Analysis of 18F-AV-1451 PET Imaging in Cognitively Healthy, MCI, and AD Subjects

• Sponsor: Avid Radiopharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02016560
• Collaborator: (none)
• Enrollment: 383
• Locations: 27
• Arms: 4
• Actual Duration (Months): 43.9
• Patients Per Site: 14.2
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

A Phase 2/3 cross-sectional and longitudinal observational study evaluating imaging characteristics of flortaucipir in control subjects and patients with clinically defined MCI and AD dementia (AD).

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Disease	Drug: florbetapir F 18; Drug: Flortaucipir F18; Procedure: Brain PET Scan	Phase 2/Phase 3

Detailed Description

This study was conducted in 2 phases: a Phase 2 Exploratory Phase and a Phase 3 Confirmatory Phase. An overarching goal of the Exploratory Phase of this protocol was to further investigate the pattern of flortaucipir PET imaging across the disease course, in cognitively healthy subjects through patients with cognitive decline. To accomplish this goal, the protocol investigated flortaucipir results in younger and older cognitively healthy normal volunteers and patients with clinical diagnoses for cognitive complaints, ranging from MCI to mild and moderate AD dementia. Additionally, the Exploratory Phase of this protocol investigated relationships between flortaucipir PET signal and cognitive decline over the 18-month study period.

The second, Confirmatory Phase of the study was designed to provide independent validation of the relationships observed in the exploratory analyses of the first phase. In particular, the goal of the second phase was to confirm the relationship between flortaucipir uptake in the brain as measured by PET signals at baseline and the subsequent rate of cognitive decline observed over the 18-month longitudinal follow up.

Study Design

• Study Type: Interventional
• Actual Enrollment: 383 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: All subjects in both the exploratory and confirmatory phases of the study, receive both florbetapir and florbetapir scans, regardless of subgroup assignment.All subjects in both the exploratory and confirmatory phases of the study, receive both florbetapir and florbetapir scans, regardless of subgroup assignment.
• Masking: Single (Outcomes Assessor)
• Masking Description: Applies only to confirmatory phase: the independent readers are blinded to all clinical information.
• Primary Purpose: Diagnostic
• Official Title: An Open Label, Multicenter Study, Evaluating the Safety and Imaging Characteristics of 18F-AV-1451 in Cognitively Healthy Volunteers, Subjects With Mild Cognitive Impairment, and Subjects With Alzheimer's Disease
• Actual Study Start Date: Dec 1, 2013
• Actual Primary Completion Date: Jul 28, 2017
• Actual Study Completion Date: Jul 28, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Exploratory Cognitively Healthy Subjects Subjects will receive an IV injection, 370 megabecquerel (MBq) (10 millicurie [mCi]), single dose of florbetapir F 18 at baseline. Subjects will receive an IV injection, 370 MBq (10 mCi), single dose of flortaucipir at baseline.	Drug: florbetapir F 18; Other Names: Amyvid 18F-AV-45 ; Drug: Flortaucipir F18; Other Names: T807 18F-AV-1451 ; Procedure: Brain PET Scan; positron emission tomography (PET) scan of the brain
Experimental: Exploratory MCI Subjects Subjects will receive an IV injection, 370 MBq (10 mCi), single dose of florbetapir F 18 at baseline. Subjects will receive an IV injection, 370 MBq (10 mCi), single dose of flortaucipir at baseline, 9 months and 18 months.	Drug: florbetapir F 18; Other Names: Amyvid 18F-AV-45 ; Drug: Flortaucipir F18; Other Names: T807 18F-AV-1451 ; Procedure: Brain PET Scan; positron emission tomography (PET) scan of the brain
Experimental: Exploratory AD Subjects Subjects will receive an IV injection, 370 MBq (10 mCi), single dose of florbetapir F 18 at baseline. Subjects will receive an IV injection, 370 MBq (10 mCi), single dose of flortaucipir at baseline, 9 months and 18 months.	Drug: florbetapir F 18; Other Names: Amyvid 18F-AV-45 ; Drug: Flortaucipir F18; Other Names: T807 18F-AV-1451 ; Procedure: Brain PET Scan; positron emission tomography (PET) scan of the brain
Experimental: Confirmatory Subjects Subjects will receive an IV injection, 370 MBq (10 mCi), single dose of florbetapir F 18 and flortaucipir at baseline.	Drug: florbetapir F 18; Other Names: Amyvid 18F-AV-45 ; Drug: Flortaucipir F18; Other Names: T807 18F-AV-1451 ; Procedure: Brain PET Scan; positron emission tomography (PET) scan of the brain

