Conditions: Coronary Artery Disease (CAD)
Keywords: Positron emission tomography myocardial perfusion imaging (PET MPI) Single photon emission computed tomography myocardial perfusion imaging (SPECT MPI) Invasive coronary angiography (ICA) Coronary artery disease (CAD)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 730
Healthy volunteers: no

Brief summary:
This is a Phase 3, prospective, open-label, international, multicentre study of Flurpiridaz (18F) Injection for PET MPI in patients referred for ICA because of suspected CAD.

Detailed description:

Arms:
arm 1: Flurpiridaz PET MPI (following off-study SPECT MPI)

Interventions: intervention 1: PET MPI intervention 2: SPECT MPI intervention 3: Pharmacological stress agents
Intervention descriptions: intervention 1: Flurpiridaz (18F) Injection. All participants received 2 IV boluses of Flurpiridaz (18F) Injection in a large peripheral vein: 1 at rest and 1 during stress. The dosages of Flurpiridaz (18F) Injection administered at rest and during stress conditions did not exceed a total of 14 mCi (520 MBq) for an individual participant. intervention 2: SPECT imaging was used 99mTc-based myocardial tracers. SPECT agents utilised for the purposes of this clinical study was administered as per American Society of Nuclear Cardiology or European Association of Cardiovascular Imaging standards, where applicable. All participants undergone SPECT MPI. intervention 3: Pharmacologic stress agents were restricted to the following 3 agents, as permitted by local marketing authorisations and availability: adenosine, dipyridamole, and regadenoson. Administration was through an IV line.

Protocol document:
Prot_002.pdf: 
GE Confidential 
Page 1 of 142 
Clinical Study Protocol 
GE Healthcare 
GE Healthcare Protocol GE-265-303 
Title: A Phase 3, Open-Label, Multicentre Study of Flurpiridaz (18F) Injection for Positron 
Emission Tomography (PET) Imaging for Assessment of Myocardial Perfusion in Patients 
Referred for Invasive Coronary Angiography Because of Suspected Coronary Artery Disease. 
REVISED TO INCORPORATE AMENDMENT A03 
Sponsor 
GE Healthcare Ltd. and its Affiliates (hereinafter referred to as the “Sponsor”) 
EudraCT Number: 2017-005011-14 
IND Number: 75,307 
ClinicalTrials.gov Identifier: NCT03354273 
Medical Director 
 
 
GE Healthcare 
Pollards Wood, Nightingales Lane 
Chalfont St Giles 
Buckinghamshire HP8 4SP 
United Kingdom 
Phone: 
 
Email: 
 
Confidentiality Statement 
This protocol is provided for conducting a clinical research study.  The information contained 
in this document is confidential and, except to the extent necessary to obtain informed consent 
or IEC/IRB approval, cannot be disclosed unless required by governmental regulation.  Persons 
to whom any portion of the contents of this document is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 
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Investigator’s Signature Page 
I have read this protocol and all associated case report forms and agree to conduct this study in 
full accordance with the stipulations of the protocol described herein. 
 
 
 
Signature 
 
 
 
Date 
Print Name 
 
 
 
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1 
SYNOPSIS 
Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier 
in Which the Individual 
Study or Study Table is 
Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
Flurpiridaz (18F) Injection 
Name of Active Ingredient: 
[18F]Flurpiridaz 
Title of Study: A Phase 3, Open-Label, Multicentre Study of Flurpiridaz (18F) Injection for Positron 
Emission Tomography (PET) Imaging for Assessment of Myocardial Perfusion in Patients Referred for 
Invasive Coronary Angiography Because of Suspected Coronary Artery Disease (CAD) 
Protocol Number:  GE-265-303 
Investigators and Study Centres: Approximately 60 centres in Europe and North America (United 
States and Canada) 
Phase of Development: Phase 3 
Objectives:  
Primary Objective: 
• 
Assess the diagnostic efficacy (sensitivity and specificity) of Flurpiridaz (18F) Injection PET 
myocardial perfusion imaging (MPI) in the detection of significant CAD, as defined by invasive 
coronary angiography (ICA), in patients with suspected CAD. 
Secondary Objectives: 
• 
Evaluate the diagnostic efficacy (sensitivity and specificity) of Flurpiridaz (18F) Injection PET MPI 
compared with that of single photon emission computed tomography (SPECT) MPI in the detection 
of CAD, as defined by ICA, in the following groups of subjects: 
o 
All subjects (key secondary endpoint) 
o 
Female subjects 
o 
Subjects with body mass index (BMI) ≥30 kg/m2 
o 
Diabetic subjects 
• 
Assess the safety of Flurpiridaz (18F) Injection PET MPI. 
Exploratory Objectives: 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier 
in Which the Individual 
Study or Study Table is 
Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
Flurpiridaz (18F) Injection 
Name of Active Ingredient: 
[18F]Flurpiridaz 
 
 
 
 
 
 
 
 
 
 
 
Study Design:  
This is a Phase 3, prospective, open-label, international, multicentre study of Flurpiridaz (18F) Injection 
for PET MPI in patients referred for ICA because of suspected CAD.  Five hundred and fifty-two (552) 
evaluable subjects will be enrolled in this study, and will undergo SPECT MPI and Flurpiridaz (18F) 
Injection PET MPI, prior to ICA. 
Patients can be considered for enrolment if: 
• 
They are being scheduled via written documentation at the time of enrolment to undergo ICA, and 
• 
They have undergone a clinically indicated SPECT study which meets all study-specified imaging 
and stress testing (Section 9.3) criteria, or are willing to undergo SPECT MPI for the purposes of the 
clinical study.  
Study Population:  
Five hundred and fifty-two (552) evaluable subjects will be enrolled in this study. Assuming a 15% drop-
out rate, 650 subjects will need to be enrolled initially. 
While enrolment will not be formally stratified, enrolment will be monitored and the recruitment plan 
may be adjusted during the course of the study to ensure adequate representation of subjects aged ≥65 
years of age and that at least one third of the enrolled subjects will be diabetic, one third but no more than 
one half will have BMI ≥30 kg/m2, and one-third will be women.  
Inclusion Criteria: 
Subjects may be included in the study if they meet all of the following criteria: 
1) 
The subject is a man or woman 18 years of age. 
2) 
The subject has read, signed, and dated an informed consent form (ICF) prior to any study 
procedures being performed, and is willing to allow the study investigator to make the subject’s 
medical records available to GE Healthcare (including clinically indicated SPECT studies occurring 
prior to the signing of the ICF as stipulated in inclusion criteria #4). 
3) 
At the time of enrolment, the subject has been scheduled via written documentation to undergo an 
ICA for the assessment of CAD. 
4) 
The subject has undergone a clinically indicated SPECT which meets all study-specific imaging and 
stress testing (Section 9.3) criteria and conforms to local guidelines (such as American Society of 
Nuclear Cardiology or European Association of Nuclear Medicine), OR the patient is willing to 
undergo SPECT MPI for the purposes of the clinical study. 
5) 
The subject is male or is a nonpregnant, nonlactating female who is either surgically sterile (has a 
documented bilateral tubal ligation and oophorectomy and/or documented hysterectomy [bilateral 
tubal ligation alone is insufficient]) or is post-menopausal (cessation of menses for more than 1 
year); enrolment in the study without a pregnancy test at Screening is allowed for these categories of 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier 
in Which the Individual 
Study or Study Table is 
Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
Flurpiridaz (18F) Injection 
Name of Active Ingredient: 
[18F]Flurpiridaz 
female patients.  For women of childbearing potential, the results of either a urine or serum human 
chorionic gonadotropin pregnancy test (with the result known on the day of radiopharmaceutical 
administration) must be negative; these subjects must be practicing appropriate birth control from 
the time of the screening to 30 days after the radiopharmaceutical administration. 
6) 
The subject is able and willing to comply with all study procedures as described in the protocol. 
Exclusion Criteria: 
Patients who meet the following criteria will be excluded from the study: 
1) 
Patients who are pregnant, may possibly be pregnant, or wish (including their partners) to become 
pregnant during the study period, or are lactating. 
2) 
Patients who are unable to undergo all of the imaging procedures. 
3) 
Patients who have an established diagnosis of CAD as confirmed by any of the following: 
a. 
Previous myocardial infarction (MI); 
b. 
Previous cardiac catheter angiography showing 50% stenosis; 
c. 
Previous coronary revascularisation, such as percutaneous coronary intervention (PCI), 
thrombolysis or coronary artery bypass graft (CABG) placement. 
4) 
Patients incapable of undergoing either exercise or pharmacological cardiac stress testing  
5) 
Patients who have a current illness or pathology that, in the opinion of the investigator, would pose a 
significant safety risk for the patient during cardiac stress testing. 
6) 
For patients for whom pharmacological stress testing is being considered, the following additional 
exclusion criteria will apply: 
a. 
Known hypersensitivity to adenosine, regadenoson, dipyridamole, or aminophylline; 
b. 
Use of a caffeinated substance, dipyridamole-containing medication, or methylxanthine-
containing medication within 12 hours prior to vasodilator administration; 
c. 
Bronchoconstrictive or bronchospastic disease that in the opinion of the investigator poses a 
significant safety risk for the patient; 
d. 
Second- or third-degree atrioventricular block or sinus node dysfunction without functioning 
artificial pacemaker; 
e. 
Any additional contraindication to the pharmacological stress agent listed in the product’s 
package insert/summary of product characteristics (SmPCs). 
7) 
Patients with unstable cardiovascular condition, including but not limited to: 
a. 
Unstable angina, acute coronary syndrome within 6 months of enrolment; 
b. 
Transient ischaemic attack/stroke within 3 months of enrolment; 
c. 
Significant congenital heart disease; 
d. 
Uncontrolled hypertension; 
e. 
Uncontrolled tachyarrhythmia leading to symptoms or haemodynamic compromise. 
8) 
Documented history of heart failure and/or cardiomyopathy (including nonischaemic 
cardiomyopathy, hypertrophic obstructive cardiomyopathy, or infiltrative cardiomyopathy). 
9) 
Primary haemodynamically significant uncorrected valvular heart disease, obstructive or regurgitant. 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier 
in Which the Individual 
Study or Study Table is 
Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
Flurpiridaz (18F) Injection 
Name of Active Ingredient: 
[18F]Flurpiridaz 
10) Patients scheduled for or planning to undergo any cardiac interventional procedures between 
enrolment and ICA. 
11) Patients with screening laboratory findings as follows: 
a. 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3 times the 
upper limit of normal; 
b. 
Total bilirubin 2.0 mg/dL (34.2 µmol/L); 
c. 
Serum creatinine 3.0 mg/dL (265.2 µmol/L). 
12) Patients who present with any clinically active, serious, life-threatening disease, medical, or 
psychiatric condition, and/or who have a life expectancy of <6 months, or for whom study 
participation may compromise their management; and patients whom the investigator judges to be 
unsuitable for participation in the study for any reason. 
13) Patients undergoing evaluation for heart transplantation or with history of heart transplantation. 
14) Patients enrolled in another clinical study within the 30 days prior to being enrolled in this study or 
scheduled to participate in another clinical study during the 17-day follow-up period of this study. 
15) Patients previously enrolled in this study or any Flurpiridaz (18F) Injection study. 
Test Product, Dose, and Mode of Administration: 
Flurpiridaz (18F) Injection is a novel PET MPI agent labelled with the radioisotope fluorine-18 and 
administered as an intravenous (IV) injection.  All subjects will receive 2 IV boluses of Flurpiridaz (18F) 
Injection in a large peripheral vein: 1 at rest and 1 during stress.  The dosages of Flurpiridaz (18F) 
Injection administered at rest and during stress conditions will not exceed a total of 14 mCi (520 MBq) 
for an individual subject. 
Other Products Administered, Dose, and Mode of Administration: 
SPECT agents utilised for the purposes of this clinical study will be administered as per American Society 
of Nuclear Cardiology or European Association of Cardiovascular Imaging standards corresponding to 
study site location.  For each subject, the same stress type (pharmacologic or exercise) should be used for 
the SPECT and Flurpiridaz (18F) Injection PET MPI.  Also, if pharmacological stress is used, the same 
agent and the same dose of pharmacological stress agent should be used for both types of imaging for the 
same subject. 
Pharmacological stress agents utilised for the purposes of this clinical study will be administered 
according to the respective Package Insert (as applicable) or American Society of Nuclear Cardiology or 
European Association of Cardiovascular Imaging standards corresponding to study site location. During 
pharmacologic stress, radiopharmaceutical injection will be administered during the peak vasodilatory 
effect according to the respective Package Insert (as applicable) of each stressor. 
Duration of Study 
All screening assessments will occur within 60 days prior to ICA. Flurpiridaz (18F) Injection PET MPI 
test and SPECT MPI (including SPECT exams preceding informed consent) must precede the ICA and 
occur within 60 days prior to the ICA. Subjects will have Flurpiridaz (18F) Injection rest and stress PET 
MPI performed on the same day.  Subjects will have their last follow-up safety contact at approximately 2 
weeks (14 to 17 days) following Flurpiridaz (18F) Injection or at the time of their ICA, whichever occurs 
later. 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier 
in Which the Individual 
Study or Study Table is 
Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
Flurpiridaz (18F) Injection 
Name of Active Ingredient: 
[18F]Flurpiridaz 
Efficacy Assessments: 
Primary Efficacy Endpoints: 
• 
The sensitivity and specificity of Flurpiridaz (18F) Injection PET MPI in the detection of significant 
CAD as defined by cardiac catheterisation (ICA). 
Secondary Efficacy Endpoints: 
The diagnostic efficacy (sensitivity and specificity) of Flurpiridaz (18F) Injection PET MPI compared to 
that of SPECT MPI, when the diagnosis of CAD by ICA is the standard of truth, in the following: 
• 
All subjects (key secondary endpoint) 
• 
Female subjects 
• 
Subjects with BMI ≥30 kg/m2 
• 
Diabetic subjects  
Exploratory Efficacy Endpoints: 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
Standard of Truth: Subjects will be considered to have CAD if quantitative coronary angiography 
(QCA) reveals ≥50% stenosis of ≥1 major coronary artery or major branch. Three qualified independent 
readers will perform a blinded assessment of each subject’s PET image pair (rest and stress images) and 
each subject’s SPECT image pair.   
One blinded reviewer will perform QCA for all ICA images. 
Safety Assessments: 
Subjects will be closely monitored for safety until completion of all study procedures.  Safety monitoring 
will include adverse events (AEs), medication errors, treatment-emergent adverse events (TEAEs), and 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier 
in Which the Individual 
Study or Study Table is 
Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
Flurpiridaz (18F) Injection 
Name of Active Ingredient: 
[18F]Flurpiridaz 
serious adverse events (SAE) assessments, vital signs, electrocardiograms (ECGs), haematology, clinical 
chemistry laboratory tests, and urinalysis.  All subjects will be followed up by telephone assessments for 
AEs within 2 days (+24 hours) following Flurpiridaz (18F) Injection administration, and for AEs and 
SAEs at approximately 2 weeks (14 to 17 days) following the last Flurpiridaz (18F) Injection dose 
administration and at the time of their ICA.  For subjects undergoing SPECT for the purposes of this 
clinical study, their safety will be monitored as per institutional standards. 
Statistical Methods: 
General Considerations 
All statistical analyses will be performed with SAS software (version 9.3 or higher).  Subject data 
listings and tabular presentations of results will be provided.  Presentation of summary statistics for 
continuous variables will include n, mean, median, and standard deviation (SD), as well as the minimum 
and maximum values.  For categorical variables, the number and percent of each category within a 
parameter for nonmissing data will be calculated.  Further details of the criteria and conduct of the 
statistical analyses will be included in the Statistical Analysis Plan (SAP) for this study. 
Analysis Populations 
Intent-to-Treat (ITT) Population: The ITT population will consist of all enrolled subjects who received 
≥1 dose of Flurpiridaz (18F) Injection in the study. 
Modified Intent-to-Treat (MITT) Population: The MITT population will include all ITT subjects who 
completed the rest and stress Flurpiridaz (18F) Injection PET MPI procedures and who have evaluable 
truth standard data.  The MITT population will be the primary analysis set for the primary efficacy 
endpoints.   
Secondary MITT Population (SMITT): The SMITT population will include the subjects in the MITT 
population who completed the rest and stress SPECT MPI (if the subject’s SPECT MPI is “off-study,” 
that SPECT MPI must meet minimal quality standards, as specified by the imaging core lab). The SMITT 
population will be the primary analysis set for the secondary and exploratory efficacy endpoints.   
A summary of subject disposition, including the number and percent of ITT subjects who do not have 
evaluable PET or truth standard or who are not in the MITT analysis set, will be provided, with the 
reasons for nonevaluability.   
Safety Population: The Safety Population will include all subjects who have received ≥1 dose of 
Flurpiridaz (18F) Injection in the study.  All safety data will be summarised for the Safety Population. 
Efficacy Endpoints:  
Coronary Angiography Evaluations: All coronary angiograms will be performed within 60 days of 
screening or SPECT if SPECT occurs prior to informed consent.  ICA data for the diagnosis of CAD will 
be generated by QCA. 
Myocardial Perfusion Imaging Evaluations: Three qualified readers (independent from the study) will 
perform independent reads of all MPI images.  The PET MPI and SPECT MPI reads will be performed by 
the same set of readers in cross-over sessions independent of one another. In each session, PET and 
SPECT images will be displayed in a randomised order, nonsequentially, with PET and SPECT MPI 
exams corresponding to individual subjects randomly allotted into reading session batches. For each 
modality, perfusion and gated acquisitions of rest and stress images will be rated for image quality and 
reviewed.  After the results of each individual MPI (PET or SPECT) are locked as the “blinded” read, 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier 
in Which the Individual 
Study or Study Table is 
Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
Flurpiridaz (18F) Injection 
Name of Active Ingredient: 
[18F]Flurpiridaz 
then clinical information will be provided.  The reader will then be given the opportunity to submit a 
revised assessment of the existence of any perfusion defects as an “unblinded” read. 
The primary efficacy read for MPI status will be the overall qualitative diagnosis of the paired Flurpiridaz 
(18F) PET MPI (rest/stress) using perfusion and gated assessments from independent blinded reads. The 
overall qualitative diagnosis will be scored by each reader for each subject as normal, ischaemic, 
ischaemic + scar, or scar on the basis of the perfusion + gated images.  These scores will be dichotomised 
into MPI negative (normal) and MPI positive (ischaemic, ischaemic +scar, or scar) for each subject and 
reader.   
Primary Efficacy Endpoint(s): The primary endpoints of the study are the sensitivity and specificity of 
Flurpiridaz (18F) Injection PET MPI in the detection of significant CAD as defined by ICA.  The truth 
standard used in this study is the presence of CAD as evidenced by the presence of stenosis of ≥50% in 
≥1 coronary artery or major branch of a coronary artery as determined by QCA analysis. 
For each of the 3 readers, a binary decision for each subject will be derived by using the overall 
qualitative diagnosis criteria as MPI-negative or MPI-positive; sensitivity and specificity will then be 
calculated for each of the 3 readers. 
Sensitivity and specificity are defined as follows: 
• 
True Positives (TP): Subjects with abnormal PET MPI and disease positive by the truth standard 
• 
True Negatives (TN): Subjects with normal PET MPI and disease negative by the truth standard 
• 
False Positives (FP): Subjects with abnormal PET MPI and disease negative by the truth standard 
• 
False Negatives (FN): Subjects with normal PET MPI and disease positive by the truth standard 
• 
Sensitivity: TP/(TP+ FN)  
• 
Specificity: TN/(TN + FP) 
• 
Accuracy: (TN + TP)/(TN + TP + FN + FP) 
A dosed subject whose PET MPI images are incomplete (i.e., a missing rest and/or stress image) will be 
excluded from the MITT analysis population.  Also, a subject with a missing truth standard will be 
excluded from the MITT analysis population.  A summary of reasons for all missing data will be 
provided, with number and percent in each category.  To eliminate bias between modalities, once a 
subject is included in the MITT population, the readers will be asked to read SPECT MPI and PET MPI 
images and to classify the images as normal or abnormal, regardless of image quality and interpretability.  
To indicate when a diagnosis is forced, the reader will record in the blinded-read case report form (CRF) 
which images are considered uninterpretable.  The data on image quality and interpretability will be 
collected separately during the blinded read and will be analysed separately by modality.   
The 2 primary efficacy endpoints are calculated as follows from different subsets of the population:  
• 
The calculation of sensitivity of Flurpiridaz (18F) Injection PET MPI includes data only from subjects 
with CAD, per the standard of truth.   
• 
The calculation of specificity of Flurpiridaz (18F) Injection PET MPI includes data only from subjects 
without CAD, per the standard of truth. 
Let s1 = true sensitivity of Flurpiridaz (18F) Injection PET MPI: 
Let p1 = true specificity of Flurpiridaz (18F) Injection PET MPI: 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier 
in Which the Individual 
Study or Study Table is 
Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
Flurpiridaz (18F) Injection 
Name of Active Ingredient: 
[18F]Flurpiridaz 
The criteria for primary efficacy will be proving the statistical superiority of both the true specificity and 
sensitivity to a threshold of 60% in Flurpiridaz (18F) Injection PET MPI.  To meet the criteria for success 
in this study, both the sensitivity and the specificity of Flurpiridaz (18F) Injection PET MPI must exceed 
60%.  Thus, the lower bound of the 2-sided 95% confidence interval for both sensitivity and specificity 
must exceed 60%. 
Therefore, the test of hypotheses will be as follows: 
H01 : s1 ≤ 0.60; H02: p1 ≤ 0.60, where s1 is sensitivity in Flurpiridaz (18F) Injection PET MPI and p1 is 
specificity in Flurpiridaz (18F) Injection PET MPI. 
Ha1: s1 > 0.60; Ha2: p1 > 0.60 
Since sensitivity and specificity are calculated for separate subsets of the MITT analysis population, and 
since both null hypotheses need to be rejected for the study to be considered a success, each of the above 
endpoint comparisons will be performed by using a 1-sided 1-sample test with type 1 error (α)= 0.025.  
The test will be based on the 1-sample z-test for proportions, using the normal approximation to the 
binomial distribution. The analysis will be done for each reader and for all readers.  If each null 
hypothesis is rejected in the analysis of all readers or by the same 2 out of 3 readers, the study will be 
considered a statistical success. 
There will be no formal interim efficacy analysis for this study. 
A summary of diagnostic efficacy, including sensitivity, specificity, accuracy, positive predictive value, 
and negative predictive value, will be provided along with 2-sided 95% confidence intervals (CIs) based 
on the normal approximation to the binomial distribution (for each of sensitivity and specificity; if the 
null hypothesis above is rejected by the z-test, then the lower bound of the 2-sided 95% CI will 
mathematically be above the threshold of 60%). 
The above summary will be provided for each modality separately and for the following subgroups: 
• 
Age groups (<65 years and ≥65 years) 
• 
BMI <30 kg/m2 and BMI ≥30 kg/m2 
• 
Diabetic and nondiabetic 
• 
Sex (male and female) 
• 
Race (White, Black or African-American, other) 
• 
Presence or absence of multivessel CAD (per the standard of truth) 
• 
Presence or absence of renal impairment (i.e., serum creatinine level at predose evaluation is above 
normal range)  
• 
Presence or absence of hepatic impairment (i.e., either ALT or AST value at predose evaluation is 
above normal range) 
• 
Type of stress test (pharmacological, exercise) 
Secondary Efficacy Endpoints: 
• 
The diagnostic efficacy (sensitivity and specificity) of Flurpiridaz (18F) Injection PET MPI compared 
to SPECT MPI in the detection of CAD, as defined by ICA, in the following sets of subjects: 
o 
All subjects (key secondary endpoint) 
o 
Female subjects 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier 
in Which the Individual 
Study or Study Table is 
Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
Flurpiridaz (18F) Injection 
Name of Active Ingredient: 
[18F]Flurpiridaz 
o 
Subjects with BMI ≥30 kg/m2 
o 
Diabetic subjects 
To control the false-positive rate at a 1-sided 0.025 level across the testing of the secondary endpoints, the 
above endpoints will be tested hierarchically in the order given above.  Each endpoint will be tested at a 
1-sided 0.025 level of significance; when a statistical test for a given endpoint fails to reach statistical 
significance in the appropriate direction, testing on all remaining secondary endpoints in the hierarchy 
will cease and the study will be considered successful on all secondary endpoints up to that point.   
In the secondary efficacy analysis, the criteria for success will be the statistical superiority of sensitivity in 
Flurpiridaz (18F) Injection PET MPI over that of SPECT MPI, and the noninferiority of specificity in 
Flurpiridaz (18F) Injection PET MPI over that of SPECT MPI, when the detection of CAD by ICA is the 
standard of truth.  Since the sensitivity calculation includes only the subjects with CAD and the 
specificity analysis includes only the subjects without CAD, the analysis of sensitivity and specificity will 
be separate, as follows:   
Let s1 = sensitivity in Flurpiridaz (18F) Injection PET MPI, and s2 = sensitivity in SPECT MPI; 
Let p1 =specificity in Flurpiridaz (18F) Injection PET MPI, and p2 = specificity in SPECT MPI. 
Therefore, the test of hypotheses will be as follows: 
H01: s1 – s2 ≤ 0, 
H02: p1 – p2 ≤ –0.1 
Ha1: s1 – s2 > 0, 
Ha2: p1 –p2 > –0.1 
Each of the above endpoint comparisons will be performed with a 1-sided paired test with type l error (α) 
= 0.025. 
The tests of comparisons are based on paired responses, as the Flurpiridaz (18F) Injection PET MPI and 
SPECT MPI will be performed on a within-subject basis, and the images will be read by the same readers 
in a cross-over design.  The test of sensitivity comparison between Flurpiridaz (18F) Injection PET MPI 
and SPECT MPI will be performed with a 1-sided McNemar's test at α = 0.025.  Similarly, the test of 
specificity noninferiority between Flurpiridaz (18F) Injection PET MPI and SPECT MPI will be 
performed with a paired test for noninferiority [Liu et al 2002] at a 1-sided α = 0.025.  The criterion for 
the demonstration of diagnostic efficacy for the secondary endpoints will be meeting the tests of 
hypotheses for both sensitivity and specificity for the same 2 of the 3 readers for whom the null 
hypotheses was rejected in the analysis of the primary endpoint.   
A minimal performance for SPECT in the targeted population for comparison to Flurpiridaz PET will be 
specified in the SAP.  
Exploratory Endpoints: 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier 
in Which the Individual 
Study or Study Table is 
Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
Flurpiridaz (18F) Injection 
Name of Active Ingredient: 
[18F]Flurpiridaz 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
   
 
 
 
 
   
 
 
 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier 
in Which the Individual 
Study or Study Table is 
Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
Flurpiridaz (18F) Injection 
Name of Active Ingredient: 
[18F]Flurpiridaz 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
   
 
 
 
 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier 
in Which the Individual 
Study or Study Table is 
Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
Flurpiridaz (18F) Injection 
Name of Active Ingredient: 
[18F]Flurpiridaz 
 
   
Safety Endpoint(s): For safety, descriptive summary statistics will be reported for AEs, TEAEs, and 
SAEs, changes from baseline for clinical laboratory tests, ECGs, physical examination, and vital signs for 
all treated subjects.   
Sample Size Estimates 
The sample size was calculated to ensure that a sufficient number of evaluable negative and positive 
patients (by ICA) are enrolled to achieve 90% power at a 1-sided significance level of 0.025 for both 
sensitivity and specificity in the primary analysis. Assuming the true sensitivity and true specificity are 
both 70%, and testing the hypothesis that they are both >60%, 237 negative and 237 positive patients in 
the MITT population are required.  Assuming a prevalence of 43%, approximately 552 total patients will 
be enrolled to ensure there are ≥237 positive patients.  Enrolment will be monitored and the recruitment 
plan may be adjusted during the course of the study to ensure an adequate number of diseased patients. 
Assuming a dropout rate of 15%, up to 650 total patients will be enrolled to ensure that there are at least 
552 evaluable MITT patients.  
 
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2 
TABLE OF CONTENTS 
2.1 
Overall Table of Contents 
Page Number 
1 
SYNOPSIS ..................................................................................................................... 3 
2 
TABLE OF CONTENTS ............................................................................................. 15 
2.1 
Overall Table of Contents ................................................................................ 15 
2.2 
List of Tables .................................................................................................... 18 
2.3 
List of Figures ................................................................................................... 18 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................. 19 
4 
BACKGROUND INFORMATION ............................................................................. 21 
5 
STUDY OBJECTIVES AND PURPOSE .................................................................... 27 
6 
STUDY DESIGN ......................................................................................................... 29 
6.1 
Overall Study Design and Plan ......................................................................... 29 
6.2 
Study Rationale ................................................................................................ 31 
6.3 
Study Timeframe .............................................................................................. 32 
6.4 
Risks and Benefits to Subjects.......................................................................... 32 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS................................................ 34 
7.1 
Procedures for Enrolment ................................................................................. 34 
7.2 
Inclusion Criteria .............................................................................................. 34 
7.3 
Exclusion Criteria ............................................................................................. 35 
7.3.1 
Subject Withdrawal ........................................................................ 36 
7.3.2 
Study or Site Termination .............................................................. 37 
8 
TREATMENT OF SUBJECTS .................................................................................... 38 
8.1 
Description of Medicinal Products ................................................................... 38 
8.1.1 
Investigational Medicinal Product: Flurpiridaz (18F) Injection ...... 38 
8.1.2 
Other Medicinal Products (Non-IMP) ............................................ 38 
8.1.3 
Medicinal Product Accountability .................................................. 39 
8.1.4 
Registration of Investigational Medicinal Product(s) Complaints . 39 
8.2 
Method of Numbering Subjects and Assigning Subjects to Treatment Groups39 
8.3 
Selection of Doses and Timing ......................................................................... 40 
8.4 
Blinding ............................................................................................................ 40 
8.5 
Prior and Concurrent Medications .................................................................... 40 
8.6 
Contraception and Pregnancy Avoidance Procedure ....................................... 41 
8.7 
Treatment Compliance ..................................................................................... 42 
9 
STUDY PROCEDURES .............................................................................................. 43 
9.1 
Screening Visit ................................................................................................. 46 
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9.2 
Baseline Visit (≤30 Days After Screening) ...................................................... 47 
9.3 
Rest and Stress SPECT MPI Visit .................................................................... 47 
9.4 
Rest and Stress Flurpiridaz (18F) PET-MPI Visit ............................................. 50 
9.5 
Safety Follow-up 2 Days (+24 hours) After Flurpiridaz (18F) PET MPI ......... 53 
9.6 
Safety Follow-up 14 to 17 Days After Flurpiridaz (18F) PET MPI .................. 53 
9.7 
ICA Visit (≤60 Days of Screening) .................................................................. 54 
9.8 
Clinical Pharmacology ..................................................................................... 54 
10 
EFFICACY AND SAFETY ......................................................................................... 55 
10.1 
Efficacy Assessments ....................................................................................... 55 
10.1.1 
Primary Efficacy Endpoints ........................................................... 55 
10.1.2 
Secondary Efficacy Endpoints........................................................ 55 
10.1.3 
Exploratory Efficacy Endpoints ..................................................... 55 
10.1.4 
Image Acquisition .......................................................................... 56 
10.1.5 
Image Interpretation and Correlation with Standard of Truth ........ 56 
10.2 
Safety Assessments .......................................................................................... 57 
10.2.1 
Clinical Laboratory Evaluation ...................................................... 57 
10.2.2 
Vital Signs ...................................................................................... 58 
10.2.3 
Electrocardiograms ......................................................................... 59 
10.2.4 
Physical Examination ..................................................................... 60 
10.2.5 
Injection Site Monitoring ............................................................... 60 
10.2.6 
Adverse Events ............................................................................... 61 
10.2.7 
Serious Adverse Events .................................................................. 62 
10.2.8 
Other Significant Adverse Events .................................................. 62 
10.2.9 
Adverse Event and Serious Adverse Event Reporting ................... 63 
10.2.10 
Urgent Safety Measures.................................................................. 64 
10.2.11 
Pregnancy Reporting ...................................................................... 64 
10.3 
Other Variables ................................................................................................. 65 
10.3.1 
Demographic Data .......................................................................... 65 
10.3.2 
Medical and Surgical History ......................................................... 65 
10.3.3 
Prior and Concurrent Medication ................................................... 65 
10.4 
Appropriateness of Measurements ................................................................... 66 
11 
DATA HANDLING AND QUALITY ASSURANCE ................................................ 67 
11.1 
Completing and Signing Case Report Forms ................................................... 67 
11.2 
Clinical Data Management ............................................................................... 67 
11.3 
Archiving .......................................................................................................... 67 
12 
STATISTICAL METHODS AND PLANNED ANALYSIS ...................................... 68 
12.1 
General Statistical Considerations .................................................................... 68 
12.2 
Populations for Analysis ................................................................................... 68 
12.2.1 
Intent-to-Treat Population .............................................................. 68 
12.2.2 
Modified Intent-to-Treat (MITT) Population ................................. 68 
12.2.3 
Secondary Modified Intent-to-Treat (SMITT) Population ............. 68 
12.2.4 
Determination of Safety Population ............................................... 69 
12.3 
Subject Demographics/Other Baseline Characteristics .................................... 69 
12.4 
Study Treatments .............................................................................................. 69 
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12.5 
Primary Efficacy Analysis ................................................................................ 69 
12.5.1 
Efficacy Variables .......................................................................... 69 
12.5.2 
Primary Efficacy Endpoints ........................................................... 70 
12.5.3 
Statistical Hypothesis, Model, and Method of Analysis ................ 71 
12.5.4 
Handling of Missing Values/Censoring/Discontinuations ............. 72 
12.5.5 
Supportive Analyses ....................................................................... 72 
12.5.6 
Handling of Uninterpretable Images .............................................. 73 
12.5.7 
Reader Difference ........................................................................... 73 
12.6 
Secondary Analyses .......................................................................................... 73 
12.6.1 
Secondary Efficacy Variables and Analyses .................................. 73 
12.7 
Exploratory Analyses ....................................................................................... 75 
12.7.1 
Exploratory Endpoints: ................................................................... 75 
12.8 
Safety Variables and Analyses ......................................................................... 78 
12.8.1 
Clinical Laboratory Evaluation ...................................................... 78 
12.8.2 
Vital Signs ...................................................................................... 78 
12.8.3 
Electrocardiograms ......................................................................... 79 
12.8.4 
Physical Examination ..................................................................... 79 
12.8.5 
Adverse Events ............................................................................... 80 
12.9 
Interim Analysis ............................................................................................... 80 
12.10 Sample Size Calculation ................................................................................... 80 
12.11 Procedures for Missing, Unused, and Spurious Data ....................................... 80 
12.12 Rules for Excluding Subjects from Analysis .................................................... 80 
12.13 Procedures for Reporting Deviations from Original Statistical Plan ............... 81 
13 
SPECIAL REQUIREMENTS AND PROCEDURES ................................................. 82 
13.1 
Regulatory, Institutional and Ethical Review ................................................... 82 
13.2 
Ethical Considerations ...................................................................................... 82 
13.3 
Investigator’s Responsibilities .......................................................................... 82 
13.3.1 
Overall Responsibilities .................................................................. 82 
13.3.2 
Subject Informed Consent .............................................................. 82 
13.3.3 
Direct Access to Source Data/Documents ...................................... 83 
13.3.4 
Confidentiality Regarding Study Subjects ..................................... 83 
13.4 
Protocol Deviations .......................................................................................... 83 
13.5 
Study Monitoring .............................................................................................. 83 
13.6 
Audit and Inspection ......................................................................................... 84 
13.7 
Financial Disclosure ......................................................................................... 84 
13.8 
Insurance ........................................................................................................... 84 
13.9 
Publication Policy ............................................................................................. 84 
14 
REFERENCES ............................................................................................................. 85 
15 
APPENDICES .............................................................................................................. 88 
15.1 
Information on Investigational and Registered Products ................................. 88 
15.2 
Equipment Parameters ...................................................................................... 88 
15.3 
Normal Limits for Vital Signs and ECG Intervals ........................................... 88 
15.4 
Pre-test Probability of Obstructive Coronary Artery Disease in Patients with 
Stable Chest Pain Symptoms ............................................................................ 89 
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15.5 
Seattle Angina Questionnaire ........................................................................... 90 
16 
CLINICAL PROTOCOL AMENDMENT SUMMARIES .......................................... 93 
16.1 
Amendment A01 .............................................................................................. 93 
16.1.1 
Reasons for Amendment ................................................................ 93 
16.1.2 
Description of Changes .................................................................. 95 
16.2 
Amendment A02 ............................................................................................ 133 
16.2.1 
Reasons for Amendment .............................................................. 133 
16.2.2 
Description of Changes ................................................................ 133 
16.3 
Amendment A03 ............................................................................................ 140 
16.3.1 
Reasons for Amendment .............................................................. 140 
16.3.2 
Description of Changes ................................................................ 141 
2.2 
List of Tables 
Table 1 
Study Schedule of Events ......................................................................................... 44 
Table 2 
GE-265-303: Flurpiridaz (18F) Injection Doses for Exercise and Pharmacologic 
Stress ......................................................................................................................... 53 
Table 3 
Clinical Laboratory Parameters ................................................................................ 58 
Table 4 
Criteria for Normal Limits for Vital Signs ............................................................... 88 
Table 5 
Criteria for Normal Limits for ECGs ....................................................................... 89 
Table 6 
Clinical Pre-test Probabilities in Patients with Stable Chest Pain Symptoms 
[Montalescot et al 2013] ........................................................................................... 89 
 
2.3 
List of Figures 
Figure 1 
Study Diagram .......................................................................................................... 30 
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3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACLS 
Advanced cardiac life support 
AE 
Adverse event 
AHA 
American Heart Association 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
APMHR 
Age-predicted maximum heart rate 
BMI 
Body mass index  
CABG 
Coronary artery bypass graft surgery 
CAD 
Coronary artery disease 
CHD 
Coronary heart disease 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence Interval 
CRF 
Case report form 
CRO 
Contract research organisation 
CT 
Computed tomography 
CTFG 
Clinical Trial Facilitation Group 
CTECS 
Clinical Trial Emergency Contact Service 
DSMB 
Data and safety monitoring board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ED 
Effective dose 
EEG 
Electroencephalogram 
FDA 
Food and Drug Administration 
FFR 
Fractional flow reserve 
FN 
False negative(s) 
FP 
False positive(s) 
GCP 
Good Clinical Practice 
IB 
Investigator’s brochure 
ICA 
Invasive coronary angiography 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
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IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IRB 
Institutional/Independent Review Board 
ICL 
Imaging core laboratory 
IV 
Intravenous 
IVUS 
Intravascular Ultrasound 
LV 
Left ventricle 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
MITT 
Modified intent-to-treat  
MPI 
Myocardial perfusion imaging 
NHANES 
National Health and Nutrition Examination Survey 
NPV 
Negative predictive value 
PCI 
Percutaneous Coronary Intervention 
PET 
Positron emission tomography 
PPV 
Positive predictive value 
QCA 
Quantitative coronary angiography 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDS 
Summed difference score 
SMITT 
Secondary modified intent-to-treat 
SmPC 
Summary of product characteristics 
SOPs 
Standard operating procedures 
SPECT 
Single photon emission computed tomography 
SRS 
Summed rest score 
SSS 
Summed stress score 
TEAE 
Treatment-emergent adverse event 
TN 
True negative(s) 
TP 
True positive(s) 
US 
United States 
 
