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A Reader Study to Assess Accuracy and Reliability of Flortaucipir F 18 Positron Emission Tomography (PET) Scan Interpretation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03901092
Recruitment Status : Completed
First Posted : April 3, 2019
Results First Posted : August 11, 2020
Last Update Posted : September 9, 2020
Sponsor:
Information provided by (Responsible Party):
Avid Radiopharmaceuticals

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Diagnostic
Condition Alzheimer Disease
Intervention Drug: flortaucipir F 18
Enrollment 242
Recruitment Details 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.
Pre-assignment Details  
Arm/Group Title All Autopsy Cases Non-Autopsy Cases
Hide Arm/Group Description Cases that had a valid scan and came to autopsy in in study A16 and the A16 supplemental cohort Mild cognitive impairment (MCI) and AD cases from the A05 confirmatory cohort
Period Title: Overall Study
Started 83 159
Completed 83 159
Not Completed 0 0
Arm/Group Title All Cases
Hide Arm/Group Description All eligible subject scans from contributing studies
Overall Number of Baseline Participants 242
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Study A16 Autopsy Cases Number Analyzed 83 participants
81.6  (9.91)
Study A05 Non-autopsy Cases Number Analyzed 159 participants
72.9  (9.64)
[1]
Measure Analysis Population Description: Baseline analysis includes Study A16 autopsy cases (n=83) and Study A05 Non-autopsy cases (n=159).
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Study A16 Autopsy Cases Number Analyzed 83 participants
Female
41
  49.4%
Male
42
  50.6%
Study A05 Non-autopsy Cases Number Analyzed 159 participants
Female
74
  46.5%
Male
85
  53.5%
[1]
Measure Analysis Population Description: Baseline analysis includes Study A16 autopsy cases (n=83) and Study A05 Non-autopsy cases (n=159).
Ethnicity (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Study A16 Autopsy Cases Number Analyzed 83 participants
Hispanic or Latino
4
   4.8%
Not Hispanic or Latino
79
  95.2%
Unknown or Not Reported
0
   0.0%
Study A05 Non-autopsy Cases Number Analyzed 159 participants
Hispanic or Latino
9
   5.7%
Not Hispanic or Latino
150
  94.3%
Unknown or Not Reported
0
   0.0%
[1]
Measure Analysis Population Description: Measure Analysis Population Description: Baseline analysis includes Study A16 autopsy cases (n=83) and Study A05 Non-autopsy cases (n=159).
Race (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Study A16 Autopsy Cases Number Analyzed 83 participants
American Indian or Alaska Native
0
   0.0%
Asian
1
   1.2%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
1
   1.2%
White
81
  97.6%
More than one race
0
   0.0%
Unknown or Not Reported
0
   0.0%
Study A05 Non-autopsy Cases Number Analyzed 159 participants
American Indian or Alaska Native
0
   0.0%
Asian
2
   1.3%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
3
   1.9%
White
154
  96.9%
More than one race
0
   0.0%
Unknown or Not Reported
0
   0.0%
[1]
Measure Analysis Population Description: Measure Analysis Population Description: Baseline analysis includes Study A16 autopsy cases (n=83) and Study A05 Non-autopsy cases (n=159).
1.Primary Outcome
Title Primary Objective 1 Analysis 1: Diagnostic Performance of Individual Readers (NFT Score)
Hide Description 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.
Time Frame baseline scan
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Sensitivity of Flortaucipir vs Autopsy NFT Score Specificity of Flortaucipir vs Autopsy NFT Score
Hide Arm/Group Description:
Subjects with a positive autopsy NFT score truth standard (NFT B3)
Subjects with a negative autopsy NFT score truth standard (NFT B2 or lower)
Overall Number of Participants Analyzed 47 35
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of cases correctly identified
Reader 1
91.5
(80.07 to 96.64)
77.1
(60.98 to 87.93)
Reader 2
89.4
(77.41 to 95.37)
91.4
(77.62 to 97.04)
Reader 3
87.2
(74.83 to 94.02)
85.7
(70.62 to 93.74)
Reader 4
93.6
(82.84 to 97.81)
62.9
(46.34 to 76.83)
Reader 5
89.4
(77.41 to 95.37)
77.1
(60.98 to 87.93)
2.Primary Outcome
Title Primary Objective 1 Analysis 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis)
Hide Description 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.
