PET Fibrin Imaging of DVT and PE
Phase: PHASE1
Conditions: Pulmonary Embolism, Deep Vein Thrombosis, Venous Thromboembolism
Sponsor: Peter Caravan

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PARTNERS HUMAN RESEARCH COMMITTEE DETAILED 
PROTOCOL 
 
 
Version Date: 2/15/2022 
 
Protocol Title: PET fibrin imaging of DVT and PE 
 
Principal Investigator: Tilo Winkler, PhD 
 
 
I. 
BACKGROUND AND SIGNIFICANCE 
 
Venous thromboembolism (VTE), comprising deep venous thrombosis (DVT) and pulmonary embolism (PE), is 
a major public health problem. The estimated average annual incidence rate of overall VTE among persons of 
European ancestry ranges from 104 to 183 per 100,000 person-years and is similar to that of stroke,1 the fifth 
leading cause of death in 2013.2 For those of African descent, the incidence may be higher.3–5 Incidence rates 
for PE ± DVT are 29 to 78 per 100,000 person-years and for leg DVT alone are 45 to 117 per 100,000 person-
years.1 Over the decade from 2002 to 2012, the incidence of VTE has been rising.6 This has raised the question 
of whether this increase represents a true rise in incidence or potentially over-diagnosis with more available, but 
not necessarily more accurate, imaging techniques. Whatever the reason, it is clear from this data that it is vitally 
important to improve the accuracy of identifying VTE with targeted diagnostic tools. 
The tools for diagnosis of VTE have evolved from contrast venography, ventilation-perfusion (V-Q) scans and 
pulmonary angiograms to D-dimer testing, venous duplex ultrasound and CT-angiograms. While these newer 
modalities are less invasive and more available; none is perfectly accurate and must rely on indirect 
measurements of clot, whether that is non-compressibility with ultrasound or filling defects with CT angiograms. 
Because of these limitations, it is recommended to improve the performance of the test through the use of Bayes’ 
theorem, which incorporates pre-test probability to enrich the population for those that might or might not have 
VTE.7 Despite the high value of this recommendation when there is concordance between the pre-test probability 
and the test result, problems arise when there is discordance. For CT-angiograms, if the pre-test probability of 
PE is high, the negative predictive value is 60%.8 Conversely, if the pre-test probability of PE is low, the positive 
predictive value is 58%.8 In contrast, if pre- and post-test results are concordant, the positive and negative 
predictive value is 96%.8 The discordant situations lead to both under- and overdiagnosis if pulmonary artery 
angiogram is not pursued, and represent an area where targeted diagnostics utilizing a highly specific probe for 
newly cross-linked fibrin could help. 
There are many other groups of patients at high risk for VTE that need targeted diagnostics. Venous 
thromboembolism is a disease of older age, with VTE virtually non-existent in adolescence but increasing in 
incidence rapidly with older age. Diagnosis becomes more difficult in older patients because of the diminished 
discriminatory power of D-dimer,9,10 the high prevalence of renal dysfunction that increases the risk of contrast 
dye nephropathy and precludes the use of contrast-enhanced CT angiography, and/or the high prevalence of 
lung disease that renders interpretation of V-Q scans difficult or impossible. Patients with prior DVT or PE present 
another diagnostic challenge. When the imaging method relies on filling defects to diagnose VTE, it is nearly 
impossible to distinguish old versus new clot. Here again is an area where targeted diagnostics utilizing a highly 
specific PET probe for newly cross-linked fibrin could help distinguish old clot from new, throughout the body. 
Furthermore, there are other patient groups that represent a challenge to our current diagnostic tools. Patients 
with contrast dye allergy may need premedication that delays or sometimes even prevents those patients from 
receiving intravenous contrast. Typically, these patients would receive corticosteroids and antihistamines starting 
13 hours prior to injection.11,12 However, even those that receive premedication can have contrast reactions.13 
Patients with PE who have negative venous duplex ultrasound exams are sometimes suspected to have pelvic 
vein thrombi, or those with suspected chronic thromboembolic pulmonary hypertension or angiosarcomas of the 