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4 
BACKGROUND INFORMATION 
Coronary artery disease (CAD) is a major cause of death in modern industrialised countries.  
CAD is the single largest cause of death in the United States (US) [Roger et al 2012].  
According to data from the US National Health and Nutrition Examination Survey (NHANES) 
from 2011 to 2014, the prevalence of CAD in all adults >20 years of age was 6.3% (16.5 
million Americans); and in 2014, mortality from CAD accounted for 1 in every 7 deaths 
(364,593 directly related to coronary heart disease [CHD], and there were 530,989 deaths 
where CHD was mentioned).  In 2017, an estimated 695,000 Americans will have a new CHD 
event (defined as hospitalisation for myocardial infarction [MI] or CHD death) and 325,000 
will have a recurrent event.  Not only is CHD morbid, it strains healthcare resources.  In 2011, 
hospital care associated with MI cost the US healthcare system $11.5 billion and CHD cost 
$10.4 billion, representing 2 of the 10 most expensive hospital principal discharge diagnoses. 
These costs are projected to double between 2013 and 2030.  Therefore, prevention, early 
diagnosis, and treatment of CAD are essential to reduce mortality [Benjamin et al 2017]. 
Invasive coronary angiography (ICA) is the definitive procedure for diagnosis of obstructive 
CAD.  It is an invasive examination that involves catheterisation of the heart, allowing an 
anatomical evaluation that defines the presence, location, and severity of stenoses in the 
coronary arteries.  However, limitations exist to the sensitivity and specificity of ICA for 
defining myocardial perfusion.  ICA does not determine whether a stenosis causes ischemia. 
ICA is restricted to the assessment of large vessels, providing no visualisation of arterioles and 
capillaries.  Fractional flow reserve (FFR) assessment, a measure of the decrease in perfusion 
pressure across a stenotic vessel under hyperaemic conditions, better defines the 
haemodynamic consequence of a stenosis.  However, FFR analysis does not account for the 
presence of scar, collateral flow, or microvascular dysfunction of the area subtended by the 
vessel; these limitations may affect clinical interpretation of FFR analysis [Hussain et al 
2016].  Despite guideline recommendations for its use to define the haemodynamic 
significance of intermediate stenoses, FFR is performed in only 27% of the cases where it is 
indicated [Toth et al 2014].  Cardiac catheterisation, including FFR analysis, is not without 
risk.  Estimates of the incidence of periprocedural stroke range from 0.18% to 0.44%, while the 
incidence of coronary artery perforation ranges from 0.5% to 3%.  The overall risk of 
periangiographic death in patients undergoing catheterisation without intervention is about 
0.08% [Tavakol et al 2012]. 
Radionuclide myocardial perfusion imaging (MPI) is the most mature cardiovascular imaging 
technique, with advanced quantitative tools and a vast evidence base in over 100,000 patients 
[Shaw and Iskandrian 2004].  Stress MPI with single photon emission computed tomography 
(SPECT MPI) and positron emission tomography (PET MPI) are widely used to identify the 
haemodynamic significance of CAD.  However, the greatest strength of MPI is its established 
value for risk assessment [Shaw et al 2012].  The extent and severity of ischemia and scarring 
on SPECT MPI and PET MPI are powerful predictors of future cardiovascular events [Shaw et 
al 2012].  MPI is cost-effective for the management of CAD.  In patients with stable angina 
pectoris, a noninvasive SPECT-MPI–guided management strategy has been shown to be 
economically superior to an anatomic approach guided by ICA, without significant differences 
in clinical outcomes [Shaw et al 1999].  Radionuclide imaging of myocardial blood flow has 
been shown to be an indispensable tool for the evaluation and management of CAD [Murthy et 
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al 2011] [Naya et al 2014].  With these unique capabilities, the clinical benefits of an 
appropriately performed MPI study are indisputable.   
In nuclear cardiology, assessments of regional myocardial blood flow are performed in patients 
under rest and stress conditions with a radiolabelled MPI agent by using SPECT MPI (using 
tracers labelled with thallium-201 [201Tl] or technetium-99m [99mTc]) or PET MPI (using 
tracers labelled with rubidium-82 [82Rb] or nitrogen-13 [13N] ammonia).  The continued 
success of nuclear cardiology demands ongoing re-evaluation of imaging practices to optimise 
patient care.  An important challenge is choosing the proper imaging procedure for the 
individual patient.  Tailoring imaging to the patient is critical for providing accurate and 
clinically meaningful information to the physician.   
There are several integral components to a successful patient-centred imaging approach.  
Patient safety is of paramount importance when one is contemplating any diagnostic and/or 
therapeutic medical option.  For MPI, this approach includes not only the risk of the stress 
protocol but also the “risk” of performing unnecessary additional procedures or administering 
inappropriate therapy because of a suboptimally performed test.  High-quality imaging limits 
the latter through improved diagnostic sensitivity and specificity, enhanced risk stratification, 
and less intra- and inter-observer variability when interpreting clinically significant changes in 
serial images.   
Another safety consideration is the risk from radiation exposure, which should be weighed in 
each individual case prior to initiating a study.  Consequently, a major factor influencing the 
choice of MPI protocol is the radiopharmaceutical and its dose.  This issue is particularly 
relevant to younger patients and women of childbearing potential.  However, even in older 
individuals and in those in whom the risk/benefit ratio is low, radiation exposure should be 
limited to that dose required to obtain a diagnostic study. 
Like SPECT MPI, PET MPI can provide diagnostic and prognostic information in patients 
with CAD.  PET has several technical advantages over SPECT that account for improved 
image quality and therefore improved efficacy, including: 
• Higher photon penetration combined with routinely measured (depth-dependent) 
attenuation correction because the high energy of the annihilation photons and the 
“coincidence detection” technique of PET imaging systems result in significant advantages 
in image quality. 
• High spatial and contrast resolution that allows for improved detection of small perfusion 
defects. 
• High temporal resolution that allows fast dynamic imaging of tracer kinetics. 
• High efficiency resulting in lower administered radioactivity and therefore lower radiation 
dose to patients.   
A clear advantage of PET imaging is its use of attenuation correction in all PET systems.  
Initial dedicated PET imaging systems used rotating line-sources (caesium-137, germanium-
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68/gallium-68) to generate a transmission attenuation map, whereas currently manufactured 
PET systems use x-ray computed tomography (CT) technology for attenuation correction, 
resulting in an improved image quality and quantification opportunity.  Unlike SPECT, cardiac 
PET allows acquisition of gated “stress” data during peak hyperaemic blood flow, with 
calculation of a peak stress left ventricular ejection fraction (LVEF).  This may improve 
identification of high-risk patients or those with multivessel CAD [Dorbala et al 2009].  
Furthermore, software solutions allow for absolute quantification of regional myocardial blood 
flow from dynamically acquired 82Rb and 13N ammonia cardiac PET studies ([Klein et al 2010] 
[El Fakhri et al 2009]), and this may be particularly important and useful in evaluating 
multivessel and small vessel coronary disease, responses to medical therapy, and transplant 
vasculopathy.  When combined with the low dose from PET tracers, PET MPI offers a 
significantly lower radiation dose than does SPECT MPI. 
Despite the obvious clinical value of current-generation SPECT-MPI and PET-MPI agents in 
patients with known or suspected CAD, there is a well-recognised need for the development of 
a new perfusion imaging agent with more nearly ideal properties.  Both rubidium-82 (82Rb) and 
nitrogen-13 ammonia (13N ammonia) are approved by the US Food and Drug Administration 
(FDA) for use in PET MPI.  82Rb offers the advantage of being generator-produced on site, 
with a strong dependency upon strontium supply, as opposed to 13N ammonia, whose potential 
use is limited by the requirement for an on-site cyclotron.   
The ''ideal'' MPI agent should have a very high first-pass extraction fraction and would track 
regional myocardial blood flow over a wider range, permitting accurate estimation of absolute 
blood flow, particularly under conditions of either physical or pharmacologic stress.  The agent 
should exhibit excellent target-to-nontarget uptake ratios, with high uptake in the myocardium 
and low uptake or rapid clearance from adjacent organs [Glover and Gropler 2007].   
Most PET-MPI studies are performed with pharmacologic stress.  Exercise PET-MPI is 
possible but is challenging because of the short half-lives of the radiotracers.  In addition, a 
PET-MPI agent that could be used with both exercise and pharmacologic stress will find more 
universal application, as compared to agents limited to pharmacologic stress.  Thus, the 
opportunity exists for a new PET imaging agent using Fluorine-18 (18F) that exhibits high 
extraction fraction.  Such an agent would take advantage of the high resolution, quantitative 
power, resistance to attenuation artefacts, and logistical simplicity of unit dosing of 18F PET, 
and would be expected to exhibit improved sensitivity overall and specifically in detecting 
multivessel CAD.  It also has the potential to reduce diagnostic uncertainty and reduce 
radiation dose when compared with studies using SPECT agents.   
The objective of using PET tracers such as Flurpiridaz (18F) is to take advantage of the high 
extraction of this radiotracer, leading to a substantial difference in tracer uptake in normal vs 
underperfused regions.  Therefore, the uptake ratio of this tracer between an underperfused 
region and a normal region is expected to be higher than is observed with other tracers, which 
have either a low extraction rate or a roll-off phenomenon.  This increased ratio could possibly 
lead to an improved diagnostic efficacy.  Whereas the current SPECT guidelines tend to 
propose performing stress MPI first, for identifying patients with very low likelihood of CAD 
presenting with normal stress perfusion images, a rest-stress acquisition sequence is 
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recommended for PET MPI.  Giving the patient the highest PET radiotracer dose at peak stress 
could enhance the induced perfusion defects.   
Clinical studies conducted with Flurpiridaz (18F) Injection include safety, dosimetry, and 
radiokinetics studies in healthy subjects, as well as 1 Phase 2 study and 1 Phase 3 study in 
subjects with known or suspected CAD. Through the course of these studies, a total of 1003 
patients have received Flurpiridaz (18F) Injection.  The results of these studies are detailed in 
the Flurpiridaz (18F) Injection Investigator’s Brochure (IB).  Overall, Flurpiridaz (18F) Injection 
was well-tolerated, and no clinically significant safety concerns were noted. 
Two consecutive Phase 1 studies administering Flurpiridaz (18F) Injection to healthy subjects 
were conducted to assess safety, dosimetry, and radiokinetics.  Safety assessments in both 
studies included adverse events (AEs), serious AEs (SAEs), vital signs, electrocardiograms 
(ECGs), electroencephalograms (EEGs), laboratory values, and physical and neurological 
examinations. 
The primary dosimetry endpoints in single-centre, single-dose Study BMS747158-101 
conducted in 12 healthy subjects were the estimated radiation dose delivered to the standard 
target organs, the salivary glands, and the total body and the effective dose (ED)—all for 
subjects at rest.  This study demonstrated that good cardiac uptake can be achieved in humans.  
The organ that showed the largest uptake was the liver (with 19.1% of the injected activity), 
followed by the kidneys and the brain (with approximately 9.4% and 8.3%, respectively, of the 
injected activity).  Therefore, the maximum injected Flurpiridaz (18F) Injection dose that may 
be administered at rest without exceeding 5 rem to the critical organ is 21 mCi (760 MBq), and 
the mean ED for Flurpiridaz (18F) Injection is 0.071 rem/mCi (0.019 mSv/MBq).  The 
maximum injected dose that may be administered without exceeding l rem ED was estimated 
to be 14 mCi (520 MBq). 
BMS747158-102 was a Phase 1, nonrandomised, 2-dose, open-label study conducted at 2 
medical centres in the US to assess radiation exposure from Flurpiridaz (18F) Injection to 
patients following stress.  A total of 12 healthy subjects were enrolled in 2 cohorts.  Six 
subjects (Cohort l) underwent 2-day rest and exercise treadmill stress PET imaging using a 
Bruce protocol, and 6 subjects (Cohort 2) underwent 2-day rest and pharmacologic stress PET 
imaging using adenosine as the stress agent.  Doses of Flurpiridaz (18F) Injection were 
administered at rest on the first day (Day l) and during stress on the second day (Day 2).   
From the exposure data, the critical organ for Flurpiridaz (18F) Injection following exercise 
stress was determined to be the heart wall, with a mean estimated dose of 0.15 rem/mCi 
(0.039 mSv/MBq).  The critical organ for Flurpiridaz (18F) Injection following pharmacologic 
stress was also determined to be the heart wall, with a mean estimated dose of 0.33 rem/mCi 
(0.090 mSv/MBq).  Consequently, the maximum injected dose of the compound that may be 
administered following exercise stress without exceeding 5 rem to the critical organ was 
determined to be 35 mCi (1276 MBq).  The maximum injected dose of the compound that may 
be administered following pharmacologic stress without exceeding 5 rem to the critical organ 
was determined to be 15 mCi (554 MBq). 
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The mean ED for Flurpiridaz (18F) Injection following exercise stress was 0.054 rem/mCi 
(0.015 mSv/MBq).  The mean ED for Flurpiridaz (18F) Injection following pharmacologic 
stress was 0.069 rem/mCi (0.019 mSv/MBq).  Consequently, the maximum injected dose that 
may be administered during exercise stress without exceeding 1 rem ED was determined to be 
19 mCi (685 MBq).  The maximum injected dose that may be administered during 
pharmacologic stress without exceeding 1 rem ED was determined to be 15 mCi (539 MBq). 
Flurpiridaz (18F) Injection was rapidly cleared from the blood within the first few minutes.  
Afterward, there was a modest rise in blood radioactivity, which remained at low levels (3% to 
5% of the injected dose per estimated whole-body blood volume over the next few hours.  
Subjects undergoing exercise stress exhibited significantly lower 18F blood concentrations after 
the first few minutes when compared to subjects undergoing pharmacologic stress.  Overall, 
the kinetics of 18F radioactivity in blood after Flurpiridaz (18F) Injection were found to provide 
an acceptably low background activity for PET cardiac imaging. 
A third Phase I single-centre study (BMS747l58-103) was conducted in 7 healthy adult male 
subjects who were administered a targeted intravenous (IV) dose of 100 ± 20 µCi (targeted at 
2.98 µg) of [3H]BMS747158, a tritiated preparation of BMS-747158-01 (the 19F analogue of 
the active component in Flurpiridaz [18F] Injection).  The assessed metabolic disposition 
parameters comprised blood and plasma radioactivity, plasma pharmacokinetics of parent 
compound, mass balance (urinary and faecal radioactivity excretion), and metabolite 
assessments in the various matrices.  The mean dose was 89.45 ± 0.68 µCi, corresponding to 
2.88 ± 0.02 µg of BMS747158 drug substance.  BMS747158 was extensively metabolised, 
with no unchanged drug detected in urine or faeces.  The major identified radiolabelled 
metabolite (M1) was a benzoic acid derivative, which appears to be formed by O-dealkylation 
of the fluroethoxy side chain. The product was considered safe and well-tolerated.   
Phase 2 study, BMS747158-201, consisting of 2 cohorts, was conducted to develop and 
subsequently to evaluate the diagnostic efficacy of 1-day rest/stress PET imaging protocols in 
patients with known or suspected CAD.  An initial cohort was used to identify the appropriate 
dose and timing of Flurpiridaz (18F) Injection dose administration for a 1-day rest/stress 
protocol that identified the minimum acceptable rest dose and the minimum stress dose that 
ensured that residual activity from the rest dose did not contaminate the stress image.  An 
optimised 1-day rest/stress protocol was subsequently adopted for the second cohort to assess 
efficacy in patients with a broad spectrum of pre-test likelihood of CAD. 
In the first cohort, 33 patients presenting with reversible perfusion defects of varying severity 
as identified by prior rest/stress SPECT MPI studies were enrolled and 32 completed the study, 
with 1 subject withdrawing voluntarily.  All subjects underwent a 1-day rest/stress, Flurpiridaz 
(18F) Injection PET MPI protocol (Day 1) with a dosing interval of either 60 minutes or 120 
minutes between rest and stress injections of Flurpiridaz (18F) Injection, followed by a second 
stress Flurpiridaz (18F) Injection PET MPI study within 16-48 hours of the Day 1 rest dose.  
Subjects were enrolled in Arm A (pharmacologic stress, with adenosine as the pharmacologic 
stressor) or Arm B (exercise stress) on the basis of the stressor used in their qualifying SPECT 
study.  Acquired PET MPI data were modelled to assess adequate rest/stress Flurpiridaz (18F) 
Injection PET MPI doses and dosing intervals between rest and stress Flurpiridaz (18F) 
Injection dose administrations as well as PET imaging parameters for 1-day rest/stress 
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protocols.  Dose and acquisition duration for reading perfusion imaging parameters were 
identified for 1-day rest/stress PET MPI (4.66 ± 2.119 mCi of BMS747158). 
In the second cohort, 143 patients presenting with a broad spectrum of pre-test likelihood of 
CAD were enrolled to evaluate the sensitivity, specificity, and accuracy of Flurpiridaz (18F) 
Injection in a 1-day rest/stress protocol; coronary angiography or 3-month follow-up for 
cardiac events was used as the truth standard.  Of the 143 subjects enrolled, 125 were evaluable 
for efficacy.  PET MPI sensitivity was 76.9% for all readers, and specificity ranged from 
74.0% to 87.7%.  SPECT MPI sensitivity ranged from 59.6% to 71.2%, and specificity ranged 
from 76.7% to 89.0%.   
Phase 3 Study BMS747158-301 was an open-label, international multicentre study for the 
assessment of CAD using Flurpiridaz (18F) Injection PET MPI compared with SPECT MPI in 
patients with suspected or known CAD who were referred for ICA. Patients underwent a 1-day 
rest/stress protocol with coronary angiography as the truth standard. The primary objective was 
to assess the diagnostic efficacy (sensitivity and specificity) of Flurpiridaz (18F) Injection PET 
MPI compared to SPECT MPI in the detection of significant CAD, as defined by cardiac 
catheterisation or a documented history of MI. 
A total of 795 received ≥1 dose of Flurpiridaz (18F) Injection (the safety population), and 764 
patients completed the trial. The modified intent-to-treat (MITT) population comprised the 755 
patients who had rest and stress SPECT MPI and Flurpiridaz (18F) Injection PET MPI 
procedures resulting in evaluable data and had evaluable truth-standard data. In the safety 
population, the mean (standard deviation [SD]) decay-corrected total dose was 9.35 (1.28) 
mCi, with a range of 6.69 to 12.27 mCi. The mean (SD) decay-corrected dose for patients who 
underwent pharmacologic stress was 8.59 (0.46) mCi, with a range of 6.69 to 12.01 mCi. The 
mean (SD) decay-corrected dose of patients who underwent exercise stress was 11.20 (0.54) 
mCi, with a range of 8.28 to 12.27 mCi.  
In a majority-rule assessment of the overall dataset of patient qualitative diagnosis, Flurpiridaz 
(18F) Injection PET MPI had a sensitivity of 71.9%. Sensitivity results for readers 1, 2, and 3 
were 73.3%, 62.4%, and 76.7%, respectively. Statistically significant superiority in sensitivity 
was demonstrated for Flurpiridaz (18F) Injection PET MPI over SPECT MPI across readers 
(P ≤.001). However, the endpoint that was intended to demonstrate the noninferiority of 
Flurpiridaz (18F) Injection PET MPI to SPECT MPI in specificity was not met. The overall 
dataset of patient qualitative diagnosis (when majority rule was used) provided a Flurpiridaz 
(18F) Injection PET MPI specificity of 76.2%, compared to SPECT specificity of 86.8%. 
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5 
STUDY OBJECTIVES AND PURPOSE 
The primary, secondary, and exploratory objectives of the study are as follows: 
Primary Objective 
• Assess the diagnostic efficacy (sensitivity and specificity) of Flurpiridaz (18F) Injection 
PET MPI in the detection of significant CAD, as defined by ICA, in patients with suspected 
CAD. 
Secondary Objectives  
• Evaluate the diagnostic efficacy (sensitivity and specificity) of Flurpiridaz (18F) Injection 
PET MPI compared with that of SPECT MPI in the detection of CAD, as defined by ICA, 
in the following groups of subjects: 
o All subjects (key secondary endpoint) 
o Female subjects 
o Subjects with body mass index (BMI) ≥30 kg/m2 
o Diabetic subjects 
• Assess the safety of Flurpiridaz (18F) Injection PET MPI. 
Exploratory Objectives 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6 
STUDY DESIGN 
6.1 
Overall Study Design and Plan 
This is a Phase 3, prospective, open-label, international, multicentre study of Flurpiridaz (18F) 
Injection for PET MPI in patients referred for ICA because of suspected CAD.   
This study will be conducted at approximately 60 centres in Europe and North America 
(United States and Canada). 
The procedure order will not be randomised but will be dependent upon the presentation of the 
patient at the site; however, in all cases SPECT and Flurpiridaz (18F) PET MPI must be 
performed within 60 days prior to ICA.  Included in these 60 days are clinically indicated 
SPECT exams that may precede screening, which otherwise meet all study-specific imaging 
and stress testing (Section 9.3) criteria (hereby called  “Off-study” SPECT exams) (see Study 
Diagram, Figure 1).  
All subjects will be followed up for AEs within 2 days following Flurpiridaz (18F) Injection 
administration, and for AEs and SAEs at approximately 2 weeks (14 to 17 days) following the 
last Flurpiridaz (18F) Injection dose administration and at the time of their ICA.   
Therefore, study subjects will participate in the study for up to 77 days. 
Each subject will attend a Screening Visit up to 30 days prior to enrolment.  The investigator 
will explain what participation in the study entails and check to determine that the subject 
meets all the inclusion criteria but none of the exclusion criteria.   
Patients can be considered for enrolment if: 
• They are being scheduled via written documentation at the time of enrolment to undergo 
ICA, and 
• They have undergone a clinically indicated SPECT study which meets all study-specified 
imaging and stress testing (Section 9.3) criteria, or are willing to undergo SPECT MPI for 
the purposes of the clinical study.  
ICA represents the regulatory accepted truth standard for the determination of presence or 
absence of significant coronary stenosis.   
Study Population:  
Five hundred and fifty-two (552) evaluable subjects will be enrolled in this study.  Assuming a 
15% dropout rate, 650 subjects will need to be enrolled initially. 
While enrolment will not be formally stratified, enrolment will be monitored and the 
recruitment plan may be adjusted during the course of the study to ensure adequate 
representation of subjects aged ≥65 years of age and that at least one third of the enrolled 
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subjects will be diabetic, one third but no more than one half will have BMI ≥30 kg/m2, and 
one third will be women.   
An overview of study procedures is presented in Figure 1.   
Figure 1 Study Diagram 
 
 
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6.2 
Study Rationale 
PET MPI may be particularly beneficial for patients whose SPECT MPI images are likely to be 
degraded by artefacts due to photon attenuation by soft tissue.  This includes women, whose 
SPECT MPI images can be degraded by breast shadow artefacts, and obese patients.  CAD 
remains one of the most important causes of morbidity and mortality among women [Mosca 
2007].  Although overall cardiac mortality has declined on average 3% per year, with rates in 
men having decreased substantially, little change has been reported in women [Mieres 2005].  
Even though women reportedly have a lower frequency of clinically significant CAD (>70% 
stenosis in 1 or more coronary arteries; adjusted odds ratio for women vs men, 0.34; P<.0001) 
and a lower rate of sudden cardiac death from coronary events (37% for women vs 56% for 
men), the prevalence of angina and mortality associated with ischaemic heart disease is higher 
in women than in men.  Mortality 1 year after MI remains greater than 1 in 5 for women 
[Benjamin et al 2017].  Emerging evidence suggests that coronary microvascular disease, with 
or without obstructive CAD, contributes to the pathophysiology of ischaemic disease in women 
[Tailor et al 2017]. In women, attenuation of the SPECT MPI signal by breast tissue can create 
artefacts that can be mistaken for a fixed or reversible perfusion defect, thus leading to 
decreased specificity of SPECT MPI.  Given inherent attenuation correction with PET MPI, 
Flurpiridaz (18F) PET imaging may offer improved diagnostic accuracy when compared to 
SPECT MPI.   
PET MPI may also be less subject than SPECT MPI to obesity-related signal attenuation. The 
prevalence of obesity has been increasing markedly over the past several decades, with more 
than 78 million adults in the United States (~35% of the adult population) being assessed as 
obese in 2009-2010. Once considered a problem only in high-income nations, the obesity 
epidemic is now global, with a dramatic rise in low- and middle-income countries, particularly 
in urban settings, even replacing more traditional problems such as undernutrition.  Obesity is 
associated with numerous comorbidities such as cardiovascular diseases, type 2 diabetes, 
hypertension, the metabolic syndrome, heart failure with preserved ejection fraction, non-
alcoholic steatohepatitis, certain cancers, and sleep apnoea/sleep-disordered breathing.   
Obesity is an independent risk factor for cardiovascular disease and cardiac mortality [Jensen 
et al 2014].  As obesity is a major risk factor for cardiovascular disease, assessing ischemia in 
obese patients is clinically important.  The cardiovascular clinical evaluation of obese patients 
is limited by several factors: rest ECG is influenced by adipose tissue and stress ECG by an 
impaired maximal exercise testing capacity.  Imaging modalities may therefore be of interest in 
the evaluation of ischemia for obese patients.  SPECT is frequently suboptimal, with 
artefactual myocardial perfusion defects resulting from the marked photon attenuation by soft 
tissue [DePuey 1994] [DePuey and Garcia 1989], even with more recent equipment such as 
cadmium-zinc-telluride cameras [Fiechter et al 2012]. 
Since the Framingham study report, an increased burden of CVD has been observed in patients 
with type 2 diabetes.  The increase in the risk of CVD and mortality from diabetes represents 
an important decrease in life expectancy and in CVD-free life expectancy, given that diabetes 
is still associated with approximately an overall 2- to 3-fold increased risk of CVD mortality.  
On top of that, the prevalence of obesity has been reported to be dramatically higher among 
individuals with diabetes than among those without diabetes [Fox et al 2004].  When diabetic 
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patients are compared with patients with other medical conditions, the diabetic patients’ first 
ischaemic events are more frequently silent and more likely to involve the small vessels, as 
opposed to large vessels.  These findings highlight the need for high sensitivity, to accurately 
detect ischaemic lesions at an early stage, to improve secondary prevention. 
This study’s safety monitoring plan is justifiable and adequate from a safety standpoint in view 
of the following: 
• The design of the safety plan permits a comparison of the safety variables in each subject at 
Baseline and after administration of investigational medicinal product (IMP). 
• The design of the safety plan allows a comparison of this study’s safety data set with those 
from other related studies. 
• Consideration of a 2-week safety monitoring follow-up permits the evaluation of late-
appearing adverse effects that may emerge or progress after the administration of IMP. 
• The measures used to assess safety are well defined and reliable, and the proposed safety 
analyses are adequate to assess the effects of the administration of Flurpiridaz (18F) 
Injection. 
6.3 
Study Timeframe 
The proposed trial will last from 
. 
Study subjects will participate in the study for up to 77 days. 
6.4 
Risks and Benefits to Subjects 
A total of 1003 patients have received Flurpiridaz (18F) Injection in Phase I through Phase III 
clinical studies: BMS-747158-101, BMS-747158-102, BMS-747158-103, BMS-747158-201, 
and BMS-747158-301.  
In 3 Phase I clinical studies of healthy volunteers, there were no adverse events related to 
Flurpiridaz (18F) Injection.  In the most recent study (BMS-747158-201), 2 separate groups of 
patients (Cohort 1 [n=33] and Cohort 2 [n=143]) with known or suspected CAD were studied 
while having a stress test. Five patients (2 in Cohort 1 and 3 in Cohort 2) reported a total of 10 
AEs; none of these adverse events were reported by another study patient, and all were judged 
by the investigator to be possibly or probably related to Flurpiridaz (18F) Injection dose 
administration.  The AEs in Cohort 1 included pain in extremity (1; 3%) and headache (1; 3%). 
The AEs in Cohort 2 included chest pressure (1; 0.6%), bradycardia (1; 0.6%), diarrhoea (1; 
0.6%), nausea (1; 0.6%), electrocardiogram ST-segment depression (1; 0.6%), metallic taste in 
mouth (1, 0.6%); cough (1; 0.6%), and high blood pressure (1; 0.6%).  None of these events 
were considered serious, and all resolved in a short period of time without any complications.  
In the most recent study, BMS747158-301, a total of 795 subjects received ≥1 dose of 
Flurpiridaz (18F) Injection.  Of these, 31 subjects (3.9%) did not complete the study.  The 
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majority of cases of discontinuation were due to inability to perform all study-mandated 
procedures (SPECT or coronary angiography).  Only 4 (0.5%) discontinuations were due to 
treatment-emergent AEs (TEAEs). In BMS747158-301, TEAEs were reported in 555 (69.8%) 
subjects; the majority of TEAEs were associated with either exercise or pharmacological stress 
testing or the underlying disease.  Forty-four (5.5%) patients experienced TEAEs deemed to be 
related to Flurpiridaz (18F) Injection.  Of these, 41 (5.2%) were subcategorised as “possibly 
related” and 3 (0.4%) as “related.”  The most common (≥0.5%) related TEAEs reported were 
headache (0.9%), angina pectoris (0.6%), dysgeusia (0.6%), diarrhoea (0.5%), dyspnoea 
(0.5%), flushing (0.5%), and nausea (0.5%). 
Therefore, we do not expect a significant risk for the subjects enrolled in the present Phase 3 
study.  The risk is mainly related to the need to induce a stress for increasing the myocardial 
blood flow to detect reversible or non-reversible perfusion defects.  The expected diagnostic 
potential of Flurpiridaz (18F) Injection should offset this limited risk by offering the 
opportunity for improving the detection of ischaemic lesions in patients who are typically 
suffering from diagnostic limitations with SPECT techniques.  Therefore, we consider the 
benefit-risk ratio as positive for conducting this trial.   
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7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
Procedures for Enrolment 
Patients will be considered for enrolment if they have been scheduled via written 
documentation provided by a cardiologist to undergo an ICA for the assessment of CAD 
because of medical history and/or symptoms calling for this assessment.   
The population will include patients with intermediate and high pre-test probability of CAD, 
reflecting the spectrum of patients who would be expected to undergo nuclear imaging tests.  
However, enrolment will not be based on pre-test likelihood of CAD.  The performance of 
other functional stress tests (such as stress echocardiography, exercise stress 
electrocardiography, nuclear stress tests including 82Rb or 13N-ammonia MPI imaging or 
SPECT MPI) or coronary CT angiography prior to enrolment is permitted.  Recent 
intracoronary angiography (within the last 6 months) prior to enrolment is not permitted. 
7.2 
Inclusion Criteria 
Subjects may be included in the study if they meet all of the following criteria: 
1) The subject is a man or woman 18 years of age. 
2) The subject has read, signed, and dated an informed consent form (ICF) prior to any study 
procedures being performed, and is willing to allow the study investigator to make the 
subject’s medical records available to GE Healthcare (including clinically indicated 
SPECT studies occurring prior to the signing of the ICF as stipulated in inclusion criteria 
#4). 
3) At the time of enrolment, the subject has been scheduled via written documentation to 
undergo an ICA for the assessment of CAD. 
4) The subject has undergone a clinically indicated SPECT which meets all study-specific 
imaging and stress testing (Section 9.3) criteria and conforms to local guidelines (such as 
American Society of Nuclear Cardiology or European Association of Nuclear Medicine), 
OR the patient is willing to undergo SPECT MPI for the purposes of the clinical study. 
5) The subject is male or is a nonpregnant, nonlactating female who is either surgically sterile 
(has a documented bilateral tubal ligation and oophorectomy and/or documented 
hysterectomy [bilateral tubal ligation alone is insufficient]) or is post-menopausal 
(cessation of menses for more than 1 year); enrolment in the study without a pregnancy 
test at screening is allowed for these categories of female patients.  For women of 
childbearing potential, the results of either a urine or serum human chorionic gonadotropin 
pregnancy test (with the result known on the day of radiopharmaceutical administration) 
must be negative; these subjects must be practicing appropriate birth control from the time 
of the screening to 30 days after the radiopharmaceutical administration. 
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6) The subject is able and willing to comply with all study procedures as described in the 
protocol. 
7.3 
Exclusion Criteria 
Patients who meet the following criteria will be excluded from the study: 
1) Patients who are pregnant, may possibly be pregnant, or wish (including their partners) to 
become pregnant during the study period, or are lactating. 
2) Patients who are unable to undergo all of the imaging procedures. 
3) Patients who have an established diagnosis of CAD as confirmed by any of the following: 
a. Previous myocardial infarction (MI); 
b. Previous cardiac catheter angiography showing 50% stenosis; 
c. Previous coronary revascularisation, such as percutaneous coronary intervention (PCI), 
thrombolysis or coronary artery bypass graft (CABG) placement. 
4) Patients incapable of undergoing either exercise or pharmacological cardiac stress testing. 
5) Patients who have a current illness or pathology that, in the opinion of the investigator, 
would pose a significant safety risk for the patient during cardiac stress testing. 
6) For patients for whom pharmacological stress testing is being considered, the following 
additional exclusion criteria will apply: 
a. Known hypersensitivity to adenosine, regadenoson, dipyridamole, or aminophylline; 
b. Use of a caffeinated substance, dipyridamole-containing medication, or 
methylxanthine-containing medication within 12 hours prior to vasodilator 
administration; 
c. Bronchoconstrictive or bronchospastic disease that, in the opinion of the investigator, 
poses a significant safety risk for the patient; 
d. Second- or third-degree atrioventricular block or sinus node dysfunction without 
functioning artificial pacemaker; 
e. Any additional contraindication to the pharmacological stress agent listed in the 
product’s package insert/summary of product characteristics (SmPCs). 
7) Patients with unstable cardiovascular condition, including but not limited to: 
a. Unstable angina, acute coronary syndrome within 6 months of enrolment; 
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b. Transient ischaemic attack/stroke within 3 months of enrolment; 
c. Significant congenital heart disease; 
d. Uncontrolled hypertension; 
e. Uncontrolled tachyarrhythmia leading to symptoms or haemodynamic compromise. 
8) Documented history of heart failure and/or cardiomyopathy (including nonischaemic 
cardiomyopathy, hypertrophic obstructive cardiomyopathy, or infiltrative 
cardiomyopathy). 
9) Primary haemodynamically significant uncorrected valvular heart disease, obstructive or 
regurgitant. 
10) Patients scheduled for or planning to undergo any cardiac interventional procedures 
between enrolment and ICA. 
11) Patients with screening laboratory findings as follows: 
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3 
times the upper limit of normal; 
b. Total bilirubin 2.0 mg/dL (34.2 µmol/L); 
c. Serum creatinine 3.0 mg/dL (265.2 µmol/L). 
12) Patients who present with any clinically active, serious, life-threatening disease, medical, 
or psychiatric condition and/or who have a life expectancy of <6 months or for whom 
study participation may compromise their management; and patients whom the 
investigator judges to be unsuitable for participation in the study for any reason. 
13) Patients undergoing evaluation for heart transplantation or with history of heart 
transplantation. 
14) Patients enrolled in another clinical study within the 30 days prior to being enrolled in this 
study or scheduled to participate in another clinical study during the 17-day follow-up 
period of this study. 
15) Patients previously enrolled in this study or any Flurpiridaz (18F) Injection study. 
7.3.1 
Subject Withdrawal 
There are no formal withdrawal criteria for this study.  During the conduct of the study, the 
Sponsor will review the safety data for trends and signals that would indicate the need for 
withdrawal of a subject. 
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In accordance with the Declaration of Helsinki, each subject is free to withdraw from the study 
at any time.  Investigator(s) also have the right to withdraw subjects from the study in the event 
of illness, adverse events (AEs), or other reasons concerning the health or well-being of the 
subject, or in the case of lack of co-operation. 
Should a subject decide to withdraw after administration of the IMP(s), or should the 
investigator(s) decide to withdraw the subject, all efforts will be made to complete and report 
the observations up to the time of withdrawal as thoroughly as possible.  A complete final 
evaluation at the time of the subject’s withdrawal should be made and an explanation given of 
why the subject is withdrawing or being withdrawn from the study.  Safety data will be 
considered once the subject has received ≥1 Flurpiridaz (18F) Injection.   
The reason for withdrawal must be noted in the case report form (CRF).  If the reason for 
withdrawal is an AE, monitoring will continue until the outcome is evident.  The specific event 
or test result(s) must be recorded in the CRF.  Depending on the time of their withdrawal, these 
subjects will be followed up for AEs and SAEs for approximately 2 weeks (14 to 17 days) 
following the last Flurpiridaz (18F) Injection dose administration. 
Withdrawn subjects will not be replaced. 
7.3.2 
Study or Site Termination 
The Sponsor reserves the right to terminate the study at any time. 
The Sponsor also reserves the right to discontinue participation of a study centre at which no 
patients have been enrolled within 3 months of initiation or in case of safety concerns or major 
protocol violations. 
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8 
TREATMENT OF SUBJECTS 
8.1 
Description of Medicinal Products 
8.1.1 
Investigational Medicinal Product: Flurpiridaz (18F) Injection 
Flurpiridaz (18F) Injection, the IMP in this study, is a novel PET MPI agent labelled with the 
radioisotope fluorine-18.  Flurpiridaz (18F) is delivered as a sterile solution to be administered 
as an IV injection.  This agent is a structural analogue of pyridaben, a known mitochondrial 
complex 1 (MC-1) inhibitor.  However, Flurpiridaz does not inhibit cardiac mitochondrial 
function. Mitochondria constitute 20% to 30% of the myocardial intracellular volume.  
Consequently, molecules that target mitochondrial proteins may be enriched and retained 
selectively in the myocardium.  The isotopic half-life of 18F is 110 minutes.   
All subjects will receive 2 IV boluses of Flurpiridaz (18F) Injection in a large peripheral vein: 1 
at rest and 1 during stress.  The dosages of Flurpiridaz (18F) Injection administered at rest and 
during stress conditions will not exceed a total of 14 mCi (520 MBq) for an individual subject. 
• Appearance: Clear, colourless, and free of visible particulate matter 
• Strength/concentration: [18F]Flurpiridaz ≥70 mCi in a nominal volume of 10 mL 
• Storage and handling conditions: Flurpiridaz is stable upon storage at 15°C to 25°C up to 
a maximum of 12 hours.  The exact expiry time of each dose will be included on the label.   
8.1.2 
Other Medicinal Products (Non-IMP) 
8.1.2.1 
SPECT Agents 
SPECT imaging must use 99mTc-based myocardial tracers, e.g., [99mTc]tetrofosmin or 
[99mTc]sestamibi. SPECT agents utilised for the purposes of this clinical study will be 
administered as per American Society of Nuclear Cardiology or European Association of 
Cardiovascular Imaging standards, where applicable, and recorded in the subject’s CRF. 
8.1.2.2 
Pharmacological Stress Agents 
The Flurpiridaz (18F) Injection PET MPI study must use the same stress type (pharmacological 
or exercise) as used for SPECT MPI in the same subject.  Also, if pharmacological stress is 
used, the same agent and the same dose of pharmacological stress agent should be used for 
both types of studies in the same subject and recorded. 
Pharmacologic stress agents will be restricted to the following 3 agents, as permitted by local 
marketing authorisations and availability: adenosine, dipyridamole, and regadenoson.  
Instructions regarding their administration are available in their respective Package Inserts. 
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Pharmacological stress agents utilised for the purposes of this clinical study will be 
administered as per American Society of Nuclear Cardiology or European Association of 
Cardiovascular Imaging standards and drug labelling as per package insert; the administration 
will be through an IV line.  During pharmacologic stress, the radiopharmaceutical will be 
administered during the peak vasodilatory effect according to the respective Package Insert (if 
applicable) of each stressor.  If a pharmacologic stress is performed using adenosine, the 
Flurpiridaz (18F) Injection and the adenosine must be administered via separate lines or via 
separate ports on the same IV line. 
8.1.3 
Medicinal Product Accountability 
Each investigator is responsible for ensuring that deliveries of IMP, other medicinal products 
(specified above), and other study materials from the Sponsor are correctly received, recorded, 
handled, and stored safely and properly in accordance with all applicable regulatory guidelines, 
and used in accordance with this protocol. 
All IMP containers (opened, unopened, or empty) must be destroyed on site after its scheduled 
use in accordance with site policies.  See IMP handling procedures for further details on 
receipt, recording, handling, and accountability procedures related to IMP.  A list of IMP, other 
medicinal products, and other materials that were destroyed, must be prepared and signed by 
the principal investigator or designee.  If there are any discrepancies, an explanation for these 
should also be provided. 
The site will be provided with the IB for the IMP. 
8.1.4 
Registration of Investigational Medicinal Product(s) Complaints 
In the event of an IMP complaint (e.g., breakage, leakage, particulate matter, discoloration), the 
investigator or recipient of the IMP is requested to report the problem on the IMP shipping 
documentation (e.g., ‘Delivery Note for Product,’ Drug Shipping and Receiving Form, or 
equivalent form).  This should be promptly forwarded to the person indicated on the shipping 
documentation.  Once the complaint is received, the Clinical Supplies Manager will register the 
complaint and determine, per Sponsor procedures, if the complaint is minor or significant.  All 
complaints will be followed up and the appropriate action will be implemented, per Sponsor 
procedures. 
8.2 
Method of Numbering Subjects and Assigning Subjects to 
Treatment Groups 
Each subject will be given a unique identification number. The identification number will be 
assigned to the subject during the Screening Visit, after the informed consent document has 
been signed and dated.  Once an identification number has been assigned, it cannot be 
reassigned, even if the subject is deemed ineligible or withdraws consent.  No subject may 
enter the study more than once.  Nor may a subject be re-screened for the study after having 
failed to meet the inclusion/exclusion criteria.  If the investigator has any question about any 
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subject’s eligibility to participate in the study, the investigator or study personnel should 
contact the Sponsor to discuss the subject’s eligibility. 
Each subject’s identification number will consist of a 3-digit site code plus a 4-digit 
consecutive number.  For example, site “999” will assign the number “999-0001” to its first 
subject, “999-0002” to its second subject, and so on. To preserve the integrity of the study, it is 
crucial that these numbers be assigned in consecutive numerical order.  
All subjects will receive the same treatment. Therefore, there will be no assignment to 
treatment groups.  
8.3 
Selection of Doses and Timing 
Duration of Study 
All screening assessments will occur within 60 days prior to ICA.  Flurpiridaz (18F) Injection 
PET MPI test and SPECT MPI (including SPECT exams preceding informed consent) must 
precede the ICA and occur within 60 days prior to the ICA.  Subjects will have Flurpiridaz 
(18F) Injection rest and stress PET MPI performed on the same day (dose specified in Section 
9.4).  Subjects will have their last follow-up safety contact at approximately 2 weeks (14 to 17 
days) following Flurpiridaz (18F) Injection or at the time of their ICA, whichever occurs later. 
8.4 
Blinding 
This is a Phase 3, open-label study. 
Personnel 
Blinded To: 
Subjects, site personnel, contract research 
organisation (CRO), and Sponsor 
Centrally read efficacy assessment of PET and 
SPECT MPI, intracoronary angiography (quantitative 
coronary angiography [QCA]) assessments (partial 
unblinding will occur with regards the report of the 
prevalence of CAD+ patients to the Sponsor 
occurring in 1-month or 2-month increments after the 
first 100 patients have had QCA analysis) 
Blinded independent image reviewers 
Medical history (until staged unblinding), SPECT 
MPI results, and standard of truth 
Centrally read intracoronary angiography QCA 
assessments 
 
