Evaluation of Flortaucipir PET Signal and Cognitive Change in Early Alzheimer's Disease

• Sponsor: Avid Radiopharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03901105
• Collaborator: (none)
• Enrollment: 205
• Location: 1
• Arm: 1
• Actual Duration (Months): 1
• Patients Per Site Per Month: 201.3

Study Details

Study Description

Brief Summary

This study will evaluate whether visual interpretation of flortaucipir-PET (positron emission tomography) scans, examining patterns of tracer uptake at baseline, can predict the rate of clinically-meaningful cognitive decline due to AD after 18 months. All scans are acquired from cohorts of a previously completed study, I8D-MC-AZES (NCT02245737, lanabecestat, Eli Lilly and Company sponsor).

Condition or Disease	Intervention/Treatment	Phase
Alzheimer Disease	Drug: flortaucipir F18; Procedure: Brain PET Scan	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 205 participants
• 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.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
• Official Title: Evaluation of the Relationship Between Baseline Flortaucipir PET Signal and Cognitive Change in Subjects With Early Alzheimer's Disease Participating in the I8D-MC-AZES Protocol Addendum D5010C00009 (2.1) (Tau Imaging)
• Actual Study Start Date: Mar 28, 2019
• Actual Primary Completion Date: Apr 28, 2019
• Actual Study Completion Date: Apr 28, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Flortaucipir PET Scan No study drug will be administered. Scans previously acquired from Study I8D-MC-AZES (NCT02245737, Eli Lilly and Company sponsor) will be read by independent, blinded readers.

Drug: flortaucipir F18; No study drug will be administered. Scans previously acquired from Study I8D-MC-AZES (NCT02245737, Eli Lilly and Company sponsor) at baseline will be read by independent, blinded readers. IV injection, 240 megabecquerel (MBq) (6.5 mCi), single dose in AZES; Other Names: 18F-AV-1451 [F-18]T807 LY3191748 ; Procedure: Brain PET Scan; positron emission tomography (PET) scan of the brain

Outcome Measures

Primary Outcome Measures

1. Risk Ratio for AD Symptom Progression on CDR-SB [Within 18 months of scan]

   Baseline flortaucipir F 18 PET imaging results were determined by majority read (see Baseline Characteristics for description). Clinically meaningful deterioration (CMD) was defined for the primary endpoint as a worsening of the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score of one point or more. The clinical dementia rating (CDR) examines 6 categories of cognitive functioning domains. Each domain is scored on a scale ranging from 0 to 3 (including 0.5). A CDR-SB was generated as the sum of the values in each of the 6 domains. The CDR-SB sum scores range from 0 to 18, with higher scores indicating greater cognitive impairment and a 1 point worsening is considered a clinically significant symptom change.

Secondary Outcome Measures

1. Risk Ratio for AD Symptom Progression on Various Clinical Measures [Within 18 months of scan]

   Baseline flortaucipir F 18 PET imaging results were determined by majority read (see Baseline Characteristics for description). Clinically meaningful deterioration (CMD) was defined for the cognitive endpoints as follows: mini-mental status exam (MMSE) worsening of 3 points or greater, Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) worsening of 4 points or greater, Pfeffer's Functional Activities Questionnaire (FAQ) worsening of 3 points or greater, CDR global worsening of greater than 0 points. MMSE scores range from 0 to 30 with lower scores indicating worsening cognitive function. ADAS-Cog11 scores range from 0 to 70 with higher scores indicating worsening cognitive function. FAQ scores range from 0 to 30 with higher scores indicating worsening cognitive function. CDR global is scored on a 5 point scale (0, 0.5, 1, 2, 3) with higher scores indicating worsening cognitive function.

2. Mean Change in Cognitive/Functional Assessments [baseline and 18 months]

   Mean change in cognitive/functional measures baseline between τAD++ and non-τAD++ (determined by baseline tau status), calculated by Mixed Model Repeat Measures (MMRM). CDR-SB scores range from 0 to 18, with higher scores indicating worsening cognitive impairment. MMSE scores range from 0 to 30 with lower scores indicating worsening cognitive function. ADAS-Cog11 scores range from 0 to 70 with higher scores indicating worsening cognitive function. FAQ scores range from 0 to 30 with higher scores indicating worsening cognitive function.