Outcome Measures

Primary Outcome Measures

1. Confirmatory Phase: Relationship Between Neocortical Flortaucipir Uptake and the Subsequent Rate of Cognitive Decline [between baseline and 18 months]

   Confirm the relationship between neocortical flortaucipir uptake and the subsequent rate of cognitive decline at longitudinal follow up that was observed in the Exploratory Phase of the study. Patients were assigned to groups by majority classification of the flortaucipir positron emission tomography (PET) scan by five independent imaging physicians. Clinically meaningful cognitive and functional deterioration was defined as a 1 point or greater worsening on clinical dementia rating - sum of boxes (CDR-SB) score over the follow-up period.

2. Exploratory Phase: Cross-sectional Flortaucipir Imaging Results [baseline scan]

   Flortaucipir standardized uptake value ratio (SUVr). A value of 1 signifies no flortaucipir activity above background, values greater than 1 signify increasing flortaucipir activity in the brain.

3. Exploratory Phase: Longitudinal Change in Tau Deposition Over Time, by Amyloid Status [baseline and 18 months]

   Assess the rate of change of tau deposition as measured by flortaucipir uptake (SUVr) over time. Change = 18 months SUVr - baseline SUVr.

Secondary Outcome Measures

1. Confirmatory Phase: Diagnostic Performance of Flortaucipir Visual Read [baseline and 18 months]

   This analysis used dichotomized CDR-SB change as a truth standard (1 point or more worsening = true positive vs. less than 1 point worsening = true negative) to assess the diagnostic performance of baseline Advanced AD tau status (τAD++) as determined by flortaucipir scan interpretation. Sensitivity and Specificity were calculated for each of the 5 independent imaging readers. Sensitivity is the percentage of true positive cases correctly identified by an Advanced AD pattern scan. Specificity is the percentage of true negative cases correctly identified by scans that were not classified as Advanced AD pattern.

2. Exploratory Phase: Correlation Between Flortaucipir SUVr and Age [baseline scan]

   Flortaucipir standardized uptake value ratio (SUVr). A value of 1 signifies no flortaucipir activity above background, values greater than 1 signify increasing flortaucipir activity in the brain.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

Exploratory Cognitively Healthy Subjects

• ≥ 20 to ≤ 40 years of age OR ≥ 50 years of age

• Mini-mental state examination (MMSE) ≥ 29

• No significant history of cognitive impairment

Exploratory MCI Subjects

• ≥ 50 years of age

• MMSE ≥ 24

• Have MCI consistent with National Institute on Aging-Alzheimer's Association (NIA-AA) working group's diagnostic guidelines for AD

• Have a study partner that can report on subject's activities of daily living

Exploratory AD Subjects

• ≥ 50 years of age

• MMSE > 10

• Have possible or probable AD based on the NIA-AA working group's diagnostic guidelines for AD

• Have a study partner that can report on subject's activities of daily living

Confirmatory Subjects

• ≥ 50 years of age

• MMSE ≥ 20 and ≤ 27

• Cognitively impaired subjects with either MCI or dementia with a suspected neurodegenerative cause

• Have a study partner that can report on subject's activities of daily living

Exclusion Criteria:

• Current clinically significant psychiatric disease

• Evidence of structural brain abnormalities

• History of moderate or severe traumatic brain injury

• Current clinically significant cardiovascular disease or ECG abnormalities, or additional risk factors for Torsades de Pointes

• Current clinically significant infectious disease, endocrine or metabolic disease, pulmonary, renal or hepatic impairment, or cancer

• History of alcohol or substance abuse or dependence

• Females of childbearing potential who are not surgically sterile, not refraining from sexual activity or not using reliable methods of contraception

• Have received or participated in a trial with investigational medications in the past 30 days