Page 2 of 14 
 
pulmonary arteries could benefit from a diagnostic tool that can image fresh intravascular thrombi and distinguish 
it from tumor or organized, endothelialized old thrombus. 
All these shortcomings of current diagnostic strategies mean that physicians often are either uncertain whether 
a patient truly has an acute VTE or feels certain when none is present. These situations invariably lead to errors 
in diagnosis and lead to two dangerous problems. Either patients have an acute thrombosis and do not receive 
anticoagulation, putting them at risk for a deadly pulmonary embolus, or, they are subjected to anticoagulation 
unnecessarily and the significant risk of life-threatening hemorrhage. 
The development of a fibrin-specific targeted diagnostic that identifies fresh thrombotic foci anywhere in the body 
has the potential to be a transformative tool for VTE assessment that would greatly enhance our diagnostic 
accuracy and capability for an extremely common and deadly disease. 64Cu-FBP8 (Copper-64 labeled fibrin 
binding probe 8, Scheme 1) is a molecular imaging probe which selectively binds the main constituent of human 
thrombi: fibrin. Thrombus formation and fibrin deposition are pivotal events in several human conditions including 
major cardiovascular diseases, cancer, and inflammation. 64Cu-FBP8 combines the high specificity of a fibrin-
binding peptide and the great sensitivity and potential full-body applications of nuclear imaging.  Studies in rats 
showed that 64Cu-FBP8 has excellent pharmacological and pharmacokinetic profile, with high target uptake and 
low retention in background tissues and organs.14  
Our long-term research objective of this translational study is to establish a novel thrombus body scan 
(TBS) using a new fibrin-specific probe for positron emission tomography (PET) imaging to overcome 
the limitations of indirect VTE diagnosis, and, with one single test, provide a total-body assessment of 
fresh intravascular clot. 
 
Scheme 1. Simplified synthetic route and chemical structure of 64Cu-FBP8. The sequence of the core fibrin-
binding peptide is reported on the bottom. 
 
II. 
SPECIFIC AIMS 
 
This proposal aims to generate strong evidence for VTE diagnosis using the thrombus body scan (TBS) from an 
initial small translational study that will justify a larger clinical study to obtain clinical approval for the TBS. We 
hypothesize that TBS using our new PET fibrin probe that specifically binds to fresh polymerized fibrin clot (< 1 
week old), can directly detect thrombus anywhere in the body similar to 18F-FDG PET scans for cancer nodules, 
will have better diagnostic accuracy for deep venous thrombosis and pulmonary embolus (DVT-PE) compared 
to current imaging modalities, can quantify the total body burden of fresh clot and can be performed in patients 
with renal dysfunction. Before we can fully test this hypothesis in an appropriately-powered clinical study, we 
propose a proof-of-concept study in a smaller cohort of patients to test the following specific aims and 
hypotheses: 

Page 3 of 14 
 
1. Compare the presence, location and extent of PE diagnosed with the PET 64Cu-FBP8 probe to conventional 
imaging. Hypothesis: The PET fibrin probe will allow direct imaging of acute thrombi causing PE, which is 
currently only indirectly diagnosed by filling defects on CT-angiogram or mismatched perfusion defects on V-Q 
scans. 
2. Compare the presence, location and extent of DVT diagnosed with the PET 64Cu-FBP8 probe to conventional 
imaging. Hypothesis: The PET fibrin probe will allow direct imaging of acute thrombi causing DVT diagnosed 
indirectly by incompressibility and loss of flow on lower extremity venous Doppler ultrasound. 
3. In addition to PE and lower extremity DVT, assess for upper extremity and pelvic clot and compare the extent 
of total body clot burden imaged with the 64Cu-FBP8 probe to the plasma D-dimer level. Hypothesis: The PET 
fibrin probe will discover acute thrombi including areas not assessed by current imaging methods and the total 
clot burden will correlate with the plasma D-dimer. 
Successful execution of this study will lay the groundwork for a clinical trial to compare the efficacy of a clot-
specific imaging modality (thrombus body scan or TBS) that has the potential to be more accurate for the 
diagnosis of VTE, better able to establish the total clot burden in the body with a single test and more widely 
applicable to patients with renal failure and lung disease.  
 
III. 
SUBJECT SELECTION 
 
A total of eighty (80) subjects will be recruited for this study, which will be performed at the Massachusetts 
General Hospital (MGH). All eighty (80) subjects will be studied with the same protocol:  a single injection of 
64Cu-FBP8 and PET-CT imaging at least three hours after injection at four bed positions, which will provide the 
imaging data for fresh blood clot at the three locations covering all three specific aims. 
 
Inclusion Criteria: 
Each subject must meet the following criteria to be enrolled in the study: 
• 
18 years of age or older with a clinically significant pulmonary embolus (PE) confirmed by a filling defect 
in CT angiography (CTA), and 
• 
Subjects must receive the radiotracer injection within 72 hours of their diagnosis. 
 
