Conditions: Cardiac Amyloidosis
Keywords: Amyloidosis Cardiac Heart Imaging Diagnosis
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 23
Healthy volunteers: yes

Brief summary:
The primary aim of this pilot study is to determine whether amyloid deposits in the heart can be measured non-invasively by F-18 florbetapir (Trade Name: Amyvid) positron emission tomography (PET) in 30 individuals with documented cardiac amyloidosis. We will also enroll 15 individuals without cardiac amyloidosis to undergo the F-18 florbetapir imaging as a control group.

The primary hypothesis of this study is that a specific amyloid binding radiotracer will bind to the myocardial amyloid deposits and help quantify cardiac amyloid burden.

A secondary aim of this study is to determine reproducibility of F-18 florbetapir imaging of the myocardium.

Detailed description:
F-18 florbetapir has been studied in multiple clinical trials to image beta-amyloid deposition in the brain of subjects with Alzheimers' disease. Florbetapir F-18 has been well tolerated in studies of more than 2000 human subjects. Biodistribution studies in humans revealed predominantly hepatobiliary excretion. The tracer clears rapidly from the blood pool in about 20 minutes. This radiotracer has been recently approved for clinical imaging of brain amyloid in subjects with suspected Alzheimers disease. The investigators propose to test this FDA approved radiotracer for an off label indication in a pilot study to evaluate its potential utility, if any, to image cardiac amyloidosis.

Amyloid related heart disease is associated with LV wall thickening due to infiltration; however, this myocardial wall thickening is not definitively distinguishable from left ventricular myocyte hypertrophy from increased afterload to the heart from hypertension or aortic stenosis. Typically myocardial or other tissue biopsy with typical echo features of amyloidosis is required for confirmation of amyloidosis. This pilot study is designed to understand whether cardiac amyloid burden can be measured using a specific radiotracer targeted against amyloid protein (F-18 Florbetapir). At this point it is unknown of F-18 Florbetapir will bind to either AL or TTR amyloid protein or to both of them or to neither of them. The investigators would like to study 15 patients with AL and 15 patients with TTR amyloidosis to understand these differences if any. The investigators also seek to understand if the signal to noise ratio of the circulating amyloid protein in the blood pool (AL amyloid disease) allows for good differentiation of myocardial amyloid uptake. 15 individuals without cardiac amyloidosis will also be enrolled as controls for this study.

The purpose of the proposed research study is to examine in detail, using quantitative PET, myocardial F-18 Florbetapir uptake in cardiac amyloidosis in order to better understand mechanisms of heart damage in this disease. A secondary aim of this study is to determine reproducibility of F-18 florbetapir imaging of the myocardium in a subset of patients with amyloidosis who return for a second F-18 florbetapir scan within 30 days.

Arms:
arm 1: Individuals with documented cardiac amyloidosis will undergo F-18 florbetapir (Trade Name: Amyvid) positron emission tomography (PET). arm 2: Individuals without documented cardiac amyloidosis will undergo F-18 florbetapir (Trade Name: Amyvid) positron emission tomography (PET). arm 3: Some of the individuals with documented cardiac amyloidosis from arm 1 will undergo a second F-18 florbetapir (Trade Name: Amyvid) positron emission tomography (PET) within 30 days to measure reproducibility

Interventions: intervention 1: F-18 florbetapir PET
Intervention descriptions: intervention 1: Cardiac PET images will be obtained following injection of F-18 labeled Florbetapir (Trade Name: Amyvid)

Protocol document:
Prot_000.pdf: 
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Detailed Protocol 01/08/2018 
 
 
 
Study Title: Imaging Cardiac Amyloid Burden: A pilot Study Using F-18 Florbetapir Positron 
Emission Tomography 
NCT Number: NCT01683825 
Document Date: Jan 8, 2018 
 
 


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Detailed Protocol 01/08/2018 
 
 
IMAGING CARDIAC AMYLOID BURDEN: A PILOT STUDY USING F-18 FLORBETAPIR POSITRON EMISSION 
TOMOGRAPHY 
 
 
 
Version Date:   January 8, 2018 
 
Study Type: Single Center Pilot Study 
 
Sponsors: BWH Internal funds (XXXXX Sundry Account) 
 
