156 • Number of events 1 • 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.
|
|
Injury, poisoning and procedural complications
fall
|
0.64%
1/156 • Number of events 1 • 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.
|
|
Injury, poisoning and procedural complications
procedural vomiting
|
0.64%
1/156 • Number of events 1 • 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.
|
|
Metabolism and nutrition disorders
hypomagnesaemia
|
0.64%
1/156 • Number of events 1 • 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.
|
|
Musculoskeletal and connective tissue disorders
myopathy
|
0.64%
1/156 • Number of events 1 • 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.
|
|
Nervous system disorders
headache
|
1.3%
2/156 • Number of events 2 • 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.
|
|
Nervous system disorders
dizziness postural
|
0.64%
1/156 • Number of events 1 • 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.
|
|
Nervous system disorders
hypoxic-ischaemic encephalopathy
|
0.64%
1/156 • Number of events 1 • 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.
|
|
Nervous system disorders
tremor
|
0.64%
1/156 • Number of events 1 • 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.
|
|
Psychiatric disorders
agitation
|
1.9%
3/156 • Number of events 3 • 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.
|
|
Psychiatric disorders
mental disorder
|
0.64%
1/156 • Number of events 1 • 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.
|
|
Psychiatric disorders
restlessness
|
0.64%
1/156 • Number of events 1 • 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.
|
|
Cardiac disorders
Cardiac failure congestive
|
0.64%
1/156 • Number of events 1 • 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.
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place
Restriction type: LTE60