Time Frame baseline scan
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Sensitivity of Flortaucipir vs NIA-AA Autopsy Diagnosis Specificity of Flortaucipir vs NIA-AA Autopsy Diagnosis
Hide Arm/Group Description:
Subjects with a positive truth standard (High ADNC)
Subjects with a negative truth standard (No/Low/Intermediate ADNC)
Overall Number of Participants Analyzed 41 41
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of cases correctly identified
Reader 1
95.1
(83.86 to 98.65)
70.7
(55.52 to 82.39)
Reader 2
95.1
(83.86 to 98.65)
85.4
(71.56 to 93.12)
Reader 3
95.1
(83.86 to 98.65)
82.9
(68.74 to 91.47)
Reader 4
97.6
(87.40 to 99.57)
58.5
(43.37 to 72.24)
Reader 5
95.1
(83.86 to 98.65)
73.2
(58.07 to 84.31)
3.Primary Outcome
Title Primary Objective 2: Inter-reader Reliability of Reader Interpretation of Flortaucipir-PET Imaging
Hide Description 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%.
Time Frame baseline scan
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis included all subjects who had a valid flortaucipir PET scan in the autopsy and non-autopsy groups (n=241)
Arm/Group Title All Cases
Hide Arm/Group Description:
All autopsy and non-autopsy cases
Overall Number of Participants Analyzed 241
Measure Type: Number
Unit of Measure: percentage agreement of cases
Reader 1 v Reader 2 95.0
Reader 1 v Reader 3 93.4
Reader 1 v Reader 4 94.6
Reader 1 v Reader 5 97.1
Reader 2 v Reader 3 97.1
Reader 2 v Reader 4 91.3
Reader 2 v Reader 5 94.6
Reader 3 v Reader 4 91.3
Reader 3 v Reader 5 93.8
Reader 4 v Reader 5 95.0
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection All Cases
Comments 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. The primary hypothesis to be tested was that the lower bound of two-sided 95% confidence interval of Fleiss' Kappa will be greater than or equal to 0.6.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Fleiss' kappa
Estimated Value 0.87
Confidence Interval (2-Sided) 95%
0.83 to 0.91
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Secondary Objective 1 Analysis 1: Diagnostic Performance of τAD++ Flortaucipir PET Images to Detect B3 NFTs
Hide Description Flortaucipir F 18 PET imaging will be classified by each reader as either neocortical uptake not consistent with AD (τAD-), neocortical uptake consistent with AD (τAD+), or neocortical uptake consistent with AD with uptake beyond the temporal/occipital regions (τAD++). NFT scoring is according to Hyman, et al 2012. Truth positive is a NFT B3 score. Truth negative is NFT <B3 score.
Time Frame baseline scan
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Sensitivity of Flortaucipir tAD++ vs Autopsy NFT Score Specificity of Flortaucipir tAD++ vs Autopsy NFT Score
Hide Arm/Group Description:
Subjects with a positive autopsy NFT score truth standard (NFT B3)
Subjects with a negative autopsy NFT score truth standard (NFT B2 or lower)
Overall Number of Participants Analyzed 47 35
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage cases correctly identified
Reader 1
87.2
(74.83 to 94.02)
88.6
(74.05 to 95.46)
Reader 2
80.9
(67.46 to 89.58)
100.0
(90.11 to 100.00)
Reader 3
76.6
(62.78 to 86.40)
94.3
(81.39 to 98.42)
Reader 4
89.4
(77.41 to 95.37)
82.9
(67.32 to 91.90)
Reader 5
83.0
(69.86 to 91.11)
94.3
(81.39 to 98.42)
5.Secondary Outcome
Title Secondary Objective 1 Analysis 2: Diagnostic Performance of τAD++ Flortaucipir PET Images to Detect High ADNC
Hide Description 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.
Time Frame baseline scan
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Sensitivity Specificity
Hide Arm/Group Description:
Sensitivity individual Flortaucipir PET scan interpreted as τAD++ pattern versus NIA-AA autopsy Diagnosis Truth Standard
Specificity individual Flortaucipir PET scan interpreted as τAD++ pattern versus NIA-AA autopsy Diagnosis Truth Standard
Overall Number of Participants Analyzed 41 41
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of cases correctly identified
Reader 1
92.7
(80.57 to 97.48)
82.9
(68.74 to 91.47)
Reader 2
85.4
(71.56 to 93.12)
92.7
(80.57 to 97.48)
Reader 3
85.4
(71.56 to 93.12)
92.7
(80.57 to 97.48)
Reader 4
92.7
(80.57 to 97.48)
75.6
(60.66 to 86.17)
Reader 5
87.8
(74.46 to 94.68)
87.8
(74.46 to 94.68)
6.Secondary Outcome
Title Secondary Objective 2: Inter-reader Reliability of Reader Interpretation of τAD++ Flortaucipir PET Images
Hide Description Overall reader agreement as measured by Fleiss' Kappa statistic. Scan results binarized as τAD++ versus τAD+/τAD-. 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%.