Study Enrollment Period: February 2013 to October 2018 
 
Principal Investigator: Sharmila Dorbala, MBBS 
 
Co-investigators: _________, MD and ___________, MD 
 
 
 
 


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Detailed Protocol 01/08/2018 
 
TABLE OF CONTENTS 
Topic 
Page Number 
I. 
ABBREVIATIONS 
 
3 
II. 
SYNOPSIS 
 
4-5 
III. 
BACKGROUND AND SIGNIFICANCE 
 
6-7 
IV. 
SPECIFIC AIMS 
 
7 
V. 
SUBJECT SELECTION 
 
8 
VI. 
SUBJECT ENROLLMENT 
 
9 
VII. 
STUDY PROCEDURES 
 
10-11 
VIII. 
BIOSTATISTICAL ANALYSIS 
 
11 
IX. 
RISKS AND DISCOMFORT 
 
11-12 
X. 
POTENTIAL BENEFITS 
 
12 
XI. 
MONITORING AND QUALITY ASSURANCE 
 
12-13 
XII. 
REREFENCES 
 
14 


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Detailed Protocol 01/08/2018 
 
ABBREVIATIONS USED: 
Myocardial Blood Flow: MBF 
Positron Emission Tomography: PET 
Computed Tomography: CT 
Myocardial perfusion imaging: MPI 
Amyloid light chain: AL 
Transthyretin amyloid: TTR 
Senile systemic amyloidosis: SSA 
New York Heart Association: NYHA 
Intravenous: IV 
 
 


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Detailed Protocol 01/08/2018 
 
SYNOPSIS 
 
Title of Study: Imaging Cardiac Amyloid Burden: A Pilot Study Using F-18 Florbetapir Positron Emission 
Tomography 
 
Planned Study Period:  From 2Q2013 - 2Q2017  
 
Study Objective(s)  
Specific Aim:  The primary aim of this pilot study is to determine whether amyloid deposits in the heart 
can be measured non-invasively by F-18 florbetapir (Trade Name: Amyvid) positron emission 
tomography (PET) in 30 individuals with documented cardiac amyloidosis and in 15 volunteers  without 
cardiac amyloidosis.   
A secondary aim of this study is to determine reproducibility of F-18 florbetapir uptake in the 
myocardium. 
 
Planned Total Number of Study Centers and Location  
Single study center in the United States  
 
Design and Methodology  
This is a single-center pilot study in subjects with cardiac amyloidosis. All subjects will undergo 
evaluation of myocardial amyloid burden using F-18 labeled florbetapir PET/CT, blood tests, 6 Minute 
Walk Test, and 24 hour urine collection. No more than 45 subjects (15 cardiac light chain amyloid 
subjects and 15 cardiac senile/TTR amyloid subjects, 15 volunteers without amyloidosis including 10 
elderly subjects with clinical heart failure with preserved ejection fraction (HFpEF) without amyloidosis) 
will be enrolled into the study.  After successful screening, subjects will undergo PET/CT scanning 
following one intravenous injection of 10 mCi of F-18 florbetapir.  One set of F18 florbetapir images will 
be acquired in a 3D list mode starting with the injection of F-18 florbetapir for 90 minutes.  Images will 
be unlisted and quantitation of radiotracer uptake performed. Mean and maximum F-18 florbetapir 
uptake will be measured. Radiotracer biodistribution in the liver and subdiaphragmatic regions will be 
measured. A total of 10 AL and 10 ATTR amyloid patients will undergo a repeat F-18 florbetapir PET scan 
within a month of the initial study (next day to one month). 
 


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Detailed Protocol 01/08/2018 
 
Number of Subjects Planned  
No more than 45 subjects will be enrolled into the study.  
 
Main Selection Criteria 
Subjects will be eligible if they meet all of the following inclusion criteria and none of the exclusion criteria:  
Inclusion criteria for amyloid subjects: 
• 
Age > 18 years 
• 
Biopsy proven amyloidosis outside the heart with typical echocardiographic appearance of 
cardiac involvement, or a positive cardiac biopsy. 
• 
Diagnosis of AL amyloidosis by standard criteria (evidence of plasma cell dyscrasia with 
appropriate tissue staining for AL) OR 
• 
Diagnosis of TTR amyloidosis (no evidence of plasma call dyscrasia and positive TTR staining 
of amyloid in tissue biopsy) 
• 
Able and willing to provide informed consent to participate in the study 
• 
10 subjects with HFpEF age >70 years will be included in the control group.  
 
