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

Study Overview
=================
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).

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.

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

Conditions
-----------------
Alzheimer's Disease

Intervention / Treatment
-----------------
* Drug: florbetapir F 18
* Drug: Flortaucipir F18
* Procedure: Brain PET Scan


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: All subjects in both the exploratory and confirmatory phases of the study, receive both florbetapir and florbetapir scans, regardless of subgroup assignment.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exploratory Cognitively Healthy Subjects<br>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<br> <br> * Other names: 18F-AV-45;Drug: Flortaucipir F18<br> <br> * Other names: 18F-AV-1451;Procedure: Brain PET Scan<br>* positron emission tomography (PET) scan of the brain<br>|
| Experimental: Exploratory MCI Subjects<br>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<br> <br> * Other names: 18F-AV-45;Drug: Flortaucipir F18<br> <br> * Other names: 18F-AV-1451;Procedure: Brain PET Scan<br>* positron emission tomography (PET) scan of the brain<br>|
| Experimental: Exploratory AD Subjects<br>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<br> <br> * Other names: 18F-AV-45;Drug: Flortaucipir F18<br> <br> * Other names: 18F-AV-1451;Procedure: Brain PET Scan<br>* positron emission tomography (PET) scan of the brain<br>|
| Experimental: Confirmatory Subjects<br>Subjects will receive an IV injection, 370 MBq (10 mCi), single dose of florbetapir F 18 and flortaucipir at baseline. | Drug: florbetapir F 18<br> <br> * Other names: 18F-AV-45;Drug: Flortaucipir F18<br> <br> * Other names: 18F-AV-1451;Procedure: Brain PET Scan<br>* positron emission tomography (PET) scan of the brain<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmatory Phase: Relationship Between Neocortical Flortaucipir Uptake and the Subsequent Rate of Cognitive Decline | 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. | between baseline and 18 months | 
| Exploratory Phase: Cross-sectional Flortaucipir Imaging Results | 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. | baseline scan | 
| Exploratory Phase: Longitudinal Change in Tau Deposition Over Time, by Amyloid Status | Assess the rate of change of tau deposition as measured by flortaucipir uptake (SUVr) over time. Change = 18 months SUVr - baseline SUVr. | baseline and 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmatory Phase: Diagnostic Performance of Flortaucipir Visual Read | 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. | baseline and 18 months | 
| Exploratory Phase: Correlation Between Flortaucipir SUVr and Age | 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. | baseline scan |