Comparison of Myocardial Blood Flow Measurements With Dedicated Solid State SPECT Camera Imaging and 99mTc-Tetrofosmin Versus PET Imaging and Rubidium-82
Phase: NA
Conditions: Coronary Heart Disease
Sponsor: Ottawa Heart Institute Research Corporation

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Cover Page for Protocol  
 
Document: Protocol  
 
Official Study Title: Comparison of Myocardial Blood Flow Measurements with 
Dedicated Solid State SPECT Camera Imaging versus PET Imaging  
 
Document Date: August 2, 2018  
 
NCT: NCT02280941 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Comparison of Myocardial Blood Flow Measurements with Dedicated Solid State 
SPECT Camera Imaging 
versus PET Imaging 
 
 
 
Principal Investigator: 
 
 
 
Terrence D. Ruddy, MD, FRCPC 
 
Co-Investigators:  
 
 
 
Benjamin Chow, MD, FRCPC 
Rob deKemp, PhD 
Ran Klein, PhD 
 
 
 
Glenn Wells, PhD 
 
 
 
 
Study Centre 
The University of Ottawa Heart Institute at the Ottawa Hospital 
 
 
Study Funding Support 
GE Healthcare,  
Global Research Headquarters 
9900 Innovation Drive, 
Wauwatosa, Wisconsin, United States, 53226 
 
 
Protocol Version 4: August 2, 2018 
 

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Contents 
Clinical Protocol Synopsis ............................................................................................... 5 
Abbreviations .................................................................................................................. 8 
1.1 Background and Rationale ..................................................................................... 9 
1.2 Hypothesis ........................................................................................................... 10 
2. Study Objectives ....................................................................................................... 10 
3. Study Design ............................................................................................................. 10 
5. Sample Size and Statistical Analysis......................................................................... 12 
6. Study Population ....................................................................................................... 13 
6.1 Source of Participants .......................................................................................... 13 
6.2 Inclusion Criteria .................................................................................................. 13 
6.3 Exclusion Criteria ................................................................................................. 13 
6.4 Withdrawal from Study ......................................................................................... 14 
6.5 Early Termination ................................................................................................. 14 
7. Data Collection .......................................................................................................... 14 
7.1 Demographic Information ..................................................................................... 14 
7.2 Medical History .................................................................................................... 14 
7.3 Clinical Status ...................................................................................................... 14 
7.4 Caffeine Ingestion ................................................................................................ 14 
7.5 Pregnancy Assessment ....................................................................................... 15 
8. Risk Benefit Assessment ........................................................................................... 15 
8.1 SPECT and PET Imaging .................................................................................... 15 
8.2 Dipyridamole Pharmacological Stress.................................................................. 15 
9. Safety and Tolerability ............................................................................................... 15 
9.1 Safety Variables ................................................................................................... 15 
9.2. Safety Reporting ................................................................................................. 16 
9.3 Pregnancy ............................................................................................................ 16 
10. Study Records ......................................................................................................... 16 
10.1 Investigator Study Files ...................................................................................... 16 
10.2 Participant Clinical Trial Files ............................................................................. 16 
11. Monitoring/Access to Files for Inspection ................................................................ 16 

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12. Publication ............................................................................................................... 17 
13. Budget ..................................................................................................................... 17 
13.1 Budget Details ...................................................... Error! Bookmark not defined. 
14. References .............................................................................................................. 18 
 
 
 

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Clinical Protocol Synopsis 
 
Study Title: Comparison of Myocardial Blood Flow Measurements with Dedicated 
Solid State SPECT Camera Imaging versus PET Imaging  
 
Version 4: August 2, 2018 
 
Study Centre 
 
University of Ottawa Heart Institute 
Study Objectives 
 
 
 
1. To evaluate the correlation of global and regional 
myocardial blood flow (MBF) measurements and calculated 
myocardial flow reserve (MFR) using single photon 
emission computed tomography (SPECT) and 
99mTc-
tetrofosmin (99mTc) to positron emission tomography (PET) 
with Rubidium-82 (Rb-82) or N-13-ammonia (13NH3) in 
patients with an intermediate to high probability of CAD 
(Phase 1); 
 
2. To determine the reproducibility of global and regional 
myocardial blood flow measurements and calculated 
myocardial flow reserve using SPECT and 
99mTc-
tetrofosmin in patients with an intermediate to high 
probability of CAD (Phase 2); 
 
3. To evaluate the correlation of global and regional 
myocardial blood flow measurements and calculated 
myocardial flow reserve using SPECT and 
99mTc-
tetrofosmin to PET with Rb-82 or 13NH3 in normal volunteers 
(Phase 3). 
 
