Clinical trial NCT01917136
Conditions: Pulmonary Hypertension
Keywords: pulmonary hypertension right ventricular function 11C acetate FDG ranolazine
Sponsor: University of Pennsylvania
Start date: 2013-08-01; Completion date: 2018-10-01
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is looking at differences in metabolism and functional imaging between pulmonary hypertension subjects with normal right ventricular function and persistent right ventricular dysfunction.

Detailed description:
We will measure right ventricular metabolic and structural changes using serial 11C-acetate and 18F-FDG PET/CT and cardiac MRI as response to treatment with ranolazine. Subjects undergo imaging procedures at week 0 and week 26 (optional for normal function patients). This is a companion imaging trial for patients who are eligible for the treatment trial entitled "A randomized, double-blind, placebo controlled, multi-center study to assess the effect of ranolazine on outcomes in subjects with pulmonary hypertension and right ventricular dysfunction accompanied by a comparative study of cellular metabolism in subjects with pulmonary hypertension with and without right ventricular dysfunction". Subjects must enroll in companion treatment protocol to qualify for the imaging protocol.

The cardiac MRI portion of the study continued, but the PET portion of the study was discontinued due to funding.

The treatment protocol is registered under: NCT01839110. Due to funding issues, the completed study was registered under NCT02829034.

Arms: arm 1: For each PET/CT imaging session subjects will receive a 15-25 millicurie intravenous injection of 11C-acetate and a 10 millicurie injection of 18F-FDG At baseline/6 months follow up, a cardiac MRI will be performed.
Interventions: intervention 1: 11C-acetate intervention 2: [18F]Fluoro-2-deoxy-2-D-glucose intervention 3: Cardiac MRI
Intervention descriptions: intervention 1: For each PET/CT imaging session subjects will receive a 15-25 millicurie intravenous injection of 11C-acetate intervention 2: For each PET/CT imaging session subjects will receive a 10 millicurie injection of 18F-FDG intervention 3: Cardiac MRI is performed at 6 months to measure any change in structure and function of the treatment groups.

Protocol documents:
Prot_SAP_000.pdf: 
 
CLINICAL RESEARCH 
 
 
 
EVALUATION OF RV FUNCTION AND METABOLISM IN 
PATIENTS WITH PULMONARY HYPERTENSION USING 
COMBINED [11C]ACETATE AND 
[18F]FLUORODEOXYGLUCOSE (FDG) PET/CT AND 
CARDIOVASCULAR MR  
 
 
 
 
 
Principal Investigator: 
Yuchi Han M.D. M.M.Sc. 
Assistant Professor of Medicine 
University of Pennsylvania 
Cardiovascular Division  
Room 9022 East Gates 
3400 Spruce Street 
Philadelphia, PA 19104 
215-662-2855 
Regulatory Sponsor: 
 
 
Funding Sponsor: 
The Department of Radiology, University of Pennsylvania, 
School of Medicine 
 
Cardiovascular Medical Research and Education Fund  
 
Study Product: 
 
11C acetate 
18F-Fluorodeoxyglucose (18F-FDG) 
 
Protocol Number: 
 
817786 
 
IND Number: 
 
11C acetate: 119179 
18F-FDG: 112950 
 
 
 
 
 
Initial version: 
v1 July 12, 2013 
Amended:             v2 September 9, 2013 
Amended:  
 
v3 October 8, 2013 
Amended:  
 
v4 April 11, 2014 
 
 


11C-acetate/18F-FDG PET/CT and CMR in PAH  
 
 
 
 
 
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Table of Contents 
 
1 
INTRODUCTION ...................................................................................................... 8 
1.1 
BACKGROUND ..................................................................................................... 8 
1.2 
INVESTIGATIONAL AGENT ..................................................................................... 9 
1.2.1 
11C-acetate ................................................................................................. 9 
1.2.2 
18F-FDG ................................................................................................... 10 
1.3 
PRECLINICAL DATA ............................................................................................ 12 
1.3.1 
11C-acetate ............................................................................................... 12 
1.3.2 
18F-FDG ................................................................................................... 13 
1.4 
CLINICAL DATA TO DATE .................................................................................... 13 
1.4.1 
11C–acetate .............................................................................................. 13 
1.4.2 
18F-FDG ................................................................................................... 14 
1.5 
DOSE RATIONALE AND RISK/BENEFITS ................................................................ 14 
1.5.1 
11C-acetate ............................................................................................... 14 
1.5.2 
18F-FDG ................................................................................................... 14 
2 
STUDY OBJECTIVES ........................................................................................... 15 
3 
STUDY DESIGN .................................................................................................... 15 
3.1 
GENERAL DESIGN .............................................................................................. 15 
3.2 
PRIMARY STUDY ENDPOINTS .............................................................................. 16 
3.3 
EXPLORATORY ENDPOINTS ................................................................................ 16 
3.3.1 
PET .......................................................................................................... 16 
3.3.2 
Additional imaging parameters by CMR ................................................... 16 
4 
SUBJECT SELECTION AND WITHDRAWAL ...................................................... 17 
4.1 
INCLUSION CRITERIA .......................................................................................... 17 
4.2 
EXCLUSION CRITERIA ........................................................................................ 17 
4.3 
EARLY WITHDRAWAL OF SUBJECTS .................................................................... 17 
4.3.1 
When and How to Withdraw Subjects ...................................................... 17 
5 
STUDY DRUG ....................................................................................................... 18 
5.1 
DESCRIPTION .................................................................................................... 18 
5.1.1 
11C-acetate ............................................................................................... 18 
5.1.2 
18F-FDG ................................................................................................... 19 
5.2 
RADIOTRACER REGIMEN .................................................................................... 19 
5.3 
PREPARATION, PACKAGING AND ADMINISTRATION OF STUDY DRUG ...................... 19 
5.4 
RECEIVING, STORAGE, DISPENSING AND RETURN ................................................ 19 
5.4.1 
Receipt of Drug Supplies ......................................................................... 19 
5.4.2 
Storage .................................................................................................... 20 
5.4.3 
Dispensing of Study Drug ........................................................................ 20 
5.4.4 
Return or Destruction of Study Drug ........................................................ 20 
6 
STUDY PROCEDURES ......................................................................................... 20 


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6.1 
INFORMED CONSENT ......................................................................................... 20 
6.2 
BASELINE IMAGING VISIT .................................................................................... 20 
6.3 
WEEK 26 IMAGING VISIT .................................................................................... 22 
7 
METHODS ............................................................................................................. 23 
7.1 
PET IMAGING .................................................................................................... 23 
7.1.1 
PET Imaging Protocol .............................................................................. 23 
7.1.2 
Analysis of PET data ............................................................................... 23 
7.2 
CMR IMAGING .................................................................................................. 24 
7.2.1 
CMR Imaging Protocol ............................................................................. 24 
7.2.2 
Analysis of CMR data .............................................................................. 24 
7.3 
LABORATORY DETERMINATIONS ......................................................................... 24 
7.3.1 
Metabolic profiling .................................................................................... 24 
8 
STATISTICAL PLAN ............................................................................................. 24 
8.1 
SAMPLE SIZE DETERMINATION ............................................................................ 24 
8.2 
STATISTICAL METHODS ...................................................................................... 25 
8.2.1 
General Considerations ........................................................................... 25 
8.2.2 
Background Characteristics ..................................................................... 25 
8.2.3 
Efficacy Analysis ...................................................................................... 26 
8.2.4 
Safety Analysis ........................................................................................ 26 
8.3 
SUBJECT POPULATION(S) FOR ANALYSIS ............................................................. 27 
9 
SAFETY AND ADVERSE EVENTS ....................................................................... 27 
9.1 
DEFINITIONS ..................................................................................................... 27 
9.2 
RECORDING OF ADVERSE EVENTS ...................................................................... 29 
9.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS......... 29 
9.3.1 
Investigator reporting: notifying the study sponsor ................................... 30 
9.3.2 
Investigator reporting: notifying the Penn IRB .......................................... 30 
9.3.3 
Investigator reporting: Notifying a non-Penn IRB ..................................... 32 
9.3.4 
Sponsor reporting: Notifying the FDA ...................................................... 32 
9.3.5 
Sponsor reporting: Notifying participating investigators ........................... 33 
9.4 
SAFETY MONITORING ......................................................................................... 33 
9.5 
DATA AND SAFETY MONITORING BOARD .............................................................. 33 
10 
DATA HANDLING AND RECORD KEEPING ................................................... 33 
10.1 
CONFIDENTIALITY .............................................................................................. 33 
10.2 
SOURCE DOCUMENTS ........................................................................................ 34 
10.3 
DATA MANAGEMENT PLAN ................................................................................. 34 
10.4 
DATA SHARING PLAN ......................................................................................... 34 
10.5 
RECORDS RETENTION ....................................................................................... 35 
11 
STUDY MONITORING, AUDITING, AND INSPECTING ................................... 35 
11.1 
STUDY MONITORING PLAN ................................................................................. 35 
FREQUENCY ................................................................................................................ 35 
DATA REVIEW .............................................................................................................. 36 