• Have had a non-study related radiopharmaceutical imaging or treatment procedure within 7 days prior to the study imaging session.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Banner Alzheimer's Institute	Phoenix	Arizona	United States	85006
2	Four Peaks Neurology	Scottsdale	Arizona	United States	85258
3	Mayo Clinic	Scottsdale	Arizona	United States	85259
4	Banner Sun Health Research Institute	Sun City	Arizona	United States	85351
5	UC Irvine	Irvine	California	United States	92697
6	Hoag Memorial	Newport Beach	California	United States	92663
7	Norther California PET Imaging Center	Sacramento	California	United States	95816
8	UC Davis	Sacramento	California	United States	95817
9	UC San Francisco	San Francisco	California	United States	94158
10	Neurological Research Institute	Santa Monica	California	United States	90404
11	Molecular NeuroImaging	New Haven	Connecticut	United States	06510
12	Quantum Laboratories	Deerfield Beach	Florida	United States	33064
13	21st Century Oncology	Fort Myers	Florida	United States	33912
14	Sandlake Imaging	Orlando	Florida	United States	32806
15	Meridien Research	Saint Petersburg	Florida	United States	33709
16	USF Health Byrd Alzheimer's Center	Tampa	Florida	United States	33613
17	Independent Imaging	West Palm Beach	Florida	United States	33407
18	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
19	Boston University	Boston	Massachusetts	United States	02118
20	Alzheimer's Disease Center	Quincy	Massachusetts	United States	02169
21	Center for Clinical Imaging Research	Saint Louis	Missouri	United States	63110
22	Las Vegas Radiology	Las Vegas	Nevada	United States	89147
23	Center for Brain Health - NYU Langone Medical Center	New York	New York	United States	10016
24	Duke University Medical Center	Durham	North Carolina	United States	27710
25	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
26	Rhode Island Hospital	Providence	Rhode Island	United States	02903
27	Butler Hospital	Providence	Rhode Island	United States	02906

Sponsors and Collaborators

• Avid Radiopharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Aug 7, 2015
• Statistical Analysis Plan: Confirmatory Phase SAP - Jan 5, 2018
• Statistical Analysis Plan: Confirmatory Phase Addendum SAP - Jan 5, 2018
• Statistical Analysis Plan: Exploratory Phase SAP - Nov 27, 2017

More Information

Publications

None provided.

• Responsible Party: Avid Radiopharmaceuticals
• ClinicalTrials.gov Identifier: NCT02016560
• Other Study ID Numbers: 18F-AV-1451-A05
• First Posted: Dec 20, 2013
• Last Update Posted: Sep 22, 2020
• Last Verified: Sep 1, 2020

• Additional relevant MeSH terms: Alzheimer Disease

Study Results

Participant Flow

Recruitment Details	Exploratory cohort subjects were enrolled starting in Dec 2013. Confirmatory cohort subjects were enrolled Dec 2014-July 2017. Exploratory cohort subjects were not eligible for the confirmatory phase.
Pre-assignment Detail	To ensure a distribution of disease severity in the confirmatory phase, a target was set to recruit at least one-third of the enrolled subjects with dementia

Arm/Group Title	Exploratory Young Cognitively Healthy Subjects	Exploratory Older Cognitively Healthy Subjects	Exploratory MCI Subjects	Exploratory AD Subjects	Confirmatory Subjects MCI	Confirmatory Subjects AD
Arm/Group Description	Male or female subjects ≥20 to ≤40 years of age with mini-mental status exam (MMSE) score ≥29	Male or female subjects ≥50 years of age with MMSE Score ≥29	Subjects with mild cognitive impairment consistent with National Institute of Aging (NIA)-Alzheimer's Association working group's diagnostic guidelines for AD (Albert et al. 2011) and MMSE Score ≥24	Subjects with possible or probable AD dementia based on the NIA-Alzheimer's Association working group's diagnostic guidelines for AD (McKhann et al. 2011) and MMSE Score >10	Clinically diagnosed mild cognitive impairment with a suspected neurodegenerative cause with an MMSE score ≥20 and ≤27	Clinically diagnosed dementia with a suspected neurodegenerative cause with an MMSE score ≥20 and ≤27
Period Title: Exploratory Phase
STARTED	16	58	98	51	0	0
COMPLETED	16	54	62	35	0	0
NOT COMPLETED	0	4	36	16	0	0
Period Title: Exploratory Phase
STARTED	0	0	0	0	98	62
COMPLETED	0	0	0	0	76	35
NOT COMPLETED	0	0	0	0	22	27