8.5 
Prior and Concurrent Medications 
Any medications taken by the subject within 12 hours before the screening (or 12 hours before 
the SPECT stress test if the SPECT stress tests precede screening) at the time of ICA and up to 
study completion will be recorded in the CRF, along with the indication and dosage.  Either the 
generic or the trade name may be recorded.  The Sponsor/contract research organisation (CRO) 
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will encode all therapy and medication per a current well-recognised dictionary of medical 
codes. 
8.6 
Contraception and Pregnancy Avoidance Procedure 
Women of childbearing potential who are sexually active with a non-sterilized male partner 
and males who are sexually active with a partner of childbearing potential must use adequate 
contraception from Screening until 30 days after the Flurpiridaz (18F) Injection.  A woman 
NOT of childbearing potential is defined as surgically sterile (has a documented bilateral tubal 
ligation or oophorectomy and/or documented hysterectomy) or postmenopausal (cessation of 
menses for more than 1 year).   
An acceptable method of contraception is defined as one that has no higher than a 1% failure 
rate based on those methods identified in the Clinical Trial Facilitation Group (CTFG) 
document for clarification of effective contraception [CTFG Guidance 2014].  Such methods 
include:  
• 
combined (oestrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1: 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
progestogen-only hormonal contraception associated with inhibition of ovulation1: 
• 
oral 
• 
injectable 
• 
implantable2 
• 
intrauterine device2 
• 
intrauterine hormone-releasing system2 
• 
bilateral tubal occlusion2 
                                                 
1 Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. 
2 Contraception methods that in the context of CTFG guidance are considered to have low user dependency. 
 
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• 
vasectomized partner2,3 
• 
sexual abstinence4 
Patients will be provided with information on acceptable methods of contraception as part of 
the subject informed consent process.  Women of childbearing potential must have a negative 
result for a urine or serum human chorionic gonadotropin pregnancy test at the time points 
detailed in Table 1. 
8.7 
Treatment Compliance 
Subjects will receive the IMP under direct supervision of study personnel.  Each radioactivity 
dose injected will be checked and the vial code and volume per administration will be recorded 
in each subject’s CRF.  Doses administered outside of specific dose requirements or defined 
range must be reported as protocol deviations (see Sections 9.4 and 13.4, and Table 2). 
                                                 
3 Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of 
the woman of childbearing potential trial participant and that the vasectomized partner has received medical 
assessment of the surgical success. 
4 In the context of CTFG guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 
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9 
STUDY PROCEDURES 
All efficacy and safety measurements obtained during the study are summarised in the Study 
Schedule of Events (Table 1). 
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Table 1 
Study Schedule of Events 
Variables 
Screening 
Baseline (≤30 days 
after Screening) 
Can occur in either order. 
SPECT may precede Screening a 
Safety Follow-up 
(2 to 3 days after 
PET MPI) 
Safety Follow-up 
(14 to 17 days after 
PET MPI) 
ICA (within 60 
days of Screening 
or “Off-study” a 
SPECT) 
Rest and Stress 
SPECT MPI 
Rest and Stress 
PET MPI 
Informed consent 
X 
 
 
 
 
 
 
Entry criteria 
X 
 
 
 
 
 
 
Pregnancy test b 
X 
X 
 
X 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
Blood sampling 
Xc 
 
 
Xd 
 
 
 
Urine sampling 
X 
 
 
Xd 
 
 
 
Seattle Angina Questionnaire 
X 
 
 
 
 
 
 
Prior/concurrent medications 
X 
X 
X 
X 
X 
X 
Xm 
Vital signs 
 
X 
Xe 
Xe 
 
 
Xm 
Pulse oximetry 
 
X 
X 
X 
 
 
Xm 
12-lead ECG recording 
Xf 
 
 
X 
 
 
 
Physical examination g 
 
X 
 
X 
 
 
 
Full neurologic examination h 
 
X 
 
X 
 
 
 
Injection site monitoring 
 
 
 
Xi 
 
 
 
IMP administration 
 
 
 
X 
 
 
 
Image acquisition  
 
 
Xj 
Xk 
 
 
X 
Adverse events (including 
AEs and SAEs)l 
X 
X 
X 
X 
X 
X 
X 
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Table 1 
Study Schedule of Events 
Variables 
Screening 
Baseline (≤30 days 
after Screening) 
Can occur in either order. 
SPECT may precede Screening a 
Safety Follow-up 
(2 to 3 days after 
PET MPI) 
Safety Follow-up 
(14 to 17 days after 
PET MPI) 
ICA (within 60 
days of Screening 
or “Off-study” a 
SPECT) 
Rest and Stress 
SPECT MPI 
Rest and Stress 
PET MPI 
AE = adverse events; ECG = electrocardiogram; ICA = invasive coronary angiography; IMP = investigational medicinal product; MPI = myocardial perfusion imaging; PET = 
positron emission tomography; SAE = serious adverse events; SPECT = single photon emission computed tomography 
a Results of “off-study” SPECT MPI that was performed prior to signing of the ICF but in accordance with procedures developed by the imaging core laboratory (ICL) and on a 
validated camera can be used. The “off-study” SPECT MPI must also achieve the minimal quality standard specified by the ICL in the same manner as a study SPECT MPI 
performed prospectively. If an “off-study” SPECT MPI does not achieve the minimal quality standards of the ICL, a repeat SPECT MPI can be performed and used as a study 
SPECT MPI if performed during the study.   
b For women of childbearing potential, the results of either a urine or serum human chorionic gonadotropin pregnancy test (with the result known the day of radiopharmaceutical 
administration) must be negative.   
c If for scheduling reasons, the study SPECT or PET MPI must occur rapidly after the screening visit (e.g., within 48 hours), an additional blood sample may be analysed by local 
labs to determine if the subject meets exclusion criteria. For all subjects, blood must be sent for central analysis for all protocol specified laboratory parameters, whether or not 
blood is sent to a local lab for limited biochemical analysis for screening purposes. 
d Before the first IMP injection (blood and urine) and 1 hour after the last IMP injection (blood).  
e For rest SPECT-MPI and rest PET-MPI, vital signs will be collected up to 20 minutes prior to dose and 30 (±5) minutes post-dose.  For stress SPECT-MPI and stress PET-MPI, 
vital signs will be collected up to 20 minutes prior to dose (if >60 minutes between rest and stress injections) and 30 (±5) minutes post-dose.   
f 12 lead ECG collected on local ECG machine and interpreted by the investigator or a designee at the investigative site. A clinically indicated ECG obtained up to 48 hours prior 
to Screening is acceptable.   
g Physical examination will comprise a full examination with a specific focus on neurological and cardiovascular signs. During the Rest/Stress PET MPI Visit, a physical 
examination will be performed before the rest portion of the Flurpiridaz (18F) Injection PET MPI and 1 hour after the stress portion of the Flurpiridaz (18F) Injection PET MPI. 
Additionally, a focused clinical screen for new or worsening symptoms indicative of unstable coronary artery disease will be conducted prior to performing any procedures at 
the Flurpiridaz (18F) PET Visit.  If the clinical status screening is positive, the Flurpiridaz (18F) PET Visit can either be rescheduled (up to 1 time) after symptoms stabilize or the 
subject can be discontinued from the study. 
h If any neurologic abnormalities are noted during physical examination. 
i Immediately prior to the first injection, and then immediately after the first injection of IMP for the rest exam, immediately after the second injection of IMP for the stress exam, 
and ultimately at 1 hour after the last injection of IMP. 
j Rest SPECT MPI and then stress (exercise or physiologic) SPECT MPI, per the institution’s standard practices (the same stressor used for PET MPI, if PET MPI precedes 
SPECT MPI). 
k Rest PET MPI and then stress (exercise or physiologic, the same stressor used for SPECT MPI) PET MPI, per the institution’s standard practices. 
l All serious and non-serious AEs will be collected from the time of informed consent and followed for a final outcome until the end of the follow-up period. 
m Pre-procedure vitals, pulse-oximetry and concomitant medications can be extracted from the clinical record. 
 
 
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9.1 
Screening Visit 
All screening assessments will occur within 30 days prior to Baseline Visit.  The Screening and 
Baseline Visits can be combined with the SPECT MPI Visit. The investigator must be mindful 
of the 60-day window between screening and ICA procedures.  The following will be done 
during the screening period: 
• Signed and dated ICF must be obtained from all subjects prior to their entering the study.  
Study informed consent must be obtained from each subject prior to the initiation of any 
study-related procedures. Rest and stress SPECT MPI studies that were performed before 
the subject signed the ICF (i.e., “off-study” SPECT) can be used if the SPECT MPI was 
performed in accordance with the study imaging manual and was performed on a camera 
that had already been validated for use in the study. 
• Medical and surgical history will be checked and recorded.  This medical history will 
include any significant past or present illnesses, by body system, as well as a complete 
cardiac history (including 5-year general medical history) and a pretest likelihood of CAD. 
The pretest likelihood of CAD will be derived from the European Society of Cardiology 
(ESC) guidelines on the management of stable CAD [Montalescot et al 2013] (see 
Appendix 15.4).  In addition, a Seattle Angina Questionnaire [Spertus et al 1995] (see 
Appendix 15.5) will be administered. 
• Prior and concurrent medications. 
• Demographic information will be recorded. 
• Blood and urine samples will be collected for assessing haematology, abnormal glucose 
metabolism, liver and renal insufficiency.  If for scheduling reasons, the study SPECT or 
study PET MPI must occur rapidly after the screening visit (e.g. within 48 hours), an 
additional blood sample may be analysed by local labs specifically to determine if the 
subject meets exclusion criteria (i.e. serum creatinine, AST, ALT and total bilirubin).  For 
all subjects, blood must be sent for central analysis of all protocol-specified laboratory 
parameters, whether or not blood is sent to a local lab for limited biochemical analysis for 
screening purposes (as noted above). 
• All subjects must satisfy all the inclusion criteria and none of the exclusion criteria listed in 
Sections 7.2 and 7.3.   
• For women of childbearing potential, the results of either a urine or serum human chorionic 
gonadotropin pregnancy test (with the result known on the day of Flurpiridaz (18F) 
Injection) must be negative; these subjects must be instructed to practice appropriate birth 
control from time of the screening to 30 days after the Flurpiridaz (18F) Injection.  A 
pregnancy test is not needed for women who are either surgically sterile (has a documented 
bilateral tubal ligation and oophorectomy and/or documented hysterectomy) or post-
menopausal (cessation of menses for more than 1 year).   
• 12-lead ECG recording will be performed. (A clinically indicated ECG performed within 
48 hours prior to screening, without intervening episodes of chest pain or instability, can be 
used as the Screening ECG). 
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• For subjects on beta-blocker therapy, a determination should be made, in concert with their 
treating physician, if there are any conditions in which discontinuation of beta-blocker 
therapy could be contraindicated (e.g., tachyarrhythmias, uncontrolled or poorly controlled 
hypertension).  If medically safe, beta-blocker therapy should be withheld for 24 hours 
prior to PET and SPECT stress test. 
• All AEs and SAEs that occur after informed consent will be recorded (see Table 1 for 
scheduled AE query points in time, and Sections 10.2.6, 10.2.7, and 10.2.8).   
Waivers or protocol exceptions will not be granted prospectively by the Sponsor under any 
circumstances.  Any exceptions to protocol-specified requirements will be considered as 
protocol deviations. 
9.2 
Baseline Visit (≤30 Days After Screening) 
The Baseline Visit will take place between Screening and either of the SPECT or Flurpiridaz 
PET MPI imaging visits.  The Baseline Visit can be combined with the Screening and SPECT 
MPI imaging visit.  Investigators must be mindful of the maximum 60-day window between 
Screening or “off-study” SPECT and ICA.   
At the Baseline Visit, the following will be performed: 
• Physical examination will comprise a full examination with a specific focus on 
neurological and cardiovascular signs. 
• If neurologic abnormalities are found during the physical examination, a full neurologic 
examination will be performed.   
• Pregnancy test, for women of child-bearing potential (see the Study Schedule of Events 
[Table 1]). 
• Concurrent medications will be recorded.   
• Vital signs will be recorded during the Baseline Visit.  If the Baseline Visit is combined 
with the Rest and Stress SPECT MPI Visit, vital signs should be recorded up to 20 minutes 
before administration of the rest dose.   
• Pulse oximetry will be recorded. 
• AEs and SAEs will be recorded. 
9.3 
Rest and Stress SPECT MPI Visit  
The Rest and Stress SPECT MPI Visit can be combined with the Screening or Baseline Visit.  
Results of rest and stress SPECT MPI studies that were performed before the subject signed the 
ICF (i.e., an “off-study” SPECT MPI) can be used if the SPECT MPI was performed in 
accordance with the study imaging manual and was performed on a camera that had already 
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been validated for use in the study.  The “off-study” SPECT MPI must also achieve the 
minimal quality standard specified by the imaging core lab (ICL) in the same manner as a 
study SPECT MPI performed prospectively.  If an “off-study” SPECT MPI does not achieve 
the minimal quality standards of the ICL, a repeat SPECT MPI can be performed and used as a 
study SPECT MPI if performed during the study.  Depending on the institution’s standard 
practices, the rest and stress SPECT MPI procedures can take place on the same day or on 2 
days (either consecutive or non-consecutive).  The Rest and Stress SPECT MPI Visit may take 
place before or after the Rest and Stress Flurpiridaz (18F) PET-MPI Visit.  The investigator 
must be mindful of the 60-day window between SPECT MPI and ICA procedures.   
Subjects who are scheduled to undergo a pharmacologic stress test must not drink or eat 
caffeinated substances or take any dipyridamole-containing medication or methylxanthine-
containing medication within 12 hours prior to vasodilator administration for SPECT MPI.  In 
addition, it is recommended that patients who are scheduled to undergo exercise stress refrain 
from consuming any caffeinated substances, dipyridamole-containing medication, or 
methylxanthine-containing medication within 12 hours prior to the exercise stress test, to allow 
for the use of a pharmacologic stressor in the event that the subject does not reach the protocol-
required minimum 85% of age-predicted maximum heart rate (APMHR) or does not develop 
ischaemic symptoms during the exercise stress.  
No food will be allowed within 3 hours prior to either the pharmacologic stress or exercise 
stress. 
For subjects on beta-blocker therapy, a determination should be made, in concert with their 
treating physician, if there are any conditions in which discontinuation of beta-blocker therapy 
could be contraindicated (e.g., tachyarrhythmias, uncontrolled or poorly controlled 
hypertension).  If medically safe, beta-blocker therapy should be withheld for 24 hours prior to 
the SPECT MPI 
If the SPECT MPI Visit is combined with the Screening or Baseline Visits, all of the following 
elements that were scheduled for the Screening or Baseline Visit will be performed during the 
SPECT MPI Visit: 
• Informed consent will be obtained (Screening). 
• Entry criteria will be evaluated and recorded (Screening). 
• Medical/surgical history will be recorded (Screening). 
• 12-lead ECG recording will be performed (Screening Visit). (A clinically-indicated ECG 
performed within 48 hours prior to screening, without intervening episodes of chest pain or 
instability, can be used as the Screening ECG). 
• Blood samples for laboratory testing will be collected.  If for scheduling reasons, the study 
SPECT or study PET MPI must occur rapidly after the screening visit (e.g. within 
48 hours), an additional blood sample may be analysed by local labs specifically to 
determine if the subject meets exclusion criteria (i.e. serum creatinine, AST, ALT and total 
bilirubin).  For all subjects, blood must be sent for central analysis of all protocol-specified 
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laboratory parameters, whether or not blood is sent to a local lab for limited biochemical 
analysis for screening purposes (as noted above) (Screening). 
• Urine samples for laboratory testing will be collected (Screening). 
• Pregnancy test, for women of child-bearing potential (see the Study Schedule of Events 
[Table 1]; Screening/Baseline). 
• Demographic information will be recorded (Screening). 
• Concurrent medications will be recorded (Baseline Visit). 
• Vital signs will be recorded (Baseline Visit).  If the Baseline Visit is combined with the 
Rest and Stress SPECT MPI Visit, vital signs should be recorded up to 20 minutes before 
administration of the rest dose.   
• Pulse oximetry will be recorded (Baseline Visit). 
• A physical examination will be performed (Baseline Visit). 
• If neurologic abnormalities are found during the physical examination, a full neurologic 
examination will be performed (Baseline Visit). 
At the Rest and Stress SPECT MPI Visit, the following will be performed for all subjects: 
• Concurrent medications will be recorded. 
• Vital signs will be recorded.  For rest SPECT-MPI, vital signs will be collected up to 
20 minutes prior to dose and 30 (±5) minutes post-dose.  For stress SPECT-MPI, vital signs 
will be collected up to 20 minutes prior to dose (if >60 minutes between rest and stress 
injections) and 30 (±5) minutes post-dose. 
• Pulse oximetry will be recorded. 
• Rest SPECT MPI will be performed, per the as per American Society of Nuclear 
Cardiology or European Association of Cardiovascular Imaging standards.   
• After the rest SPECT MPI, stress SPECT MPI will be performed, per American Society of 
Nuclear Cardiology or European Association of Cardiovascular Imaging standards.  
• If the subject has already undergone stress Flurpiridaz (18F) PET MPI, the same type of 
stress (pharmacologic or exercise) should be used in the stress SPECT MPI, including 
the same dose of the same pharmacologic stressor, unless otherwise clinically indicated.  
During pharmacologic stress, radiopharmaceutical injection will be administered during 
the peak vasodilatory effect, according to the respective prescribing information or 
SmPC (as applicable) of each stressor.  Acceptable pharmacologic stress agents are 
listed in Section 8.1.2.2.  
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• If the subject has already undergone exercise stress Flurpiridaz (18F) PET MPI, the 
same exercise protocol should be used for the stress SPECT MPI, unless otherwise 
clinically indicated.   
• During exercise stress, the radiopharmaceutical for SPECT should be administered 
during peak stress, defined as ≥85% of the APMHR or following the occurrence of 
typical cardiac ischaemic symptoms.  Patients should continue to exercise for an 
additional 1 to 2 minutes, as clinically advisable, after the radiopharmaceutical 
injection.  If a patient cannot reach the study-required minimum of 85% of the APMHR 
or does not develop ischaemic symptoms, the radiopharmaceutical should not be 
administered. 
• The standard clinical practice should be used for determining early termination of 
exercise or pharmacologic stress testing in the presence of any absolute or relative 
indications, including the presence of ischaemic symptoms (i.e., angina, or angina 
equivalent) for early termination.  The exercise stress test should be performed only by 
experienced site personnel with access to resuscitation equipment.  Detailed 
recommendations for exercise testing performance must be followed as described in 
detail in the 2009 Recommendations for clinical exercise laboratories: a scientific 
statement from the American Heart Association (AHA) [Myers et al 2009]  
• AEs and SAEs will be recorded. 
• The images acquired during these procedures will be stored for the secondary blinded 
review, as specified in the Imaging Manual. 
9.4 
Rest and Stress Flurpiridaz (18F) PET-MPI Visit 
The Rest and Stress Flurpiridaz (18F) PET-MPI Visit may take place before or after the Rest 
and Stress SPECT MPI Visit.  
Subjects who are scheduled for pharmacologic stress must not drink or eat caffeinated 
substances or take dipyridamole-containing medication or methylxanthine-containing 
medication within 12 hours prior to vasodilator administration for Flurpiridaz (18F) PET MPI.  
In addition, it is recommended that patients who are scheduled to undergo exercise stress 
refrain from consuming any caffeinated substances, dipyridamole-containing medication, or 
methylxanthine-containing medication within 12 hours prior to the exercise stress test, to allow 
for the use of a pharmacologic stressor in the event that the patient does not reach the protocol-
required minimum 85% of APMHR or does not develop ischaemic symptoms.   
No food will be allowed within 3 hours prior to either the pharmacologic stress or exercise 
stress. 
For subjects on beta-blocker therapy, a determination should be made, in concert with their 
treating physician, if there are any conditions in which discontinuation of beta-blocker therapy 
could be contraindicated (e.g., tachyarrhythmias, uncontrolled or poorly controlled 
hypertension).  If medically safe, beta-blocker therapy should be withheld for 24 hours prior to 
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the PET MPI.  A focused clinical screen for new or worsening symptoms indicative of unstable 
coronary artery disease will be conducted prior to performing any procedures at the Flurpiridaz 
(18F) PET visit.  If the clinical status screening is positive, the Flurpiridaz (18F) PET visit can 
either be rescheduled (up to 1 time) after symptoms stabilize or the subject can be discontinued 
from the study.   
During the Rest and Stress Flurpiridaz (18F) PET-MPI Visit, the following will be performed: 
• Blood samples for laboratory testing will be collected prior to the PET MPI and 1 hour 
after the last PET-MPI injection.  If for scheduling reasons, the study SPECT or study PET 
MPI must occur rapidly after the screening visit (e.g. within 48 hours), an additional blood 
sample may be analysed by local labs specifically to determine if the subject meets 
exclusion criteria (i.e., serum creatinine, AST, ALT and total bilirubin).  For all subjects, 
blood must be sent for central analysis of all protocol-specified laboratory parameters, 
whether or not blood is sent to a local lab for limited biochemical analysis for screening 
purposes (as noted above).   
• Urine samples for laboratory testing will be collected prior to the PET MPI. 
• Pregnancy test, for women of child-bearing potential (see the Study Schedule of Events 
[Table 1]). 
• Concurrent medications will be recorded.   
• Vital signs will be recorded.  For rest PET-MPI, vital signs will be collected up to 
20 minutes prior to dose and 30 (±5) minutes post-dose.  For stress PET-MPI, vital signs 
will be collected up to 20 minutes prior to dose (if >60 minutes between rest and stress 
injections) and 30 (±5) minutes post-dose.   
• Pulse oximetry will be recorded. 
• Eight 12-lead ECG recordings will be performed (See Section 10.2.3). 
• A physical examination will be performed. 
• If neurologic abnormalities are found during the physical examination, a full neurologic 
examination will be performed.   
• During the rest test, all subjects will receive an IV bolus injection of Flurpiridaz (18F) 
Injection in a large peripheral vein.  The dose (volume and radioactivity) will be recorded 
in the CRF. 
• A stress test (exercise or pharmacologic) will be performed after the rest test, and on the 
same day.   
• 
The type of stress (exercise or pharmacologic) will be the same type used for that 
subject for the SPECT MPI test.   
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• 
For subjects who received a pharmacologic stressor during the stress SPECT MPI, 
the same agent and dose will be used during the stress Flurpiridaz (18F) PET-MPI 
test.  During pharmacologic stress, radiopharmaceutical injection will be 
administered during the peak vasodilatory effect, according to the respective 
prescribing information or SmPC (as applicable) of each stressor.  Acceptable 
pharmacologic stress agents are listed in Section 8.1.2.2. 
• 
If adenosine is used as a pharmacologic stressor, the Flurpiridaz (18F) 
Injection and the adenosine must be administered through separate lines or 
through separate ports of the same IV line.  Note: Central lines should NOT be 
used for the administration of Flurpiridaz (18F) Injection.  The Flurpiridaz 
(18F) Injection will be administered after the administration of the 
pharmacologic stressor.  The administration of Flurpiridaz (18F) Injection will 
be timed to coincide with maximal coronary vasodilation, which depends on 
the vasodilatory agent used. 
• 
For a subject who underwent exercise stress for SPECT MPI, the investigator is 
required to use the same exercise stress protocol for the Flurpiridaz (18F) Injection 
PET that was used for the SPECT MPI, unless otherwise clinically indicated. 
• 
During exercise stress, the radiopharmaceutical for both SPECT and PET should be 
administered at peak stress, defined as ≥85% of the APMHR or following the 
occurrence of typical cardiac ischaemic symptoms.  Patients should continue to 
exercise for an additional 1 to 2 minutes, as clinically advisable, after the 
radiopharmaceutical injection.  If a patient cannot reach the study-required 
minimum of 85% of the APMHR or does not develop ischaemic symptoms, the 
radiopharmaceutical should not be administered. 
• 
The standard clinical practice should be used for determining early termination of 
exercise or pharmacologic stress testing in the presence of any absolute or relative 
indications, including the presence of ischaemic symptoms (i.e., angina, or angina 
equivalent) for early termination.  The exercise stress test should be performed only by 
experienced site personnel with access to resuscitation equipment.  Detailed 
recommendations for exercise testing performance must be followed as described in 
detail in the 2009 Recommendations for clinical exercise laboratories: a scientific 
statement from the AHA [Myers et al 2009]  
• At 1 hour after administration of Flurpiridaz (18F) Injection for the stress exam, a physical 
examination will be performed. 
• If any neurologic abnormalities are noted during the physical examination, a full neurologic 
examination will be performed. 
• Injection-site monitoring (immediately prior to the first injection, immediately after the first 
injection of IMP for the rest exam, then immediately after the second injection of IMP for 
the stress exam, and ultimately at 1 hour after the last injection of IMP). 
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• The images acquired during the rest and stress Flurpiridaz (18F) PET MPI will be stored for 
the secondary blinded review. 
• AEs and SAEs will be recorded. 
The dose and dosing interval protocol that has been adopted is presented in Table 2. 
Table 2 
GE-265-303: Flurpiridaz (18F) Injection Doses for Exercise and 
Pharmacologic Stress 
 