Exclusion criteria for both amyloid and volunteer subjects: 
• 
Pregnancy 
• 
In the 10 subjects with HFpEF age >70 years, prior coronary artery disease, coronary 
revascularization or severe valvular heart disease 
• 
Serious non-cardiac medical illness (e.g., disseminated malignancy, severe neurological 
dysfunction at time of baseline PET study) which will preclude research study participation 
 
Statistical Methods:  
This is a pilot feasibility study using F-18 florbetapir to image myocardial amyloid deposits.  Mean and 
maximal myocardial uptake of F-18 florbetapir will be estimated in the subjects with diagnosed cardiac 
amyloid.  Mean liver to heart ratio will be estimated. 
 
 


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Detailed Protocol 01/08/2018 
 
I. BACKGROUND AND SIGNIFICANCE: 
 
a) Introduction 
Cardiac involvement is a common manifestation of light-chain (AL) amyloidosis and is a ubiquitous and 
predominant finding in senile systemic amyloidosis (SSA).1 In AL amyloidosis, it is a major determinant of 
treatment options and prognosis2 and in SSA, it is almost invariably the cause of death.3 In amyloidosis 
with cardiac involvement, the coronary microvasculature is subject both to extrinsic compression and to 
direct deposition of amyloid within the vessel wall. The resultant abnormalities in coronary microvascular 
perfusion (the small vessels of the heart) may be responsible for the high incidence of sudden death in AL 
amyloidosis4 and the high treatment-related mortality in AL patients with cardiac involvement undergoing 
high-dose chemotherapy with autologous stem cell transplant.5 Microvascular ischemia can be diagnosed 
noninvasively using standard rest and stress nuclear imaging techniques utilizing isotopes such as 
sestamibi or thallium, or N-13 ammonia or rubidium-82. However, these tests involve use of stress testing 
with vasodilator stress which is not well tolerated by patients with amyloidosis particularly those with 
neuropathy. At this time, although we can measure myocardial ischemia as an effect of myocardial 
amyloid deposition and/or toxicity, we do not have the capability to assess myocardial amyloid burden 
directly.  
A newly developed radiotracer F-18 labeled florbetapir has been recently approved by the FDA for 
imaging beta amyloid in the brain of patients with Alzheimer’s’ disease.6-10 If these F-18 labeled florbetapir 
binds to cardiac amyloid protein, then the potential to quantify myocardial amyloid burden is available. 
Assessment of myocardial amyloid burden holds the potential for better understanding the nature of 
cardiac dysfunction and can potentially help assess response of therapy specifically targeted against 
amyloid production. Data from this pilot study will aid the principal investigator in designing a more 
definitive larger prospective multicenter study of cardiac amyloidosis, a rare disease, using F-18 
florbetapir to estimate myocardial amyloid burden and follow response to therapy with novel therapeutic 
agents.   
 
b)  Previous studies leading up to or supporting the proposed research 
F-18 florbetapir has been studied in multiple clinical trials to image beta-amyloid deposition in the brain 
of subjects with Alzheimers’ disease.6-10  Florbetapir F-18 has been well tolerated in studies of more than 
2000 human subjects.9-10  Biodistribution studies in humans revealed predominantly hepatobiliary 
excretion. The tracer clears rapidly from the blood pool in about 20 minutes (6). This radiotracer has 
been recently approved for clinical imaging of brain amyloid in subjects with suspected Alzheimer’s 


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Detailed Protocol 01/08/2018 
 
disease. In this pilot study, F-18 florbetapir images will be acquired immediately after injection and at 90 
minutes after injection to study radiotracer bio-distribution and understand the optimal time for 
imaging. 
 