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ADDITIONAL SUBJECTS/EVENTS TO BE REVIEWED: ........................................................... 36 
11.2 
REGULATORY DOCUMENTS REVIEWED ................................................................ 36 
11.3 
DOCUMENTATION OF THE MONITORING VISIT ....................................................... 36 
11.4 
AUDITING AND INSPECTING ................................................................................. 37 
12 
ETHICAL CONSIDERATIONS ........................................................................... 37 
13 
STUDY FINANCES ............................................................................................ 37 
13.1 
FUNDING SOURCE ............................................................................................. 37 
13.2 
CONFLICT OF INTEREST ..................................................................................... 37 
13.3 
SUBJECT STIPENDS OR PAYMENTS ..................................................................... 38 
14 
PUBLICATION PLAN ........................................................................................ 38 
15 
REFERENCES ................................................................................................... 38 
 
 
 


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Study Summary 
Title 
Evaluation of regional myocardial perfusion, glucose utilization 
and oxidative metabolism  in patients with pulmonary 
hypertension using combined [11C]Acetate and 
[18F]Fluorodeoxyglucose (FDG) PET/CT and Cardiovascular MRI 
Short Title 
11C-acetate/18F-FDG PET/CT and CMR in PAH 
Protocol Number 
817786   
Phase 
N/A   


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Study Design 
This is a companion imaging trial for patients who are eligible for 
the treatment trial entitled “A randomized, double-blind, placebo 
controlled, multi-center study to assess the effect of ranolazine on 
outcomes in subjects with pulmonary hypertension and right 
ventricular dysfunction accompanied by a comparative study of 
cellular metabolism in subjects with pulmonary hypertension with 
and without right ventricular dysfunction”. 
 
Patients will be identified and screened to participate in the 
treatment trial entitled “A randomized, double-blind, placebo 
controlled, multi-center study to assess the effect of ranolazine on 
outcomes in subjects with pulmonary hypertension and right 
ventricular dysfunction accompanied by a comparative study of 
cellular metabolism in subjects with pulmonary hypertension with 
and without right ventricular dysfunction”. Subjects that meet 
eligibility will be asked to consent separately for this imaging 
companion trial involving PET/CT imaging with the investigational 
radiotracers [11C]Acetate and [18F]FDG and Cardiovascular MRI 
(CMR). 
All patients will undergo a baseline cardiac PET/CT scan. The 
PET/CT imaging session will include injection of 15-25 mCi of 
11C-acetate followed by a 30 minute dynamic scan. After 
administration of oral glucose patients will undergo subsequent 
injection of 10 mCi of 18F-FDG with one hour wait followed by a 
15 minute scan. Some patients will undergo a baseline CMR 
scan if they haven’t clinically. Some patients will undergo a 
second cardiac PET/CT scan and CMR scan at 26±2 weeks after 
the start of their treatment, depending on the treatment group to 
which they are assigned.  
11C-acetate may not be available for some subjects due to tracer 
production associated technical difficulties. If 11C-acetate is 
unavailable it will be at the discretion of an investigator to omit the 
11C-acetate portion of the PET/CT scanning procedure and 
proceed with the FDG portion of the imaging only.  Although 11C-
acetate use is preferred, the investigator decision to omit it will be 
documented and any PET/CT scan done without it will not be 
considered a protocol deviation. 
Study Duration 
2.5 years 
Study Center(s) 
This imaging trial will be conducted at the University of 
Pennsylvania. 
 
The companion treatment trial will be completed at 3 sites: 
University of Pennsylvania (Penn) 
Brigham and Women’s Hospital (BWH) 
University of Maryland (UMD) 


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Primary Objective 
To demonstrate that there are differences in metabolism and 
function between subjects with near normal RV function and 
persistent RV dysfunction as defined by CMR RVEF of <= 40%.   
 
To measure changes in RV energy and contractility in subjects 
with persistent RV dysfunction using serial 11C-acetate and 18F-
FDG PET/CT and CMR. 
Number 
of 
Subjects 
Approximately 54 subjects will participate in this imaging study at 
the University of Pennsylvania  
Diagnosis 
and 
Main 
Inclusion 
Criteria 
Planned enrollment will include up to 54 NYHA class II/III/IV PAH 
patients who are eligible and consent to participate in the 
companion treatment trial “A randomized, double-blind, placebo 
controlled, multi-center study to assess the effect of ranolazine on 
outcomes in subjects with pulmonary hypertension and right 
ventricular dysfunction accompanied by a comparative study of 
cellular metabolism in subjects with pulmonary hypertension with 
and without right ventricular dysfunction” at either the University 
of Pennsylvania or the University of Maryland. Patients must be 
willing to undergo imaging procedures at the University of 
Pennsylvania. 
Study 
Product, 
Dose, 
Route, 
Regimen, Duration 
For each PET/CT imaging session subjects will receive a 15-25 
mCi intravenous injection of 11C-acetate and a 10 mCi injection 
of 18F-FDG. The total radiation dose to patients for each PET/CT 
exam will be approximately 12 mSv. 
Statistical 
Methodology 
Primary Efficacy Analysis:  
All variables (eg. Myocardial oxygen consumption/FDG ratio, 
perfusion absolute change, perfusion relative change, RVEF, RV 
size and RV mass, etc) from the imaging exams will be 
summarized and listed. Treatment effect will be tested using 
Analysis of covariance (ANOVA), with treatment in the model. If 
the normality assumption fails, non-parametric method will be 
employed. Difference between Arm 1 and Arm 2 will be 
summarized and tested using t-test. Difference between pre and 
post treatment in Arm 1 ranolazine group will be summarized and 
tested using t-test. Significance will be established at alpha level 
of 0.05. The efficacy analysis will be conducted on the all-
randomized population. 
Safety:  
The overall safety profile will be assessed in terms of imaging 
agent related AEs, and vital signs.  
 


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1 Introduction 
This document is a protocol for a human research study. This study is to be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 
312 and International Conference on Harmonization guidelines), applicable government 
regulations and Institutional research policies and procedures.  
1.1 Background 
During the progression of PAH, many of the molecular mechanisms that drive transition 
from compensated hypertrophy to dilatation and failure in the RV remain enigmatic. 
Much of our understanding is based on cell culture and animal models or is extrapolated 
from data of left ventricular (LV) dysfunction. Reflected by re-expression of fetal-type 
contractile proteins, angiogenic rarefaction, and alterations in calcium handling, 
numerous molecular signaling pathways are thought to be activated in RV dysfunction, 
leading to increased levels of reactive oxygen (ROS) or nitrogen (RNS) species, 
inflammation, RV ischemia, cardiomyocyte apoptosis, and decreased contractility, as 
recently reviewed1. However, further mechanistic insight into the progression of RV 
dysfunction has been hampered by an inability to obtain RV specimens in sufficient 
quantity for molecular analysis from subjects with progressive PAH and RV failure. 
Moreover, substantial differences exist among animal models of PAH and human PAH2, 
making animal-derived insights suboptimal and sometimes misleading regarding PAH 
and RV dysfunction in human subject populations. Thus, the development of targeted 
therapeutics in RV failure has been slow. 
 