Rest 
Pharmacologic Stress 
Exercise Stress 
Dose in the syringe at 
time of assay (in mCi) a 
2.5-3.0 mCi 
6.0-6.5 mCi b 
9.0-9.5 mCi a 
Dose in the syringe at 
time of assay (in MBq) a 
95-120 MBq 
230-250 MBq 
340-360 MBq 
Targeted dose in the body  
1.7 -3.0 mCi  
(62.9-111 MBq) 
Minimum rest:stress 
ratio of 1:2 
Minimum rest:stress of 
1:3 
a The dose in the syringe at the time of assay is presented in both mCi and MBq units for the 
convenience of the sites.  Sites will record dose measurement units (mCi or MBq) in keeping with their 
standard institutional practice. 
b The total dose that individual subjects receive (rest plus stress) must not exceed 14 mCi (520 MBq). 
Each of the PET acquisitions (rest and stress) consists of a dynamic series for quantitative 
analysis, with an extended final frame for semiquantitative analysis with and without cardiac 
gating. Full details of the image protocol are presented in the GE-265-303 PET Imaging 
Manual. 
9.5 
Safety Follow-up 2 Days (+24 hours) After Flurpiridaz (18F) PET 
MPI 
All subjects will be followed up by telephone assessments for AEs and SAEs within 2 days 
(+24 hours) following administration of Flurpiridaz (18F) Injection. During the assessment, the 
following will be recorded: 
• Concurrent medications 
• AEs and SAEs. 
9.6 
Safety Follow-up 14 to 17 Days After Flurpiridaz (18F) PET MPI 
All subjects will be followed up by telephone assessments for AEs and SAEs within 14 to 17 
days following administration of Flurpiridaz (18F) Injection.  During the assessment, the 
following will be recorded: 
• Concurrent medications 
• AEs and SAEs. 
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9.7 
ICA Visit (≤60 Days of Screening) 
Within 60 days after the Screening Visit or “off-study” SPECT, the subject will undergo ICA, 
according to the institution’s standard practices.  At the ICA Visit, the following will be 
performed: 
• Concurrent medications will be recorded. 
• Preprocedure vital signs will be recorded (from the clinical record). 
• Preprocedure pulse oximetry will be recorded (from the clinical record). 
• Events since PET MPI acquisition (and prior to the ICA visit) will be recorded.  
• Coronary angiography will be performed in accordance with investigational site 
institutional practice.  The site will communicate imaging parameters via a Data 
Transmission Form sent with each set of images to the ICA Core Laboratory; in these 
communications, the site will follow the Angiography Imaging Guidelines and 
Transmission Procedures for GE-265-303.  Ventriculograms, when performed for clinical 
reasons, will also be included.  Doppler flow or pressure-wire measurements or 
intravascular ultrasound (IVUS) may also be performed at the time of the ICA. If a Doppler 
flow or pressure wire is used, the measurements will be collected on the electronic case 
report form (eCRF). 
• AEs and SAEs will be recorded. 
See Section 10.2 and the Study Schedule of Events Table (Table 1) for further details. 
9.8 
Clinical Pharmacology 
Selected sites may participate in a separate substudy focused on obtaining pharmacokinetic 
and/or pharmacodynamic data that will assess the role of potential adjustments of the dose of 
Flurpiridaz (18F) Injection for subsets of patients, including those with atypical demographic 
characteristics. 
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10 
EFFICACY AND SAFETY 
10.1 
Efficacy Assessments 
10.1.1 
Primary Efficacy Endpoints 
The primary endpoints of the study are the sensitivity and specificity of Flurpiridaz (18F) 
Injection PET MPI in the detection of significant CAD as defined by cardiac catheterisation 
(ICA). 
Subjects will be considered to have CAD if QCA reveals ≥50% stenosis of ≥1 major coronary 
artery or major branch. 
10.1.2 
Secondary Efficacy Endpoints 
The secondary endpoints of the study are the diagnostic efficacy (sensitivity and specificity) of 
Flurpiridaz (18F) Injection PET MPI compared to that of SPECT, when the diagnosis of CAD 
by ICA is the standard of truth, in the following: 
• All subjects (key secondary endpoint) 
• Female subjects 
• Subjects with BMI ≥30 kg/m2 
• Diabetic subjects 
10.1.3 
Exploratory Efficacy Endpoints 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.1.4 
Image Acquisition 
Imaging procedures include PET MPI, SPECT MPI, and ICA.  
Image acquisition with SPECT and PET at rest and under stress procedures will be defined in 
the dedicated PET and SPECT Imaging Manual. 
ICA will be performed in accordance with investigational site institutional practice.   
Ventriculograms, when performed for clinical reasons, will also be included. 
Doppler flow or pressure-wire measurements and/or IVUS may also be performed at the time 
of the ICA.  If a Doppler flow or pressure wire is used, the measurements will be collected on 
the electronic CRF (eCRF). 
The truth standard used in this study is the presence of CAD (i.e., disease-positive) as 
evidenced by the presence of stenosis of ≥50% in ≥1 major epicardial coronary artery or major 
branch by quantitative coronary angiography (QCA). 
Further details of the ICA protocol will be provided in the Imaging Manual. 
10.1.5 
Image Interpretation and Correlation with Standard of Truth 
Three qualified independent readers will perform a blinded assessment of each subject’s PET 
image pair (rest and stress images) and each subject’s SPECT image pair.  Further details will 
be provided in the study PET and SPECT Independent Review Charter. 
One blinded reviewer will perform QCA, according to the Angiography Independent Review 
Charter, for all ICA images.   
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10.2 
Safety Assessments 
Subjects will be closely monitored for safety until completion of all study procedures..  Safety 
monitoring will include adverse events (AEs), medication errors, TEAEs, and SAE 
assessments, vital signs, ECGs, haematology, clinical chemistry laboratory tests, and 
urinalysis.  All subjects will be followed up by telephone assessments for AEs within 2 days 
(+24 hours) following Flurpiridaz (18F) Injection administration, and for AEs and SAEs at 
approximately 2 weeks (14 to 17 days) following the last Flurpiridaz (18F) Injection dose 
administration.  For subjects undergoing SPECT for the purposes of this clinical study, their 
safety will be monitored as per institutional standards.   
The investigator(s) and the Sponsor/CRO will review the safety data.  The following safety 
data will be collected and evaluated: 
• 
Clinical laboratory parameters: serum biochemistry, haematology, and urinalysis (Table 
3) 
• 
Vital signs: systolic/diastolic blood pressure, heart rate, pulse oximetry, and intermittent 
respiration rate and body temperature 
• 
Continuous ECG monitoring 
• 
Lead II rhythm strip and 12-lead ECG 
• 
Physical examination 
• 
Injection site monitoring 
• 
Post-treatment events (AEs and SAEs) 
Prespecified normal limits for vital signs and ECG intervals are provided in Section 15.3.   
10.2.1 
Clinical Laboratory Evaluation 
Clinical laboratory parameters assessed in this study are displayed in Table 3. 
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Table 3 
Clinical Laboratory Parameters 
Serum Biochemistry 
Haematology 
Urinalysis 
Alanine aminotransferase (ALT) 
Albumin 
Aspartate aminotransferase (AST) 
Bicarbonate 
Bilirubin (total) 
Calcium 
Chloride 
Creatinine 
Gamma-glutamyltransferase 
Glucose 
Hemoglobin A1c 
Lactate dehydrogenase 
Potassium 
Protein (total) 
Sodium 
Urea nitrogen 
Haematocrit 
Platelet count 
White blood cell (WBC) count 
Bilirubin 
Glucose 
Ketone 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
The signed and interpreted laboratory results will be kept together with the subject’s CRF 
(paper or electronic) as supplemental pages, both centrally and at the site. 
Blood samples will be obtained for assessment of serum biochemistry and haematology at the 
various pre- and post-treatment time point ranges described in Table 1.  It is anticipated that the 
maximum amount of blood taken will not be more than 50 mL for all the samples taken during 
the subject’s study participation.  Samples will be analysed at a central laboratory (for 
parameters, see Table 3).  All blood samples will be processed and handled per standard 
laboratory procedures.  All retained samples will be destroyed after completion of the study.  
For the purposes of screening, an additional blood sample may be analysed by local labs 
specifically to determine if the subject meets exclusion criteria (i.e., serum creatinine, AST, 
ALT and total bilirubin). 
Urine will be collected at the various pre-treatment time point ranges described in Table 1.  
The time of void will be documented on the CRF.  Urine voided will be analysed for 
parameters listed in Table 3. Any abnormal laboratory findings that constitute an AE (e.g., any 
abnormal findings leading to an intervention other than repeating the laboratory test) should be 
reported as such and should be followed up until the outcome is known.  Also, additional 
diagnostic tests may be indicated to determine a more precise diagnosis of the subject’s 
condition (e.g., ordering a WBC differential to help characterise a high or low WBC count, or 
ordering a determination of red cell indices to help characterise a low haematocrit).   
10.2.2 
Vital Signs 
Vital signs (pulse oximetry, blood pressure, heart rate, respiratory rate, temperature) will be 
monitored at Baseline (prior to IMP administration) and during the in- and out-patient follow-
up periods, according to the Study Schedule of Events (Table 1).  Before vital signs are 
measured, the subject should rest for ≥5 minutes in a supine position (if possible).  The same 
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position will be used each time vital signs are measured for a given subject, and blood pressure 
will be measured from the arm contralateral to the site of IMP administration whenever 
possible. 
10.2.3 
Electrocardiograms 
A standard 12-lead ECG will be obtained at Screening and during Flurpiridaz (18F) MPI rest 
imaging.  The Screening ECG can be obtained on any local ECG machine and will be 
interpreted by the investigator or a designee at the investigative site. A clinically indicated 
ECG performed within 48 hours prior to screening, without intervening episodes of chest pain 
or instability, can be used as the Screening ECG. The results of this ECG will be captured in 
the eCRF but not submitted to the ECG Core Laboratory for analysis.  
Before the administration of the Flurpiridaz (18F) Injection for the rest examination, three 12-
lead ECGs, separated by at least 5 minutes, will be obtained with equipment provided by the 
ECG Core Laboratory. ECG clocks should be synchronised with imaging equipment.  Note: 
pre-dose ECGs should be obtained within 20 minutes before the transmission scan, and the 
patient should rest for 5 minutes prior to the first measurement.  Three additional ECGs (each 
separated by 30-60 seconds) will be obtained starting at 2 minutes (± 30-60 seconds) after the 
administration of the Flurpiridaz (18F) injection for the rest examination. Single ECGs will also 
be obtained at 10 and 30 minutes post injection.  These 8 ECGs will be submitted to the ECG 
Core Laboratory for analysis.  The investigator will be asked to provide a determination of 
clinical significance on the eCRF only for the 3 ECGs obtained at 2, 10, and 30 minutes after 
injection of Flurpiridaz (18F).  If the investigator determines that there are any clinically 
significant changes from the 3 ECGs obtained before Flurpiridaz (18F) injection, those changes 
will be reported as AEs. 
No additional ECGs are required for this study.  However, sites should perform stress testing 
with ECG monitoring as required by the site’s institutional standards for stress testing. ECGs 
acquired in association with the stress test will not be collected by the Sponsor unless one or 
more become relevant to a reported TEAE.  Reports generated during stress testing, including 
ECG analysis and interpretation, will be collected by the Sponsor. 
10.2.3.1 
Investigational Site Responsibilities 
Each 12-lead ECG will be evaluated at US sites by a board-certified cardiologist or advanced 
cardiac life support (ACLS)-certified licensed physician.  Each 12-lead ECG will be evaluated 
at European sites by a cardiologist.  An ACLS-certified licensed physician reading ECGs may 
make clinical management decisions as needed.  However, the hardcopy ECG strips will be 
read on the same day or day after the ECG examination by a board-certified cardiologist at the 
site who signs off on the ECG interpretation. 
Subject management decisions may be based on the 12-lead ECG findings.   
Pre-specified normal limits and expanded normal limits for 12-lead ECG intervals are provided 
in Section 15.3.  Each 12-lead ECG tracing must be signed and dated, and the assessment 
results collected in the CRF.  During continuous ECG monitoring, the investigator or 
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appropriate delegate (concordant with local practice) will observe the real-time ECG findings 
and take note of any changes in intervals and/or waveforms.  The continuous ECG monitoring 
need not be 12-lead. 
Each 12-lead ECG at each time point (all intervals, heart rate and interpretation, and identified 
with the subject’s initials, subject’s study number, and date and time of recording), will be 
retained in the investigator’s study record for each subject.  The investigator will not be 
expected to calculate QTc intervals.   
10.2.3.2 
ECG Core Laboratory Responsibilities 
The ECG data from all time points will be electronically transferred and independently read at 
an ECG core laboratory by a board-certified cardiologist or an internist who will measure the 
QTc interval.  The core ECG laboratory cardiologist will review, interpret, and provide a 
written assessment of the ECGs, determining all intervals (e.g., PR, QRS, QT, and RR) and 
wave changes and calculating QTc intervals.  The reports will be signed and dated.  These data 
will be transmitted electronically directly to the Sponsor/CRO. 
10.2.4 
Physical Examination 
A qualified physician or a non-physician medically certified individual who is certified either 
by State/National law to perform physical examinations will conduct physical examinations at 
the baseline time point, before the Flurpiridaz (18F) Injection rest MPI exam and 1 hour after 
the Flurpiridaz (18F) Injection stress MPI exam.  Ideally, the same individual should conduct 
the physical examination at all required time points.  The physical examination will include 
recording an assessment for the presence of abnormalities of the following: general 
appearance, skin, head, eyes, ears, nose, throat, lungs, cardiovascular system, back and spine, 
abdomen, extremities, injection site, lymph nodes, and neurological exam. 
A full neurological exam will be performed if neurologic abnormalities are observed during the 
physical neurological examination.  It will include recording an assessment for the presence of 
abnormalities of the following: level of consciousness, motor function, sensory function, 
proprioception/position sense of extremities, reflexes (biceps, triceps, patellar, ankle), mood 
and affect, cognitive function, cerebellar, speech, orientation, memory, and gait. 
In the event that new abnormal physical findings and worsening abnormal physical findings are 
encountered during the study, these terms are defined as follows: a new abnormal physical 
finding is defined as one that occurs when a subject’s normal baseline physical examination 
becomes abnormal post-baseline.  A worsening abnormal physical finding is defined as one 
that occurs when a subject's abnormal baseline physical examination becomes worse post-
baseline.  These new findings will be recorded as AEs. 
10.2.5 
Injection Site Monitoring 
The injection site will be evaluated at the following time points: immediately prior to first 
injection of IMP, immediately after the first injection of IMP (for the rest exam) then 
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immediately after the second injection of IMP (for stress exam) and ultimately at 1 hour after 
the last injection.   
Abnormal injection site findings include, but are not limited to, radiopharmaceutical 
extravasation, bleeding, haematoma, redness, and infection.  They will be recorded as AEs in 
the CRF. 
10.2.6 
Adverse Events 
All AEs/SAEs that occur after informed consent shall be recorded in the AE/SAE report form 
(see the Study Schedule of Events, Table 1).   
Study personnel must remain vigilant for the occurrence of AEs after administration of IMP 
(see Section 8.1), particularly those that may be life threatening.  Personnel who are trained in 
the acute management of anaphylaxis and other emergencies and who have access to 
appropriate clinical supplies must be immediately available for 1 hour after dosing.  Treatment 
of SAEs should be primarily supportive of vital functions. 
AE and TEAE Definition: An AE is defined as any untoward medical occurrence or an 
already present event that worsens either in intensity or frequency.  A treatment-emergent 
adverse event (TEAE) is defined as an AE that starts on or after the time of the first injection of 
Flurpiridaz until the follow-up visit 14-17 days later.  The TEAE does not necessarily have to 
have a causal relationship with exposure to the investigational agent.  A TEAE can therefore be 
any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the exposure to the IMP, whether or not considered related 
to that product.   
The subjects will be closely observed and questioned for any kind of AE during the study 
procedures and at follow-up appointments throughout the study period with non-leading 
questioning (e.g., “How do you feel?”).  The subjects will be instructed to immediately report 
any symptoms and signs to the study staff (i.e., between formal observations). 
Both the investigator(s) and Sponsor/CRO will perform a causality assessment on any AE, to 
assess whether or not there is a reasonable possibility (evidence to suggest) that the IMP 
caused the event.   
Suspected Adverse Reaction: A reasonable possibility exists for causality between the IMP 
and the AE. 
Laboratory AE Evaluation 
Interpretation and follow-up of abnormal laboratory test results should be conducted in 
consideration of the clinical situation of the subject.  Any abnormal laboratory findings that 
constitute an AE should be reported as such and should be followed up until the outcome is 
known.  Also, additional diagnostic tests may be indicated to determine a more precise 
diagnosis of the subject’s condition (e.g., ordering a WBC differential to help characterise a 
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high or low WBC count, or ordering a determination of red cell indices to help characterise a 
low haematocrit); see also Section 10.2.8 (Other Significant Adverse Events). 
10.2.7 
Serious Adverse Events 
A serious adverse event (SAE) is defined as any AE that: 
• 
Results in death. 
• 
Is life threatening (requires that, in the view of either the investigator or Sponsor, the 
adverse event occurrence places the patient or subject at immediate risk of death. It 
does not include an adverse event or suspected adverse reaction that, had it occurred in 
a more severe form, might have caused death). 
• 
Requires in-patient hospitalisation or prolongation of existing hospitalisation. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly or birth defect. 
• 
Is another important medical event.* 
*Other important medical events are those that may not result in death, be life threatening, or 
require hospitalisation, but may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardise the subject and may require medical intervention to prevent one 
of the outcomes listed above.   
For this Study, it is expected that the following may occur: 
• Observations and findings (previously unknown) discovered during the ICA, and 
medically assessed as most likely pre-existing (e.g., coronary artery occlusions). 
• Hospitalisations for greater than 24 hours for the ICA (without an AE) may be 
necessary for other reasons (non-AE) e.g., patient-convenience. 
• Hospitalisations for post-ICA interventions deemed necessary following the ICA 
(without an AE) may occur (e.g., patient kept in hospital to undergo CABG for pre-
existing coronary artery occlusions discovered during ICA). 
For this study, these types of hospitalisations and/or imaging findings will not be considered 
AEs or SAEs and will not be reported as such in the CRFs.  
10.2.8 
Other Significant Adverse Events 
Clinical laboratory abnormalities that qualify as AEs (other than those meeting the definition 
for serious) and any events that lead to an intervention (including premature discontinuation of 
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IMP, dose reduction or significant additional concomitant therapy), other than those reported as 
SAEs, will be reported and evaluated as other significant AEs. 
10.2.9 
Adverse Event and Serious Adverse Event Reporting 
All AEs/SAEs shall be recorded in the AE/SAE report form using acceptable diagnoses, if 
possible.  If an AE has already been reported, it is not necessary to report each individual sign 
and symptom of that AE as a separate AE.  For example, if myocardial infarction (MI) is 
reported as an AE, there is no need to report elevated creatine kinase and abnormal ECG, or 
other related signs, symptoms, or laboratory values as separate AEs.  However, if both 
occurred in isolation and MI was not diagnosed, then each event would be reported as an AE. 
The intensity of all AEs will be graded as mild, moderate, or severe using the following 
definitions: 
Mild: 
Tolerable. 
Moderate: 
Interferes with normal activity. 
Severe: 
Incapacitating (causes inability to perform usual activity or work). 
The investigator will be instructed to closely monitor each subject who experiences an AE 
(whether ascribed to the IMP or not) until the outcome of the AE has been determined. 
In addition to the investigator’s own description of the AEs, each AE will be encoded by the 
Sponsor/CRO according to a well-recognised dictionary of medical codes, e.g., Medical 
Dictionary for Regulatory Activities (MedDRA). 
All AEs/SAEs must be followed for a final outcome until the end of the follow-up period.  An 
outcome of “unknown” is not considered to be an acceptable final outcome.  An outcome of 
“not yet resolved” is an acceptable final outcome for non-serious AEs at the end of a subject’s 
participation in a study, and for SAEs at database lock. 
Study centres are instructed to report all SAEs, together with a causality assessment, to 
the Sponsor (or a service provider/CRO acting on behalf of the Sponsor) within 24 hours. 
AEs and SAEs are reported in the AE form of the eCRF. Detailed information about 
management of AE information will be provided, e.g., in a Safety Management Plan.   
Safety information from SAE reports will be submitted to local health authorities, IECs or 
IRBs and investigators as required by local regulations and applicable SOPs.   
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For any protocol or safety-related questions please contact the Medical Director: 
 
 
GE Healthcare 
Pollards Wood, Nightingales Lane 
Chalfont St Giles 
Buckinghamshire HP8 4SP 
United Kingdom 
Phone: 
 
E-mail: 
 
Subjects enrolled at sites in the European Union will be provided with a Clinical Trial 
Participant card at the time of IMP administration.  This card will list contact details for the 
investigator and for GE Healthcare medical emergency cover services (Clinical Trial 
Emergency Contact Service [CTECS]).  The CTECS provides 24-hour, 7-day-a-week 
emergency cover service for Healthcare professionals to seek advice on trial–related medical 
questions or problems should a medical emergency arise and the investigator is not available. 
10.2.10 
Urgent Safety Measures 
In accordance with the principles of Good Clinical Practice (GCP) as laid out in the 
International Council for Harmonisation (ICH) E6, the investigator(s) has/have primary 
responsibility for assuring subject safety throughout the performance of study procedures.  An 
urgent safety measure is defined as any measure which an investigator may need to implement 
which is a deviation from, or a change in, the protocol to eliminate an immediate hazard(s) to 
trial subjects without prior IEC/IRB approval/favourable opinion. 
The investigator may take appropriate urgent safety measures in order to protect the subjects of 
a clinical trial against any immediate hazards to their health or safety.  However, the 
investigator must inform the Sponsor/CRO within 24 hours of having taken such measures. 
The Sponsor in turn shall immediately, and in any event no later than 3 days from the date the 
measures are taken, give written notice to the licensing authority and the relevant IEC/IRB of 
the measures taken and the circumstances giving rise to those measures. 
All urgent safety measures must be reported to the Sponsor/CRO by using the contact details 
listed in Section 10.2.9 within 24 hours of having to take such a measure(s).  Such reports can 
be initiated by telephone but must be officially documented by the investigator (by email or 
fax) and must include details of what measures were taken and the circumstances giving rise to 
those measures. 
10.2.11 
Pregnancy Reporting 
This process is aimed at ensuring the appropriate monitoring of the potential risk related to 
IMP exposure of pregnant women and/or foetuses as well as the risks associated with exposure 
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of a father, regarding congenital abnormalities or birth defects in their offspring.  It also 
ensures compliance with applicable international and local regulations. 
The requirements are applicable to all subjects following exposure to IMP. 
Female trial subjects: The trial subject must be advised by the investigator to inform him/her 
immediately if she suspects she may be pregnant during 1 month after dosing.   
Male trial subjects: The trial subject must be advised by the investigator to inform him/her 
immediately if they suspect their partner became pregnant after the subject was administered 
IMP during 1 month after dosing.   
When a trial subject reports a pregnancy (post-IMP administration) to the investigator, a 
pregnancy test should be arranged for the trial subject (or their partner) by the investigator 
within 7 days of the pregnancy being reported. 
The investigator must inform the Sponsor/CRO within 24 hours of receiving positive 
pregnancy test results by using either a copy of the relevant CRF pages (demography, exposure 
to medicinal products, and/or AE) or via email.  The investigator should include an estimated 
date of conception when communicating with the Sponsor/CRO. 
10.3 
Other Variables 
10.3.1 
Demographic Data 
Subject demographic data (date of birth/age, race, ethnicity, sex, weight, and height) will be 
recorded at Screening.  Subject age at the time of enrolment will be calculated from the date of 
birth and the date of baseline.  BMI will be calculated from height and weight.  If local 
regulations do not permit collection of specific demographic items (e.g., date of birth), either 
age will be entered on the eCRF or a partial date will be used in accordance with local practice. 
10.3.2 
Medical and Surgical History 
The subjects’ relevant medical and surgical history will be recorded at Screening and will be 
summarised. 
10.3.3 
Prior and Concurrent Medication 
Any medications taken by the subject within 12 hours before the screening or the SPECT stress 
test if it precedes screening, at the time of ICA and up to study completion will be recorded in 
the CRF, along with the indication and dosage.  Either the generic or the trade name may be 
recorded.  The CRO will encode all therapy and medication per a current well-recognised 
dictionary of medical codes.  
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10.4 
Appropriateness of Measurements 
All assessments and measurements are appropriate and generally regarded as standard medical 
practice. 
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11 
DATA HANDLING AND QUALITY ASSURANCE 
11.1 
Completing and Signing Case Report Forms 
For electronic CRFs (eCRFs), data will be entered by trained site personnel with reasons given 
for any missing data.  Any errors should be corrected within the electronic system.  The audit 
trail will record all changes made, the reason for the change, the date and time of the 
correction, and the person correcting the error.  The appropriate electronic signature will be 
provided. 
11.2 
Clinical Data Management 
The CRO will be responsible for the processing and quality control of the data.  Data 
management will be carried out by the CRO.  The handling of data, including data quality 
control, will comply with all applicable regulatory guidelines. 
11.3 
Archiving 
All study documentation at the investigator site and Sponsor site will be archived in accordance 
with ICH E6- GCP and the Sponsor/CRO’s quality standards and SOPs. 
All study documentation at the Investigator site and Sponsor site will be archived for a 
minimum of 15 years following completion or discontinuation of the study, unless the site is 
notified otherwise by the Sponsor or a longer period is required by local legislation.  The 
Investigator must request written agreement from the Sponsor before destruction of archived 
study documentation. 
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12 
STATISTICAL METHODS AND PLANNED ANALYSIS 
The data will be analysed by the Sponsor and/or designated CRO.  Any data analysis carried 
out independently by the investigator should be submitted to the Sponsor before publication or 
presentation. 
Data from participating centres in this protocol will be combined so that an adequate number of 
subjects will be available for analysis.  The data will be summarised with respect to 
demographic and baseline characteristics, efficacy observations and measurements, and safety 
observations and measurements. 
12.1 
General Statistical Considerations 
Tabulations of summary statistics, graphical presentations, and statistical analyses will be 
performed with SAS software, Version 9.3 or higher.  Descriptive statistics for continuous 
data in summary tables will include the number of subjects in the analysis (n), mean, SD, 
median, and range (minimum, maximum).  Descriptive statistics for categorical data in 
summary tables will include counts and percentages.  The last observation prior to 
administration of IMP will be used as the baseline value for calculating changes from baseline 
after administration of IMP.  All data obtained on the CRF and entered into the database will 
be provided in separate data listings showing individual subject values.  The planning and 
reporting of statistical analysis will be carried out as described in the Sponsor/CRO’s SOPs 
governing clinical studies. Further details of the criteria and conduct of the statistical analyses 
will be included in the Statistical Analysis Plan for this study. 
12.2 
Populations for Analysis 
12.2.1 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population will consist of all enrolled subjects who received ≥1 dose 
of Flurpiridaz (18F) Injection in the study. 
12.2.2 
Modified Intent-to-Treat (MITT) Population 
The MITT population will include all ITT subjects who have completed the rest and stress 
Flurpiridaz (18F) Injection PET MPI procedures and who have evaluable truth standard data. 
The MITT population will be the primary analysis set for the primary efficacy endpoints.   
12.2.3 
Secondary Modified Intent-to-Treat (SMITT) Population 
The secondary MITT (SMITT) population will include the subjects in the MITT population 
who have completed the rest and stress SPECT MPI (if the subject’s SPECT MPI is “off-
study,” that SPECT MPI must meet minimal quality standards, as specified by the ICL). The 
SMITT population will be the primary analysis set for the secondary efficacy and exploratory 
efficacy endpoints.   
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A summary of subject disposition, including the number and percentage of ITT subjects who 
do not have evaluable results for PET or the truth standard or who are not in the MITT analysis 
set, will be provided, with the reasons for nonevaluability.   
12.2.4 
Determination of Safety Population 
The Safety Population will include all subjects who have received ≥1 dose of Flurpiridaz (18F) 
Injection in the study.  All safety data will be summarised for the Safety Population. 
12.3 
Subject Demographics/Other Baseline Characteristics 
A table will be provided with the following information: 
• Number of subjects enrolled. 
• Number of subjects included in the efficacy analysis populations (ITT, MITT, SMITT). 
• Number of subjects included in the safety analysis population. 
• Number of subjects withdrawn from the study and the reason for withdrawal. 
Demographic information (age, height, weight, and BMI) will be summarised by using 
descriptive statistics.  Sex, ethnicity, and race will be summarised by counts and percentages. 
Medical histories will be summarised by counts and percentages.  Concurrent medications will 
be recorded and coded using a standard classification system and grouped by primary and 
secondary classes, if applicable. 
12.4 
Study Treatments 
The dosages of Flurpiridaz (18F) Injection administered at rest and during stress conditions will 
be summarised by volume and radioactivity administered.   
Any other medications taken by the subject within 12 hours before and up to study completion 
will be recorded in the CRF along with the indication and dosage.  Either the generic or the 
trade name may be recorded.  The CRO will encode all therapy and medication according to a 
current well-recognized dictionary of medical codes. 
12.5 
Primary Efficacy Analysis 
12.5.1 
Efficacy Variables 
12.5.1.1 
Myocardial Perfusion Imaging Evaluations 
Three qualified readers (independent from the study) will perform independent reads of all 
MPI images. The PET MPI and SPECT MPI reads will be performed by the same set of 
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readers in cross-over sessions independent of one another.  In each session, PET and SPECT 
images will be displayed in a randomised order, nonsequentially, with PET and SPECT MPI 
exams corresponding to individual subjects randomly allotted into reading session batches.  For 
each modality, perfusion and gated acquisitions of rest and stress images will be rated for 
image quality and reviewed.  After the results of each individual MPI (PET or SPECT) are 
locked as the “blinded” read, then clinical information will be provided.  The reader will then 
be given the opportunity to submit a revised assessment of the existence of any perfusion 
defects as an “unblinded” read. 
The primary efficacy read for MPI status will be the overall qualitative diagnosis of the paired 
Flurpiridaz (18F) PET MPI (rest/stress) using perfusion and gated assessments from 
independent blinded reads.  The overall qualitative diagnosis will be scored by each reader for 
each subject as normal, ischaemic, ischaemic + scar, or scar on the basis of the perfusion + 
gated images.  These scores will be dichotomised into MPI negative (normal) and MPI positive 
(ischaemic, ischaemic + scar, or scar) for each subject and reader.   
12.5.1.2 
Coronary Angiography Evaluations 
All coronary angiograms will be performed within 60 days of screening or SPECT if SPECT 
occurs prior to informed consent.  ICA data for the diagnosis of CAD will be generated by 
QCA. 
12.5.1.3 
Image Quality 
The data on image quality and interpretability will be collected separately during the blinded 
read and will be analysed separately by modality.   
12.5.2 
Primary Efficacy Endpoints 
The primary efficacy endpoints of the study are the sensitivity and specificity of Flurpiridaz 
(18F) Injection PET MPI in the detection of significant CAD as defined by ICA.  The truth 
standard used in this study is the presence of CAD as evidenced by the presence of stenosis of 
≥50% in ≥1 coronary artery or major branch of a coronary artery as determined by QCA 
analysis. 
For each of the 3 readers, a binary decision will be derived by using the overall qualitative 
diagnosis criteria as MPI-negative or MPI-positive; sensitivity and specificity will then be 
calculated for each of the 3 readers. 
Sensitivity and specificity are defined as follows: 
• True Positives (TP): Subjects with abnormal PET MPI and disease positive by the truth 
standard 
• True Negatives (TN): Subjects with normal PET MPI and disease negative by the truth 
standard 
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• False Positives (FP): Subjects with abnormal PET MPI and disease negative by the truth 
standard 
• False Negatives (FN): Subjects with normal PET MPI and disease positive by the truth 
standard 
• Sensitivity: TP/(TP + FN) 
• Specificity: TN/(TN + FP)  
• Accuracy: TN + TP/(TN + TP + FN + FP) 
A dosed subject whose PET MPI images are incomplete (i.e., a missing rest and/or stress 
image) will be excluded from the MITT analysis population.  Also, a subject with a missing 
truth standard will be excluded from the MITT analysis population.  A summary of reasons for 
all missing data will be provided, with number and percent in each category.  To eliminate bias 
between modalities, once a subject is included in the MITT population, the readers will be 
asked to read SPECT MPI and PET MPI images and to classify the images as normal or 
abnormal, regardless of image quality and interpretability.  To indicate when a diagnosis is 
forced, the reader will record in the blinded-read CRF which images are considered 
uninterpretable. The data on image quality and interpretability will be collected separately 
during the blinded read and will be analysed separately by modality.  
12.5.3 
Statistical Hypothesis, Model, and Method of Analysis 
The 2 primary efficacy endpoints are calculated as follows from different subsets of the 
population:  
• The calculation of sensitivity of Flurpiridaz (18F) Injection PET MPI includes data only 
from subjects with CAD, per the standard of truth.   
• The calculation of specificity of Flurpiridaz (18F) Injection PET MPI includes data only 
from subjects without CAD, per the standard of truth.   
Let s1 = true sensitivity of Flurpiridaz (18F) Injection PET MPI: 
Let p1 = true specificity of Flurpiridaz (18F) Injection PET MPI: 
The criteria for primary efficacy will be proving the statistical superiority of both the true 
specificity and sensitivity to a threshold of 60% in Flurpiridaz (18F) Injection PET MPI.  To 
meet the criteria for success in this study, both the sensitivity and the specificity of Flurpiridaz 
(18F) Injection PET MPI must exceed 60%.  Thus, the lower bound of the 2-sided 95% 
confidence interval for both sensitivity and specificity must exceed 60%. 
Therefore, the test of hypotheses will be as follows: 
H01 : s1 ≤ 0.60; H02: p1 ≤ 0.60, where s1 is sensitivity in Flurpiridaz (18F) Injection PET MPI 
and p1 is specificity in Flurpiridaz (18F) Injection PET MPI. 
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Ha1: s1 > 0.60; Ha2: p1 > 0.60 
Since sensitivity and specificity are calculated for separate subsets of the MITT analysis 
population, and since both null hypotheses need to be rejected for the study to be considered a 
success, each of the above endpoint comparisons will be performed by using a 1-sided 1-
sample test with type 1 error (α)= 0.025.  The test will be based on the 1-sample z-test for 
proportions, using the normal approximation to the binomial distribution.  The analysis will be 
done for each reader and for all readers.  If each null hypothesis is rejected in the analysis of all 
readers or by the same 2 out of 3 readers, the study will be considered a statistical success.   
There will be no formal interim efficacy analysis for this study. 
A summary of diagnostic efficacy including sensitivity, specificity, accuracy, positive 
predictive value (PPV), and negative predictive value (NPV) will be provided along with 2-
sided 95% confidence intervals (CIs) based on the normal approximation to the binomial 
distribution (for each of sensitivity and specificity, if the null hypothesis above is rejected by 
the z-test, then the lower bound of the 2-sided 95% CI will mathematically be above the 
threshold of 60%). 
12.5.4 
Handling of Missing Values/Censoring/Discontinuations 
Missing values will not be imputed, and only observed values will be used in data analyses and 
reports, unless otherwise specified in the Statistical Analysis Plan (SAP).   
12.5.5 
Supportive Analyses 
Sensitivity analyses will be performed to assess the impact of missing data on the primary 
analysis results (i.e., patients in the ITT population with incomplete PET MPI scans or missing 
truth standard). Details will be provided in the SAP.  
The summary outlined in Section 12.5.3 will be provided for each modality separately and for 
the following subgroups: 
• Age groups (<65 years and ≥65 years) 
• BMI <30 kg/m2 and BMI ≥30 kg/m2 
• Diabetic and nondiabetic 
• Sex (male and female) 
• Race (White, Black or African-American, other) 
• Presence or absence of multivessel CAD (per the standard of truth) 
• Presence or absence of renal impairment (i.e., serum creatinine level at predose evaluation 
is above normal range)  
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• Presence or absence of hepatic impairment (i.e., either ALT or AST value at predose 
evaluation is above normal range) 
• Type of stress test (pharmacological, exercise) 
Additionally, sensitivity and specificity of PET MPI and SPECT MPI based on the unblinded 
reads with clinical information will be summarised. The percentage of read results that were 
changed after clinical information was made available will be presented by modality.  
12.5.6 
Handling of Uninterpretable Images 
Once a subject is included in the MITT population, the readers will be asked to read PET MPI 
images and to classify the images as normal or abnormal, regardless of image quality and 
interpretability. 
12.5.7 
Reader Difference 
The inter-reader agreement and intra-reader reproducibility of blinded visual interpretations of 
PET MPI and SPECT MPI will be reported as percent agreement and kappa scores. Intra-
reader reproducibility will be determined based on a re-read of images from approximately 
10% of the subjects, selected at random from all study subjects. Each reader will re-read the 
same subset of images. 
12.6 
Secondary Analyses 
12.6.1 
Secondary Efficacy Variables and Analyses 
The secondary endpoints in this study are the diagnostic efficacy (sensitivity and specificity) of 
Flurpiridaz (18F) Injection PET MPI compared with that of SPECT MPI, when the detection of 
CAD as defined by ICA is the standard of truth, for the following sets of subjects: 
• All subjects (key secondary endpoint) 
• Female subjects 
• Subjects with BMI ≥30 kg/m2 
• Diabetic subjects 
To control the false-positive rate at a 1-sided 0.025 level across the testing of the secondary 
endpoints, the above endpoints will be tested hierarchically in the order given above.  Each 
endpoint will be tested at a 1-sided 0.025 level of significance; when a statistical test for a 
given endpoint fails to reach statistical significance in the appropriate direction, testing on all 
remaining secondary endpoints in the hierarchy will cease and the study will be considered 
successful on all secondary endpoints up to that point.   
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12.6.1.1 
Hypothesis Testing for the Key Secondary Endpoint 
In the secondary efficacy analysis, the criteria for success will be the statistical superiority of 
sensitivity in Flurpiridaz (18F) Injection PET MPI over that of SPECT MPI, and the 
noninferiority of specificity in Flurpiridaz (18F) Injection PET MPI over that of SPECT MPI, 
when the detection of CAD by ICA is the standard of truth. Since the sensitivity calculation 
includes only the subjects with CAD and the specificity analysis includes only the subjects 
without CAD, the analysis of sensitivity and specificity will be separate, as follows:   
Let s1 = sensitivity in Flurpiridaz (18F) Injection PET MPI, and s2 = sensitivity in SPECT MPI. 
Let p1 =specificity in Flurpiridaz (18F) Injection PET MPI, and p2 = specificity in SPECT MPI. 
Therefore, the test of hypotheses will be as follows: 
H01: s1 − s2 ≤ 0, 
H02: p1 − p2 ≤ −0.1 
Ha1: s1 − s2 > 0, 
Ha2: p1 − p2 > –0.1 
Each of the above endpoint comparisons will be performed with a 1-sided paired test with a 
type l error (α) = 0.025. 
The tests of comparisons are based on paired responses, as the Flurpiridaz (18F) Injection PET 
MPI and SPECT MPI will be performed on a within-subject basis, and the images will be read 
by the same readers in a cross-over design.  The test of sensitivity comparison between 
Flurpiridaz (18F) Injection PET MPI and SPECT MPI will be performed with a 1-sided 
McNemar's test at α = 0.025.  Similarly, the test of specificity noninferiority between 
Flurpiridaz (18F) Injection PET MPI and SPECT MPI will be performed with a paired test for 
noninferiority [Liu et al 2002] at a 1-sided α = 0.025.  The criterion for the demonstration of 
diagnostic efficacy for the secondary endpoints will be meeting the tests of hypotheses for both 
sensitivity and specificity for the same 2 of the 3 readers for whom the null hypotheses were 
rejected in the analysis of the primary endpoint.   
A minimal performance for SPECT in the targeted population for comparison to Flurpiridaz 
PET will be specified in the SAP.  
12.6.1.2 
Hypothesis testing for other secondary endpoints 
The methodology used for evaluating diagnostic efficacy within these populations will be 
similar to that used for analysis of the key secondary endpoint.   
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12.7 
Exploratory Analyses 
12.7.1 
Exploratory Endpoints: 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
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12.8 
Safety Variables and Analyses 
Safety Endpoint(s): Descriptive summary statistics will be reported for AEs, TEAEs, and 
SAEs, changes from baseline for clinical laboratory tests, ECGs, physical examination, and 
vital signs for all treated subjects.   
Post-administration changes from baseline will be summarised by mean, SD, minimum, and 
maximum at each time point.   
12.8.1 
Clinical Laboratory Evaluation 
Descriptive statistics will be displayed for the observed values and changes from baseline.  In 
addition, for each clinical laboratory variable and each time point, the following safety 
endpoints will be summarised by counts and percentages: 
• 
The occurrence of 1 or more changes from baseline, at each post-administration time 
point, greater than 40% and 80% of the span of the normal limits (not applicable to 
qualitative parameters). 
• 
The occurrence of post-administration values outside the normal limits (Section 15.3) 
(not applicable to qualitative parameters).  Shift tables based on the normal range will 
be prepared.   
12.8.2 
Vital Signs 
Descriptive statistics will be displayed for the observed values and changes from baseline.  For 
each vital-sign variable and each time point (see Table 1), the following safety endpoints will 
be summarised by counts and percentages by additional/other characteristics deemed necessary 
by study team: 
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• 
The occurrence of 1 or more changes from baseline, at each post-administration time 
point, greater than a pre-specified magnitude (20 mm Hg for systolic blood pressure, 
10 mm Hg for diastolic blood pressure, 10 beats per minute for heart rate, 1.5 C for 
body temperature, 10 breaths per minute for respiration rate). 
• 
The occurrence of post-administration values outside the normal limits (Section 15.3).  
Shift tables based on the normal range will be prepared.   
12.8.3 
Electrocardiograms 
Descriptive statistics will be displayed for the observed values and changes from baseline.  For 
each ECG variable and each time-point, the following safety endpoints will be summarised by 
counts and percentages or by additional/other characteristics deemed necessary by study team: 
• 
The occurrence of post-administration values outside the normal limits in the PR, QTc, 
QRS or RR interval (Section 15.3).  Shift tables based on the normal range will be 
prepared.   
ECGs for which the overall interpretation was abnormal will be summarised by counts and 
percentages at each post-administration time point or by additional/other characteristics 
deemed necessary by study team. 
QTc-specific analyses: 
Two correction formulae will be employed in analysing QTc data in an attempt to reduce the 
bias resulting from over- or undercorrection: 
 
