Clinical trial NCT04594941
Conditions: Coronary Artery Disease (CAD) Ischemic Heart Disease
Sponsor: GE Healthcare
Start date: 2022-01-27; Completion date: 2022-05-26
Enrollment: 38 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This was a Phase 2 prospective, randomized, crossover study of Flurpiridaz (18F) Injection for PET-MPI in participants referred for evaluation of known coronary artery disease (CAD) or for suspected CAD with intermediate to high pre-test probability (PTP). The objective is to assess the difference and variability between 2 sets of rest images synthesized by the same or 2 different manufacturing processes. Twenty-eight evaluable \[participants were enrolled in this study and underwent 2 Flurpiridaz (18F) Injection PET-MPI at rest. Each participant attended a Screening Visit at least 2 days and up to 14 days prior to the first Flurpiridaz (18F) Injection PET-MPI. The participants were randomized 1:1:1:1 to 4 possible sequences of receiving 2 doses of Flurpiridaz (18F) Injection: 2 groups of 7 participants received 2 Flurpiridaz (18F) Injection doses synthesized by the same manufacturing processes (either HPLC or SPE) and 2 groups of 7 subjects will receive 2 Flurpiridaz (18F) Injection doses synthesized by different manufacturing processes (1 dose by HPLC followed by 1 dose by SPE or 1 dose by SPE followed by 1 dose by HPLC). All participants were followed up by telephone for adverse events (AEs) and serious AEs (SAEs) at 24 (+8) hours following each Flurpiridaz (18F) Injection administration.

Detailed description:

Arms: arm 1: Participants received 2 intravenous (IV) boluses of Flurpiridaz (18F) Injection manufactured by SPE process at Visit 1 and 2.

The targeted dose to the body of Flurpiridaz (18F) Injection was to be in the range of 1.7 to 2.5 millicurie (mCi) (63 to 93 megabecquerel \[MBq\]) for each administration and not exceed a total of 6 mCi (222 MBq) for an individual participant. arm 2: Participants received 2 IV boluses of Flurpiridaz (18F) Injection manufactured by HPLC process at Visit 1 and 2.

The targeted dose to the body of Flurpiridaz (18F) Injection was to be in the range of 1.7 to 2.5 mCi (63 to 93 MBq) for each administration and not exceed a total of 6 mCi (222 MBq) for an individual participant. arm 3: Participants received 2 IV boluses of Flurpiridaz (18F) Injection manufactured by 2 different processes (1 dose manufactured by SPE followed by 1 dose manufactured by HPLC) at Visit 1 and 2.

The targeted dose to the body of Flurpiridaz (18F) Injection was to be in the range of 1.7 to 2.5 mCi (63 to 93 MBq) for each administration and not exceed a total of 6 mCi (222 MBq) for an individual participant. arm 4: Participants received 2 IV boluses of Flurpiridaz (18F) Injection manufactured by 2 different processes (1 dose manufactured by HPLC followed by 1 dose manufactured by SPE) at Visit 1 and 2.

The targeted dose to the body of Flurpiridaz (18F) Injection was to be in the range of 1.7 to 2.5 mCi (63 to 93 MBq) for each administration and not exceed a total of 6 mCi (222 MBq) for an individual participant.
Interventions: intervention 1: Flurpiridaz (18F) Injection
Intervention descriptions: intervention 1: All participants received 2 IV boluses of Flurpiridaz (18F) Injection in a large peripheral vein at rest.

Protocol documents:
Prot_002.pdf: 
GE Confidential 
Page 1 of 73 
Clinical Study Protocol 
GE Healthcare 
GE-265-001 
Title: A Descriptive, Comparative, Randomized, Crossover Study of Flurpiridaz (18F) Injection 
for Positron Emission Tomography (PET) Imaging for Assessment of Myocardial Perfusion 
Imaging Quality using High Performance Liquid Chromatography (HPLC) and Solid Phase 
Extraction (SPE) Manufacturing Processes 
REVISED TO INCORPORATE AMENDMENT A01 
Sponsor 
GE Healthcare 
IND Number: 75,307 
Medical Director 
 
 
GE Healthcare 
Pollards Wood, Nightingales Lane 
Chalfont St Giles 
Buckinghamshire HP8 4SP 
United Kingdom 
Phone 
 
Email:
 
GE Healthcare 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 IRB approval, cannot be disclosed unless required by governmental regulation or without 
written authorization of GE Healthcare.  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. 
GE-265-001 Clinical Protocol Amendment A01
Version 1.0 Approved  03 Feb 2022
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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 
Name of Finished Product: 
Flurpiridaz (18F) Injection 
Name of Active Ingredient: 
[18F]Flurpiridaz 
Title of Study:  A Descriptive, Comparative, Randomized, Crossover Study of Flurpiridaz (18F) Injection for 
Positron Emission Tomography (PET) Imaging for Assessment of Myocardial Perfusion Imaging Quality using 
High Performance Liquid Chromatography (HPLC) and Solid Phase Extraction (SPE) Manufacturing 
Processes 
Protocol Number:  GE-265-001 
Investigators and Study Centers: Approximately 4 centers in the United States (US) 
Phase of Development: Phase 2 
Objectives:  
Primary Objective: 
• Assess difference and variability between 2 sets of visually-based global rest scores resulting from 2 at-rest 
myocardial perfusion imaging (MPI) sessions using Flurpiridaz (18F) Injection doses synthesized by the 
same or 2 different manufacturing processes 
Secondary Objectives: 
• Assess the intra-reader agreement of the detection of ischemic defect on PET-MPI at rest between 2 MPI 
acquisitions using 2 Flurpiridaz (18F) Injection doses 
• Assess the detection of myocardial segmental defect similarity from 2 sets of images acquired from doses 
synthesized by the same or 2 different manufacturing processes of Flurpiridaz (18F) Injection PET for MPI 
at rest 
• Assess the equivalence of 2 sets of [18F]flurpiridaz time-activity curves (TACs) (blood, myocardium, lungs, 
liver) resulting from MPI using Flurpiridaz (18F) Injection doses synthesized by the same or 2 different 
manufacturing processes 
• Assess the safety of Flurpiridaz (18F) Injection PET doses synthesized by 2 different manufacturing 
processes 
Study Design:  
This is a Phase 2 prospective, randomized, crossover study of Flurpiridaz (18F) Injection for PET-MPI in 
subjects referred for evaluation of known coronary artery disease (CAD) or for suspected CAD with 
intermediate to high pre-test probability (PTP).  Twenty-eight evaluable subjects will be enrolled in this study 
and will undergo 2 Flurpiridaz (18F) Injection PET-MPI at rest.  Each subject will attend a Screening Visit at 
least 2 days and up to 14 days prior to the first Flurpiridaz (18F) Injection PET-MPI.  The subjects will be 
randomized 1:1:1:1 to 4 possible sequences of receiving 2 doses of Flurpiridaz (18F) Injection: 2 groups of 7 
subjects will receive 2 Flurpiridaz (18F) Injection doses synthesized by the same manufacturing processes 
(either HPLC or SPE) and 2 groups of 7 subjects will receive 2 Flurpiridaz (18F) Injection doses synthesized by 
different manufacturing processes (1 dose by HPLC followed by 1 dose by SPE or 1 dose by SPE followed by 
1 dose by HPLC).  All subjects will be followed up by telephone for adverse events (AEs) and serious AEs 
(SAEs) at 24 (+8) hours following each Flurpiridaz (18F) Injection administration. 
Selection of Subjects:  
Twenty-eight evaluable subjects will be enrolled in this study. Assuming a 20% drop-out rate, approximately 
34 subjects will need to be enrolled initially.  At least 30% of subjects enrolled should have a documented 
history of myocardial infarction, defined by history of a fixed defect. 
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. 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its Affiliates 
Name of Finished Product: 
Flurpiridaz (18F) Injection 
Name of Active Ingredient: 
[18F]Flurpiridaz 
2) 
The subject is undergoing evaluation of known CAD or for suspected CAD with an intermediate to high 
PTP.   
3) 
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. 
4) 
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); 
enrollment in the study without a pregnancy test at Screening is allowed for these categories of female 
subjects.  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 each radiopharmaceutical 
administration) must be negative.  These subjects must be practicing appropriate birth control from the 
time of the screening to 30 days after the second radiopharmaceutical administration.  Such methods 
include: hormonal contraception including oral contraceptives; intrauterine device; intrauterine hormone-
releasing system; bilateral tubal occlusion; vasectomized partner; sexual abstinence; adequate barrier 
method with spermicide (e.g., diaphragm, condom). 
5) 
The subject is able and willing to comply with all study procedures as described in the protocol. 
Exclusion Criteria: 
Subjects who meet any of the following criteria will be excluded from the study: 
1) 
Subjects who are pregnant, may possibly be pregnant, or wish (including their partners) to become 
pregnant during the study period, or are lactating. 
2) 
Subjects who are unable to undergo all of the imaging procedures. 
3) 
Subjects with unstable cardiovascular condition, including but not limited to: 
a. 
Transient ischemic attack/stroke within 3 months of enrollment; 
b. 
Significant congenital heart disease; 
c. 
Uncontrolled hypertension; 
d. 
Uncontrolled tachyarrhythmia leading to symptoms or hemodynamic compromise. 
4) 
Subjects requiring cardiac intervention (i.e., percutaneous coronary intervention or coronary artery bypass 
graft) before completing the study. 
5) 
Primary hemodynamically significant uncorrected valvular heart disease, obstructive or regurgitant. 
6) 
Subjects 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). 
7) 
Subjects 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 subjects whom the investigator judges to be unsuitable for 
participation in the study for any reason. 
8) 
Subjects undergoing evaluation for heart transplantation or with a history of heart transplantation. 
9) 
Subjects enrolled in another clinical study within the 30 days before enrollment in this study. 
10) Subjects previously enrolled in this study or any Flurpiridaz (18F) Injection study. 
Number of Subjects/Centers Planned: Twenty-eight evaluable subjects enrolled at approximately 4 centers 
in the US. 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its Affiliates 
Name of Finished Product: 
Flurpiridaz (18F) Injection 
Name of Active Ingredient: 
[18F]Flurpiridaz 
Treatment of Subjects:  
Investigational Medicinal Product: 
Flurpiridaz (18F) Injection is a novel PET-MPI agent labelled with the radioisotope fluorine-18 (18F) and 
administered as an intravenous (IV) injection.  All subjects will be randomized 1:1:1:1 to receive 2 doses of 
Flurpiridaz (18F) Injection: 
Group 1: 2 doses of Flurpiridaz (18F) Injection manufactured by the HPLC method 
Group 2: 2 doses of Flurpiridaz (18F) Injection manufactured by the SPE method 
Group 3: 1 dose of Flurpiridaz (18F) Injection manufactured by the HPLC method followed by 1 dose of 
Flurpiridaz (18F) Injection manufactured by the SPE method 
Group 4: 1 dose of Flurpiridaz (18F) Injection manufactured by the SPE method followed by 1 dose of 
Flurpiridaz (18F) Injection manufactured by the HPLC method.   
All doses will be administered at rest by bolus IV injection in a large peripheral vein.  The targeted dose to the 
body of Flurpiridaz (18F) Injection will be in the range of 1.7 to 2.5 mCi (63 to 93 MBq) for each 
administration and will not exceed a total of 6 mCi (222 MBq) for an individual subject.  The image 
acquisitions in a list-mode at a single bed position centered on the heart will start 10 seconds before Flurpiridaz 
(18F) Injection and last 15 minutes.  In an effort to avoid bias in image acquisition, the test product 
manufacturing status will not be specified on the syringe. 
Duration of Treatment: Subjects will have 2 rest Flurpiridaz (18F) Injection PET-MPI procedures performed 
no more than 2 weeks apart.  To allow for adequate decay of the first dose, at least 24 hours must separate the 2 
injections/imaging procedures.  Subjects will have their last follow-up safety contact 24 (+8) hours after the 
second Flurpiridaz (18F) Injection. 
Efficacy and Safety Variables 
Primary Efficacy Endpoint: 
• 
Intra-reader correlation and difference between the summed perfusion rest scores (SRS) and summed rest 
percent (SR%) after 2 MPI sessions using 2 Flurpiridaz (18F) Injection doses synthesized using the same 
or 2 different manufacturing processes 
Secondary Efficacy Endpoints: 
• 
Variability of the SRS after MPI sessions using 2 Flurpiridaz (18F) Injection doses synthesized for the 
subjects receiving 2 doses of the product manufactured by the SPE process 
• 
Variability of the SRS after MPI sessions using 2 Flurpiridaz (18F) Injection doses synthesized for the 
subjects receiving 2 doses of the product manufactured by the HPLC process 
• 
Intra-reader agreement of the detection of ischemic defect on PET-MPI at rest between 2 MPI 
acquisitions using 2 Flurpiridaz (18F) Injection doses 
• 
Difference between the perfusion rest scores for each of the 17 segments and each reader using 
2 Flurpiridaz (18F) Injection doses synthesized using the same or 2 different manufacturing processes 
• 
Difference in the standard uptake value (SUV) TACs and the relative difference in SUV (5- to 15-minute 
perfusion image) in left ventricular cavity, myocardium, lungs and liver measured after two 
[18F]flurpiridaz injections using doses of Flurpiridaz (18F) Injection synthesized by 2 different 
manufacturing processes 
• 
Difference in the SUV TACs and the relative difference in SUV (5- to 15-minute perfusion image) in left 
ventricular cavity, myocardium, lungs and liver measured after two [18F]flurpiridaz injections using doses 
of Flurpiridaz (18F) Injection for the subjects receiving 2 doses of the product manufactured by the HPLC 
process 
• 
Difference in the SUV TACs and the relative difference in SUV (5- to 15-minute perfusion image) in left 
ventricular cavity, myocardium, lungs and liver measured after two [18F]flurpiridaz injections using doses 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its Affiliates 
Name of Finished Product: 
Flurpiridaz (18F) Injection 
Name of Active Ingredient: 
[18F]Flurpiridaz 
of Flurpiridaz (18F) Injection for the subjects receiving 2 doses of the product manufactured by the SPE 
process 
• 
Intra-reader agreement of the image quality score between the 2 sets of PET images acquired after two 
[18F]flurpiridaz injections using doses of Flurpiridaz (18F) Injection 
Safety Endpoints: 
Subjects will be closely monitored for safety until completion of all study procedures.  Safety monitoring will 
include AEs, medication errors, treatment-emergent AEs (TEAEs), and SAE assessments, vital signs, 
electrocardiograms (ECGs), hematology, clinical chemistry laboratory tests, and urinalysis.   
Statistical Methods and Planned Analysis:  
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 non-missing 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 subjects randomized to receive ≥1 
dose of Flurpiridaz (18F) Injection in the study. 
Modified ITT (MITT) Population: The MITT population will include all ITT subjects who have completed 
the 2 rest Flurpiridaz (18F) Injection PET-MPI procedures.  The MITT population will be the primary analysis 
set for the primary efficacy endpoint.   
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 summarized for the Safety Population. 
Efficacy Endpoints:  
Primary Efficacy Variable 
Myocardial Perfusion Imaging Evaluations: Three qualified readers (independent from the study) will 
perform independent reads of all MPI images, inclusive of standard 17-segment polar-maps of perfusion 
defects.  Each reader will score the perfusion pattern in each segment (17 segments) using a 5-point scale 
scoring:  
- 
Normal 0,  
- 
Minimal, mild impairment of perfusion, ambiguous image 1, 
- 
Moderate impairment of perfusion 2, 
- 
Significant impairment of perfusion 3, 
- 
No perfusion 4. 
The summed score of the 17 segments SRS, as well as the SR%, will be used as the primary endpoint, and 
summarized as a continuous variable by reader and using the median of the results of the 3 readers.  
The primary analysis for the primary endpoint will be based on the mixed-effects model for repeated measures 
(MMRM).  The model will include the median SRS in each dosing period as the dependent variable, with 
manufacturing process, period and dosing sequence as fixed effects, and subject nested within sequence as the 
random effect.  The estimated mean SRS difference and 90% CI will be provided from the MMRM analysis. 
Similarity will be established if the 90% CI of the difference is within a margin of (-0.75, 0.75).  The margin 
size is defined as 0.75 to allow the difference of, at most, 43% of the mean SRS score (mean PET SRS score is 
1.75 based on empirical data [Berman et al. 2013]).   
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its Affiliates 
Name of Finished Product: 
Flurpiridaz (18F) Injection 
Name of Active Ingredient: 
[18F]Flurpiridaz 
The correlation analysis will be stratified by the following 3 groups: 1) subjects who have received 2 doses of 
product manufactured by 2 different processes; 2) subjects who have received 2 doses of product both 
manufactured by the SPE process; and 3) subjects who have received 2 doses of product both manufactured by 
the HPLC process.  The intra-reader (within-subject) correlation between the 2 manufacturing processes will be 
assessed by Pearson’s correlation, Kendall’s τ and Bland-Altman difference for the summed score stratified by 
the above 3 groups.  The mean of paired difference between the 2 manufacturing processes, t-statistics based 
95% confidence interval (CI), the median difference and 95% CI based on Hodges-Lehman method, and p-
value obtained by Wilcoxon signed rank test will also be provided for descriptive purpose for the summed 
score of 17 segments among subjects who have received 2 doses of product manufactured by 2 different 
processes. 
Sensitivity analyses will be performed to assess the impact of missing data on the primary analysis results 
(i.e., subjects in the ITT population with incomplete PET-MPI scans) using similar MMRM analysis for 
primary analysis.  Details will be provided in the SAP. 
Secondary Efficacy Variables 
The intra-reader variability of the SRS will be estimated by the SD of the paired difference divided by √2, for 
subjects receiving 2 doses of the product both manufactured by the SPE process and separately for subjects 
receiving 2 doses of the product both manufactured by the HPLC process. 
For the individual scores of 17 segments, the mean of paired difference between the 2 manufacturing 
processes, t-statistics based 95% CI, the median difference and 95% CI based on Hodges-Lehman method, and 
p-value obtained by Wilcoxon signed rank test will also be provided for descriptive purpose among subjects 
who have received 2 doses of product manufactured by 2 different processes. 
The PET-MPI reads will be performed by the same set of readers. In each session, PET images will be 
displayed in a randomized order, non-sequentially, with PET-MPI exams corresponding to individual subjects 
randomly allotted into reading session batches. The intra-reader agreement of the detection of ischemic defect 
on PET-MPI will be assessed by percent agreement and Cohen’s kappa value stratified by the 3 groups as used 
in the primary analysis.  
Perfusion and gated acquisitions of rest images will be rated for image quality (excellent, good, fair, poor or 
non-diagnostic).  The image quality score will be summarized descriptively for the 3 groups of data sets and 
the intra-reader agreement will be assessed between the 2 acquisitions stratified by the 3 groups as used in the 
primary analysis.  
Within left ventricle, myocardium, lungs and liver regions of interest (ROIs), a TAC (in SUV units) will be 
generated for the dynamic scan during the 15-minute acquisition period.  The SUV for each ROI will be 
generated using the following formula:  
 
 
SUV= Decay Corrected Uptake (kBq/cc) / (Injected Dose (MBq) / Weight (kg)) 
There will be a descriptive statistical analysis only.  The relative difference D in the SUV expressed as  
D = 100 (SUV1-SUV2)/[0.5 * (SUV1 + SUV2)] between the 2 processes will be summarized descriptively for 
each region among subjects who have received 2 doses of product.  The mean absolute percentage difference 
(MAPD) will be determined as the mean of the absolute value of D over all subjects.   
Safety Endpoints: 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 for this clinical investigation has been determined a priori to be 28 subjects to assess the 
clinical imaging similarity and safety profiles of Flurpiridaz (18F) Injection synthesized by 2 different 
manufacturing processes in subjects with suspected or established CAD.  To account for 20% dropout, 
approximately 34 subjects will be randomized in a 1:1:1:1 ratio to each of the 4 treatment sequences. 
 