Exclusion Criteria: 
• 
Subjects < 18 years of age 
• 
Time of expected radiotracer injection > 72 hours from the time of a positive venous duplex ultrasound 
or CT- angiogram, 
• 
Women subjects of childbearing potential who are pregnant, seeking to become pregnant, or have a 
positive serum pregnancy (beta-HCG) test, 
• 
Unable to lie flat for 45 minutes as assessed by physical examination and medical history (e.g. back 
pain, arthritis, dyspnea), 
• 
Weight that exceeds the PET camera table limit (300 kg) 
• 
The subject will not be enrolled in the study if the radiation exposure for research studies during the 
prior 12 months, combined with the exposure from this study would exceed 50 mSv. 
• 
Due to the radiation exposure from imaging studies, all women of childbearing potential will be 
required to have a negative serum pregnancy test performed prior to any imaging procedures on the 
same day (if not already done that day). Patients with a positive serum pregnancy test will be 
excluded. Breast feeding women will also be excluded.  
• 
A pre-existing condition or use of a medication including vasopressors and tPA (due to its effects on 
clot) that in the opinion of the investigator may place the subject at a substantially increased risk  
• 
Hemodynamic instability, including requiring escalating doses of vasopressor medication.  
• 
No groups designated as “special vulnerable populations” will be studied.  
• 
No exclusions will be made based on race, sex, or ethnic origin. 
• 
64Cu-FBP8 (Copper-64 labeled fibrin binding probe 8) is cleared by the kidneys, patients with eGFR 
< 30 will be excluded. 
 

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IV. 
SUBJECT ENROLLMENT 
 
Identification of eligible subjects will be done from 1) admissions to the Massachusetts General Hospital for 
treatment of pulmonary embolus (PE) 2) admissions to MGH for other indications but with an acute PE at 
admission or during hospitalization, 3) patients who present to the Emergency Department with an acute PE, 
but will not be admitted to the hospital. The subjects will be identified through the MGH Pulmonary Embolus 
Response Team (PERT), radiology notifications or running PeRC Epic team report, which could identify 
inpatients who were not picked by PERT or radiology notifications, or through patients physician investigators 
may be aware of that have an acute PE. PERT is a well-established group of cardiologists, pulmonologists, 
interventional radiologists, emergency room physicians, and cardiac surgeons who are “on-call” when a 
clinician anywhere in the hospital suspects a patient has a clinically significant pulmonary embolus. When 
PERT is activated, a fellow organizes a web-based meeting within minutes through a page and email to the 
participating physicians. The data is reviewed via “go-to-meeting” conference and a treatment plan is decided 
upon by consensus. An email will be sent to Dr. Witkin, and Mamary Kone when PERT is activated and Dr. 
Witkin will assess whether the patient is appropriate and potentially eligible for the study. Also, since the fibrin 
probe must be manufactured at MGH Navy Yard and sent to MGH main campus, only patients diagnosed at a 
time when they can receive the radiotracer within 72 hours of their diagnosis will be included. If the patient 
meets eligibility criteria, the patient’s treating physician will be contacted to ask the patient for permission to be 
contacted by the study staff. During the first contact, the physician co-investigator will screen the subject for 
eligibility and describe the study and its implications, risks and benefits. If the subject is interested, the consent 
form will be given to the subject to read. The subject will be given as much time as necessary to decide, 
however if a decision cannot be made within the 72-hour limit from initial diagnostic imaging to the fibrin probe 
injection, or not before a scheduling time window for fibrin injection, the subject will be excluded. We will allow 
as much time as necessary for the subject’s questions to be answered or for the subject to consult family 
members or treating doctors before the consent form is signed. After the subject signs the consent form, the 
original signed consent form will be kept on file, a copy will be given to the subject, and a copy will be scanned 
to the subject EMR. No study procedures will be performed prior to the subject signing the informed consent 
document. The informed consent process will be accurately documented in the subject medical records.  
 
V. 
STUDY PROCEDURES 
 
Subject Screening:  Subjects will be studied while admitted in the hospital and followed up as an outpatient (via 
phone or after clinic follow up visit) for 1 year at 3, 6 and 12 months after their imaging. Additionally, subjects 
recently presenting to the MGH and / or admitted but discharged before enrolling into the study may return to 
MGH for the purpose of participating in this study. Initially, they will be screened only after the patient’s treating 
physician has ask the patient for permission to be contacted by the study staff. The screening will consist of an 
in-depth review of the medical records (notes, labs, imaging tests, medications, etc.) to ensure that the subjects 
meet the inclusion and exclusion criteria for the study. After the informed consent is obtained, a physician 
investigator will take a detailed history, perform a physical exam and assess the subject’s capacity to lie flat for 
imaging. Once inclusion criteria have been met and the subject consents to the study procedures, labs will be 
drawn daily (D-Dimer, PT, PTT, INR, platelets and fibrinogen) if not done so clinically for a maximum of 3 days 
from the day of initial CTA to the day of PET-CT. 
 