Hypotheses 
1. The correlation of global and regional myocardial blood flow 
measurements and calculated myocardial flow reserve 
using SPECT to PET in patients with an intermediate to high 
probability of CAD will be r > 0.6 (Phase 1); 
 
2. The test-retest reproducibility of global and regional 
myocardial blood flow measurements and calculated 
myocardial flow reserve using SPECT in patients with an 
intermediate to high probability of CAD will be within10 to 
15% (Phase 2); 
 
3. The correlation of global and regional myocardial blood flow 
measurements and calculated myocardial flow reserve 
using SPECT to PET in normal volunteers will be   r > 0.6 
(Phase 3). 
Study Type 
 
Investigator-initiated, imaging research. 
 
Study Design 
 

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For the Phase 1 correlation study, participants will undergo a 
standard clinical rest/stress PET study with either Rb-82 or 13NH3 
with a low dose CT and a rest/stress SPECT study with 99mTc 
within a 4 week period. Participants with CAD will be recruited from 
patients already referred for clinical SPECT or PET imaging and 
with an intermediate to high probability of CAD. Any participants 
who have an intervention or undergo a significant cardiac event 
during the 4 week interval will be excluded. 
 
For the Phase 2 reproducibility study, participants will be recruited 
from patients already referred for clinical rest/stress SPECT 
imaging and with an intermediate to high probability of CAD.  
Participants will undergo a second rest/stress SPECT with 99mTc 
within a 4 week period. Any participants who have an intervention 
or undergo a significant cardiac event during the 4 week interval 
will be excluded. 
 
For the Phase 3 correlation study, normal volunteer participants 
will undergo a standard rest/stress PET study with either Rb-82 or 
13NH3 with a low dose CT and a rest/stress SPECT study with 99mTc 
within a 4 week period.  
 
 
Number of 
Participants 
 
For the correlation studies (hypothesis 1 and 3), two specific 
populations including 1) 30 participants with an intermediate to 
high probability of CAD (Phase 1) and 2) 30 healthy volunteers 
without known heart disease (Phase 3). 
For the reproducibility study (hypothesis 2), 30 participants with an 
intermediate to high probability of CAD (Phase 2).  
  
Inclusion and  
Exclusion Criteria 
Inclusion Criteria 
For all participants 
- 
Age ≥ 18 years old 
- 
BMI ≤ 40 kg/m2 
- 
Able and willing to comply with the study procedures 
 
1. Participants with an intermediate to high probability of CAD 
- 
Suspected or known CAD on a stable medication regime 
 
2. Healthy volunteers without known heart disease OR 
- 
Low risk of CAD (ACC Guidelines Pre-test Probability of 
CAD by Symptoms, Gender and Age)  
 
Exclusion Criteria: 
- 
History or risk of severe bradycardia (heart rate < 50 beats 
per minute) not related to chronotropic drugs 

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- 
Known second- or third-degree AV block without 
pacemaker 
- 
Dyspnea (NYHA III/IV), wheezing asthma or severe COPD 
- 
Coronary artery bypass graft (CABG) surgery within 60 
days prior to screening or at any time after consent 
- 
Percutaneous coronary intervention (PCI) within 30 days 
prior to screening or at any time following consent 
- 
Acute myocardial infarction or acute coronary syndrome 
within 60 days prior to screening or at any time following 
consent 
- 
Recent use of dipyridamole-containing medications (e.g. 
Aggrenox) 
- 
Known hypersensitivity to dipyridamole  
- 
Breastfeeding or pregnancy 
- 
Claustrophobia or inability to lie still in a supine position 
- 
Unwillingness or inability to provide informed consent 
 
Study Duration for 
Participants 
Duration of participation is a maximum of 4 weeks. No changes to 
clinical care in the CAD population will be made.  
 
Safety and 
Tolerability 
 
Safety variables will include the recurrence of procedure related 
adverse events. Adverse events (AE) and serious adverse events 
(SAE) will be defined and reported according to regulatory 
standards.  AEs and SAEs will be reported from the signing of the 
consent and followed until resolution or determined to be not 
clinically significant.   
 
