18F-AV-1451 Autopsy Study

• Sponsor: Avid Radiopharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02516046
• Collaborator: (none)
• Enrollment: 156
• Locations: 31
• Arm: 1
• Duration (Months): 34.4
• Patients Per Site: 5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Disease	Drug: Flortaucipir F18; Procedure: PET Scan	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 156 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: A Clinico-Pathological Study of the Correspondence Between 18F-AV-1451 PET Imaging and Post-Mortem Assessment of Tau Pathology
• Study Start Date: Sep 1, 2015
• Actual Primary Completion Date: Jun 13, 2018
• Actual Study Completion Date: Jul 15, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Flortaucipir PET Scan	Drug: Flortaucipir F18; 370 megabecquerel (MBq) IV single-dose; Other Names: [F-18]T807 18F-AV-1451 LY3191748 ; Procedure: PET Scan; positron emission tomography (PET) scan

Outcome Measures

Primary Outcome Measures

1. Primary Outcome 1: Diagnostic Performance of Individual Readers (NFT Score) [at autopsy within 9 months of baseline scan]

   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.

2. Primary Outcome 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis) [at autopsy within 9 months of baseline scan]

   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.

Secondary Outcome Measures

1. Flortaucipir Diagnostic Performance (NFT Score) [at autopsy within 9 months of baseline scan]

   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.

2. Flortaucipir Diagnostic Performance (NIA-AA Autopsy Diagnosis) [at autopsy within 9 months of baseline scan]

   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.

3. Inter-Reader Agreement [baseline scan]

   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.

Other Outcome Measures

1. Diagnostic Performance of Individual Readers (NFT Score B2-B3 as Truth Positive) [at autopsy within 9 months of baseline scan]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Have a projected life expectancy of ≤ 6 months

• Can tolerate a 20 minute PET scan

• Give informed consent or have a legally authorized representative to consent for study procedures and brain donation consistent with the legal requirements of the State in which they die

Exclusion Criteria:

• Aggressively being treated with life sustaining measures

• Known to have a structural brain lesion that would interfere either with PET imaging or pathological assessment

• Clinically significant infectious disease

• Currently receiving any investigational medications except with permission from the study sponsor

• Participated in an experimental study with an amyloid or tau targeting agent

• Suspected encephalopathy due to alcoholism or end-stage liver disease

• Females of childbearing potential

• History of risk factors for Torsades de Pointes or are currently taking medication known to cause QT prolongation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Banner Alzheimer's Institute	Phoenix	Arizona	United States	85006
2	St. Joseph's Hospital and Medical Center	Phoenix	Arizona	United States	85013
3	Cherlin Research	Los Gatos	California	United States	95032
4	Hoag Memorial Hospital Presbyterian	Newport Beach	California	United States	92658
5	California Research Foundation	San Diego	California	United States	92103
6	Pacific Research Network	San Diego	California	United States	92103
7	Ray Dolby Brain Health Center	San Francisco	California	United States	94114
8	Syrentis Clinical Research	Santa Ana	California	United States	92705
9	Neuropsychiatric Research Center of Southwest Florida	Fort Myers	Florida	United States	33912
10	Galiz Research	Hialeah	Florida	United States	33016
11	Merritt Island Medical Research	Merritt Island	Florida	United States	32952
12	Miami Jewish Health Systems	Miami	Florida	United States	33137
13	D de la Vega MD Research Group	Miami	Florida	United States	33185
14	Bioclinica	Orlando	Florida	United States	32806
15	Emory University Brain Health Center	Atlanta	Georgia	United States	30329
16	Alzheimer's Disease Center	Quincy	Massachusetts	United States	02169
17	Steinberg Diagnostics	Henderson	Nevada	United States	89052
18	Adirondack Medical Research Center	Glens Falls	New York	United States	12801
19	Clarity Clinical Research, LLC	Syracuse	New York	United States	13210
20	Duke University Medical Center	Durham	North Carolina	United States	27710
21	Wake Forest School of Medicine	Winston-Salem	North Carolina	United States	27157
22	Valley Medical Primary Care	Centerville	Ohio	United States	45459
23	Hospice of the Western Reserve	Cleveland	Ohio	United States	44119
24	American Clinical Trials, LLC (Site 1216)	Oklahoma City	Oklahoma	United States	73112
25	Oklahoma Behavioral Health	Oklahoma City	Oklahoma	United States	73112
26	Rhode Island Hospital	Providence	Rhode Island	United States	02903
27	Houston Methodist Research Institute	Houston	Texas	United States	77030
28	Sante Clinical Research	Kerrville	Texas	United States	78028
29	Overlake Internal Medicine Associates, PS	Bellevue	Washington	United States	98004
30	University of Washington Medicine	Seattle	Washington	United States	98104
31	University of Melbourne	Parkville	Victoria	Australia	3010

Sponsors and Collaborators

• Avid Radiopharmaceuticals

Investigators

• Study Chair: Chief Medical Officer, Avid Radiopharmaceuticals, Inc.