Time Frame baseline scan
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis included all subjects who had a valid flortaucipir PET scan in the autopsy and non-autopsy groups (n=241)
Arm/Group Title All Cases
Hide Arm/Group Description:
All autopsy and non-autopsy cases
Overall Number of Participants Analyzed 241
Measure Type: Number
Unit of Measure: percentage agreement of cases
Reader 1 v Reader 2 92.5
Reader 1 v Reader 3 90.0
Reader 1 v Reader 4 91.3
Reader 1 v Reader 5 95.0
Reader 2 v Reader 3 91.7
Reader 2 v Reader 4 90.5
Reader 2 v Reader 5 94.2
Reader 3 v Reader 4 88.8
Reader 3 v Reader 5 92.5
Reader 4 v Reader 5 92.9
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection All Cases
Comments 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. The primary hypothesis to be tested was that the lower bound of two-sided 95% confidence interval of Fleiss' Kappa will be greater than or equal to 0.6.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Fleiss' kappa
Estimated Value 0.84
Confidence Interval (2-Sided) 95%
0.80 to 0.88
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Secondary Objective 3: Inter-reader Reliability of Flortaucipir PET Scan Interpretation in the Population of Intended Use
Hide Description 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%.
Time Frame baseline scan
Hide Outcome Measure Data
Hide Analysis Population Description
Non-autopsy cases from Study A05
Arm/Group Title A05 Cases
Hide Arm/Group Description:
All non-autopsy cases from the Study A05 population of intended use
Overall Number of Participants Analyzed 159
Measure Type: Number
Unit of Measure: percentage agreement of cases
Reader 1 v Reader 2 97.5
Reader 1 v Reader 3 93.1
Reader 1 v Reader 4 95.6
Reader 1 v Reader 5 97.5
Reader 2 v Reader 3 93.1
Reader 2 v Reader 4 94.3
Reader 2 v Reader 5 96.2
Reader 3 v Reader 4 93.7
Reader 3 v Reader 5 93.1
Reader 4 v Reader 5 96.9
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection A05 Cases
Comments 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. The hypothesis to be tested was that the lower bound of two-sided 95% confidence interval of Fleiss' Kappa will be greater than or equal to 0.6.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Fleiss' kappa
Estimated Value 0.90
Confidence Interval (2-Sided) 95%
0.85 to 0.95
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Secondary Objective 4: Intra-reader Reliability of Reader Interpretation of Flortaucipir-PET Imaging
Hide Description 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%.
Time Frame baseline scan
Hide Outcome Measure Data
Hide Analysis Population Description
20 scans read twice to assess the intra-reader reliability
Arm/Group Title Randomly Selected Re-reads
Hide Arm/Group Description:
Cases randomly selected to be read twice by the same reader
Overall Number of Participants Analyzed 20
Measure Type: Number
Unit of Measure: percentage agreement of cases
Reader 1 95.0
Reader 2 85.0
Reader 3 80.0
Reader 4 95.0
Reader 5 90.0
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Randomly Selected Re-reads
Comments Cohen's kappa statistic for Reader 1
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Cohen's kappa
Estimated Value 0.89
Confidence Interval (2-Sided) 95%
0.69 to 1.00
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Randomly Selected Re-reads
Comments Cohen's kappa statistic for Reader 2
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Cohen's kappa
Estimated Value 0.71
Confidence Interval (2-Sided) 95%
0.41 to 1.00
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Randomly Selected Re-reads
Comments Cohen's kappa statistic for Reader 3
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Cohen's kappa
Estimated Value 0.60
Confidence Interval (2-Sided) 95%
0.24 to 0.95
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Randomly Selected Re-reads
Comments Cohen's kappa statistic for Reader 4
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Cohen's kappa
Estimated Value 0.89
Confidence Interval (2-Sided) 95%
0.67 to 1.00
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Randomly Selected Re-reads
Comments Cohen's kappa statistic for Reader 5
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Cohen's kappa
Estimated Value 0.79
Confidence Interval (2-Sided) 95%
0.52 to 1.00
Estimation Comments [Not Specified]
Time Frame Not applicable. Adverse events were not assessed during this study.
Adverse Event Reporting Description Adverse events were not assessed during this study.
 
Arm/Group Title All Cases
Hide Arm/Group Description No study drug will be administered. Scans previously acquired from Study A16 (NCT02516046) and A05 (NCT02016560) will be read by independent, blinded readers.
All-Cause Mortality
All Cases
Affected / at Risk (%)
Total   0/0 
Hide Serious Adverse Events
All Cases
Affected / at Risk (%)
Total   0/0 
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0.5%
All Cases
Affected / at Risk (%)
Total   0/0 
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Director
Organization: Avid Radiopharmaceuticals, Inc.
Phone: 215-298-0700
EMail: clinicaloperations@avidrp.com
Layout table for additonal information
Responsible Party: Avid Radiopharmaceuticals
ClinicalTrials.gov Identifier: NCT03901092    
Other Study ID Numbers: 18F-AV-1451-FR01
First Submitted: March 27, 2019
First Posted: April 3, 2019
Results First Submitted: June 27, 2020
Results First Posted: August 11, 2020
Last Update Posted: September 9, 2020