Multi-Center Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve
Conditions: Coronary Artery Disease
Sponsor: Ottawa Heart Institute Research Corporation

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
Document Cover Page  
Document: Protocol  
Version Date: June 4, 2021 
NCT: 03427749 
 
 

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
Multi-Center Evaluation of Feasibility of SPECT Measurement of 
Myocardial Blood Flow and Reserve  
 
 
Potential participating Centers (alphabetically by country) and Investigators: 
 
Belgium: 
Universitaire ziekenhuizen Leuven 
Leuven, Belgium 
Olivier Gheysens, MD  
 
Canada: 
The University of Ottawa Heart Institute 
 
 
Ottawa, ON, Canada 
Terrence D. Ruddy, MD, FRCPC 
R Glenn Wells, PhD  
 
 
 
 
London Health Sciences Centre 
 
 
London, ON, Canada 
 
 
 
Jonathan Romsa, MD, FRCPC 
 
 
 
William Vezina, MD, FRCPC 
 
Germany: 
Medizinische Hochschule Hannover 
 
 
Hannover, Germany 
 
 
 
Frank Bengel, MD 
 
Japan: 
Ehime University Hospital 
 
 
Shitsukawa, Toon, Ehime, Japan  
 
 
 
 
 
 
 
 
Masao Miyagawa, MD, PhD 
 
Singapore:  National Heart Center Singapore 
 
 
Singapore 
 
 
 
Keng Yung Jih Felix MBBS, MRCP(UK)(Int Med), MMed (Int Med) 
 
 
Core Laboratory: R Glenn Wells, PhD 
University of Ottawa Heart Institute 
 
 
 
Ottawa, ON, Canada 
 
 
Study Funding Support 
GE Healthcare  
Global Research Headquarters 
9900 Innovation Drive 
Wauwatosa, Wisconsin, United States, 53226 
 
 
Protocol Version 2: June 10, 2019 
 

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
Investigator Statement 
 
I agree to the terms and conditions relating to this study as defined in this protocol. I will 
conduct this study as outlined and will make a reasonable effort to complete the study 
within the time designated. 
 
I agree to conduct this study in accordance with the Declaration of Helsinki and its 
amendments, International Conference on Harmonization (ICH) Good Clinical Practice 
(GCP) guidelines, and applicable regulations and laws. In particular, I will obtain the 
approval of a Research Ethics Board or Institutional Review Board (REB/IRB) for this 
protocol prior to its implementation. 
 
 
 
Principal Investigator (Printed Name) 
 
 
Signature 
 
 
Date 
 
 
 
 
 
 
 
 

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
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 1–8. 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 9 and provides useful prognostic information 10.  If 
the camera can perform serial rapid rotations, then dynamic tomographic data can be 
acquired with conventional SPECT cameras and accurate measures of MBF might be 
possible with SPECT 11–13.   
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 14.  These features allow dynamic imaging with high temporal resolution 
and improved count density, thereby facilitating MBF measurement with SPECT.   
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 using the 
NM530c camera. The three standard SPECT tracers, 201Tl, 99mTc-tetrofosmin and 99mTc-
sestamibi, were separately shown to correlate with simultaneously injected microspheres 
(between r=0.75 and r=0.83; p<0.01 for all).   These experiments demonstrated that non-
invasive measurement of absolute MBF with a stationary dedicated cardiac SPECT is 
feasible using common perfusion tracers. In human studies, Ben-Haim et al 16 showed 
using 99mTc-sestamibi that an index of global MFR was lower (p=0.02) in regions supplied 
by obstructed vessels (>50% occluded by coronary angiograph (CA)) than in non-
obstructed vessels. Ben Bouallèque et al 17 showed that the accuracy of regional MFR 
measured with 99mTc-tetrofosmin was 81% for the detection of obstructed vessels with 
CA and 85% for the detection of abnormal fractional flow reserve (FFR). Shiraishi et al 18 
found that the accuracy of 201Tl for the prediction of left main or triple-vessel disease, 
identified by CA, was 80%.  Finally, more recent studies have shown that the flow 
parameter K1 calculated from kinetic analysis of 99mTc-tetrofosmin studies yields an MFR-
index that predicts the presence of abnormal MFR as measured by PET 82Rb and 
ammonia studies with an accuracy ≥ 75% 19,20.  However, while extremely promising, 
these studies have all been performed in single centers with relatively small numbers of 
patients. To successfully translate this technology into a wide-spread, routinely employed 