Bazett’s:  QTcB = QT/RR 
 
Fridericia’s:  QTcF = QT/3RR 
The following analyses will employ both methods of correction: 
(1) 
Changes from baseline in the QTc interval will be displayed according to Committee 
for Medicinal Products for Human Use (CHMP) criteria (absolute QTc interval 
prolongation, of >450, >480, <500 ms and change from baseline in QTc interval >30 
and >60 ms). 
(2) 
Number and percentage of subjects with absolute QTc values above the upper limit of 
normal will be provided.  Shift tables based on the normal range will be prepared.   
12.8.4 
Physical Examination 
The number and percentage of subjects with changes in physical examination status from 
normal at Baseline to abnormal at each post-administration time point (and vice versa) will be 
presented.  Shift tables based on the normal range will be prepared.   
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12.8.5 
Adverse Events 
AEs and SAEs will be coded by using a current version of MedDRA, and all reported events 
will be listed for the safety population. The number and percentage of patients with 1 or more 
TEAEs will be summarized by system organ class and preferred term.  Summaries and listings 
will also be presented by AE intensity and judged relationship to IMP.  Treatment-emergent 
SAEs will also be presented for the safety population.   
12.9 
Interim Analysis 
No formal interim analyses will be performed in this study.   
12.10 
Sample Size Calculation 
The sample size was calculated to ensure that a sufficient number of evaluable negative and 
positive patients (by ICA) are enrolled to achieve 90% power at a 1-sided significance level of 
0.025 for both sensitivity and specificity in the primary analysis.  Assuming the true sensitivity 
and true specificity are both 70%, and testing the hypothesis that they are both >60%, 
237 negative and 237 positive patients in the MITT population are required.  Assuming a 
prevalence of 43%, approximately 552 total patients will be enrolled to ensure there are 
≥237 positive patients.  Enrolment will be monitored and the recruitment plan may be adjusted 
during the course of the study to ensure an adequate number of diseased patients.  Assuming a 
dropout rate of 15%, up to 650 total patients will be enrolled to ensure that there are at least 
552 evaluable MITT patients.  
12.11 
Procedures for Missing, Unused, and Spurious Data 
Missing values will not be substituted by estimated values, but treated as missing in the 
statistical evaluation.  All data from all subjects dosed in the study will be included in all 
listings, plots, summary tables, and statistical analyses when appropriate. 
12.12 
Rules for Excluding Subjects from Analysis 
All dosed subjects will be included in the analyses unless otherwise specified.  The Sponsor 
will make any decisions regarding whether any subjects or any individual values belonging to a 
subject will be excluded from the evaluations when the protocol violation is considered to have 
a negative impact on the scientific aspects and interpretation of the study results.  Such 
judgments should be made in a blinded fashion (with regards to the central MPI and ICA reads) 
before database lock and before any analyses have been performed.  If the subject has received 
any IMP, all available safety data will be used.  The reason(s) for any exclusion will be 
described in the report. 
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12.13 
Procedures for Reporting Deviations from Original Statistical Plan 
Any deviations from the statistical analysis outlined in this protocol will be described, and 
reasons for the deviations listed, in the final Clinical Study Report. 
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13 
SPECIAL REQUIREMENTS AND PROCEDURES 
13.1 
Regulatory, Institutional and Ethical Review 
Before the start of this study, the protocol (authorised by the Sponsor) will be submitted to the 
regulatory bodies/local health authorities (in accordance with local regulations) and to the 
IEC/IRB for evaluation.  The protocol will also be signed by the principal investigator before 
submission to the IEC/IRB.  The study will not start before the IEC/IRB gives written approval 
or a favourable opinion in accordance with ICH E6 GCP and all applicable regulatory 
bodies/local health authorities give approval or a favourable opinion as required. 
No changes from the final approved (authorised) protocol will be initiated without the 
IEC’s/IRB’s prior written approval or favourable opinion of a written amendment, except when 
necessary to eliminate immediate hazards to the subjects or when the change involves only 
logistics or administration.  The Sponsor will authorise and the principal investigator(s) will 
sign the protocol amendment prior to submission to the IEC/IRB.  Protocol amendments 
should be submitted to the IEC/IRB without delay.   
13.2 
Ethical Considerations 
The subject will not benefit directly from the results of the proposed study since his or her 
treatment is not influenced by the results of the proposed PET MPI injection.  However, the 
existing literature on PET MPI and the results from the previous phase 3 trials tend to indicate 
an increased diagnostic accuracy of PET MPI over SPECT MPI, this being more obvious for 
certain categories of patients.  The risks from the proposed PET MPI are considered minimal 
based on the previously reported results.  Therefore, the risk/benefit is considered as acceptable 
from a patient perspective.   
13.3 
Investigator’s Responsibilities 
13.3.1 
Overall Responsibilities 
The investigator(s) is/are responsible for conducting the study in full accordance with the 
Protocol and the Declaration of Helsinki, the Good Clinical Practice: Consolidated Guideline, 
approved by the ICH, and any applicable national and local laws and regulations.  Information 
regarding any investigational centres participating in this study that cannot comply with these 
standards will be documented. 
13.3.2 
Subject Informed Consent 
Written and oral information about the study in a language understandable by the subject will 
be given to all subjects.  Each subject’s willingness to participate in the study will be 
documented in a signed and dated ICF before any procedures or assessments are done and after 
the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force 
are explained.  It will also be explained to the subjects that they are free to refuse entry into the 
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study and free to withdraw from the study at any time without prejudice to future treatment.  
The informed consent process will be documented in the subject's medical record; and the 
investigator will sign and date the ICF after the subject has signed and dated the ICF.  The 
investigator(s) will keep the original consent forms, and copies will be given to the subjects. 
13.3.3 
Direct Access to Source Data/Documents 
The monitor(s), auditor(s), authorised personnel of the Sponsor/CRO, health authority 
inspector(s) or their agents, and authorised members of IECs/IRBs will be given direct access 
to source data and documentation (e.g., medical charts/records, laboratory results, printouts, 
videotapes, etc.) for source data verification, provided that subject confidentiality is maintained 
in accordance with local requirements. 
13.3.4 
Confidentiality Regarding Study Subjects 
The investigator(s) must assure that the privacy of the subjects, including their personal 
identity and all other personal medical information, will be maintained at all times.  In CRFs 
and other documents or image material (including materials from all examinations, e.g., PET, 
SPECT, and ICA imaging) submitted to the Sponsor/CRO, subjects will not be identified by 
their names, but by an identification code (e.g., study subject number). 
Personal medical information may be scrutinised for the purpose of verifying data recorded in 
the CRF.  This may be done by the monitor(s), properly authorised persons on behalf of the 
Sponsor, the quality assurance unit, or regulatory authorities.  Personal medical information 
will always be treated as confidential. 
13.4 
Protocol Deviations 
Any deviation from the protocol when no approved amendment exists must be documented as 
a protocol deviation and reported according to local requirements.  If appropriate, corrective 
and preventative action must be implemented to avoid repetition.  Protocol deviations and any 
potential impact on the study results will be discussed during the reporting of the study. 
Waivers or protocol exceptions will not be granted prospectively by the Sponsor under any 
circumstances. 
13.5 
Study Monitoring 
Study monitoring will be performed in accordance with ICH E6-GCP, the Sponsor or CRO’s 
SOPs, the protocol, and applicable local regulations. 
An independent data and safety monitoring board (DSMB) will be established to monitor the 
safety of patients participating in this clinical study. The DSMB will provide safety 
assessments including, but not limited to, review of study patient demographics, vital signs, 
diagnostic tests, laboratory tests, and adverse events. The DSMB  will conduct reviews of the 
safety data and will make recommendations to the Sponsor based on conclusions reached after 
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careful consideration of the patient safety data. Complete details concerning the DSMB are 
contained in a separate DSMB Charter. 
13.6 
Audit and Inspection 
According to ICH E6 GCP, the Sponsor or regulatory authorities may audit the investigational 
site.  The Sponsor’s Quality Assurance Unit, independent of the Clinical Research and 
Development Department, is responsible for auditing the study. 
The investigator(s) must accept that regulatory authorities may conduct an inspection to verify 
compliance of the study with GCP. 
13.7 
Financial Disclosure 
The Sponsor will cover all the expenses related to the present study, and no external 
contribution is considered for any of the aspects described in the present protocol.  
13.8 
Insurance 
This study is covered under the Sponsor’s Liability Insurance Policy (under General Electric 
Insurance Company and/or a company designated by the study Sponsor).  A Certificate of 
Insurance and/or an information leaflet containing essential information about the insurance 
coverage can be provided upon request. 
13.9 
Publication Policy 
The investigator and/or Institution shall have the right to publish the results of their work 
conducted under this protocol, subject to providing the Sponsor with the opportunity to review 
the contents of any proposed abstract or publication concerning the work, including any results 
of the study, in advance of publication and if necessary to delay publication for a limited time 
not to exceed 60 days in order to protect the confidentiality or proprietary nature of any 
information contained therein.  The Sponsor will make every reasonable effort to consider and 
release each proposed publication within 30 days, or proposed abstract within 15 days, of 
submission. 
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14 
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Hussain ST, Chiribiri A, Morton G, Bettencourt N, Schuster A, Paul M, et al. Perfusion 
cardiovascular magnetic resonance and fractional flow reserve in patients with angiographic 
multivessel coronary artery disease. J Cardiovasc Magn Reson. 2016;18(1):44. 
[Jensen et al 2014] 
Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, et al. 2013 
AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of 
the American College of Cardiology/American Heart Association Task Force on Practice 
Guidelines and The Obesity Society. J Am Coll Cardiol. 2014;63(25 pt B):2985–3023. Erratum 
in: J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):3029-3030. 
[Klein et al 2010] 
Klein R, Renaud JM, Ziadi MC, Thorn SL, Adler A, Beanlands RS, deKemp RA. Intra- and 
inter-operator repeatability of myocardial blood flow and myocardial flow reserve 
measurements using rubidium-82 PET and a highly automated analysis program. J Nucl 
Cardiol. 2010;17(4):600-616.   
[Liu et al 2002] 
Liu JP, Hsueh HM, Hsieh E, Chen JJ. Tests for equivalence or non-inferiority for paired binary 
data. Stat Med. 2002;21(2):231-245. 
[Mieres 2005] 
Mieres JH, Shaw LJ, Arai A, Budoff MJ, Flamm SD, Hundley WG, et al. Role of noninvasive 
testing in the clinical evaluation of women with suspected coronary artery disease: consensus 
statement from the Cardiac Imaging Committee, Council on Clinical Cardiology, and the 
Cardiovascular Imaging and Intervention Committee, Council on Cardiovascular Radiology 
and Intervention, American Heart Association. Circulation. 2005;111(5):682–696. 
[Montalescot et al 2013] 
Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A, et al. 2013 ESC 
guidelines on the management of stable coronary artery disease: the Task Force on the 
management of stable coronary artery disease of the European Society of Cardiology. Eur 
Heart J. 2013 Oct;34(38):2949-3003. 
[Mosca 2007] 
Mosca L, Banka CL, Benjamin EJ, Berra K, Bushnell C, Dolor RJ, et al. Evidence-based 
guidelines for cardiovascular disease prevention in women: 2007 update. Circulation. 
2007;115(11):1481–1501. 
[Murthy et al 2011] 
Murthy VL, Naya M, Foster CR, Hainer J, Gaber M, DiCarli G, et al. Improved cardiac risk 
assessment with noninvasive measures of coronary flow reserve. Circulation. 
2011;124(20):2215–2224.   
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[Myers et al 2009] 
Myers J, Arena R, Franklin B, Pina I, Kraus WE, McInnis K, et al. Recommendations for 
clinical exercise laboratories: A scientific statement from the American Heart Association. 
Circulation. 2009;119(24):3144-3161. 
[Naya et al 2014] 
Naya M, Murthy VL, Taqueti VR, Foster CR, Klein J, Garber M, et al. Preserved coronary 
flow reserve effectively excludes high-risk coronary artery disease on angiography. J Nucl 
Med. 2014;55(2):248–255. 
[Roger et al 2012] 
Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease 
and stroke statistics—2012 update: a report from the American Heart Association. Circulation 
2012;125(1):188-197. Erratum in: Circulation. 2012 Jun 5;125(22):e1001. 
[Shaw et al 1999] 
Shaw LJ, Hachamovitch R, Berman DS, et al.  The economic consequences of available 
diagnostic and prognostic strategies for the evaluation of stable angina patients: an 
observational assessment of the value of precatheterization ischemia.  Economics of 
Noninvasive Diagnosis (END) Multicenter Study Group. J Am Coll Cardiol. 1999;33(3):661–
669. 
[Shaw et al 2012] 
Shaw LJ, Hage FG, Berman DS, Hachamovitch R, Iskandrian A.  Prognosis in the era of 
comparative effectiveness research: where is nuclear cardiology now and where should it be? J 
Nucl Cardiol. 2012;19(5):1026–1043. 
[Shaw and Iskandrian 2004] 
Shaw LJ, Iskandrian AE. Prognostic value of gated myocardial perfusion SPECT. J Nucl 
Cardiol. 2004;11(2):171–185. 
[Spertus et al 1995] 
Spertus JA1, Winder JA, Dewhurst TA, Deyo RA, Prodzinski J, McDonell M, Fihn SD. 
Development and evaluation of the Seattle Angina Questionnaire: a new functional status 
measure for coronary artery disease. J Am Coll Cardiol. 1995 Feb;25(2):333-41. 
[Tailor et al 2017] 
Tailor TT, Kicska GA, Jacobs JE, Pampaloni MH, Litmanovich DE, Reddy GP. Imaging of 
heart disease in women. Radiology. 2017;282(1):34-53. 
[Tavakol et al 2012] 
Tavakol M, Ashraf S, Brener SJ.  Risks and complications of coronary angiography: a 
comprehensive review. Glob J Health Sci. 2012;4(1):65-93. 
[Toth et al 2014] 
Toth GG, Toth B, Johnson NP, De Vroey F, Di Serafino L, Pyxaras S, et al. Revascularization 
decisions in patients with stable angina and intermediate lesions: results of the international 
survey on interventional strategy. Circ Cardiovasc Interv. 2014;7(6):751-759. 
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15 
APPENDICES 
15.1 
Information on Investigational and Registered Products 
The reference document for the IMP in this study is the current IB.  The reference document 
provides up-to-date information on the efficacy and safety of Flurpiridaz (18F) Injection and is 
used for assessing expectedness of Serious Adverse Drug Reactions, in order to determine 
regulatory reportability.  An unexpected adverse drug reaction is a reaction for which the 
nature, seriousness, severity or outcome is not consistent with the IB.   
GE Healthcare marketed medicinal products like Myoview (99mTc based SPECT MPI agent) 
and Rapiscan (a pharmacological stress agent) may be used in this trial.  Reference safety 
information for assessment of expectedness are company core safety information, and 
approved SmPC or US Package Insert in the country of occurrence. 
No expectedness assessment will be performed for other medicinal products. 
15.2 
Equipment Parameters 
Hardware and software functionality for SPECT and PET acquisition are specified in the 
reference imaging manuals.  
15.3 
Normal Limits for Vital Signs and ECG Intervals 
Table 4 
Criteria for Normal Limits for Vital Signs 
Vital Signs Parameter 
Normal Limits 
Low 
High 
Systolic BP, mm Hg 
85 
139 
Diastolic BP, mm Hg 
60 
89 
Heart rate, beats/min 
60 
100 
Respiration rate, breaths/min 
12 
22 
Body temperature 
36.4C 
97.5F 
37.7C 
99.5F 
Oxygen saturation, % 
93 
100 
Body weight, kg a 
41 
113 
Body mass index (BMI), kg/m² b 
18.5 
24.9 
a Changes in body weight are evaluated by the investigator (without 
taking height into account), since BMI is not collected on the CRF. 
b BMI is calculated and analysed retrospectively by the Sponsor, at 
which time height is taken into account. 
 
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Table 5 
Criteria for Normal Limits for ECGs 
 
Normal Limits (ms) 
ECG Variable 
Low 
High 
PR interval 
120 
200 
QRS interval 
50 
100 
RR interval 
600 
1000 
QT interval 
(sex not specified) 
— 
440 
QTc intervala 
(sex not specified) 
— 
440 
a No lower boundary set for QTc. 
15.4 
Pre-test Probability of Obstructive Coronary Artery Disease in 
Patients with Stable Chest Pain Symptoms 
Table 6 
Clinical Pre-test Probabilities in Patients with Stable Chest Pain Symptoms 
[Montalescot et al 2013] 
 
ECG = electrocardiogram; PTP = pre-test probability; SCAD = stable coronary artery disease. 
a Probabilities of obstructive coronary disease shown reflect the estimates for patients aged 35, 45, 55, 65, 75 and 
85 years. 
• Groups in white boxes have a PTP <15% and hence can be managed without further testing. 
• Groups in blue boxes have a PTP of 15–65%. They could have an exercise ECG if feasible as the initial test. 
However, if local expertise and availability permit a non-invasive imaging based test for ischaemia this 
would be preferable given the superior diagnostic capabilities of such tests. In young patients radiation issues 
should be considered. 
• Groups in light red boxes have PTPs between 66–85% and hence should have a non-invasive imaging 
functional test for making a diagnosis of SCAD. 
• In groups in dark red boxes the PTP is >85% and one can assume that SCAD is present. They need risk 
stratification only. 
 
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15.5 
Seattle Angina Questionnaire 
 
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16 
CLINICAL PROTOCOL AMENDMENT SUMMARIES 
16.1 
Amendment A01 
16.1.1 
Reasons for Amendment 
• 
LVEF <50% has been removed from exclusion criterion (8).  The purpose of exclusion 
criterion 8 is to eliminate known/confirmed heart failure.  The inclusion of an EF lower 
limit to specify which patients should be included does not address this aim.  Ejection 
fraction defines different heart failure phenotypes (e.g. heart failure with preserved, 
reduced or mid-range ejection fraction) and as such is not relevant to the aim of 
excluding those with a heart failure diagnosis as a whole.  Even if the purpose was to 
exclude only patients with reduced EF, the EF of 50% corresponds to ‘normal’ EF 
when echocardiography is performed but does not correspond to the appropriate value 
to demark normal and abnormal ejection fractions for other modalities such as SPECT. 
• 
Clarification of follow-up period for the study.  
• 
Clarification of medicinal products in the study and update of storage and handling 
conditions for Flurpiridaz (18F) Injection.   
• 
Corrections to text to ensure recording of concurrent medications to study completion. 
• 
Removal of requirement for drug and alcohol screening.  Drug and alcohol abuse 
screening is useful to address: (1) unique safety concerns associated with potential 
interactions of IMP with illicit drugs, (2) concerns regarding confounding of an efficacy 
signal, and (3) concerns that follow-up would be compromised given occult substance 
abuse.   
GE Healthcare feels that these concerns are minimal, given: (1) There are no unique 
concerns regarding drug / illicit drug interactions.  This is particularly the case given 
that Flurpiridaz is administered to subjects in one sitting (as opposed to repeatedly) at a 
tracer dose. (2) Concerns of confounding the correlation between the anatomical gold 
standard of the QCA and the PET MPI blinded reads are minimal.  It is possible that 
toxic effects of illicit drugs (such as cocaine) could affect the microvascular function 
that in turn could lead to perfusion abnormalities as seen on MPI in the absence of 
significant epicardial coronary stenoses evidenced on QCA.  GE Healthcare believes 
that these discrepancies are likely to be minimal and encountered infrequently. 
(3) Subjects are already screened for psychiatric conditions which could impair 
participation in all study visits (exclusion #12).  Substance abuse is an axis II disorder 
and investigators are counselled to exclude patients with ongoing drug abuse that may 
lead to poor compliance in the manual of procedures.  Given the short-term follow-up 
of this study, it is unlikely that occult substance abuse (missed as part of the medical 
history) would frequently impair patient follow up. 
Since we believe that active substance abuse is likely to be rare and to have minimal if 
any effect on efficacy, no effect on safety, and minimal if any effect on follow-up 
compliance, the collection of this sensitive health information is not justified. 
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• 
Guidance regarding use of beta-blocker therapy has been added.  To ensure that the 
PET and SPECT MPI will be conducted according to guidelines and in accordance with 
standard clinical care, study sites are advised to withhold the beta-blocker when 
possible for at least 24 hours prior to the stress test.  Evidence demonstrates that beta-
blockade at the time of stress testing may reduce the sensitivity of MPI.  GE Healthcare 
acknowledges that withholding the beta-blocker might not always be possible due to 
clinical concerns such as difficult to control hypertension or arrhythmia (as per the 
guidelines) [Dorbala et al. 2013].  In patients using beta blockers, the investigator must 
discuss with the treating physician the safety of withholding the beta-blocker.  Subjects 
who require continued beta-blockade during MPI will not be eliminated. 
• 
Clarification that an additional blood sample at screening may be analysed by the local 
lab to determine if the subject meets exclusion criteria.  Dependence on central lab 
results for screening purposes will result in a delay from screening to the earliest 
performance of in study visits (including the PET or on-study SPECT) of at least 
48 hours from the time of the lab draw (in most cases).  This delay adds a significant 
hurdle to patient recruitment and retainment in a study where all study visits must occur 
prior to a prescheduled invasive coronary angiography.  In most cases the window 
between screening and the clinical intracoronary angiography is expected to be less 
than 7 days.  Permitting screening through the uses of local labs permits patients to be 
screened, enrolled and have a SPECT scan in a minimal amount of time (or even in the 
same day) with a PET scan following as closely after as doses are available.  Central 
labs results may still be used for screening if local labs are not drawn.  The 
determination of whether to draw local labs for this purpose rests with the investigator 
and will depend on the rapidity with which the study visits must occur (e.g. if the 
window between screening and ICA is brief, local labs are advised, if this window is 
more lengthy than local labs should not be drawn).  
Significant discordance between local and central lab results are unlikely since the 
central and local labs will be drawn in the same sitting at screening.  If they do occur 
the local lab should take precedence for the screening purposes.  The safety data set will 
use the exclusively the central labs to analyse changes in biochemistry, since all 
patients will systematically have labs analysed centrally at screening and pre- and post-
scan timepoints. Listings and summary tables will describe the local lab data. 
• 
Safety reporting for AEs and SAEs has been updated and clarified.   
• 
Minor typographical errors have been corrected. 
Where appropriate, the changes documented below are also made in the synopsis.  Where 
appropriate the changes are indicated in italics. 
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16.1.2 
Description of Changes 
Section 6.1, Overall Study Design and Plan, Third Paragraph 
Previously read: 
The procedure order will not be randomised but will be dependent upon the presentation of the 
patient at the site; however, in all cases SPECT and Flurpiridaz (18F) PET MPI must be 
performed within 60 days prior to ICA. Included in this 60 days are clinically indicated SPECT 
exams that may precede screening, which otherwise meet all study-specific imaging and stress 
testing (Section 9.3) criteria (hereby called  “Off-study” SPECT exams) (see Study Diagram, 
Figure 1).  
Now reads: 
The procedure order will not be randomised but will be dependent upon the presentation of the 
patient at the site; however, in all cases SPECT and Flurpiridaz (18F) PET MPI must be 
performed within 60 days prior to ICA. Included in these 60 days are clinically indicated 
SPECT exams that may precede screening, which otherwise meet all study-specific imaging 
and stress testing (Section 9.3) criteria (hereby called  “Off-study” SPECT exams) (see Study 
Diagram, Figure 1).  
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Section 6.1, Figure 1, Study Diagram 
Previously read: 
 
 
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Section 6.4, Risks and Benefits to Subjects, Third Paragraph 
Previously read: 
In the most recent study, BMS747158-301, a total of 795 subjects received ≥1 dose of study 
drug.  Of these, 31 subjects (3.9%) did not complete the study.  The majority of cases of 
discontinuation were due to inability to perform all study-mandated procedures (SPECT or 
coronary angiography).  Only 4 (0.5%) discontinuations were due to treatment-emergent AEs 
(TEAEs). In BMS747158-301, TEAEs were reported in 555 (69.8%) subjects; the majority of 
TEAEs were associated with either exercise or pharmacological stress testing or the underlying 
disease.  Forty-four (5.5%) patients experienced TEAEs deemed to be related to study drug.  
Of these, 41 (5.2%) were subcategorised as “possibly related” and 3 (0.4%) as “related.”  The 
most common (≥0.5%) related TEAEs reported were headache (0.9%), angina pectoris (0.6%), 
dysgeusia (0.6%), diarrhoea (0.5%), dyspnoea (0.5%), flushing (0.5%), and nausea (0.5%). 
Now reads: 
In the most recent study, BMS747158-301, a total of 795 subjects received ≥1 dose of 
Flurpiridaz (18F) Injection.  Of these, 31 subjects (3.9%) did not complete the study.  The 
majority of cases of discontinuation were due to inability to perform all study-mandated 
procedures (SPECT or coronary angiography).  Only 4 (0.5%) discontinuations were due to 
treatment-emergent AEs (TEAEs). In BMS747158-301, TEAEs were reported in 555 (69.8%) 
subjects; the majority of TEAEs were associated with either exercise or pharmacological stress 
testing or the underlying disease.  Forty-four (5.5%) patients experienced TEAEs deemed to be 
related to Flurpiridaz (18F) Injection.  Of these, 41 (5.2%) were subcategorised as “possibly 
related” and 3 (0.4%) as “related.”  The most common (≥0.5%) related TEAEs reported were 
headache (0.9%), angina pectoris (0.6%), dysgeusia (0.6%), diarrhoea (0.5%), dyspnoea 
(0.5%), flushing (0.5%), and nausea (0.5%). 
 
Section 7.1, Procedures for Enrolment, Second Paragraph 
Previously read: 
The population will include patients with intermediate and high pre-test probability of CAD, 
reflecting the spectrum of patients who would be expected to undergo nuclear imaging tests.  
However, enrolment will not be based on pre-test likelihood of CAD.  The performance of 
other functional stress tests (such as stress echocardiography, exercise stress 
electrocardiography, nuclear stress tests including 82Rb or 13N MPI imaging or SPECT MPI) or 
coronary CT angiography prior to enrolment is permitted.  Recent intracoronary angiography 
(within the last 6 months) prior to enrolment is not permitted. 
Now reads: 
The population will include patients with intermediate and high pre-test probability of CAD, 
reflecting the spectrum of patients who would be expected to undergo nuclear imaging tests.  
However, enrolment will not be based on pre-test likelihood of CAD.  The performance of 
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other functional stress tests (such as stress echocardiography, exercise stress 
electrocardiography, nuclear stress tests including 82Rb or 13N-ammonia MPI imaging or 
SPECT MPI) or coronary CT angiography prior to enrolment is permitted.  Recent 
intracoronary angiography (within the last 6 months) prior to enrolment is not permitted. 
 
Section 7.3, Exclusion Criteria, Exclusion Criterion (8) 
Previously read: 
(8) 
Documented history of heart failure and/or cardiomyopathy (including nonischaemic 
cardiomyopathy, hypertrophic obstructive cardiomyopathy, or infiltrative 
cardiomyopathy) and/or prior LVEF <50%. 
Now reads: 
(8) 
Documented history of heart failure and/or cardiomyopathy (including nonischaemic 
cardiomyopathy, hypertrophic obstructive cardiomyopathy, or infiltrative 
cardiomyopathy). 
 
Section 7.3, Exclusion Criteria, Exclusion Criterion (14) 
Previously read: 
(14) 
Patients enrolled in another clinical study within the 30 days prior to being enrolled in 
this study or scheduled to participate in another clinical study during the 7-day follow-
up period of this study. 
Now reads: 
(14) 
Patients enrolled in another clinical study within the 30 days prior to being enrolled in 
this study or scheduled to participate in another clinical study during the 17-day follow-
up period of this study. 
 
Section 7.3.1, Subject Withdrawal, Fourth Paragraph, First Sentence 
Previously read: 
The reason for withdrawal must be noted in the case report form (CRF).  If the reason for 
withdrawal is a clinical AE, monitoring will continue until the outcome is evident.   
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Now reads: 
The reason for withdrawal must be noted in the case report form (CRF).  If the reason for 
withdrawal is an AE, monitoring will continue until the outcome is evident.   
 
Section 8.1, Title 
Previously read: 
Investigational Medicinal Product(s) 
Now reads: 
Description of Medicinal Products 
 
Section 8.1.1, Investigational Medicinal Product: Flurpiridaz (18F) Injection (previously 
Flurpiridaz (18F) Injection) 
Previously read: 
Flurpiridaz (18F) Injection is a novel PET MPI agent labelled with the radioisotope fluorine-18.  
Flurpiridaz (18F) is delivered as a sterile solution to be administered as an IV injection.  This 
agent is a structural analogue of pyridaben, a known mitochondrial complex 1 (MC-1) 
inhibitor.  However, Flurpiridaz does not inhibit cardiac mitochondrial function. Mitochondria 
constitute 20% to 30% of the myocardial intracellular volume.  Consequently, molecules that 
target mitochondrial proteins may be enriched and retained selectively in the myocardium.  The 
isotopic half-life of 18F is 110 minutes.   
All subjects will receive 2 IV boluses of Flurpiridaz (18F) Injection in a large peripheral vein: 1 
at rest and 1 during stress.  The dosages of Flurpiridaz (18F) Injection administered at rest and 
during stress conditions will not exceed a total of 14 mCi (520 MBq) for an individual subject. 
• Appearance: Clear, colourless, and free of visible particulate matter 
• Strength/concentration: [18F]Flurpiridaz ≥ 70 mCi in a nominal volume of 10 mL 
• Storage and handling conditions: Flurpiridaz is stable upon storage at 25°C/60% relative 
humidity over a 12-hour period.   
Now reads: 
Flurpiridaz (18F) Injection, the IMP in this study, is a novel PET MPI agent labelled with the 
radioisotope fluorine-18.  Flurpiridaz (18F) is delivered as a sterile solution to be administered 
as an IV injection.  This agent is a structural analogue of pyridaben, a known mitochondrial 
complex 1 (MC-1) inhibitor.  However, Flurpiridaz does not inhibit cardiac mitochondrial 
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function. Mitochondria constitute 20% to 30% of the myocardial intracellular volume.  
Consequently, molecules that target mitochondrial proteins may be enriched and retained 
selectively in the myocardium.  The isotopic half-life of 18F is 110 minutes.   
All subjects will receive 2 IV boluses of Flurpiridaz (18F) Injection in a large peripheral vein: 1 
at rest and 1 during stress.  The dosages of Flurpiridaz (18F) Injection administered at rest and 
during stress conditions will not exceed a total of 14 mCi (520 MBq) for an individual subject. 
• Appearance: Clear, colourless, and free of visible particulate matter 
• Strength/concentration: [18F]Flurpiridaz ≥ 70 mCi in a nominal volume of 10 mL 
• Storage and handling conditions: Flurpiridaz is stable upon storage at 15°C to 25°C up to 
a maximum of 12 hours.  The exact expiry time of each dose will be included on the label.   
 
Section 8.1.2.2, Pharmacological Stress Agents, First Sentence 
Previously read: 
The Flurpiridaz (18F) Injection PET MPI study should use the same stress type 
(pharmacological or exercise) as used for SPECT MPI in the same subject.   
Now reads: 
The Flurpiridaz (18F) Injection PET MPI study must use the same stress type (pharmacological 
or exercise) as used for SPECT MPI in the same subject.   
 
Section 8.1.2, Other Medicinal Products (Non-IMP) 
New section heading introduced. 
 
Section 8.1.2.1, SPECT Agents 
Previously read: 
SPECT imaging must use 99mTc-based myocardial tracers. SPECT agents utilised for the 
purposes of this clinical study will be administered as per American Society of Nuclear 
Cardiology or European Association of Cardiovascular Imaging standards, where applicable, 
and recorded in the subject’s CRF. 
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Now reads: 
SPECT imaging must use 99mTc-based myocardial tracers, e.g., [99mTc]tetrofosmin or 
[99mTc]sestamibi. SPECT agents utilised for the purposes of this clinical study will be 
administered as per American Society of Nuclear Cardiology or European Association of 
Cardiovascular Imaging standards, where applicable, and recorded in the subject’s CRF. 
 
Section 8.1.3, Medicinal Product Accountability (previously IMP Accountability) 
Previously read: 
Each investigator is responsible for ensuring that deliveries of IMP(s) and other study materials 
from the Sponsor are correctly received, recorded, handled, and stored safely and properly in 
accordance with all applicable regulatory guidelines, and used in accordance with this protocol. 
All IMP containers (opened, unopened, or empty) must be destroyed on site after its scheduled 
use in accordance with site policies. See IMP handling procedures for further details on receipt, 
recording, handling, and accountability procedures. A list of IMP(s) and other  materials that 
were destroyed, must be prepared and signed by the principal investigator or designee. If there 
are any discrepancies, an explanation for these should also be provided. 
Package inserts, SmPCs, or other safety documents for IMPs will be supplied to the site by the 
Sponsor. 
Now reads: 
Each investigator is responsible for ensuring that deliveries of IMP, other medicinal products 
(specified above), and other study materials from the Sponsor are correctly received, recorded, 
handled, and stored safely and properly in accordance with all applicable regulatory guidelines, 
and used in accordance with this protocol. 
All IMP containers (opened, unopened, or empty) must be destroyed on site after its scheduled 
use in accordance with site policies.  See IMP handling procedures for further details on 
receipt, recording, handling, and accountability procedures related to IMP.  A list of IMP, 
other medicinal products and other materials that were destroyed, must be prepared and signed 
by the principal investigator or designee.  If there are any discrepancies, an explanation for 
these should also be provided. 
The site will be provided with the IB for the IMP. 
 
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Section 8.5, Prior and Concurrent Medications (previously Prior and Concurrent 
Therapy) 
Previously read: 
Any medications taken by the subject within 12 hours before the screening (or 12 hours before 
the SPECT stress test if the SPECT stress tests precede screening) and up to the end of the 
observation period of 2 weeks after Flurpiridaz (18F) Injection will be recorded in the CRF, 
along with the indication and dosage.  Either the generic or the trade name may be recorded.  
The Sponsor/contract research organisation (CRO) will encode all therapy and medication per 
a current well-recognised dictionary of medical codes. 
Now reads: 
Any medications taken by the subject within 12 hours before the screening (or 12 hours before 
the SPECT stress test if the SPECT stress tests precede screening) at the time of ICA and up to 
study completion will be recorded in the CRF, along with the indication and dosage.  Either the 
generic or the trade name may be recorded.  The Sponsor/contract research organisation (CRO) 
will encode all therapy and medication per a current well-recognised dictionary of medical 
codes. 
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Section 9, Study Procedures, Table 1 Study Schedule of Events 
Previously read: 
Variables 
Screening 
Baseline (≤30 days 
after Screening) 
Can occur in either order. 
SPECT may precede Screening a 
Safety Follow-up 
(2 to 3 days after 
PET MPI) 
Safety Follow-up 
(14 to 17 days after 
PET MPI) 
ICA (within 60 
days of Screening 
or “Off-study” a 
SPECT) 
Rest and Stress 
SPECT MPI 
Rest and Stress 
PET MPI 
Informed consent 
X 
 
 
 
 
 
 
Entry criteria 
X 
 
 
 
 
 
 
Drug and alcohol screening 
X 
 
 
 
 
 
 
Pregnancy test b 
X 
X 
 
X 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
Medical/surgical history 
X 
X 
 
 
 
 
 
Blood sampling 
X 
 
 
Xc 
 
 
 
Urine sampling 
X 
 
 
Xc 
 
 
 
Seattle Angina Questionnaire 
X 
 
 
 
 
 
 
Concurrent Medications 
 
X 
X 
X 
X 
X 
Xk 
Vital signs 
 
X 
X 
X 
 
 
Xk 
Pulse oximetry 
 
X 
X 
X 
 
 
Xk 
12-lead ECG recording 
Xd 
 
 
X 
 
 
 
Physical examination e 
 
X 
 
X 
 
 
 
Full neurologic examination f 
 
X 
 
X 
 
 
 
Injection site monitoring 
 
 
 
Xg 
 
 
 
IMP administration 
 
 
 
X 
 
 
 
Image acquisition  
 
 
Xh 
X i 
 
 
X 
Adverse events (including 
AEs and SAEs)j 
X 
X 
X 
X 
X 
X 
X 
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Variables 
Screening 
Baseline (≤30 days 
after Screening) 
Can occur in either order. 
SPECT may precede Screening a 
Safety Follow-up 
(2 to 3 days after 
PET MPI) 
Safety Follow-up 
(14 to 17 days after 
PET MPI) 
ICA (within 60 
days of Screening 
or “Off-study” a 
SPECT) 
Rest and Stress 
SPECT MPI 
Rest and Stress 
PET MPI 
a Results of “off-study” SPECT MPI that was performed prior to signing of the ICF but in accordance with procedures developed by the imaging core laboratory (ICL) and on a 
validated camera can be used. The “off-study” SPECT MPI must also achieve the minimal quality standard specified by the ICL in the same manner as a study SPECT MPI 
performed prospectively. If an “off-study” SPECT MPI does not achieve the minimal quality standards of the ICL, a repeat SPECT MPI can be performed and used as a study 
SPECT MPI if performed during the study.   
b For women of childbearing potential, the results of either a urine or serum human chorionic gonadotropin pregnancy test (with the result known the day of radiopharmaceutical 
administration) must be negative.   
c Before the first IMP injection and 1 hour after the last IMP injection.  
d 12 lead ECG collected on local ECG machine and interpreted by the investigator or a designee at the investigative site. A clinically indicated ECG obtained up to 48 hours prior 
to Screening is acceptable.   
e Physical examination will comprise a full examination with a specific focus on neurological and cardiovascular signs. During the Rest/Stress PET MPI Visit, a physical 
examination will be performed before and 1 hour after the administration of Flurpiridaz (18F) Injection for the stress exam. Additionally, a focused clinical screen for new or 
worsening symptoms indicative of unstable coronary artery disease will be conducted prior to the Flurpiridaz (18F) PET stress MPI 
f If any neurologic abnormalities are noted during physical examination. 
g Immediately after the first and second IMP administration and at 1 hour after the last IMP injection. 
h Rest SPECT MPI and then stress (exercise or physiologic) SPECT MPI, per the institution’s standard practices (the same stressor used for PET MPI, if PET MPI precedes 
SPECT MPI). 
i Rest PET MPI and then stress (exercise or physiologic, the same stressor used for SPECT MPI) PET MPI, per the institution’s standard practices. 
j Events collected from the time of informed consent through study completion. 
k Preprocedure vitals, pulse-oximetry and concomitant medications can be extracted from the clinical record 
 
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Now reads: 
Variables 
Screening 
Baseline (≤30 days 
after Screening) 
Can occur in either order. 
SPECT may precede Screening a 
Safety Follow-up 
(2 to 3 days after 
PET MPI) 
Safety Follow-up 
(14 to 17 days after 
PET MPI) 
ICA (within 60 
days of Screening 
or “Off-study” a 
SPECT) 
Rest and Stress 
SPECT MPI 
Rest and Stress 
PET MPI 
Informed consent 
X 
 
 
 
 
 
 
Entry criteria 
X 
 
 
 
 
 
 
Pregnancy test b 
X 
X 
 
X 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
Blood sampling 
Xl 
 
 
Xc 
 
 
 
Urine sampling 
X 
 
 
Xc 
 
 
 
Seattle Angina Questionnaire 
X 
 
 
 
 
 
 
Prior/concurrent medications 
X 
X 
X 
X 
X 
X 
Xk 
Vital signs 
 
X 
X 
X 
 
 
Xk 
Pulse oximetry 
 
X 
X 
X 
 
 
Xk 
12-lead ECG recording 
Xd 
 
 
X 
 
 
 
Physical examination e 
 
X 
 
X 
 
 
 
Full neurologic examination f 
 
X 
 
X 
 
 
 
Injection site monitoring 
 
 
 
Xg 
 
 
 
IMP administration 
 
 
 
X 
 
 
 
Image acquisition  
 
 
Xh 
X i 
 
 
X 
Adverse events (including 
AEs and SAEs)j 
X 
X 
X 
X 
X 
X 
X 
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Variables 
Screening 
Baseline (≤30 days 
after Screening) 
Can occur in either order. 
SPECT may precede Screening a 
Safety Follow-up 
(2 to 3 days after 
PET MPI) 
Safety Follow-up 
(14 to 17 days after 
PET MPI) 
ICA (within 60 
days of Screening 
or “Off-study” a 
SPECT) 
Rest and Stress 
SPECT MPI 
Rest and Stress 
PET MPI 
AE = adverse events; ECG = electrocardiogram; ICA = invasive coronary angiography; IMP = investigational medicinal product; MPI = myocardial perfusion imaging; PET = 
positron emission tomography; SAE = serious adverse events; SPECT = single photon emission computed tomography 
a Results of “off-study” SPECT MPI that was performed prior to signing of the ICF but in accordance with procedures developed by the imaging core laboratory (ICL) and on a 
validated camera can be used. The “off-study” SPECT MPI must also achieve the minimal quality standard specified by the ICL in the same manner as a study SPECT MPI 
performed prospectively. If an “off-study” SPECT MPI does not achieve the minimal quality standards of the ICL, a repeat SPECT MPI can be performed and used as a study 
SPECT MPI if performed during the study.   
b For women of childbearing potential, the results of either a urine or serum human chorionic gonadotropin pregnancy test (with the result known the day of radiopharmaceutical 
administration) must be negative.   
c Before the first IMP injection (blood and urine) and 1 hour after the last IMP injection (blood).  
d 12 lead ECG collected on local ECG machine and interpreted by the investigator or a designee at the investigative site. A clinically indicated ECG obtained up to 48 hours prior 
to Screening is acceptable.   
e Physical examination will comprise a full examination with a specific focus on neurological and cardiovascular signs. During the Rest/Stress PET MPI Visit, a physical 
examination will be performed before the rest portion of the Flurpiridaz (18F) Injection PET MPI and 1 hour after the stress portion of the Flurpiridaz (18F) Injection PET MPI. 
Additionally, a focused clinical screen for new or worsening symptoms indicative of unstable coronary artery disease will be conducted prior to performing any procedures at 
the Flurpiridaz (18F) PET Visit.  If the clinical status screening is positive, the Flurpiridaz (18F) PET Visit can either be rescheduled (up to 1 time) after symptoms stabilize or 
the subject can be discontinued from the study.   
f If any neurologic abnormalities are noted during physical examination. 
g Immediately prior to the first injection, and then immediately after the first injection of IMP for the rest exam, immediately after the second injection of IMP for the stress exam, 
and ultimately at 1 hour after the last injection of IMP. 
h Rest SPECT MPI and then stress (exercise or physiologic) SPECT MPI, per the institution’s standard practices (the same stressor used for PET MPI, if PET MPI precedes 
SPECT MPI). 
i Rest PET MPI and then stress (exercise or physiologic, the same stressor used for SPECT MPI) PET MPI, per the institution’s standard practices. 
j All serious and non-serious AEs will be collected from the time of informed consent and followed for a final outcome until the end of the follow-up period. 
k Preprocedure vitals, pulse-oximetry and concomitant medications can be extracted from the clinical record. 
l If for scheduling reasons, the study SPECT or PET MPI must occur rapidly after the screening visit (e.g., within 48 hours), an additional blood sample may be analysed by 
local labs to determine if the subject meets exclusion criteria. For all subjects, blood must be sent for central analysis for all protocol specified laboratory parameters, whether 
or not blood is sent to a local lab for limited biochemical analysis for screening purposes. 
 