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2 
TABLE OF CONTENTS 
2.1 
Overall Table of Contents 
Page Number 
1 
SYNOPSIS ..................................................................................................................... 3 
2 
TABLE OF CONTENTS ............................................................................................... 8 
2.1 
Overall Table of Contents .................................................................................. 8 
2.2 
List of Tables .................................................................................................... 11 
2.3 
List of Figures ................................................................................................... 11 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................. 12 
4 
BACKGROUND INFORMATION ............................................................................. 14 
5 
STUDY OBJECTIVES AND ENDPOINTS ............................................................... 20 
5.1 
Objectives ......................................................................................................... 20 
5.2 
Study Endpoints ................................................................................................ 20 
5.2.1 
Primary Efficacy Endpoint ............................................................. 20 
5.2.2 
Secondary Efficacy Endpoints........................................................ 20 
5.3 
Safety Endpoints ............................................................................................... 21 
6 
STUDY DESIGN ......................................................................................................... 22 
6.1 
Overall Study Design and Plan ......................................................................... 22 
6.2 
Scientific Rationale for Study Design .............................................................. 23 
6.3 
Study Timeframe .............................................................................................. 24 
6.4 
End of Study Definition .................................................................................... 24 
6.5 
Risks and Benefits to Subjects.......................................................................... 24 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS................................................ 26 
7.1 
Procedures for Enrollment ................................................................................ 26 
7.2 
Inclusion Criteria .............................................................................................. 26 
7.3 
Exclusion Criteria ............................................................................................. 27 
7.4 
Screen Failures ................................................................................................. 28 
7.5 
Withdrawal and Termination Criteria............................................................... 28 
7.5.1 
Subject Withdrawal ........................................................................ 28 
7.5.2 
Subject Lost to Follow-Up ............................................................. 28 
7.5.3 
Study or Site Termination .............................................................. 29 
8 
TREATMENT OF SUBJECTS .................................................................................... 30 
8.1 
Investigational Medicinal Product .................................................................... 30 
8.1.1 
Flurpiridaz (18F) Injection ............................................................... 30 
8.1.2 
IMP Accountability ........................................................................ 30 
8.1.3 
Registration of Investigational Medicinal Product Complaints ..... 31 
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8.2 
Method of Numbering Subjects ........................................................................ 31 
8.3 
Selection of Doses and Timing ......................................................................... 31 
8.4 
Randomization and Blinding ............................................................................ 32 
8.5 
Prior and Concomitant Medications or Procedures .......................................... 33 
8.6 
Contraception and Pregnancy Avoidance Procedure ....................................... 33 
8.7 
Treatment Compliance ..................................................................................... 34 
9 
STUDY PROCEDURES .............................................................................................. 35 
9.1 
Screening Period ............................................................................................... 37 
9.2 
Flurpiridaz (18F) Injection PET-MPI Visits 1 and 2 ......................................... 38 
9.3 
24 (+8) hours Safety Follow-up (after Flurpiridaz (18F) Injection PET-MPI 
Visits 1 and 2) ................................................................................................... 39 
9.4 
Unscheduled Visits ........................................................................................... 39 
10 
EFFICACY AND SAFETY ASSESSMENTS ............................................................ 40 
10.1 
Efficacy Assessments ....................................................................................... 40 
10.1.1 
Image Acquisition .......................................................................... 41 
10.1.2 
Image Interpretation ....................................................................... 41 
10.2 
Safety Assessments .......................................................................................... 41 
10.2.1 
Clinical Laboratory Evaluation ...................................................... 42 
10.2.2 
Vital Signs ...................................................................................... 43 
10.2.3 
Electrocardiograms ......................................................................... 43 
10.2.4 
Physical Examination ..................................................................... 44 
10.2.5 
Injection Site Monitoring ............................................................... 44 
10.3 
Adverse Events and Serious Adverse Events ................................................... 44 
10.3.1 
Definition of Adverse Event ........................................................... 44 
10.3.2 
Definition of Serious Adverse Event .............................................. 46 
10.3.3 
Time Period and Frequency for Collecting AE and SAE 
Information ..................................................................................... 47 
10.3.4 
Adverse Event and Serious Adverse Event Recording and 
Evaluation ....................................................................................... 47 
10.3.5 
Follow-up of AEs and SAEs .......................................................... 49 
10.3.6 
Reporting Requirements for SAEs ................................................. 49 
10.3.7 
Urgent Safety Measures.................................................................. 50 
10.3.8 
Pregnancy Reporting ...................................................................... 50 
10.4 
Other Variables ................................................................................................. 52 
10.4.1 
Demographic Data .......................................................................... 52 
10.4.2 
Medical and Surgical History ......................................................... 52 
10.4.3 
Prior and Concomitant Medication................................................. 52 
10.5 
Appropriateness of Measurements ................................................................... 52 
11 
DATA HANDLING AND QUALITY ASSURANCE ................................................ 53 
11.1 
Clinical Data Management ............................................................................... 53 
11.2 
Completing and Signing Case Report Forms ................................................... 53 
11.3 
Data Quality Assurance .................................................................................... 53 
11.4 
Record Retention .............................................................................................. 54 
12 
STATISTICAL METHODS AND PLANNED ANALYSIS ...................................... 55 
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12.1 
General Statistical Considerations .................................................................... 55 
12.2 
Populations for Analysis ................................................................................... 55 
12.2.1 
Intent-to-Treat Population .............................................................. 55 
12.2.2 
Modified Intent-to-Treat Population .............................................. 55 
12.2.3 
Safety Population ............................................................................ 55 
12.3 
Subject Demographics/Other Baseline Characteristics .................................... 56 
12.4 
Study Treatments .............................................................................................. 56 
12.5 
Primary Efficacy Analysis ................................................................................ 56 
12.5.1 
Efficacy Variables .......................................................................... 56 
12.5.2 
Statistical Hypothesis, Model, and Method of Analysis ................ 57 
12.5.3 
Handling of Missing Values/Censoring/Discontinuations ............. 57 
12.5.4 
Supportive Analyses ....................................................................... 58 
12.5.5 
Handling of Uninterpretable Images .............................................. 58 
12.6 
Secondary Analyses .......................................................................................... 58 
12.6.1 
Efficacy Variables and Analyses (Secondary) ............................... 58 
12.6.2 
Safety Variables and Analyses ....................................................... 59 
12.6.3 
Reader Difference ........................................................................... 61 
12.6.4 
Resource Utilization ....................................................................... 61 
12.7 
Interim Analysis ............................................................................................... 61 
12.8 
Sample Size Calculation ................................................................................... 61 
12.9 
Procedures for Missing, Unused and Spurious Data ........................................ 62 
12.10 Rules for Excluding Subjects from Analysis .................................................... 62 
12.11 Procedures for Reporting Deviations from Original Statistical Plan ............... 62 
13 
SPECIAL REQUIREMENTS AND PROCEDURES ................................................. 63 
13.1 
Regulatory and Ethical Considerations ............................................................ 63 
13.2 
Investigator’s Responsibilities .......................................................................... 63 
13.2.1 
Overall Responsibilities .................................................................. 63 
13.2.2 
Subject Informed Consent .............................................................. 64 
13.2.3 
Source Data/Documents ................................................................. 64 
13.2.4 
Confidentiality Regarding Study Subjects ..................................... 65 
13.2.5 
Data Protection ............................................................................... 65 
13.2.6 
Dissemination of Clinical Study Data ............................................ 65 
13.3 
Protocol Deviations .......................................................................................... 66 
13.4 
Study Monitoring .............................................................................................. 66 
13.5 
Audit and Inspection ......................................................................................... 66 
13.6 
Financial Disclosure ......................................................................................... 66 
13.7 
Insurance ........................................................................................................... 67 
13.8 
Publication Policy ............................................................................................. 67 
14 
REFERENCES ............................................................................................................. 68 
15 
APPENDICES .............................................................................................................. 70 
15.1 
Information on Investigational and Registered Products ................................. 70 
15.2 
Equipment Parameters ...................................................................................... 70 
15.3 
Normal Limits for Vital Signs and ECG Intervals ........................................... 70 
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15.4 
Pre-test Probability of Obstructive Coronary Artery Disease in Symptomatic 
Patients ............................................................................................................. 71 
16 
CLINICAL PROTOCOL AMENDMENT SUMMARIES .......................................... 72 
16.1 
Amendment A01 .............................................................................................. 72 
16.1.1 
Reasons for Amendment ................................................................ 72 
16.1.2 
Description of Changes .................................................................. 72 
2.2 
List of Tables 
Table 1 
Study Schedule of Events ......................................................................................... 36 
Table 2 
Clinical Laboratory Parameters ................................................................................ 42 
Table 3 
Criteria for Normal Limits for Vital Signs ............................................................... 70 
Table 4 
Criteria for Normal Limits for ECGs ....................................................................... 70 
Table 5 
Clinical Pre-test Probabilities of Obstructive Coronary Artery Disease in 15,815 
Symptomatic Patients [Knuuti et al. 2020] ............................................................... 71 
 
2.3 
List of Figures 
Figure 1 
Study Diagram .......................................................................................................... 23 
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3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACLS 
Advanced cardiac life support 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BMI 
Body mass index  
CAD 
Coronary artery disease 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CRF 
Case report form 
CRO 
Contract research organization 
CT 
Computed tomography 
CTFG 
Clinical Trial Facilitation Group 
ECG 
Electrocardiogram 
ED 
Effective dose 
18F 
Fluorine-18 
GCP 
Good Clinical Practice 
HPLC 
High performance liquid chromatography 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IMP 
Investigational medicinal product 
IRB 
Institutional/Independent Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous 
IxRS 
Interactive web/voice response system 
MAPD 
Mean absolute percentage difference 
MI 
Myocardial infarction 
MITT 
Modified intent-to-treat  
MMRM 
Mixed-effects model for repeated measures 
MPI 
Myocardial perfusion imaging 
13N 
Nitrogen-13 
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PET 
Positron emission tomography 
PTP 
Pre-test probability 
82Rb 
Rubidium-82 
ROI 
Region of interest 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOP 
Standard operating procedure 
SPE 
Solid phase extraction 
SPECT 
Single photon emission computed tomography 
SR% 
Summed Rest Percent 
SRS 
Summed Perfusion Rest Score(s) 
SUV 
Standard uptake value 
TAC 
Time-activity curve 
TEAE 
Treatment-emergent adverse event 
US 
United States 
 
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4 
BACKGROUND INFORMATION 
Coronary artery disease (CAD) is a major cause of death in modern industrialized countries.  
CAD is the single largest cause of death in the United States (US) [Benjamin et al 2017].  CAD 
is also the single most common cause of death in Europe: accounting for 1.92 million deaths in 
Europe each year.  Over 1 in 5 women (22%) and over 1 in 5 men (21%) die from the disease 
according to data from “European Cardiovascular Disease statistics – 2008” [Allender et al. 
2008].  Prevention, early diagnosis, and treatment of CAD are essential to reduce mortality.  
Not only is CAD morbid, but also it strains health care resources.  In 2011, hospital care 
associated with myocardial infarction (MI) cost the US healthcare system $11.5 billion and 
care associated with coronary heart disease cost the US healthcare system $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. 
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 
hemodynamic significance of CAD.  These imaging modalities are non-invasive and widely 
used in patients with suspected CAD and in Europe almost 90% of perfusion studies are 
performed using SPECT.  The prognostic value of rest and stress SPECT-MPI using 
201Thallium or 99mTechnetium-labelled tracers in individuals with suspected CAD has been 
well established in millions of patients [Ritchie et al. 1995] [Clark and Beller 2005].  The 
greatest strength of MPI, however, 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 invasive coronary angiography, without significant differences in clinical 
outcomes [Shaw et al 1999].  More recently, radionuclide imaging of myocardial blood flow 
has been shown to be an indispensable tool for the evaluation and management of CAD 
[Murthy et al 2011] [Naya et al 2014].  With these unique capabilities, the clinical benefits of 
an appropriately performed MPI study are indisputable.   
Patient safety is of paramount importance when contemplating any diagnostic and/or 
therapeutic medical option.  One 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 in 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 image interpretation and lower radiation dose to patients, 
including: higher photon penetration combined with depth-dependent attenuation correction, 
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high spatial, contrast and temporal resolution, and high efficiency allowing for lower 
administered radioactivity. 
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 (cesium-137, germanium-
68/gallium-68) to generate a transmission attenuation map, whereas currently manufactured 
PET systems use x-ray 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 hyperemic blood flow with calculation of a peak stress left 
ventricular ejection fraction.  This may improve identification of high-risk patients or those 
with multi-vessel CAD [Dorbala et al 2009].  Furthermore, recent software solutions allow for 
absolute quantification of regional myocardial blood flow from dynamically acquired 
rubidium-82 (82Rb) and nitrogen-13 (13N) ammonia cardiac PET studies, [Klein et al. 2010] [El 
Fakhri et al 2009] and this may be particularly important and useful in evaluating multi-vessel 
and small vessel coronary disease, responses to medical therapy, and transplant vasculopathy.  
Finally, due to the low dose from PET tracers, PET-MPI offers a significantly lower effective 
radiation dose than 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-recognized need for the development of 
a new perfusion imaging agent with more ideal properties.  Both 82Rb chloride and 13N 
ammonia are approved by the US Food and Drug Administration 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].  The 
opportunity exists for developing a new PET imaging agent using fluorine-18 (18F) that 
exhibits high extraction fraction.  Such an agent as [18F]flurpiridaz 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 multi-vessel disease.  It also has the potential to reduce diagnostic 
uncertainty and reduce radiation dose compared with studies using SPECT agents.   
Clinical studies conducted with Flurpiridaz (18F) Injection include safety, dosimetry, and 
radiokinetic studies in healthy subjects, as well as 1 Phase 2 study and 1 Phase 3 study in 
subjects with known or suspected CAD.  In the clinical studies completed to date, a total of 996 
subjects have received Flurpiridaz (18F) Injection.  An additional 7 subjects have received 
[3H]flurpiridaz.  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. 
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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, laboratory values, and physical and neurological 
examinations. 
The primary dosimetry endpoints in single-center, 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). 
Study BMS747158-102 was a Phase 1, nonrandomized, 2-dose, open-label study conducted at 
2 medical centers 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). 
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 
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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 1 single-center 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 fecal 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 metabolized, 
with no unchanged drug detected in urine or feces.  The major identified radiolabeled 
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.   
The 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 
subjects 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 
optimized 1-day rest/stress protocol was subsequently adopted for the second cohort to assess 
efficacy in subjects with a broad spectrum of pre-test likelihood of CAD. 
In the first cohort, 33 subjects 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 to 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 
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 subjects 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%.   
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The Phase 3 Study BMS747158-301 was an open-label, international multicenter study for the 
assessment of CAD using Flurpiridaz (18F) Injection PET-MPI compared with SPECT-MPI in 
subjects with suspected or known CAD who were referred for invasive coronary angiography.  
Subjects 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 catheterization or a documented history of MI. 
A total of 795 received ≥1 dose of Flurpiridaz (18F) Injection (the safety population), and 
764 subjects completed the trial; 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 
(single photon emission computed tomography [SPECT] or coronary angiography).  Only 
4 (0.5%) discontinuations were due to treatment emergent AEs (TEAEs).  Overall, TEAEs 
were reported in 555 subjects (69.8%), the majority being associated with either exercise or 
pharmacological stress testing or the underlying disease.  Forty-four subjects (5.5%) 
experienced TEAEs deemed to be related to Flurpiridaz (18F) Injection.  Of these, 41 (5.2%) 
were sub-categorized 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%), diarrhea (0.5%), dyspnea (0.5%), flushing (0.5%), and nausea (0.5%).  The modified 
intent-to-treat (MITT) population comprised the 755 subjects 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 subjects 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 
subjects 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 subject 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 ≤0.001).  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 subject 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%. 
Doses of Flurpiridaz (18F) Injection used in the nonclinical and clinical studies performed by 
Lantheus Medical Imaging were manufactured using high performance liquid chromatography 
(HPLC) purification.  This process is also being used to manufacture doses of Flurpiridaz (18F) 
Injection for the current GE Healthcare clinical study (GE-265-303).  The HPLC method is not 
ideal for future routine manufacturing of [18F]fluorine tracers.  GE Healthcare has, therefore, 
developed the manufacturing process for Flurpiridaz (18F) Injection on the FASTlab synthesis 
module, a current and supported synthesis platform.  This process enables the production of 
Flurpiridaz (18F) Injection batches with approximately 4 times the product radioactivity 
compared to the HPLC process.  This will significantly improve the availability of Flurpiridaz 
(18F) Injection.  In addition, the solid phase extraction (SPE) manufacturing process on 
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FASTlab is expected to enhance control, consistency and production reliability because it 
eliminates the manual cut required for HPLC purification.  Also, it uses single-use 
commercially available cartridges, reagents and other disposable materials supplied in a pre-
assembled cassette that is assembled, controlled and released by GE Healthcare under current 
Good Manufacturing Practice.  The drug product from the SPE manufacturing process will 
have improved compatibility with dispensing equipment at manufacturing sites and pharmacy 
syringes.  The latter is important for hospitals to use their standard radiation protection 
equipment to ensure low radiation dose for hospital staff.  It is also important to avoid errors in 
dosing with use of non-compatible syringes.   
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5 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
The primary and secondary objectives of the study are as follows: 
Primary: 
• 
Assess difference and variability between 2 sets of visually-based global rest scores 
resulting from 2 at-rest MPI sessions using Flurpiridaz (18F) Injection doses synthesized 
by the same or 2 different manufacturing processes 
Secondary: 
• 
Assess the intra-reader agreement of the detection of ischemic defect on PET-MPI at 
rest between 2 MPI acquisitions using 2 Flurpiridaz (18F) Injection doses 
• 
Assess the detection of myocardial segmental defect similarity from 2 sets of images 
acquired from doses synthesized by the same or 2 different manufacturing processes of 
Flurpiridaz (18F) Injection PET for MPI at rest 
• 
Assess the equivalence of 2 sets of [18F]flurpiridaz time-activity curves (TACs) (blood, 
myocardium, lungs, liver) resulting from MPI using Flurpiridaz (18F) Injection doses 
synthesized by the same or 2 different manufacturing processes 
• 
Assess the safety of Flurpiridaz (18F) Injection PET doses synthesized by 2 different 
manufacturing processes 
5.2 
Study Endpoints 
5.2.1 
Primary Efficacy Endpoint 
• 
Intra-reader correlation and difference between the summed perfusion rest scores (SRS) 
and summed rest percent (SR%) after 2 MPI sessions using 2 Flurpiridaz (18F) Injection 
doses synthesized using the same or 2 different manufacturing processes 
5.2.2 
Secondary Efficacy Endpoints 
• 
Variability of the SRS after MPI sessions using 2 Flurpiridaz (18F) Injection doses 
synthesized for the subjects receiving 2 doses of the product manufactured by the SPE 
process 
• 
Variability of the SRS after MPI sessions using 2 Flurpiridaz (18F) Injection doses 
synthesized for the subjects receiving 2 doses of the product manufactured by the 
HPLC process 
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• 
Intra-reader agreement of the detection of ischemic defect on PET-MPI at rest between 
2 MPI acquisitions using 2 Flurpiridaz (18F) Injection doses 
• 
Difference between the perfusion rest scores for each of the 17 segments and each 
reader using 2 Flurpiridaz (18F) Injection doses synthesized using the same or 2 
different manufacturing processes 
• 
Difference in the standard uptake value (SUV) TACs and the relative difference in 
SUV (5- to 15-minute perfusion image) in left ventricular cavity, myocardium, lungs 
and liver measured after two [18F]flurpiridaz injections using doses of Flurpiridaz (18F) 
Injection synthesized by 2 different manufacturing processes 
• 
Difference in the SUV TACs and the relative difference in SUV (5- to 15-minute 
perfusion image) in left ventricular cavity, myocardium, lungs and liver measured after 
two [18F]flurpiridaz injections using doses of Flurpiridaz (18F) Injection for the subjects 
receiving 2 doses of the product manufactured by the HPLC process 
• 
Difference in the SUV TACs and the relative difference in SUV (5- to 15-minute 
perfusion image) in left ventricular cavity, myocardium, lungs and liver measured after 
two [18F]flurpiridaz injections using doses of Flurpiridaz (18F) Injection for the subjects 
receiving 2 doses of the product manufactured by the SPE process 
• 
Intra-reader agreement of the image quality score between the 2 sets of PET images 
acquired after two [18F]flurpiridaz injections using doses of Flurpiridaz (18F) Injection 
5.3 
Safety Endpoints 
• 
Subjects will be closely monitored for safety until completion of all study procedures.  
Safety monitoring will include AEs, medication errors, TEAEs, and SAE assessments, 
vital signs, ECGs, hematology, clinical chemistry laboratory tests, and urinalysis. 
 
