Clinical trial NCT02676843
Conditions: Frontotemporal Lobar Degeneration (FTLD) Frontotemporal Dementia (FTD) Tauopathies
Keywords: FTLD FTD
Sponsor: Columbia University
Start date: 2016-04-01; Completion date: 2018-11-25
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study will investigate the ability of a new PET tracer, 18F-AV-1451, to detect depositions of a protein, called tau, in the brains of people with a mutation in the tau gene that causes deposition of the protein, and in people without the mutation. Up to three 18F-AV-1451 scans will be performed (one per year) on control subjects without MAPT mutations, presymptomatic mutation carriers, and symptomatic mutation carriers.

Detailed description:
Approximately 40% of cases of Frontotemporal lobar Degeneration (FTLD) are also associated with abnormal deposition of tau protein. The purpose of this study is to image MAPT mutation carriers and their non-carrier relatives in order to study the use of this tracer as a biomarker in Frontotemporal Lobar Degeneration with tau deposition (FTLD-tau).

Arms: arm 1: Subjects who are microtubule associated protein tau (MAPT) family carriers and non-carriers will receive 18F-AV-1451 by injection, and undergo a Positron Emission Tomography (PET) scan, which will then be qualitatively analyzed to examine tau deposition in the brain.
Interventions: intervention 1: 18F-AV-1451
Intervention descriptions: intervention 1: A single injection of up to 10 millicuries of 18F-AV-1451 will be administered to subjects, followed by a 20-minute PET scan.

Protocol documents:
Prot_SAP_000.pdf: 
NCT02676843 
Study Title: Tau PET imaging with 18F-AV-1451 in subjects with MAPT mutations 
IRB Protocol Number: AAAP4551 
Version: 07/24/2015 
Principal Investigator: Edward Huey, MD 
Co-Investigator: William Kreisl, MD 
Study Coordinator: Masood Manoochehri 


PROTOCOL SUMMARY 
Research question(s): 
A novel PET tracer (18F-AV-1451) designed to measure the amount of tau protein in the brain 
will detect abnormal accumulations of tau in the brains of patients with tau mutations, but not 
their unaffected relatives. 
Scientific abstract: 
Objective: To determine the ability of a new PET tracer that binds to tau, 18F-AV-1451, to 
detect tau in subjects with and without mutations in the MAPT gene the codes for the protein tau. 
Study Population: Control subjects without MAPT mutations, presymptomatic mutation carriers, 
and symptomatic mutation carriers. 
Outcome measures:  
The primary outcome measure will be a qualitative assessment of tau deposition on the 18FAV-
1451 scans 
Lay abstract: 
We will be testing the ability of a new PET tracer, 18F-AV-1451, to detect depositions of a 
protein, called tau, in the brains of people with a mutation in the tau gene that causes deposition 
of the protein and in people without the mutation. 
Subject Selection 
Patients will be recruited from existing studies and from patients seen in the Columbia memory 
disorders clinic.  
Inclusion criteria: Members of families with established MAPT mutations, who either have the 
capacity to consent to participate in the protocol, or else have designated a surrogate/proxy to 
consent to participate in this study. 
Exclusion criteria: Unwillingness to participate and/or on a medication which significantly 
prolongs QT interval. 
Safeguards for Vulnerable Populations 
The proposed study, including the potential risks and benefits, will be discussed with the 
potential subjects, and they will be given copies of the consent form to read. Decision-making 
capacity to provide informed consent, including understanding the purpose of the study and the 
risks and benefits of participating, will be assessed by the evaluating physician and documented 
in the chart. Individuals with intact decision-making capacity will sign the consent form. We 
expect the majority of subjects to have capacity to provide informed consent. 
All subjects with impaired capacity to provide informed consent will be evaluated by the 
physician for their ability to assign a surrogate. Subjects who demonstrate capacity to assign a 
surrogate will identify a surrogate for the remainder of the study. Surrogates permitted are 