3. Inter-Reader Reliability of Reader Interpretation of Flortaucipir F 18 PET Imaging [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 -1 to 1 with 1 indicating perfect agreement between the readers. Read results binarized as τAD++ or non-τAD++.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Scan Reader Criteria (5 total readers):

• Board-certified in radiology or nuclear medicine

• Professional experience interpreting PET scans

Scan Criteria (205 total scans):

• Former enrollment in AZES Study

• Flortaucipir scan at baseline

• clinical dementia rating - sum of boxes (CDR-SB) assessment at 18 months

Scan Study Population (AZES Study):

• 55 to 85 years

• MCI due to AD or probable AD by National Institute on Aging-Alzheimer's Association criteria (Albert 2011

• mini-mental status exam (MMSE) of 20 to 30 inclusive

• CDR global score of 0.5 (MCI), or 0.5 or 1 (AD) with a memory box score ≥ 0.5, and a score of ≤85 on the Delayed Memory Index of the Repeatable Battery for the Assessment of Neuropsychological Status.

• Amyloid positive status confirmed by florbetapir PET or lumbar puncture

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	American College of Radiology	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• Avid Radiopharmaceuticals

Investigators

• Study Director: Study Director, Avid Radiopharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Mar 12, 2019
• Statistical Analysis Plan - Apr 16, 2019

More Information

Publications

None provided.

• Responsible Party: Avid Radiopharmaceuticals
• ClinicalTrials.gov Identifier: NCT03901105
• Other Study ID Numbers: 18F-AV-1451-PX01
• First Posted: Apr 3, 2019
• Last Update Posted: Aug 28, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Alzheimer Disease

Study Results

Participant Flow

Recruitment Details	Scans were acquired from subjects previously enrolled in the AZES (NCT02245737) PET substudy (N=205), including mild AD (n=141) and mild cognitive impairment (MCI) due to AD (n=64).
Pre-assignment Detail	To be included in the study, subjects had to have a valid baseline flortaucipir PET scan and clinical dementia rating (CDR) assessments at baseline and 18 months.

Arm/Group Title	All Subjects
Arm/Group Description	Mild AD and MCI due to AD from the flortaucipir PET scan arm
Period Title: Overall Study
STARTED	205
COMPLETED	205
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	All Scans
Arm/Group Description	Mild AD and MCI due to AD from the flortaucipir PET scan arm
Overall Participants	205
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	71.0 (7.74)
Sex: Female, Male (Count of Participants)
Female	100 48.8%
Male	105 51.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	27 13.2%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	5 2.4%
White	172 83.9%
More than one race	0 0%
Unknown or Not Reported	1 0.5%
Flortaucipir PET Scan Result (Count of Participants)
tAD++	162 79%
tAD+	15 7.3%
tAD-	28 13.7%
Mean CDR-SB (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	3.69 (1.475)

Outcome Measures

1. Primary Outcome

Title	Risk Ratio for AD Symptom Progression on CDR-SB
Description	Baseline flortaucipir F 18 PET imaging results were determined by majority read (see Baseline Characteristics for description). Clinically meaningful deterioration (CMD) was defined for the primary endpoint as a worsening of the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score of one point or more. The clinical dementia rating (CDR) examines 6 categories of cognitive functioning domains. Each domain is scored on a scale ranging from 0 to 3 (including 0.5). A CDR-SB was generated as the sum of the values in each of the 6 domains. The CDR-SB sum scores range from 0 to 18, with higher scores indicating greater cognitive impairment and a 1 point worsening is considered a clinically significant symptom change.
Time Frame	Within 18 months of scan

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	CMD (CDR-SB Change >=1)	No CMD
Arm/Group Description	Subjects who experienced at least a 1 point worsening in CDR-SB score over 18 months	Subjects who experienced less than a 1 point worsening in CDR-SB score over 18 months
Measure Participants	143	62
tAD++	119 58%	43 NaN
tAD+	10 4.9%	5 NaN
tAD-	14 6.8%	14 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CMD (CDR-SB Change >=1), No CMD
	Comments	Scan results were grouped into τAD++ vs. non-τAD++ (τAD+ and τAD-) for the analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0313
	Comments	A priori threshold was two-sided 0.05.
	Method	log linear model
	Comments	Adjusted for treatment arm (lanabecestat 20 mg, 50 mg, or placebo), baseline age, years of education (categorical), and baseline CDR-SB score.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.36
	Confidence Interval	(2-Sided) 95%; 1.028 to 1.785
	Parameter Dispersion	Type: Value:
	Estimation Comments	τAD++ scans represent the numerator for risk, and τAD+/τAD- scans represent the denominator