Statistical Methods 
For 
the 
correlation 
studies, 
global 
and 
regional 
MBF 
measurements acquired using SPECT and PET and calculated 
MFR measurements will be correlated with Spearman correlation 
analysis.  For the reproducibility study, Bland-Altman plots will be 
used to determine significant bias and the coefficient of 
repeatability of global and regional MBF measurements acquired 
using SPECT and calculated MFR. 
 
 
 

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Abbreviations 
 
3D 
 
three dimensional 
ACC  
American College of Cardiology 
AC 
 
attenuation correction 
AE 
 
Adverse Event 
AV 
 
atrial-ventricular 
BMI 
 
body mass index 
CABG  
coronary artery bypass graft 
CAD  
coronary artery disease 
CRF  
case report form 
COPD  
chronic obstructive pulmonary disease 
CT 
 
computed tomography 
g 
 
gram 
ICH GCP 
International Conference on Harmonization Good Clinical Practice 
kg 
 
kilograms 
kVp 
 
kilo-volt potential 
MBF  
myocardial blood flow 
MBq  
megabequerels 
mcg 
 
micrograms 
mCi 
 
millicurie 
MFR  
myocardial flow reserve 
mg 
 
milligrams 
min 
 
minute 
mm 
 
month 
MRN  
medical record number 
mSv  
milliseverts 
13NH3  
Nitrogen-13-ammonia 
NC 
 
no correction 
NYHA  
New York Heart Association 
OHSN-REB Ottawa Health Science Network Research Ethics Board 
PET  
positron emission tomography 
PCI   
percutaneous coronary intervention 
PHI 
 
Personal Health Information 
82Rb  
Rubidium-82 Chloride 
SAE  
Serious Adverse Event 
SC 
 
scatter correction 
SPECT 
single photon emission computed tomography 
SOP  
Standard Operating Procedures 
99mTc  
Technetium-99m 
201Tl  
Thallium Chloride 
TOH  
The Ottawa Hospital 
UOHI  
University of Ottawa Heart Institute 
yyyy  
year 
 

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1. Introduction 
 
 
1.1 Background and Rationale 
Absolute myocardial blood flow (MBF) and myocardial flow reserve (MFR) using positron 
emission tomography (PET) provide additional diagnostic and prognostic power 
compared to relative perfusion results [1-7]. Myocardial perfusion imaging is much more 
widely carried out with single photon emission tomography (SPECT) than with PET.  
However, measurements of MBF or MFR are rarely obtained with SPECT due to technical 
reasons (need for attenuation and scatter correction and the requirement of the camera 
to rotate around the patient for 3-dimensional imaging).  An estimate of MFR without a 
direct measurement of MBF can be determined with a combination of dynamic planar 
followed by static SPECT acquisitions [8] and provides useful prognostic information [9].  
Dynamic tomographic data can be acquired with rapid rotation of SPECT camera and 
provide 1) a measure of MFR [10] and 2) the arterial input function [11] suggesting that 
accurate measures of MBF could be possible with SPECT [12].   
The recent development of dedicated solid state cardiac SPECT cameras has made the 
possibility of MBF measurement much more feasible and practical. Cameras such as the 
NM 530c/570c cameras (GE Healthcare, Haifa, Israel) and the DSPECT system 
(Spectrum Dynamics Medical Inc., Palo Alto, CA) have greatly improved sensitivity and 
are stationary [13].  These features allow dynamic imaging with high temporal resolution 
and improved count density and facilitate MBF measurement with SPECT.  Recent work 
has shown the capability to provide an index of global MFR [14], but no studies have 
demonstrated measurement of MBF.   
For the first time, Dr. Glenn Wells and our group recently demonstrated the accurate 
quantification of MBF in a pig model of rest and transient occlusion at stress [15]. Data 
were acquired using attenuation and scatter corrected dynamic SPECT data with a NM 
530c camera with 201Tl, 99mTc-tetrofosmin and 99mTc-sestamibi. MBF was measured with 
gold-standard microspheres injected simultaneously with the SPECT tracers.  Measured 
extraction fraction data agreed with those obtained previously using invasive techniques.  
MBF determined using the measured extraction fractions produced accurate values and 
good correlations with microsphere MBF between r=0.75 and r=0.83 (p<0.01 for all) and 
the resulting correlation in the MFR was up to 0.89 (p<0.01).  Thus, non-invasive 
measurement of absolute MBF with a stationary dedicated cardiac SPECT is feasible 
using common perfusion tracers.  
The goal of this study is to compare SPECT and PET measurement of MBF and MFR 
and determine the reproducibility of SPECT MFR measurements in patients. 