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6 
STUDY DESIGN 
6.1 
Overall Study Design and Plan 
This is a Phase 2 prospective, randomized, crossover study of Flurpiridaz (18F) Injection for 
PET-MPI in subjects referred for evaluation of known CAD or for suspected CAD with 
intermediate to high pre-test probability (PTP).   
This study will be conducted at approximately 4 centers in the US.  Twenty-eight evaluable 
subjects will be enrolled.  Assuming a 20% drop-out rate, approximately 34 subjects will need 
to be enrolled initially.  At least 30% of subjects enrolled should have a documented history of 
MI, defined by history of a fixed defect. 
Each subject will attend a Screening Visit at least 2 days and up to 14 days prior to the first 
Flurpiridaz (18F) Injection PET-MPI (PET-MPI Visit 1).  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. 
Subjects will undergo 2 Flurpiridaz (18F) Injection PET-MPI procedures at rest performed no 
more than 2 weeks apart.  To allow for adequate decay of the first dose, at least 24 hours must 
separate the 2 injections/imaging procedures.  The subjects will be randomized 1:1:1:1 to 
4 possible sequences of receiving 2 doses of Flurpiridaz (18F) Injection: 7 subjects will receive 
2 Flurpiridaz (18F) Injection doses synthesized by the same HPLC manufacturing process, 
7 subjects will receive 2 Flurpiridaz (18F) Injection doses synthesized by the same SPE 
manufacturing process, and 14 subjects will receive 2 Flurpiridaz (18F) Injection doses 
synthesized by 2 different manufacturing processes (7 subjects will receive 1 dose 
manufactured by HPLC followed by 1 dose manufactured by SPE and 7 subjects will receive 
1 dose manufactured by SPE followed by 1 dose manufactured by HPLC).  All doses will be 
administered at rest by bolus IV injection in a large peripheral vein.   
The targeted dose to the body of Flurpiridaz (18F) Injection will be in the range of 1.7 to 
2.5 mCi (63 to 93 MBq) for each administration and will not exceed a total of 6 mCi 
(222 MBq) for an individual subject.  The image acquisitions in a list-mode at a single bed 
position centered on the heart will start 10 seconds before Flurpiridaz (18F) Injection and last 
15 minutes.  In an effort to avoid bias in image acquisition, the test product manufacturing 
status will not be specified on the syringe. 
All subjects will be followed up by telephone for AEs and SAEs at 24 (+8) hours following 
each Flurpiridaz (18F) Injection administration.   
Therefore, study subjects will participate in the study for up to 30 days. 
A subject will be considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled procedure shown in the Study Schedule of Events (Table 
1). 
An overview of study procedures is presented in Figure 1.   
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Figure 1 Study Diagram 
6.2 
Scientific Rationale for Study Design 
GE Healthcare is currently conducting a clinical study titled “A Phase 3, Open-Label, 
Multicenter 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 Phase 3 study (GE-265-
303) is being conducted in North America and Europe to assess the diagnostic efficacy 
(sensitivity and specificity) of Flurpiridaz (18F) Injection PET-MPI in the detection of 
significant CAD, as defined by the standard of truth of invasive coronary angiography, in 
patients with suspected CAD.  The first subject was enrolled on 
 
  The study is 
expected to be completed by 
.  
Doses of Flurpiridaz (18F) Injection produced for the GE-265-303 study are being 
manufactured with HPLC purification on synthesis platforms that are approaching their end of 
life.  This is not sustainable for future commercial manufacturing of [18F]fluorine tracers.  
GE Healthcare has, therefore, developed the manufacturing process for Flurpiridaz (18F) 
Injection on the FASTlab synthesis module which is a current and supported synthesis 
platform.   
The Chemistry, Manufacturing and Controls development of the SPE process has resulted in a 
product which is not significantly different to that produced with the HPLC process used so far 
in clinical development.  Nonclinical studies have shown equivalent biodistribution in rats for 
the product manufactured by the 2 different processes.   
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GE Healthcare now plans to conduct a dedicated comparative study for a systematic and 
qualitative evaluation of any imaging differences.  Clinical data will be collected to 
substantiate the clinical comparability of the products obtained with the 2 manufacturing 
processes in addition to a test-retest for each of the manufacturing processes to assess their 
respective reliability.   
In reference to the guidelines on the investigation of bioequivalence, this study will be a 
prospective, randomized, crossover study of Flurpiridaz (18F) Injection for PET-MPI in patients 
referred for evaluation of suspected or established CAD.  This corresponds to the proposed 
indication of Flurpiridaz (18F) Injection as it has been explored during the clinical development 
of Flurpiridaz (18F) Injection.  The sample size of 28 evaluable clinical subjects in a crossover 
study will be able to identify any important qualitative and quantitative signals of imaging 
discordance between Flurpiridaz (18F) Injection manufactured by the SPE and HPLC processes.   
Safety surveillance in this study is justifiable and adequate in view of the following: 
• 
The design of the study permits a comparison of safety variables at baseline and post-
investigational medicinal product (IMP) administration in the same subject. 
• 
Consideration of a 24-hour safety monitoring follow-up after each administration of 
Flurpiridaz (18F) Injection 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 study enrollment is expected to start in 
 and to be completed by 
. 
Individual subjects will participate in the study for up to 30 days. 
6.4 
End of Study Definition 
The end of the study is defined as the date of the last scheduled procedure shown in the Study 
Schedule of Events (Table 1) for the last subject in the study globally. 
6.5 
Risks and Benefits to Subjects 
A total of 996 subjects have received Flurpiridaz (18F) Injection in Phase 1 through Phase 3 
clinical studies completed to date: BMS-747158-101, BMS-747158-102, BMS-747158-201, 
and BMS-747158-301.  An additional 7 subjects have received [3H]flurpiridaz in a Phase 1 
study: BMS747158-103.   
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In 3 Phase 1 clinical studies of healthy volunteers, there were no AEs related to Flurpiridaz 
(18F) Injection or [3H]flurpiridaz.  In the Phase 2 study (BMS-747158-201), 2 separate groups 
of subjects (Cohort 1 [n=33] and Cohort 2 [n=143]) with known or suspected CAD were 
studied while having a stress test.  Five subjects (2 in Cohort 1 and 3 in Cohort 2) reported a 
total of 10 AEs; none of these AEs were reported by another study subject, 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%), diarrhea 
(1; 0.6%), nausea (1; 0.6%), ECG 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 completed Phase 3 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 
TEAEs.  In Study 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%) subjects experienced TEAEs deemed to be related to 
Flurpiridaz (18F) Injection.  Of these, 41 (5.2%) were subcategorized 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%), diarrhea (0.5%), dyspnea (0.5%), flushing 
(0.5%), and nausea (0.5%). 
In the ongoing GE-265-303 study, no safety signals have led the Data and Safety Monitoring 
Board to recommend to stop the study.  
Therefore, we do not expect a significant risk for the subjects enrolled in this comparative 
study.  The expected diagnostic potential of Flurpiridaz (18F) Injection should offset this 
limited radiation risk by offering the opportunity for improving the detection of ischemic 
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.   
Further information about the known and expected benefits and risks and reasonably expected 
AEs of Flurpiridaz (18F) Injection may be found in the IB. 
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7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
Procedures for Enrollment 
Subjects will be considered for enrollment if they are undergoing assessment for suspected or 
known CAD. 
The population will include subjects with known CAD or suspected CAD with intermediate to 
high PTP, reflecting the spectrum of patients who would be expected to undergo nuclear 
imaging tests.  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 enrollment is 
permitted.  At least 30% of subjects enrolled should have a documented history of MI, defined 
by history of a fixed defect. 
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 is undergoing evaluation of known CAD or for suspected CAD with an 
intermediate to high PTP. 
(3) 
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. 
(4) 
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); enrollment in the study without a pregnancy 
test at Screening is allowed for these categories of female subjects.  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 each 
radiopharmaceutical administration) must be negative.  These subjects must be 
practicing appropriate birth control from the time of the screening to 30 days after the 
second radiopharmaceutical administration.  Such methods include: hormonal 
contraception including oral contraceptives; intrauterine device; intrauterine hormone-
releasing system; bilateral tubal occlusion; vasectomized partner; sexual abstinence; 
adequate barrier method with spermicide (e.g., diaphragm, condom). 
(5) 
The subject is able and willing to comply with all study procedures as described in the 
protocol. 
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7.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
(1) 
Subjects who are pregnant, may possibly be pregnant, or wish (including their partners) 
to become pregnant during the study period, or are lactating. 
(2) 
Subjects who are unable to undergo all of the imaging procedures. 
(3) 
Subjects with unstable cardiovascular condition, including but not limited to: 
a. Transient ischemic attack/stroke within 3 months of enrollment; 
b. Significant congenital heart disease; 
c. Uncontrolled hypertension; 
d. Uncontrolled tachyarrhythmia leading to symptoms or hemodynamic 
compromise. 
(4) 
Subjects requiring cardiac intervention (i.e., percutaneous coronary intervention or 
coronary artery bypass graft) before completing the study. 
(5) 
Primary hemodynamically significant uncorrected valvular heart disease, obstructive or 
regurgitant. 
(6) 
Subjects 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). 
(7) 
Subjects 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 subjects whom 
the investigator judges to be unsuitable for participation in the study for any reason. 
(8) 
Subjects undergoing evaluation for heart transplantation or with a history of heart 
transplantation. 
(9) 
Subjects enrolled in another clinical study within the 30 days before enrollment in this 
study. 
(10) 
Subjects previously enrolled in this study or any Flurpiridaz (18F) Injection study. 
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7.4 
Screen Failures 
Screen failures are subjects who consent to participate in the clinical study but are not 
subsequently randomly assigned to study intervention.  
Individuals who do not meet the criteria for participation in this study (screen failure) may not 
be rescreened.  
7.5 
Withdrawal and Termination Criteria 
7.5.1 
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. 
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, 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 Flurpiridaz (18F) Injection, 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 for any subject who has received ≥1 Flurpiridaz (18F) Injection, however the 
imaging data will not be included in the blinded image evaluation if both Flurpiridaz (18F) 
Injection PET-MPI scans are not completed.   
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.  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 by telephone for AEs and SAEs for 
24 (+8) hours following each Flurpiridaz (18F) Injection dose administration. 
Withdrawn subjects will not be replaced. 
7.5.2 
Subject Lost to Follow-Up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
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The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• 
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 
• 
Before a subject is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods).  These contact attempts should be documented in the subject’s 
medical record. 
• 
Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
7.5.3 
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 center at which no 
subjects have been enrolled within 1 month of initiation or in case of safety concerns or major 
protocol violations. 
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8 
TREATMENT OF SUBJECTS 
8.1 
Investigational Medicinal Product 
8.1.1 
Flurpiridaz (18F) Injection 
Flurpiridaz (18F) Injection is a novel PET-MPI agent labelled with the radioisotope 18F.  
Flurpiridaz (18F) Injection 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 obtained either by the same  
manufacturing process (both HPLC or both SPE) or by 2 different manufacturing processes 
(1 HPLC and 1 SPE), in a large peripheral vein at rest.  The subjects will be randomized 
1:1:1:1 to 4 possible sequences of receiving 2 Flurpiridaz (18F) Injection.  Seven subjects will 
receive 2 doses manufactured with the same HPLC process, 7 subjects will receive 2 doses 
manufactured with the same SPE process, and 2 groups of 7 subjects will receive 2 Flurpiridaz 
(18F) Injection doses synthesized by different manufacturing processes (1 dose by HPLC 
followed by 1 dose by SPE or 1 dose by SPE followed by 1 dose by HPLC).  The targeted dose 
to the body of Flurpiridaz (18F) Injection will be in the range of 1.7 to 2.5 mCi (63 to 93 MBq) 
for each administration and will not exceed a total of 6 mCi (222 MBq) for an individual 
subject.  Sites will record dose measurement units (mCi or MBq) in keeping with their standard 
institutional practices. 
8.1.2 
IMP Accountability 
Each investigator is responsible for ensuring that deliveries of IMP, 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 syringes (used, unused, or empty) must be destroyed on site after their scheduled use 
in accordance with site policies.  See IMP handling procedures or similar document (e.g., 
Pharmacy Manual) 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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8.1.3 
Registration of Investigational Medicinal Product Complaints 
In the event of an IMP complaint (e.g., breakage, leakage, particulate matter, discoloration, 
labelling mistakes), 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) or through interactive web/voice response system (IxRS) 
(if possible).  This should be indicated on the shipping documentation.  The Responsible 
Person will register the complaint and determine if the complaint is minor or significant 
according to Sponsor procedures.  All complaints will be followed-up and the appropriate 
action will be implemented according to Sponsor procedures. 
8.2 
Method of Numbering Subjects 
A unique allocation number will be assigned to each subject at a center in successive order of 
entering the study after signing the ICF.  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 subject’s eligibility to participate in the 
study, the investigator or study personnel should contact the Sponsor or Sponsor representative 
to discuss the subject’s eligibility. 
The allocation number will be unique for each subject in the study and will consist of 7 
numbers in total: 3 numbers for the center identification and 4 numbers for the subject 
identification at the center (e.g., 002-0001: first subject in center No. 2).  Once a subject 
number has been assigned, it cannot be reassigned, even if the subject is deemed ineligible or 
withdraws consent.  To preserve the scientific integrity of the study, numbers must be assigned 
in consecutive numerical order at each center. 
Subjects will be randomized 1:1:1:1 to 4 possible sequences of receiving 2 Flurpiridaz (18F) 
Injection.  Seven subjects will receive 2 doses of the product manufactured with the same 
HPLC process, 7 subjects will receive 2 doses of the product manufactured with the same SPE 
process, and 2 groups of 7 subjects will receive 2 Flurpiridaz (18F) Injection doses synthesized 
by different manufacturing processes (1 dose by HPLC followed by 1 dose by SPE or 1 dose 
by SPE followed by 1 dose by HPLC).  Therefore, there will be assignment to specific 
treatment groups.  
A subject who has given informed consent but does not fulfil the criteria to participate in the 
study will receive a subject number and will be logged as a screening failure within the IxRS.  
The subject will also be documented on the Screening Log by using the subject’s initials 
(where permitted) and subject number.  
8.3 
Selection of Doses and Timing 
All screening assessments will occur at least 2 days prior to the first Flurpiridaz (18F) Injection 
PET-MPI visit (PET-MPI Visit 1).  The Flurpiridaz (18F) Injection PET-MPI procedure must 
occur within 14 days after screening.  Subjects will have 2 rest Flurpiridaz (18F) Injection PET-
MPI performed no more than 2 weeks apart.  To allow for adequate decay of the first dose, at 
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least 24 hours must separate the 2 injections/imaging procedures.  Subjects must have 
completed the 24-hour safety follow-up after the PET-MPI Visit 1 prior to receiving the second 
Flurpiridaz (18F) Injection.  Subjects will have their last follow-up safety contact 24 (+8) hours 
after the second Flurpiridaz (18F) Injection. 
The dose of IMP to be administered has been selected on the basis of the previous clinical 
studies and is similar to the dose used in the ongoing GE-265-303 Phase 3 study.  
8.4 
Randomization and Blinding 
Randomization 
This is a randomized crossover study.  Subjects will be randomized 1:1:1:1 into 4 treatment 
sequence groups:  
Group 1: 
2 doses of Flurpiridaz (18F) Injection manufactured by the HPLC method 
Group 2: 
2 doses of Flurpiridaz (18F) Injection manufactured by the SPE method 
Group 3: 
1 dose of Flurpiridaz (18F) Injection manufactured by the HPLC method followed 
by 1 dose of Flurpiridaz (18F) Injection manufactured by the SPE method 
Group 4: 
1 dose of Flurpiridaz (18F) Injection manufactured by the SPE method followed by 
1 dose of Flurpiridaz (18F) Injection manufactured by the HPLC method 
Once subjects have completed the screening process they will be enrolled in the study and will 
be randomly assigned to one of the above 4 treatment sequences in accordance with a 
prespecified randomization list.  Allocation to the enrollment groups, including randomization, 
will be performed centrally (via the IxRS) by the contract research organization (CRO). 
No subject will be administered Flurpiridaz (18F) Injection before it has been determined that 
he/she meets the study’s inclusion criteria, does not meet the exclusion criteria and signed and 
dated informed consent has been obtained. 
Blinding 
This is a Phase 2, randomized study.   
Subjects will be blinded to the manufacturing process used to obtain Flurpiridaz (18F) Injection.  
In an effort to avoid bias in image acquisition, the test product manufacturing status will not be 
specified on the syringe. 
The independent image readers will be blinded to subjects’ medical history and the 
manufacturing process used to synthesize Flurpiridaz (18F) Injection. 
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8.5 
Prior and Concomitant Medications or Procedures 
Any medications currently taken by the subject at the time of informed consent and through to 
their last follow-up will be recorded in the CRF, along with the indication and dosage.  Either 
the generic or the trade name may be recorded.  The Sponsor/CRO will encode all therapy and 
medication per a current well-recognized dictionary of medical codes. 
8.6 
Contraception and Pregnancy Avoidance Procedure 
Women of child-bearing potential are “fertile, following menarche and until becoming post-
menopausal, unless permanently sterile.  Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy” [CTFG Guidance 2014].  
Post-menopausal means having had no menses for at least 12 months without an alternative 
medical cause.  
A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy 
or vasectomized with confirmation of success.  
Women of child-bearing potential who are sexually active with a non-sterile male partner and 
males who are sexually active with a female partner of childbearing potential must use an 
acceptable method of contraception (as defined below) from screening until 30 days after 
administration of the IMP.  
Acceptable methods of contraception considered as highly effective are those with no higher 
than a 1% failure rate.  Such methods include [CTFG Guidance 2014]:  
• 
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation, provided there is no concern about interaction with the 
IMP: 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation, 
provided there is no concern about interaction with the IMP: 
• 
oral 
• 
injectable 
• 
implantable 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system, provided there is no concern about interaction 
with the IMP 
• 
Bilateral tubal occlusion 
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• 
Vasectomized partner (provided that the vasectomized partner is the sole sexual partner 
of the women of child-bearing potential and that the vasectomized partner has received 
medical confirmation of the surgical success) 
• 
Sexual abstinence (only if the subject refrains 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). 
Acceptable, but not highly effective, birth control methods that result in a failure rate of more 
than 1% per year include [CTFG Guidance 2014]:  
• 
progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
• 
male or female condom with or without spermicide 
• 
cap, diaphragm or sponge with spermicide 
Subjects will be provided with information on acceptable methods of contraception as part of 
the subject informed consent process.  Women of child-bearing 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 Section 9.2 and 13.3). 
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9 
STUDY PROCEDURES 
All efficacy and safety measurements obtained during the course of the study are summarized 
in the Study Schedule of Events (Table 1). 
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Table 1 
Study Schedule of Events 
Variables 
Screening 
PET-MPI Visit 1 
(2 to 14 days after 
Screening) 
Safety Follow-up 
(24 +8 hours after PET-
MPI Visit 1)* 
PET-MPI Visit 2 
(≥24 hours and <2 weeks 
after PET-MPI Visit 1) 
Safety Follow-up 
(24 + 8 hours after PET-
MPI Visit 2) 
Informed consent 
X 
 