More recently, animal modeling of RVH and RV failure in PAH has revealed a 
substantial down-regulation of mitochondrial oxidative metabolism in favor of glycolysis 
(GL). The molecular mechanisms controlling this metabolic shift in the RV are unclear3, 
but, in part, may involve alterations of potassium channel function4-6. Importantly, in 
rodents with experimental PAH7, 8 or chronic RV overload9, RVH, RV electrical 
remodeling, and RV dysfunction can be normalized with dichloroacetate (DCA), an 
inhibitor of pyruvate dehydrogenase kinase (PDK) which in turn activates pyruvate 
dehydrogenase (PDH) to favor oxidative metabolism. These findings suggest that 
alterations in mitochondrial function, metabolism, and energy substrate utilization are 
keys to understanding the progression to RV failure. Observational human data through 
PET corroborate these findings by revealing increased uptake of glucose in PAH-
dependent RV dysfunction10, 11. Yet, a true causative mechanism of metabolic 
dysregulation for RV dysfunction in human PAH has not been established. Furthermore, 
data are sparse regarding the efficacy and safety profile of DCA in humans, and it is 
currently not an FDA-approved medication. Alternatively, ranolazine, which is currently 
used for refractory myocardial ischemia12, 13, also activates PDH14-16 as well as inhibits 
fatty acid oxidation, sodium currents, and sodium-dependent calcium overload, as 
previously reviewed17. Recently, in a rodent model of RVH, ranolazine was reported to 
successfully reverse metabolic dysfunction and improve cardiac output and exercise 
capacity16. Thus, ranolazine may have substantial therapeutic potential in RV 


11C-acetate/18F-FDG PET/CT and CMR in PAH  
 
 
 
 
 
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dysfunction and PAH, and could be readily “re-purposed” as an already FDA-approved 
medication.  
 
Historically, RV failure had been described as a stereotyped response to hemodynamic 
overload. More recent large patient cohort data suggests that RV, independently from 
PAP, predicts mortality18. Thus, a recent hypothesis suggests that individual genetic 
differences dysregulate cardiomyocyte function and, in doing so, predispose to RV 
failure in humans, control patient-specific manifestations of disease, and thus would 
represent key diagnostic markers and therapeutic targets. In fact, multiple key metabolic 
regulatory factors have been found to be altered in RV failure, any one of which could 
contribute to individual predisposition to RV failure. Based on their established functions 
in left ventricular injury and metabolism19 and known alterations in right ventricular 
failure20, we propose to evaluate metabolic dysfunction of the RV using positron 
emission topography (PET) and cardiac magnetic resonance imaging (CMR).  
 
1.2 Investigational Agent 
1.2.1 
11C-acetate 
1.2.1.1 Description 
11C-acetate is prepared by carboxylation of a Grignard reagent, CH3MgBr or CH3MgCl, 
with cyclotron-produced 11C-carbon dioxide, followed by hydrolysis and puriﬁcation. This 
method produces 11C-acetate in a radiochemical yield of 72 ± 12% in 20 min and in high 
specific activity (>18.5 GBq/µmol, 0.5 Ci/µmol). The radiochemical purity of  11C-acetate 
was found to be > 95%21. 11C-acetate has a molecular weight of 59.05 g/mol and a 
molecular formula of C2H4O2. 
 
1.2.1.2 Mechanism of Action 
11C-acetate is used as a positron emission tomography (PET) tracer for studying 
myocardial oxidative metabolism and regional myocardial blood flow22. Upon delivery 
and uptake to myocardium cells, 11C-acetate is activated to 11C-Acetyl-CoA in the 
mitochondria where it enters the Krebs cycle and is converted into 11CO2 and water via 
oxidative phosphorylation. Serial imaging following the IV administration of 11C-acetate 
demonstrates the passage of the radioactive bolus through the cardiac chambers, 
followed by extraction and accumulation of radiotracer in the myocardium and its 
clearance from the blood pool, and finally clearance of radiotracer from myocardial 
tissue reflecting the rate of oxidative metabolism (Kmono) 23,24. 
 
1.2.1.3 Pharmacokinetics 
11C-acetate is rapidly taken up by myocardium and metabolized to CO2 and water after 
intravenous injection. The uptake is indirectly dependent on blood flow25. Human 


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dosimetry was estimated in six healthy volunteers by intravenous injection of 525 MBq 
(14.2 mCi) of 11C-acetate26. The organs receiving the highest absorbed doses were the 
pancreas (0.017 mGy/MBq or 62.9 mrad/mCi), bowel (0.011 mGy/MBq or 40.7 
mrad/mCi), kidneys (0.0092 mGy/MBq or 34.0 mrad/mCi), and spleen (0.0092 
mGy/MBq or 34.0 mrad/mCi). No urinary excretion of tracer was detected. The effective 
dose equivalent was 0.0062 mSv/MBq (22.9 mrem/mCi). 
 
1.2.1.4 Absorption and Distribution 
11C-acetate is rapidly taken up by myocardium and metabolized to CO2 and water after 
intravenous injection. The uptake is indirectly dependent on blood flow25. The clearance 
of the tracer is a direct reflection of TCA cycle activity, which is coupled to myocardial 
oxygen consumption. Rates of clearance from myocardium of 11C-acetate reflect 
oxidative metabolism27. 
 
1.2.1.5 Metabolism and Excretion 
Upon delivery and uptake to myocardium cells, 11C-acetate is activated to 11C-Acetyl-
CoA in the mitochondria where it enters the Krebs cycle and is converted into 11CO2 and 
water via oxidative phosphorylation. 11CO2 is exhaled. The clearance of 11C-acetate is a 
direct reflection of TCA cycle activity, which is coupled to myocardial oxygen 
consumption. Rates of clearance from myocardium of 11C-acetate reflect oxidative 
metabolism27.  
1.2.2 
18F-FDG 
1.2.2.1 Description 
 [18F]Fluoro-2-deoxy-2-D-glucose has a molecular weight of 181.15 g/mol and a 
molecular formula of C6H11FO5 and the following structural formula:   
 
18F-FDG is used for diagnostic purposes in conjunction with Positron Emission 
Tomography (PET).  It is administered by intravenous injection. 
 


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1.2.2.2 Mechanism of Action 
FDG is moved into cells by glucose transporters and is then phosphorylated by HK 
to FDG-6- phosphate. The 2' hydroxyl group (—OH) in normal glucose is needed for 
further glycolysis (metabolism of glucose by splitting it), but 18F-FDG is missing this 2' 
hydroxyl. Thus, FDG-6- phosphate cannot be metabolized further in the glycolytic 
pathway and stays intracellularly in the cells. The elevated rates of glycolysis and 
glucose transport in many types of tumor cells and activated cells enhance the uptake 
of FDG in these cells relative to other normal cells. Positron emission tomography (PET) 
with 18F-FDG has been used to assess alternations in glucose metabolism in brain, 
cancer, cardiovascular diseases, Alzheimer’s disease and other central nervous system 
disorders, and infectious, autoimmune, and inflammatory diseases28-30.  
 
1.2.2.3 Pharmacokinetics 
18F-FDG, as a glucose analog, is taken up by high-glucose-using cells such as brain, 
kidney, and cancer cells, where phosphorylation prevents the glucose from being 
released again from the cell, once it has been absorbed. About 75% of the fluorine-18 
activity remains in tissues and is eliminated with a half-life of 110 minutes.  Another 
fraction of 18F-FDG, representing about 20% of the total fluorine-18 activity of an 
injection, is eliminated renally by two hours after a dose of 18F-FDG, with a rapid half-life 
of about 16 minutes. 
 