10 
 
 
 
 
1.2 Hypothesis 
1. The correlation of global and regional myocardial blood flow (MBF) measurements 
and calculated myocardial flow reserve (MFR) using SPECT  to PET in participants 
with an intermediate to high probability of CAD will be r > 0.6 (Phase 1); 
 
2. The test-retest reproducibility of global and regional MBF measurements and 
calculated MFR using SPECT in participants with an intermediate to high 
probability of CAD will be within 10 to 15% (Phase 2); 
 
3. The correlation of global and regional MBF measurements and calculated MFR 
using SPECT to PET in normal volunteers will be r > 0.6 (Phase 3). 
  
2. Study Objectives 
 
1. To evaluate the correlation of global and regional MBF and MFR measured using 
SPECT to that measured using PET in participants with an intermediate to high 
probability of CAD (Phase 1); 
 
2. To determine the reproducibility of global and regional MBF measurements and 
calculated MFR using SPECT in participants with an intermediate to high 
probability of CAD (Phase 2); 
 
3. To evaluate the correlation of global and regional MBF and MFR measured using 
SPECT to that measured using PET in normal volunteers (Phase 3).  
 
3. Study Design 
 
Phase 1: 
Patients referred to the University of Ottawa Heart Institute Diagnostic Imaging 
Department for myocardial perfusion imaging (MPI), PET or SPECT, will undergo a 
clinically indicated rest/stress PET scan using either Rb-82 or 13NH3. Research imaging 
will consist of a rest/stress SPECT scan with 99mTc completed with 4 weeks of the PET 
scan, occurring either before or after the PET scan. 
 
Study end will be defined as the completion of both the PET and SPECT scans. 
 
Phase 2: 
Patients will undergo a clinically indicated rest/stress SPECT scan as referred. 
Research imaging will consist of a second rest/stress SPECT scan with 99mTc within 4 
weeks of the clinical SPECT scan. 
 
Study end will be defined as the completion of both SPECT scans. 

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Phase3: 
Normal volunteers will undergo a rest/stress PET scan using either Rb-82 or 13NH3 and 
a rest/stress SPECT scan with 99mTc completed within a 4 week period.  
 
Study end will be defined as the completion of both the PET and SPECT scans. 
 
4. SPECT and PET Imaging 
 
4.1 99mTc SPECT Imaging 
The camera used in this study will be the Discovery NM 530c (GE Healthcare, Haifa, 
Israel).  This camera is a dedicated cardiac camera that uses 19 cadmium-zinc-telluride 
(CZT) based detectors [16].  Each detector is 8 x 8 cm divided into a 32x32 array with a 
pixel pitch of 2.46mm.  Each detector has a single-pinhole collimator with an effective 
diameter of 5.1mm.  The detectors are arranged in an arc around the field-of-view, 
providing sufficient angular sampling for 3D reconstruction without the need to rotate the 
camera.  The sensitivity of the system is approximately 4-times higher than a standard 
dual-head gamma camera. 
   
Participants will be instructed to fast for a minimum of 4 hours and to abstain from 
products containing caffeine for 24 hours prior to imaging. 
 
99mTc-tetrofosmin (370 MBq (2.8 mSv) for rest and 1100 MBq (7.7 mSv) for stress) will be 
delivered using a power injector as a 9 ml bolus over 30 s followed by a 9 ml saline flush 
over 30 s. Image data will be acquired in listmode for 11 min starting just prior to tracer 
injection.  Resting images will be acquired first and repeated just prior to stress.  For 
stress, dipyridamole (0.14 mg/kg/min over 5 min) will be given intravenously.  At 8 minutes 
following onset of dipyridamole infusion, stress imaging will start prior to the 99mTc-
tetrofosmin injection.  Aminophylline will be administered intravenously at 11 minutes 
following onset of dipyridamole infusion.  The usual post-stress images will be acquired 
approximately 45 minutes after radiotracer injection. 
 
Following acquisition, the listmode data will be rebinned into 9x10s, 6x15s, 4x120s 
frames.  The projection data for each frame will be independently reconstructed using 
manufacturer supplied MLEM iterative reconstruction that includes point-spread function 
modeling and a noise-suppression prior.  A total of 30 iterations will be used 
corresponding to the manufacturer recommendation for resting (low-count) studies.  
Images will be filtered post-reconstruction using a 3D 5th-order Butterworth filter with a 
cut-off frequency of 0.37 cycles/cm. Images will be reconstructed without corrections 
(NC), and with attenuation correction (AC) and scatter correction (SC).  When applied, 
AC will be based on the CT scan from the PET/CT acquisition which will be coregistered 
manually to the emission reconstruction using on-line quality assurance tools. SC will be 
applied to the projection data prior to reconstruction using a dual-energy window 
approach [15].  For the Phase 2 SPECT reproducibility study, an additional CT scan will 
be acquired on an Infinia/Hawkeye 4 SPECT/CT gamma camera and used in place of the 
CT from the PET/CT acquisition. 