 
 
 
Entry criteria 
X 
 
 
 
 
Pregnancy test a 
X 
X 
 
X 
 
Demographic information 
X 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
Blood sampling 
X 
Xb 
 
Xb 
 
Urine sampling 
X 
Xb 
 
Xb 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
Vital signs and pulse oximetry 
X 
Xc 
 
Xc 
 
12-lead ECG recording 
Xd 
Xd 
 
Xd 
 
Physical examination e 
 
Xe 
 
Xe 
 
Clinical screen for new/worsening symptoms 
 
Xf 
 
Xf 
 
Injection site monitoring 
 
Xg 
 
Xg 
 
IMP administration 
 
X 
 
X 
 
PET-MPI Image acquisition  
 
X 
 
X 
 
Adverse events (including AEs and SAEs)h 
X 
X 
X 
X 
X 
AE = adverse event; ECG = electrocardiogram; IMP = investigational medicinal product; MPI = myocardial perfusion imaging; PET = positron emission tomography; SAE = serious 
adverse event 
* Safety follow-up after PET-MPI Visit 1 must be complete before administration of Flurpiridaz (18F) Injection for PET-MPI Visit 2. 
a) 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 and before 
radiopharmaceutical administration) must be negative. 
b) Before the IMP injection (blood and urine) and 1 hour after the IMP injection (blood). 
c) Vital signs and pulse oximetry will be recorded up to 20 minutes pre-injection and at 30 (±5) minutes post-injection. In addition, heart rate only will be recorded at approximately 
1 minute pre-injection and at 5, 10 and 15 minutes post-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 performed within 48 hours 
prior to screening, without intervening episodes of chest pain or instability, can be used as the Screening ECG, where available. At rest PET-MPI visits, 12-lead ECG will be 
recorded at pre-dose (within 20 minutes before transmission scan) and at 10 (±5) and 30 (±5) minutes post-injection.  
e) Physical examination will comprise a full examination with a specific focus on cardiovascular signs. At rest PET-MPI visits, physical examination will be performed pre-injection 
and at 1 hour post-injection. 
f) A clinical screen for new or worsening symptoms indicative of unstable CAD disease will be conducted prior to performing any procedures at the PET-MPI visits.  If the clinical 
status screening is positive, the PET-MPI visits can either be rescheduled (up to 1 time and within the 2-week period specified) after symptoms stabilize or the subject can be 
discontinued from the study. 
g) Immediately prior to injection, immediately after injection of IMP and 1 hour after injection of IMP. 
h) 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. 
 
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9.1 
Screening Period 
All screening assessments will be performed at least 2 days and within 14 days prior to Rest 
PET-MPI Visit 1.  The following will be done during the screening period: 
• Signed and dated informed consent must be obtained from all subjects prior to their 
entering the study and prior to the initiation of any study-related procedures. 
• All subjects must satisfy all the inclusion criteria and none of the exclusion criteria 
listed in Sections 7.2 and 7.3.   
• 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 guidelines for the diagnosis and management of chronic coronary 
syndromes [Knuuti et al. 2020] (see Appendix 15.4).   
• Prior and concomitant medications. 
• Demographic information will be recorded. 
• Blood and urine samples will be collected for assessing hematology, abnormal glucose 
metabolism, liver and renal insufficiency.  If for scheduling reasons, the study PET-
MPI must occur rapidly after the Screening Visit (e.g., within 48 hours), an additional 
blood sample may be analyzed 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. 
• 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 and prior to 
Flurpiridaz (18F) Injection) must be negative; these subjects must be instructed to 
practice appropriate birth control from time of screening to 30 days after the last 
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).   
• Vital signs and pulse oximetry will be recorded. 
• 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, where available). 
• All AEs and SAEs that occur after informed consent will be recorded (see Table 1 for 
scheduled AE query time points).   
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• Subjects will be randomized to receive either 2 doses of Flurpiridaz (18F) Injection 
manufactured by the same process (HPLC or SPE) or 2 doses of Flurpiridaz (18F) 
Injection manufactured by different processes (1 dose by HPLC and 1 dose by SPE in a 
random order; see Section 8.4).   
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 
Flurpiridaz (18F) Injection PET-MPI Visits 1 and 2 
Subjects will have 2 rest Flurpiridaz (18F) Injection PET-MPI visits performed no more than 2 
weeks apart.  To allow for adequate decay of the first dose, at least 24 hours must separate the 
2 injections/imaging procedures.  The first rest Flurpiridaz (18F) Injection PET-MPI visit (PET-
MPI Visit 1) must take place at least 2 days and within 14 days after screening.  The 24-hour 
safety follow-up after PET-MPI Visit 1 must be completed before administration of Flurpiridaz 
(18F) Injection for PET-MPI Visit 2.   
A clinical screen for new or worsening symptoms indicative of unstable CAD disease will be 
conducted prior to performing any procedures at the Flurpiridaz (18F) Injection PET-MPI visits.  
If the clinical status screening is positive, the Flurpiridaz (18F) Injection PET-MPI visits can 
either be rescheduled (up to 1 time and within the 2-week period specified) after symptoms 
stabilize or the subject can be discontinued from the study.   
During PET-MPI Visits 1 and 2, the following will be performed: 
• Blood samples for laboratory testing will be collected prior to the PET-MPI and 1 hour 
after the PET-MPI injections.  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.   
• 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]). 
• Concomitant medications will be recorded.   
• Vital signs and pulse oximetry will be recorded up to 20 minutes pre-injection and at 
30 (±5) minutes post-injection. In addition, heart rate only will be recorded at 
approximately 1 minute pre-injection and at 5, 10 and 15 minutes post-injection. 
• 12-lead ECGs will be recorded pre-injection (within 20 minutes before transmission 
scan) and at 10 (±5) and 30 (±5) minutes post-injection (See Section 10.2.3). 
• A physical examination will be performed pre-injection and at 1 hour post-injection. 
• During the rest test, all subjects will receive an IV bolus injection of Flurpiridaz (18F) 
Injection in a large peripheral vein (see Section 8.1.1).  The dose (volume and 
radioactivity) will be recorded in the CRF. 
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• Injection-site monitoring (immediately prior to and immediately after the injection and 
1 hour after injection of IMP) 
• The images acquired during Flurpiridaz (18F) Injection PET-MPI will be stored for the 
secondary blinded review. 
• AEs and SAEs will be recorded. 
9.3 
24 (+8) hours Safety Follow-up (after Flurpiridaz (18F) Injection 
PET-MPI Visits 1 and 2) 
All subjects will be followed up by telephone for assessment of AEs and SAEs at 24 (+8) hours 
after each administration of Flurpiridaz (18F) Injection, i.e., after PET-MPI Visits 1 and 2.  The 
following will be recorded: 
• 
Concomitant medications 
• 
AEs and SAEs. 
9.4 
Unscheduled Visits 
Unscheduled visits can be arranged at the discretion of the investigator.  At a minimum, the 
date and reason for the visit will be captured.  Any procedures performed will also be captured 
in the CRF.   
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10 
EFFICACY AND SAFETY ASSESSMENTS 
10.1 
Efficacy Assessments 
The efficacy endpoints will assess: 
Primary endpoint: 
• Intra-reader correlation and difference between the SRS and SR% after 2 MPI sessions 
using 2 Flurpiridaz (18F) Injection doses synthesized using the same or 2 different 
manufacturing processes 
Secondary endpoints: 
• 
Variability of the SRS after MPI sessions using 2 Flurpiridaz (18F) Injection doses 
synthesized for the subjects receiving 2 doses of the product manufactured by the SPE 
process 
• 
Variability of the SRS after MPI sessions using 2 Flurpiridaz (18F) Injection doses 
synthesized for the subjects receiving 2 doses of the product manufactured by the 
HPLC process 
• 
Intra-reader agreement of the detection of ischemic defect on PET-MPI at rest between 
2 MPI acquisitions using 2 Flurpiridaz (18F) Injection doses 
• 
Difference between the perfusion rest scores for each of the 17 segments and each 
reader using 2 Flurpiridaz (18F) Injection doses synthesized using the same or 2 
different manufacturing processes 
• 
Difference in the SUV TACs and the relative difference in SUV (5- to 15-minute 
perfusion image) in left ventricular cavity, myocardium, lungs and liver measured after 
two [18F]flurpiridaz injections using doses of Flurpiridaz (18F) Injection synthesized by 
2 different manufacturing processes 
• 
Difference in the SUV TACs and the relative difference in SUV (5- to 15-minute 
perfusion image) in left ventricular cavity, myocardium, lungs and liver measured after 
two [18F]flurpiridaz injections using doses of Flurpiridaz (18F) Injection for the subjects 
receiving 2 doses of the product manufactured by the HPLC process 
• 
Difference in the SUV TACs and the relative difference in SUV (5- to 15-minute 
perfusion image) in left ventricular cavity, myocardium, lungs and liver measured after 
two [18F]flurpiridaz injections using doses of Flurpiridaz (18F) Injection for the subjects 
receiving 2 doses of the product manufactured by the SPE process 
• 
Intra-reader agreement of the image quality score between the 2 sets of PET images 
acquired after two [18F]flurpiridaz injections using doses of Flurpiridaz (18F) Injection 
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10.1.1 
Image Acquisition 
Imaging procedures include PET-MPI.   
The image acquisitions in a list-mode at a single bed position centered on the heart will start 
10 seconds before Flurpiridaz (18F) Injection and last 15 minutes.  Both PET images must be 
acquired on the same PET camera. 
The PET list-mode acquisition will be reframed to produce a dynamic series for TAC analysis 
(0 to 15 minutes) and a static image (5 to 15 minutes) with and without cardiac gating for 
visual and semiquantitative analysis.  Full details of the imaging protocol are presented in the 
GE-265-001 PET Imaging Manual. 
Incidental findings are not likely. 
10.1.2 
Image Interpretation 
Three qualified independent readers will perform a blinded assessment of each subject’s PET 
image pair (with each injection images).  Further details will be provided in the GE-265-001 
PET Independent Review Charter. 
Details of the TAC and SUV analysis will be provided in the GE-265-001 PET Image 
Processing Manual. 
10.2 
Safety Assessments 
Subjects will be closely monitored for safety until completion of all study procedures.  Safety 
monitoring will include AEs, medication errors, TEAEs, and SAE assessments, vital signs, 
ECGs, hematology, clinical chemistry laboratory tests, and urinalysis.  All subjects will be 
followed up by telephone for AEs at 24 (+8) hours following each Flurpiridaz (18F) Injection 
administration.  The 24-hour safety follow-up after PET-MPI Visit 1 must be completed before 
administration of Flurpiridaz (18F) Injection for PET-MPI Visit 2.   
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, hematology and urinalysis (Table 
2). 
• 
Vital signs: systolic/diastolic blood pressure, heart rate, respiration rate, and pulse 
oximetry. 
• 
12-lead ECG. 
• 
Physical examination. 
• 
Injection site monitoring 
• 
Post-treatment events (AEs and SAEs). 
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Pre-specified 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 2. 
Table 2 
Clinical Laboratory Parameters 
Serum Biochemistry 
Hematology 
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 
Hematocrit 
Platelet count 
White blood cell (WBC) count 
Bilirubin 
Glucose 
Ketone 
Occult blood 
pH 
Protein 
Urobilinogen 
 