1.2.2.4 Absorption and Distribution 
18F-FDG, as a glucose analog, is taken up by high-glucose-using cells such as brain, 
kidney, and cancer cells, where phosphorylation prevents the glucose from being 
released again from the cell, once it has been absorbed. The 2' hydroxyl group (—OH) 
in normal glucose is needed for further glycolysis (metabolism of glucose by splitting it), 
but 18F-FDG is missing this 2' hydroxyl. Thus, in common with its sister molecule 2-
deoxy-D-glucose, FDG cannot be further metabolized in cells. The 18F-FDG-6-
phosphate formed when 18F-FDG enters the cell thus cannot move out of the cell before 
radioactive decay. As a result, the distribution of18F-FDG is a good reflection of the 
distribution of glucose uptake and phosphorylation by cells in the body. 
 
After 18F-FDG decays radioactively, however, its 2'-fluorine is converted to 18O–, and 
after picking up a proton H+ from a hydronium ion in its aqueous environment, the 
molecule becomes glucose-6-phosphate labeled with harmless nonradioactive "heavy 
oxygen" in the hydroxyl at the 2' position. The new presence of a 2' hydroxyl now allows 
it to be metabolized normally in the same way as ordinary glucose, producing non-
radioactive end-products. Although in theory all 18F-FDG is metabolized as above with a 
radioactivity elimination half-life of 110 minutes (the same as that of fluorine-18), clinical 
studies have shown that the radioactivity of 18F-FDG partitions into two major fractions. 
About 75% of the fluorine-18 activity remains in tissues and is eliminated with a half-life 
of 110 minutes, presumably by decaying in place to O-18 to form 18O-glucose-6-


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phosphate, which is non-radioactive (this molecule can soon be metabolized to carbon 
dioxide and water, after nuclear transmutation of the fluorine to oxygen ceases to 
prevent metabolism). Another fraction of 18F-FDG, representing about 20% of the total 
fluorine-18 activity of an injection, is eliminated renally by two hours after a dose of 18F-
FDG, with a rapid half-life of about 16 minutes (this portion makes the renal-collecting 
system and bladder prominent in a normal PET scan). This short biological half-life 
indicates that this 20% portion of the total fluorine-18 tracer activity is eliminated 
pharmacokinetically (through the renal system) much more quickly than the isotope 
itself can decay. The rapidity also suggests that some of this 18F is no longer attached to 
glucose, since low concentrations of glucose in the blood are retained by the normal 
kidney and not passed into the urine. Because of this rapidly excreted urine 18F, the 
urine of a patient undergoing a PET scan may therefore be especially radioactive for 
several hours after administration of the isotope. 
 
1.2.2.5 Metabolism and Excretion 
All radioactivity of 18F-FDG, both the 20% which is rapidly excreted in the first several 
hours of urine which is made after the exam, and the 80% which remains in the patient, 
decays with a half-life of 110 minutes (just under 2 hours). Thus, within 24 hours (13 
half-lives after the injection), the radioactivity in the patient and in any initially voided 
urine which may have contaminated bedding or objects after the PET exam, will have 
decayed to 2−13 = 1/8192 of the initial radioactivity of the dose. In practice, patients who 
have been injected with 18F-FDG are told to avoid the close vicinity of especially 
radiation-sensitive persons such as infants, children and pregnant women, for at least 
12 hours (7 half-lives, or decay to 1/128th the initial radioactive dose). 
 
1.3 Preclinical Data 
1.3.1 
11C-acetate 
 
11C-acetate has been used to study myocardial oxygen consumption rate (MVO2) with 
the metabolic fate of the tracer in normoxic, hypoxic, and ischemic conditions in isolated 
perfused rat hearts. Model-estimated MVO2 correlated well with experimentally 
measured MVO2 for these conditions correlated strongly with the myocardial clearance 
rate determined from the tissue kinetics31. 
 
In a rat model of an occluded, acute left anterior descending (LAD) coronary 
artery, 60Cu-ATSM was used to visualize hypoxic rat heart tissue using an ex vivo tissue 
slice imaging technique31. In addition, 11C-acetate was used to monitor myocardial 
blood flow. Low 11C-acetate uptake (low blood flow) and high 60Cu-ATSM uptake 
(hypoxia) were observed in mildly ischemic regions. In the center of severely ischemic 
regions with no blood flow, little accumulation of 11C or 60Cu radioactivity was observed. 
 


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The use of 11C-acetate for determination of myocardial oxidative consumption has been 
well validated in a number of animal studies32. Acetate clearance showed a close 
correlation with myocardial oxygen consumption when measured in dogs under different 
disease states (normal, ischemia, and increased workload).   
11C-acetate PET was used to study cardiac output in a pig model33. The tracer uptake in 
the right and left heart cavities was measured as well as in the lung. Myocardial output 
measured by 11C-acetate PET was linearly related to cardiac output by thermodilution. 
Lung uptake of 11C-acetate was also linearly related to stroke volume. 
1.3.2 
18F-FDG 
18F-FDG was accumulated rapidly into kidneys, liver, lung, and small intestine of normal 
mice, followed by a rapid clearance34. On the other hand, the accumulation of the tracer 
in the brain and heart remained relatively constant during the 2 h of the experiment. 18F-
FDG was tested as a tumor diagnostic agent in a transplantable rat tumor35. Tissue 
distribution studies in rats showed high uptakes of 18F-FDG in the tumor, heart, 
intestine, and brain. Tumor uptake reached 2.65% dose 18F-FDG/g at 60 min and 
remained relatively constant until 120 min. Blood clearance 18F-FDG was very rapid, 
and tumor/blood ratios reached 22.1 at 60 min. Tumor/tissue ratios were very high in 
most organs, especially in the liver, kidneys, and pancreas.  
 
1.4 Clinical Data to Date 
1.4.1 
11C–acetate 
Myocardial oxygen consumption can be estimated with PET from analysis of the 
myocardial turnover rate constant (k) after administration of 11C-acetate. 11C-acetate 
was administered to five normal volunteers and six patients with myocardial infarction. 
Uptake of 11C-acetate by the myocardium was avid, and its clearance from the blood 
pool was rapid, yielding myocardial images of excellent quality. Regional k was 
homogeneous in the myocardiums of healthy volunteers. In patients, k in regions 
remote from the area of infarction was not different from values in the myocardiums of 
healthy human volunteers. In contrast, k in the center of the infarct region of necrotic 
myocardium was significantly reduced36. 
 
In humans, 11C-acetate has been used in coronary disease to determine metabolic 
reserve and in cardiomyopathy to study changes in oxygen consumption with cardiac 
resynchronization therapy37.11C-acetate has also been used in heart failure patients to 
determine the effects of sleep apnea, selective beta1-blockade, or exercise on 
myocardial oxygen consumption and energy efficiency38-44. There have been no noted 
pharmacologic or hemodynamic side effects of 11C-acetate in multiple studies32, 37-40, 42, 
44-52.   11C-acetate has also been used in a few studies on RV metabolism53, 54 in the 
research setting, but not in subjects with pulmonary arterial hypertension. 
 
 


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1.4.2 18F-FDG  
In 1976, the first images of 18F-FDG metabolism in humans were obtained and showed 
high uptake in the bladder, heart, and brain55, 56. Human dosimetry was estimated from 
absorbed dose in organs after intravenous administration of 18F-FDG using whole-body 
PET scans in six normal volunteers57. The bladder received the highest dose of 
radioactivity, followed by the spleen, heart, and brain. Mejia et al.58 estimated the 
effective dose equivalent to be 0.024 mSv/MBq (81 mrem/mCi). 18F-FDG PET imaging 
techniques are widely used in clinical applications. In central nervous system disorders, 
the clinical applications are in Alzheimer’s disease, dementia, epilepsy, brain trauma, 
Huntington disease, cerebrovascular disorders, brain tumors, schizophrenia, and mood 
disorders. In oncology, the clinical applications are in diagnosis, treatment monitoring, 
and tumor staging and have been used in non-small cell lung cancer, colorectal 
carcinoma, malignant melanoma, Hodgkin and non-Hodgkin lymphoma, esophageal 
carcinoma, head and neck cancer, breast cancer, and thyroid carcinoma. In 
cardiovascular disorders, the clinical applications are in myocardial viability and 
atherosclerosis59. In infectious and inflammatory diseases, the clinical applications are 
in orthopedic infections, osteomyelitis, ileitis, sarcoidosis, rheumatologic disease, and 
vasculitis.  
 