designated family members (only patient, spouse, or adult child), or may be another individual 
chosen by Patient Chosen Surrogate (PCS) method. The study will be explained to each potential 
subject and surrogate, and written informed consent must be obtained from the surrogate. If the 
participant does not have the capacity to assign a surrogate, he or she will not be allowed to 
participate in the study. The consent process will be repeated at each evaluation, and the above 
procedures will be followed for any individual that loses capacity during the course of the study. 
Subjects will not be given diagnoses as part of their participation in this protocol. Some may be 
symptomatic and have received a diagnosis and others may be presymptomatic and had genetic 
testing and know their status. This knowledge will not preclude their participation in the study, 
but diagnosis and genetic information will not be given to subjects through their participation in 
this study. 
Study Purpose and Rationale 
We will examine tau deposition in patients with MAPT mutations and their family members 
using a new PET tracer, 18F-AV-1451. MAPT mutations cause Frontotemporal dementia (FTD). 
We have an opportunity to examine the tau deposition in genetic FTD by obtaining 18F-AV-
1451 tau tracer imaging on symptomatic, pre-symptomatic, and non-carrier subjects in families 
with MAPT mutations. This will achieve the following important aims: 1. Elucidate the early 
course of genetic FTD due to tau. When does tau start to be laid down? What are the earliest 
brain regions affected? 2. Validate the 18F-AV-1451 tau tracer by demonstrating its ability to 
distinguish MAPT mutation carriers from non-carriers. 
Study Design and Statistical Procedures 
This is an initial proof of concept study. As such, we will qualitatively examine each scan for tau 
positivity and not perform quantitative statistical analyses. 
Study Procedures 
We propose to perform 18F-AV-1451 scanning on 16 subjects from families with known tau 
mutations over 2 years (8 per year) including 6 controls, 5 presymptomatic mutation carriers, and 
5 symptomatic mutation carriers. The controls will be non-mutation carrying members of 
families in which some family members have MAPT mutations. Pregnant women will be 
excluded from the study. The tracer will be manufactured at Avid Radiopharmaceuticals in 
Philadelphia, PA and transported to Columbia University Medical Center by courier for 
administration. See (Zhang et al., 2012) for details of 18F-AV-1451 synthesis and quality 
control. Adverse events will be monitored continuously during the imaging session. Subjects 
who experience any adverse event during an imaging session will not be discharged until the 
event has resolved or stabilized. 
Study Drug 
18F-AV-1451, also known as [18F] T807, is a tracer that was developed by Avid 
Radiopharmaceuticals, a company later acquired by Lilly, to image tau protein in humans in 
vivo. It has shown suitable tau affinity, target selectivity, and pharmacokinetic characteristics for 
tau imaging (see below) (Zhang et al., 2012). The developers of 18F-AV-1451 have reviewed the 
effects of the 10 +14 C>T mutation observed in our family and the mutation should not interfere 
with 18F-AV-1451 binding to tau in the 10 +14 C>T mutation carriers. We have successfully 


applied to Avid radiopharmaceuticals for the use of 18F-AV-1451 and they have approved us to 
use 18F-AV-1451 for investigation and are providing us the tracer for free. 
Autoradiography studies have demonstrated that 18F-AV-1451 binds with high affinity to tau 
positive brain sections from AD patients, whereas minimal to no binding was observed in tau 
negative, amyloid positive samples or in tau negative and amyloid negative control groups 
(Chien et al., 2013). The correlation of 18F-AV-1451 in these autoradiography studies was high 
(r2=0.9036) for paired helical filament-tau (PHF-tau, the aggregated fibrillary form) and low for 
-amyloid (r2=0.0827). The Kd calculated for 18F-AV-1451 binding to tau protein in human 
brain slices was measured to be approximately 15 nM. Subsequently, the Kd calculated for 18F-
AV-1451 binding to PHF-tau purified from the human brain samples was measured at 0.7 nM. In 
vivo animal kinetic studies were supportive of further development as 18F-AV-1451 
demonstrated rapid uptake in mouse, rat, and monkey brain followed by moderate clearance 
(Zhang et al., 2012; Chien et al., 2013). 18F-AV-1451 is being used for research purposes and 
will be handled in accordance with the CUMC Research Pharmacy procedures and NYP policy 
P168, Version 4. Effective date: August 24, 2009 34 Investigational Drugs: Use and Control. 
Study Subjects 
We propose to perform 18F-AV-1451 scanning on 16 subjects over 2 years (8 per year) 
including 6 controls, 5 presymptomatic mutation carriers, and 5 symptomatic mutation carriers. 
Recruitment 
Subjects who previously participated in a previous protocol at Columbia will be recruited for this 
study. These subjects already have an existing relationship with the PI. Subjects participating in 
that protocol who meet the inclusion, but not the exclusion, criteria of this study will be told 
about the study and given the contact information of this study team by Dr. Huey.  
Participants will also be recruited from patients seen at the Columbia Memory Disorders Clinic. 
The physicians at this clinic will be informed of this study so that if they identify a potential 
subject for this study, they can give that patient our contact information for potential 
participation in this study. 
Informed Consent Process 
We will obtain informed consent prior to any procedures. Only subjects with capacity to provide 
their own consent may consent or subjects who have a legally-authorized representative or 
guardian or a designated health care proxy that does not exclude research may consent on behalf 
of the subject to participate in this study. The study will be explained to each prospective patient 
or representative, and written informed consent must be obtained from the patient or 
representative before the patient participates in any study-related procedures. 
Confidentiality of Study Data 
Each participant's identity and participation in this study will be kept confidential in our 
database. All records will be stored in a computer file and access will be restricted to research 
staff. All questionnaires and other forms generated from the data collection will be kept in locked 
file cabinets, and only the investigators will have access to this information. Participant names 
will not be used. Rather, we will assign a code number that will be associated with all 