Preliminary studies using C-11 labeled PiB (another agent used to image beta-amyloid in the brain of 
patients with Alzheimer’s disease)11 show that this tracer can be taken up by cardiac amyloidosis 
(unpublished data in abstract form from Uppsala University, Sweden). However, this tracer is produced 
by a cyclotron and has a short half-life of 20 minutes; hence it can only be used in sites with a cyclotron 
on site, limiting its applicability for multicenter studies. We propose to test a longer half life tracer, F-18 
florbetapir in a pilot study to evaluate their potential utility to image cardiac amyloidosis. If this agents 
works, that will enable us to plan a large multicenter study of this rare disorder allowing us the potential 
to detect preclinical disease as well as follow response to therapy.   
 
Amyloid related heart disease is associated with LV wall thickening due to infiltration; however, this 
myocardial wall thickening is not definitively distinguishable from left ventricular myocyte hypertrophy 
from increased afterload to the heart from hypertension or aortic stenosis. Typically myocardial or other 
tissue biopsy with typical echo features of amyloidosis is required for confirmation of amyloidosis. This 
pilot study is designed to understand whether we can measure cardiac amyloid burden using a specific 
radiotracer targeted against amyloid protein (F-18 florbetapir). The longer half-life (120 minutes) of F-18 
florbetapir, makes it a more attractive tracer for conducting a multicenter clinical study, since this 
radiotracer can be delivered to sites without an onsite cyclotron. At this point it is unknown if F-18 
florbetapir will bind to either AL or TTR amyloid protein or to both of them or to neither of them. Hence, 
we would like to study 15patients with AL, 15 patients with TTR amyloidosis and 15 volunteer subjects 
without amyloidosis [including 10 elderly subjects with clinical heart failure with preserved ejection 
fraction (HFpEF)] to understand these differences if any.  We also seek to understand if the signal to noise 
ratio of the circulating amyloid protein in the blood pool (AL amyloid disease) allows for good 
differentiation of myocardial amyloid uptake. 
 
The purpose of the proposed research study is to examine in detail, using quantitative PET, myocardial F-
18 florbetapir uptake in cardiac amyloidosis in order to better understand mechanisms of heart damage 
in this disease. The following specific aim is proposed: 
 
 


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Detailed Protocol 01/08/2018 
 
II. SPECIFIC AIM: 
 
The primary aim of this pilot study is to determine whether amyloid deposits in the heart can be measured 
non-invasively by F-18 florbetapir (Trade Name: Amyvid) positron emission tomography (PET) in 10 
individuals with documented cardiac amyloidosis and in 5 individuals without cardiac amyloidosis. 
 
A secondary aim of this study is to determine reproducibility of F-18 florbetapir uptake in the 
myocardium. 
 
III. SUBJECT SELECTION 
 
a) Inclusion and Exclusion Criteria: 
The main goal of this pilot study is to prospectively study myocardial amyloid deposition using 
quantitative F-18 florbetapir PET/CT in 30 subjects with cardiac amyloidosis and 15 volunteers without 
cardiac amyloidosis including, 10 elderly subjects with clinical heart failure with preserved ejection 
fraction (HFpEF) over a period of 2 years. A total of 10 AL and 10 ATTR amyloid patients will undergo a 
repeat F-18 florbetapir PET scan within a month of the initial study (next day to one month). Subjects 
will be eligible if they meet all of the following inclusion criteria and none of the exclusion criteria: 
 
Main Selection Criteria 
Subjects will be eligible if they meet all of the following inclusion criteria and none of the exclusion criteria:  
Inclusion criteria for amyloid subjects: 
• 
Age > 18 years 
• 
Biopsy proven amyloidosis outside the heart with typical echocardiographic appearance of 
cardiac involvement, or a positive cardiac biopsy. 
• 
Diagnosis of AL amyloidosis by standard criteria (evidence of plasma cell dyscrasia with 
appropriate tissue staining for AL) OR 
• 
Diagnosis of TTR amyloidosis (no evidence of plasma call dyscrasia and positive TTR staining 
of amyloid in tissue biopsy) 
• 
Able and willing to provide informed consent to participate in the study procedures  
• 
10 subjects with HFpEF age >70 years will be included in the control group.  
 