FDG has been studied in PAH and was found to be increased in PAH60, 61, but the 
studies did not differentiate between near normal RV and failing RV patients. Rather, 
Oikawa et al60demonstrated that treating PAH patients with epoprostenol decreased RV 
FDG uptake. Bokhari et al61 demonstrated that RV uptake correlated with PA pressures. 
 
1.5 Dose Rationale and Risk/Benefits 
1.5.1 11C-acetate 
 
11C-acetate is an investigational imaging drug, which has been extensively used in 
cardiac and oncologic PET imaging. Acetate is normally produced in the body through 
metabolism of glucose and free fatty acids. The radiopharmaceutical preparation of 11C-
acetate uses trace amounts of acetate without observed pharmacological effect. The 
radiation exposure from a single injection of 11C-acetate is equivalent to the amount 
received from background radiation in the US. There are no reported adverse reactions 
from the administration of radiolabeled acetate. 
 
1.5.2 
18F-FDG 
18F-Fluorodeoxyglucose (FDG) is FDA approved for cardiac PET imaging and well 
tolerated by patients. We will use standard dosage. The health risks associated with 
chronic radiation exposure are believed to involve levels of radiation exposure which are 
much higher than those permitted occupationally. There are no reported adverse 
reactions from the administration of FDG. 
 


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PET/CT scanning uses short-lived radiopharmaceuticals, 11C-acetate (Physical half life: 
20 minutes) and 18F-Fluorodeoxyglucose (FDG; Physical half life: 110 minutes).  The 
study requires an IV line for administration of radiopharmaceuticals. The PET exams will 
expose subjects to radiation. The total radiation dose to the subjects per exam will be 
approximately 12 mSv (a mSv is a unit of radiation dose).   
This is equivalent to approximately 5 time of the natural environmental radiation 
exposure we all receive every year, 2 conventional chest CTs62, and 25% of the 50 mSv 
annual limit for a person who works with radiation.  
 
The risk of exposure is reasonable given the potential benefit that we might derive from 
the potential mechanistic insight of RV dysfunction on PAH therapy and whether or not 
ranolazine can partially reverse the RV dysfunction in PAH patients who are already on 
background  PAH specific therapy.  
 
2 Study Objectives 
 
Primary objectives:  
1. To demonstrate that there are differences in metabolism and function between 
subjects with near normal RV function and persistent RV dysfunction as defined 
by CMR RVEF of <= 40%.   
 
2. To measure changes in RV energy and contractility in subjects with persistent 
RV dysfunction using serial 11C-acetate and 18F-FDG PET/CT and CMR. 
 
Secondary objective:  
To characterize the metabolic and structural stability of the RV over 6 month in subjects 
with near normal RV function.  
3 Study Design 
3.1 General Design 
This is a companion imaging trial for patients who are eligible for the treatment trial 
entitled “A randomized, double-blind, placebo controlled, multi-center study to assess 
the effect of ranolazine on outcomes in subjects with pulmonary hypertension and right 
ventricular dysfunction accompanied by a comparative study of cellular metabolism in 
subjects with pulmonary hypertension with and without right ventricular dysfunction”. 
 
Patients will be identified and screened to participate in the treatment trial entitled “A 
randomized, double-blind, placebo controlled, multi-center study to assess the effect of 
ranolazine on outcomes in subjects with pulmonary hypertension and right ventricular 
dysfunction accompanied by a comparative study of cellular metabolism in subjects with 
pulmonary hypertension with and without right ventricular dysfunction”. Subjects that 
meet eligibility will be asked to consent separately for this imaging companion trial 


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involving PET/CT imaging with the investigational radiotracers [11C]Acetate and 
[18F]FDG and Cardiovascular MR (CMR). 
All patients will undergo a baseline cardiac PET/CT scan and CMR scan(if they haven’t 
clinically). The PET/CT imaging session will include injection of 15-25 mCi of 11C-
acetate followed by a 30 minute dynamic scan.  After administration of oral glucose 
patients will undergo subsequent injection of 10 mCi (± 20%) of 18F-FDG with one hour 
wait followed by a 15 minute scan. Some patients will undergo a second cardiac 
PET/CT scan and CMR following the same imaging protocol at 26±2 weeks after the 
start of their treatment, depending on the treatment group to which they are assigned. 
Please see the companion treatment trial for description of the randomization process 
and treatment groups. 
 
3.2 
11C-acetate may not be available for some subjects due to tracer production 
associated technical difficulties. If 11C-acetate is unavailable it will be at the 
discretion of an investigator to omit the 11C-acetate portion of the PET/CT 
scanning procedure and proceed with the FDG portion of the imaging only. 
 Although 11C-acetate use is preferred, the investigator decision to omit it 
will be documented and any PET/CT scan done without it will not be 
considered a protocol deviation. Primary Study Endpoints 
 
1. Compare Myocardial oxygen consumption/FDG uptake ratio at baseline for 
subjects with near normal RV function and those with persistent RV dysfunction 
 
2. Assess change from baseline in Myocardial oxygen consumption/FDG ratio and 
perfusion rate in subjects with persistent RV dysfunction 
 
3.3 Exploratory Endpoints 
3.3.1 PET 
In patients with near normal RV function, characterize the stability of metabolism over 6 
month follow up period.  
3.3.2 Additional imaging parameters by CMR  
 
1. Assess RVEF, RV size and RV mass using CMR for subjects with pulmonary 
hypertension 
 
2. Compare extracellular volume in RV and fibrosis of the RV at baseline for 
subjects with near normal RV function and those with persistent RV dysfunction 
 
3. Assess change from baseline in extracellular volume in RV and fibrosis of the RV 
over 6 months. 
 


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Additional exploratory analyses will be performed in the PET/CT and CMR imaging. 
 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
 
1) Participation in the companion treatment protocol “A randomized, double-blind, 
placebo controlled, multi-center study to assess the effect of ranolazine on outcomes 
in subjects with pulmonary hypertension and right ventricular dysfunction 
accompanied by a comparative study of cellular metabolism in subjects with 
pulmonary hypertension with and without right ventricular dysfunction” defined as: 
a) Subject must have consented for and be willing to participate in the companion 
treatment protocol  
b) Subject must meet all non-imaging inclusion and exclusion criteria in companion 
treatment protocol 
2) Age >18 and < 80 years of age  
3) Subjects must be capable of giving informed consent 
4) Subjects must be willing to comply with all study-related procedures. 
 