On the day of PET-CT imaging, an intravenous catheter will be placed if there is not one already in place that 
can be used in the case of subjects admitted to the hospital. All women of childbearing potential will be tested 
for pregnancy unless a test result is available in the medical record that is valid for the day of PET-CT imaging. 
Women who are documented by medical history of not having child-bearing potential (i.e. tubal ligation or 
hysterectomy) or are post-menopausal with a minimum one year without menses will not need to undergo 
pregnancy testing. A STAT quantitative serum hCG pregnancy test will be performed on the day of the scan. 
Blood samples (up to 8 ml total) will be drawn for pregnancy test, coagulation panel (PT, PTT, INR), platelets 
and D-dimer if not already done that day by the clinical team. If the test performed comes back negative for 
pregnancy (<6 IU/L), the subject will be enrolled. If the test performed comes back positive for pregnancy the 
subject will not be enrolled in the study. Blood samples will be taken via indwelling catheters already present for 
hospitalized patients. If the subject’s intravenous access is unable to be used, a new peripheral intravenous 
catheter will be placed by study staff to draw the required blood for beta-HCG (if required), D-dimer and 

Page 5 of 14 
 
administer the radiopharmaceutical. For subjects coming for PET-CT as an outpatient an intravenous catheter 
will be placed to allow for obtaining blood samples and radiopharmaceutical administration. 
 
Once finished, arrangements will be made to conduct the PET-CT imaging in a way that does not interfere with 
treatment for subjects admitted to the hospital.  
 
Prior to radiotracer injection for PET imaging: 
- 
The procedure will be explained to the subject and any questions he/she has about the procedure will be 
answered. 
- 
Subject information such as height and weight will be obtained if not available. 
- 
Vitals and ECG will be obtained prior to radiotracer injection. 
 
Radiotracer injection: 
- 
Up to 10 mCi 64Cu-FBP8 will be injected at least 3 hours before the scheduled time for PET-CT imaging. 
The injected dose and time of injection will be recorded. The injection will take place at the bed side. 
- 
The catheter will be flushed post-injection of 64Cu-FBP8 with 10ml 0.9% saline solution.  
- 
Vitals will be obtained immediately after radiotracer injection.  
 
PET-CT imaging: 
- 
For subjects admitted to the hospital close to the scheduled time for imaging, which is at least 3 hours 
after injection, the subject will be escorted (transported) in the wheelchair or stretcher/bed by hospital 
transport and/or study staff depending on the subject conditions to the PET-CT suite; we will follow the 
hospital standard procedures for patient transport. The PET-CT technician will submit a patient transport 
order through Epic.  When the PET suite becomes available, the hospital transport team will transport to 
the PET-CT location. If the subjects need to be monitored during the transport, then one of the study 
physicians will be present during the transport. 
- 
Subjects coming as outpatient will come to the hospital (Anesthesia or Pulmonary Research area) at 
least 4 hours prior to the imaging where they will be injected and monitored before taking them to the 
PET-CT imaging suite.  
 
- 
Prior to the scan subjects will be asked to urinate to minimize the possibility that they will need to move 
during the scan.  
- 
The subjects will be positioned on the scanner table; support devices under the back and/or legs will be 
used as needed to enable the patient to comfortably maintain his/her position throughout the scan. 
- 
A scout image (Topogram) which takes about 10 seconds will be obtained to locate the proper fields for 
imaging.  
- 
Afterwards, CT and PET scans will be obtained for four bed positions: thorax, pelvis and thighs (2 
positions). The CT scan for each position of the PET scans is necessary to correct for the attenuation of 
the 64Cu-FBP8 activity caused by body tissue. We will perform an additional PET/CT scan of the lower 
portion of the thighs in order to image the full/whole thighs to the knees. Consequently, a total of 4 CT 
and 4 PET scans will be performed in four different positions. Imaging duration will be less than 10 
seconds for each CT, and 10 minutes for each PET scan. The total time of imaging is expected to be 
approximately 45 minutes. 
- 
We may have to repeat a PET-CT scan if we have an unexpected problem (for example, if subjects need 
to change position during a scan). 
- 
Subjects will be monitored throughout the imaging session, and measurements including heart rate, 
blood pressure, and pulse oximetry will be recorded.  
 
Post-scan procedures: 
- 
After the scans are completed and last vital signs collected, the subject will be escorted back to his/her room 
on the ward if applicable 
- 
The subject will be asked to void again immediately after the scan, and he/she will be counseled on the 
importance of continuing to drink fluids for several more hours. This will increase urine flow rate, which will 
help minimize the radiation dose to the bladder wall. 