12 
 
 
The reconstructed dynamic image series will be processed using FlowQuant (Ottawa, 
ON), our in-house kinetic analysis software [17] as well as Infinia (GE Canada).  With this 
semi-automatic software, a 1-tissue-compartment model will be fit to the myocardium 
time-activity data to generate a parameterized map of the uptake rate constant K1 
(ml/min/g) for the heart. K1 values will be scaled to MBF based on the K1-MBF 
relationship determined from the pig studies (15). Finally, the results from the FlowQuant 
(Ottawa, ON) will be compared to those of the commercially released Infinia software (GE 
Canada) to determine the similarities between the two software packages.  
 
4.2 82Rb / 13NH3 PET Imaging  
Rb-82 or 13NH3 PET Imaging will be performed according to the UOHI standard clinical 
protocol [18].  Briefly, the participants will be positioned in a 3D PET system (GE 
Discovery 690 PET/VCT). The initial rest PET scan will include a low-dose CT for 
attenuation correction (0.4 mSv; fast helical 2 s, 120 kVp with axial and angular mA-
modulation at noise-index = 50). Hyperemic stress flow will be induced with dipyridamole 
(0.14 mg/kg/minute for 5 minutes). PET imaging will be performed using 1000 MBq (0.73 
mSv) of Rb-82 or 3 MBq/kg (0.7 mSv) of 13NH3 at rest and during stress with radiotracer 
injected 8 minutes following the start of dipyridamole infusion.  MBF and MFR will be 
quantified and polar-maps generated for each rest and stress state using in-house 
FlowQuant© software [17] as well as Infinia (GE Canada).    
 
4.3 Concentration of 99mTc SPECT tracer 
SPECT perfusion tracers are known to bind to red blood cells limiting the amount of tracer 
available to the myocardium for extraction [15]. Thus, concentration function used in the 
kinetic analysis is better represented by the plasma concentration of tracer instead of the 
whole blood concentration, as measured by the image-based methods used in this study.  
Correction for the plasma to whole blood ratio can be done by applied using a correction 
curve.  The correction curve has been determined with pig experiments but needs to be 
calibrated to humans.  To estimate this correction, we will measure the whole-blood to 
plasma tracer concentration ratio at equilibrium (~30min post injection) which will then be 
used to rescale the full curve that was measured in the pig study.  For this purpose, a 
12ml blood sample (2x6ml) at 30min after the rest tracer injection and a 2nd 12ml (2x6ml) 
blood sample at 30min will be drawn after the stress injection.  Whole blood and serum 
aliquots will be prepared and then measured in a well-counter to determine the 
concentration ratio. 
 
 
5. Sample Size and Statistical Analysis 
 
The sample size for the correlation studies (hypotheses 1and 3) was calculated to 
provide a 95% confidence interval around r=0.6 that excludes r=0.25, which is 
considered the upper bound of no correlation. To obtain a difference in the z-transform 
of r=0.6 and r=0.25 of 1.96 requires an n of 24. A withdrawal rate of 10 to 15 % 
increases the number of patients required to 30 per group. 
 

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The sample size for the reproducibility study (hypothesis 2) is estimated to detect a 10% 
difference on background of 15% variability (assuming a SPECT MBF uncertainty 
similar to the high end of PET variability). This requires a sample size of 26 (power = 
0.95; alpha =0.05).  A withdrawal rate of 10 to 15 % increases the number of patients 
required to ~ 30 per group. 
  
Adverse events will be listed on an individual basis. All safety variables and demographic 
data will be tabulated with descriptive statistics, if appropriate. 
  
For the correlation studies global and regional MBF measurements acquired using 
SPECT and PET and calculated MFR will be correlated with Spearman correlation 
analysis.  For the reproducibility study Bland-Altman plots will be used to determine 
significant bias and the coefficient of repeatability of global and regional MBF 
measurements acquired using SPECT and calculated MFR. 
 