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Detailed Protocol 01/08/2018 
 
 
Exclusion criteria for both amyloid and volunteer subjects: 
• 
Pregnancy 
• 
In the 10 subjects with HFpEF age >70 years, prior coronary artery disease, coronary 
revascularization or severe valvular heart disease 
 
b) Source of subjects and recruitment methods 
Patients will be recruited from the advanced heart failure group at the _______ Hospital and from the 
cardiology practice of Dr. _________, an expert in cardiac amyloidosis. Among them, stable and eligible 
patients meeting all inclusion and exclusion criteria will be invited to participate in this study and those 
who provide informed consent will be enrolled. Majority of the subjects with be enrolled from the clinical 
practice of Dr. _______, an expert in Cardiac amyloidosis. 
 
IV. SUBJECT ENROLLMENT 
 
a) Methods of enrollment including procedures for patient registration and or randomization 
The following recruitment methods will be used: 
• 
This is a pilot study of subjects with a rare disease. Typically these subjects are well characterized 
clinically in terms of their evaluation. Majority of the subjects will be recruited from the clinical 
practice of Dr________ and we will enroll normal volunteers from internet advertising (for 
example RSVP for health, clinicaltrials.gov, Craigslist). Dr. _______ will introduce the study to the 
subjects and those subjects that are willing to consider the study will be given the written 
informed consent for the study for review. Subjects’ questions will be answered by Dr______ 
and/or by Dr. _______. There will be no time restriction to sign the consent form or participate in 
this study. Subjects that express an interest will be evaluated and provided they meet all the 
inclusion and exclusion criteria, they will be considered for this study. 
• 
Special attention will be paid to enroll women and minorities in the study, although equitable 
patient selection may be challenging in this pilot study of a rare disease in 25 subjects.  
 
b) Procedures for obtaining informed consent (including timing of the consent process) 
For subjects interested in the speaking to a study staff, Dr._______ will go over the inclusion and 
exclusion criteria and will describe the study and procedures to the potential subject over the phone 
or in person.  If the subject qualifies and is interested he/she is encouraged to discuss the study with 


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Detailed Protocol 01/08/2018 
 
his/her primary care physician or family members. Upon arrival for the study, the subject will be given 
a copy of the consent form to read. After the subject has finished reading the consent form, Dr. ______ 
will describe the study in detail and answer any questions or concerns the subject might have. If the 
subject agrees to participate in the study they will be asked to provide his/her written informed 
consent. Subjects will be given a copy of the signed consent form for their records. The investigator 
will inform the subject that they have the alternative not to participate in the study and can withdraw 
their consent at any point during the study. 
 
The subjects will be given as much time as needed to consider participation in the trial. Pregnant 
women and minors are excluded from this trial. Subjects that are determined by the physician to be 
unable to consent due to their physical or mental condition will not be enrolled in this trial.  
 
V. STUDY PROCEDURES  
 
a. Screening/Study visit 1 
a. The subjects that are interested in the study will discuss in person or on phone with Dr. 
_____and or Dr. _____and go over the consent form and details of study participation. 
b. This screening visit will take about 1 hour. The research study team will ask the subject 
questions about medical history to make sure that the subject qualifies for this study. 
Pregnancy is not allowed due to the unknown risks radioactivity may have on the mother or 
the unborn baby from the beginning of the study period through the end of the study.    
b. Study visit 2 
The screening and study visit 1 can be conducted on the same day. Study visit 1 is for the performance 
of the rest F-18 florbetapir imaging study, 6-minute walk test, and 24 hour urine collection as 
described below. This visit will take about 2 hours, preparation time of 30 minutes, scan time of one 
and a half hours, and 6 minutes of walking. A blood pregnancy test will be performed on the day of 
the PET scan in women with child bearing potential, using 5 cc / one teaspoonful of blood. The 
research procedures will include intravenous injection of 10 mCi a radiotracer agent (F-18 florbetapir) 
followed by a ninety minute image acquisition. Three teaspoonfuls of blood will be drawn for 
florbetapir metabolite analyses.   
 
b. Study visit 3 


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Detailed Protocol 01/08/2018 
 
The study visit 3 can be conducted on the next day or within the next 30 days. Study visit 3 is for the 
performance of the rest F-18 florbetapir imaging study as described below. This visit will take about 2 
hours, preparation time of 30 minutes, and scan time of one and a half hours. A blood pregnancy test 
will be performed on the day of the PET scan in women with child bearing potential, using 5 cc / one 
teaspoonful of blood. The research procedures will include intravenous injection of 10 mCi a 
radiotracer agent (F-18 florbetapir) followed by a ninety minute image acquisition. Two teaspoonfuls 
of blood will be drawn for florbetapir metabolite analyses.   
 