Baseline Characteristics

Arm/Group Title	Exploratory Young Cognitively Healthy Subjects	Exploratory Older Cognitively Healthy Subjects	Exploratory MCI Subjects	Exploratory AD Subjects	Confirmatory Subjects MCI	Confirmatory Subjects AD	Total
Arm/Group Description	Male or female subjects ≥20 to ≤40 years of age with MMSE ≥29	Male or female subjects ≥50 years of age with MMSE ≥29	Subjects with mild cognitive impairment consistent with National Institute of Aging (NIA)-Alzheimer's Association working group's diagnostic guidelines for AD (Albert et al. 2011) and MMSE ≥24	Subjects with possible or probable AD dementia based on the NIA-Alzheimer's Association working group's diagnostic guidelines for AD (McKhann et al. 2011) and MMSE >10	Clinically diagnosed mild cognitive impairment with a suspected neurodegenerative cause with an MMSE score ≥20 and ≤27	Clinically diagnosed dementia with a suspected neurodegenerative cause with an MMSE score ≥20 and ≤27	Total of all reporting groups
Overall Participants	16	58	98	51	98	62	383
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28.9 (4.88)	68.5 (10.29)	70.8 (9.3)	73.9 (9.01)	67.9 (14.36)
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	72.5 (9.69)	73.6 (9.53)	72.9 (9.61)
Sex: Female, Male (Count of Participants)
Female	7 43.8%	26 44.8%	49 50%	28 54.9%	44 44.9%	30 48.4%	184 48%
Male	9 56.3%	32 55.2%	49 50%	23 45.1%	54 55.1%	32 51.6%	199 52%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 6.3%	1 1.7%	4 4.1%	0 0%	5 5.1%	4 6.5%	15 3.9%
Not Hispanic or Latino	15 93.8%	57 98.3%	94 95.9%	51 100%	93 94.9%	58 93.5%	368 96.1%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Asian	1 6.3%	1 1.7%	1 1%	0 0%	1 1%	1 1.6%	5 1.3%
Black or African American	3 18.8%	9 15.5%	7 7.1%	2 3.9%	3 3.1%	0 0%	24 6.3%
White	11 68.8%	47 81%	89 90.8%	47 92.2%	94 95.9%	61 98.4%	349 91.1%
American Indian or Alaska Native	0 0%	0 0%	0 0%	1 2%	0 0%	0 0%	1 0.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Other	1 6.3%	1 1.7%	1 1%	1 2%	0 0%	0 0%	4 1%
Clinical Dementia Rating - Sum of Boxes (CDR-SB) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	2.8 (1.73)	4.3 (1.69)	3.4 (1.88)

Outcome Measures

1. Primary Outcome

Title	Confirmatory Phase: Relationship Between Neocortical Flortaucipir Uptake and the Subsequent Rate of Cognitive Decline
Description	Confirm the relationship between neocortical flortaucipir uptake and the subsequent rate of cognitive decline at longitudinal follow up that was observed in the Exploratory Phase of the study. Patients were assigned to groups by majority classification of the flortaucipir positron emission tomography (PET) scan by five independent imaging physicians. Clinically meaningful cognitive and functional deterioration was defined as a 1 point or greater worsening on clinical dementia rating - sum of boxes (CDR-SB) score over the follow-up period.
Time Frame	between baseline and 18 months

Outcome Measure Data

Analysis Population Description

Subjects from the confirmatory phase with valid flortaucipir visual read and 9 or 18 month clinical follow-up.