 
6. Study Population 
 
6.1 Source of Participants 
The CAD study population will be adult male and female patients who are referred to the 
outpatient cardiology clinics and/or the non-invasive Diagnostic Imaging Department at 
the University of Ottawa Heart Institute (UOHI).  The healthy volunteer population will be 
recruited 
from 
the 
Diagnostic 
Imaging 
Department 
or 
by 
the 
use 
of 
advertisements/posters located in UOHI and/or The Ottawa Hospital (TOH). 
 
6.2 Inclusion Criteria 
For all participants 
- 
Age ≥ 18 years old 
- 
BMI ≤ 40 kg/m2 
- 
Able and willing to comply with the study procedures 
Participants with intermediate to high probability of CAD 
- 
Suspected or known CAD on a stable medication regime. 
 
Healthy volunteers without known heart disease 
- 
Low risk of CAD (ACC Guidelines Pre-test Probability of Coronary Disease by 
Symptoms, Gender and Age)  
 
6.3 Exclusion Criteria 
- 
History or risk of severe bradycardia (heart rate < 50 beats per minute) not 
related to chronotropic drugs 
- 
Known second- or third-degree AV block without pacemaker 
- 
Dyspnea (NYHA III/IV), wheezing asthma or severe COPD 
- 
Coronary artery bypass graft (CABG) surgery within 60 days prior to screening or 
at any time after consent 
- 
Percutaneous coronary intervention (PCI) within 30 days prior to screening or at 
any time following consent 

14 
 
- 
Acute myocardial infarction or acute coronary syndrome within 60 days prior to 
screening or at any time following consent 
- 
Recent use of dipyridamole-containing medications (e.g. Aggrenox) 
- 
Known hypersensitivity to dipyridamole 
- 
Breastfeeding or pregnancy 
- 
Claustrophobia or inability to lie still in a supine position 
- 
Unwillingness or inability to provide informed consent 
 
6.4 Withdrawal from Study 
Participants may withdraw from the study at any time without penalty or prejudice. No 
data will be collected from the time of withdrawal. 
 
6.5 Early Termination 
Participants may be terminated for reasons such as, but not limited to: 
• Noncompliance with study procedures. 
• Participant experiences a cardiac event. 
• Secondary illness requiring intervention during the study. 
• Pregnancy. 
• Participant safety may be compromised in the opinion of the investigator. 
• Study may be stopped at the request of a regulatory authority or the REB. 
If study discontinuance occurs, the date and reason must be documented in the CRF.  If 
the participant is lost to follow-up, documentation must be made as to the steps taken to 
contact the participant.  Every attempt will be made to perform end of study follow-up with 
the participant who withdraws or is terminated. 
 
7. Data Collection 
 
All participant information and data will be collected respecting participant confidentiality 
and privacy and following written informed consent. 
 
7.1 Demographic Information 
Demographic information will include the participant’s date of birth (mm/yyyy), gender, 
height and weight.  
 
7.2 Medical History 
Medical history and results from any standard of care testing related to a participant’s 
cardiovascular disease and inclusion/exclusion criteria will be collected. Clinical data 
obtained at scan visits will be included as part of the study data. 
 
7.3 Clinical Status 
The blood pressure, heart rate and clinical status will be monitored according to current 
clinical protocols during imaging procedures. Clinical protocol will be followed for 
dipyridamole stress testing. 
 
7.4 Caffeine Ingestion 

15 
 
The ingestion of caffeine will be restricted for 24 hours prior to all imaging procedures as 
per standard clinical practice.  
 
 
7.5 Pregnancy Assessment 
A woman of child bearing potential will have a urine pregnancy test performed on the 
days of imaging. 
 
8. Risk Benefit Assessment 
 
8.1 SPECT and PET Imaging   
 
Phase 1: 
Participants undergoing SPECT/CT imaging with 99mTc will receive a total radiation dose 
of 10.5 mSv (rest dose 2.8 mSv and stress dose 7.7 mSv)   
 
Phase 2:  
Participants undergoing research SPECT/CT imaging with 99mTc will receive a total 
radiation dose of 10.9 mSv (rest dose 2.8 mSv and stress dose 7.7 mSv) and one SPECT 
CT attenuation scan (0.4 mSv)).   
 
 
Phase 3: 
Participants undergoing PET imaging with Rb-82 and SPECT imaging with 99mTc will 
receive a total radiation dose of 12.6 mSv (10.5 mSv for the SPECT and 2.1 mSv for the 
PET, including low-dose CT (0.4mSv) attenuation scan).  
 