Page 6 of 14 
 
 
Data acquisition and image reconstruction: 
PET-CT images will be acquired using commercial, FDA-approved scanners using conventional sequences for 
image acquisition. Images will be reconstructed using the algorithms provided by the scanner manufacturer. All 
images will be completely anonymized and de-identified and labeled only with a study number. No personal 
information whatsoever will be contained in the images or header files. The images will be transferred 
electronically over a secure internal network to the storage site at the Pulmonary and Bioengineering Laboratory, 
where they are securely stored and backed-up. Only study staff will have the required permissions and ability to 
access these files. 
 
A separate database file, linking the study number to the relevant clinical data on each subject will be generated. 
These data will be stored in a password-protected Redcap (Research Electronic Data Capture) database 
supported by the Massachusetts General Hospital and Partners Healthcare. Only study staff involved in data 
collection and analysis will have access to this database. For this study, we will record basic demographic data 
(age, gender, race/ethnicity), and clinical data (results of laboratory values such as serum creatinine, D-dimer 
and NT-pro-BNP, results of CT-angiogram, including de-identified DICOM files, results of venous duplex 
ultrasound, echocardiographic parameters of cardiac size/function/hemodynamics, and treatment, height, weight 
and baseline hemodynamics and hospital mortality), as available. Additionally, images will be stored for data 
analysis on a password protected file server at the Pulmonary Imaging and Bioengineering Laboratory at 
Massachusetts General Hospital, and access will be restricted to study staff involved in data analysis. 
 
Sources of research material will include a) results of history and physical examination, b) medical record review 
(EPIC, Epic Systems, Verona, Wisconsin, USA) for pertinent clinical and laboratory results, and c) review of 
clinically relevant imaging studies including CT-angiograms, venous ultrasound with Doppler, echocardiograms, 
and drug and/or mechanical treatment for VTE. In the case of women of childbearing potential, a serum sample 
will be collected for the purposes of determining pregnancy status. The data will be used only for research 
purposes and will be kept anonymous (by using a number without names) and confidential. In addition to PET- 
CT data acquired as above,  
 
 
Study Events 
PRE-IMAGING 
IMAGING 
Follow up 
Events 
Pre-
dosing 
Dosing (at 
least 3 
hours 
before 
imaging) 
CTs 
PET 
 
3 
months 
6 
months 
12 
months 
 
PERT or 
Radiology 
Notifications 
X 
 
 
 
 
 
 
 
 
Eligibility checklist 
X 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
 
 
 
Vital Signsa 
X 
 
 
 
 
 
 
 
 
IV placement 
X 
 
 
 
 
 
 
 
 
Pregnancy Testb 
X 
 
 
 
 
 
 
 
 
D-dimer 
X 
 
 
 
 
 
 
 
 
64Cu-FBP8 
injection 
 
X 
 
 
 
 
 
 
 
PET-CT  
 
 
X 
X 
 
 
 
 
 

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Hemodynamic 
measuresc 
X 
X 
X 
X 
 
 
 
 
 
ECGf 
X 
X 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
 
 
 
 
 
VEINES -QOL 
X 
 
 
 
 
X 
X 
X 
 
6 MWTg 
X 
 
 
 
 
X 
X 
X 
 
EMR Review 
X 
 
 
 
 
X 
X 
X 
 
 
a. Vital signs: respiratory rate, pulse, blood pressure, and temperature. 
b. Pregnancy serum HCG test: Women of childbearing potential. 
c. Hemodynamic measures: During the scan heart rate, respiration rate, heart rhythm, pulse oximetry will 
be measured. Values will be recorded before probe injection, immediately after probe injection and 
throughout the scan. 
d. Blood draws: If not done for clinical purposes, blood will be drawn prior to radiotracer injection - blood 
will be sent for a coagulation panel [Fibrinogen, PTT (PTT, ARPT), PT/INR (INR/ARINR)], platelets and 
D-dimer. 
e. Anticoagulants used as well as timing and dosing will be recorded.  
f. ECG: All subjects will have ECGs for monitoring before and after the scans if available. 
 
 
Follow up: 
Patients will be contacted at 3, 6 and 12 months following the diagnosis of PE. Death and recurrence of DVT-
PE will be assessed. Results of any imaging studies (CT angiograms, echocardiograms, or venous duplex 
ultrasound studies) and serologic studies (follow up d-dimer) will be collected and patients will undergo a survey 
to collect information about symptoms attributable to PE-DVT as well as quality of life using Standard Form 36,28 
VEINES QOL29 and the patient’s self-assessment of their overall health status on a 1 – 10 scale, with 1 indicating 
the worst possible and 10 the best possible health. For patients followed at MGH this will be done in person at 
the end of their PERT or pulmonary clinic follow up clinic visit. For those followed elsewhere, this will be done by 
telephone with subjects and their treating physicians. NYHA functional class, 6-min walk distance, and change 
in pulse oximetry with walking will be assessed. 
 