The signed and interpreted laboratory results will be kept together with the subject’s CRF 
(paper or electronic) as supplemental pages, both centrally (in an electronic format only) and at 
the site. 
Blood samples will be obtained for assessment of serum biochemistry and hematology 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 analyzed at a central laboratory (for 
parameters, see Table 2).  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 analyzed 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 time points described in Table 1.  The time of void will be 
documented on the CRF.  Urine voided will be analyzed for parameters listed in Table 2. 
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.   
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10.2.2 
Vital Signs 
Vital signs (pulse oximetry, blood pressure, heart rate, respiratory rate) will be monitored at 
Screening and at PET-MPI Visits 1 and 2, 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 position will be used each time vital signs are measured for a given 
subject and blood pressure will be measured from the arm contra-lateral to the site of IMP 
administration whenever possible. 
10.2.3 
Electrocardiograms 
A standard 12-lead ECG will be obtained at Screening and at PET-MPI Visits 1 and 2, 
according to the study schedule of events (Table 1).  ECGs 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 CRF.  
ECG clocks should be synchronized with imaging equipment.  Note: pre-dose ECGs should be 
obtained within 20 minutes before the transmission scan, and the subject should rest for 5 
minutes prior to this.  Single ECGs will also be obtained at 10 (±5) and 30 (±5) minutes post-
injection.  The investigator will be asked to provide a determination of clinically significant 
changes on the CRF for the ECGs obtained at 10 and 30 minutes after administration of 
Flurpiridaz (18F) Injection.  If the investigator determines that there are any clinically 
significant changes from the ECG obtained before Flurpiridaz (18F) injection, those changes 
will be reported as AEs. 
10.2.3.1 
Investigational Site Responsibilities 
Each 12-lead ECG will be evaluated by a board-certified cardiologist or advanced cardiac life 
support (ACLS)-certified licensed physician.  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.   
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 is expected to 
calculate QTc intervals.   
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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 PET-MPI visits before the Flurpiridaz (18F) Injection rest MPI exam and 1 hour post-
injection.  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 new abnormal physical finding is one that occurs when a subject’s normal baseline physical 
examination becomes abnormal post baseline.  A worsening abnormal physical finding is one 
that occurs when a subject’s abnormal baseline physical examination becomes worse post 
baseline. 
10.2.5 
Injection Site Monitoring 
The injection site will be evaluated at the following time points: immediately prior to and 
immediately after each injection of IMP, and at 1 hour after each injection.   
Abnormal injection site findings include, but are not limited to, radiopharmaceutical 
extravasation, bleeding, hematoma, redness, and infection.  They will be recorded as AEs in 
the CRF. 
10.3 
Adverse Events and Serious Adverse Events 
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. 
10.3.1 
Definition of Adverse Event 
AE Definition: An AE is defined as any untoward medical occurrence in a patient or clinical 
investigation subject which does not necessarily have to have a causal relationship with their 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
IMP, whether or not considered related to that product.  Only symptoms/signs that begin or 
worsen in severity and/or frequency after signing informed consent will be recorded as AEs.   
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Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, vital signs measurements), including those that 
worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator (i.e., not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
A new condition detected or diagnosed after IMP administration even though it may 
have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of IMP or a 
concomitant medication.  Overdose per se will not be reported as an AE/SAE unless it 
is an intentional overdose taken with possible suicidal/self-harming intent. Such 
overdoses should be reported regardless of sequelae. 
Events NOT Meeting the AE Definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
Treatment-emergent AE: A treatment-emergent AE is defined as an AE that occurs from 
time of administration of IMP to the end of the follow-up period.   
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. 
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10.3.2 
Definition of Serious Adverse Event 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease). 
An SAE is defined as any untoward medical occurrence that: 
a) Results in death 
b) Is life-threatening 
- 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
- 
In general, hospitalization signifies that the subject has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting.  Complications that occur during hospitalization are AEs.  If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious.  When 
in doubt as to whether “hospitalization” occurred or was necessary, the AE should be 
considered serious. 
- 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d) Results in persistent disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) Is another medically important event 
- 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
- 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse. 
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Subjects (or, when appropriate, a caregiver, surrogate, or the subject’s legally authorized 
representative) will report AEs to the investigator and/or qualified designee. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the IMP or study procedures, or that 
cause the subject to discontinue the study. 
10.3.3 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the ICF until the last follow-up visit at 
the time points specified in the Schedule of Events (Table 1). 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours.  The investigator will submit any updated SAE data 
to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation.  However, if the investigator learns of any SAE, including a death, at any time 
after a subject has been discharged from the study, and he/she considers the event to be 
reasonably related to the IMP or study participation, the investigator must promptly notify the 
Sponsor. 
10.3.4 
Adverse Event and Serious Adverse Event Recording and Evaluation 
Adverse Event and Serious Adverse Event Recording: 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
The investigator will then record all relevant AE/SAE information in the CRF and/or the SAE 
reporting form.  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. 
It is not acceptable for the investigator to send photocopies of the subject’s medical records to 
the Sponsor/CRO in lieu of completion of the AE/SAE CRF page/reporting form. 
There may be instances when copies of medical records for certain cases are requested by the 
Sponsor/CRO.  In this case, all subject identifiers, with the exception of the subject number, 
will be redacted on the copies of the medical records before submission to the Sponsor/CRO. 
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The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information.  Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity: 
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories:  
• 
Mild: An event that is easily tolerated by the subject, causing minimal discomfort and 
not interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE (Section 10.3.2), NOT when it is rated as severe. 
Other measures to evaluate AEs and SAEs may be utilized (e.g., National Cancer Institute 
Common Terminology Criteria for Adverse Events). 
Assessment of Causality: 
Causality should be assessed as Related or Not Related (Unrelated). 
The investigator is obligated to assess the relationship between IMP and each occurrence of 
each AE/SAE. 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
The investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to IMP administration will be considered and 
investigated. 
The investigator will also consult the IB in his/her assessment. 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the Sponsor/CRO.  However, it is very important 
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that the investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to the Sponsor/CRO. 
The investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  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.  Open-ended and non-leading verbal questioning 
of the subject (e.g., “How do you feel?”) is the preferred method to inquire about 
AE occurrences.  Subjects will be instructed to immediately report any symptoms and signs to 
the study staff (i.e., between formal observations). 
10.3.5 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject 
at subsequent visits/contacts.  All SAEs will be followed until resolution, stabilization, the 
event is otherwise explained, or the subject is lost to follow-up (as defined in Section 7.5.2).  
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor/CRO 
to elucidate the nature and/or causality of the AE or SAE as fully as possible.  This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
If a subject dies during participation in the study or during a recognized follow-up period, the 
investigator will provide the Sponsor/CRO with a copy of any post-mortem findings including 
histopathology.  
New or updated information will be recorded in the originally completed CRF. 
The investigator will submit any updated SAE data to the Sponsor/CRO within 24 hours of 
receipt of the information. 
10.3.6 
Reporting Requirements for SAEs 
Prompt notification by the investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of an IMP 
under clinical investigation are met.  Study centers are instructed to report all SAEs to the 
Sponsor/CRO within 24 hours.   
Details of the procedures for notifying the Sponsor/CRO of SAEs and contact details for any 
protocol or safety-related questions are provided in a separate guidance document. 
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The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of an IMP under clinical investigation.  The sponsor will 
comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional/Independent Review Boards (IRBs), and investigators. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs or a MedWatch/Council for International 
Organizations of Medical Sciences [CIOMS]) from the sponsor will review and then file it 
along with the IB and will notify the IRB, if appropriate according to local requirements. 
10.3.7 
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 
study subjects without prior IRB approval/favorable opinion. 
The investigator may take appropriate urgent safety measures in order to protect the subjects of 
a clinical study 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.  
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. 
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 IRB of the 
measures taken and the circumstances giving rise to those measures. 
10.3.8 
Pregnancy Reporting 
This process is aimed at ensuring the appropriate monitoring of the potential risk related to 
IMP exposure of pregnant women and/or fetuses as well as the risks associated with exposure 
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.   
The investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this study.  The initial information will be recorded on the 
appropriate form and submitted to the sponsor within 24 hours of learning of a subject’s 
confirmed pregnancy.  
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The subject will be followed to determine the outcome of the pregnancy.  The investigator will 
collect follow-up information on the subject and the neonate, and the information will be 
forwarded to the sponsor.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  Any termination of pregnancy will be reported, 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 
Any female subject who becomes pregnant while participating in the study will discontinue 
IMP or be withdrawn from the study. 
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.   
The investigator will attempt to collect pregnancy information on any male subject’s female 
partner who becomes pregnant while the male subject is in this study.  This applies only to 
male subjects who receive IMP. 
After obtaining the necessary signed informed consent from the pregnant female partner, the 
investigator will record pregnancy information on the appropriate form and submit it to the 
sponsor within 24 hours of learning of the partner’s confirmed pregnancy.  The female partner 
will also be followed to determine the outcome of the pregnancy.  Information on the status of 
the mother and child will be forwarded to the sponsor.  Generally, the follow-up will be no 
longer than 6 to 8 weeks following the estimated delivery date.  Any termination of the 
pregnancy will be reported regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure.  
When a study subject reports a pregnancy (post-IMP administration) to the investigator, a 
pregnancy test should be arranged for the study subject (or their partner) by the investigator if 
the pregnancy has not been confirmed by another physician. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE.  
A spontaneous abortion (occurring at ≤22 weeks gestational age) or still birth (occurring 
at >22 weeks gestational age) is always considered to be an SAE and will be reported as such.  
Any post-study pregnancy-related SAE considered reasonably related to the IMP by the 
investigator will be reported to the sponsor as described in Section 10.3.6.  While the 
investigator is not obligated to actively seek this information in former study subjects, he or she 
may learn of an SAE through spontaneous reporting. 
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10.4 
Other Variables 
10.4.1 
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 screening will be calculated from the date of 
birth and the date of screening.  Body mass index (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 CRF or a partial date will be used in accordance with 
local practice. 
10.4.2 
Medical and Surgical History 
The subjects’ relevant medical and surgical history will be recorded at Screening and will be 
summarized. 
10.4.3 
Prior and Concomitant Medication 
Any medications currently taken by the subject at the time of informed consent, and through to 
their last follow-up 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-recognized dictionary of medical codes.  
10.5 
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 
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.  Full details of procedures for 
data handling will be documented in the Data Management Plan. 
11.2 
Completing and Signing Case Report Forms 
For electronic CRFs, 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 date and time of the correction, and the person correcting the error 
and the reason for the correction.  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). 
11.3 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRFs unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB review, and regulatory 
agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the Monitoring 
Plan or similar document. 
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (e.g., CROs). 
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Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records, including, but not limited 
to, the image data, may be destroyed during the retention period without the written approval 
of the sponsor.  No records may be transferred to another location or party without written 
notification to the sponsor. 
11.4 
Record Retention 
All study documentation at the investigator site and Sponsor site will be retained in accordance 
with ICH E6-GCP and the Sponsor/CRO’s quality standards and standard operating procedures 
(SOPs). 
All study documentation at the Investigator site and Sponsor site will be retained 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 analyzed 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 centers in this protocol will be combined so that an adequate number of 
subjects will be available for analysis.  The data will be summarized 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 using 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.  All summary tables 
and data listings will be separated by treatment groups.  The planning and reporting of 
statistical analysis will be carried out as described in the Sponsor/CRO’s SOPs governing 
clinical studies and will be described in further detail in the Statistical Analysis Plan (SAP). 
12.2 
Populations for Analysis 
12.2.1 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population will consist of all subjects randomized to receive ≥1 dose 
of Flurpiridaz (18F) Injection in the study. 
12.2.2 
Modified Intent-to-Treat Population 
The Modified Intent-to-Treat (MITT) population will include all ITT subjects who have 
completed the 2 rest Flurpiridaz (18F) Injection PET-MPI procedures.  The MITT population 
will be the primary analysis set for the primary efficacy endpoint.   
12.2.3 
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 summarized for the Safety Population. 
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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). 
• 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 summarized by using 
descriptive statistics.  Sex, ethnicity, and race will be summarized by counts and percentages. 
Medical histories will be summarized by counts and percentages.  Concomitant 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 will be summarized by volume 
and radioactivity administered.   
Any other medications taken by a subject at time of informed consent, and through to the last 
follow-up 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 reads will be performed by the same set of readers in crossover 
sessions independent of one another.  In each session, PET images will be displayed in a 
randomized order, non-sequentially, with PET-MPI exams corresponding to individual subjects 
randomly allotted into reading session batches.   
The independent reads of all MPI images will be based on standard 17-segment polar-maps of 
perfusion defects.  Each reader will score the perfusion pattern in each segment (17 segments) 
using a 5-point scale scoring:  
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- 
Normal 0,  
- 
Minimal, mild impairment of perfusion, ambiguous image 1, 
- 
Moderate impairment of perfusion 2, 
- 
Significant impairment of perfusion 3, 
- 
No perfusion 4. 
The summed score of the 17 segments SRS, as well as the SR%, will be used as the primary 
endpoint, and summarized as a continuous variable by reader and using the median of the 
results of the 3 readers.  
12.5.2 
Statistical Hypothesis, Model, and Method of Analysis 
The SRS will be summarized as a continuous variable by reader and using the median of the 
results of the 3 readers. 
The primary analysis for the primary endpoint will be based on the mixed-effects model for 
repeated measures (MMRM).  The model will include the median SRS in each dosing period as 
the dependent variable, with manufacturing process, period and dosing sequence as fixed 
effects, and subject nested within sequence as the random effect.  The estimated mean SRS 
difference and 90% CI will be provided from the MMRM analysis.  Similarity will be 
established if the 90% CI of the difference is within a margin of (-0.75, 0.75).  The margin size 
is defined as 0.75 to allow the difference of, at most, 43% of the mean SRS score (mean PET 
SRS score is 1.75 based on empirical data [Berman et al. 2013]). 
The correlation analysis will be stratified by the following 3 groups: 1) subjects who have 
received 2 doses of product manufactured by 2 different processes; 2) subjects who have 
received 2 doses of product both manufactured by the SPE process; and 3) subjects who have 
received 2 doses of product both manufactured by the HPLC process.  The intra-reader (within-
subject) correlation between the 2 manufacturing processes will be assessed by Pearson’s 
correlation, Kendall’s τ and Bland-Altman difference for the summed score stratified by the 
above 3 groups.  The mean of paired difference between the 2 manufacturing processes, t-
statistics based 95% confidence interval (CI), the median difference and 95% CI based on 
Hodges-Lehman method, and p-value obtained by Wilcoxon signed rank test will also be 
provided for descriptive purpose for the summed score of 17 segments among subjects who 
have received 2 doses of product manufactured by 2 different processes. 
12.5.3 
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 SAP.   
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12.5.4 
Supportive Analyses 
Sensitivity analyses will be performed to assess the impact of missing data on the primary 
analysis results (i.e., subjects in the ITT population with incomplete PET-MPI scans) using 
similar MMRM analysis for primary analysis.  Details will be provided in the SAP.  
12.5.5 
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. 
12.6 
Secondary Analyses 
12.6.1 
Efficacy Variables and Analyses (Secondary) 
Secondary efficacy endpoints include: 
• 
Variability of the SRS after MPI sessions using 2 Flurpiridaz (18F) Injection doses 
synthesized for the subjects receiving 2 doses of the product manufactured by the SPE 
process 
• 
Variability of the SRS after MPI sessions using 2 Flurpiridaz (18F) Injection doses 
synthesized for the subjects receiving 2 doses of the product manufactured by the 
HPLC process 
• 
Intra-reader agreement of the detection of ischemic defect on PET-MPI at rest between 
2 MPI acquisitions using 2 Flurpiridaz (18F) Injection doses 
• 
Difference between the perfusion rest scores for each of the 17 segments and each 
reader using 2 Flurpiridaz (18F) Injection doses synthesized using the same or 2 
different manufacturing processes 
• 
Difference in the SUV TACs and relative difference in SUV (5- to 15-minute perfusion 
image) in left ventricular cavity, myocardium, lungs and liver measured after two 
[18F]flurpiridaz injections using doses of Flurpiridaz (18F) Injection synthesized by 2 
different manufacturing processes 
• 
Difference in the SUV TACs and relative difference in SUV (5- to 15-minute perfusion 
image) in left ventricular cavity, myocardium, lungs and liver measured after two 
[18F]flurpiridaz injections using doses of Flurpiridaz (18F) Injection for the 7 subjects 
receiving 2 doses of the product manufactured by the HPLC process 
• 
Difference in the SUV TACs and relative difference in SUV (5- to 15-minute perfusion 
image) in left ventricular cavity, myocardium, lungs and liver measured after two 
[18F]flurpiridaz injections using doses of Flurpiridaz (18F) Injection for the 7 subjects 
receiving 2 doses of the product manufactured by the SPE process 
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• 
Intra-reader agreement of the image quality score between the 2 sets of PET images 
acquired after two [18F]flurpiridaz injections using doses of Flurpiridaz (18F) Injection. 
The intra-reader variability of the SRS will be estimated by the SD of the paired difference 
divided by √2, for subjects receiving 2 doses of the product both manufactured by the SPE 
process and separately for subjects receiving 2 doses of the product both manufactured by the 
HPLC process. 
For the individual scores of 17 segments, the mean of paired difference between the 
2 manufacturing processes, t-statistics based 95% CI, the median difference and 95% CI based 
on Hodges-Lehman method, and p-value obtained by Wilcoxon signed rank test will also be 
provided for descriptive purpose among subjects who have received 2 doses of product 
manufactured by 2 different processes. 
The PET-MPI reads will be performed by the same set of readers. In each session, PET images 
will be displayed in a randomized order, non-sequentially, with PET-MPI exams corresponding 
to individual subjects randomly allotted into reading session batches.  The intra-reader 
agreement of the detection of ischemic defect on PET-MPI will be assessed by percent 
agreement and Cohen’s kappa value stratified by the 3 groups as used in the primary analysis.  
Perfusion and gated acquisitions of rest images will be rated for image quality (excellent, good, 
fair, poor or non-diagnostic).  The image quality score will be summarized descriptively for the 
3 groups of data sets and the intra-reader agreement will be assessed between the 2 acquisitions 
stratified by the 3 groups as used in the primary analysis.  
Within left ventricle, myocardium, lungs and liver regions of interest (ROIs), a TAC (in SUV 
units) will be generated for the dynamic scan during the 15-minute acquisition period.  The 
SUV for each ROI will be generated using the following formula:  
 