Arm/Group Title	Predicted to Progress	Not Predicted to Progress
Arm/Group Description	Subjects with an Advanced AD Scan Pattern (τAD++). In either hemisphere, increased neocortical activity in the parietal/precuneus region(s), or frontal region(s) with increased uptake in the PLT, parietal, or occipital region(s).	Subjects with a Moderate AD Scan Pattern (τAD+) or Not AD Scan Pattern (τAD-). Moderate scans were defined as in either hemisphere, increased neocortical activity limited to the posterolateral temporal (PLT) or occipital region(s). Not AD scans were defined as no increased neocortical activity, or increased neocortical activity isolated to the mesial temporal, anterolateral temporal, and/or frontal regions.
Measure Participants	63	68
Clinically meaningful progression	36 225%	31 53.4%
Did Not Progress	27 168.8%	37 63.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Predicted to Progress, Not Predicted to Progress
	Comments	The specific hypothesis tested was that the hazard of progressing to the clinically meaningful event (defined as CDR-SB value change of at least 1 within 18 months) will be significantly greater for subjects with flortaucipir scans rated by majority interpretation as predicted to progress (Advanced AD scan pattern), as compared to subjects with scans rated as not predicted to progress (Moderate or Not AD scan pattern).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.067
	Comments	A p-value of <0.05 was the a priori threshold for statistical significance.
	Method	Cox proportional hazards
	Comments	The Cox proportional hazard model was adjusted for baseline age, American National Adult Reading Test (ANART) score, and baseline CDR-SB score.
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.581
	Confidence Interval	(2-Sided) 95%; 0.968 to 2.581
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Exploratory Phase: Cross-sectional Flortaucipir Imaging Results
Description	Flortaucipir standardized uptake value ratio (SUVr). A value of 1 signifies no flortaucipir activity above background, values greater than 1 signify increasing flortaucipir activity in the brain.
Time Frame	baseline scan

Outcome Measure Data

Analysis Population Description

Analysis included all subjects who received an injection of flortaucipir, had valid quantifiable flortaucipir imaging data available, and valid quantifiable florbetapir PET data.

Arm/Group Title	Exploratory AD Subjects	Exploratory MCI Subjects	Exploratory Older Cognitively Healthy Subjects	Exploratory Young Cognitively Healthy Subjects
Arm/Group Description	Subjects with possible or probable AD dementia based on the NIA-Alzheimer's Association working group's diagnostic guidelines for AD (McKhann et al. 2011) and MMSE >10	Subjects with mild cognitive impairment consistent with National Institute of Aging (NIA)-Alzheimer's Association working group's diagnostic guidelines for AD (Albert et al. 2011) and MMSE ≥24	Male or female subjects ≥50 years of age with MMSE ≥29	Male or female subjects ≥20 to ≤40 years of age with MMSE ≥29
Measure Participants	48	97	57	16
Aβ+ SUVr	1.53 (0.037)	1.26 (0.030)	1.08 (0.093)
Aβ- SUVr	1.03 (0.051)	0.99 (0.029)	0.98 (0.029)	1.01 (0.039)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Predicted to Progress, Exploratory Older Cognitively Healthy Subjects
	Comments	ANCOVA model comparing the mean SUVr between AD and Older Cognitively Healthy within amyloid positive group.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	No adjustment for multiple comparisons. No a priori threshold was set.
	Method	ANCOVA
	Comments	Adjusted for age

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Not Predicted to Progress, Exploratory Older Cognitively Healthy Subjects
	Comments	ANCOVA model comparing the mean SUVr between MCI and Older Cognitively Healthy within the amyloid positive group.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0622
	Comments	No adjustment for multiple comparisons. No a priori threshold was set.
	Method	ANCOVA
	Comments	Adjusted for age

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Predicted to Progress, Not Predicted to Progress
	Comments	ANCOVA model comparing the mean SUVr between AD and MCI within the amyloid positive group.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	No adjustment for multiple comparisons. No a priori threshold was set.
	Method	ANCOVA
	Comments	Adjusted for age

3. Primary Outcome

Title	Exploratory Phase: Longitudinal Change in Tau Deposition Over Time, by Amyloid Status
Description	Assess the rate of change of tau deposition as measured by flortaucipir uptake (SUVr) over time. Change = 18 months SUVr - baseline SUVr.
Time Frame	baseline and 18 months

Outcome Measure Data

Analysis Population Description

Analysis of flortaucipir SUVr Change Over Time by Amyloid Status, Exploratory Phase Efficacy Population (AD and MCI subjects only)