2. Secondary Outcome

Title	Risk Ratio for AD Symptom Progression on Various Clinical Measures
Description	Baseline flortaucipir F 18 PET imaging results were determined by majority read (see Baseline Characteristics for description). Clinically meaningful deterioration (CMD) was defined for the cognitive endpoints as follows: mini-mental status exam (MMSE) worsening of 3 points or greater, Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) worsening of 4 points or greater, Pfeffer's Functional Activities Questionnaire (FAQ) worsening of 3 points or greater, CDR global worsening of greater than 0 points. MMSE scores range from 0 to 30 with lower scores indicating worsening cognitive function. ADAS-Cog11 scores range from 0 to 70 with higher scores indicating worsening cognitive function. FAQ scores range from 0 to 30 with higher scores indicating worsening cognitive function. CDR global is scored on a 5 point scale (0, 0.5, 1, 2, 3) with higher scores indicating worsening cognitive function.
Time Frame	Within 18 months of scan

Outcome Measure Data

Analysis Population Description

All subjects were eligible for this analysis; however, row totals reflect subjects for whom clinical measure data was available at baseline and 18 months.

Arm/Group Title	CMD Yes	No CMD
Arm/Group Description	Subjects who experienced CMD for the clinical measure as described above	Subjects who did not experience CMD for the clinical measure as described above
Measure Participants	205	205
tAD++	112 54.6%	49 NaN
tAD+	6 2.9%	8 NaN
tAD-	15 7.3%	13 NaN
tAD++	98 47.8%	59 NaN
tAD+	6 2.9%	8 NaN
tAD-	8 3.9%	20 NaN
tAD++	111 54.1%	47 NaN
tAD+	9 4.4%	5 NaN
tAD-	14 6.8%	14 NaN
tAD++	71 34.6%	91 NaN
tAD+	7 3.4%	8 NaN
tAD-	9 4.4%	19 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CMD (CDR-SB Change >=1), No CMD
	Comments	Risk ratio for MMSE CMD. Scan results were grouped into τAD++ vs. non-τAD++ (τAD+ and τAD-) for the analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	.0833
	Comments	A priori threshold was two-sided 0.05. No adjustment for multiple comparisons.
	Method	log linear model
	Comments	Adjusted for treatment arm (lanabecestat 20 mg, 50 mg, or placebo), baseline age, years of education (categorical), and baseline score.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.35
	Confidence Interval	(2-Sided) 95%; 0.962 to 1.886
	Parameter Dispersion	Type: Value:
	Estimation Comments	τAD++ scans represent the numerator for risk, and τAD+/τAD- scans represent the denominator

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CMD (CDR-SB Change >=1), No CMD
	Comments	Risk ratio for ADAS-Cog11 CMD. Scan results were grouped into τAD++ vs. non-τAD++ (τAD+ and τAD-) for the analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	.0141
	Comments	A priori threshold was two-sided 0.05. No adjustment for multiple comparisons.
	Method	log linear model
	Comments	Adjusted for treatment arm (lanabecestat 20 mg, 50 mg, or placebo), baseline age, years of education (categorical), and baseline score.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.77
	Confidence Interval	(2-Sided) 95%; 1.122 to 2.796
	Parameter Dispersion	Type: Value:
	Estimation Comments	τAD++ scans represent the numerator for risk, and τAD+/τAD- scans represent the denominator

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	CMD (CDR-SB Change >=1), No CMD
	Comments	Risk ratio for FAQ CMD. Scan results were grouped into τAD++ vs. non-τAD++ (τAD+ and τAD-) for the analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	.0639
	Comments	A priori threshold was two-sided 0.05. No adjustment for multiple comparisons.
	Method	log linear model
	Comments	Adjusted for treatment arm (lanabecestat 20 mg, 50 mg, or placebo), baseline age, years of education (categorical), and baseline score.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.32
	Confidence Interval	(2-Sided) 95%; 0.984 to 1.776
	Parameter Dispersion	Type: Value:
	Estimation Comments	τAD++ scans represent the numerator for risk, and τAD+/τAD- scans represent the denominator

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	CMD (CDR-SB Change >=1), No CMD
	Comments	Risk ratio for CDR Global CMD. Scan results were grouped into τAD++ vs. non-τAD++ (τAD+ and τAD-) for the analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	.2814
	Comments	A priori threshold was two-sided 0.05. No adjustment for multiple comparisons.
	Method	log linear model
	Comments	Adjusted for treatment arm (lanabecestat 20 mg, 50 mg, or placebo), baseline age, years of education (categorical), and baseline score.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.28
	Confidence Interval	(2-Sided) 95%; 0.815 to 2.020
	Parameter Dispersion	Type: Value:
	Estimation Comments	τAD++ scans represent the numerator for risk, and τAD+/τAD- scans represent the denominator