4.2 Exclusion Criteria 
1) Pregnancy or lactation: Women of childbearing potential must have a negative urine 
or blood pregnancy test on the day of the PET/CT scan.  
2) Anxiety or claustrophobia prohibiting completion of imaging 
3) Inability to tolerate imaging procedures (up to 2 hrs on scanner) 
4) Moderate to severe chronic renal disease defined as an eGFR < 30 ml/min/1.73m2  
5) ICD, Pacemaker, hazardous metallic implants or any other contraindication to MRI. 
6) Uncontrolled diabetes mellitus with fasting glucose > 150 mg/dL  
4.3 Early Withdrawal of Subjects 
4.3.1 When and How to Withdraw Subjects 
The criteria for enrollment must be followed explicitly.  If a subject who does not meet 
enrollment criteria is inadvertently enrolled, that subject should be discontinued from the 
study.  A subject may voluntarily discontinue participation in this study at any time.  The 
investigator may also, at his or her discretion, discontinue the subject from participating 
in this study at any time.  If a subject is prematurely discontinued from participation in 
the study for any reason, at any time, at either the investigator’s discretion or the 
subject’s request, an effort must be made to document the reason(s) why a subject fails 
to return to the study clinic for necessary visits or is discontinued from the study.  The 


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primary reason for discontinuing participation in the study must be stated in the CRF 
and may include, but is not limited to, one of the following: 
 
 Occurrence of intolerable AEs 
 Withdrawal of consent for either treatment protocol or imaging protocol by patient 
 Noncompliance with protocol, e.g., the patient fails to appear at one or more imaging 
procedures 
 Development of an intercurrent illness, injury, or medical condition likely to interfere 
with subject safety, the overall assessment, or the required administration of study 
medication 
 Pregnancy 
 Development of any condition for which the investigator feels treatment withdrawal is 
justified 
 Termination of the study  
When a subject discontinues or is withdrawn, the investigator, will perform the 
procedures indicated for the end of treatment visit when possible.  
Follow-up information will be obtained for subjects who discontinue the treatment phase 
of the study.  See the flowcharts for procedures to be performed at end of treatment and 
follow-up visits. 
Subjects withdrawn from the study will not be replaced, regardless of the reason for 
withdrawal. 
An effort must be made to determine why a subject fails to return for the necessary 
visits or is dropped from the study.  This information will be recorded in the medical 
record and on the subject’s eCRF. 
 
5 Study Drug  
5.1 Description 
5.1.1 
11C-acetate 
11C-acetate is prepared by carboxylation of a Grignard reagent, CH3MgBr or CH3MgCl, 
with cyclotron-produced 11C-carbon dioxide, followed by hydrolysis and puriﬁcation. 
Upon delivery and uptake to myocardium cells,11C-acetate is activated to 11C-Acetyl-
CoA in the mitochondria where it enters the Krebs cycle and is converted into 11CO2 and 
water via oxidative phosphorylation. 11C-acetate is used as a positron emission 
tomography (PET) tracer for studying myocardial oxidative metabolism and regional 
myocardial blood flow.  


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5.1.2 
18F-FDG 
[18F]Fluoro-2-deoxy-2-D-glucose has a molecular weight of 181.15 g/mol and a 
molecular formula of C6H11FO5. 18F-FDG is administered by intravenous injection. 
Positron emission tomography (PET) with 18F-FDG has been used to assess 
alternations in glucose metabolism in brain, cancer, cardiovascular diseases.   
5.2 Radiotracer Regimen 
PET/CT scanning uses short-lived radiopharmaceuticals, 11C-acetate (Physical half life: 
20 minutes) and 18F-Fluorodeoxyglucose (FDG; Physical half life: 110 minutes).  The 
study requires an IV line for administration of radiopharmaceuticals and contrast for the 
MRI studies. The PET exams will expose subjects to radiation. The total radiation dose 
to the subjects per PET exam will be approximately 12mSv (a mSv is a unit of radiation 
dose). This is equivalent to approximately 5 time of the natural environmental radiation 
exposure we all receive every year, 2 conventional chest CTs62, and 25% of the 50 mSv 
annual limit for a person who works with radiation.  
 
5.3 Preparation, Packaging and Administration of Study Drug 
The manufacturing of 11C-acetate and18F-FDG will occur in the Cyclotron Facility of the 
Department of Radiology at the University of Pennsylvania.  This facility manufactures 
USP compliant radio-labeled compounds for human use on a daily basis.  The 11C-
acetate drug manufacturing will be fully documented and controlled by a set of Standard 
Operating Procedures (SOPs) prepared by the University of Pennsylvania Cyclotron 
which have been forwarded to the FDA under IND #119,179..  The 18F-FDG drug 
manufacturing is documented and controlled by a set of Standard Operating Procedures 
(SOPs) prepared by the University of Pennsylvania Cyclotron which has an IND 
#112950.  The dose of 11C-acetate will be administered by a certified Authorized User 
from the Nuclear Medicine Division of the University of Pennsylvania Medical Center.  
The dose of 18F-FDG will be administered by authorized technical staff.  All standard 
hospital procedures will also apply. 
 
5.4 Receiving, Storage, Dispensing and Return 
5.4.1 Receipt of Drug Supplies 
11C-acetate and 18F-FDG will be delivered to the Nuclear Medicine Division of the 
University of Pennsylvania Medical Center by a trained Cyclotron team member 
according to the standard procedures outlined by the Cyclotron Facility.  Once the drug 
has been delivered to the Nuclear Medicine Division all standard hospital procedures 
will apply for handling, processing, and destruction of any residual amounts if 
applicable. 


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5.4.2 Storage 
We will be drawing 18F-FDG doses from separate vials synthesized in the Cyclotron 
facility on the campus of the University of Pennsylvania for clinical use scheduled for the 
same day. 18F- FDG and 11C-acetate will not be stored.  
5.4.3 Dispensing of Study Drug 
Prescribed doses of 11C-acetate and 18F-FDG will be drawn and accurately measured 
by the dose calibrator in the imaging facility and immediately administered by bolus 
injection to the subject under the direct supervision of a Nuclear Medicine Authorized 
User (acetate) or an authorized technical staff (FDG).  
 
5.4.4 Return or Destruction of Study Drug 
The remaining activity in the vials that exists in the lab will be stored until the activity 
decays to undetectable level.  All vials will be disposed of according to the standard 
operating procedure set forth by the hospital. 
 
6 Study Procedures 
6.1 Informed Consent 
The investigator will provide for the protection of the subjects by following all applicable 
regulations.  These regulations are available upon request from the sponsor.  The 
sponsor and IRB must review the informed consent form used during the informed 
consent process, and it must be available for inspection.   
Before any procedures specified in this protocol are performed, a subject must: 
 Be informed of all pertinent aspects of the study and all elements of informed 
consent.  
 Be given time to ask questions and time to consider the decision to participate. 
 Voluntarily agree to participate in the study.  
 Sign and date an IRB/IEC-approved informed consent form. 
 
(* If a procedure is done routinely as standard of care, then it is not study-specific, and it 
may be done before the consent is signed.) 
6.2 Baseline Imaging Visit 
Subject must meet all non-imaging inclusion and exclusion criteria in the companion 
treatment protocol prior to undergoing imaging procedures.    
 
Consent for the imaging study and treatment study will be obtained at the same time for 
Penn patients.  Consent for the imaging study will be obtained separately for the 
Maryland patients.  A copy of the signed treatment study consent form from Maryland 
will be maintained on file at Penn. 


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All baseline imaging procedures must be completed within 28 days before 
randomization in the companion treatment protocol unless otherwise noted.   The 
following procedures will be done for baseline imaging: 
 
 
Informed consent will be obtained within 90 days prior to performing any 
research procedures, to include: a signed and dated IRB-approved ICF and 
documentation of the consenting process in the source documents.   
 
Demography, including gender, date of birth, and race 
 
Review of concomitant medications and any changes in health since 
screening for the treatment study  
 
Pregnancy test (serum or urine; for women of childbearing potential) on the 
day of the scans.  
 
Screening clinical CMR (unless already performed within 30 days) 
 
Oral glucose (25-50g) will be given. Finger sticks will be obtained to evaluate 
glucose levels prior to FDG administration and prior to imaging.  
 
Vital signs including heart rate, blood pressure, respiratory rate, and oxygen 
saturation are obtained prior to injection of radiotracers.  Additional vitals will 
be taken on an as needed basis determined by the physician monitoring the 
scan. 
 
Insertion of up to two IV catheters (for injection and/or blood draws) 
 
Research 11C-acetate and 18F-FDG PET/CT. 11C-acetate may be omitted in 
some subjects at the discretion of the investigator.  
 