information collected. Information presented or published for scientific purposes will not include 
participant names. 
Privacy Protections 
Research records are maintained in locked paper files and secured computer files, available only 
to research staff and institutional personnel as part of routine audits. Information is coded and 
password protected. Access is restricted to the authorized scientific investigators. 
Identity of participants will not be shared with any investigators. Data that has been stripped of 
all identifying information from genetic analysis will be kept separate from the clinical and 
demographic data stored at the Taub Institute and can only be accessed by authorized 
individuals. 
Potential Risks 
Preclinical toxicity studies of 18F-AV-1451 (i.e. using non-radioactive 18F-AV-1451) showed a 
good safety profile with no observable effects at high multiples of the intended maximum human 
dose (Chien et al., 2013). The initial exploratory investigations of 18F-AV-1451 have been 
performed as part of two studies in older human subjects with a low probability of AD, in older 
subjects with a high probability of AD and in middle aged and young control subjects. 
The objectives of the two studies were to establish the preliminary safety of 18F-AV-1451 and to 
assess the feasibility of 18F-AV-1451 as a potential PET biomarker for imaging pathological tau 
in human brains. As of the cutoff date of 19 September 2013, a total of 18 subjects have been 
enrolled in these studies (unpublished data from Avid Radiopharmaceuticals). Each subject 
received one intravenous bolus dose of approximately 10 mCi (370 MBq) of 18F-AV-1451. 18F-
AV-1451 was well-tolerated; three subjects reported adverse events that were mild in severity 
and not considered related to study drug administration (two subjects reported headache, one 
subject reported diarrhea). 
No consistent or clinically significant changes in vital signs, laboratory, and ECG values were 
observed in a completed analysis of 11 subjects. Preliminary human dosimetry results for 18F-
AV-1451 have been computed for 3 subjects. The results showed both hepatobiliary and, to a 
smaller extent, renal excretion, and total effective dose similar to other approved F-18 
radiopharmaceuticals. The organs of the gastrointestinal tract (upper large intestine, small 
intestine and liver) received the greatest exposure. The whole body effective dose for a 10 mCi 
(370 MBq) dose of 18F-AV-1451 was calculated to be 9.18 mSv (unpublished data from Avid 
Radiopharmaceuticals). 
Data and Safety Monitoring 
We will not have a specific Data and Safety Monitoring Board. Adverse events will be 
documented in the patient’s chart. As far as possible, each adverse event will be described in the 
following manner and tabulated: 1) duration; 2) severity grade (i.e. mild, moderate, serious); 3) 
relationship to study; and 4) actions taken by the investigators. Unexpected and serious adverse 
events will be reported to the IRB within 2 days for death or life threatening events, and within 
15 days for all others. We will also report all adverse events to Avid Radiopharmaceuticals who 
is monitoring safety data for this compound. 


We will ensure proper monitoring per FDA and IRB guidelines, including ensuring that the study 
is conducted in accordance with the protocol. We will review all ongoing investigations of 18F-
AV-1451 and give our evaluations of the safety and usefulness of this compound to the FDA and 
the IRB. We will keep all records per FDA and IRB guidelines and submit all amendments, IND 
safety reports and annual reports to the FDA and IRB. 
Potential Benefits 
This study will not benefit subjects directly. But the development of an early measure of tau 
deposition in this patient population would be a benefit as in diagnosis and a possible marker of 
treatment response. 
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