Arm/Group Title	Exploratory AB+ (Amyloid Beta Positive)	Exploratory AB- (Amyloid Beta Negative)
Arm/Group Description	Exploratory MCI or AD subjects with a positive florbetapir PET scan for amyloid	Exploratory MCI or AD subjects with a negative florbetapir PET scan for amyloid
Measure Participants	55	90
Least Squares Mean (Standard Error) [standardized uptake value ratio (SUVr)]	0.052359 (0.008536)	0.000655 (0.002394)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Predicted to Progress
	Comments	SUVr change from baseline as dependent variable, baseline SUVr, age, and visit as independent variables, using an unstructured covariance structure for amyloid positive subjects only.
	Type of Statistical Test	Equivalence
	Comments	Test of whether the least squares mean change is significantly different than zero
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Not Predicted to Progress
	Comments	SUVr change from baseline as dependent variable, baseline SUVr, age, and visit as independent variables, using an unstructured covariance structure for amyloid negative subjects only.
	Type of Statistical Test	Equivalence
	Comments	Test of whether the least squares mean change is significantly different than zero
Statistical Test of Hypothesis	p-Value	0.7851
	Comments
	Method	Mixed Models Analysis
	Comments

4. Secondary Outcome

Title	Confirmatory Phase: Diagnostic Performance of Flortaucipir Visual Read
Description	This analysis used dichotomized CDR-SB change as a truth standard (1 point or more worsening = true positive vs. less than 1 point worsening = true negative) to assess the diagnostic performance of baseline Advanced AD tau status (τAD++) as determined by flortaucipir scan interpretation. Sensitivity and Specificity were calculated for each of the 5 independent imaging readers. Sensitivity is the percentage of true positive cases correctly identified by an Advanced AD pattern scan. Specificity is the percentage of true negative cases correctly identified by scans that were not classified as Advanced AD pattern.
Time Frame	baseline and 18 months

Outcome Measure Data

Analysis Population Description

All confirmatory phase subjects who completed 18 months of follow-up for the cognitive endpoint were read by each reader

Arm/Group Title	Independent Readers
Arm/Group Description	Scans were interpreted by 5 imaging physicians, blind to clinical data, after training by an Avid expert.
Measure Participants	110
Reader 1 Sensitivity	59.6
Reader 1 Specificity	65.5
Reader 2 Sensitivity	53.8
Reader 2 Specificity	65.5
Reader 3 Sensitivity	55.8
Reader 3 Specificity	65.5
Reader 4 Sensitivity	59.6
Reader 4 Specificity	65.5
Reader 5 Sensitivity	50.0
Reader 5 Specificity	65.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Predicted to Progress
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		The hypothesis tested was that, of the 5 independent imaging physicians, at least 3 will have the lower bounds of 2-sided 95% confidence intervals ≥50%, for both sensitivity and specificity.

5. Secondary Outcome

Title	Exploratory Phase: Correlation Between Flortaucipir SUVr and Age
Description	Flortaucipir standardized uptake value ratio (SUVr). A value of 1 signifies no flortaucipir activity above background, values greater than 1 signify increasing flortaucipir activity in the brain.
Time Frame	baseline scan

Outcome Measure Data

Analysis Population Description

Exploratory Young and Old healthy control subjects with a valid flortaucipir PET scan