Participants undergoing PET imaging with 13NH3 and SPECT imaging with 99mTc will 
receive a total radiation dose of 12.3 mSv (10.5 mSv for the SPECT and 1.8 mSv for the 
PET, including low-dose CT (0.4mSv) attenuation scan).  
 
8.2 Dipyridamole Pharmacological Stress  
Dipyridamole is a vasodilator commonly used in the clinical practice of nuclear cardiology 
and will be used as the stress agent for all stress studies. Rare serious adverse reactions 
associated with the administration of intravenous dipyridamole for MPI have been 
reported. These have included fatal and non-fatal myocardial infarction, ventricular 
fibrillation, symptomatic ventricular tachycardia, stroke and transient cerebral ischemia. 
The infusion rate is monitored to minimize this risk and the symptoms can generally be 
reversed with an intravenous injection of 50 - 250 mg of aminophylline over several 
minutes. 
 
9. Safety and Tolerability 
 
9.1 Safety Variables 
Safety variables will include the occurrence of procedure-related adverse events and 
changes in clinical status. 

16 
 
 
9.2. Safety Reporting 
Adverse events (AE) and Serious Adverse Events (SAE) will be defined and reported 
according to ICH/GCP and Regulatory Standards. AEs and SAEs will be reported from 
the signing of the consent and followed until resolution or determined to be not clinically 
significant.  
 
9.3 Pregnancy 
During the conduct of the trial should a pregnancy be actual (positive result with testing) 
or suspected, the participant will be advised to contact the Investigator immediately. 
Participation in the trial will be terminated. 
 
10. Study Records 
 
Study files will be divided into two categories: Investigator Study Files and Participant 
Clinical Trial Files. Study files will be retained for a period of 25 years from the study end. 
GE Healthcare will have access to de-identified data and images plus other deliverables 
which are generated from this study as specified in the contractual agreement.  
 
10.1 Investigator Study Files 
Regulatory files will contain all essential documents relating to trial conduct and 
management including Ottawa Health Science Network Research Ethics Board (OHSN-
REB) and regulatory communications.  
 
 
10.2 Participant Clinical Trial Files 
The participant files will include the consent form, screening and enrollment logs, Master 
List, source documents and the case report form (CRF). Personal Health Information 
(PHI) relevant to the conduct of the trial will be collected and will include medical history, 
inclusion and exclusion criteria details, medical records generated during the conduct of 
the trial and medical record number (MRN). These documents will be maintained as paper 
and electronic files under the responsibility of the Principal Investigator.  
 
11. Monitoring/Access to Files for Inspection 
 
The investigator agrees to provide access to all study related files for conduct of 
inspections or auditing by regulatory authorities. 
 
Ongoing review of safety parameters and events will be recorded and reported according 
to applicable regulations and OHSN-REB requirements. No formal Data Safety 
Monitoring Board will be specified due to the low level of risk associated with this trial.  
 
Periodic study monitoring will be conducted to assure adherence to the protocol, ICH 
GCP guidelines and that data is accurate, complete and verifiable. An internal monitoring 
plan, following local SOPs, will be developed. The designated internal monitor will have 
the training and qualifications necessary to provide an appropriate and thorough 

17 
 
verification of the study files. Confidentiality will be consistent with local requirements and 
national regulations. 
 
12. Publication 
 
Review and Publication will be according to contractual agreements in place at the time 
of the trial. 
 
13. Budget 
 
This investigator initiated study will be funded by a research grant from GE Healthcare 
with funding for 2 years to carry out the Phase 1 (Correlation in CAD participants) and 
Phase 2 (Reproducibility studies).  Funding for a third year for the Phase 3 study will be 
negotiated during year 2.   The necessary software licences for acquisition and 
processing of image data will be provided by GE Healthcare for the 2 year duration of the 
project.    
 