Blood samples will be drawn prior to 18F-FDG injection and after 18F-FDG 
scan to measure plasma concentrations of insulin, glucose, and free fatty 
acids.  
 
Collection of fasting blood sample for metabolic profiling 
 
For PET/CT, images will be acquired for 30 minutes after administration of 11C-acetate 
and for 15 minutes one hour after administration of 18F-FDG.  For CMR, gadolinium 
contrast will be used. 
If the subject has undergone a clinical CMR according to institutional standards within 
30 days of the baseline PET/CT then the clinical scan may be used as the baseline 
scan and does not need to be repeated for the purposes of this study. If a clinical CMR 
is not planned, the subject will undergo a baseline research CMR as part of this imaging 
protocol, to be completed at the University of Pennsylvania. 
 


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Adverse events will be recorded for the period up to 24 hours post injection of the 
radiotracers and gadolinium.  Research personnel will conduct a telephone follow-up 
visit 24-72 hours after the scans for adverse events monitoring. 
 
6.3 
Week 26 Imaging Visit  
Subjects will return to Penn 26 weeks (+/- 2 weeks) after treatment for the Week 26 
imaging tests.  Subjects who meet endpoint criteria (defined in the treatment protocol) 
may have these procedures prior to week 26.  The following will be done during this 
visit: 
 
 
Review of concomitant medications and any changes in health since the last 
visit  
 
Pregnancy test (serum or urine; for women of childbearing potential) on the 
day of the scans. 
 
Oral glucose (25-50g) will be given. Finger sticks will be obtained to evaluate 
glucose levels prior to FDG administration and prior to imaging.  
 
Insertion of up to two IV catheters (for injection and/or blood draws) 
 
Collection of fasting blood sample for metabolic profiling  
 
Vital signs including heart rate, blood pressure, respiratory rate, and oxygen 
saturation are obtained prior to injection of radiotracers. Additional vitals will 
be taken on an as needed basis determined by the physician monitoring the 
scan. 
 
Research CMR 
 
Research 11C-acetate and 18F-FDG PET/CT. 11C-acetate may be omitted in 
some subjects at the discretion of the investigator.   
 
Blood samples will be drawn prior to 18F-FDG injection and after 18F-FDG 
scan to measure plasma concentrations of insulin, glucose, and free fatty 
acids.  
 
For PET/CT, images will be acquired for 30 minutes after administration of 11C-acetate 
and for 15 minutes one hour after administration of 18F-FDG.  For CMR, gadolinium 
contrast will be used. 
 
The repeat CMR and PET imaging at week 26 are optional for patients in the 
observational arm of the treatment protocol.   
 


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Adverse events will be recorded for the period up to 24 hours post injection of the 
radiotracers.  Research personnel will conduct a telephone follow-up visit 24-72 hours 
after the scans for adverse events monitoring. 
 
The subject will complete participation in the imaging protocol at the end of the week 26 
imaging procedures including the follow-up telephone call.   
 
7 Methods 
7.1 PET Imaging  
7.1.1 PET Imaging Protocol 
Positron emission tomography (PET) imaging will be used to evaluate regional 
myocardial perfusion, glucose utilization, and oxidative metabolism at rest using 11C-
acetate and 18F-Fluorodeoxyglucose (FDG).  Imaging will be performed using a whole-
body PET/CTscanner (Germini TF or Gemini TF BigBore Philips Medical Systems, 
Netherland or Siemens MCT, Siemens AG, Germany) (Penn). The protocol will be 
performed under the regulatory approval of the local IRB and FDA IND. 
Following a scout transmission scan to confirm proper position of the subject in the field 
of view, a CT attenuation scan will be acquired for subsequent correction of photon 
attenuation. Beginning with the intravenous bolus administration of 11C-acetate (15-25 
mCi), list mode images will be acquired over 30 min. After which 10 mCi (± 20%) of 18F-
FDG will be administered intravenously. Patients will then rest for approximately 60 
minutes before a second CT attenuation will be obtained followed by static FDG images 
acquired for 15 minutes. All images will be corrected for scatter and measured photon 
attenuation, and reconstructed using iterative reconstruction techniques. To account for 
possible differences in substrate levels, two separate blood samples will be taken prior 
to 18F-FDG injection and after 18F-FDG scan to measure plasma concentrations of 
insulin, glucose, and free fatty acids. 
 
7.1.2 Analysis of PET data 
From the list mode images, multi-frame imaging data will be generated for 11C-acetate. 
All the reconstructed dynamic imaging data will be anonymized and will be transferred 
to the PET core laboratory at Brigham and Women’s Hospital for analysis. Absolute 
quantification of regional myocardial blood flow (in mL/min/g) will be performed using 
the dynamic data acquired between 0-5 minutes following 11C-acetate injection 25, 63, 64. 
We will use 2-compartment (blood pool compartment and tissue compartment) kinetic 
model of 11C-acetate to determine regional blood flow in the RV free wall 63, 65. The 
extraction fraction determined by van den Hoff will be used 65. RV free wall glycolytic 
rate will be quantified as the SUV of the static FDG images. Myocardial oxidative 
metabolism and glucose uptake estimates will be corrected for partial volume effect 
based on measures of RV free wall thickness obtained from the cardiac MRI studies. 


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7.2 CMR Imaging  
7.2.1 CMR Imaging Protocol 
CMR will be performed on the clinical 1.5T MR systems (Avanto, Siemens, Erlangen, 
Germany). Cine images of the short axis, 4-chamber, 2 chamber RV inflow, and oblique 
coronal RV views will be obtained. Phase contrast velocity images will be obtained.  
Mapping sequences for tissue characterization will be acquired. Resting perfusion and 
late gadolinium enhancement images will also be obtained.  
7.2.2 Analysis of CMR data 
From the cine images, RV ventricular size, volumes, mass, and function are analyzed 
using Segment (Medviso) and then indexed to body surface area.  PC images will be 
processed using software tools. T1 weighted, and T2 weighted mapping images and 
late gadolinium enhancement images will be analyzed on a workstation using Matlab 
(Mathworks, Natick, Masschusetts) and compared between Arm 1 and Arm 2 subjects 
and Arm1 pre and post treatment.  
 
7.3 Laboratory Determinations 
 
A urine dipstick pregnancy test must be done on the day of CMR/PET in child 
bearing age women.   
 
To account for possible differences in substrate levels, two separate blood samples 
will be taken prior to 18F-FDG injection and after 18F-FDG scan to measure plasma 
concentrations of insulin, glucose, and free fatty acids. 
 
Peripheral blood at the baseline and end of treatment visit will be obtained from 
subjects to send for metabolic profiling.   
 
7.3.1 
Metabolic profiling  
Analytical platform uses gas chromatography-mass spectrometry method (Metabolon 
Inc) to provide increased overall coverage of small molecules and allows high-
throughput data analysis to identify biomarkers and mechanistic underpinnings of 
disease. Following peak identification and quality control filtering, integrated peak ion 
counts for each compound in each sample are used for statistical analysis. 
 