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Section 9.1, Screening Visit 
Previously read: 
All screening assessments will occur within 30 days prior to Baseline Visit.  The Screening and 
Baseline Visits can be combined with the SPECT MPI Visit. The investigator must be mindful 
of the 60-day window between screening and ICA procedures.  The following will be done 
during the screening period: 
• Signed and dated ICF must be obtained from all subjects prior to their entering the study.  
Study informed consent must be obtained from each subject prior to the initiation of any 
study-related procedures. Rest and stress SPECT MPI studies that were performed before 
the subject signed the ICF (i.e., “off-study” SPECT) can be used if the SPECT MPI was 
performed in accordance with the study imaging manual and was performed on a camera 
that had already been validated for use in the study. 
• Medical and surgical history will be checked and recorded.  This medical history will 
include any significant past or present illnesses, by body system, as well as a complete 
cardiac history (including 5-year general medical history) and a pretest likelihood of CAD. 
The pretest likelihood of CAD will be derived from the European Society of Cardiology 
(ESC) guidelines on the management of stable CAD [Montalescot et al 2013] (see 
Appendix 15.4).  In addition, a Seattle Angina Questionnaire [Spertus et al 1995] (see 
Appendix 15.5) will be administered. 
• Demographic information will be recorded. 
• Subjects will be screened for current illicit drug and/or alcohol abuse. 
• Blood and urine samples will be collected for assessing haematology, abnormal glucose 
metabolism, liver or renal insufficiency, and alcohol and drug screening. 
• All subjects must satisfy all the inclusion criteria and none of the exclusion criteria listed in 
Sections 7.2 and 7.3.   
• For women of childbearing potential, the results of either a urine or serum human chorionic 
gonadotropin pregnancy test (with the result known on the day of Flurpiridaz (18F) 
Injection) must be negative; these subjects must be instructed to practice appropriate birth 
control from time of the screening to 30 days after the Flurpiridaz (18F) Injection.  A 
pregnancy test is not needed for women who are either surgically sterile (has a documented 
bilateral tubal ligation and oophorectomy and/or documented hysterectomy) or post-
menopausal (cessation of menses for more than 1 year).   
• 12-lead ECG recording will be performed. (A clinically indicated ECG performed within 
48 hours prior to screening, without intervening episodes of chest pain or instability, can be 
used as the Screening ECG). 
Waivers or protocol exceptions will not be granted prospectively by the Sponsor under any 
circumstances.  Any exceptions to protocol-specified requirements will be considered as 
protocol deviations. 
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Now reads: 
All screening assessments will occur within 30 days prior to Baseline Visit.  The Screening and 
Baseline Visits can be combined with the SPECT MPI Visit. The investigator must be mindful 
of the 60-day window between screening and ICA procedures.  The following will be done 
during the screening period: 
• Signed and dated ICF must be obtained from all subjects prior to their entering the study.  
Study informed consent must be obtained from each subject prior to the initiation of any 
study-related procedures. Rest and stress SPECT MPI studies that were performed before 
the subject signed the ICF (i.e., “off-study” SPECT) can be used if the SPECT MPI was 
performed in accordance with the study imaging manual and was performed on a camera 
that had already been validated for use in the study. 
• Medical and surgical history will be checked and recorded.  This medical history will 
include any significant past or present illnesses, by body system, as well as a complete 
cardiac history (including 5-year general medical history) and a pretest likelihood of CAD. 
The pretest likelihood of CAD will be derived from the European Society of Cardiology 
(ESC) guidelines on the management of stable CAD [Montalescot et al 2013] (see 
Appendix 15.4).  In addition, a Seattle Angina Questionnaire [Spertus et al 1995] (see 
Appendix 15.5) will be administered. 
• Prior and concurrent medications. 
• Demographic information will be recorded. 
• Blood and urine samples will be collected for assessing haematology, abnormal glucose 
metabolism, liver and renal insufficiency.  If for scheduling reasons, the study SPECT or 
study PET MPI must occur rapidly after the screening visit (e.g. within 48 hours), an 
additional blood sample may be analysed by local labs specifically to determine if the 
subject meets exclusion criteria (i.e. serum creatinine, AST, ALT and total bilirubin).  For 
all subjects, blood must be sent for central analysis of all protocol-specified laboratory 
parameters, whether or not blood is sent to a local lab for limited biochemical analysis for 
screening purposes (as noted above). 
• All subjects must satisfy all the inclusion criteria and none of the exclusion criteria listed in 
Sections 7.2 and 7.3.   
• For women of childbearing potential, the results of either a urine or serum human chorionic 
gonadotropin pregnancy test (with the result known on the day of Flurpiridaz (18F) 
Injection) must be negative; these subjects must be instructed to practice appropriate birth 
control from time of the screening to 30 days after the Flurpiridaz (18F) Injection.  A 
pregnancy test is not needed for women who are either surgically sterile (has a documented 
bilateral tubal ligation and oophorectomy and/or documented hysterectomy) or post-
menopausal (cessation of menses for more than 1 year).   
• 12-lead ECG recording will be performed. (A clinically indicated ECG performed within 
48 hours prior to screening, without intervening episodes of chest pain or instability, can be 
used as the Screening ECG). 
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• For subjects on beta-blocker therapy, a determination should be made, in concert with 
their treating physician, if there are any conditions in which discontinuation of beta-
blocker therapy could be contraindicated (e.g., tachyarrhythmias, uncontrolled or poorly 
controlled hypertension).  If medically safe, beta-blocker therapy should be withheld for 24 
hours prior to PET and SPECT stress test. 
• All AEs and SAEs that occur after informed consent will be recorded (see Table 1 for 
scheduled AE query points in time, and Sections 10.2.6, 10.2.7, and 10.2.8).   
Waivers or protocol exceptions will not be granted prospectively by the Sponsor under any 
circumstances.  Any exceptions to protocol-specified requirements will be considered as 
protocol deviations. 
 
Section 9.2, Baseline Visit (≤30 Days After Screening), Start of Bulleted List 
Previously read: 
At the Baseline Visit, the following will be performed: 
• Medical/surgical history will be recorded. 
• Physical examination will comprise a full examination with a specific focus on 
neurological and cardiovascular signs. 
…………………………….. 
Now reads: 
At the Baseline Visit, the following will be performed: 
• Physical examination will comprise a full examination with a specific focus on 
neurological and cardiovascular signs. 
…………………………. 
 
Section 9.3, Rest and Stress SPECT MPI Visit 
Previously read: 
The Rest and Stress SPECT MPI Visit can be combined with the Screening or Baseline Visit.  
Results of rest and stress SPECT MPI studies that were performed before the subject signed the 
ICF (i.e., an “off-study” SPECT MPI) can be used if the SPECT MPI was performed in 
accordance with the study imaging manual and was performed on a camera that had already 
been validated for use in the study.  The “off-study” SPECT MPI must also achieve the 
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minimal quality standard specified by the imaging core lab (ICL) in the same manner as a 
study SPECT MPI performed prospectively.  If an “off-study” SPECT MPI does not achieve 
the minimal quality standards of the ICL, a repeat SPECT MPI can be performed and used as a 
study SPECT MPI if performed during the study.  Depending on the institution’s standard 
practices, the rest and stress SPECT MPI procedures can take place on the same day or on 2 
consecutive days.  The Rest and Stress SPECT MPI Visit may take place before or after the 
Rest and Stress Flurpiridaz (18F) PET-MPI Visit.  The investigator must be mindful of the 60-
day window between SPECT MPI and ICA procedures.   
Subjects who are scheduled to undergo a pharmacologic stress test must not drink or eat 
caffeinated substances or take any dipyridamole-containing medication or methylxanthine-
containing medication within 12 hours prior to vasodilator administration for SPECT MPI.  In 
addition, it is recommended that patients who are scheduled to undergo exercise stress refrain 
from consuming any caffeinated substances, dipyridamole-containing medication, or 
methylxanthine-containing medication within 12 hours prior to the exercise stress test, to allow 
for the use of a pharmacologic stressor in the event that the subject does not reach the protocol-
required minimum 85% of age-predicted maximum heart rate (APMHR) or does not develop 
ischaemic symptoms during the exercise stress.  
No food will be allowed within 3 hours prior to either the pharmacologic stress or exercise 
stress. 
If the SPECT MPI Visit is combined with the Screening or Baseline Visits, all of the following 
elements that were scheduled for the Screening or Baseline Visit will be performed during the 
SPECT MPI Visit: 
• Informed consent will be obtained (Screening). 
• Entry criteria will be evaluated and recorded (Screening). 
• Medical/surgical history will be recorded (Screening/Baseline). 
• 12-lead ECG recording will be performed (Screening Visit). (A clinically-indicated ECG 
performed within 48 hours prior to screening, without intervening episodes of chest pain or 
instability, can be used as the Screening ECG). 
• Blood samples for laboratory testing will be collected (Screening). 
• Urine samples for laboratory testing will be collected (Screening). 
• Pregnancy test, for women of child-bearing potential (see the Study Schedule of Events 
[Table 1]; Screening/Baseline). 
• Drug and alcohol screening will be performed (Screening). 
• Demographic information will be recorded (Screening). 
• Concurrent medications will be recorded (Baseline Visit). 
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• Vital signs will be recorded (Baseline Visit). 
• Pulse oximetry will be recorded (Baseline Visit). 
• A physical examination will be performed (Baseline Visit). 
• If neurologic abnormalities are found during the physical examination, a full neurologic 
examination will be performed (Baseline Visit). 
At the Rest and Stress SPECT MPI Visit, the following will be performed for all subjects: 
• Concurrent medications will be recorded. 
• Vital signs will be recorded. 
• Pulse oximetry will be recorded. 
• Rest SPECT MPI will be performed, per the as per American Society of Nuclear 
Cardiology or European Association of Cardiovascular Imaging standards.   
• After the rest SPECT MPI, stress SPECT MPI will be performed, per American Society of 
Nuclear Cardiology or European Association of Cardiovascular Imaging standards.  
• If the subject has already undergone stress Flurpiridaz (18F) PET MPI, the same type of 
stress (pharmacologic or exercise) should be used in the stress SPECT MPI, including 
the same dose of the same pharmacologic stressor, unless otherwise clinically indicated.  
During pharmacologic stress, radiopharmaceutical injection will be administered during 
the peak vasodilatory effect, according to the respective prescribing information or 
SmPC (as applicable) of each stressor.  Acceptable pharmacologic stress agents are 
listed in Section 8.1.2.2.  
• If the subject has already undergone exercise stress Flurpiridaz (18F) PET MPI, the 
same exercise protocol should be used for the stress SPECT MPI, unless otherwise 
clinically indicated.   
• During exercise stress, the radiopharmaceutical for SPECT should be administered 
during peak stress, defined as ≥85% of the APMHR or following the occurrence of 
typical cardiac ischaemic symptoms.  Patients should continue to exercise for an 
additional 1 to 2 minutes, as clinically advisable, after the radiopharmaceutical 
injection. If a patient cannot reach the study-required minimum of 85% of the APMHR 
or does not develop ischaemic symptoms, the radiopharmaceutical should not be 
administered. 
• The standard clinical practice should be used for determining early termination of 
exercise or pharmacologic stress testing in the presence of any absolute or relative 
indications, including the presence of ischaemic symptoms (i.e., angina, or angina 
equivalent) for early termination.  The exercise stress test should be performed only by 
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experienced site personnel with access to resuscitation equipment.  Detailed 
recommendations for exercise testing performance must be followed as described in 
detail in the 2009 Recommendations for clinical exercise laboratories: a scientific 
statement from the American Heart Association (AHA) [Myers et al 2009]  
• Adverse events will be recorded per institution’s standard practices. 
• The images acquired during these procedures will be stored for the secondary blinded 
review, as specified in the Imaging Manual. 
Now reads: 
The Rest and Stress SPECT MPI Visit can be combined with the Screening or Baseline Visit.  
Results of rest and stress SPECT MPI studies that were performed before the subject signed the 
ICF (i.e., an “off-study” SPECT MPI) can be used if the SPECT MPI was performed in 
accordance with the study imaging manual and was performed on a camera that had already 
been validated for use in the study.  The “off-study” SPECT MPI must also achieve the 
minimal quality standard specified by the imaging core lab (ICL) in the same manner as a 
study SPECT MPI performed prospectively.  If an “off-study” SPECT MPI does not achieve 
the minimal quality standards of the ICL, a repeat SPECT MPI can be performed and used as a 
study SPECT MPI if performed during the study.  Depending on the institution’s standard 
practices, the rest and stress SPECT MPI procedures can take place on the same day or on 2 
consecutive days.  The Rest and Stress SPECT MPI Visit may take place before or after the 
Rest and Stress Flurpiridaz (18F) PET-MPI Visit.  The investigator must be mindful of the 60-
day window between SPECT MPI and ICA procedures.   
Subjects who are scheduled to undergo a pharmacologic stress test must not drink or eat 
caffeinated substances or take any dipyridamole-containing medication or methylxanthine-
containing medication within 12 hours prior to vasodilator administration for SPECT MPI.  In 
addition, it is recommended that patients who are scheduled to undergo exercise stress refrain 
from consuming any caffeinated substances, dipyridamole-containing medication, or 
methylxanthine-containing medication within 12 hours prior to the exercise stress test, to allow 
for the use of a pharmacologic stressor in the event that the subject does not reach the protocol-
required minimum 85% of age-predicted maximum heart rate (APMHR) or does not develop 
ischaemic symptoms during the exercise stress.  
No food will be allowed within 3 hours prior to either the pharmacologic stress or exercise 
stress. 
For subjects on beta-blocker therapy, a determination should be made, in concert with their 
treating physician, if there are any conditions in which discontinuation of beta-blocker therapy 
could be contraindicated (e.g., tachyarrhythmias, uncontrolled or poorly controlled 
hypertension).  If medically safe, beta-blocker therapy should be withheld for 24 hours prior to 
the SPECT MPI. 
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If the SPECT MPI Visit is combined with the Screening or Baseline Visits, all of the following 
elements that were scheduled for the Screening or Baseline Visit will be performed during the 
SPECT MPI Visit: 
• Informed consent will be obtained (Screening). 
• Entry criteria will be evaluated and recorded (Screening). 
• Medical/surgical history will be recorded (Screening). 
• 12-lead ECG recording will be performed (Screening Visit). (A clinically-indicated ECG 
performed within 48 hours prior to screening, without intervening episodes of chest pain or 
instability, can be used as the Screening ECG). 
• Blood samples for laboratory testing will be collected.  If for scheduling reasons, the study 
SPECT or study PET MPI must occur rapidly after the screening visit (e.g. within 
48 hours), an additional blood sample may be analysed by local labs specifically to 
determine if the subject meets exclusion criteria (i.e. serum creatinine, AST, ALT and total 
bilirubin).  For all subjects, blood must be sent for central analysis of all protocol-specified 
laboratory parameters, whether or not blood is sent to a local lab for limited biochemical 
analysis for screening purposes (as noted above) (Screening). 
• Urine samples for laboratory testing will be collected (Screening). 
• Pregnancy test, for women of child-bearing potential (see the Study Schedule of Events 
[Table 1]; Screening/Baseline). 
• Demographic information will be recorded (Screening). 
• Concurrent medications will be recorded (Baseline Visit). 
• Vital signs will be recorded (Baseline Visit). 
• Pulse oximetry will be recorded (Baseline Visit). 
• A physical examination will be performed (Baseline Visit). 
• If neurologic abnormalities are found during the physical examination, a full neurologic 
examination will be performed (Baseline Visit). 
At the Rest and Stress SPECT MPI Visit, the following will be performed for all subjects: 
• Concurrent medications will be recorded. 
• Vital signs will be recorded. 
• Pulse oximetry will be recorded. 
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• Rest SPECT MPI will be performed, per the as per American Society of Nuclear 
Cardiology or European Association of Cardiovascular Imaging standards.   
• After the rest SPECT MPI, stress SPECT MPI will be performed, per American Society of 
Nuclear Cardiology or European Association of Cardiovascular Imaging standards.  
• If the subject has already undergone stress Flurpiridaz (18F) PET MPI, the same type of 
stress (pharmacologic or exercise) should be used in the stress SPECT MPI, including 
the same dose of the same pharmacologic stressor, unless otherwise clinically indicated.  
During pharmacologic stress, radiopharmaceutical injection will be administered during 
the peak vasodilatory effect, according to the respective prescribing information or 
SmPC (as applicable) of each stressor.  Acceptable pharmacologic stress agents are 
listed in Section 8.1.2.2.  
• If the subject has already undergone exercise stress Flurpiridaz (18F) PET MPI, the 
same exercise protocol should be used for the stress SPECT MPI, unless otherwise 
clinically indicated.   
• During exercise stress, the radiopharmaceutical for SPECT should be administered 
during peak stress, defined as ≥85% of the APMHR or following the occurrence of 
typical cardiac ischaemic symptoms.  Patients should continue to exercise for an 
additional 1 to 2 minutes, as clinically advisable, after the radiopharmaceutical 
injection.  If a patient cannot reach the study-required minimum of 85% of the APMHR 
or does not develop ischaemic symptoms, the radiopharmaceutical should not be 
administered. 
• The standard clinical practice should be used for determining early termination of 
exercise or pharmacologic stress testing in the presence of any absolute or relative 
indications, including the presence of ischaemic symptoms (i.e., angina, or angina 
equivalent) for early termination.  The exercise stress test should be performed only by 
experienced site personnel with access to resuscitation equipment.  Detailed 
recommendations for exercise testing performance must be followed as described in 
detail in the 2009 Recommendations for clinical exercise laboratories: a scientific 
statement from the American Heart Association (AHA) [Myers et al 2009]  
• AEs and SAEs will be recorded. 
• The images acquired during these procedures will be stored for the secondary blinded 
review, as specified in the Imaging Manual. 
 
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Section 9.4, Rest and Stress Flurpiridaz (18F) PET-MPI Visit 
Previously read: 
……………………………………………………………. 
No food will be allowed within 3 hours prior to either the pharmacologic stress or exercise 
stress. 
A focused clinical screen for new or worsening symptoms indicative of unstable coronary 
artery disease will be conducted prior to the Flurpiridaz (18F) PET stress MPI.   
During the Rest and Stress Flurpiridaz (18F) PET-MPI Visit, the following will be performed: 
• Blood samples for laboratory testing will be collected prior to the PET MPI and 1 hour 
after the last PET-MPI injection.   
• Urine samples for laboratory testing will be collected prior to the PET MPI and 1 hour after 
the last PET-MPI injection. 
• Pregnancy test, for women of child-bearing potential (see the Study Schedule of Events 
[Table 1]). 
• Concurrent medications will be recorded.   
• Vital signs will be recorded. 
• Pulse oximetry will be recorded. 
• Eight 12-lead ECG recordings will be performed (See Section 10.2.3). 
• A physical examination will be performed. 
• If neurologic abnormalities are found during the physical examination, a full neurologic 
examination will be performed.   
• During the rest test, all subjects will receive an IV bolus injection of Flurpiridaz (18F) 
Injection in a large peripheral vein.  The dose (volume and radioactivity) will be recorded 
in the CRF. 
• A stress test (exercise or pharmacologic) will be performed after the rest test, and on the 
same day.   
• 
The type of stress (exercise or pharmacologic) will be the same type used for that 
subject for the SPECT MPI test.   
• 
For subjects who received a pharmacologic stressor during the stress SPECT MPI, 
the same agent and dose will be used during the stress Flurpiridaz (18F) PET-MPI 
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test.  During pharmacologic stress, radiopharmaceutical injection will be 
administered during the peak vasodilatory effect, according to the respective 
prescribing information or SmPC (as applicable) of each stressor.  Acceptable 
pharmacologic stress agents are listed in Section 8.1.2.2. 
• 
If adenosine is used as a pharmacologic stressor, the Flurpiridaz (18F) 
Injection and the adenosine must be administered through separate lines or 
through separate ports of the same IV line.  Note: Central lines should NOT be 
used for the administration of Flurpiridaz (18F) Injection.  The Flurpiridaz 
(18F) Injection will be administered after the administration of the 
pharmacologic stressor.  The administration of Flurpiridaz (18F) Injection will 
be timed to coincide with maximal coronary vasodilation, which depends on 
the vasodilatory agent used. 
• 
For a subject who underwent exercise stress for SPECT MPI, the investigator is 
required to use the same exercise stress protocol for the Flurpiridaz (18F) Injection 
PET that was used for the SPECT MPI, unless otherwise clinically indicated. 
• 
During exercise stress, the radiopharmaceutical for both SPECT and PET should be 
administered at peak stress, defined as ≥85% of the APMHR or following the 
occurrence of typical cardiac ischaemic symptoms.  Patients should continue to 
exercise for an additional 1 to 2 minutes, as clinically advisable, after the 
radiopharmaceutical injection.  If a patient cannot reach the study-required 
minimum of 85% of the APMHR or does not develop ischaemic symptoms, the 
radiopharmaceutical should not be administered. 
• 
The standard clinical practice should be used for determining early termination of 
exercise or pharmacologic stress testing in the presence of any absolute or relative 
indications, including the presence of ischaemic symptoms (i.e., angina, or angina 
equivalent) for early termination.  The exercise stress test should be performed only by 
experienced site personnel with access to resuscitation equipment.  Detailed 
recommendations for exercise testing performance must be followed as described in 
detail in the 2009 Recommendations for clinical exercise laboratories: a scientific 
statement from the AHA [Myers et al 2009]  
• At 1 hour after administration of Flurpiridaz (18F) Injection for the stress exam, a physical 
examination will be performed. 
• If any neurologic abnormalities are noted during the physical examination, a full neurologic 
examination will be performed. 
• Injection-site monitoring (immediately after the first injection of IMP for the rest exam, 
then immediately after the second injection of IMP for the stress exam, and ultimately at 1 
hour after the last injection of IMP). 
………………………………………………………………………………. 
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Now reads: 
……………………………………………………………. 
No food will be allowed within 3 hours prior to either the pharmacologic stress or exercise 
stress. 
For subjects on beta-blocker therapy, a determination should be made, in concert with their 
treating physician, if there are any conditions in which discontinuation of beta-blocker therapy 
could be contraindicated (e.g., tachyarrhythmias, uncontrolled or poorly controlled 
hypertension).  If medically safe, beta-blocker therapy should be withheld for 24 hours prior to 
the PET MPI.  A focused clinical screen for new or worsening symptoms indicative of unstable 
coronary artery disease will be conducted prior to performing any procedures at the Flurpiridaz 
(18F) PET visit.  If the clinical status screening is positive, the Flurpiridaz (18F) PET visit can 
either be rescheduled (up to 1 time) after symptoms stabilize or the subject can be discontinued 
from the study.   
During the Rest and Stress Flurpiridaz (18F) PET-MPI Visit, the following will be performed: 
• Blood samples for laboratory testing will be collected prior to the PET MPI and 1 hour 
after the last PET-MPI injection.  If for scheduling reasons, the study SPECT or study PET 
MPI must occur rapidly after the screening visit (e.g. within 48 hours), an additional blood 
sample may be analysed by local labs specifically to determine if the subject meets 
exclusion criteria (i.e., serum creatinine, AST, ALT and total bilirubin).  For all subjects, 
blood must be sent for central analysis of all protocol-specified laboratory parameters, 
whether or not blood is sent to a local lab for limited biochemical analysis for screening 
purposes (as noted above).   
• Urine samples for laboratory testing will be collected prior to the PET MPI. 
• Pregnancy test, for women of child-bearing potential (see the Study Schedule of Events 
[Table 1]). 
• Concurrent medications will be recorded.   
• Vital signs will be recorded. 
• Pulse oximetry will be recorded. 
• Eight 12-lead ECG recordings will be performed (See Section 10.2.3). 
• A physical examination will be performed. 
• If neurologic abnormalities are found during the physical examination, a full neurologic 
examination will be performed.   
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• During the rest test, all subjects will receive an IV bolus injection of Flurpiridaz (18F) 
Injection in a large peripheral vein.  The dose (volume and radioactivity) will be recorded 
in the CRF. 
• A stress test (exercise or pharmacologic) will be performed after the rest test, and on the 
same day.   
• 
The type of stress (exercise or pharmacologic) will be the same type used for that 
subject for the SPECT MPI test.   
• 
For subjects who received a pharmacologic stressor during the stress SPECT MPI, 
the same agent and dose will be used during the stress Flurpiridaz (18F) PET-MPI 
test.  During pharmacologic stress, radiopharmaceutical injection will be 
administered during the peak vasodilatory effect, according to the respective 
prescribing information or SmPC (as applicable) of each stressor.  Acceptable 
pharmacologic stress agents are listed in Section 8.1.2.2. 
• 
If adenosine is used as a pharmacologic stressor, the Flurpiridaz (18F) 
Injection and the adenosine must be administered through separate lines or 
through separate ports of the same IV line.  Note: Central lines should NOT be 
used for the administration of Flurpiridaz (18F) Injection.  The Flurpiridaz 
(18F) Injection will be administered after the administration of the 
pharmacologic stressor.  The administration of Flurpiridaz (18F) Injection will 
be timed to coincide with maximal coronary vasodilation, which depends on 
the vasodilatory agent used. 
• 
For a subject who underwent exercise stress for SPECT MPI, the investigator is 
required to use the same exercise stress protocol for the Flurpiridaz (18F) Injection 
PET that was used for the SPECT MPI, unless otherwise clinically indicated. 
• 
During exercise stress, the radiopharmaceutical for both SPECT and PET should be 
administered at peak stress, defined as ≥85% of the APMHR or following the 
occurrence of typical cardiac ischaemic symptoms.  Patients should continue to 
exercise for an additional 1 to 2 minutes, as clinically advisable, after the 
radiopharmaceutical injection.  If a patient cannot reach the study-required 
minimum of 85% of the APMHR or does not develop ischaemic symptoms, the 
radiopharmaceutical should not be administered. 
• 
The standard clinical practice should be used for determining early termination of 
exercise or pharmacologic stress testing in the presence of any absolute or relative 
indications, including the presence of ischaemic symptoms (i.e., angina, or angina 
equivalent) for early termination.  The exercise stress test should be performed only by 
experienced site personnel with access to resuscitation equipment.  Detailed 
recommendations for exercise testing performance must be followed as described in 
detail in the 2009 Recommendations for clinical exercise laboratories: a scientific 
statement from the AHA [Myers et al 2009]  
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• At 1 hour after administration of Flurpiridaz (18F) Injection for the stress exam, a physical 
examination will be performed. 
• If any neurologic abnormalities are noted during the physical examination, a full neurologic 
examination will be performed. 
• Injection-site monitoring (immediately prior to the first injection, immediately after the first 
injection of IMP for the rest exam, then immediately after the second injection of IMP for 
the stress exam, and ultimately at 1 hour after the last injection of IMP). 
………………………………………………………………………………. 
 
Section 9.6, Safety Follow-up 14 to 17 Days After Flurpiridaz (18F) PET MPI, First 
Sentence 
Previously read: 
All subjects will be followed up by telephone assessments for AEs and SAEs within 2 days 
(+24 hours) following administration of Flurpiridaz (18F) Injection.   
Now reads: 
All subjects will be followed up by telephone assessments for AEs and SAEs within 14 to 17 
days following administration of Flurpiridaz (18F) Injection.   
 
Section 10.1.4, Image Acquisition, Second Paragraph 
Previously read: 
Image acquisition with SPECT and PET at rest and under stress procedures will be defined in 
the dedicated Imaging Manual. 
Now reads: 
Image acquisition with SPECT and PET at rest and under stress procedures will be defined in 
the dedicated PET and SPECT Imaging Manual. 
 
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Section 10.1.5, Image Interpretation and Correlation with Standard of Truth 
Previously read: 
Three qualified independent readers will perform a blinded assessment of each subject’s PET 
image pair (rest and stress images) and each subject’s SPECT image pair.  Further details will 
be provided in the study Independent Review Charter. 
One blinded reviewer will perform QCA, according to the Imaging Manual, for all ICA 
images.   
Now reads: 
Three qualified independent readers will perform a blinded assessment of each subject’s PET 
image pair (rest and stress images) and each subject’s SPECT image pair.  Further details will 
be provided in the study PET and SPECT Independent Review Charter. 
One blinded reviewer will perform QCA, according to the Angiography Independent Review 
Charter, for all ICA images.   
 
Section 10.2.1, Clinical Laboratory Evaluation, Table 3 and following paragraphs 
Previously read: 
Table 3 
Clinical Laboratory Parameters 
Serum Biochemistry 
Haematology 
Urinalysis 
Alanine aminotransferase (ALT) 
Albumin 
Aspartate aminotransferase (AST) 
Bicarbonate 
Bilirubin (total) 
Calcium 
Chloride 
Creatinine 
Gamma-glutamyltransferase 
Glucose 
Lactate dehydrogenase 
Potassium 
Protein (total) 
Sodium 
Urea nitrogen 
Haematocrit 
Platelet count 
White blood cell (WBC) count 
Bilirubin 
Glucose 
Ketone 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
The signed and interpreted laboratory results will be kept together with the subject’s CRF 
(paper or electronic) as supplemental pages, both centrally and at the site. 
Blood samples will be obtained for assessment of serum biochemistry and haematology at the 
various pre- and post-treatment time point ranges described in Table 1.  It is anticipated that the 
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maximum amount of blood taken will not be more than 50 mL for all the samples taken during 
the subject’s study participation.  Samples will be analysed at a central laboratory (for 
parameters, see Table 3).  All blood samples will be processed and handled per standard 
laboratory procedures.  All retained samples will be destroyed after completion of the study.   
………………. 
Now reads: 
Table 3 
Clinical Laboratory Parameters 
Serum Biochemistry 
Haematology 
Urinalysis 
Alanine aminotransferase (ALT) 
Albumin 
Aspartate aminotransferase (AST) 
Bicarbonate 
Bilirubin (total) 
Calcium 
Chloride 
Creatinine 
Gamma-glutamyltransferase 
Glucose 
Hemoglobin A1c 
Lactate dehydrogenase 
Potassium 
Protein (total) 
Sodium 
Urea nitrogen 
Haematocrit 
Platelet count 
White blood cell (WBC) count 
Bilirubin 
Glucose 
Ketone 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
The signed and interpreted laboratory results will be kept together with the subject’s CRF 
(paper or electronic) as supplemental pages, both centrally and at the site. 
Blood samples will be obtained for assessment of serum biochemistry and haematology at the 
various pre- and post-treatment time point ranges described in Table 1.  It is anticipated that the 
maximum amount of blood taken will not be more than 50 mL for all the samples taken during 
the subject’s study participation.  Samples will be analysed at a central laboratory (for 
parameters, see Table 3).  All blood samples will be processed and handled per standard 
laboratory procedures.  All retained samples will be destroyed after completion of the study.  
For the purposes of screening, an additional blood sample may be analysed by local labs 
specifically to determine if the subject meets exclusion criteria (i.e., serum creatinine, AST, 
ALT and total bilirubin). 
………………. 
 
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Section 10.2.2, Vital Signs, First Sentence 
Previously read: 
Vital signs (blood pressure, heart rate, respiratory rate, temperature) will be monitored at 
Baseline (prior to IMP administration) and during the in- and outpatient follow-up periods, 
according to the Study Schedule of Events (Table 1).   
Now reads: 
Vital signs (pulse oximetry, blood pressure, heart rate, respiratory rate, temperature) will be 
monitored at Baseline (prior to IMP administration) and during the in- and outpatient follow-up 
periods, according to the Study Schedule of Events (Table 1).   
 
Section 10.2.3.1, Investigational Site Responsibilities, Third and Fourth Paragraphs 
Previously read: 
Pre-specified normal limits and expanded normal limits for 12-lead ECG intervals are provided 
in Section 15.3.  Each 12-lead ECG tracing must be signed and dated, and the assessment 
results collected in the CRF.  During continuous ECG monitoring, the investigator will observe 
the real-time ECG findings and take note of any changes in intervals and/or waveforms.  The 
continuous ECG monitoring need not be 12-lead. 
Each 12-lead ECG at each time point (all intervals, heart rate and interpretation, and identified 
with the subject’s initials, subject’s study number, and date and time of recording), will be 
retained in the investigator’s study record for each subject.  The investigator will not be 
expected to calculate QTc intervals.  A copy of the ECG strips will be provided to the Sponsor 
or the Sponsor’s representative with the subject’s CRF. 
Now reads: 
Pre-specified normal limits and expanded normal limits for 12-lead ECG intervals are provided 
in Section 15.3.  Each 12-lead ECG tracing must be signed and dated, and the assessment 
results collected in the CRF.  During continuous ECG monitoring, the investigator or 
appropriate delegate (concordant with local practice) will observe the real-time ECG findings 
and take note of any changes in intervals and/or waveforms.  The continuous ECG monitoring 
need not be 12-lead. 
Each 12-lead ECG at each time point (all intervals, heart rate and interpretation, and identified 
with the subject’s initials, subject’s study number, and date and time of recording), will be 
retained in the investigator’s study record for each subject.  The investigator will not be 
expected to calculate QTc intervals.   
 
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Section 10.2.4, Physical Examination, First Paragraph 
Previously read: 
A qualified physician or a non-physician medically certified individual who is certified either 
by State/National law to perform physical examinations will conduct physical examinations at 
the baseline time point, 30 minutes prior to administration, and at the 1 hour post-treatment 
time point. The same individual should conduct the physical examination at all required time 
points. The physical examination will include recording an assessment for the presence of 
abnormalities of the following: general appearance, skin, head, eyes, ears, nose, throat, lungs, 
breasts and axillae, cardiovascular system, back and spine, abdomen, extremities, injection site, 
lymph nodes, and neurological exam. 
Now reads: 
A qualified physician or a non-physician medically certified individual who is certified either 
by State/National law to perform physical examinations will conduct physical examinations at 
the baseline time point, before the Flurpiridaz (18F) Injection rest MPI exam and 1 hour after 
the Flurpiridaz (18F) Injection stress MPI exam.  Ideally, the same individual should conduct 
the physical examination at all required time points.  The physical examination will include 
recording an assessment for the presence of abnormalities of the following: general 
appearance, skin, head, eyes, ears, nose, throat, lungs, cardiovascular system, back and spine, 
abdomen, extremities, injection site, lymph nodes, and neurological exam. 
 
Section 10.2.6, Adverse Events (previously Treatment-emergent Adverse Events) 
Previously read: 
Study personnel must remain vigilant for the occurrence of AEs, particularly those that may be 
life threatening.  Personnel who are trained in the acute management of anaphylaxis and other 
emergencies and who have access to appropriate clinical supplies must be immediately 
available for 1 hour after dosing.  Treatment of SAEs should be primarily supportive of vital 
functions. 
AE Definition: An AE is defined as any untoward medical occurrence or an already present 
event that worsens either in intensity or frequency.  A treatment-emergent adverse event 
(TEAE) is an AE which occurs temporally following exposure to the investigational agent.  A 
TEAE is defined as an AE that starts on or after the time of the first injection of Flurpiridaz 
until the follow-up visit 14-17 days later.  The TEAE does not necessarily have to have a 
causal relationship with exposure to the investigational agent.  A TEAE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the exposure to an IMP, whether or not considered related 
to that product.   
The subjects will be closely observed and questioned for any kind of AE during the study 
procedures and at follow-up appointments throughout the study period with non-leading 
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questioning (e.g., “How do you feel?”).  The subjects will be instructed to immediately report 
any symptoms and signs to the study staff (i.e., between formal observations). 
Both the investigator(s) and Sponsor/CRO will perform a causality assessment on any AE, to 
assess whether or not there is a reasonable possibility (evidence to suggest) that the IMP 
caused the event.   
Adverse Reaction: An AE that is caused by the IMP. 
Suspected Adverse Reaction: A reasonable possibility exists for causality between the IMP 
and the AE. 
Laboratory AE Evaluation 
Interpretation and follow-up of abnormal laboratory test results should be conducted in 
consideration of the clinical situation of the subject.  Any abnormal laboratory findings that 
constitute an AE should be reported as such and should be followed up until the outcome is 
known.  Also, additional diagnostic tests may be indicated to determine a more precise 
diagnosis of the subject’s condition (e.g., ordering a WBC differential to help characterise a 
high or low WBC count, or ordering a determination of red cell indices to help characterise a 
low haematocrit). 
Now reads: 
All AEs/SAEs that occur after informed consent shall be recorded in the AE/SAE report form 
(see the Study Schedule of Events, Table 1).   
Study personnel must remain vigilant for the occurrence of AEs after administration of IMP 
(see Section 8.1), particularly those that may be life threatening.  Personnel who are trained in 
the acute management of anaphylaxis and other emergencies and who have access to 
appropriate clinical supplies must be immediately available for 1 hour after dosing.  Treatment 
of SAEs should be primarily supportive of vital functions. 
AE and TEAE Definition: An AE is defined as any untoward medical occurrence or an 
already present event that worsens either in intensity or frequency.  A treatment-emergent 
adverse event (TEAE) is defined as an AE that starts on or after the time of the first injection of 
Flurpiridaz until the follow-up visit 14-17 days later.  The TEAE does not necessarily have to 
have a causal relationship with exposure to the investigational agent.  A TEAE can therefore be 
any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the exposure to the IMP, whether or not considered related 
to that product.   
The subjects will be closely observed and questioned for any kind of AE during the study 
procedures and at follow-up appointments throughout the study period with non-leading 
questioning (e.g., “How do you feel?”).  The subjects will be instructed to immediately report 
any symptoms and signs to the study staff (i.e., between formal observations). 
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Both the investigator(s) and Sponsor/CRO will perform a causality assessment on any AE, to 
assess whether or not there is a reasonable possibility (evidence to suggest) that the IMP 
caused the event.   
Suspected Adverse Reaction: A reasonable possibility exists for causality between the IMP 
and the AE. 
Laboratory AE Evaluation 
Interpretation and follow-up of abnormal laboratory test results should be conducted in 
consideration of the clinical situation of the subject.  Any abnormal laboratory findings that 
constitute an AE should be reported as such and should be followed up until the outcome is 
known.  Also, additional diagnostic tests may be indicated to determine a more precise 
diagnosis of the subject’s condition (e.g., ordering a WBC differential to help characterise a 
high or low WBC count, or ordering a determination of red cell indices to help characterise a 
low haematocrit); see also Section 10.2.8 (Other Significant Adverse Events). 
 
Section 10.2.7, Serious Adverse Events, Final Paragraph 
Previously read: 
For this study, these types of hospitalisations and/or imaging findings will not be considered 
AEs or SAEs and will not be reported as such in the CRFs. However, these observations and 
hospitalisations will be reported elsewhere in the eCRF. 
Now reads: 
For this study, these types of hospitalisations and/or imaging findings will not be considered 
AEs or SAEs and will not be reported as such in the CRFs. 
 
Section 10.2.9, Adverse Event and Serious Adverse Event Reporting 
Previously read: 
All AEs should be recorded using acceptable diagnoses, if possible.  If an AE has already been 
reported, it is not necessary to report each individual sign and symptom of that AE as a 
separate AE.  For example, if MI is reported as an AE, there is no need to report elevated 
creatine kinase and abnormal ECG, or other related signs, symptoms, or laboratory values as 
separate AEs.  However, if both occurred in isolation and MI was not diagnosed, then each 
event would be reported as an AE. 
The intensity of all AEs will be graded as mild, moderate, or severe using the following 
definitions: 
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Mild: 
Tolerable. 
Moderate: 
Interferes with normal activity. 
Severe: 
Incapacitating (causes inability to perform usual activity or work). 
The investigator will be instructed to closely monitor each subject who experiences an AE 
(whether ascribed to the IMP or not) until the outcome of the AE has been determined. 
In addition to the investigator’s own description of the AEs, each AE will be encoded by the 
Sponsor/CRO according to a well-recognised dictionary of medical codes. 
SAEs will be recorded in the CRF if they occurred as follows: 
• 
After a subject first received an IMP and throughout the subject’s follow-up period*, 
whether or not considered related to the IMP, and 
• 
After the subject’s follow-up period, and for which a causal relationship to the IMP 
cannot be ruled out. 
(*Follow-up period is defined as the protocol-stipulated period or, for subjects prematurely 
withdrawn from a study, the duration of a subject’s participation.) 
All serious and non-serious AEs must be followed for a final outcome until the end of the 
follow-up period.  An outcome of “unknown” is not considered to be an acceptable final 
outcome.  An outcome of “not yet resolved” is an acceptable final outcome for non-serious 
AEs at the end of a subject’s participation in a study, and for SAEs at database lock. 
Study centres are instructed to report all SAEs, together with a causality assessment, to 
the Sponsor (or a service provider acting on behalf of the Sponsor) within 24 hours. 
Detailed information will be provided in a Safety Management Plan.   
……………………………………….. 
Now reads: 
All AEs/SAEs shall be recorded in the AE/SAE report form using acceptable diagnoses, if 
possible.  If an AE has already been reported, it is not necessary to report each individual sign 
and symptom of that AE as a separate AE.  For example, if myocardial infarction (MI) is 
reported as an AE, there is no need to report elevated creatine kinase and abnormal ECG, or 
other related signs, symptoms, or laboratory values as separate AEs.  However, if both 
occurred in isolation and MI was not diagnosed, then each event would be reported as an AE. 
The intensity of all AEs will be graded as mild, moderate, or severe using the following 
definitions: 
Mild: 
Tolerable. 
Moderate: 
Interferes with normal activity. 
Severe: 
Incapacitating (causes inability to perform usual activity or work). 
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The investigator will be instructed to closely monitor each subject who experiences an AE 
(whether ascribed to the IMP or not) until the outcome of the AE has been determined. 
In addition to the investigator’s own description of the AEs, each AE will be encoded by the 
Sponsor/CRO according to a well-recognised dictionary of medical codes, e.g., Medical 
Dictionary for Regulatory Activities (MedDRA). 
All AEs/SAEs must be followed for a final outcome until the end of the follow-up period.  An 
outcome of “unknown” is not considered to be an acceptable final outcome.  An outcome of 
“not yet resolved” is an acceptable final outcome for non-serious AEs at the end of a subject’s 
participation in a study, and for SAEs at database lock. 
Study centres are instructed to report all SAEs, together with a causality assessment, to 
the Sponsor (or a service provider/CRO acting on behalf of the Sponsor) within 24 hours. 
AEs and SAEs are reported in the AE form of the eCRF. Detailed information about 
management of AE information will be provided, e.g., in a Safety Management Plan.   
………………………………….. 
 