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
tool for cardiac imaging requires demonstration of the feasibility of implementing an MBF 
protocol in multiple centers which may or may not have previous experience with MBF 
imaging.   
The primary objective of this study is to perform a multi-center trial to demonstrate the 
feasibility of measuring MBF and MFR using 99mTc-tetrofosmin and a CZT-based NM530c 
cardiac SPECT camera. 
A secondary objective is to evaluate the need for delayed imaging for relative MPI 
assessment (per ASNC 2016 guidelines: 15-45-minute delay for Stress; 30-60 minutes 
for Rest 21) (“delayed imaging”). The current MBF protocol requires additional imaging 
sessions to accommodate a dynamic acquisition during tracer injection for MBF 
calculation and delayed imaging post-injection for static MPI evaluation. PET protocols 
with 82Rb and 13N-ammonia use the latter portion of the dynamic imaging series for 
relative MPI assessment.  Studies that have considered this for SPECT tracers have had 
mixed results 22,23.  Images acquired as part of the feasibility study will provide pilot data 
for evaluating the potential to use the latter portion of the SPECT MBF dynamic 
acquisition for relative MPI assessment. Additional secondary objectives are to assess 
the impact of measuring SPECT MBF on patient throughput and to evaluate a 50% 
reduction in the activity used to measure SPECT MBF. 
1.2 Hypotheses 
a) Primary hypotheses 
1. Feasibility: It is practical to obtain reliable SPECT measurements of MBF 
routinely within the workflow of a standard clinical practice. 
2. MBF reproducibility: Global MBF measured at remote sites will agree within 
10% with the same data processed at an expert core laboratory. 
b) Secondary hypotheses 
1. Impact on throughput: Routine implementation of a SPECT MBF protocol will 
have at most minimal impact on patient throughput (defined as <10% reduction 
in patient volumes). 
2. Delayed imaging: static reconstruction of the last 6 min of the dynamic 
acquisition will provide images that are clinically equivalent (less than 10% 
change in patient diagnosis from normal (summed stress score < 4) to 
abnormal or vice versa), compared to standard static images obtained following 
a 45-min delay post-injection. 
3. Half-dose MBF measurement: The difference between MBF measurements 
with full-data and half-data dynamic acquisitions will be less than or equal to 
the inter-observer variation in MBF measurements with full-data. 
 
 

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
2. Study Objectives 
 
To demonstrate that the proposed approach to measuring SPECT MBF can be applied 
routinely in a clinical setting and produce consistent data with minimal reduction in patient 
throughput. 
To explore optimization of the acquisition using 1) early imaging post-stress instead of 
delayed imaging and 2) half-data instead of full-data acquisitions (leading to half dose 
MBF radiotracer studies).       
3. Study Design 
 
Patients will be recruited from those referred to the local site’s Diagnostic Imaging 
Department for SPECT myocardial perfusion imaging (MPI) and who have an 
intermediate to high pre-test likelihood of disease (Diamond-Forrester criteria ≥ 30%). 
Research imaging will consist of a SPECT acquisition at the time of rest and stress 
radiotracer injection in addition to the standard (delayed) clinical stress/rest SPECT 
scan with 99mTc-tetrofosmin.  This is an observational study; patients will be managed 
according to the standard clinical care of the local site. Where available, a CT scan will 
also be acquired for attenuation and/or scatter correction.  Studies may be one day 
(rest/stress or stress/rest) or two day (rest and stress on separate days)  
Study end will be defined as completion of all SPECT imaging at rest and stress. 
A core lab will be established at the University of Ottawa Heart Institute. Initial studies 
acquired at the local site according to the protocol will be evaluated for technical image 
quality (e.g. patient positioning, CT-SPECT coregistration, noise levels, patient motion 
and motion correction, artifacts).  The core lab will work with local sites, as needed, to 
implement the protocol and ensure adequate data quality.  All studies will be analyzed 
locally but the raw data will also be anonymized and forwarded to the core facility for 
reprocessing.  Central processing will allow comparison between sites and the repeat 
processing will provide an estimate of inter-operator variability in the measurements.  
The core lab will also compare the relative perfusion from immediate and delayed 
imaging for image quality and diagnostic accuracy (visual and quantitative).  
Studies will be acquired at 6 initial sites with mixed prior experience at MBF imaging, to 
demonstrate feasibility of use in a clinical setting. Each site will acquire 5 studies during 
an initial start-up period to become comfortable with the SPECT MBF protocol for data 
acquisition and processing. Studies acquired during the start-up period will not be used 
in the final analysis but will be processed by the core lab and used to evaluate site 
training. Following the start-up period, each site will acquire 25 studies within 60 
working days to show that the protocol can be implemented without major disruption to 
clinical throughput.   
 