Detailed Description of F-18 florbetapir PET/CT Methods: The proposed research will utilize the 
resources of the Cardiovascular Imaging center at Brigham and Women’s Hospital, Boston MA. 
Specifically, PET imaging will be performed on a state-of-the-art 64 slice cardiac PET/CT unit.   
 
Before the test: All patients will receive written instructions to have a light breakfast such as toast or 
cereal with coffee, tea or juice prior to their scan and to bring all their medications (including prescription, 
over the counter, dietary supplements, herbal and vitamins) with them. Upon arrival for the test, all 
patients are given a written questionnaire about allergies and possibility of pregnancy. Women of child 
bearing age will undergo a blood pregnancy test prior to the injection of F-18 florbetapir, as per laboratory 
protocol. Written informed consent for the study is checked and IV line inserted and the patient brought 
into the PET/CT room for imaging. 
 
F-18 florbetapir PET/CT image acquisition:  
A typical image acquisition protocol will include a CT scout image (10 mA, AP scout) to localize the heart 
followed by a CT transmission image (10 mA, 120 KVp, non-gated, free tidal breathing) for correction of 
photon attenuation by soft tissues, followed by injection of 10 mCi of F-18 florbetapir. F-18 florbetapir 
images are acquired in a 3D list mode for 90 minutes. Rest emission images will be unlisted for analysis 
into a static file, a gated file and dynamic image frames. The same protocol will be used for study visit 3. 
2.5 cc blood samples will be drawn for metabolite analyses at 6 time points for the first 60 minutes. 
 
 
 
 
Interpretation and quantification of F-18 florbetapir images: 


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Detailed Protocol 01/08/2018 
 
The myocardial F-18 florbetapir images will be processed and viewed in the standard cardiac imaging 
planes. Visual assessment of relative myocardial uptake of F-18 florbetapir will be performed and scored 
using a 0-3 scale (0=normal, 1= mild uptake, 2= moderate uptake, 3=significant uptake). Myocardial 
uptake of F-18 florbetapir will be quantified using software on the Hermes system (image viewing station). 
Also, specific uptake values of the radiotracer in the myocardium will be computed. 
 
6-minute walk: 
Subjects will be asked to walk back and forth along a flat corridor between two markers set a distance 
apart at their own pace.  The test takes 6 minutes and the distance that is walked will be measured.  
 
Total Amount of Blood Drawn: 
During the course of this research study, we will draw a total of 35-40cc of blood. This includes 10 cc of 
blood for oxidative stress markers (if subject provides additional consent), 15 cc of blood for florbetapir 
metabolite analysis, 10 cc of blood for metabolomics and mito DNA measures (if subject provides 
additional consent), 5 cc for pregnancy test (in individuals who need them). Pregnant women and 
breastfeeding women cannot take part in this research study. 
 
Serum F2-isoprostane and Peroxynitrite— 10 cc of blood samples will be collected in EDTA tube before 
the PET/CT scan of Study Visit 2 to measure serum markers of oxidative stress. F2-isoprostanes will be 
measured in Dr. Jane Leopold’s laboratory using serum isolated from whole blood collected with EDTA 
and stored at -80°C using immunoassay (8-isoprostane EIA kit, Cayman Biochemical). If needed, findings 
can be confirmed using mass spectroscopy. Nitrotyrosine levels will be measured in serum that is stored 
at -80°C by immunoassay (Nitrotyrosine EIA kit, Oxis). 
 
Serum metabolomic analysis—10 cc of blood samples will be collected in EDTA tubes before the PET/CT 
scan of Study Visit 2 for metabolomic and mitochondrial DNA analyses. 
 
Urine Samples: 24 hour urine sample will be collected. The urine samples will be deindentified by a study 
subject code and used to extract light chains that will be infused into zebra fish with or without 
pretreatment with rapamycin to study cardiac function and survival. 
 
VI. BIOSTATISTICAL ANALYSIS 
This is a pilot feasibility study using F-18 florbetapir. Mean myocardial uptake will be estimated in the 
subjects.  Mean liver to heart ratio will be estimated. 
 