VI. 
BIOSTATISTICAL ANALYSIS 
 
Once a patient is enrolled, the subjects will receive an injection of up to 10 mCi 64Cu-FBP8 and imaged with CT-
PET approximately at least 3 hours after injection, when the “target-to-background” ratio (TBR) of activity is 
expected to be high based on previous studies.27 With CT-PET the attenuation correction is done using a low-
dose CT volumetric scan. Afterwards, PET acquisitions of 10 min duration each are performed in four positions, 
thorax, pelvis and thighs (2 positions), which are used to assess regional 64Cu-FBP8 activity. 
 
Specific data variables: 
The standardized uptake value (SUV) of 64Cu-FBP8 uptake in the lungs, pelvis and thighs will be calculated. The 
target to background ratio (TBR) for 64Cu-FBP8 activity will be calculated using as background a region of interest 
(ROI) created from large cardiac and vascular structures. This corrects the 64Cu-FBP8 activity for differences in 
injected dose and timing of imaging and allows for flexibility in the image timing. One member of our group (T. 
Winkler) and another from Nuclear Medicine (U. Mahmood) will be blinded to the clinical results and will identify 
the presence or absence of clot in the three imaged locations as well as the anatomic location(s) and extent as 
best as possible from the overlay of the fibrin activity on the attenuation correction CT scans. Additionally, we 
will perform quantitative image analyses including the volume of the thrombus ROI, activity of imaged clot in 
each imaged section and clot burden. The thrombus ROI is defined by a threshold of 50% between peak activity 
of the ROI and background activity. Multiple ROIs will be used in the case of separated thrombi. Clot burden will 
be estimated using the sum of 64Cu-FBP8 activity within a thrombus ROI and then normalized by the injected 
dose. 
 

Page 8 of 14 
 
Outcome Measures: 
Specific Aim 1: The location and extent of the thrombus region of interest (ROI), its volume and clot burden 
within the lung ROI will be compared with the ROI of filling defects on CT-angiogram. We will determine the 
number and location of the thrombus ROI(s) within the lungs, and the overall clot burden as sum of 64Cu-FBP8 
activity within a thrombus ROI(s) within the lungs. Additionally, we will calculate the intersection of the thrombus 
ROI and filling defects ROI relative to volume of the thrombus ROI. That will quantify the fraction of thrombus 
ROI(s) using a scale from being are completely outside (0) to completely inside (1). Also, we will perform a lung 
segmentation using the software APOLLO (VIDA Diagnostics) and determine in which lung lobe the thrombus 
ROI(s) are located. 
 
Specific Aim 2: The thrombus ROI, its volume and clot burden within the thigh ROI will be compared with the 
location and extent of the clot on venous duplex ultrasound. We will determine the number and location of the 
thrombus ROI(s) within the thigh ROI, and the overall clot burden as sum of 64Cu-FBP8 activity within a thrombus 
ROI(s) within the thigh ROI. Additionally, we will quantify the volumes and locations of the thrombus ROIs of the 
PET scan and the venous duplex ultrasound relative to each other. Also, we will perform a vessel segmentation 
using the 3D Slicer (open source software) and determine the location of thrombus ROI(s) with the blood vessel. 
 
Specific Aim 3: The prevalence of high 64Cu-FBP8 fibrin activity in the pelvic ROI and upper extremity ROI’s 
will be reported. Additionally, as a secondary analysis, both the total fibrin activity in the imaged fields, excluding 
the liver, gallbladder, kidneys and urinary bladder normalized by injected dose for all patients will be correlated 
with the plasma D-dimer drawn at the time of imaging. D-dimer levels will be drawn daily from the time of first 
diagnostic imaging to the fibrin probe imaging (up to 3 days maximum in total) as well as PT, PTT, platelets and 
fibrinogen. Anticoagulants used, as well as timing and dose will be carefully recorded during this period. 
 
For all Specific Aims, death, VTE recurrence, and quality of life measures will be compared with the clot burden 
measured by PET and conventional imaging modalities, stratified by treatment (systemic thrombolysis, catheter 
thrombolysis, or heparin alone) using multiple correlation, ANOVA, and t-tests for pairwise comparisons. 
 