 
SUV= Decay Corrected Uptake (kBq/cc) / (Injected Dose (MBq) / Weight (kg)) 
There will be a descriptive statistical analysis only.  The relative difference D in the SUV 
expressed as D = 100 (SUV1-SUV2)/[0.5 * (SUV1 + SUV2)] between the 2 processes will be 
summarized descriptively for each region among subjects who have received 2 doses of 
product.  The mean absolute percentage difference (MAPD) will be determined as the mean of 
the absolute value of D over all subjects. 
12.6.2 
Safety Variables and Analyses 
Safety Endpoints: 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 summarized by mean, SD, minimum, and 
maximum at each time point.   
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12.6.2.1 
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 summarized by counts and percentages for each manufacturing process: 
• 
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.   
12.6.2.2 
Vital Signs 
Descriptive statistics will be displayed for the observed values and changes from baseline.  For 
each vital-sign variable and each time point, the following safety endpoints will be summarized 
by counts and percentages and by manufacturing process: 
• 
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, 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.   
12.6.2.3 
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 summarized by 
counts and percentages and by manufacturing process: 
• 
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 summarized by counts and 
percentages at each post-administration time point or by additional/other characteristics 
deemed necessary by study team. 
QTc correction: 
The following correction formula will be employed in analyzing QTc data in an attempt to 
reduce the bias resulting from over- or under-correction: 
 
Fridericia’s:  QTcF = QT/3RR 
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The following analyses will employ this method of correction: 
(1) 
Changes from baseline in the QTc interval will be displayed according to Committee 
for Medicinal Products for Human Use 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.   
12.6.2.4 
Physical Examination 
The number and percentage of subjects with changes in physical examination status from 
normal at pre-administration to abnormal at 1 hour post-administration (and vice versa) will be 
presented by manufacturing process.  Shift tables based on the normal range will be prepared.   
12.6.2.5 
Adverse Events 
AEs and SAEs will be coded using a current version of Medical Dictionary for Regulatory 
Activities and all reported events will be listed for the safety population.  TEAEs are defined as 
AEs that occur from the time of IMP administration through the end of the follow-up period.  
The number and percentage of subjects 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 are defined as SAEs that occur 
from the time of IMP administration through the end of the follow-up period.  Treatment-
emergent SAEs will also be presented for the safety population.   
12.6.3 
Reader Difference 
Reader variability will be assessed by the reread of images.  Further details can be found in the 
GE-265-001 Independent Review Charter. 
12.6.4 
Resource Utilization 
The summed score of the 17 myocardial segments and the individual scores of 17 segments, 
the SUV values between the injection time-point and 15 minutes in left ventricular cavity, 
myocardium, lungs and liver will be analyzed.  
12.7 
Interim Analysis 
No formal interim analyses will be performed in this study.   
12.8 
Sample Size Calculation 
The sample size for this clinical investigation has been determined a priori to be 28 subjects to 
assess the clinical imaging similarity and safety profiles of Flurpiridaz (18F) Injection 
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synthesized by 2 different manufacturing processes in subjects with suspected or established 
CAD.  To account for 20% dropout, approximately 34 subjects will be randomized in a 1:1:1:1 
ratio to each of the 4 treatment sequences.   
12.9 
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. 
12.10 
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 read) 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. 
12.11 
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 and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines 
• 
Applicable ICH GCP Guidelines 
• 
Applicable laws and regulations 
Before starting this study, the protocol, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB and reviewed and approved by the IRB.  The 
protocol will also be submitted to regulatory bodies/local health authorities in accordance with 
local regulations as required.  The study will not start before the IRB gives written approval or 
a favorable opinion in accordance with ICH E6-GCP and all applicable regulatory bodies/local 
health authorities give approval or a favorable opinion as required. 
Any amendments to the protocol will require IRB approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to 
study subjects (see Section 10.3.7). 
The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB in accordance with 
the requirements, policies, and procedures established by the IRB 
• 
Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures 
• 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB, and all other applicable local 
regulations 
13.2 
Investigator’s Responsibilities 
13.2.1 
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 centers participating in this study that cannot comply with these 
standards will be documented. 
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13.2.2 
Subject Informed Consent 
Written and oral information about the study in a language understandable by the subject will 
be given to all subjects.  The investigator or his/her representative will explain the nature of the 
study to the subject and answer all questions regarding the study. 
Subjects must be informed that their participation is voluntary and 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.   
Subjects will be required to sign and date a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the IRB or study center.  A subject’s 
ICF must be obtained before any procedures or assessments are done and after the aims, 
methods, anticipated benefits, potential hazards, and insurance arrangements in force are 
explained.   
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was obtained.  The 
authorized person obtaining the informed consent must also sign the ICF. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
The investigator(s) will keep the original consent forms.  A copy of the signed ICF(s) must be 
provided to the subject or the subject’s legally authorized representative. 
13.2.3 
Source Data/Documents 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator’s site. 
Data reported or entered on the CRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained.  The investigator 
may need to request previous medical records or transfer records, depending on the study.  
Also, current medical records must be available. 
The monitor(s), auditor(s), authorized personnel of the Sponsor/CRO, health authority 
inspector(s) or their agents, and authorized members of 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. 
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13.2.4 
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 PET examinations) 
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 scrutinized for the purpose of verifying data recorded in 
the CRF.  This may be done by the monitor(s), properly authorized persons on behalf of the 
Sponsor, the quality assurance unit, or regulatory authorities.  Personal medical information 
will always be treated as confidential. 
13.2.5 
Data Protection 
Subjects will be assigned a unique identifier by the sponsor.  Any subject records or datasets 
that are transferred to the sponsor will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred. 
The subject must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the subject who will be required to give consent for their data to be used as 
described in the informed consent.   
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB members, and by inspectors from regulatory authorities. 
13.2.6 
Dissemination of Clinical Study Data 
The sponsor will disclose clinical study reports, periodic safety reports, and clinical study 
summary reports after review by regulatory authorities.   
The sponsor will post company-sponsored study information and tabular study results on the 
US National Institutes of Health’s website www.ClinTrials.gov and other publicly-accessible 
sites. 
The sponsor will take appropriate measures to ensure that the results will be published in peer-
reviewed journal, to warrant the scientific integrity and credibility of publication activities 
performed by or on behalf of the company.  The sponsor will grant access to analyzable 
datasets from the clinical study through a secure system, following an independent assessment 
of the scientific merit of a rigorously defined research question from a third party. 
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13.3 
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. 
13.4 
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. 
13.5 
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. 
13.6 
Financial Disclosure 
According to 21 CFR, Part 54, the Sponsor is required to completely and accurately disclose or 
certify information concerning the financial interests of a clinical investigator (or investigating 
institution) who is not a full-time or part-time employee to the FDA.  Therefore, the 
investigator(s) (or investigating institution) must provide the Sponsor with sufficient, accurate 
financial certification that none of the following financial arrangements (further defined in 
21CFR Part 54.2) exist with the Sponsor or fully disclose the nature of the arrangement.  This 
financial disclosure also applies to any financial arrangements that exist between the Sponsor 
and the investigator’s spouse(s) or dependent children: 
• 
Compensation for participation in the study is affected by the outcome of the study. 
• 
Significant equity (greater than $50,000) interest in the Sponsor’s company. 
• 
Proprietary interest in the tested product. 
• 
Significant payments of other sorts, exceeding a monetary value of $25,000. 
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13.7 
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. 
13.8 
Publication Policy 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission.  This allows the sponsor to protect proprietary information and to provide 
comments. 
The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data.  In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
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14 
REFERENCES 
[Allender et al. 2008] 
Allender S, Scarborough P, Peto V, et al.  European cardiovascular disease statistics, 2008 
edition.  European Heart Network.  2008. 
[Benjamin et al 2017] 
Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart Disease and 
Stroke Statistics—2017 Update: A Report From the American Heart Association. Circulation. 
2017;135(10):e146-e603. Erratum in: Correction to: Heart disease and stroke statistics—2017 
update: a report from the American Heart Association. Circulation. 2017;135(10):e646.  
[Berman et al. 2013] 
Berman DS, Maddahi J, Tamarappoo BK, Czernin J, Taillefer R, Udelson JE, et al.  Phase II 
safety and clinical comparison with single-photon emission computed tomography myocardial 
perfusion imaging for detection of coronary artery disease: flurpiridaz F 18 positron emission 
tomography.  J Am Coll Cardiol. 2013;61(4):469-477.  
[Clark and Beller 2005] 
Clark AN, Beller GA. The present role of nuclear cardiology in clinical practice. Q J Nucl Med 
Mol Imaging. 2005;49(1):43-58. 
[CTFG Guidance 2014] 
Clinical Trial Facilitation Group (CTFG) (2014) Recommendations related to contraception 
and pregnancy testing in clinical trials. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf.  Accessed 
29 October 2019. 
[Dorbala et al 2009] 
Dorbala S, Hachamovitch R, Curillova Z, Thomas D, Vangala D, Kwong RY, Di Carli MF. 
Incremental prognostic value of gated Rb-82 positron emission tomography myocardial 
perfusion imaging over clinical variables and rest LVEF. JACC Cardiovasc Imaging. 
2009;2(7):846-854. 
[El Fakhri et al 2009] 
El Fakhri G, Kardan A, Sitek A, Dorbala S, Abi-Hatem N, Lahoud Y, et al. Reproducibility 
and accuracy of quantitative myocardial blood flow assessment with 82Rb PET: Comparison 
with 13N-ammonia PET. J Nucl Med. 2009;50(7):1062-1071. 
[Glover and Gropler 2007] 
Glover DK, Gropler RJ. Journey to find the ideal PET flow tracer for clinical use: are we there 
yet? J Nucl Cardiol. 2007;14(6):765-768. 
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Page 69 of 73 
[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.   
[Knuuti et al. 2020] 
Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, Funck-Brentano C, et al; ESC 
Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of 
chronic coronary syndromes.  Eur Heart J. 2020;41(3):407-477.  
[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.   
[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. 
[Ritchie et al. 1995] 
Ritchie JL, Bateman TM, Bonow RO, Crawford MH, Gibbons RJ, Hall RJ, et al. Guidelines 
for clinical use of cardiac radionuclide imaging. Report of the American College of 
Cardiology/American Heart Association Task Force on Assessment of Diagnostic and 
Therapeutic Cardiovascular Procedures (Committee on Radionuclide Imaging), developed in 
collaboration with the American Society of Nuclear Cardiology. J Am Coll Cardiol. 
1995;25(2):521-47. 
[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. 
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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.   
15.2 
Equipment Parameters 
Hardware and software functionality for PET acquisition are specified in the reference imaging 
manual.  
15.3 
Normal Limits for Vital Signs and ECG Intervals 
Table 3 
Criteria for Normal Limits for Vital Signs 
Vital Signs Parameter 
Normal Limits 
Low 
High 
Systolic BP (mmHg) 
85 
139 
Diastolic BP (mmHg) 
60 
89 
Heart Rate (beats/min) 
60 
100 
Respiration Rate (breaths/min) 
12 
22 
Oxygen Saturation (%) 
93 
100 
Body Weight (kg)a 
41 
113 
Body Mass Index (kg/m²)b 
18.5 
24.9 
a Changes in body weight are evaluated by the investigator (without taking height into account) since body 
mass index (BMI) is not collected on the CRF. 
b BMI is calculated and analyzed retrospectively by the Sponsor, at which time height is taken into account. 
 
Table 4 
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. 
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Page 71 of 73 
15.4 
Pre-test Probability of Obstructive Coronary Artery Disease in 
Symptomatic Patients 
Table 5 
Clinical Pre-test Probabilities of Obstructive Coronary Artery Disease in 
15,815 Symptomatic Patients [Knuuti et al. 2020] 
 
Pre-test probabilities of obstructive coronary artery disease in 15,815 symptomatic patients according to age, sex, 
and the nature of symptoms in a pooled analysis of contemporary data.  
In addition to the classic Diamond and Forrester classes, 59 patients with dyspnoea only or dyspnoea as the 
primary symptom are included.  
The regions shaded dark green denote the groups in which non-invasive testing is most beneficial (PTP >15%). 
The regions shaded light green denote the groups with PTPs of CAD between 5–15%, in which testing for 
diagnosis may be considered after assessing the overall clinical likelihood based on the modifiers of PTPs 
presented in the 2019 ESC guidelines. 
 
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16 
CLINICAL PROTOCOL AMENDMENT SUMMARIES 
16.1 
Amendment A01 
16.1.1 
Reasons for Amendment 
• 
Medical director details updated following a change in personnel. 
• 
Number of centers in the study updated from ‘up to 4’ to ‘approximately 4’. 
• 
Correction of minor typographical errors. 
Where appropriate, the changes documented below are also made in the synopsis. Where 
appropriate, the changes are indicated in italics. 
16.1.2 
Description of Changes 
Title Page, Medical Director Details 
Previously read: 
 
GE Healthcare 
100 Results Way,  
Marlborough, MA 01752,  
United States 
Phone 
 
Email: 
 
Now reads: 
 
 
GE Healthcare 
Pollards Wood, Nightingales Lane 
Chalfont St Giles 
Buckinghamshire HP8 4SP 
United Kingdom 
Phone 
 
Email: 
 
 
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Page 73 of 73 
Section 6.1, Overall Study Design and Plan, Second Paragraph, First Sentence 
Previously read: 
This study will be conducted at up to 4 centers in the US.   
Now reads: 
This study will be conducted at approximately 4 centers in the US.   
 
Section 8.4, Randomization and Blinding, Second Sentence 
Previously read: 
Thirty-two subjects will be randomized 1:1:1:1 into 4 treatment sequence groups: 
Now reads: 
Subjects will be randomized 1:1:1:1 into 4 treatment sequence groups: 
 
Section 9, Study Procedures, Table 1 - Study Schedule of Events, Footnote b 
Previously read: 
b) 
Before the first IMP injection (blood and urine) and 1 hour after the IMP injection 
(blood). 
Now reads: 
b) 
Before the IMP injection (blood and urine) and 1 hour after the IMP injection (blood). 
 
GE-265-001 Clinical Protocol Amendment A01
Version 1.0 Approved  03 Feb 2022


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Date of signature: 
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SAP_003.pdf: 
STATISTICAL ANALYSIS PLAN 
GE Healthcare 
GE-265-001 
Title: 
A Descriptive, Comparative, Randomized, Crossover Study of Flurpiridaz 
(18F) Injection for Positron Emission Tomography (PET) Imaging for 
Assessment of Myocardial Perfusion Imaging Quality using High 
Performance Liquid Chromatography (HPLC) and Solid Phase Extraction 
(SPE) Manufacturing Processes 
This Statistical Analysis Plan was prepared by the following personnel: 
Name 
 
 
Title 
  
Company 
 
GE-265-001 Statistical Analysis Plan
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Page 2 of 29 
 
Table of Contents 
REVISION HISTORY ................................................................................................................. 4 
ABBREVIATIONS ...................................................................................................................... 5 
1 
INTRODUCTION .................................................................................................... 6 
2 
STUDY OBJECTIVES, DESIGN AND PROCEDURES ....................................... 7 
2.1 
Objectives.................................................................................................................. 7 
2.2 
Study Design ............................................................................................................. 7 
2.3 
Sample Size Calculation ......................................................................................... 10 
2.4 
Interim Analysis ...................................................................................................... 10 
2.5 
Randomization and Blinding .................................................................................. 10 
3 
STUDY ENDPOINTS ............................................................................................ 12 
3.1 
Primary Efficacy Endpoint...................................................................................... 12 
3.2 
Secondary Efficacy Endpoints ................................................................................ 12 
3.3 
Image Acquisition ................................................................................................... 12 
3.4 
Image Interpretation ................................................................................................ 13 
3.5 
Safety Endpoints ..................................................................................................... 13 
4 
ANALYSIS POPULATIONS................................................................................. 15 
4.1 
Intent-to-Treat (ITT) Population ............................................................................. 15 
4.2 
Modified Intent-to-Treat (MITT) Population ......................................................... 15 
4.3 
Safety Population .................................................................................................... 15 
5 
ANALYSIS CONVENTIONS ............................................................................... 16 
5.1 
Definition of Analysis Windows............................................................................. 17 
5.2 
Definition of Missing Data Imputation ................................................................... 17 
5.3 
Handling of Missing Data/Censoring/Discontinuation ........................................... 17 
5.4 
Handling of Uninterpretable Images ....................................................................... 18 
5.5 
Protocol Deviations ................................................................................................. 18 
6 
STATISTICAL ANALYSES ................................................................................. 19 
6.1 
Subject Disposition ................................................................................................. 19 
6.2 
Demographics, Baseline Characteristics, Medical History, and Prior/Concomitant 
Medications ............................................................................................................. 19 
6.2.1 
Demographic and Baseline Characteristics ............................................... 19 
6.2.1 
Medical/Surgical History ........................................................................... 19 
6.2.2 
Prior and Concomitant Medications .......................................................... 20 
6.3 
Study Drug Exposure .............................................................................................. 20 
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6.4 
Primary Efficacy Analyses ...................................................................................... 21 
6.4.1 
Efficacy Variables ..................................................................................... 21 
6.4.2 
Statistical Hypothesis, Model, and Method of Analysis ........................... 21 
6.4.3 
Reader Difference ...................................................................................... 22 
6.5 
Secondary Efficacy Analyses .................................................................................. 22 
6.5.1 
Secondary Efficacy Endpoint Analyses .................................................... 22 
6.5.2 
Secondary Endpoint Analyses ................................................................... 23 
6.6 
Safety Variables and Analyses ................................................................................ 24 
6.6.1 
Analysis of Adverse Events ....................................................................... 25 
6.6.2 
Clinical Laboratory Evaluation ................................................................. 25 
6.6.3 
Vital Signs ................................................................................................. 26 
6.6.4 
Electrocardiograms .................................................................................... 27 
6.6.5 
Physical Examinations ............................................................................... 27 
6.6.6 
Injection Site Monitoring .......................................................................... 28 
7 
REFERENCES........................................................................................................ 29 
 
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REVISION HISTORY 
Version 
Date 
Changes implemented 
1.0 
 
Not applicable. 
2.0 
Refer to the signature 
page. 
Updates to presentation of subject disposition table. 
Clarification of time of recording for medical history 
and baseline periods for clinical laboratory 
evaluation. 
 
