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

• 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: Avid Radiopharmaceuticals
• Information provided by (Responsible Party): Avid Radiopharmaceuticals

Tracking Information

• First Submitted Date: March 27, 2019
• First Posted Date: April 3, 2019
• Results First Submitted Date: June 27, 2020
• Results First Posted Date: August 11, 2020
• Last Update Posted Date: September 9, 2020
• Actual Study Start Date: March 26, 2019
• Actual Primary Completion Date: April 26, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 21, 2020)

• Primary Objective 1 Analysis 1: Diagnostic Performance of Individual Readers (NFT Score) [ Time Frame: baseline scan ]
  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.
• Primary Objective 1 Analysis 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis) [ Time Frame: baseline scan ]
  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.
• Primary Objective 2: Inter-reader Reliability of Reader Interpretation of Flortaucipir-PET Imaging [ Time Frame: baseline scan ]
  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%.

Original Primary Outcome Measures (submitted: April 1, 2019)

• Sensitivity and specificity of reader interpretation of Flortaucipir-PET images read as τAD+/τAD++, to detect NFT (neurofibrillary tangles) score of B3. [ Time Frame: Within 6 months of autopsy ]
  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 and likely to progress (τAD++). Truth standard is autopsy NFT score (Hyman, et al 2012).
• Sensitivity and specificity of reader interpretation of Flortaucipir-PET images read as τAD+/τAD++, to detect high AD neuropathological change. [ Time Frame: Within 6 months of autopsy ]
  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 and likely to progress (τAD++). Truth standard is NIA-AA autopsy diagnosis (Hyman, et al 2012).
• Inter-reader reliability of reader interpretation of Flortaucipir-PET imaging [ Time Frame: Within 6 months of autopsy ]
  As measured by Fleiss' Kappa across all scans read. Scan results binarized as τAD+/τAD++ versus τAD-.

Current Secondary Outcome Measures (submitted: July 21, 2020)

• Secondary Objective 1 Analysis 1: Diagnostic Performance of τAD++ Flortaucipir PET Images to Detect B3 NFTs [ Time Frame: baseline scan ]
  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.
• Secondary Objective 1 Analysis 2: Diagnostic Performance of τAD++ Flortaucipir PET Images to Detect High ADNC [ Time Frame: baseline scan ]
  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.
• Secondary Objective 2: Inter-reader Reliability of Reader Interpretation of τAD++ Flortaucipir PET Images [ Time Frame: baseline scan ]
  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%.
• Secondary Objective 3: Inter-reader Reliability of Flortaucipir PET Scan Interpretation in the Population of Intended Use [ Time Frame: baseline scan ]
  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%.
• Secondary Objective 4: Intra-reader Reliability of Reader Interpretation of Flortaucipir-PET Imaging [ Time Frame: baseline scan ]
  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%.

Original Secondary Outcome Measures (submitted: April 1, 2019)

• Sensitivity and specificity of reader interpretation of Flortaucipir-PET images read as τAD++, to detect NFT (neurofibrillary tangles) score of B3 (Hyman, et al 2012). [ Time Frame: Within 6 months of autopsy ]
  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 and likely to progress (τAD++). Truth standard is autopsy NFT score (Hyman, et al 2012).
• Sensitivity and specificity of reader interpretation of Flortaucipir-PET images read as τAD++, to detect high AD neuropathological change (Hyman, et al 2012). [ Time Frame: Within 6 months of autopsy ]
  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 and likely to progress (τAD++). Truth standard is NIA-AA autopsy diagnosis (Hyman, et al 2012).
• Inter-reader reliability of reader interpretation of Flortaucipir-PET imaging [ Time Frame: Within 6 months of autopsy ]
  As measured by Fleiss' Kappa across all scans read. Scan results binarized as τAD++ versus τAD+/τAD-.
• Inter-reader reliability of reader interpretation of Flortaucipir-PET imaging [ Time Frame: Within 6 months of autopsy ]
  As measured by Fleiss' Kappa across 60 scans from Study A05. Scan results binarized as τAD+/τAD++ versus τAD-.
• Intra-reader reliability of reader interpretation of Flortaucipir-PET imaging [ Time Frame: Within 6 months of autopsy ]
  Twenty scans will be randomly selected from the 143 cases included for this study, and the 5 readers will read them in random sequence along with other scans. Cohen's Kappa will be calculated for each of these 5 readers, based on these 20 scans read twice to assess the intra-reader reliability of flortaucipir F 18 PET scan visual interpretation.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Reader Study to Assess Accuracy and Reliability of Flortaucipir F 18 Positron Emission Tomography (PET) Scan Interpretation
• Official Title: A Reader Study to Assess Accuracy and Reliability of Flortaucipir F 18 PET Scan Interpretation
• Brief Summary: This study will evaluate the performance of physician readers trained to read flortaucipir-PET (positron emission tomography) scans.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

Physician PET scan readers are participants, blinded to demographic and clinical data from the source PET scans.

Masking: None (Open Label)
Masking Description:

PET scans were obtained in an open-label fashion.

Primary Purpose: Diagnostic

• Condition: Alzheimer Disease

Intervention

Drug: flortaucipir F 18

No study drug will be administered.

Other Names:

• 18F-AV-1451
• [F-18]T807
• LY3191748

Study Arms

Experimental: Flortaucipir PET Scan

Scans previously acquired from Study A16 (NCT02516046) and A05 (NCT02016560) will be read by independent, blinded readers.

Intervention: Drug: flortaucipir F 18

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 27, 2020): 242
• Original Estimated Enrollment (submitted: April 1, 2019): 143
• Actual Study Completion Date: April 26, 2019
• Actual Primary Completion Date: April 26, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Scan Reader Criteria (5 total):

• Board-certified in radiology or nuclear medicine
• Professional experience interpreting PET scans
• Naive to study protocol
• No previous training or exposure to Avid Flortaucipir F 18 read methodology

Scan Criteria:

- Previous enrollment in Study A05 confirmatory cohort (NCT02016560), or A16 (NCT02516046)

Scan Study Population Criteria for FR01 (A05 confirmatory cohort):

• Cognitively-impaired
• mild cognitive impairment (MCI) or dementia with suspected neurodegenerative cause
• mini-mental status exam (MMSE) score of 20-27, inclusive

Scan Study Population Criteria for FR01 (Study A16):

• Subjects at end of life (less than or equal to 6 months)
• Imaged with flortaucipir F18 and came to autopsy

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03901092
• Other Study ID Numbers: 18F-AV-1451-FR01
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Avid Radiopharmaceuticals
• Original Responsible Party: Same as current
• Current Study Sponsor: Avid Radiopharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Study Director; Avid Radiopharmaceuticals

• PRS Account: Avid Radiopharmaceuticals
• Verification Date: August 2020