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
 
Timeline (12 months):   
For each site, we anticipate 2-3 months for protocol approval by local ethics 
committees, 1-2 month for local site training and initial training studies, 2 months for 
feasibility study acquisitions.  We will stagger the entry of sites into the study to facilitate 
“one-on-one” consultation between the core (Ottawa) site and local sites during initial 
training period.  Reprocessing of local data sets by the core lab will be ongoing with final 
review and analysis of results during the last quarter. 
 
4. SPECT MBF Imaging with Tetrofosmin 
 
4.1 Camera  
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 24.  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. 
4.2 Patient Preparation  
Patient preparation will be the same as for a standard clinical myocardial perfusion study. 
Participants will be instructed to fast per local procedures (3 hours per ASNC 
guidelines21), and to abstain from products containing caffeine for no less than 12 hours 
prior to imaging. 
4.3 Radiotracer 
The tracer to be used is 99mTc-tetrofosmin. 99mTc-tetrofosmin will be mechanically 
delivered using a syringe pump at a constant rate over a 30 s period, followed immediately 
by a saline flush at the same injection rate as the tracer. The volume of the saline flush 
should be greater than the volume of the lines connecting the pump to the patient to 
ensure that the full tracer activity is delivered. There should be no delay between tracer 
and saline flush injections. Manual injection of radiotracer will not be used for this study 
to increase standardization but will be evaluated in future studies. 
The measurement of CFR with CZT SPECT has been validated with full doses of 
radiotracer but is most likely possible with half doses.  For this feasibility study, full doses 
will be used to provide the best CFR results possible.  The listmode data from the full-
dose studies with be reprocessed by the core laboratory to simulate half doses and 

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
confirm that half doses are adequate.  The planned subsequent studies of diagnostic 
accuracy and prognosis would evaluate half doses. 
The activity of the radiotracer injected at stress and rest will be full clinical doses with a 
minimal activity of 370 MBq for the first study and 1100 MBq for the second study for a 
one day protocol.  Injected doses will be 370 MBq at both rest and stress for 2-day 
protocols.  
4.4 Image Acquisition 
Images will be acquired using either a 1-day rest/stress, a 1-day stress/rest, or a 2-day 
protocol according to local site preferences.  Protocols illustrated in Appendix A. 
4.4.1 Stress Imaging 
Patient will be positioned according to standard clinical practice for myocardial perfusion 
imaging with the heart centered in the field of view. Image data will be acquired in listmode 
for 11 min starting just prior to tracer injection. There should be no movement of the 
patient or camera from the start of the vasodilator injection through to the end of image 
acquisition. Stress will be induced using a vasodilator, either dipyridamole, adenosine, 
Adenosine Tri-phosphate or regadenoson according to local site preference.   
• Dipyridamole: Dipyridamole (0.14 mg/kg/min over 4 or 5 min depending on local 
laboratory practice) will be given intravenously.  99mTc-tetrofosmin is injected at 3-5 
minutes following the end of the dipyridamole infusion. Stress imaging will start 
immediately prior to the 
99mTc-tetrofosmin injection.  Aminophylline will be 
administered intravenously as needed, no earlier than 3 minutes following injection of 
tracer.   
• Adenosine/Adenosine Tri-phosphate: Protocol will follow ASNC guidelines. 
• Regadenoson:  Protocol will follow ASNC guidelines. 
The usual post-stress images (delayed stress) will be acquired as per standard clinical 
practice. 
4.4.2 Resting Images 
If a stress-first protocol is being used, then the acquisition of additional resting imaging 
will be decided based on local-site standard clinical practice.   
For rest imaging, the patient will be positioned according to standard clinical practice for 
myocardial perfusion imaging with the heart centered in the field of view. Image data will 
be acquired in listmode for 11 min starting just prior to tracer injection. There should be 
no movement of the patient or camera from the start of the tracer injection through to the 
end of image acquisition. 
Acquisition of a clinical resting relative perfusion image (delayed rest) will be acquired as 
per standard clinical practice. 