 
 
VII. RISKS AND DISCOMFORT 


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Detailed Protocol 01/08/2018 
 
 
Time: Participation in this trial entails a rest F-18 florbetapir PET/CT scan. The total time spent for the 
study procedures is approximately 2 hours. 
 
Intravenous line insertion: Possible side effects intravenous line insertion are pain, bruising, or infection 
where the needle entered the skin.   Some people faint or get dizzy during insertion of the intravenous 
line. 
Radioactive imaging agents may have the following side effects: The radiation exposure to the subjects 
from the use of F-18 florbetapir  is calculated to be at 7.93 mSv that is equivalent to about 19 31  
months of background radiation in Boston.  In the 20 subjects undergoing reproducibility evaluation, the 
scan will be repeated in another day, with additional radiation exposure from the use of F-18 florbetapir  
of 7.93 mSv for a total study related radiation dose of (15.86 mSv).  Other side effects include: 
headache, musculoskeletal pain, nausea and fatigue. Radiation exposure associated imaging is within 
acceptable safety standards as set forth by the FDA.  Radiation may cause physical or genetic damage to 
a fetus, so subjects that are pregnant or breast feeding will be excluded. A pregnancy test will be 
performed prior to enrolling patients with childbearing potential.  
 
Risks from 6-minute walk test: The risks and discomforts associated with this procedure are very similar 
to those that subjects would incur with exercising on their own. 
 
In addition to the risks or discomforts listed above, the study drug and procedures may have unknown 
side effects. There is always the possibility that subjects will have a reaction that is currently not known 
or not expected.  All drugs can cause an allergic reaction that, if not treated promptly, could be life-
threatening. Symptoms of such a reaction are: throat tightness, itching, hives, wheals, vomiting, difficulty 
breathing or turning blue. 
 
VIII. POTENTIAL BENEFITS 
 
No direct benefit is anticipated to individual subjects.  The results of this study may benefit society through 
evaluation of the diagnostic utility of a novel radiotracer for directly imaging myocardial amyloid burden 
in subjects with cardiac amyloidosis. 
 


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Detailed Protocol 01/08/2018 
 
IX. MONITORING AND QUALITY ASSURANCE 
 
Subject safety will be ensured by strict adherence to inclusion and exclusion criteria and close monitoring. 
Subjects that experienced serious adverse events during the study will be removed from the study and 
followed up, but no other study procedures will be performed. This study does not involve treatment and 
hence a data safety monitoring board.  
 
This is a pilot clinical study of about 45 subjects (15 light chain AL amyloid, 15 TTR or senile amyloid, 15 
volunteers without cardiac amyloidosis, including 10 elderly volunteers with HFpEF). The study PI, Dr. 
________ will be responsible for monitoring the study procedures after every subject is enrolled, including 
the accuracy and completeness of the case report form entries, source documents and informed consent 
after every enrollment. These documents will be appropriately maintained on submission.  
 
Specification of Source Documents 
The following information will be included in the source medical records: 
• Demographic data (age, sex, and race) 
• Inclusion and exclusion criteria details 
• Participation in study and signed and dated informed consent forms 
• Visit dates 
• Adverse events and concomitant medication 
• Results of relevant examinations 
• Laboratory printouts 
• Reason for premature discontinuation 
 
Ethical Conduct of the Study 
The investigator(s) and all parties involved in this study will conduct the study in adherence to GCP, ICH 
Guidelines and the applicable laws and regulations. 
 
Subject Confidentiality 
The principal investigator will be responsible for oversight on maintaining subject confidentiality. All study 
staff are trained in Partners HIPAA procedures as well as in ethical conduct of research. Documents 
relating to the study that contain personal data that may disclose the identity of the subject will remain 
with the investigator and kept confidential in a locked cabinet accessible only to study staff. Subject 


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Detailed Protocol 01/08/2018 
 
confidentiality will be maintained by utilizing subject identification code numbers to correspond to 
treatment data in the study computer files.  All study center personnel will comply with privacy rules of 
this institution, the ICH guideline for good clinical practice, HIPAA and applicable state law.  Subject 
confidentiality will be maintained by limiting access to data collected to only co-investigators, study staff.  
Data and specimens will not be stored at Partners or non-Partners sites for future uses not described in 
the protocol.  
 