Arm/Group Title	Exploratory Young Cognitively Healthy Subjects	Exploratory Older Cognitively Healthy Subjects 50-59	Exploratory Older Cognitively Healthy Subjects 60-69	Exploratory Older Cognitively Healthy Subjects 70-79	Exploratory Older Cognitively Healthy Subjects >=80
Arm/Group Description	Male or female subjects ≥20 to ≤40 years of age with MMSE ≥29	Male or female subjects 50-59 years of age with MMSE ≥29	Male or female subjects 60-69 years of age with MMSE ≥29	Male or female subjects 70-79 years of age with MMSE ≥29	Male or female subjects 80 years of age or older with MMSE ≥29
Measure Participants	16	15	15	16	11
Mean (Standard Deviation) [standardized uptake value ratio (SUVr)]	1.0083 (0.03905)	1.0203 (0.03693)	1.0110 (0.04149)	1.0010 (0.02604)	1.0048 (0.03978)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Predicted to Progress, Not Predicted to Progress, Exploratory Older Cognitively Healthy Subjects, Exploratory Young Cognitively Healthy Subjects, Exploratory Older Cognitively Healthy Subjects >=80
	Comments	Pearson's correlation coefficient
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4361
	Comments
	Method	Pearson
	Comments
Method of Estimation	Estimation Parameter	Pearson's correlation coefficient
	Estimated Value	-0.0925
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	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 either drug.
Arm/Group Title	Exploratory Younger Cognitively Healthy Subjects		Exploratory Older Cognitively Healthy Subjects		Exploratory MCI Subjects		Exploratory AD Subjects		Confirmatory Subjects MCI		Confirmatory Subjects AD
Arm/Group Description	Male or female subjects ≥20 to ≤40 years of age with MMSE ≥29		Male or female subjects ≥50 years of age with MMSE ≥29		Subjects with mild cognitive impairment consistent with National Institute of Aging (NIA)-Alzheimer's Association working group's diagnostic guidelines for AD (Albert et al. 2011) and MMSE ≥24		Subjects with possible or probable AD dementia based on the NIA-Alzheimer's Association working group's diagnostic guidelines for AD (McKhann et al. 2011) and MMSE >10		Clinically diagnosed mild cognitive impairment with a suspected neurodegenerative cause with an MMSE score ≥20 and ≤27		Clinically diagnosed dementia with a suspected neurodegenerative cause with an MMSE score ≥20 and ≤27
All Cause Mortality
	Exploratory Younger Cognitively Healthy Subjects		Exploratory Older Cognitively Healthy Subjects		Exploratory MCI Subjects		Exploratory AD Subjects		Confirmatory Subjects MCI		Confirmatory Subjects AD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/58 (0%)		0/98 (0%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Serious Adverse Events
	Exploratory Younger Cognitively Healthy Subjects		Exploratory Older Cognitively Healthy Subjects		Exploratory MCI Subjects		Exploratory AD Subjects		Confirmatory Subjects MCI		Confirmatory Subjects AD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/58 (0%)		1/98 (1%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Cardiac disorders
angina pectoris	0/16 (0%)	0	0/58 (0%)	0	1/98 (1%)	0	0/51 (0%)	0	0/98 (0%)	0	0/62 (0%)	0
Other (Not Including Serious) Adverse Events
	Exploratory Younger Cognitively Healthy Subjects		Exploratory Older Cognitively Healthy Subjects		Exploratory MCI Subjects		Exploratory AD Subjects		Confirmatory Subjects MCI		Confirmatory Subjects AD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/16 (18.8%)		17/58 (29.3%)		21/98 (21.4%)		13/51 (25.5%)		13/98 (13.3%)		0/62 (0%)
Cardiac disorders
Angina pectoris	0/16 (0%)		1/58 (1.7%)		2/98 (2%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Bradycardia	0/16 (0%)		1/58 (1.7%)		0/98 (0%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Supraventricular extrasystoles	0/16 (0%)		0/58 (0%)		0/98 (0%)		0/51 (0%)		1/98 (1%)		0/62 (0%)
Eye disorders