Study Documents (Full-Text)

• Study Protocol - Dec 18, 2017
• Statistical Analysis Plan - Aug 15, 2018

More Information

Publications

• 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.
• 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.

• Responsible Party: Avid Radiopharmaceuticals
• ClinicalTrials.gov Identifier: NCT02516046
• Other Study ID Numbers: 18F-AV-1451-A16
• First Posted: Aug 5, 2015
• Last Update Posted: Sep 7, 2020
• Last Verified: Sep 1, 2020

• Additional relevant MeSH terms: Alzheimer Disease

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	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.

Arm/Group Title	All Enrolled Cohort
Arm/Group Description	End-of-life subjects consenting to brain donation at autopsy from the flortaucipir PET scan arm
Period Title: Overall Study
STARTED	156
Died While on Study	73
Valid Autopsy Results and PET Scan	67
COMPLETED	64
NOT COMPLETED	92

Baseline Characteristics

Arm/Group Title	All Enrolled Cohort
Arm/Group Description	All subjects consenting to flortaucipir PET and brain donation at autopsy
Overall Participants	156
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	80.2 (12.51)
Sex: Female, Male (Count of Participants)
Female	86 55.1%
Male	70 44.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	20 12.8%
Not Hispanic or Latino	136 87.2%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 1.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	11 7.1%
White	143 91.7%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	151 96.8%
Australia	5 3.2%

Outcome Measures

1. Primary Outcome

Title	Primary Outcome 1: Diagnostic Performance of Individual Readers (NFT Score)
Description	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.
Time Frame	at autopsy within 9 months of baseline scan

Outcome Measure Data

Analysis Population Description

Autopsy cohort N=64. n=39 were truth positive for NFTs. n=25 were truth negative for NFTs.

Arm/Group Title	Sensitivity of Flortaucipir vs Autopsy NFT Score B3	Specificity of Flortaucipir vs Autopsy NFT Score <B3
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)
Measure Participants	39	25
Reader 1	97.4	68.0
Reader 2	92.3	92.0
Reader 3	92.3	88.0
Reader 4	92.3	76.0
Reader 5	100	52.0

2. Primary Outcome

Title	Primary Outcome 2: Diagnostic Performance of Individual Readers (NIA-AA Autopsy Diagnosis)
Description	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.
Time Frame	at autopsy within 9 months of baseline scan

Outcome Measure Data

Analysis Population Description

Autopsy cohort N=64. n=38 were truth positive for NFTs. n=26 were truth negative for NFTs.

Arm/Group Title	Sensitivity of Flortaucipir vs NIA-AA Autopsy Diagnosis	Specificity of Flortaucipir vs NIA-AA Autopsy Diagnosis
Arm/Group Description	Subjects with a positive truth standard (High ADNC)	Subjects with a negative truth standard (No/Low/Intermediate ADNC)
Measure Participants	38	26
Reader 1	97.5	65.4
Reader 2	95.0	92.3
Reader 3	95.0	88.5
Reader 4	95.0	76.9
Reader 5	100	50.0

3. Secondary Outcome

Title	Flortaucipir Diagnostic Performance (NFT Score)
Description	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.
Time Frame	at autopsy within 9 months of baseline scan

Outcome Measure Data

Analysis Population Description

Autopsy cohort N=64. n=39 were truth positive for NFTs. n=25 were truth negative for NFTs.

Arm/Group Title	Sensitivity of Flortaucipir vs Autopsy NFT Score B3	Specificity of Flortaucipir vs Autopsy NFT Score <B3
Arm/Group Description	Subjects with a truth positive NFT Score (B3)	Subjects with a truth negative NFT Score (B2 or lower)
Measure Participants	39	25
Number (95% Confidence Interval) [percentage of cases correctly identified]	92.3	80.0

4. Secondary Outcome

Title	Flortaucipir Diagnostic Performance (NIA-AA Autopsy Diagnosis)
Description	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.
Time Frame	at autopsy within 9 months of baseline scan

Outcome Measure Data

Analysis Population Description

Autopsy cohort N=64. n=38 were truth positive for NFTs. n=26 were truth negative for NFTs.