Section 10.2.11, Pregnancy Reporting, Final Paragraph 
Previously read: 
The investigator must inform the Sponsor/CRO within 24 hours of receiving positive 
pregnancy test results by using either a copy of the relevant CRF page (demography or AE) or 
via email.  The investigator should include an estimated date of conception when 
communicating with the Sponsor/CRO. 
Now reads: 
The investigator must inform the Sponsor/CRO within 24 hours of receiving positive 
pregnancy test results by using either a copy of the relevant CRF pages (demography, exposure 
to medicinal products, and/or AE) or via email.  The investigator should include an estimated 
date of conception when communicating with the Sponsor/CRO. 
 
Section 10.3.1, Demographic Data 
Previously read: 
Subject demographic data (date of birth, race, sex, weight, and height) will be recorded at 
Screening.  Subject age at the time of randomisation will be calculated from the date of birth 
and the date of baseline.  BMI will be calculated from height and weight.  If local regulations 
do not permit collection of specific demographic items (e.g., date of birth), a dummy date will 
be used in accordance with local practice. 
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Now reads: 
Subject demographic data (date of birth/age, race, ethnicity, sex, weight, and height) will be 
recorded at Screening.  Subject age at the time of enrolment will be calculated from the date of 
birth and the date of baseline.  BMI will be calculated from height and weight.  If local 
regulations do not permit collection of specific demographic items (e.g., date of birth), either 
age will be entered on the eCRF or a partial date will be used in accordance with local 
practice. 
 
Section 10.3.2, Medical and Surgical History 
Previously read: 
The subjects’ relevant medical and surgical history will be recorded at Screening and Baseline 
and will be summarised. 
Now reads: 
The subjects’ relevant medical and surgical history will be recorded at Screening and will be 
summarised. 
 
Section 10.3.3, Prior and Concurrent Medication 
Previously read: 
Any medications taken by the subject within 12 hours before the screening or the SPECT stress 
test if it precedes screening and up to the end of the observation period of 2 weeks after 
Flurpiridaz (18F) Injection will be recorded in the CRF, along with the indication and dosage.  
Either the generic or the trade name may be recorded.  The CRO will encode all therapy and 
medication per a current well-recognised dictionary of medical codes. 
Now reads: 
Any medications taken by the subject within 12 hours before the screening or the SPECT stress 
test if it precedes screening, at the time of ICA and up to study completion will be recorded in 
the CRF, along with the indication and dosage.  Either the generic or the trade name may be 
recorded.  The CRO will encode all therapy and medication per a current well-recognised 
dictionary of medical codes. 
 
Section 10.3.4, Drug and Alcohol Screening 
Section deleted. 
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Section 11.1, Completing and Signing Case Report Forms 
Previously read: 
For electronic CRFs (eCRFs), data will be entered by trained site personnel with reasons given 
for any missing data.  Any errors should be corrected within the electronic system.  The audit 
trail will record all changes made, the reason for the change, the date and time of the 
correction, and the person correcting the error.  The appropriate electronic signature will be 
provided. 
Any data recorded directly in the CRF, for which no other written or electronic record will be 
maintained in the subject’s medical record, will be considered source data and should be signed 
by the investigator(s) (e.g., results of physical examinations, vital signs testing, or the IMP 
administration procedure). 
Now reads: 
For electronic CRFs (eCRFs), data will be entered by trained site personnel with reasons given 
for any missing data.  Any errors should be corrected within the electronic system.  The audit 
trail will record all changes made, the reason for the change, the date and time of the 
correction, and the person correcting the error.  The appropriate electronic signature will be 
provided. 
 
Section 12.3, Subject Demographics/Other Baseline Characteristics, Second Paragraph 
Previously read: 
Demographic information (age, height, weight, and BMI) will be summarised by using 
descriptive statistics.  Sex and race will be summarised by counts and percentages. 
Now reads: 
Demographic information (age, height, weight, and BMI) will be summarised by using 
descriptive statistics.  Sex, ethnicity, and race will be summarised by counts and percentages. 
 
Section 12.4, Study Treatments, Second Paragraph 
Previously read: 
Any medications taken by the subject within 12 hours before and up to the end of the 
observation period (including the drug stressor) will be recorded in the CRF along with the 
indication and dosage.  Either the generic or the trade name may be recorded.  The CRO will 
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encode all therapy and medication according to a current well-recognized dictionary of medical 
codes. 
Now reads: 
Any other medications taken by the subject within 12 hours before and up to study completion 
will be recorded in the CRF along with the indication and dosage.  Either the generic or the 
trade name may be recorded.  The CRO will encode all therapy and medication according to a 
current well-recognized dictionary of medical codes. 
 
Section 12.5.6, Handling of Uninterpretable Images 
Previously read: 
Once a subject is included in the MITT population, the readers will be asked to read PET MPI 
images and to classify the images as normal or abnormal, regardless of image quality and 
interpretability.  To document when a diagnosis is forced, the reader will use the blinded read 
CRF to record which images are considered uninterpretable. 
Now reads: 
Once a subject is included in the MITT population, the readers will be asked to read PET MPI 
images and to classify the images as normal or abnormal, regardless of image quality and 
interpretability.   
 
Section 12.8.5, Adverse Events, First Sentence 
Previously read: 
AEs and SAEs will be coded by using the Medical Dictionary for Regulatory Activities 
(MedDRA), and all reported events will be listed for the safety population. 
Now reads: 
AEs and SAEs will be coded by using a current version of MedDRA, and all reported events 
will be listed for the safety population. 
 
Section 13.3.2, Subject Informed Consent 
Previously read: 
Written and oral information about the study in a language understandable by the subject will 
be given to all subjects.  Each subject’s willingness to participate in the study will be 
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documented in a signed and dated ICF before any procedures or assessments are done and after 
the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force 
are explained.  It will also be explained to the subjects that they are free to refuse entry into the 
study and free to withdraw from the study at any time without prejudice to future treatment.  
The informed consent process will be documented in the subject's medical record; and the 
investigator will sign, date, and time the ICF after the subject has signed, dated, and recorded 
the time.  The investigator(s) will keep the original consent forms, and copies will be given to 
the subjects. 
Now reads: 
Written and oral information about the study in a language understandable by the subject will 
be given to all subjects.  Each subject’s willingness to participate in the study will be 
documented in a signed and dated ICF before any procedures or assessments are done and after 
the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force 
are explained.  It will also be explained to the subjects that they are free to refuse entry into the 
study and free to withdraw from the study at any time without prejudice to future treatment.  
The informed consent process will be documented in the subject's medical record; and the 
investigator will sign and date the ICF after the subject has signed and dated the ICF.  The 
investigator(s) will keep the original consent forms, and copies will be given to the subjects. 
 
Section 15.1, Information on Investigational and Registered Products 
Previously read: 
The reference document for this study is the current Investigator’s Brochure (IB).  The 
reference document provides up-to-date information on the efficacy and safety of Flurpiridaz 
(18F) Injection and is used for assessing expectedness of Serious Adverse Drug Reactions, in 
order to determine regulatory reportability.  An unexpected adverse drug reaction is a reaction 
for which the nature, seriousness, severity or outcome is not consistent with the applicable 
product information (e.g., the IB for an unapproved IMP).   
Now reads: 
The reference document for the IMP in this study is the current IB.  The reference document 
provides up-to-date information on the efficacy and safety of Flurpiridaz (18F) Injection and is 
used for assessing expectedness of Serious Adverse Drug Reactions, in order to determine 
regulatory reportability.  An unexpected adverse drug reaction is a reaction for which the 
nature, seriousness, severity or outcome is not consistent with the IB.   
GE Healthcare marketed medicinal products like Myoview (99mTc based SPECT MPI agent) 
and Rapiscan (a pharmacological stress agent) may be used in this trial.  Reference safety 
information for assessment of expectedness are company core safety information, and 
approved SmPC or US Package Insert in the country of occurrence. 
No expectedness assessment will be performed for other medicinal products. 
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16.2 
Amendment A02 
16.2.1 
Reasons for Amendment 
• 
Clarification of time points for recording vital signs.  
• 
Section 10.2.1 corrected to clarify urine will be collected at pre-treatment time points 
only, in line with the Schedule of Events. 
• 
Medical Director details are updated following a change in personnel. 
Where appropriate the changes are indicated in italics. 
16.2.2 
Description of Changes 
Title Page, Medical Director Details 
Previously read: 
 
 
The Grove Centre, GC-18 
White Lion Road 
Bucks Amersham HP7 9LL 
Phone:
 
Mobile:
 
Email: 
 
Now reads: 
 
 
GE Healthcare 
Pollards Wood, Nightingales Lane 
Chalfont St Giles 
Buckinghamshire HP8 4SP 
United Kingdom 
Phone:
 
Email:
 
 
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Section 9, Study Procedures, Table 1 Study Schedule of Events 
Previously read: 
Table 1 
Study Schedule of Events 
Variables 
Screening 
Baseline (≤30 days 
after Screening) 
Can occur in either order. 
SPECT may precede Screening a 
Safety Follow-up 
(2 to 3 days after 
PET MPI) 
Safety Follow-up 
(14 to 17 days after 
PET MPI) 
ICA (within 60 
days of Screening 
or “Off-study” a 
SPECT) 
Rest and Stress 
SPECT MPI 
Rest and Stress 
PET MPI 
Informed consent 
X 
 
 
 
 
 
 
Entry criteria 
X 
 
 
 
 
 
 
Pregnancy test b 
X 
X 
 
X 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
Blood sampling 
Xl 
 
 
Xc 
 
 
 
Urine sampling 
X 
 
 
Xc 
 
 
 
Seattle Angina Questionnaire 
X 
 
 
 
 
 
 
Prior/concurrent medications 
X 
X 
X 
X 
X 
X 
Xk 
Vital signs 
 
X 
X 
X 
 
 
Xk 
Pulse oximetry 
 
X 
X 
X 
 
 
Xk 
12-lead ECG recording 
Xd 
 
 
X 
 
 
 
Physical examination e 
 
X 
 
X 
 
 
 
Full neurologic examination f 
 
X 
 
X 
 
 
 
Injection site monitoring 
 
 
 
Xg 
 
 
 
IMP administration 
 
 
 
X 
 
 
 
Image acquisition  
 
 
Xh 
X i 
 
 
X 
Adverse events (including 
AEs and SAEs)j 
X 
X 
X 
X 
X 
X 
X 
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Table 1 
Study Schedule of Events 
Variables 
Screening 
Baseline (≤30 days 
after Screening) 
Can occur in either order. 
SPECT may precede Screening a 
Safety Follow-up 
(2 to 3 days after 
PET MPI) 
Safety Follow-up 
(14 to 17 days after 
PET MPI) 
ICA (within 60 
days of Screening 
or “Off-study” a 
SPECT) 
Rest and Stress 
SPECT MPI 
Rest and Stress 
PET MPI 
AE = adverse events; ECG = electrocardiogram; ICA = invasive coronary angiography; IMP = investigational medicinal product; MPI = myocardial perfusion imaging; PET = 
positron emission tomography; SAE = serious adverse events; SPECT = single photon emission computed tomography 
a Results of “off-study” SPECT MPI that was performed prior to signing of the ICF but in accordance with procedures developed by the imaging core laboratory (ICL) and on a 
validated camera can be used. The “off-study” SPECT MPI must also achieve the minimal quality standard specified by the ICL in the same manner as a study SPECT MPI 
performed prospectively. If an “off-study” SPECT MPI does not achieve the minimal quality standards of the ICL, a repeat SPECT MPI can be performed and used as a study 
SPECT MPI if performed during the study.   
b For women of childbearing potential, the results of either a urine or serum human chorionic gonadotropin pregnancy test (with the result known the day of radiopharmaceutical 
administration) must be negative.   
c Before the first IMP injection (blood and urine) and 1 hour after the last IMP injection (blood).  
d 12 lead ECG collected on local ECG machine and interpreted by the investigator or a designee at the investigative site. A clinically indicated ECG obtained up to 48 hours prior 
to Screening is acceptable.   
e Physical examination will comprise a full examination with a specific focus on neurological and cardiovascular signs. During the Rest/Stress PET MPI Visit, a physical 
examination will be performed before the rest portion of the Flurpiridaz (18F) Injection PET MPI and 1 hour after the stress portion of the Flurpiridaz (18F) Injection PET MPI. 
Additionally, a focused clinical screen for new or worsening symptoms indicative of unstable coronary artery disease will be conducted prior to performing any procedures at 
the Flurpiridaz (18F) PET Visit.  If the clinical status screening is positive, the Flurpiridaz (18F) PET Visit can either be rescheduled (up to 1 time) after symptoms stabilize or the 
subject can be discontinued from the study. 
f If any neurologic abnormalities are noted during physical examination. 
g Immediately prior to the first injection, and then immediately after the first injection of IMP for the rest exam, immediately after the second injection of IMP for the stress exam, 
and ultimately at 1 hour after the last injection of IMP. 
h Rest SPECT MPI and then stress (exercise or physiologic) SPECT MPI, per the institution’s standard practices (the same stressor used for PET MPI, if PET MPI precedes 
SPECT MPI). 
i Rest PET MPI and then stress (exercise or physiologic, the same stressor used for SPECT MPI) PET MPI, per the institution’s standard practices. 
j All serious and non-serious AEs will be collected from the time of informed consent and followed for a final outcome until the end of the follow-up period. 
k Pre-procedure vitals, pulse-oximetry and concomitant medications can be extracted from the clinical record. 
l If for scheduling reasons, the study SPECT or PET MPI must occur rapidly after the screening visit (e.g., within 48 hours), an additional blood sample may be analysed by local 
labs to determine if the subject meets exclusion criteria. For all subjects, blood must be sent for central analysis for all protocol specified laboratory parameters, whether or not 
blood is sent to a local lab for limited biochemical analysis for screening purposes. 
 
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Now reads: 
Table 1 
Study Schedule of Events 
Variables 
Screening 
Baseline (≤30 days 
after Screening) 
Can occur in either order. 
SPECT may precede Screening a 
Safety Follow-up 
(2 to 3 days after 
PET MPI) 
Safety Follow-up 
(14 to 17 days after 
PET MPI) 
ICA (within 60 
days of Screening 
or “Off-study” a 
SPECT) 
Rest and Stress 
SPECT MPI 
Rest and Stress 
PET MPI 
Informed consent 
X 
 
 
 
 
 
 
Entry criteria 
X 
 
 
 
 
 
 
Pregnancy test b 
X 
X 
 
X 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
Blood sampling 
Xc 
 
 
Xd 
 
 
 
Urine sampling 
X 
 
 
Xd 
 
 
 
Seattle Angina Questionnaire 
X 
 
 
 
 
 
 
Prior/concurrent medications 
X 
X 
X 
X 
X 
X 
Xm 
Vital signs 
 
X 
Xe 
Xe 
 
 
Xm 
Pulse oximetry 
 
X 
X 
X 
 
 
Xm 
12-lead ECG recording 
Xf 
 
 
X 
 
 
 
Physical examination g 
 
X 
 
X 
 
 
 
Full neurologic examination h 
 
X 
 
X 
 
 
 
Injection site monitoring 
 
 
 
Xi 
 
 
 
IMP administration 
 
 
 
X 
 
 
 
Image acquisition  
 
 
Xj 
Xk 
 
 
X 
Adverse events (including 
AEs and SAEs)l 
X 
X 
X 
X 
X 
X 
X 
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Table 1 
Study Schedule of Events 
Variables 
Screening 
Baseline (≤30 days 
after Screening) 
Can occur in either order. 
SPECT may precede Screening a 
Safety Follow-up 
(2 to 3 days after 
PET MPI) 
Safety Follow-up 
(14 to 17 days after 
PET MPI) 
ICA (within 60 
days of Screening 
or “Off-study” a 
SPECT) 
Rest and Stress 
SPECT MPI 
Rest and Stress 
PET MPI 
AE = adverse events; ECG = electrocardiogram; ICA = invasive coronary angiography; IMP = investigational medicinal product; MPI = myocardial perfusion imaging; PET = 
positron emission tomography; SAE = serious adverse events; SPECT = single photon emission computed tomography 
a Results of “off-study” SPECT MPI that was performed prior to signing of the ICF but in accordance with procedures developed by the imaging core laboratory (ICL) and on a 
validated camera can be used. The “off-study” SPECT MPI must also achieve the minimal quality standard specified by the ICL in the same manner as a study SPECT MPI 
performed prospectively. If an “off-study” SPECT MPI does not achieve the minimal quality standards of the ICL, a repeat SPECT MPI can be performed and used as a study 
SPECT MPI if performed during the study.   
b For women of childbearing potential, the results of either a urine or serum human chorionic gonadotropin pregnancy test (with the result known the day of radiopharmaceutical 
administration) must be negative.   
c If for scheduling reasons, the study SPECT or PET MPI must occur rapidly after the screening visit (e.g., within 48 hours), an additional blood sample may be analysed by 
local labs to determine if the subject meets exclusion criteria. For all subjects, blood must be sent for central analysis for all protocol specified laboratory parameters, whether 
or not blood is sent to a local lab for limited biochemical analysis for screening purposes. 
d Before the first IMP injection (blood and urine) and 1 hour after the last IMP injection (blood).  
e For rest SPECT-MPI and rest PET-MPI, vital signs will be collected up to 20 minutes prior to dose and 30 (±5) minutes post-dose.  For stress SPECT-MPI and stress PET-
MPI, vital signs will be collected up to 20 minutes prior to dose (if >60 minutes between rest and stress injections) and 30 (±5) minutes post-dose.   
f 12 lead ECG collected on local ECG machine and interpreted by the investigator or a designee at the investigative site. A clinically indicated ECG obtained up to 48 hours prior 
to Screening is acceptable.   
g Physical examination will comprise a full examination with a specific focus on neurological and cardiovascular signs. During the Rest/Stress PET MPI Visit, a physical 
examination will be performed before the rest portion of the Flurpiridaz (18F) Injection PET MPI and 1 hour after the stress portion of the Flurpiridaz (18F) Injection PET MPI. 
Additionally, a focused clinical screen for new or worsening symptoms indicative of unstable coronary artery disease will be conducted prior to performing any procedures at 
the Flurpiridaz (18F) PET Visit.  If the clinical status screening is positive, the Flurpiridaz (18F) PET Visit can either be rescheduled (up to 1 time) after symptoms stabilize or the 
subject can be discontinued from the study. 
h If any neurologic abnormalities are noted during physical examination. 
i Immediately prior to the first injection, and then immediately after the first injection of IMP for the rest exam, immediately after the second injection of IMP for the stress exam, 
and ultimately at 1 hour after the last injection of IMP. 
j Rest SPECT MPI and then stress (exercise or physiologic) SPECT MPI, per the institution’s standard practices (the same stressor used for PET MPI, if PET MPI precedes 
SPECT MPI). 
k Rest PET MPI and then stress (exercise or physiologic, the same stressor used for SPECT MPI) PET MPI, per the institution’s standard practices. 
l All serious and non-serious AEs will be collected from the time of informed consent and followed for a final outcome until the end of the follow-up period. 
m Pre-procedure vitals, pulse-oximetry and concomitant medications can be extracted from the clinical record. 
 
 
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Section 9.2, Baseline Visit (≤30 Days After Screening), Bullet Point #5 
Previously read: 
Vital signs will be recorded. 
Now reads: 
Vital signs will be recorded during the Baseline Visit.  If the Baseline Visit is combined with 
the Rest and Stress SPECT MPI Visit, vital signs should be recorded up to 20 minutes before 
administration of the rest dose.   
 
Section 9.3, Rest and Stress SPECT MPI Visit, First Bulleted List, Bullet Point #10 
Previously read: 
Vital signs will be recorded (Baseline Visit). 
Now reads: 
Vital signs will be recorded (Baseline Visit).  If the Baseline Visit is combined with the Rest 
and Stress SPECT MPI Visit, vital signs should be recorded up to 20 minutes before 
administration of the rest dose.   
 
Section 9.3, Rest and Stress SPECT MPI Visit, Second Bulleted List, Bullet Point #2 
Previously read: 
Vital signs will be recorded. 
Now reads: 
Vital signs will be recorded.  For rest SPECT-MPI, vital signs will be collected up to 
20 minutes prior to dose and 30 (±5) minutes post-dose.  For stress SPECT-MPI, vital signs 
will be collected up to 20 minutes prior to dose (if >60 minutes between rest and stress 
injections) and 30 (±5) minutes post-dose. 
 
Section 9.4, Rest and Stress Flurpiridaz (18F) PET-MPI Visit, Bulleted List, Bullet Point 
#5 
Previously read: 
Vital signs will be recorded. 
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Now reads: 
Vital signs will be recorded.  For rest PET-MPI, vital signs will be collected up to 20 minutes 
prior to dose and 30 (±5) minutes post-dose.  For stress PET-MPI, vital signs will be collected 
up to 20 minutes prior to dose (if >60 minutes between rest and stress injections) and 30 (±5) 
minutes post-dose.   
 
Section 10.2.1, Clinical Laboratory Evaluation, Final Paragraph, First Sentence 
Previously read: 
Urine will be collected at the various pre- and post-treatment time point ranges described in 
Table 1.   
Now reads: 
Urine will be collected at the various pre-treatment time point ranges described in Table 1.   
 
Section 10.2.9, Adverse Event and Serious Adverse Event Reporting, Medical Director 
Details 
Previously read: 
For any protocol or safety-related questions please contact the Medical Director: 
 
 
The Grove Centre, GC-18 
White Lion Road 
Bucks Amersham HP7 9LL 
Office telephone:
 
Mobile telephone:
 
E-mail:
 
In case of a medical emergency and none of the above persons can be reached, call
 
 
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Now reads: 
For any protocol or safety-related questions please contact the Medical Director: 
 
 
GE Healthcare 
Pollards Wood, Nightingales Lane 
Chalfont St Giles 
Buckinghamshire HP8 4SP 
United Kingdom 
Phone:
 
E-mail:
 
 
Section 12.8.2, Vital Signs, Second Sentence 
Previously read: 
For each vital-sign variable and each time point, the following safety endpoints will be 
summarised by counts and percentages by additional/other characteristics deemed necessary by 
study team: 
Now reads: 
For each vital-sign variable and each time point (see Table 1), the following safety endpoints 
will be summarised by counts and percentages by additional/other characteristics deemed 
necessary by study team: 
16.3 
Amendment A03 
16.3.1 
Reasons for Amendment 
• 
Editorial correction to clarify that rest and stress SPECT MPI procedures can take place 
on 2 separate days that do not have to be consecutive. 
• 
Correction of typographical error in the description of the semi-quantitative read 
(exploratory analysis). 
Where appropriate the changes are indicated in italics. 
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16.3.2 
Description of Changes 
Section 9.3, Rest and Stress SPECT MPI Visit, First Paragraph 
Previously read: 
The Rest and Stress SPECT MPI Visit can be combined with the Screening or Baseline Visit.  
Results of rest and stress SPECT MPI studies that were performed before the subject signed the 
ICF (i.e., an “off-study” SPECT MPI) can be used if the SPECT MPI was performed in 
accordance with the study imaging manual and was performed on a camera that had already 
been validated for use in the study.  The “off-study” SPECT MPI must also achieve the 
minimal quality standard specified by the imaging core lab (ICL) in the same manner as a 
study SPECT MPI performed prospectively.  If an “off-study” SPECT MPI does not achieve 
the minimal quality standards of the ICL, a repeat SPECT MPI can be performed and used as a 
study SPECT MPI if performed during the study.  Depending on the institution’s standard 
practices, the rest and stress SPECT MPI procedures can take place on the same day or on 2 
consecutive days.  The Rest and Stress SPECT MPI Visit may take place before or after the 
Rest and Stress Flurpiridaz (18F) PET-MPI Visit.  The investigator must be mindful of the 
60-day window between SPECT MPI and ICA procedures.   
Now reads: 
The Rest and Stress SPECT MPI Visit can be combined with the Screening or Baseline Visit.  
Results of rest and stress SPECT MPI studies that were performed before the subject signed the 
ICF (i.e., an “off-study” SPECT MPI) can be used if the SPECT MPI was performed in 
accordance with the study imaging manual and was performed on a camera that had already 
been validated for use in the study.  The “off-study” SPECT MPI must also achieve the 
minimal quality standard specified by the imaging core lab (ICL) in the same manner as a 
study SPECT MPI performed prospectively.  If an “off-study” SPECT MPI does not achieve 
the minimal quality standards of the ICL, a repeat SPECT MPI can be performed and used as a 
study SPECT MPI if performed during the study.  Depending on the institution’s standard 
practices, the rest and stress SPECT MPI procedures can take place on the same day or on 2 
days (either consecutive or non-consecutive).  The Rest and Stress SPECT MPI Visit may take 
place before or after the Rest and Stress Flurpiridaz (18F) PET-MPI Visit.  The investigator 
must be mindful of the 60-day window between SPECT MPI and ICA procedures.   
 
Section 12.7.1, Exploratory Endpoints, First Paragraph after Bulleted List 
Previously read: 
 
 
 
 
 
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Now reads: 
 
 
 
 
 
 
GE-265-303 CPR REV A03
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Date / Name
Justification / Role
Signed By: 
Date of signature: 20-Jul-2021 14:05:16 GMT+0000
Justification: Approved
Role:
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Date of signature: 20-Jul-2021 16:28:34 GMT+0000
Justification: Approved
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Date of signature: 22-Jul-2021 16:06:15 GMT+0000
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SAP_003.pdf: 
STATISTICAL ANALYSIS PLAN 
GE Healthcare 
GE-265-303 
Title: 
A Phase 3, Open-Label, Multicentre Study of Flurpiridaz (18F) Injection for 
Positron Emission Tomography (PET) Imaging for Assessment of 
Myocardial Perfusion in Patients Referred for Invasive Coronary 
Angiography Because of Suspected Coronary Artery Disease. 
This Statistical Analysis Plan was prepared by the following personnel: 
Name 
 
Title 
  
Company 
 
GE-265-303 Statistical Analysis Plan
Version 2.0 Approved  06 Jan 2022
ClinicalTrials.gov ID: NCT03354273


Page 2 of 37 
 
Table of Contents 
Table of Contents ......................................................................................................................... 2 
REVISION HISTORY ................................................................................................................. 4 
ABBREVIATIONS ...................................................................................................................... 5 
1 
INTRODUCTION .................................................................................................... 6 
2 
STUDY OBJECTIVES, DESIGN AND PROCEDURES ....................................... 7 
2.1 
Objectives.................................................................................................................. 7 
2.2 
Study Design ............................................................................................................. 8 
2.3 
Sample Size Calculation ......................................................................................... 13 
2.4 
Interim Analysis ...................................................................................................... 13 
2.5 
Randomisation and Blinding ................................................................................... 13 
3 
STUDY ENDPOINTS ............................................................................................ 14 
3.1 
Efficacy Endpoints .................................................................................................. 14 
3.1.1 
Primary Efficacy Endpoints ...................................................................... 14 
3.1.2 
Secondary Efficacy Endpoints................................................................... 14 
3.1.3 
Exploratory Efficacy Endpoints ................................................................ 14 
3.1.4 
Image Acquisition ..................................................................................... 15 
3.1.5 
Image Interpretation and Correlation with Standard of Truth ................... 15 
3.2 
Safety Endpoints ..................................................................................................... 16 
4 
ANALYSIS POPULATIONS................................................................................. 17 
4.1 
Definition for Analysis Populations ........................................................................ 17 
4.1.1 
Enrolled Population ................................................................................... 17 
4.1.2 
Intent-to-Treat Population ......................................................................... 17 
4.1.3 
Modified Intent-to-Treat (MITT) Population ............................................ 17 
4.1.4 
Secondary Modified Intent-to-Treat (SMITT) Population ........................ 17 
4.1.5 
Determination of Safety Population .......................................................... 17 
5 
ANALYSIS CONVENTIONS ............................................................................... 18 
5.1 
Definition of Analysis Windows............................................................................. 19 
5.2 
Definition of Missing Data Imputation ................................................................... 20 
5.3 
Protocol Deviations ................................................................................................. 20 
6 
STATISTICAL ANALYSES ................................................................................. 21 
6.1 
Subject Disposition ................................................................................................. 21 
6.2 
Demographics, Baseline Characteristics, Medical History, and Prior/Concomitant 
Medications ............................................................................................................. 21 
6.2.1 
Demographic and Baseline Characteristics ............................................... 21 
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Page 3 of 37 
 
6.2.2 
Medical/Surgical History ........................................................................... 21 
6.2.3 
Prior and Concomitant Medications .......................................................... 21 
6.3 
Study Drug Exposure .............................................................................................. 22 
6.4 
Primary Efficacy Analyses ...................................................................................... 22 
6.4.1 
Efficacy Variables ..................................................................................... 22 
6.4.1.1 Myocardial Perfusion Imaging Evaluations .............................................. 22 
6.4.1.2 Coronary Angiography Evaluations .......................................................... 23 
6.4.1.3 Image Quality ............................................................................................ 23 
6.4.2 
Primary Efficacy Endpoints Analyses ....................................................... 23 
6.4.3 
Statistical Hypothesis, Model, and Method of Analysis ........................... 24 
6.4.4 
Primary Efficacy Endpoint Subgroup Analysis ........................................ 25 
6.4.5 
Reader Difference ...................................................................................... 26 
6.4.6 
Handling of Missing Values/Censoring/Discontinuations ........................ 26 
6.4.7 
Handling of Uninterpretable Images ......................................................... 26 
6.5 
Secondary Efficacy Analyses .................................................................................. 27 
6.5.1 
Secondary Efficacy Endpoint Analyses .................................................... 27 
6.5.2 
Hypothesis Testing for the Key Secondary Endpoint ............................... 27 
6.5.3 
Hypothesis testing for other secondary endpoints ..................................... 28 
6.6 
Exploratory Analyses .............................................................................................. 28 
6.6.1 
Exploratory Endpoints: .............................................................................. 28 
6.7 
Safety Variables and Analyses ................................................................................ 32 
6.7.1 
Analysis of Adverse Events ....................................................................... 32 
6.7.2 
Clinical Laboratory Evaluation ................................................................. 33 
6.7.3 
Vital Signs ................................................................................................. 34 
6.7.4 
Electrocardiograms .................................................................................... 34 
6.7.5 
Physical Examination ................................................................................ 36 
6.7.6 
Injection Site Monitoring .......................................................................... 36 
7 
REFERENCES........................................................................................................ 37 
 
GE-265-303 Statistical Analysis Plan
Version 2.0 Approved  06 Jan 2022


Page 4 of 37 
 
REVISION HISTORY 
Version 
Date 
Changes implemented 
1.0 
 
Not applicable. 
2.0 
Refer to the signature 
page. 
Edits to the study schedule of events are 
incorporated (Table 1). 
Minor typographical edits and corrections. 
The analysis for some efficacy endpoints has been 
described in more detail. 
The analysis for several safety endpoints has been 
described in more detail (e.g., adverse events, vital 
signs). 
 
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Page 5 of 37 
 
ABBREVIATIONS 
AE 
Adverse event 
BMI 
Body mass index  
CAD 
Coronary artery disease 
CI 
Confidence Interval 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
FN 
False negative(s) 
FP 
False positive(s) 
ICA 
Invasive coronary angiography 
ICF 
Informed consent form 
IMP 
Investigational medicinal product 
ICL 
Imaging core laboratory 
IVUS 
Intravascular Ultrasound 
LV 
Left ventricle 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified intent-to-treat  
MPI 
Myocardial Perfusion Imaging 
NPV 
Negative predictive value 
PET 
Positron emission tomography 
PPV 
Positive predictive value 
QCA 
Quantitative coronary angiography 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDS 
Summed difference score 
SMITT 
Secondary modified intent-to-treat 
SPECT 
Single photon emission computed tomography 
SRS 
Summed rest score 
SSS 
Summed stress score 
TEAE 
Treatment-emergent adverse event 
TN 
True negative(s) 
TP 
True positive(s) 
WHO-DD 
World Health Organization Drug Dictionary 
 
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Page 6 of 37 
 
1 
INTRODUCTION  
GE-265-303 is a Phase 3, prospective, open-label, international, multicentre study of 
Flurpiridaz (18F) Injection for Positron Emission Tomography (PET) Myocardial Perfusion 
Imaging (MPI) in patients referred for Invasive Coronary Angiography (ICA) because of 
suspected Coronary Artery Disease (CAD).  Five hundred and fifty-two (552) evaluable 
subjects will be enrolled in this study and will undergo Single Photon Emission Computed 
Tomography (SPECT) MPI and Flurpiridaz (18F) Injection PET MPI, prior to ICA.  Flurpiridaz 
(18F) Injection is the IMP in this study. 
This document presents the statistical analysis plan (SAP) for Study GE-265-303. Reference 
material for this SAP includes Protocol GE-265-303 CPR REV A03 Version 1.0. 
The SAP will provide details to further elaborate statistical methods as outlined in the protocol 
and will describe analysis conventions to guide the statistical programming work. The SAP 
will be signed off before the study database is locked. 
Exploratory analyses, not identified in this SAP, may be performed to support the clinical 
development program. Any post-hoc, or unplanned, analyses that are performed but not 
identified in this SAP will be clearly identified in the clinical study report. 
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2 
STUDY OBJECTIVES, DESIGN AND PROCEDURES 
2.1   Objectives 
Primary Objective: 
• Assess the diagnostic efficacy (sensitivity and specificity) of Flurpiridaz (18F) Injection 
PET MPI in the detection of significant CAD, as defined by ICA, in patients with suspected 
CAD. 
Secondary Objectives: 
• Evaluate the diagnostic efficacy (sensitivity and specificity) of Flurpiridaz (18F) Injection 
PET MPI compared with that of SPECT MPI in the detection of CAD, as defined by ICA, 
in the following groups of subjects: 
o All subjects (key secondary endpoint) 
o Female subjects 
o Subjects with body mass index (BMI) ≥30 kg/m2 
o Diabetic subjects 
• Assess the safety of Flurpiridaz (18F) Injection PET MPI. 
Exploratory Objectives: 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.2   Study Design 
This is a Phase 3, prospective, open-label, international, multicentre study of Flurpiridaz (18F) 
Injection for PET MPI in patients referred for ICA because of suspected CAD.   
This study will be conducted at approximately 60 centres in Europe and North America 
(United States and Canada). 
The procedure order will not be randomised but will be dependent upon the presentation of the 
patient at the site; however, in all cases SPECT and Flurpiridaz (18F) PET MPI must be 
performed within 60 days prior to ICA.  Included in these 60 days are clinically indicated 
SPECT exams that may precede screening, which otherwise meet all study-specific imaging 
and stress testing criteria (hereby called “Off-study” SPECT exams) (see Study Diagram, 
Figure 1).  
All subjects will be followed up for adverse events (AEs) within 2 days following Flurpiridaz 
(18F) Injection administration, and for AEs and serious adverse events (SAEs) at approximately 
2 weeks (14 to 17 days) following the last Flurpiridaz (18F) Injection dose administration and at 
the time of their ICA.   
Therefore, study subjects will participate in the study for up to 77 days. 
Each subject will attend a Screening Visit up to 30 days prior to enrolment.  The investigator 
will explain what participation in the study entails and check to determine that the subject 
meets all the inclusion criteria but none of the exclusion criteria.   
Patients can be considered for enrolment if: 
• 
They are being scheduled via written documentation at the time of enrolment to 
undergo ICA, and 
• 
They have undergone a clinically indicated SPECT study which meets all study-
specified imaging and stress testing criteria or are willing to undergo SPECT MPI for 
the purposes of the clinical study.  
ICA represents the regulatorily-accepted truth standard for the determination of presence or 
absence of significant coronary stenosis.   
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Study Population:  
Five hundred and fifty-two (552) evaluable subjects will be enrolled in this study.  Assuming a 
15% dropout rate, 650 subjects will need to be enrolled initially. 
While enrolment will not be formally stratified, enrolment will be monitored and the 
recruitment plan may be adjusted during the course of the study to ensure adequate 
representation of subjects aged ≥65 years of age and that at least one third of the enrolled 
subjects will be diabetic, one third but no more than one half will have BMI ≥30 kg/m2, and 
one third will be women.   
An overview of study procedures is presented in Figure 1.  A schedule of study procedures is 
provided in Table 1. 
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Figure 1 Study Diagram 
 
 
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Table 1 
Study Schedule of Events 
Variables 
Screening 
Baseline (≤30 days 
after Screening) 
Can occur in either order. 
SPECT may precede Screening a 
Safety Follow-up 
(2 to 3 days after 
PET MPI) 
Safety Follow-up 
(14 to 17 days after 
PET MPI) 
ICA (within 60 
days of Screening 
or “Off-study” a 
SPECT) 
Rest and Stress 
SPECT MPI 
Rest and Stress 
PET MPI 
Informed consent 
X 
 
 
 
 
 
 
Entry criteria 
X 
 
 
 
 
 
 
Pregnancy test b 
X 
X 
 
X 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
Blood sampling 
Xc 
 
 
Xd 
 
 
 
Urine sampling 
X 
 
 
Xd 
 
 
 
Seattle Angina Questionnaire 
X 
 
 
 
 
 
 
Prior/concurrent medications 
X 
X 
X 
X 
X 
X 
Xm 
Vital signs 
 
X 
Xe 
Xe 
 
 
Xm 
Pulse oximetry 
 
X 
X 
X 
 
 
Xm 
12-lead ECG recording 
Xf 
 
 
X 
 
 
 
Physical examination g 
 
X 
 
X 
 
 
 
Full neurologic examination h 
 
X 
 
X 
 
 
 
Injection site monitoring 
 
 
 
Xi 
 
 
 
IMP administration 
 
 
 
X 
 
 
 
Image acquisition  
 
 
Xj 
Xk 
 
 
X 
Adverse events (including 
AEs and SAEs)l 
X 
X 
X 
X 
X 
X 
X 
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Table 1 
Study Schedule of Events 
Variables 
Screening 
Baseline (≤30 days 
after Screening) 
Can occur in either order. 
SPECT may precede Screening a 
Safety Follow-up 
(2 to 3 days after 
PET MPI) 
Safety Follow-up 
(14 to 17 days after 
PET MPI) 
ICA (within 60 
days of Screening 
or “Off-study” a 
SPECT) 
Rest and Stress 
SPECT MPI 
Rest and Stress 
PET MPI 
AE = adverse events; ECG = electrocardiogram; ICA = invasive coronary angiography; IMP = investigational medicinal product; MPI = myocardial perfusion imaging; PET = 
positron emission tomography; SAE = serious adverse events; SPECT = single photon emission computed tomography 
a Results of “off-study” SPECT MPI that was performed prior to signing of the ICF but in accordance with procedures developed by the imaging core laboratory (ICL) and on a 
validated camera can be used. The “off-study” SPECT MPI must also achieve the minimal quality standard specified by the ICL in the same manner as a study SPECT MPI 
performed prospectively. If an “off-study” SPECT MPI does not achieve the minimal quality standards of the ICL, a repeat SPECT MPI can be performed and used as a study 
SPECT MPI if performed during the study.   
b For women of childbearing potential, the results of either a urine or serum human chorionic gonadotropin pregnancy test (with the result known the day of radiopharmaceutical 
administration) must be negative.   
c If for scheduling reasons, the study SPECT or PET MPI must occur rapidly after the screening visit (e.g., within 48 hours), an additional blood sample may be analysed by local 
labs to determine if the subject meets exclusion criteria. For all subjects, blood must be sent for central analysis for all protocol specified laboratory parameters, whether or not 
blood is sent to a local lab for limited biochemical analysis for screening purposes. 
d Before the first IMP injection (blood and urine) and 1 hour after the last IMP injection (blood).  
e For rest SPECT-MPI and rest PET-MPI, vital signs will be collected up to 20 minutes prior to dose and 30 (±5) minutes post-dose.  For stress SPECT-MPI and stress PET-MPI, 
vital signs will be collected up to 20 minutes prior to dose (if >60 minutes between rest and stress injections) and 30 (±5) minutes post-dose. 
f 12 lead ECG collected on local ECG machine and interpreted by the investigator or a designee at the investigative site. A clinically indicated ECG obtained up to 48 hours prior 
to Screening is acceptable.   
g Physical examination will comprise a full examination with a specific focus on neurological and cardiovascular signs. During the Rest/Stress PET MPI Visit, a physical 
examination will be performed before the rest portion of the Flurpiridaz (18F) Injection PET MPI and 1 hour after the stress portion of the Flurpiridaz (18F) Injection PET MPI. 
Additionally, a focused clinical screen for new or worsening symptoms indicative of unstable coronary artery disease will be conducted prior to performing any procedures at 
the Flurpiridaz (18F) PET Visit.  If the clinical status screening is positive, the Flurpiridaz (18F) PET Visit can either be rescheduled (up to 1 time) after symptoms stabilize or the 
subject can be discontinued from the study. 
h If any neurologic abnormalities are noted during physical examination. 
i Immediately prior to the first injection, and then immediately after the first injection of IMP for the rest exam, immediately after the second injection of IMP for the stress exam, 
and ultimately at 1 hour after the last injection of IMP. 
j Rest SPECT MPI and then stress (exercise or physiologic) SPECT MPI, per the institution’s standard practices (the same stressor used for PET MPI, if PET MPI precedes 
SPECT MPI). 
k Rest PET MPI and then stress (exercise or physiologic, the same stressor used for SPECT MPI) PET MPI, per the institution’s standard practices. 
l All serious and non-serious AEs will be collected from the time of informed consent and followed for a final outcome until the end of the follow-up period. 
m Pre-procedure vitals, pulse-oximetry and concomitant medications can be extracted from the clinical record. 
 