3. Secondary Outcome

Title	Mean Change in Cognitive/Functional Assessments
Description	Mean change in cognitive/functional measures baseline between τAD++ and non-τAD++ (determined by baseline tau status), calculated by Mixed Model Repeat Measures (MMRM). CDR-SB scores range from 0 to 18, with higher scores indicating worsening cognitive impairment. MMSE scores range from 0 to 30 with lower scores indicating worsening cognitive function. ADAS-Cog11 scores range from 0 to 70 with higher scores indicating worsening cognitive function. FAQ scores range from 0 to 30 with higher scores indicating worsening cognitive function.
Time Frame	baseline and 18 months

Outcome Measure Data

Analysis Population Description

All subjects were eligible for this analysis; however, row totals reflect subjects for whom clinical measure data was available at baseline and 18 months.

Arm/Group Title	τAD++ Scan Result	Non-τAD++ Scan Result
Arm/Group Description	Subjects with a τAD++ scan result	Subjects with a Non-τAD++ scan result
Measure Participants	162	43
CDR-SB	2.22 (0.215)	1.31 (0.379)
MMSE	-4.89 (0.377)	-2.12 (0.647)
ADAS-Cog11	6.53 (0.660)	1.97 (1.181)
FAQ	5.22 (0.537)	2.68 (0.895)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CMD (CDR-SB Change >=1), No CMD
	Comments	MMRM testing the difference between CDR-SB least squares mean changes of tAD++ and Non-tAD++ (tAD+ and tAD-). The unstructured covariance structure (UN) was used.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	.0305
	Comments	A priori threshold was two-sided 0.05. No adjustment for multiple comparisons.
	Method	Mixed Models Analysis
	Comments	Adjusted for baseline clinical score, age, years of education (categorical), and treatment arm (lanabecestat - 20mg or 50mg - or placebo).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CMD (CDR-SB Change >=1), No CMD
	Comments	MMRM testing the difference between MMSE least squares mean changes of tAD++ and Non-tAD++ (tAD+ and tAD-). The unstructured covariance structure (UN) was used.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	A priori threshold was two-sided 0.05. No adjustment for multiple comparisons.
	Method	Mixed Models Analysis
	Comments	Adjusted for baseline clinical score, age, years of education (categorical), and treatment arm (lanabecestat - 20mg or 50mg - or placebo).

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	CMD (CDR-SB Change >=1), No CMD
	Comments	MMRM testing the difference between ADAS-Cog11 least squares mean changes of tAD++ and Non-tAD++ (tAD+ and tAD-). The unstructured covariance structure (UN) was used.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	Comments	A priori threshold was two-sided 0.05. No adjustment for multiple comparisons.
	Method	Mixed Models Analysis
	Comments	Adjusted for baseline clinical score, age, years of education (categorical), and treatment arm (lanabecestat - 20mg or 50mg - or placebo).

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	CMD (CDR-SB Change >=1), No CMD
	Comments	MMRM testing the difference between FAQ least squares mean changes of tAD++ and Non-tAD++ (tAD+ and tAD-). The unstructured covariance structure (UN) was used.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0097
	Comments	A priori threshold was two-sided 0.05. No adjustment for multiple comparisons.
	Method	Mixed Models Analysis
	Comments	Adjusted for baseline clinical score, age, years of education (categorical), and treatment arm (lanabecestat - 20mg or 50mg - or placebo).

4. Secondary Outcome

Title	Inter-Reader Reliability of Reader Interpretation of Flortaucipir F 18 PET Imaging
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 -1 to 1 with 1 indicating perfect agreement between the readers. Read results binarized as τAD++ or non-τAD++.
Time Frame	baseline scan

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Subjects/All Readers
Arm/Group Description	All subjects scans included in the study across 5 independent readers
Measure Participants	205
Number (95% Confidence Interval) [kappa coefficient]	0.754

Adverse Events

Time Frame	Not applicable, as no new patients received treatment as part of this study.
Adverse Event Reporting Description	Adverse event data were not collected in this study.
Arm/Group Title	Single Arm, Randomly Sequenced Flortaucipir F18 Scans
Arm/Group Description	No study drug was administered for this study. Scans were previously acquired from Study I8D-MC-AZES (NCT02245737, Eli Lilly and Company sponsor) and were read by five independent, blinded readers. Flortaucipir F18: No study drug was administered for this study.
All Cause Mortality
	Single Arm, Randomly Sequenced Flortaucipir F18 Scans
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)
Serious Adverse Events
	Single Arm, Randomly Sequenced Flortaucipir F18 Scans
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Single Arm, Randomly Sequenced Flortaucipir F18 Scans
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)

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.