Arm/Group Title	Sensitivity Majority Read NIA-AA Autopsy Diagnosis	Specificity Majority Read NIA-AA Autopsy Diagnosis
Arm/Group Description	Subjects with a truth positive NIA-AA autopsy diagnosis (High ADNC)	Subjects with truth negative NIA-AA autopsy diagnosis (No/Low/Intermediate ADNC)
Measure Participants	38	26
Number (95% Confidence Interval) [percentage of cases correctly identified]	94.7	80.8

5. Secondary Outcome

Title	Inter-Reader Agreement
Description	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.
Time Frame	baseline scan

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Cases Read
Arm/Group Description	All participants from the study for which a visual read flortaucipir PET result was obtained (n=105), regardless of whether the subject had a valid autopsy
Measure Participants	105
Reader 1 v Reader 2	0.79
Reader 1 v Reader 3	0.79
Reader 1 v Reader 4	0.79
Reader 1 v Reader 5	0.81
Reader 2 v Reader 3	0.96
Reader 2 v Reader 4	0.88
Reader 2 v Reader 5	0.65
Reader 3 v Reader 4	0.92
Reader 3 v Reader 5	0.68
Reader 4 v Reader 5	0.72

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sensitivity of Flortaucipir vs Autopsy NFT Score B3
	Comments	Inter-reader agreement analysis using Fleiss' kappa. The hypothesis tested was that the observed kappa values were ≥0.64 and the lower bound of the 2-sided 95% CIs were ≥0.55 for the inter-reader agreement among readers.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Fleiss' kappa
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.74 to 0.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Other Pre-specified Outcome

Title	Diagnostic Performance of Individual Readers (NFT Score B2-B3 as Truth Positive)
Description	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.
Time Frame	at autopsy within 9 months of baseline scan

Outcome Measure Data

Analysis Population Description

Autopsy cohort N=64. n=56 were truth positive for NFTs. n=8 were truth negative for NFTs.

Arm/Group Title	Sensitivity of Flortaucipir vs Autopsy NFT Score B2-B3	Specificity of Flortaucipir vs Autopsy NFT Score B0-B1
Arm/Group Description	Subjects with a positive autopsy NFT score truth standard (NFT B2 or B3)	Subjects with a negative autopsy NFT score truth standard (NFT B0 or B1)
Measure Participants	56	8
Reader 1	80.4	87.5
Reader 2	67.9	100.0
Reader 3	67.9	87.5
Reader 4	73.2	87.5
Reader 5	85.7	62.5

Adverse Events

Time Frame	9 months after flortaucipir scan, up to a total of 18 months if a subject was re-scanned per protocol
Adverse Event Reporting Description	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.
Arm/Group Title	Safety Analysis Population
Arm/Group Description	All enrolled subjects from the flortaucipir PET scan arm who received one dose of flortaucipir
All Cause Mortality
	Safety Analysis Population
	Affected / at Risk (%)	# Events
Total	73/156 (46.8%)
Serious Adverse Events
	Safety Analysis Population
	Affected / at Risk (%)	# Events
Total	3/156 (1.9%)
Cardiac disorders
myocardial infarction	1/156 (0.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
malignant neoplasm	1/156 (0.6%)	1
Renal and urinary disorders
acute kidney injury	1/156 (0.6%)	1
Other (Not Including Serious) Adverse Events
	Safety Analysis Population
	Affected / at Risk (%)	# Events
Total	14/156 (9%)
Cardiac disorders
myocardial infarction	1/156 (0.6%)	1
Cardiac failure congestive	1/156 (0.6%)	1
Ear and labyrinth disorders
vertigo	1/156 (0.6%)	1
Gastrointestinal disorders
diarrhoea	1/156 (0.6%)	1
nausea	1/156 (0.6%)	1
General disorders
injection site bruising	1/156 (0.6%)	1
Injury, poisoning and procedural complications
fall	1/156 (0.6%)	1
procedural vomiting	1/156 (0.6%)	1
Metabolism and nutrition disorders
hypomagnesaemia	1/156 (0.6%)	1
Musculoskeletal and connective tissue disorders
myopathy	1/156 (0.6%)	1
Nervous system disorders
headache	2/156 (1.3%)	2
dizziness postural	1/156 (0.6%)	1
hypoxic-ischaemic encephalopathy	1/156 (0.6%)	1
tremor	1/156 (0.6%)	1
Psychiatric disorders
agitation	3/156 (1.9%)	3
mental disorder	1/156 (0.6%)	1
restlessness	1/156 (0.6%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.