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

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

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).

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Procedure: Brain PET Scan; Drug: florbetapir F 18; Drug: Flortaucipir F18

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 Type: Interventional
• Enrollment (Actual): 383
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Banner Alzheimer's Institute
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic
    • Scottsdale, Arizona, United States, 85258
      • Four Peaks Neurology
    • Sun City, Arizona, United States, 85351
      • Banner Sun Health Research Institute
  • California
    • Irvine, California, United States, 92697
      • UC Irvine
    • Newport Beach, California, United States, 92663
      • Hoag Memorial
    • Sacramento, California, United States, 95817
      • UC Davis
    • Sacramento, California, United States, 95816
      • Norther California PET Imaging Center
    • San Francisco, California, United States, 94158
      • UC San Francisco
    • Santa Monica, California, United States, 90404
      • Neurological Research Institute
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Molecular NeuroImaging
  • Florida
    • Deerfield Beach, Florida, United States, 33064
      • Quantum Laboratories
    • Fort Myers, Florida, United States, 33912
      • 21st Century Oncology
    • Orlando, Florida, United States, 32806
      • Sandlake Imaging
    • Saint Petersburg, Florida, United States, 33709
      • Meridien Research
    • Tampa, Florida, United States, 33613
      • USF Health Byrd Alzheimer's Center
    • West Palm Beach, Florida, United States, 33407
      • Independent Imaging
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Quincy, Massachusetts, United States, 02169
      • Alzheimer's Disease Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Center for Clinical Imaging Research
  • Nevada
    • Las Vegas, Nevada, United States, 89147
      • Las Vegas Radiology
  • New York
    • New York, New York, United States, 10016
      • Center for Brain Health - NYU Langone Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
    • Providence, Rhode Island, United States, 02906
      • Butler Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: NON_RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: SINGLE

Number of Arms

4

Arms and Interventions

Participant Group / 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.	Procedure: Brain PET Scan; positron emission tomography (PET) scan of the brain; Drug: florbetapir F 18; Other Names: Amyvid; 18F-AV-45; Drug: Flortaucipir F18; Other Names: 18F-AV-1451; T807
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.	Procedure: Brain PET Scan; positron emission tomography (PET) scan of the brain; Drug: florbetapir F 18; Other Names: Amyvid; 18F-AV-45; Drug: Flortaucipir F18; Other Names: 18F-AV-1451; T807
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.	Procedure: Brain PET Scan; positron emission tomography (PET) scan of the brain; Drug: florbetapir F 18; Other Names: Amyvid; 18F-AV-45; Drug: Flortaucipir F18; Other Names: 18F-AV-1451; T807
EXPERIMENTAL: Confirmatory Subjects; Subjects will receive an IV injection, 370 MBq (10 mCi), single dose of florbetapir F 18 and flortaucipir at baseline.	Procedure: Brain PET Scan; positron emission tomography (PET) scan of the brain; Drug: florbetapir F 18; Other Names: Amyvid; 18F-AV-45; Drug: Flortaucipir F18; Other Names: 18F-AV-1451; T807

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

Collaborators and Investigators

• Sponsor: Avid Radiopharmaceuticals

Publications and helpful links

General Publications

• Lu M, Pontecorvo MJ, Devous MD Sr, Arora AK, Galante N, McGeehan A, Devadanam C, Salloway SP, Doraiswamy PM, Curtis C, Truocchio SP, Flitter M, Locascio T, Devine M, Zimmer JA, Fleisher AS, Mintun MA; AVID Collaborators. Aggregated Tau Measured by Visual Interpretation of Flortaucipir Positron Emission Tomography and the Associated Risk of Clinical Progression of Mild Cognitive Impairment and Alzheimer Disease: Results From 2 Phase III Clinical Trials. JAMA Neurol. 2021 Apr 1;78(4):445-453. doi: 10.1001/jamaneurol.2020.5505.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 1, 2013
• Primary Completion (ACTUAL): July 28, 2017
• Study Completion (ACTUAL): July 28, 2017

Study Registration Dates

• First Submitted: December 16, 2013
• First Submitted That Met QC Criteria: December 16, 2013
• First Posted (ESTIMATE): December 20, 2013

Study Record Updates

• Last Update Posted (ACTUAL): September 22, 2020
• Last Update Submitted That Met QC Criteria: September 3, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: 18F-AV-1451-A05