VII. 
RISKS AND DISCOMFORTS 
 
64Cu-FBP8 PET probe: 
All subjects will undergo PET-CT imaging with the fibrin-targeting PET probe 64Cu-FBP8, which is covered by 
IND128547. 37 research subjects have been imaged to date with 64Cu-FBP8 without adverse effects. Also, the 
safety of 64Cu-FBP8 is being further evaluated in a separate study by a Co-Investigator of the grant (P. Caravan) 
in human volunteers. However, we expect this probe to be extremely well tolerated. A GLP toxicity study in rats, 
using the non-radioactive form of 64Cu-FBP8, indicated no observable adverse effects in rats at 0.3 mg/kg (>200 
times the anticipated dose in humans). 64Cu-FBP8 is similar to a gadolinium-based MRI contrast agent EP-
2104R. Both compounds comprise an eleven-amino acid peptide, of which there is a six-amino acid disulfide-
bridged cyclic portion, and these peptides bind to the same site on fibrin. Although the peptides in the two 
compounds are not identical, they share the same seven key amino acids necessary for fibrin recognition. Both 
64Cu-FBP8 and EP-2104R have metal chelators to bind copper and gadolinium, respectively, to generate signal 
in PET and MRI. EP-2104R underwent phase 1 and phase 2 clinical trials to assess its safety and feasibility as 
a thrombus imaging agent in patients with thrombosis.27 The results of the 52 patient phase 2 trial were published, 
and none of the 52 subjects enrolled were removed from the study because the appearance of adverse effects 
after probe administration. Mild adverse effects were present in 27% of patients (14 out of 52), but none were 
considered to be related to the study drug.27 In that study, EP-2104R was administered at the dose of 4 µmol/kg, 
which corresponds to 17.3 mg/kg or 1.2 grams for a 70 kg adult. The EP-2104R dose is greater than 10,000 
times higher than the dose of 64Cu-FBP8 proposed in this application (90 micrograms per subject). Therefore, 
we do not anticipate any adverse effects related to 64Cu-FBP8 probe administration. 64Cu-FBP8 is cleared by the 
kidneys, but it does not contain any gadolinium. There is no risk of NSF. The reference to EP-2104R was to 
demonstrate that the fibrin binding peptide that is common to both 64Cu-FBP8 and EP-2104R had been 
previously administered to human subjects at a dose more than 10,000 times the current chemical dose of 64Cu-
FBP8.  This was meant to convey that 64Cu-FBP8 should be safe and well tolerated 
 
Radiation: 

Page 9 of 14 
 
Radiation exposure has been assessed for 64Cu-FBP8 using human time-activity curves extrapolated from the 
time-dependent rat biodistribution data. The cumulative activity (Bq-h/Bq) for each source organ was determined 
by integrating the area under the time-activity curves by using the least-squares analysis, and organ absorbed 
doses were estimated by using the software program OLINDA/EXM (version 1.0, Vanderbilt University, 2003). 
Based on these data, the kidneys are the primary critical organs, followed by urinary bladder and liver. The 
estimated effective dose for humans was 0.017 mSv/MBq.23 Initial data in human volunteers confirmed this 
effective dose estimate. We plan to inject no more than 370 MBq (=10 millicuries) per subject, which would cause 
a maximal effective dose of approximately 6.2 milliSieverts (mSv), and is less than the proposed up to 15 mCi 
in the original IND. The radiation exposure in this study will be small and there is no evidence that it represents 
a major health risk. If subjects have participated in other research studies in the past 12 months that have 
involved radiation exposure, they will be asked to inform the investigators or study staff (by placing a check mark 
on the consent form verifying that they have or have not been exposed to other radiation in the past 12 months).  
If it is determined that the prior radiation exposure exceeds our current guidelines (i.e. 50 mSv/year) the subject 
will not be enrolled in this study. We estimate that the total exposure of each subject to ionizing radiation includes:  
 
1. Topogram 0.5 mSv (for identifying scanning region for CT) 
2. Low-Resolution CT scans in four positions (thorax, pelvis and thigh x2): 0.95 mSv x 4 (for attenuation-
correction of PET), which 3.8 mSv. 
3. 
64Cu-FBP8 Injection (10 mCi x 0.62 mSv/mCi): 6.2 mSv  
 
The estimated total radiation dose for a subject is 10.5 mSv. However, if we repeat  a PET-CT scan for an 
unexpected problem (for example, if subjects need to change position during a scan), the total radiation dose for 
will be 11.45 mSv.  
 
Discomfort 
The most common discomforts that we can anticipate are soreness and bruising at the intravenous placement 
site (if not already in place) and back pain from lying on the PET scanner table for a prolonged period of time. 
Both should be mild and short-lasting. We will warn subjects of these discomforts as well as assess by physical 
exam whether patients can tolerate lying flat for 45 minutes. This may require simulating this position and 
assessing the patient’s response. Those patients with severe back pain, symptomatic arthritis, or dyspnea when 
lying flat will be excluded. 
 
Drug side effects and toxicities 
Lidocaine: The small amount that may be used (1-3cc, 1%) to numb the skin is such that there are almost no 
risks associated at this dose. Unlikely but serious side effects include nausea, drowsiness, mental/mood 
changes, ringing in the ears, dizziness, vision changes, tremors, numbness, headache, or backache. 
 