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
 
 
4.4.3 Patient positioning dose 
A 40 MBq positioning tracer dose may be injected to aide in positioning of the patient, 
prior to injection of the tracer for dynamic imaging.  If a positioning dose is used, an 
additional 5-min static image of the tracer will be acquired prior to injection of the tracer 
used for dynamic imaging.  There should be no movement of the patient or camera 
between the static image of the positioning dose and the acquisition of the dynamic 
imaging for flow measurement. To note, injection of positioning dose should take place 
~20 minutes prior to injection of tracer for dynamic imaging. However, the patient should 
be on the imaging table only during the static scan prior to the injection for dynamic 
imaging, and throughout the dynamic imaging which follows.  
4.4.4 Pre-dynamic imaging 
Prior to the second scan of a 1-day protocol (ie the rest imaging in a stress-first protocol), 
a pre-dynamic static image is required to correct for residual activity from the first injection. 
A 5 min listmode static acquisition is obtained prior to injection of the radiotracer for 
dynamic imaging (and prior to injection of the vasodilator in the case of rest/stress 
protocols).  There should be no movement of the patient or camera between the static 
image and the acquisition of the dynamic imaging for flow measurement. 
4.5 Image Processing and Analysis 
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 60 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) when a CT attenuation scan is available.  
When applied, AC will be based on a CT scan acquired separately with the patient on the 
same configuration as used for the SPECT dynamic acquisitions.  
The reconstructed dynamic image series will be processed using the kinetic analysis 
software tools provided by the manufacturer (GE Healthcare).  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 previous 
single-site comparisons of clinical SPECT and Rb82 PET studies 20.   
5. Sample Size and Analysis 

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
 
Adverse events will be listed on an individual basis. All safety variables and demographic 
data will be tabulated with descriptive statistics, if appropriate.  
Bland-Altman plots will be used to determine significant bias and the coefficient of 
repeatability of global and regional MBF and MFR measurements for the core versus local 
reproducibility studies and for measurements of MBF with full and half data 
reconstructions. The mean difference in MBF between core and local-site processing will 
be assessed with a paired t-test.  A sample size of 25 studies per center provides 88% 
power (alpha=0.05) to detect a 10% difference, assuming a standard deviation in 
repeated MBF measurement of 15%1 (effect size of 0.67).  Each center will recruit 5 
practice patients and 25- 35 patients for analysis.  There will be 6 centers and each center 
will recruit 30 - 40 patients for a minimum  of 180 patients to a maximum of 240 patients(30 
practice patients and 150 - 210 patients for analysis). Global and regional MBF at rest 
and stress will be separately compared.  Differences in MFR will be similarly assessed. 
To evaluate impact on patient throughput, the following information will be collected for 
each site and each MBF study:  
 
Time patient enters the room 
 
Time of radiotracer injection (for dynamic imaging sessions) 
 
Start times of each image series (static and dynamic) 
 
Time patient exits the room 
Number of MPI studies done per day.   
Each site will also provide number of MPI studies done per day for the 2-month period 
prior to starting to apply the MBF protocol and similar timing and demographic data for 25 
standard (non-MBF) MPI studies. 
MBF/MFR analysis will be repeated with attenuation corrected images for those data 
sets which include a transmission imaging. 
Image quality will be assessed at the core lab.  The following factors will be considered: 
• Tracer bolus quality:  start of bolus is imaged, bolus duration is appropriate (total 
activity in the FOV is within 10% of final frame value 3 minutes after start), single 
peak 
• Positioning: Heart is within the quality FOV – no truncation. 
 