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ABBREVIATIONS 
AE 
Adverse event 
BMI 
Body mass index  
CAD 
Coronary artery disease 
CI 
Confidence Interval 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
HPLC 
High Performance Liquid Chromatography 
IMP 
Investigational medicinal product 
ITT 
Intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified intent-to-treat  
MMRM 
Mixed-effects model for repeated measures 
MPI 
Myocardial perfusion imaging 
PET 
Positron emission tomography 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SPE 
Solid Phase Extraction 
SRS 
Summed rest score 
SUV 
Standard uptake value 
TAC 
Time-activity curve 
TEAE 
Treatment-emergent adverse event 
WHO-DD 
World Health Organization Drug Dictionary 
 
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1 INTRODUCTION  
Doses of Flurpiridaz (18F) Injection used in the nonclinical and clinical studies performed by 
Lantheus Medical Imaging were manufactured using high performance liquid chromatography 
(HPLC) purification. This process is also being used to manufacture doses of Flurpiridaz (18F) 
Injection for the current GE Healthcare clinical study (GE-265-303). The HPLC method is not 
ideal for future routine manufacturing of [18F]fluorine tracers. GE Healthcare has, therefore, 
developed the manufacturing process for Flurpiridaz (18F) Injection on the FASTlab synthesis 
module, a current and supported synthesis platform. This process enables the production of 
Flurpiridaz (18F) Injection batches with approximately 4 times the product radioactivity 
compared to the HPLC process. This will significantly improve the availability of Flurpiridaz 
(18F) Injection. In addition, the solid phase extraction (SPE) manufacturing process on 
FASTlab is expected to enhance control, consistency and production reliability because it 
eliminates the manual cut required for HPLC purification. Also, it uses single-use 
commercially available cartridges, reagents and other disposable materials supplied in a 
preassembled cassette that is assembled, controlled and released by GE Healthcare under 
current Good Manufacturing Practice. The drug product from the SPE manufacturing process 
will have improved compatibility with dispensing equipment at manufacturing sites and 
pharmacy syringes. The latter is important for hospitals to use their standard radiation 
protection equipment to ensure low radiation dose for hospital staff. It is also important to 
avoid errors in dosing with use of non-compatible syringes. 
Study GE-265-001 is a descriptive, comparative, randomized, crossover study of Flurpiridaz 
(18F) Injection for positron emission tomography (PET) imaging for assessment of myocardial 
perfusion imaging (MPI) quality using HPLC and SPE manufacturing processes. 
The statistical analysis plan (SAP) will provide details to further elaborate statistical methods 
as outlined in the protocol (GE-265-001 Clinical Protocol Amendment A01, Approved 03 Feb 
2022) 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 difference and variability between 2 sets of visually-based global rest scores 
resulting from 2 at-rest MPI sessions using Flurpiridaz (18F) Injection doses synthesized by 
the same or 2 manufacturing processes. 
Secondary Objectives: 
• Assess the intra-reader agreement of the detection of ischemic defect on PET-MPI at rest 
between 2 MPI acquisitions using 2 Flurpiridaz (18F) Injection doses. 
• Assess the detection of myocardial segmental defect similarity from 2 sets of images 
acquired from doses synthesized by the same or 2 different manufacturing processes of 
Flurpiridaz (18F) Injection PET for MPI at rest. 
• Assess the equivalence of 2 sets of [18F]flurpiridaz time-activity curves (TACs) (blood, 
myocardium, lungs, liver) resulting from MPI using Flurpiridaz (18F) Injection doses 
synthesized by the same or 2 different manufacturing processes. 
• Assess the safety of Flurpiridaz (18F) Injection PET doses synthesized by 2 different 
manufacturing processes. 
2.2 
Study Design 
This is a Phase 2 prospective, randomized, crossover study of Flurpiridaz (18F) Injection for 
PET-MPI in subjects referred for evaluation of known coronary artery disease (CAD) or for 
suspected CAD with intermediate to high pre-test probability.  
This study will be conducted at approximately 4 centers in the US. Twenty-eight evaluable 
subjects will be enrolled. Assuming a 20% drop-out rate, approximately 34 subjects will need 
to be enrolled initially. At least 30% of subjects enrolled should have a documented history of 
MI, defined by history of a fixed defect. 
Each subject will attend a Screening Visit at least 2 days and up to 14 days prior to the first 
Flurpiridaz (18F) Injection PET-MPI (PET-MPI Visit 1). 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. 
Subjects will undergo 2 Flurpiridaz (18F) Injection PET-MPI procedures at rest performed no 
more than 2 weeks apart. To allow for adequate decay of the first dose, at least 24 hours must 
separate the 2 injections/imaging procedures. The subjects will be randomized 1:1:1:1 to 
4 possible sequences of receiving 2 doses of Flurpiridaz (18F) Injection: 7 subjects will receive 
2 Flurpiridaz (18F) Injection doses synthesized by the same HPLC manufacturing process 
(HPLC → HPLC), 7 subjects will receive 2 Flurpiridaz (18F) Injection doses synthesized by the 
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Page 8 of 29 
 
same SPE manufacturing process (SPE → SPE), and 14 subjects will receive 2 Flurpiridaz (18F) 
Injection doses synthesized by 2 different manufacturing processes (7 subjects will receive 
1 dose manufactured by HPLC followed by 1 dose manufactured by SPE (HPLC → SPE) and 
7 subjects will receive 1 dose manufactured by SPE followed by 1 dose manufactured by 
HPLC (SPE → HPLC)). All doses will be administered at rest by bolus intravenous injection in 
a large peripheral vein. 
The targeted dose to the body of Flurpiridaz (18F) Injection will be in the range of 1.7 to 
2.5 mCi (63 to 93 MBq) for each administration and will not exceed a total of 6 mCi 
(222 MBq) for an individual subject. The image acquisitions in a list-mode at a single bed 
position centered on the heart will start 10 seconds before Flurpiridaz (18F) Injection and last 
15 minutes. In effort to avoid bias in image acquisition, the test product manufacturing status 
will not be specified on the syringe. 
All subjects will be followed up by telephone for adverse events (AEs) and serious AEs 
(SAEs) at 24 (+8) hours following each Flurpiridaz (18F) Injection administration. 
Therefore, study subjects will participate in the study for up to 30 days. 
A subject will be considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled procedure shown in the Study Schedule of Events (Table 
1). 
An overview of study procedures is presented in Figure 1.  A schedule of study procedures is 
provided in Table 1. 
Figure 1 Study Diagram 
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Table 1 
Study Schedule of Events 
Variables 
Screening 
PET-MPI Visit 1  
(2 to 14 days after 
Screening) 
Safety Follow-up  
(24+8 hours after PET-MPI 
Visit 1) 
PET MPI Visit 2  
(≥24 hours and <2 weeks 
after PET-MPI Visit 1) 
Safety Follow-up 
(24 + 8 hours after PET-MPI 
Visit 2) 
Informed consent 
X 
 
 
 
 
Entry criteria 
X 
 
 
 
 
Pregnancy test a 
X 
X 
 
X 
 
Demographic information 
X 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
Blood sampling 
X 
Xb 
 
Xb 
 
Urine sampling 
X 
Xb 
 
Xb 
 
Prior/concurrent medications 
X 
X 
X 
X 
X 
Vital signs and pulse oximetry 
X 
Xc 
 
Xc 
 
12-lead ECG recording 
Xd 
Xd 
 
Xd 
 
Physical examination e 
 
Xe 
 
Xe 
 
Clinical screen for new/worsening symptoms 
 
Xf 
 
Xf 
 
Injection site monitoring 
 
Xg 
 
Xg 
 
IMP administration 
 
X 
 
X 
 
PET-MPI Image acquisition  
 
X 
 
X 
 
Adverse events (including AEs and SAEs)h 
X 
X 
X 
X 
X 
AE = adverse event; ECG = electrocardiogram; IMP = investigational medicinal product; MPI = myocardial perfusion imaging; PET = positron emission tomography; SAE = 
serious adverse event 
* Safety follow-up after PET-MPI Visit 1 must be complete before administration of Flurpiridaz (18F) Injection for PET-MPI Visit 2. 
a) 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 and before 
radiopharmaceutical administration) must be negative. 
b) Before the IMP injection (blood and urine) and 1 hour after the IMP injection (blood). 
c) Vital signs and pulse oximetry will be recorded up to 20 minutes pre-injection and at 30 (±5) minutes post-injection. In addition, heart rate only will be recorded at 
approximately 1 minute pre-injection and at 5, 10 and 15 minutes post-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 performed within 48 hours 
prior to screening, without intervening episodes of chest pain or instability, can be used as the Screening ECG, where available. At rest PET-MPI visits, 12-lead ECG will be 
recorded at pre-dose (within 20 minutes before transmission scan) and at 10 (±5) and 30 (±5) minutes post-injection. 
e) Physical examination will comprise a full examination with a specific focus on cardiovascular signs. At rest PET-MPI visits, physical examination will be performed pre-
injection and at 1 hour post-injection. 
f) A clinical screen for new or worsening symptoms indicative of unstable CAD disease will be conducted prior to performing any procedures at the PET-MPI visits. If the clinical  
status screening is positive, the PET-MPI visits can either be rescheduled (up to 1 time and within the 2-week period specified) after symptoms stabilize or the subject can be 
discontinued from the study. 
g) Immediately prior to injection, immediately after injection of IMP and 1 hour after injection of IMP. 
h) 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. 
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2.3 
Sample Size Calculation  
A sample size of 28 subjects will be assessed for the clinical imaging similarity and safety 
profiles of Flurpiridaz (18F) Injection synthesized by 2 different manufacturing processes in 
subjects with suspected or established CAD. To account for 20% dropout, approximately 34 
subjects will be randomized in a 1:1:1:1 ratio to each of the 4 treatment sequences 
(SPE → SPE, HPLC → HPLC, SPE → HPLC, HPLC → SPE). 
2.4 
Interim Analysis 
No formal interim analyses will be performed in this study.   
2.5 
Randomization and Blinding 
Randomization: 
This is a randomized crossover study. Twenty-eight evaluable subjects will be randomized 
1:1:1:1 into 4 treatment sequence groups: 
• 
Group 1: 2 doses of Flurpiridaz (18F) Injection manufactured by the HPLC method 
(HPLC → HPLC) 
• 
Group 2: 2 doses of Flurpiridaz (18F) Injection manufactured by the SPE method 
(SPE → SPE) 
• 
Group 3: 1 dose of Flurpiridaz (18F) Injection manufactured by the HPLC method 
followed by 1 dose of Flurpiridaz (18F) Injection manufactured by the SPE method 
(HPLC → SPE) 
• 
Group 4: 1 dose of Flurpiridaz (18F) Injection manufactured by the SPE method 
followed by 1 dose of Flurpiridaz (18F) Injection manufactured by the HPLC method 
(SPE → HPLC) 
Once subjects have completed the screening process they will be enrolled in the study and will 
be randomly assigned to one of the above 4 treatment sequences in accordance with a 
prespecified randomization list. Allocation to the enrollment groups, including randomization, 
will be performed centrally (via the IWRS in the EDC) by the contract research organization 
(CRO). No subject will be administered Flurpiridaz (18F) Injection before it has been 
determined that he/she meets the study’s inclusion criteria, does not meet the exclusion criteria, 
and signed and dated informed consent has been obtained.  If any early withdrawal takes place 
for a subject (e.g., a subject only completes the first injection), the EDC/IWRS will assign the 
next subject to the same dosing sequence in order to make sure the design (1:1:1:1) is balanced 
at the end of study. 
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Blinding 
This is a Phase 2, randomized study. Subjects and clinical site personnel will be blinded to the 
manufacturing process used to obtain Flurpiridaz (18F) Injection. In effort to avoid bias in 
image acquisition, the test product manufacturing status will not be specified on the syringe. 
The independent image readers will be blinded to subject number, medical history and the 
manufacturing process used to synthesize Flurpiridaz (18F) Injection. 
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3 
STUDY ENDPOINTS 
3.1 
Primary Efficacy Endpoint 
• 
Intra-reader correlation and difference between the summed perfusion rest scores (SRS) 
and summed rest percent (SR%) after 2 MPI sessions using 2 Flurpiridaz (18F) Injection 
doses synthesized using the same or 2 different manufacturing processes. 
3.2 
Secondary Efficacy Endpoints 
• 
Variability of the SRS after MPI sessions using 2 Flurpiridaz (18F) Injection doses 
synthesized for the subjects receiving 2 doses of the product manufactured by the SPE 
process. 
• 
Variability of the SRS after MPI sessions using 2 Flurpiridaz (18F) Injection doses 
synthesized for the subjects receiving 2 doses of the product manufactured by the 
HPLC process. 
• 
Intra-reader agreement of the detection of ischemic defect on PET-MPI at rest between 
2 MPI acquisitions using 2 Flurpiridaz (18F) Injection doses. 
• 
Difference between the perfusion rest scores for each of the 17 segments and each 
reader using 2 Flurpiridaz (18F) Injection doses synthesized using the same or 2 
different manufacturing processes. 
• 
Difference in the standard uptake value (SUV) TACs and the relative difference in 
SUV (5- to 15-minute perfusion image) in left ventricular cavity, myocardium, lungs, 
and liver measured after two [18F]flurpiridaz injections using doses of Flurpiridaz (18F) 
Injection synthesized by 2 different manufacturing processes. 
• 
Difference in the SUV TACs and the relative difference in SUV (5- to 15-minute 
perfusion image) in left ventricular cavity, myocardium, lungs, and liver measured after 
two [18F]flurpiridaz injections using doses of Flurpiridaz (18F) Injection for the subjects 
receiving 2 doses of the product manufactured by the HPLC process. 
• 
Difference in the SUV TACs and the relative difference in SUV (5- to 15-minute 
perfusion image) in left ventricular cavity, myocardium, lungs and liver measured after 
two [18F]flurpiridaz injections using doses of Flurpiridaz (18F) Injection for the subjects 
receiving 2 doses of the product manufactured by the SPE process. 
• 
Intra-reader agreement of the image quality score between the 2 sets of PET images 
acquired after two [18F]flurpiridaz injections using doses of Flurpiridaz (18F) Injection. 
3.3 
Image Acquisition 
Imaging procedures include PET-MPI. 
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The image acquisitions in a list-mode at a single bed position centered on the heart will start 
10 seconds before Flurpiridaz (18F) Injection and last 15 minutes. Both PET images must be 
acquired on the same PET camera. 
The PET list-mode acquisition will be reframed to produce a dynamic series for TAC analysis 
(0 to 15 minutes) and a static image (5 to 15 minutes) with and without cardiac gating for 
visual and semiquantitative analysis. Full details of the imaging protocol are presented in the 
GE-265-001 PET Imaging Manual. 
Incidental findings are not likely. 
3.4 
Image Interpretation 
Three qualified independent readers will perform a blinded assessment of each subject’s PET 
image pair (with each injection images). Further details will be provided in the GE-265-001 
PET Independent Review Charter. 
Details of the TAC and SUV analysis will be provided in the GE-265-001 PET Image 
Processing Manual. Each subject will have a test and retest perfusion series. The uptake 
statistics from the liver, lung, left ventricle, and myocardium (17-Segment, vascular territories 
and whole) will be generated. 
3.5 
Safety Endpoints 
Subjects will be closely monitored for safety until completion of all study procedures. Safety 
monitoring will include AEs, medication errors, treatment-emergent AEs (TEAEs), and SAE 
assessments, vital signs, ECGs, hematology, clinical chemistry laboratory tests, and urinalysis. 
All subjects will be followed up by telephone for AEs at 24 (+8) hours following each 
Flurpiridaz (18F) Injection administration. The 24-hour safety follow-up after PET-MPI Visit 1 
must be completed before administration of Flurpiridaz (18F) Injection for PET-MPI Visit 2. 
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, hematology and urinalysis (Table 
2). 
• 
Vital signs: systolic/diastolic blood pressure, heart rate, respiration rate, and pulse 
oximetry. 
• 
12-lead ECG. 
• 
Physical examination. 
• 
Injection site monitoring. 
• 
Post-treatment events (AEs and SAEs). 
Pre-specified normal limits for vital signs and ECG intervals are provided in Section 6.6. 
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Table 2 
Clinical Laboratory Parameters 
Serum Biochemistry 
Hematology 
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 
Hematocrit 
Platelet count 
White blood cell (WBC) count 
Bilirubin 
Glucose 
Ketone 
Occult blood 
pH 
Protein 
Urobilinogen 
 