Psychosocial risks 
Since the PET scanner, like the CT scanner and in contrast to the MRI scanner, is not a closed tunnel but an 
open "donut" there should be no problems with claustrophobia. However, if for any reason, a subject is 
uncomfortable or anxious while in the PET scanner he or she is free to withdraw from the study at any point. We 
will be monitoring blood pressure, heart rate and oxygen saturation throughout the study and if the subject is 
noted to appear anxious or demonstrate sustained increase in systolic blood pressure or heart rate (> 25% above 
baseline), we will remove the subject from the scanner and assess. 
 
Intravenous Catheter 
In the unlikely event that a subject does not have intravenous access or has access that we cannot use for any 
reason, we will place a peripheral catheter for blood draws and injecting 64Cu-FBP8. Risks of intravenous 
catheters include pain and bruising at the placement/injection site; infection; bleeding; injury to vessels, 
surrounding nerves, and tissues; air embolism, catheter fracture and embolism; hematoma; phlebitis; infiltration; 
vein thrombosis; catheter malfunction. 
 
VIII. 
POTENTIAL BENEFITS 
 
All of the CT scans will be read by a member of MGH’s Thoracic Radiology staff as part the institution’s policy 

Page 10 of 14 
 
for identification of incidental findings. If incidental findings are identified and the subject gives consent, we will 
provide this information to the subject’s primary care physician. If clot is identified by the fibrin scan in places not 
seen or not evaluated by the treating team (e.g. the pelvis), this information will be conveyed to the treating team 
and appropriate clinically-approved testing can be done to assess this if the treating team deems it necessary. 
 
Venous thromboembolism (VTE), comprising deep venous thrombosis and pulmonary embolism, is a major 
public health problem. The estimated average annual incidence rate of overall VTE among persons of European 
ancestry ranges from 104 to 183 per 100,000 person-years and is similar to that of stroke,1 the fifth leading cause 
of death in 2013.2 Incidence rates for PE±DVT are 29 to 78 per 100,000 person-years and for leg DVT alone are 
45 to 117 per 100,000 person-years.1 For those of African descent, the incidence may be higher.3–5 Over the 
decade from 2002 to 2012, the incidence of VTE has been rising.6 This has raised the question of whether this 
rise represents a true increase in incidence or potentially over diagnosis with more available imaging techniques. 
Whatever the reason, it is clear from this data that it is vitally important to improve the accuracy of identifying 
VTE with targeted diagnostics. The knowledge gained from this study will allow an assessment of whether or not 
a fibrin-specific PET probe has the potential to improve our diagnostic accuracy of VTE, diagnose VTE in 
previously difficult areas (pelvis) and broaden the patient population on which specific diagnostic testing can be 
performed, such as those with renal failure. 
 
 
 
 
IX. 
MONITORING AND QUALITY ASSURANCE 
 
This is an interventional study. Therefore, the safety monitoring will be conducted by an Independent Safety 
Monitor, Rahimi,Rod A, MD, PHD, Pulmonologist at MGH. Monitoring: Subjects will be monitored for any adverse 
health effects during the study by the PI and staff pulmonologists (Dr. Witkin or Dr. Montesi). A physician 
investigator will perform a physical exam prior to, and after the study and will also assess the subjects at times 
during the study as the subject’s symptoms and vital signs warrant. If the subject develops severe coughing, has 
a respiratory rate > 35/min for > 5 min, SpO2 < 88% for 5 min and not corrected by administering extra O2 or if 
SpO2 < 80% at any time, a HR sustained < 50/min or > 140/min, or BP falls below 90/60 or rises above 160/90 
with no history of hypertension at baseline the study will be terminated.  
 
An Independent Safety Monitor with expertise consonant with the nature of risks involved with the study will 
oversee the study safety.  Specifically, he will review the safety of the data after the first subject completed the 
study. He will be responsible for this review and decide whether the research should be altered or stopped.  After 
this initial review,  the Independent Safety Monitor will continue to monitor the study along with the investigator 
each time any adverse event or serious adverse event occurs regardless of whether such an event is study 
related or not.  
 
The independent research monitor shall have authority to stop a research protocol in progress, remove individual 
human subjects from a research protocol, and take whatever steps are necessary to protect the safety and well-
being of human subjects until the IRB can assess the monitor’s report. The independent research monitor shall 
have the responsibility to promptly report their observations and findings to the IRB. 
 
However, if any adverse effect occurs, the principal investigator will send, as immediately as possible, a report 
to the IRB for analysis. At least one physician investigator will be present throughout the entire study. Adverse 
events will be discussed with all research staff. All adverse effects associated with the use of the radioactive 
drug must will be reported directly to the RDRC and FDA. 
 
 
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