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2.3   Sample Size Calculation 
The sample size was calculated to ensure that a sufficient number of evaluable negative and 
positive patients (by ICA) are enrolled to achieve 90% power at a 1-sided significance level of 
0.025 for both sensitivity and specificity in the primary analysis.  Assuming the true sensitivity 
and true specificity are both 70% and testing the hypothesis that they are both >60%, 237 
negative and 237 positive patients in the MITT population are required.  Assuming a 
prevalence of 43%, approximately 552 total patients will be enrolled to ensure there are ≥237 
positive patients.  Enrolment will be monitored and the recruitment plan may be adjusted 
during the course of the study to ensure an adequate number of diseased patients.  Assuming a 
dropout rate of 15%, up to 650 total patients will be enrolled to ensure that there are at least 
552 evaluable MITT patients.  
2.4   Interim Analysis 
No formal interim analyses will be performed in this study.   
2.5   Randomisation and Blinding 
This is a Phase 3, open-label study (Table 2). 
Table 2 
Blinded Personnel 
Personnel 
Blinded To: 
Subjects, site personnel, contract research 
organisation (CRO), and Sponsor 
Centrally read efficacy assessment of PET and SPECT MPI, 
intracoronary angiography (quantitative coronary angiography 
[QCA]) assessments (partial unblinding will occur with regards 
to the report of the prevalence of CAD+ patients to the Sponsor 
occurring in 1-month or 2-month increments after the first 100 
patients have had QCA analysis) 
Blinded independent image reviewers 
Medical history (until staged unblinding), SPECT MPI results, 
and standard of truth 
Centrally read intracoronary angiography QCA assessments 
 
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3 
STUDY ENDPOINTS 
3.1   Efficacy Endpoints 
3.1.1   Primary Efficacy Endpoints 
The primary endpoints of the study are the sensitivity and specificity of Flurpiridaz (18F) 
Injection PET MPI in the detection of significant CAD as defined by ICA. 
Subjects will be considered to have CAD if QCA reveals ≥50% stenosis of ≥1 major coronary 
artery or major branch. 
3.1.2   Secondary Efficacy Endpoints 
The secondary endpoints of the study are the diagnostic efficacy (sensitivity and specificity) of 
Flurpiridaz (18F) Injection PET MPI compared to that of SPECT, when the diagnosis of CAD 
by ICA is the standard of truth, in the following: 
• All subjects (key secondary endpoint) 
• Female subjects 
• Subjects with BMI ≥30 kg/m2 
• Diabetic subjects 
3.1.3   Exploratory Efficacy Endpoints 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.1.4   Image Acquisition 
Imaging procedures include PET MPI, SPECT MPI, and ICA.  
Image acquisition with SPECT and PET at rest and under stress procedures will be defined in 
the dedicated PET and SPECT Imaging Manual. 
ICA will be performed in accordance with investigational site institutional practice.   
Ventriculograms, when performed for clinical reasons, will also be included. 
Doppler flow or pressure-wire measurements and/or Intravascular Ultrasound (IVUS) may also 
be performed at the time of the ICA.  If a Doppler flow or pressure wire is used to measure 
fractional flow reserve (FFR), the measurements will be collected on the electronic case report 
form (eCRF). 
The truth standard used in this study is the presence of CAD (i.e., disease-positive) as 
evidenced by the presence of stenosis of ≥50% in ≥1 major epicardial coronary artery or major 
branch by quantitative coronary angiography (QCA). 
Further details of the ICA protocol will be provided in the Angiography Imaging Manual. 
3.1.5   Image Interpretation and Correlation with Standard of Truth 
Three qualified independent readers will perform a blinded assessment of each subject’s PET 
image pair (rest and stress images) and each subject’s SPECT image pair.  Further details will 
be provided in the study PET and SPECT Independent Review Charter. 
One blinded reviewer will perform QCA, according to the Angiography Independent Review 
Charter, for all ICA images. 
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3.2   Safety Endpoints 
Subjects will be closely monitored for safety until completion of all study procedures.  Safety 
monitoring will include AEs, medication errors, treatment-emergent adverse events (TEAEs), 
and SAE assessments, vital signs, electrocardiograms (ECGs), haematology, clinical chemistry 
laboratory tests, and urinalysis.  All subjects will be followed up by telephone assessments for 
AEs within 2 days (+24 hours) following Flurpiridaz (18F) Injection administration, and for 
AEs and SAEs at approximately 2 weeks (14 to 17 days) following the last Flurpiridaz (18F) 
Injection dose administration.  For subjects undergoing SPECT for the purposes of this clinical 
study, their safety will be monitored as per institutional standards.   
The investigator(s) and the Sponsor/CRO will review the safety data.  The following safety 
data will be collected and evaluated: 
• 
Clinical laboratory parameters: serum biochemistry, haematology, and urinalysis  
• 
Vital signs: systolic/diastolic blood pressure, heart rate, pulse oximetry, and intermittent 
respiration rate and body temperature 
• 
Continuous ECG monitoring 
• 
Lead II rhythm strip and 12-lead ECG 
• 
Physical examination 
• 
Injection site monitoring 
• 
Post-treatment events (AEs and SAEs) 
 
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4 
ANALYSIS POPULATIONS 
4.1   Definition for Analysis Populations 
4.1.1   Enrolled Population 
The Enrolled population will consist of all subjects who signed the ICF. 
4.1.2   Intent-to-Treat Population 
The Intent-to-Treat (ITT) population will consist of all enrolled subjects who received ≥1 dose 
of Flurpiridaz (18F) Injection in the study. 
4.1.3   Modified Intent-to-Treat (MITT) Population 
The MITT population will include all ITT subjects who have completed the rest and stress 
Flurpiridaz (18F) Injection PET MPI procedures and who have evaluable truth standard data. 
The MITT population will be the primary analysis set for the primary efficacy endpoints.   
4.1.4   Secondary Modified Intent-to-Treat (SMITT) Population 
The secondary MITT (SMITT) population will include the subjects in the MITT population 
who have completed the rest and stress SPECT MPI (if the subject’s SPECT MPI is “off-
study,” that SPECT MPI must meet minimal quality standards, as specified by the ICL). The 
SMITT population will be the primary analysis set for the secondary efficacy and exploratory 
efficacy endpoints unless otherwise specified.   
A summary of subject disposition, including the number and percentage of ITT subjects who 
do not have evaluable results for PET or the truth standard or who are not in the MITT analysis 
set, will be provided, with the reasons for non-evaluability.   
4.1.5   Determination of Safety Population 
The Safety Population will include all subjects who have received ≥1 dose of Flurpiridaz (18F) 
Injection in the study.  All safety data will be summarised for the Safety Population. 
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5 
ANALYSIS CONVENTIONS 
Post-text tables and listings will be prepared in accordance with the ICH M2 Guidelines [ICH 
2008]. The information and explanatory notes to be provided in the “footer” or bottom of each 
table and listing will include the following information: 
1.   Date and time of output generation; 
2.   SAS® program name, including the path that generates the output; 
3.   Any other output-specific details that require further elaboration. 
Three (3) table formats will be followed for data summary: 
1. For background data, including demography, medical history, prior medications, and 
concomitant medications, one column will be presented for all enrolled patients. In 
addition, the safety population, MITT population and SMITT population will be 
presented side-by-side as 3 additional columns, where appropriate.  
2. For all safety data, 1 column displaying values for patients who have received ≥1 dose 
of Flurpiridaz (18F) Injection will be presented. 
3. For some efficacy-related tables, when comparing SPECT MPI and PET MPI, SPECT 
MPI and PET MPI will be presented side-by-side, where appropriate. 
The summary tables will clearly indicate the number of patients to which the data apply, and 
unknown or not performed will be distinguished from missing data.  
Supportive individual Patient Data Listings, as a minimum, will be sorted and presented by the 
study arm, patient number, and visit date, if applicable.  
This section details general conventions to be used for the statistical analyses. The following 
conventions will be applied to all data presentations and analyses. 
• 
Summary statistics for categorical variables will consist of the number and percentage 
of responses in each level. The number and percentage of responses will be presented in 
the form XX (XX.X%). 
• 
Summary statistics for continuous variables will consist of the sample size (n), mean, 
median, standard deviation (SD), minimum, and maximum values. 
• 
All mean and median values will be formatted to one more decimal place than the 
measured value. SD values will be formatted to two more decimal places than the 
measured value. Minimum and maximum values will be presented with the same 
number of decimal places as the measured value. 
• 
All p-values, if applicable, will be rounded to 4 decimal places. All p-values that round 
to 0.0000 will be presented as ‘<0.0001’ and p-values that round to 1.0000 will be 
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presented as ‘>0.9999’. One-sided P-values < 0.025 will be considered to be 
statistically significant unless otherwise specified. 
• 
All summary tables will include the analysis population sample size (i.e., number of 
patients). 
• 
Study Day 1 is defined as the date at which the patient received the IMP, Flurpiridaz 
(18F) Injection. All study days are determined relative to Day 1. 
• 
Study days prior to Day 1 will be calculated as: 
➢ Study Day = Assessment Date – Date of IMP received  
• 
Study days after Day 1 will be calculated as: 
➢ Study Day = Assessment Date – Date of IMP received + 1. 
• 
Baseline values will be defined as the last non-missing value recorded prior to IMP 
received. 
• 
Change from baseline will be calculated as follows: 
➢ Change = Post-baseline value - baseline value. 
• 
All pre- and post-enrolment assessments including unscheduled or repeat assessments 
will be included in the data listings. 
• 
Date variables will be formatted as YYYY-MM-DD for presentation. 
• 
Tables, figures, and listings will be presented in landscape orientation. 
• 
SAS® Version 9.4 or higher will be the statistical software package used for all data 
analyses.  
5.1   Definition of Analysis Windows  
There are no visit windows for this study. For the statistical analyses, data will be analyzed by 
the nominal visit that was collected on the eCRF. 
Unscheduled visits will not be used in the by-visit analysis but will be used for the following 
where appropriate: 1) derivations of baseline/last on-treatment measurements; 2) derivations of 
the maximum/minimum on-treatment values and maximum/minimum changes from baseline 
values for safety analyses; 3) data listings.  
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5.2   Definition of Missing Data Imputation  
Missing values will not be substituted by estimated values but treated as missing in the 
statistical evaluation. All data from all subjects dosed in the study will be included in all 
listings, plots, summary tables, and statistical analyses when appropriate. 
5.3   Protocol Deviations 
Any deviation from the protocol when no approved amendment exists must be documented as 
a protocol deviation and reported according to local requirements.  If appropriate, corrective 
and preventative action must be implemented to avoid repetition.  Protocol deviations and any 
potential impact on the study results will be discussed during the reporting of the study. 
Waivers or protocol exceptions will not be granted prospectively by the Sponsor under any 
circumstances. 
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6 
STATISTICAL ANALYSES  
6.1   Subject Disposition  
A table will be provided with the following information: 
• Number of subjects enrolled. 
• Number of subjects included in the efficacy analysis populations (ITT, MITT, SMITT). 
• Number of subjects included in the safety analysis population. 
• Number of subjects withdrawn from the study and the reason for withdrawal. 
6.2   Demographics, Baseline Characteristics, Medical History, and 
Prior/Concomitant Medications 
6.2.1   Demographic and Baseline Characteristics 
Demographic information (age, height, weight, and BMI) will be summarised by using 
descriptive statistics.  Sex, ethnicity, race, and history of Diabetes Mellitus will be summarised 
by counts and percentages. 
6.2.2   Medical/Surgical History 
The subjects’ relevant medical and surgical history as recorded at Screening will be 
summarised and the data will be presented using body systems and conditions/diagnoses as 
captured on the eCRF. The body systems will be presented in alphabetical order and the 
conditions/diagnoses will be presented in alphabetical order within each body system.  
The number and percentage of subjects with a particular condition/diagnosis will be 
summarized. Subjects reporting more than one condition/diagnosis within a body system will 
be counted only once for that body system.  
6.2.3   Prior and Concomitant Medications  
Prior and concomitant medications are defined relative to Flurpiridaz administration. Any 
medications taken by the subject within 12 hours before the screening or the SPECT stress test 
if it precedes screening, at the time of ICA and up to study completion will be summarized by 
counts and percentages using the World Health Organization Drug Dictionary (WHO-DD) 
March 2021 version, and grouped by primary and secondary classes, if applicable. 
A prior medication is defined as any medication taken prior to the start of the first dose of 
Flurpiridaz. A concurrent medication is a new medication started after the start of the first dose 
of Flurpiridaz or a prior medication but continued to post Flurpiridaz administration. 
If the medication was taken prior to Flurpiridaz administration and no information on its use is 
available after the imaging (i.e., no end date), the medication will be assumed to be ongoing 
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and therefore considered as both prior and concurrent medications. If the medication was being 
taken after the start of Flurpiridaz administration and there is no information on its use prior to 
Flurpiridaz administration (i.e., no start date), the medication will be considered as both prior 
and concurrent medications.  
Table 3 
Classification of prior and concurrent medications 
End 
date 
    Start  
    date 
Before start of IMP 
administration 
On or after start of 
IMP administration 
Missing 
Before start of IMP 
administration 
Prior 
Prior/Concurrent 
Prior/Concurrent 
On or after start of 
IMP administration 
– 
Concurrent 
Concurrent 
Missing 
Prior 
Prior/Concurrent 
Prior/Concurrent 
 
6.3   Study Drug Exposure  
Treatment exposure (SPECT agent or Flurpiridaz (18F) injected dose in mCi or MBq) will be 
summarized by descriptive summary statistics. Summary statistics will be presented by each 
dose: rest, stress (exercise and pharmacological), and total exposure. A summary of each 
subject’s dosing information will be presented in a listing.  
Treatment exposure for Flurpiridaz (18F) will be calculated using the following formula for 
decay correction:  
 
Effective dose will be calculated as the product of the dose/unit activity and the administered 
activity. For Flurpiridaz (18F) injected doses, the dose per unit injected activity depends on 
whether the study is a rest (0.071 rem/mCi), pharmacologic stress (0.069 rem/mCi) or exercise 
stress (0.054 rem/mCi) exam. For SPECT studies, the dose per unit injected activity depends 
on whether the study is a Tetrofosmin (Rest: 0.0296 rem/mCi or Stress: 0.0255 rem/mCi) or 
Sestamibi (Rest: 0.0333 rem/mCi or Stress: 0.0292 rem/mCi) exam. 
6.4   Primary Efficacy Analyses 
6.4.1   Efficacy Variables 
6.4.1.1   
Myocardial Perfusion Imaging Evaluations 
Three qualified readers (independent from the study) will perform independent blinded and 
unblinded reads of all MPI images. The PET MPI and SPECT MPI reads will be performed by 
the same set of readers in cross-over sessions independent of one another.  In each session, 
PET and SPECT images will be displayed in a randomised order, non-sequentially, with PET 
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and SPECT MPI exams corresponding to individual subjects randomly allotted into reading 
session batches.  For each modality, perfusion and gated acquisitions of rest and stress images 
will be rated for image quality and reviewed.  After the results of each blinded interpretation of 
individual MPI (PET or SPECT) scans are locked as the “blinded” read, then clinical 
information will be provided.  The reader will then be given the opportunity to submit a revised 
assessment of the existence of any perfusion defects as an “unblinded” read. 
The primary efficacy read for MPI status will be the overall qualitative diagnosis of the paired 
Flurpiridaz (18F) PET MPI (rest/stress) using perfusion and gated assessments from 
independent blinded reads.  The overall qualitative diagnosis will be scored by each reader for 
each subject as normal, ischaemic, ischaemic + scar, or scar on the basis of the perfusion + 
gated images.  These scores will be dichotomised into MPI negative (normal) and MPI positive 
(ischaemic, ischaemic + scar, or scar) for each subject and reader.   
6.4.1.2   
Coronary Angiography Evaluations 
All coronary angiograms will be performed within 60 days of screening or SPECT if SPECT 
occurs prior to informed consent.  ICA data for the diagnosis of CAD will be generated by 
QCA. 
6.4.1.3   
Image Quality 
The data on image quality and interpretability will be collected separately during the blinded 
read and will be analysed separately by modality.   
6.4.2   Primary Efficacy Endpoints Analyses 
The primary efficacy endpoints of the study are the sensitivity and specificity of Flurpiridaz 
(18F) Injection PET MPI in the detection of significant CAD as defined by ICA.  The truth 
standard used in this study is the presence of CAD as evidenced by the presence of stenosis of 
≥50% in ≥1 coronary artery or major branch of a coronary artery as determined by QCA 
analysis. 
For each of the 3 readers, a binary decision will be derived by using the overall qualitative 
diagnosis criteria as MPI-negative or MPI-positive; sensitivity and specificity will then be 
calculated for each of the 3 readers. 
Sensitivity and specificity are defined as follows: 
• True Positives (TP): Subjects with abnormal PET MPI and disease positive by the truth 
standard 
• True Negatives (TN): Subjects with normal PET MPI and disease negative by the truth 
standard 
• False Positives (FP): Subjects with abnormal PET MPI and disease negative by the 
truth standard 
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• False Negatives (FN): Subjects with normal PET MPI and disease positive by the truth 
standard 
• Sensitivity: TP/(TP + FN) 
• Specificity: TN/(TN + FP)  
• Accuracy: TN + TP/(TN + TP + FN + FP) 
A dosed subject whose PET MPI images are incomplete (i.e., a missing rest and/or stress 
image) will be excluded from the MITT analysis population.  Also, a subject with a missing 
truth standard will be excluded from the MITT analysis population.  A summary of reasons for 
all missing data will be provided, with number and percent in each category.  To eliminate bias 
between modalities, once a subject is included in the MITT population, the readers will be 
asked to read SPECT MPI and PET MPI images and to classify the images as normal or 
abnormal, regardless of image quality and interpretability.  To indicate when a diagnosis is 
forced, the reader will record in the blinded-read CRF which images are considered 
uninterpretable. The data on image quality and interpretability will be collected separately 
during the blinded read and will be analysed separately by modality.   
In addition, sensitivity and specificity using the majority rule (the majority rule uses for each 
subject the judgement [positive or negative] given by at least 2 of the 3 readers) will be 
calculated. 
6.4.3   Statistical Hypothesis, Model, and Method of Analysis 
The 2 primary efficacy endpoints are calculated as follows from different subsets of the 
population:  
• 
The calculation of sensitivity of Flurpiridaz (18F) Injection PET MPI includes data only 
from subjects with CAD, per the standard of truth.   
• 
The calculation of specificity of Flurpiridaz (18F) Injection PET MPI includes data only 
from subjects without CAD, per the standard of truth.   
Let s1 = true sensitivity of Flurpiridaz (18F) Injection PET MPI: 
Let p1 = true specificity of Flurpiridaz (18F) Injection PET MPI: 
The criteria for primary efficacy will be proving the statistical superiority of both the true 
specificity and sensitivity to a threshold of 60% in Flurpiridaz (18F) Injection PET MPI.  To 
meet the criteria for success in this study, both the sensitivity and the specificity of Flurpiridaz 
(18F) Injection PET MPI must exceed 60%.  Thus, the lower bound of the 2-sided 95% 
confidence interval (CI) for both sensitivity and specificity must exceed 60%. 
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Therefore, the tests of hypotheses will be as follows: 
H01 : s1 ≤ 0.60; H02: p1 ≤ 0.60, where s1 is sensitivity in Flurpiridaz (18F) Injection PET MPI 
and p1 is specificity in Flurpiridaz (18F) Injection PET MPI. 
Ha1: s1 > 0.60; Ha2: p1 > 0.60 
Since sensitivity and specificity are calculated for separate subsets of the MITT analysis 
population, and since both null hypotheses need to be rejected for the study to be considered a 
success, each of the above endpoint comparisons will be performed by using a 1-sided 1-
sample test with type 1 error (α)= 0.025.  The test will be based on the 1-sample z-test for 
proportions, using the normal approximation to the binomial distribution.  The analysis will be 
done for each reader and for all readers.  If each null hypothesis is rejected in the analysis of all 
readers or by the same 2 out of 3 readers, the study will be considered a statistical success.   
There will be no formal interim efficacy analysis for this study. 
A summary of diagnostic efficacy including sensitivity, specificity, accuracy, positive 
predictive value (PPV), and negative predictive value (NPV) will be provided along with 2-
sided 95% CIs based on the normal approximation to the binomial distribution (for each of 
sensitivity and specificity, if the null hypothesis above is rejected by the z-test, then the lower 
bound of the 2-sided 95% CI will mathematically be above the threshold of 60%).  
6.4.4   Primary Efficacy Endpoint Subgroup Analysis 
The summary in the last paragraph of Section 6.4.3 will also be provided for the following 
subgroups: 
• Age groups (<65 years and ≥65 years) 
• BMI <30 kg/m2 and BMI ≥30 kg/m2 
• Diabetic and nondiabetic 
• Sex (male and female) 
• Race (White, Black or African-American, Asian, other) 
• Presence or absence of multivessel CAD (per the standard of truth) 
• Presence or absence of renal impairment (i.e., serum creatinine level at pre-dose evaluation 
is above normal range)  
• Presence or absence of hepatic impairment (i.e., either ALT or AST value at pre-dose 
evaluation is above normal range) 
• Type of stress test (pharmacological (Adenosine, Dipyridamole, and Regadenoson), 
exercise) 
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There are some subjects who took a pharmacological stress test during the SPECT 
procedure but an exercise stress test during the PET procedure. For the subgroup analysis, 
the subjects who took different stress tests will be excluded. 
• Some patients took both exercise and pharmacological stress tests during both SPECT and 
PET procedures; these subjects will be classified as ‘pharmacological’ 
The primary analysis will be repeated in the MITT population using as the SOT the presence of 
stenosis of ≥30% in ≥1 coronary artery or major branch of a coronary artery as determined by 
QCA analysis. The analysis will also be repeated using stenosis of ≥70% as the SOT. 
The primary analysis will be repeated for SPECT MPI where SPECT MPI alone is compared 
to the truth standard using the SMITT population.  
Additionally, sensitivity and specificity of PET MPI and SPECT MPI based on the unblinded 
reads with clinical information will be summarised. The percentage of read results that were 
changed after clinical information was made available will be presented by modality.  
6.4.5   Reader Difference 
The inter-reader agreement and intra-reader reproducibility of blinded visual interpretations of 
PET MPI and SPECT MPI will be reported as percent agreement and kappa scores. Intra-
reader reproducibility will be determined based on a re-read of images from approximately 
10% of the subjects, selected at random from all study subjects. Each reader will re-read the 
same subset of images. 
6.4.6   Handling of Missing Values/Censoring/Discontinuations 
To explore the extent of missing data, a summary of baseline characteristics will be created to 
compare groups of subjects with non-missing results with those who have missing results to 
assess if there is a significant difference between the two groups. This summary will be 
performed separately in ITT subjects who are missing PET MPI results, missing ICA results, or 
missing both PET MPI and ICA results.  
For subjects who have ICA results available as a standard of truth but are missing PET MPI 
results, a sensitivity analysis will be performed to explore the potential impact of missing data 
on the primary analysis. In this analysis, the missing PET MPI results will be imputed by using 
the opposite result of ICA in order to obtain the conservative results for sensitivity analyses of 
the primary endpoint. PET MPI will also be imputed to match the ICA results in a separate 
summary to provide a range of possible outcomes.   
6.4.7   Handling of Uninterpretable Images 
Once a subject is included in the MITT population, the readers will be asked to read PET MPI 
images and to classify the images as normal or abnormal, regardless of image quality and 
interpretability. 
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6.5   Secondary Efficacy Analyses 
6.5.1   Secondary Efficacy Endpoint Analyses 
The secondary endpoints in this study are the diagnostic efficacy (sensitivity and specificity) of 
Flurpiridaz (18F) Injection PET MPI compared to that of SPECT MPI, when the diagnosis of 
CAD by ICA is the standard of truth, in the following: 
• All subjects (key secondary endpoint) 
• Female subjects 
• Subjects with BMI ≥30 kg/m2 
• Diabetic subjects 
To control the false-positive rate at a 1-sided 0.025 level across the testing of the secondary 
endpoints, the secondary efficacy endpoints will be tested hierarchically in the order given 
above.  Each endpoint will be tested sequentially at a 1-sided 0.025 level of significance; when 
a statistical test for a given endpoint fails to reach statistical significance in the appropriate 
direction, testing on all remaining secondary endpoints in the hierarchy will cease and the 
study will be considered successful on all secondary endpoints up to that point.   
6.5.2   Hypothesis Testing for the Key Secondary Endpoint 
In the secondary efficacy analysis, the criteria for success will be the statistical superiority of 
sensitivity in Flurpiridaz (18F) Injection PET MPI over that of SPECT MPI, and the 
noninferiority of specificity in Flurpiridaz (18F) Injection PET MPI over that of SPECT MPI, 
when the detection of CAD by ICA is the standard of truth. Since the sensitivity calculation 
includes only the subjects with CAD and the specificity analysis includes only the subjects 
without CAD, the analysis of sensitivity and specificity will be separate, as follows:   
Let s1 = sensitivity in Flurpiridaz (18F) Injection PET MPI, and s2 = sensitivity in SPECT MPI. 
Let p1 =specificity in Flurpiridaz (18F) Injection PET MPI, and p2 = specificity in SPECT MPI. 
Therefore, the test of hypotheses will be as follows: 
H01: s1 − s2 ≤ 0, 
H02: p1 − p2 ≤ −0.1 
Ha1: s1 − s2 > 0, 
Ha2: p1 − p2 > –0.1 
Each of the above endpoint comparisons will be performed with a 1-sided paired test with a 
type l error (α) = 0.025. 
The tests of comparisons are based on paired responses, as the Flurpiridaz (18F) Injection PET 
MPI and SPECT MPI will be performed on a within-subject basis, and the images will be read 
by the same readers in a cross-over design.  The test of sensitivity comparison between 
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Flurpiridaz (18F) Injection PET MPI and SPECT MPI will be performed with a 1-sided 
McNemar's test at α = 0.025.  Similarly, the test of specificity noninferiority between 
Flurpiridaz (18F) Injection PET MPI and SPECT MPI will be performed with a paired test for 
noninferiority [Liu et al 2002] at a 1-sided α = 0.025.  The criterion for the demonstration of 
diagnostic efficacy for the secondary endpoints will be meeting the tests of hypotheses for both 
sensitivity and specificity for all 3 or the same 2 of the 3 readers for whom the null hypotheses 
were rejected in the analysis of the primary endpoint.   
6.5.3   Hypothesis testing for other secondary endpoints 
The methodology used for evaluating diagnostic efficacy within these populations will be 
similar to that used for analysis of the key secondary endpoint.   
6.6   Exploratory Analyses 
6.6.1   Exploratory Endpoints: 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.7   Safety Variables and Analyses 
Safety Endpoint(s): Descriptive summary statistics will be reported for AEs, TEAEs, and 
SAEs, changes from baseline for clinical laboratory tests, ECGs, physical examination, and 
vital signs for all treated subjects.   
Post-administration changes from baseline will be summarised by mean, SD, minimum, and 
maximum at each time point.  
6.7.1   Analysis of Adverse Events 
An AE is defined as any untoward medical occurrence or an already present event that worsens 
in intensity after signing informed consent to the end of study. A TEAE is defined as an AE 
with an onset date on or after the first injection of IMP up to the end of the last injection of 
IMP + 17 days (inclusive) or from first injection of IMP to the time of first injection of the 
SPECT MPI agent--whichever interval is shorter. A TEAE does not necessarily have to have a 
causal relationship with exposure to the investigational agent. A TEAE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the exposure to the IMP, whether or not considered related 
to that product.  
AEs and SAEs will be coded by using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 24.0 or later, and all reported events will be listed for the safety population.  
The following table summarizes all analyses for AEs and TEAEs: 
Treatment-emergent Adverse Events (TEAEs) 
Adverse Events (AEs) 
Overall summary of TEAEs for safety population 
Overall summary of AEs for all enrolled patients 
 
Overall summary of AEs for safety population 
TEAEs by SOC and PT for safety population 
AEs by SOC and PT for safety population 
Serious TEAEs by SOC and PT for safety population 
Serious AEs by SOC and PT for safety population 
Severe TEAEs by SOC and PT for safety population 
Severe AEs by SOC and PT for safety population 
Drug-related TEAEs by SOC and PT for safety 
population 
Drug-related AEs by SOC and PT for safety 
population 
Common TEAEs (>5%) by SOC and PT for safety 
population 
Common AEs (>5%) by SOC and PT for safety 
population 
Common Serious TEAEs (>5%) by SOC and PT for 
safety population 
Common Serious AEs (>5%) by SOC and PT for 
safety population 
TEAEs by SOC, PT and Severity for safety 
population 
AEs by SOC, PT and Severity for safety population 
Serious TEAEs by SOC, PT and Severity for safety 
population 
Serious AEs by SOC, PT and Severity for safety 
population 
TEAEs by SOC, PT and Relationship for safety 
population 
AEs by SOC, PT and Relationship for safety 
population 
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Treatment-emergent Adverse Events (TEAEs) 
Adverse Events (AEs) 
Serious TEAE by SOC, PT and Relationship for 
safety population 
Serious AEs by SOC, PT and Relationship for safety 
population 
TEAE leading to treatment discontinuation by SOC 
and PT 
AEs leading to treatment discontinuation by SOC and 
PT 
TEAE leading to death by SOC and PT 
AEs leading to death by SOC and PT 
 
If more than one event occurs with the same PT for the same patient, the patient will be 
counted only once for that PT using the most severe and most related occurrence for the 
summarization by severity and by relationship to the IMP.  
6.7.2   Clinical Laboratory Evaluation 
Descriptive statistics will be displayed for the observed values and changes from baseline 
(Table 4).  In addition, for each clinical laboratory variable and each time point, the following 
safety endpoints will be summarised by counts and percentages: 
• 
The occurrence of 1 or more changes from baseline, at each post-administration time 
point, greater than 40% and 80% of the span of the normal limits (not applicable to 
qualitative parameters). 
• 
The occurrence of post-administration values outside the normal limits (not applicable 
to qualitative parameters).  Shift tables based on the normal range will be prepared.   
Table 4 
Clinical Laboratory Parameters 
Serum Biochemistry 
Haematology 
Urinalysis 
Alanine aminotransferase (ALT) 
Albumin 
Aspartate aminotransferase (AST) 
Bicarbonate 
Bilirubin (total) 
Calcium 
Chloride 
Creatinine 
Gamma-glutamyltransferase 
Glucose 
Hemoglobin A1c 
Lactate dehydrogenase 
Potassium 
Protein (total) 
Sodium 
Urea nitrogen 
Haematocrit 
Platelet count 
White blood cell (WBC) count 
Bilirubin 
Glucose 
Ketone 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
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6.7.3   Vital Signs 
Descriptive statistics will be displayed for the observed values and changes from baseline.  
There are two vital sign baselines, REST and STRESS. However, if the STRESS baseline 
value is not recorded (missing), the STRESS baseline value will be imputed using the REST 
post-administration value. For each vital-sign variable and each time point, the following safety 
endpoints will be summarised by counts and percentages by additional/other characteristics 
deemed necessary by the study team: 
• 
The occurrence of 1 or more changes from baseline, at each post-administration time 
point, greater than a pre-specified magnitude (20 mm Hg for systolic blood pressure, 
10 mm Hg for diastolic blood pressure, 10 beats per minute for heart rate, 1.5 C for 
body temperature, 10 breaths per minute for respiration rate. 
• 
The occurrence of post-administration values outside the normal limits (Table 5).  Shift 
tables based on the normal range will be prepared.   
Table 5 
Criteria for Normal Limits for Vital Signs 
Vital Signs Parameter 
Normal Limits 
Low 
High 
Systolic BP, mm Hg 
85 
139 
Diastolic BP, mm Hg 
60 
89 
Heart rate, beats/min 
60 
100 
Respiration rate, breaths/min 
12 
22 
Body temperature 
36.4C 
97.5F 
37.7C 
99.5F 
Oxygen saturation, % 
93 
100 
Body weight, kg a 
41 
113 
Body mass index (BMI), kg/m² b 
18.5 
24.9 
Changes in body weight are evaluated by the investigator (without taking height into account), since BMI is 
not collected on the CRF. 
BMI is calculated and analysed retrospectively by the Sponsor, at which time height is taken into account. 
 
6.7.4   Electrocardiograms 
A standard 12-lead ECG will be obtained at Screening and during Flurpiridaz (18F) MPI rest 
imaging. The Screening ECG can be obtained on any local ECG machine and will be 
interpreted by the investigator or a designee at the investigative site.   
Before the administration of the Flurpiridaz (18F) Injection for the rest examination, three 
12-lead ECGs, separated by at least 5 minutes, will be obtained with equipment provided by 
the ECG Core Laboratory. ECG clocks should be synchronised with imaging equipment. 
Note: pre-dose ECGs should be obtained within 20 minutes before the transmission scan, and 
the patient should rest for 5 minutes prior to the first measurement. Three additional ECGs 
(each separated by 30-60 seconds) will be obtained starting at 2 minutes (± 30-60 seconds) 
after the administration of the Flurpiridaz (18F) injection for the rest examination. Single ECGs 
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will also be obtained at 10 and 30 minutes post injection. These 8 ECGs will be submitted to 
the ECG Core Laboratory for analysis. 
Baseline value is defined as the average for all values measured prior to first injection time and 
on the same date of first injection. For summary purposes, the result for 2 minutes post 
injection is defined as the average value for all values that are recorded as 2 minutes post 
injection and the assessment time is after first injection time. 
Therefore, EDC data will be analyzed by the following 2 approaches:  
• The overall interpretation 
Shift analysis from Screening to each time point of post-IMP will be performed using the 
overall interpretation of the ECG that were interpreted by the investigator or a designee at the 
investigative site. 
• 12-lead ECGs measurements 
Descriptive statistics will be displayed for the observed values and changes from baseline for 
the ECG intervals.   
For each ECG variable and each time-point, the following safety endpoints will be summarized 
by counts and percentages or by additional/other characteristics deemed necessary by study 
team: 
• 
The occurrence of post-administration values outside the normal limits in the PR, QTc, 
QRS or RR interval (Table 6).   
QTc-specific analyses: 
Two correction formulae will be employed in analysing QTc data in an attempt to reduce the 
bias resulting from over- or under-correction: 
 
Bazett’s:  QTcB = QT/RR 
 
Fridericia’s:  QTcF = QT/3RR 
The following analyses will employ both methods of correction: 
• Changes from baseline in the QTc interval will be displayed according to Committee for 
Medicinal Products for Human Use (CHMP) criteria (absolute QTc interval prolongation, 
of >450, >480, >500 ms and change from baseline in QTc interval >30 and >60 ms). 
• Number and percentage of subjects with absolute QTc values above the upper limit of 
normal will be provided.  Shift tables based on the normal range will be prepared.   
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Table 6 
Criteria for Normal Limits for ECGs 
 
Normal Limits (ms) 
ECG Variable 
Low 
High 
PR interval 
120 
200 
QRS interval 
50 
100 
RR interval 
600 
1000 
QT interval 
(sex not specified) 
— 
440 
QTc intervala 
(sex not specified) 
— 
440 
a No lower boundary set for QTc. 
6.7.5   Physical Examination 
The number and percentage of subjects with changes in physical examination status from 
normal at Baseline to abnormal at each post-administration time point (and vice versa) will be 
presented.  Shift tables based on the normal range will be prepared.   
6.7.6   Injection Site Monitoring 
Findings of injection site monitoring will be summarized by time points. All monitoring 
information including date/time, reasons for not done will be listed in a listing. 
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7 
REFERENCES  
[ICH 2008] 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. Electronic Common Technical Document Specification (M2). 
2008. 
[Liu et al 2002] 
Liu JP, Hsueh HM, Hsieh E, Chen JJ. Tests for equivalence or non-inferiority for paired binary 
data. Stat Med. 2002;21(2):231-245. 
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Justification / Role
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Date of signature: 06-Jan-2022 11:30:53 GMT+0000
Justification: Approved
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Date of signature: 06-Jan-2022 13:59:05 GMT+0000
Justification: Approved
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