1 G*Power software, version 3.1.3. Faul F, Erdfelder E, Lang A-G, and Buchner A. G*Power 3: A flexible statistical 
power analysis program for the social, behavioral, and biomedical sciences. Behavior Research Methods, 39:175–
191, 2007 

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
• Sufficient injected activity: total counts in the left ventricle in the final 2-min frame is > 
1 M 
• Artifacts: no evidence of patient motion (or adequate motion correction), no other 
visible artifacts in the images 
• Number of segments with physiologically unreasonable MFR (MFR <0.8 or > 5) 
 
MBF analysis will be repeated for the half-dose MBF data sets.  Studies will be read at 
the Core Laboratory by two experienced readers to provide intra- and inter-observer 
repeatability of evaluation. 
To assess the need for delayed imaging, data sets will be reprocessed at the core lab.  
The last 6 min of each dynamic acquisition will be used to generate a late-dynamic 
static MPI image series (immediate imaging).  The immediate and delayed images will 
be reviewed blindly by two experienced readers to provide data on intra- and inter-
observer repeatability.  The summed rest, summed stress, and summed difference 
scores will be recorded for a 17-segment heart model, along with a final clinical 
evaluation and a subjective assessment of image quality (on a scale of 1-5).  All 
evaluations will be done by the core lab to ensure consistency in processing and 
evaluation. 
Subjective image quality scale will be: 
 
1 – non-diagnostic: noise or poor contrast in the myocardium prevent clinical 
interpretation, or artifact or extra-cardiac uptake prevent interpretation of the 
myocardium.  
 
 
2 – poor quality: poor contrast and noise in myocardium make interpretation 
difficult, artifacts and extra-cardiac interference are moderate and reduce confidence in 
image interpretation 
 
3 -  adequate quality: adequate myocardial contrast, artifacts and extra-cardiac 
interference are mild and may reduce confidence in image interpretation 
 
4 – good quality: good myocardial contrast, artifact and extra-cardiac activity may 
be present but do not interfere with interpretation 
 
5 – excellent quality:  good myocardial contrast, no artifacts, no interference from 
extra-cardiac activity 
6. Study Population 
 
6.1 Source of Participants 

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
The 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 local site and have known or suspected CAD.   
 
6.2 Inclusion Criteria 
• Age ≥ 18 years old 
• BMI ≤ 40 kg/m2 
• Able and willing to comply with the study procedures 
• Written informed consent 
• Intermediate to high probability of CAD 
• Suspected or known CAD on a stable medication regime. 
 
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 COPD 
• Coronary artery bypass graft (CABG) surgery within 60 days prior to 
screening or within 45 days after consent (early revascularization) 
• Percutaneous coronary intervention (PCI) within 30 days prior to screening or 
within 45 days following consent (early revascularization) 
• Recent use of dipyridamole, dipyridamole-containing medications (e.g. 
Aggrenox) 
• Known hypersensitivity to dipyridamole or adenosine 
• 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 within 45 days following consent. 
• 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 
 
 
 
 

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
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 
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. For elderly female patients, verbal confirmation is sufficient. 
 
 
 
8. Risk Benefit Assessment 
 
8.1 SPECT Imaging 
 
Patients will not receive any radiation exposure beyond that clinically indicated for their 
SPECT or SPECT/CT MPI study. 
 
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. As this does not deviate from the standard practice used in the clinical test, there 
is no increase in the risk associated with the clinical test. 
 

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
9. Safety and Tolerability 
 
9.1 Safety Variables 
Safety variables will include the occurrence of procedure-related adverse events and 
changes in clinical status. 
 
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 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 communications with Ottawa Health Science Network Research 
Ethics Board (OHSN-REB), the ethics boards of participating local sites, and all regulatory 
agencies.  
 
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 local ethics board requirements. No formal Data Safety 
Monitoring Board will be specified due to the low level of risk associated with this trial.  

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
 
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 
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 
 
 
 
13.1 Budget Details (TBD) 
  
 
 