 

18 
 
14. References 
 
1. Herzog BA, Husmann L, Gaemperli O, Valenta I, Siegrist P T, Tay F M, Burkhard N, 
Wyss C A, and Kaufmann P A: Long-term prognostic value of 13N-ammonia 
myocardial perfusion positron emission tomography added value of coronary flow 
reserve. J Am Coll Card, 2009; 54:150-156.  
2. Ziadi MC, Dekemp RA, Williams K, Guo A, Renaud JM, Chow BJ, Klein R, Ruddy 
TD, Aung M, Garrard L, and Beanlands RS: Does quantification of myocardial flow 
reserve using rubidium-82 positron emission tomography facilitate detection of 
multivessel coronary artery disease? J Nucl Cardiol, 2012; 19:670-80. 
3. deKemp RA, Yoshinaga K, and Beanlands RSB: Will 3-dimensional PET-CT enable 
the routine quantification of myocardial blood flow? J Nucl Cardiol, 2007; 14:380-
397. 
4. Saraste A, Kajander S, Han C, Nesterov SV, and Knuuti J: PET: Is myocardial flow 
quantification a clinical reality? J Nucl Cardiol, 2012; 19:1044-59. 
5. Camici PG and Rimoldi OE: The clinical value of myocardial blood flow 
measurement. J Nucl Med, 2009; 50:1076-87. 
6. Murthy VL, Naya M, Foster CR, Gaber M, Hainer J, Klein J,. Dorbala S, Blankstein 
R, and Di Carli MF: Association between coronary vascular dysfunction and cardiac 
mortality in patients with and without diabetes mellitus. Circulation, 2012; 126:1858–
1868.  
7. Valenta I, Dilsizian V, Quercioli A, Ruddy TD, and Schindler TH: Quantitative 
PET/CT measures of myocardial flow reserve and atherosclerosis for cardiac risk 
assessment and predicting adverse patient outcomes. Curr Cardiol Rep, 2013; 
15:344–53.  
8. Storto G, Sorrentino AR, Pellegrino T, Liuzzi R, Petretta M, and Cuocolo A: 
Assessment of coronary flow reserve by sestamibi imaging in patients with typical 
chest pain and normal coronary arteries. Eur J Nucl Med Mol Imaging, 2007; 
34:1156–1161. 
9. Daniele S, Nappi C, Acampa W, Storto G, Pellegrino T, Ricci F, Xhoxhi E,  Porcaro 
F, Petretta M, and Cuocolo A. Incremental prognostic value of coronary flow reserve 
assessed with single-photon emission computed tomography. J Nucl Cardiol, 2011; 
18:612-9. 
10. Gullberg GT, DiBella EVR and Sinusas AJ: Estimation of coronary flow reserve: Can 
SPECT compete with other modalities? J Nucl Cardiol, 2001; 8:620–625. 
11. Winant CD, Aparici CM, Zelnik YR, Reutter BW, Sitek A, Bacharach SL and Gullberg 
GT: Investigation of dynamic SPECT measurements of the arterial input function in 
human subjects using simulation, phantom and human studies. Phys. Med. Biol, 
2012; 57:375-393. 
12. Gullberg GT, Reutter BW, Sitek A, Maltz JS, and Budinger TF: Dynamic single 
photon emission computed tomography: basic principles and cardiac applications. 
Phys. Med. Biol, 2010; 55:R111-R191. 
13. Slomka PJ, Patton JA, Berman DS and Germano G: Advances in technical aspects 
of myocardial perfusion SPECT imaging. J Nucl Cardiol, 2009; 16:255–276. 
14. Ben-Haim S, Murthy VL, Breault C, Allie R, Sitek A, Roth N, Fantony J, Moore SC, 
Park MA, Kijewski M, Haroon A, Slomka P, Erlandsson K, Baavour R, Zilberstien Y, 

19 
 
Bomanji J, Di Carli MF: Quantification of Myocardial Perfusion Reserve Using 
Dynamic SPECT Imaging in Humans: A Feasibility Study. J Nucl Med 2013; 54:873–
879. 
15. Wells RG, Timmins R, Klein R, Lockwood J, Marvin B, deKemp RA, Wei L, Ruddy 
TD:  Dynamic SPECT Measurement of Absolute Myocardial Blood Flow in a Porcine 
Model. (J Nucl Med 2014; 55:1685-1691) 
16. Bocher M, Blevis IM, Tsukerman L, Shrem Y, Kovalski G, Volokh L: A fast cardiac 
gamma camera with dynamic SPECT capabilities: design, system validation and 
future potential. Eur J Nucl Med Mol Imaging 2010; 37:1887-1902 
17. Klein R, Beanlands RSB and deKemp RA: Quantification of myocardial blood flow 
and flow reserve: Technical aspects. J Nucl Cardiol 2010; 17:555-70 
18. Renaud JM, Dasilva JN, Beanlands RS, Dekemp RA : Characterizing the normal 
range of myocardial blood flow with ⁸²rubidium and ¹³N-ammonia PET imaging. J 
Nucl Cardiol 2013;20 :578-91