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Detailed Protocol 01/08/2018 
 
X. REFERENCES:  
1. 
Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation. 2005;112:2047-2060 
2. 
Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med. 1997;337:898-909 
3. 
Ng B, Connors LH, Davidoff R, Skinner M, Falk RH. Senile systemic amyloidosis presenting with 
heart failure: A comparison with light chain-associated amyloidosis. Arch Intern Med. 
2005;165:1425-1429 
4. 
Al Suwaidi J, Velianou JL, Gertz MA, Cannon RO, 3rd, Higano ST, Holmes DR, Jr., Lerman A. Systemic 
amyloidosis presenting with angina pectoris. Ann Intern Med. 1999;131:838-841 
5. 
Saffitz JE, Sazama K, Roberts WC. Amyloidosis limited to small arteries causing angina pectoris and 
sudden death. Am J Cardiol. 1983;51:1234-1235 
6. 
Camus V, Payoux P, Barre L, Desgranges B, Voisin T, Tauber C, La Joie R, Tafani M, Hommet C, 
Chetelat G, Mondon K, de La Sayette V, Cottier JP, Beaufils E, Ribeiro MJ, Gissot V, Vierron E, 
Vercouillie J, Vellas B, Eustache F, Guilloteau D. Using pet with 18f-av-45 (florbetapir) to quantify 
brain amyloid load in a clinical environment. Eur J Nucl Med Mol Imaging. 2012;39:621-631 
7. 
Carome M, Wolfe S. Florbetapir-pet imaging and postmortem beta-amyloid pathology. JAMA. 
2011;305:1857; author reply 1857-1858 
8. 
Joshi AD, Pontecorvo MJ, Clark CM, Carpenter AP, Jennings DL, Sadowsky CH, Adler LP, Kovnat KD, 
Seibyl JP, Arora A, Saha K, Burns JD, Lowrey MJ, Mintun MA, Skovronsky DM. Performance 
characteristics of amyloid pet with florbetapir f 18 in patients with alzheimer's disease and 
cognitively normal subjects. J Nucl Med. 2012;53:378-384 
9. 
Lister-James J, Pontecorvo MJ, Clark C, Joshi AD, Mintun MA, Zhang W, Lim N, Zhuang Z, Golding 
G, Choi SR, Benedum TE, Kennedy P, Hefti F, Carpenter AP, Kung HF, Skovronsky DM. Florbetapir 
f-18: A histopathologically validated beta-amyloid positron emission tomography imaging agent. 
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SAP_001.pdf: 
 
1 
 
Study Title: Imaging Cardiac Amyloid Burden: A pilot Study Using F-18 Florbetapir Positron 
Emission Tomography 
NCT Number: NCT01683825 
Document Date: January 2018 
 
 


 
2 
 
Analytical Plan 
 
Study Objective(s)  
Specific Aim:  The primary aim of this pilot study is to determine whether amyloid deposits in 
the heart can be measured non-invasively by F-18 florbetapir (Trade Name: Amyvid) positron 
emission tomography (PET) in 30 individuals with documented cardiac amyloidosis and in 15 
volunteers without cardiac amyloidosis.   
A secondary aim of this study is to determine reproducibility of F-18 florbetapir uptake in the 
myocardium. 
 
Study groups: 
Subjects with cardiac amyloidosis and control subjects without cardiac amyloidosis. 
 
Imaging Methods  
In this pilot feasibility study, F-18 florbetapir was used to image myocardial amyloid deposits. F-
18 florbetapir PET/CT images were acquired in a dynamic mode and reconstructed into static 
images.  Visual assessment and SUV of myocardial uptake of F-18 florbetapir was performed on 
static images from 4 minutes to 30 minutes. The left ventricular global myocardial F-18 
florbetapir images were reviewed in the standard radiological and cardiac imaging planes. We 
used PMOD software to measure global left ventricular standardized uptake value (SUV) of F-18 
florbetapir using SUV mean (SUVmean).  
 
Statistical Methods  
This is a pilot feasibility study using F-18 florbetapir to image myocardial amyloid deposits.  
Mean and maximal myocardial uptake of F-18 florbetapir will be estimated in the subjects with 
diagnosed cardiac amyloid.  Mean liver to heart ratio will be estimated.