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
14. References 
 
1.  
Herzog BA, Husmann L, Valenta I, et al. Long-term prognostic value of 13N-ammonia myocardial 
perfusion positron emission tomography added value of coronary flow reserve. J Am Coll Cardiol. 
2009;54(2):150-156. doi:10.1016/j.jacc.2009.02.069. 
2.  
Ziadi MC, Dekemp RA, Williams K, et al. Does quantification of myocardial flow reserve using 
rubidium-82 positron emission tomography facilitate detection of multivessel coronary artery 
disease? J Nucl Cardiol. 2012;19(4):670-680. doi:10.1007/s12350-011-9506-5. 
3.  
Ziadi MC, Dekemp R a., Williams K a., et al. Impaired myocardial flow reserve on rubidium-82 
positron emission tomography imaging predicts adverse outcomes in patients assessed for 
myocardial ischemia. J Am Coll Cardiol. 2011;58(7):740-748. doi:10.1016/j.jacc.2011.01.065. 
4.  
deKemp R a., Yoshinaga K, Beanlands RSB. Will 3-dimensional PET-CT enable the routine 
quantification of myocardial blood flow? J Nucl Cardiol. 2007;14:380-397. 
doi:10.1016/j.nuclcard.2007.04.006. 
5.  
Saraste A, Kajander S, Han C, Nesterov S V., Knuuti J. PET: Is myocardial flow quantification a 
clinical reality? J Nucl Cardiol. 2012;19:1044-1059. doi:10.1007/s12350-012-9588-8. 
6.  
Camici PG, Rimoldi OE. The clinical value of myocardial blood flow measurement. J Nucl Med. 
2009;50(7):1076-1087. doi:10.2967/jnumed.108.054478. 
7.  
Murthy VL, Naya M, Foster CR, et al. Improved cardiac risk assessment with noninvasive 
measures of coronary flow reserve. Circulation. 2011;124(20):2215-2224. 
doi:10.1161/CIRCULATIONAHA.111.050427. 
8.  
Valenta I, Dilsizian V, Quercioli A, Ruddy TD, 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(3):344. doi:10.1007/s11886-012-0344-0. 
9.  
Storto G, Sorrentino AR, Pellegrino T, Liuzzi R, Petretta M, 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. doi:10.1007/s00259-006-0333-x. 
10.  
Daniele S, Nappi C, Acampa W, et al. Incremental prognostic value of coronary flow reserve 
assessed with single-photon emission computed tomography. J Nucl Cardiol. 2011;18(4):612-619. 
doi:10.1007/s12350-011-9345-4. 
11.  
Gullberg GT, Reutter BW, Sitek A, Maltz JS, Budinger TF. Dynamic single photon emission 
computed tomography--basic principles and cardiac applications. Phys Med Biol. 
2010;55(20):R111-91. doi:10.1088/0031-9155/55/20/R01. 
12.  
Shrestha U, Sciammarella M, Alhassen F. Measurement of absolute myocardial blood flow in 
humans using dynamic cardiac SPECT and 99m Tc-tetrofosmin : Method and validation. J Nucl 
Cardiol. 2017;24(1):268-277. doi:10.1007/s12350-015-0320-3. 
13.  
Hsu B, Hu L, Yang B, Chen L, Chen Y. SPECT myocardial blood flow quantitation toward clinical 
use : a comparative study with 13 N-Ammonia PET myocardial blood flow quantitation. Eur J Nucl 
Med Mol Imaging. 2017:117-128. doi:10.1007/s00259-016-3491-5. 
14.  
Slomka PJ, Patton J a., Berman DS, Germano G. Advances in technical aspects of myocardial 
perfusion SPECT imaging. J Nucl Cardiol. 2009;16:255-276. doi:10.1007/s12350-009-9052-6. 
15.  
Wells RG, Timmins R, Klein R, et al. Dynamic SPECT Measurement of Absolute Myocardial Blood 
Flow in a Porcine Model. J Nucl Med. 2014;55(10):1685–1691. doi:10.2967/jnumed.114.139782. 
16.  
Ben-Haim S, Murthy VL, Breault C, et al. Quantification of Myocardial Perfusion Reserve Using 
Dynamic SPECT Imaging in Humans: A Feasibility Study. J Nucl Med. 2013;54:873-879. 
doi:10.2967/jnumed.112.109652. 
17.  
Ben Bouallègue F, Roubille F, Lattuca B, et al. SPECT Myocardial Perfusion Reserve in Patients 
with Multivessel Coronary Disease: Correlation with Angiographic Findings and Invasive 