Ocular hyperaemia	0/16 (0%)		0/58 (0%)		1/98 (1%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Cyanopsia	0/16 (0%)		0/58 (0%)		0/98 (0%)		0/51 (0%)		1/98 (1%)		0/62 (0%)
Eye irritation	0/16 (0%)		0/58 (0%)		0/98 (0%)		0/51 (0%)		1/98 (1%)		0/62 (0%)
Gastrointestinal disorders
Abdominal pain	1/16 (6.3%)		0/58 (0%)		0/98 (0%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Diarrhoea	0/16 (0%)		0/58 (0%)		1/98 (1%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Flatulence	0/16 (0%)		1/58 (1.7%)		0/98 (0%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Frequent bowel movements	1/16 (6.3%)		0/58 (0%)		0/98 (0%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Vomiting	0/16 (0%)		0/58 (0%)		0/98 (0%)		1/51 (2%)		0/98 (0%)		0/62 (0%)
General disorders
Injection site pain	0/16 (0%)		5/58 (8.6%)		8/98 (8.2%)		2/51 (3.9%)		6/98 (6.1%)		0/62 (0%)
Injection site extravasation	0/16 (0%)		0/58 (0%)		3/98 (3.1%)		1/51 (2%)		0/98 (0%)		0/62 (0%)
Fatigue	0/16 (0%)		2/58 (3.4%)		1/98 (1%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Application site irritation	0/16 (0%)		1/58 (1.7%)		0/98 (0%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Application site laceration	0/16 (0%)		0/58 (0%)		0/98 (0%)		1/51 (2%)		0/98 (0%)		0/62 (0%)
Feeling abnormal	0/16 (0%)		0/58 (0%)		1/98 (1%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Therapeutic response unexpected	0/16 (0%)		0/58 (0%)		0/98 (0%)		1/51 (2%)		0/98 (0%)		0/62 (0%)
Investigations
Blood pressure increased	0/16 (0%)		2/58 (3.4%)		2/98 (2%)		1/51 (2%)		0/98 (0%)		0/62 (0%)
Blood pressure systolic increased	0/16 (0%)		2/58 (3.4%)		0/98 (0%)		1/51 (2%)		0/98 (0%)		0/62 (0%)
Platelet count decreased	0/16 (0%)		0/58 (0%)		1/98 (1%)		1/51 (2%)		0/98 (0%)		0/62 (0%)
Heart rate increased	0/16 (0%)		1/58 (1.7%)		0/98 (0%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Metabolism and nutrition disorders
Decreased appetite	0/16 (0%)		0/58 (0%)		0/98 (0%)		1/51 (2%)		0/98 (0%)		0/62 (0%)
Musculoskeletal and connective tissue disorders
Muscle spasms	0/16 (0%)		0/58 (0%)		1/98 (1%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Pain in extremity	0/16 (0%)		0/58 (0%)		1/98 (1%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Nervous system disorders
Headache	0/16 (0%)		3/58 (5.2%)		3/98 (3.1%)		1/51 (2%)		4/98 (4.1%)		0/62 (0%)
Paraesthesia	1/16 (6.3%)		0/58 (0%)		1/98 (1%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Amnesia	0/16 (0%)		0/58 (0%)		1/98 (1%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Disturbance in attention	0/16 (0%)		1/58 (1.7%)		0/98 (0%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Dizziness	1/16 (6.3%)		0/58 (0%)		0/98 (0%)		0/51 (0%)		2/98 (2%)		0/62 (0%)
Head discomfort	1/16 (6.3%)		0/58 (0%)		0/98 (0%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Hypoaesthesia	0/16 (0%)		0/58 (0%)		1/98 (1%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Memory impairment	0/16 (0%)		0/58 (0%)		1/98 (1%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Somnolence	0/16 (0%)		0/58 (0%)		0/98 (0%)		1/51 (2%)		0/98 (0%)		0/62 (0%)
Psychiatric disorders
Panic attack	0/16 (0%)		0/58 (0%)		0/98 (0%)		0/51 (0%)		1/98 (1%)		0/62 (0%)
Renal and urinary disorders
Urinary incontinence	0/16 (0%)		1/58 (1.7%)		0/98 (0%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Skin and subcutaneous tissue disorders
Dermatitis contact	0/16 (0%)		0/58 (0%)		0/98 (0%)		1/51 (2%)		0/98 (0%)		0/62 (0%)
Rash	0/16 (0%)		0/58 (0%)		1/98 (1%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Rash papular	0/16 (0%)		1/58 (1.7%)		0/98 (0%)		0/51 (0%)		0/98 (0%)		0/62 (0%)
Erythema	0/16 (0%)		0/58 (0%)		0/98 (0%)		0/51 (0%)		1/98 (1%)		0/62 (0%)
Vascular disorders
Hypertension	0/16 (0%)		1/58 (1.7%)		0/98 (0%)		2/51 (3.9%)		0/98 (0%)		0/62 (0%)
Hot flush	0/16 (0%)		0/58 (0%)		1/98 (1%)		0/51 (0%)		0/98 (0%)		0/62 (0%)

Limitations/Caveats

[Not Specified]

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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.