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4 ANALYSIS POPULATIONS 
4.1 Intent-to-Treat (ITT) Population 
The ITT population will consist of all subjects randomized to receive ≥1 dose of Flurpiridaz 
(18F) Injection in the study. 
4.2 Modified Intent-to-Treat (MITT) Population 
The MITT population will include all ITT subjects who have completed the 2 rest Flurpiridaz 
(18F) Injection PET-MPI procedures. The MITT population will be the primary analysis set for 
the primary efficacy endpoint. 
4.3 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 summarized 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. 
In general, tables will be formatted with columns displaying findings based on the study arm 
for all subjects. The summary tables will clearly indicate the number of subjects to which the 
data apply, and unknown or not performed are distinguished from missing data.  
Supportive individual Subject Data Listings, as a minimum, will be sorted and presented by the 
study arm, subject 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 
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 
subjects). 
• 
Study Day 1 is defined as the date at which the subject received their first dose of 
investigational medicinal product (IMP). All study days are determined relative to 
Day 1. 
• 
Study days prior to Day 1 will be calculated as: 
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➢ Study Day = Assessment Date – Date first IMP dose received  
• 
Study days after Day 1 will be calculated as: 
➢ Study Day = Assessment Date – Date first IMP dose received + 1. 
• 
Baseline values will be defined as the last non-missing value recorded prior to first IMP 
dose 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 electronic case report form (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.  
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 Handling of Missing Data/Censoring/Discontinuation 
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 2 groups. This summary will be 
performed separately in ITT subjects who are missing PET MPI results. 
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5.4 Handling of Uninterpretable Images 
Once a subject has completed the 2 rest Flurpiridaz (18F) Injection PET-MPI procedures and 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. 
5.5 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 and 
finalized before database lock. 
Waivers or protocol exceptions will not be granted prospectively by the Sponsor under any 
circumstances. 
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6 
STATISTICAL ANALYSES  
In order to ensure the randomization is properly performed, summary for baseline 
characteristics will be presented by 4 sequences.  Because 2 manufacturing processes may 
result in different impurity profiles, safety analyses will be summarized and presented by 
HPLC process and SPE process. For the primary efficacy endpoint of SRS and SR% and drug 
exposure will be summarized and presented by HPLC method and SPE method.  
6.1 Subject Disposition  
A table will be provided with the following information by sequence group and overall: 
• Number of subjects enrolled. 
• Number of subjects randomized. 
• Number of subjects included in the efficacy analysis populations (ITT, MITT). 
• Number of subjects included in the safety analysis population. 
• Number of subjects withdrawn from the study and the reason for withdrawal. The 
number of subjects withdrawn from Period 1 (after the first dose) and from Period 2 
(after the 2nd dose) will be summarized as well.  
6.2 Demographics, Baseline Characteristics, Medical History, and 
Prior/Concomitant Medications 
6.2.1 Demographic and Baseline Characteristics 
Demographic information (age, height, weight, and body mass index [BMI]) will be 
summarized by using descriptive statistics. Sex, ethnicity, and race will be summarized by 
counts and percentages in MITT and safety population. 
6.2.1 Medical/Surgical History 
The subjects’ relevant medical and surgical history as recorded at Visit 1 prior to IMP injection 
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 in the MITT and safety population. Subjects reporting more than one 
condition/diagnosis within a body system will be counted only once for that body system.  
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6.2.2 Prior and Concomitant Medications  
Prior and concomitant medications are defined relative to Flurpiridaz (18F) Injection 
administration. Prior and concomitant medications will be summarized in the MITT and safety 
population by counts and percentages using the World Health Organization Drug Dictionary 
(WHO-DD), and grouped by primary and secondary classes, if applicable. The version of 
WHO-DD used will be detailed in the footnotes of related tables, figures, and listings. 
A prior medication is defined as any medication taken prior to the start of the first dose of 
Flurpiridaz (18F) Injection. A concurrent medication is a new medication started after the start 
of the first dose of Flurpiridaz (18F) Injection or a prior medication that continues after 
Flurpiridaz (18F) Injection. A medication is defined as concurrent for Period 1 if it is taken on 
the day of Period 1 Flurpiridaz (18F) Injection dosing.  A medication is defined as concurrent 
for Period 2 if it is taken on the day of Period 2 Flurpiridaz (18F) Injection dosing.  
If a medication is taken prior to Flurpiridaz (18F) Injection administration for Period 1 and no 
information on its use is available after the imaging, the medication will be assumed to be 
ongoing and therefore considered as both prior and concurrent medications. If the medication is 
taken concomitantly with Flurpiridaz (18F) Injection administration and no information is 
available on its start date relative to Flurpiridaz (18F) Injection administration, the medication 
will be considered as both prior and concurrent medications. Concomitant medications will be 
categorized to Period 1 or Period 2 based on the onset of the concomitant medication compared 
the time/date of study drug of each period. 
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 (Flurpiridaz (18F) Injection dose in mCi or MBq) and volume administered 
will be summarized by descriptive summary statistics. Summary statistics will be presented by 
each dose. A summary of each subject’s dosing information will be presented in a listing. 
Effective dose will be calculated as the product of the dose/unit activity and the administered 
activity. The targeted dose to the body Flurpiridaz (18F) Injection will be in the range of 1.7 to 
2.5 mCi (63 to 93 MBq) for each administration and will not exceed a total of 6 mCi 
(222 MBq) for an individual subject. 
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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 reads of all 
MPI images, based on standard 17-segment polar-maps of perfusion defects. Each reader will 
score the perfusion pattern in each segment (17 segments) using a 5-point scale scoring: 
- Normal 0, 
- Minimal, mild impairment of perfusion, ambiguous image 1, 
- Moderate impairment of perfusion 2, 
- Significant impairment of perfusion 3, 
- No perfusion 4.  
The summed score of the 17 segments SRS, as well as the SR%, will be used as the primary 
endpoint, and summarized as a continuous variable by reader and using the median of the 
results of the 3 readers.  SR% is calculated by dividing the SRS by a number corresponding to 
the SRS value indicating a deficit of 4 in every segment (68 points for 17 segments) and then 
multiplying the result by 100%.  
6.4.2 Statistical Hypothesis, Model, and Method of Analysis 
The primary analysis for the primary endpoint will be based on the mixed-effects model for 
repeated measures (MMRM). The model will include the median SRS in each dosing period as 
the dependent variable, with manufacturing process, period, and dosing sequence as fixed 
effects, and subject nested within sequence as the random effect. The estimated mean SRS 
difference and 90% confidence interval (CI) will be provided from the MMRM analysis. 
Similarity will be established if the 90% CI of the difference is within a margin of (-0.75, 
0.75). The margin size is defined as 0.75 to allow the difference of, at most, 43% of the mean 
SRS score (mean PET SRS score is 1.75 based on empirical data [Berman et al. 2013]). 
The correlation analysis will be stratified by the following 3 groups:  
1) subjects who have received 2 doses of product manufactured by 2 different processes.  
2) subjects who have received 2 doses of product both manufactured by the SPE process. 
3) subjects who have received 2 doses of product both manufactured by the HPLC process.  
The intra-reader (within-subject) correlation between the 2 manufacturing processes will be 
assessed by Pearson’s correlation, Kendall’s τ and Bland-Altman difference for the summed 
score stratified by the above 3 groups. The mean of paired difference between the 2 
manufacturing processes, t-statistics based 95% CI, the median difference and 95% CI based 
on Hodges-Lehman method, and p-value obtained by Wilcoxon signed rank test will also be 
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provided for descriptive purpose for the SRS among subjects who have received 2 doses of 
product manufactured by 2 different processes for each reader. 
Sensitivity analyses will be performed to assess the impact of missing data on the primary 
analysis results (i.e., subjects in the ITT population with incomplete PET-MPI scans) using 
similar MMRM analysis for primary analysis.  
6.4.3 Reader Difference 
Reader variability will be assessed by the reread of images. Intra-reader reproducibility will be 
determined based on the re-read of images from approximately 25% of the randomly selected 
exams (not subjects). The same images will be re-read by all readers. 
Intra-reader reproducibility assessed for both original read and re-read images by calculating 
Cohen's pairwise kappas and their respective 95% confidence intervals. 
6.5 
Secondary Efficacy Analyses 
6.5.1 Secondary Efficacy Endpoint Analyses 
Secondary efficacy endpoints include: 
• Variability of the SRS after MPI sessions using 2 Flurpiridaz (18F) Injection doses 
synthesized for the subjects receiving 2 doses of the product manufactured by the SPE 
process. 
 
• Variability of the SRS after MPI sessions using 2 Flurpiridaz (18F) Injection doses 
synthesized for the subjects receiving 2 doses of the product manufactured by the HPLC 
process. 
 
• Intra-reader agreement of the detection of ischemic defect on PET-MPI at rest between 2 
MPI acquisitions using 2 Flurpiridaz (18F) Injection doses. 
 
• Difference between the perfusion rest scores for each of the 17 segments and each reader 
using 2 Flurpiridaz (18F) Injection doses synthesized using the same or 2 different 
manufacturing processes. 
 
• Difference in the SUV TACs and the relative difference in SUV (5- to 15-minute perfusion 
image) in left ventricular cavity, myocardium, lungs and liver measured after two 
[18F]flurpiridaz injections using doses of Flurpiridaz (18F) Injection synthesized by 2 
different manufacturing processes.  
 
The difference in the SUV TACs between 2 manufacturing processes will be measured 
using the Euclidean distance [Pini et al. 2022] from 2 TAC curves. 
 
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d(i) = √  ∆𝑡∑
(𝑌1𝑖(𝑡) −𝑌2𝑡(𝑡))2
𝑡𝑟
𝑡=𝑡1
 
 
Where ∆= 
𝑡𝑟−𝑡1
𝑇 
 
Difference in the SUV TACs between 2 different manufacturing processes will be 
compared using a nonparametric method of the sign test for testing no difference between 2 
manufacturing processes.  
 
• Difference in the SUV TACs and the relative difference in SUV (5- to 15-minute perfusion 
image) in left ventricular cavity, myocardium, lungs and liver measured after two 
[18F]flurpiridaz injections using doses of Flurpiridaz (18F) Injection for the subjects 
receiving 2 doses of the product manufactured by the HPLC process. 
 
Difference in the SUV TACs between the 2 HPLC processes will be measured using 
Euclidean distance and will be compared using a nonparametric method of the sign test for 
testing no difference between HPLC process from Period 1 and Period 2.  
 
• Difference in the SUV TACs and the relative difference in SUV (5- to 15-minute perfusion 
image) in left ventricular cavity, myocardium, lungs and liver measured after two 
[18F]flurpiridaz injections using doses of Flurpiridaz (18F) Injection for the subjects 
receiving 2 doses of the product manufactured by the SPE process. 
 
Difference in the SUV TACs between the 2 SPE processes will be measured using the 
Euclidean distance and will be compared a nonparametric method of the sign test for 
testing no difference between SPE process from Period 1 and Period 2. 
 
• Intra-reader agreement of the image quality score between the 2 sets of PET images 
acquired after two [18F]flurpiridaz injections using doses of Flurpiridaz (18F) Injection. 
 
6.5.2 Secondary Endpoint Analyses 
The intra-reader variability of the SRS will be estimated by reader using the SD of the paired 
difference divided by √2, for subjects receiving 2 doses of the product both manufactured by 
the SPE process and separately for subjects receiving 2 doses of the product both manufactured 
by the HPLC process. 
For the individual scores of 17 segments by each reader, the mean of paired difference between 
the 2 manufacturing processes, t-statistics based 95% CI, the median difference and 95% CI 
based on Hodges-Lehman method, and p-value obtained by Wilcoxon signed rank test will also 
be provided for descriptive purpose among subjects who have received 2 doses of product 
manufactured by 2 different processes. Similar analysis will be repeated for subjects receiving 
2 Flurpiridaz (18F) Injection doses synthesized using the same processes, HPLC or SPE. 
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The PET-MPI reads will be performed by the same set of readers. In each session, PET images 
will be displayed in a randomized order, non-sequentially, with PET-MPI exams corresponding 
to individual subjects randomly allotted into reading session batches. The intra-reader 
agreement of the detection of ischemic defect on PET-MPI will be assessed by percent 
agreement and Cohen’s kappa value stratified by the 3 groups as used in the primary analysis. 
Perfusion and gated acquisitions of rest images will be rated for image quality (excellent, good, 
fair, poor or non-diagnostic). The image quality score will be summarized descriptively for the 
3 groups of data sets (by reader) and the intra-reader agreement will be assessed between the 2 
acquisitions stratified by the 3 groups as used in the primary analysis. 
The perfusion image quality and gated image quality are categorized into 5 categories 
(excellent (4), good (3), fair (2), poor (1) and uninterpretable (0)).  The image quality 
agreement for 2 doses from different processes can be defined as follows: 
 
1. SPE image is worse than HPLC image when the difference (SPE – HPLC) score is ≤-3. 
2. SPE image is slightly worse than HPTC image when the difference score is ≤-1 and 
≥-3. 
3. SPE and HPLC images are the same when the difference score is >-1 and <1, 
4. SPE image is slightly better when the difference score ≥1 and <3. 
5. SPE image is better when the difference is ≥3. 
 
The image quality agreement for 2 doses from the same process may be defined as follows: 
1. 2 images are the same when the absolute difference score is ≥0 and <1 
2. 2 images are slightly different when the absolute difference score >=1 and ≤3 
3. 2 images are different when the absolute difference score >3  
 
The image quality agreement will be summarized with the above-mentioned 5 categories and 3 
categories.  
 
Within left ventricle, myocardium, lungs and liver regions of interest (ROIs), a TAC (5-15) (in 
SUV units) will be generated for the dynamic scan during the 15-minute acquisition period. 
The SUV for each ROI will be generated using the following formula: 
SUV= Decay Corrected Uptake (kBq/cc) / (Injected Dose (MBq) / Weight (kg)) 
There will be a descriptive statistical analysis only. Bland-Altman method will be used with the 
relative difference D in the mean SUV expressed as D = 100 (SUV1-SUV2)/[0.5 * (SUV1 + 
SUV2)] between the 2 processes will be summarized descriptively for each region among 
subjects who have received 2 doses of product. The mean absolute percentage difference 
(MAPD) will be determined as the mean of the absolute value of D over all subjects.  In 
addition, the Bland-Altman plots will be presented as well. 
6.6 
Safety Variables and Analyses 
Safety Endpoints: 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.   
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Post-administration changes from baseline will be summarised by mean, SD, minimum, and 
maximum at each time point. The presentation of all summary data will be presented in 2 
manufacturing processes. 
6.6.1 Analysis of Adverse Events 
AEs and SAEs will be coded using a current version of Medical Dictionary for Regulatory 
Activities (MedDRA) and all reported events will be listed for the safety population. The 
version of MedDRA will be detailed in the footnotes of related tables, figures and listings. 
TEAEs are defined as AEs that occur from the time of IMP administration through the end of 
the follow-up period. The number and percentage of subjects 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 are 
defined as SAEs that occur from the time of IMP administration through the end of the follow-
up period. Treatment-emergent SAEs will also be presented for the safety population. 
An AE is defined as any untoward medical occurrence or an already present event that worsens 
in intensity. A TEAE for Flurpiridaz (18F) Injection is defined as an AE that starts on or after 
the time of the first injection of Flurpiridaz (18F) Injection until the last safety follow-up visit. 
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 number and percentage of subjects reporting TEAEs will be tabulated by system organ 
class (SOC) and preferred term (PT). If more than one event occurs with the same PT for the 
same subject, the subject 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 Flurpiridaz (18F) 
Injection.  
6.6.2 Clinical Laboratory Evaluation 
Descriptive statistics will be displayed for the observed values and changes from baseline for 
the clinical laboratory parameters that contain continuous values shown in Table 4. For the 
categorical urinalysis parameters, the shift analysis from baseline to post-baseline will be 
provided.  The baseline value for each Period will be defined as the last non-missing value 
prior to the Period 1 dose or the Period 2 dose.  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.   
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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 
Lactate dehydrogenase 
Potassium 
Protein (total) 
Sodium 
Urea nitrogen 
Haematocrit 
Platelet count 
White blood cell (WBC) count 
Bilirubin 
Glucose 
Ketone 
Occult blood 
pH 
Protein 
Urobilinogen 
 
6.6.3 Vital Signs 
Descriptive statistics will be displayed for the observed values and changes from baseline. For 
each vital-sign variable and each time point, the following safety endpoints will be summarized 
by counts and percentages and by manufacturing process: 
• 
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, 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 blood pressure, mm Hg 
85 
139 
Diastolic blood pressure, mm Hg 
60 
89 
Heart rate, beats/min 
60 
100 
Respiration rate, breaths/min 
12 
22 
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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6.6.4 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 summarized by 
counts and percentages and by manufacturing process: 
• The occurrence of post-administration values outside the normal limits in the PR, QTc, 
QRS or RR interval (Table 6). Shift tables based on the normal range will be prepared. 
ECGs for which the overall interpretation was abnormal will be summarized by counts and 
percentages at each post-administration time point or by additional/other characteristics 
deemed necessary by study team. 
QTc correction: 
The following correction formula will be employed in analyzing QTc data in an attempt to 
reduce the bias resulting from over- or under-correction: 
 
 
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 criteria (absolute QTc interval prolongation, 
of >450, >480, <500 ms and change from baseline in QTc interval >30 and >60 ms).) 
• The number and percentage of subjects with absolute QTc values above the upper limit of 
normal (Table 6) will be provided.  Shift tables based on the normal range will be prepared.  
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. 
6.6.5 Physical Examinations 
The number and percentage of subjects with changes in physical examination status from 
normal at pre-administration to abnormal at 1-hour post-administration (and vice versa) will be 
presented by manufacturing process. Shift tables based on the normal range will be prepared.   
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6.6.6 Injection Site Monitoring 
The findings of injection site monitoring will be summarized by time point. All monitoring 
information, including date/time and the reasons for “not done” will be listed in a listing. 
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7 
REFERENCES  
[Berman et al. 2013] 
Berman DS, Maddahi J, Tamarappoo BK, Czernin J, Taillefer R, Udelson JE, et al. Phase II 
safety and clinical comparison with single-photon emission computed tomography myocardial 
perfusion imaging for detection of coronary artery disease: flurpiridaz F 18 positron emission 
tomography. J Am Coll Cardiol. 2013;61(4):469-477. 
[Pini et al. 2022] 
Pini A, Markström JL, Schelin L. Test–retest reliability measures for curve data: an overview 
with recommendations and supplementary code, Sports Biomech. 2022;21(2):179-200. 
GE-265-001 Statistical Analysis Plan
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