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
Fractional Flow Reserve Measurements. J Nucl Med. 2015;56(11):1712-1717. 
doi:10.2967/jnumed.114.143164. 
18.  
Shiraishi S, Sakamoto F, Tsuda N, et al. Prediction of left main or 3-vessel disease using 
myocardial perfusion reserve on dynamic thallium-201 single-photon emission computed 
tomography with a semiconductor gamma camera. Circ J. 2015;79(3):623-631. 
doi:10.1253/circj.CJ-14-0932. 
19.  
Nkoulou R, Fuchs TA, Pazhenkottil AP, et al. Absolute Myocardial Blood Flow and Flow Reserve 
Assessed by Gated SPECT with Cadmium-Zinc-Telluride Detectors Using 99mTc-Tetrofosmin: 
Head to Head Comparison with 13N-Ammonia PET. J Nucl Med . 2016. 
doi:10.2967/jnumed.115.165498. 
20.  
Wells RG, Marvin B, Poirier M, Renaud JM, DeKemp RA, Ruddy TD. Optimization of SPECT 
Measurement of Myocardial Blood Flow with Corrections for Attenuation , Motion , and Blood-
Binding Compared to. J Nucl Med. 2017;[in press]. 
21.  
Henzlova MJ, Duvall WL, Einstein AJ, Travin MI, Verberne HJ. ASNC IMAGING GUIDELINES ASNC 
imaging guidelines for SPECT nuclear cardiology procedures : Stress , protocols , and tracers 
Blood pressure. J Nucl Cardiol. 2016;23(3):606-639. doi:10.1007/s12350-015-0387-x. 
22.  
Berman DS, Kang X, Tamarappoo B, et al. Stress Thallium-201/Rest Technetium-99m Sequential 
Dual Isotope High-Speed Myocardial Perfusion Imaging. JACC Cardiovasc Imaging. 2009;2(3):273-
282. doi:10.1016/j.jcmg.2008.12.012. 
23.  
Askew JW, Miller TD, Ruter RL, et al. Early image acquisition using a solid-state cardiac camera for 
fast myocardial perfusion imaging. J Nucl Cardiol. 2011;18:840-846. doi:10.1007/s12350-011-
9423-7. 
24.  
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. doi:10.1007/s00259-010-1488-z. 
 
 
 
 
 

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
Appendix A:  Protocols for SPECT MBF 
Figure 1a:  Rest/Stress protocol (option A).  If a positioning dose is used, then a pre-
scan is required prior to injection of the resting dose. Patient should be positioned on 
the table and not be moved throughout imaging.  Protocol shows a 5 min rest and 3 min 
stress delayed acquisition with a 5-min stress infusion protocol followed by a 3min delay 
before tracer injection.  These times may be adjusted as indicated in the protocol text. 
 
 
 

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
 
Figure 1b:  Rest/Stress protocol (option B).  Optionally, a time delay can be introduced 
between the rest delayed imaging and the stress injection.  If this is done, an additional 
5 min static image should be acquired of the residual activity just prior to beginning the 
dipyridamole infusion as indicated in the figure.  
 
 
 
/

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
Figure 2a: Stress/Rest protocol (option A).  If a positioning dose is used, then a pre-
scan is required prior to starting the dipyridamole infusion. Patient should be positioned 
on the table and not be moved throughout imaging. Protocol shows a 5 min rest and 3 
min stress delayed acquisition with a 5-min stress infusion protocol followed by a 3min 
delay before tracer injection.  These times may be adjusted as indicated in the protocol 
text. 
 
 
Figure 2b: Stress/Rest protocol (option B).  Optionally, a time delay can be introduced 
between the stress delayed imaging and the rest injection.  If this is done, an additional 
5 min static image should be acquired of the residual activity just prior to beginning the 
rest dynamic imaging as indicated in the figure. 
 
 
 

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
Figure 3: 2-day protocol.  If a positioning dose is used, then a pre-scan is required prior 
to starting the dipyridamole infusion at stress and prior to the resting injection of 
radiotracer. Patient should be positioned on the table and not be moved throughout 
imaging. For the 2-day protocol, both stress-first and rest-first can be used. Protocol 
shows a 5 min rest and 3 min stress delayed acquisition with a 5-min stress infusion 
protocol followed by a 3min delay before tracer injection.  These times may be adjusted 
as indicated in the protocol text. 
 
 
 

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
Figure 4: Single-syringe pump configuration. All lines are pre-loaded with saline. Activity 
to be injected (volume = VA) is then loaded onto the patient end of the shielded line 
segment. The pump pushes a minimum volume of VL + VA at a rate of 2VA/min. 
 
 
 

Multi-Centre Evaluation of Feasibility of SPECT Measurement of Myocardial Blood Flow and Reserve , V3 June 4, 2021 
 
 
 
 
Figure 5: Dual-syringe pump configuration. All lines are pre-loaded with saline. Activity 
to be injected (volume = VA) is then loaded onto syringe A.  Syringe B is loaded with 
saline.  The pump pushes a volume of VA at a rate of 2VA/min from syringe A, followed 
immediately by a minimum volume of VL from syringe B.