8 Statistical Plan 
8.1 Sample Size Determination 
Approximately 54 subjects will be enrolled in the imaging study at Penn: 18 subjects 
from Arm 1 placebo group, 18 from Arm 1 Ranolazine group, and18 from Arm 2 
Observational group. An additional 12 patients in each arm will be enrolled and undergo 


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the same imaging procedures at BWH in the companion multicentered clinical trial.  The 
imaging analyses will be combined from Penn and BWH.  Each site will assess for 
image quality after the first enrolled subject to adjust imaging parameters as necessary.  
Image quality will be assessed for combined analysis.  We allow a withdraw rate of 
15%.  We will compare imaging parameters with a sample size of 25 evaluable in each 
arm. Assuming the effect size is 50% with a standard deviation of 50%, we will have 
100% power to detect the difference between groups with a sample size of 25.  
Assuming the effect size is 25% with a standard deviation of 50%, we will have 78% 
power to detect the difference between groups with a sample size of 30 (at baseline).  
8.2 Statistical Methods 
8.2.1 General Considerations 
Continuous data (e.g., age) will be summarized using the following descriptive 
summary statistics: the number of subjects (n), mean, SD, median, minimum value 
(min), and maximum value (max). For each continuous variable, the corresponding 
mean, median, minimum and maximum will be presented to 1 decimal place and the SD 
to 2 decimal places, unless otherwise specified.  
Categorical variables (e.g., presence of an AE) will be summarized using counts and 
percentages. Percentages will be presented to 1 decimal place. Summaries of 
continuous and categorical data will be presented, as appropriate, by treatment, and by 
scheduled time points as specified in the study flow chart.  
Baseline value will be defined as the most recent non-missing measurement collected 
prior to the initial administration of study drug (screening or Day 1), unless otherwise 
specified.  
Incomplete/Missing data: Missing data (e.g., dates, post-baseline values) will not be 
imputed, unless otherwise specified; i.e., all missing values and missing post-baseline 
values will remain as missing in all statistical analyses and listings, unless otherwise 
specified. 
Outliers: No formal statistical analyses will be performed to detect and/or remedy the 
presence of statistical outliers. 
Additionally, all subject data, including derived variables, will be presented in subject 
data listings; listings will display all subjects who were randomized or enrolled in the 
study.   
8.2.2 
Background Characteristics  
8.2.2.1  Subject Disposition 
The number and percentage of subjects in each disposition category (all randomized 
population, all treated population, completed the treatment, completed the study, and 
discontinued early from treatment or study with a breakdown of the reasons for 
discontinuation) will be summarized based on all treated population. 


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8.2.2.2 Demographics and Baseline Characteristics 
Demographics and baseline characteristics (age, sex, race, ethnicity, weight, height and 
body mass index [BMI]) will be summarized. Summary will be based on the all treated 
population.  
8.2.2.3 Study Drug Exposure  
Exposure to each study drug will be summarized based on the all-treated population. 
Study drug exposure will also be presented in an individual subject data listing to 
indicate the date and time of dosing and whether the study drug was taken completely 
or not.  
8.2.3  Efficacy Analysis 
8.2.3.1 Analysis of Primary Efficacy Endpoint 
All variables including myocardial oxygen consumption/FDG ratio, perfusion absolute 
change, perfusion relative change) from metabolic imaging will be summarized and 
listed. Treatment effect will be tested using Analysis of covariance (ANOVA), with 
treatment in the model. If the normality assumption fails, non-parametric method will be 
employed. Difference between Arm 1 and Arm 2 will be summarized and tested using t-
test. Difference between pre and post treatment in Arm 1 ranolazine group will be 
summarized and tested using t-test. Significance will be established at alpha level of 
0.05. The efficacy analysis will be conducted on the all-treated population. 
8.2.3.2 Analysis of Secondary Endpoints 
All variables (RVEF, RV size and RV mass, etc) from CMR imaging will be summarized 
and listed. Treatment effect will be tested using Analysis of covariance (ANOVA), with 
treatment in the model. If the normality assumption fails, non-parametric method will be 
employed. Difference between Arm 1 and Arm 2 will be summarized and tested using t-
test. Difference between pre and post treatment in Arm 1 ranolazine group will be 
summarized and tested using t-test. Significance will be established at alpha level of 
0.05. The efficacy analysis will be conducted on the all-treated population. 
 
Additional exploratory endpoints will be summarized and tested using t-test (paired for 
pre and post data on the same patient, unpaired for Arm 1 and Arm 2 patients). If the 
normality assumption fails, non-parametric method will be employed. 
8.2.4 Safety Analysis 
All analyses/summaries will be based on the all-treated population 
The overall safety profile will be assessed in terms of the following secondary (safety) 
endpoints: 
 Incidence of imaging agent related AEs (AEs attributed to injection of imaging 
tracers or scanning and AEs occurring within 24 hours of imaging agent injection) 
 Vital signs 


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8.2.4.1 Vital Signs 
The following vital signs will be obtained on the imaging day: systolic and diastolic blood 
pressure (mmHg), pulse rate (beats per minute [bpm]), and respiratory rate (breaths per 
minute), and oxygen saturation (%).  
8.3 Subject Population(s) for Analysis 
All efficacy analyses will be performed using all-treated population.  All safety (AE, vital) 
analyses will be performed using all-treated population. Subject populations are 
specified within each of the analyses section.  
9 Safety and Adverse Events 
9.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
 Unexpected in nature, severity, or frequency  (i.e. not described in study-related 
documents such as the IRB-approved protocol or consent form, the investigators 
brochure, etc) 
 Related or possibly related to participation in the research (i.e. possibly related 
means there is a reasonable possibility that the incident experience, or outcome 
may have been caused by the procedures involved in the research) 
 Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm). 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or 
worsens in severity during the course of the study.  Intercurrent illnesses or injuries 
should be regarded as adverse events.  Abnormal results of diagnostic procedures are 
considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
In the following differentiation between medical history and AEs (see below), the term 
“condition” may include abnormal physical examination findings, symptoms, or 
diseases. 
 Conditions that started before signing of informed consent and for which no 
symptoms or treatment are present until signing of informed consent are 
recorded as medical history (e.g. seasonal allergy without acute complaints). 
 Conditions that started before signing of informed consent and for which 
symptoms or treatment are present after signing of informed consent, at 
unchanged intensity, are recorded as medical history. 


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 Conditions that pertain to primary or secondary efficacy variables of this study, 
i.e. findings in CMR and PET and which are considered pre-existing medical 
conditions, are not considered AEs unless there is worsening. This also implies 
that the indication for the imaging procedure and the confirmation of a diagnosis 
will not be considered as an AE. 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is 
any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
 
All adverse events that do not meet any of the criteria for serious should be regarded as 
non-serious adverse events.  
 
Adverse Event Reporting Period 
The study period during which adverse events will be reported is defined as 24 hours 
post injection of the radiotracers.   
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities 
that meet the definition of an adverse event must also be recorded and documented as 
an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events 
are resolved, the subject is lost to follow-up, or the adverse event is otherwise 
explained.  At the last scheduled visit, the investigator should instruct each subject to 
report any subsequent event(s) that the subject, or the subject’s personal physician, 
believes might reasonably be related to participation in this study.  The investigator 
should notify the study sponsor of any death or adverse event occurring at any time 
after a subject has discontinued or terminated study participation that may reasonably 
be related to this study.  The sponsor should also be notified if the investigator should 
become aware of the development of cancer or of a congenital anomaly in a 
subsequently conceived offspring of a subject that has participated in this study.  


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Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed 
otherwise in this protocol.  Any condition responsible for surgery should be documented 
as an adverse event if the condition meets the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are 
reported as an adverse event in the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an 
outcome of an adverse event if the purpose of the surgery was elective or 
diagnostic and the outcome was uneventful. 
 Hospitalization 
or 
prolonged 
hospitalization 
required 
to 
allow 
efficacy 
measurement for the study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study, unless it is a worsening or increase in frequency of hospital admissions as 
judged by the clinical investigator. 
9.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse 
events by specific questioning and, as appropriate, by examination.  Information on all 
adverse events should be recorded immediately in the source document, and also in the 
appropriate adverse event module of the case report form (CRF).  All clearly related 
signs, symptoms, and abnormal diagnostic procedures results should recorded in the 
source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the imaging AE reporting period must be recorded.  
The clinical course of each event should be followed until resolution, stabilization, or 
until it has been determined that the study treatment or participation is not the cause.  
Serious adverse events that are still ongoing at the end of the study period must be 
followed up to determine the final outcome.  Any serious adverse event that occurs after 
the study period and is considered to be possibly related to the study treatment or study 
participation should be recorded and reported immediately. 
9.3 Reporting of Serious Adverse Events and Unanticipated Problems 
Investigators and the protocol sponsor must conform to the adverse event reporting 
timelines, formats and requirements of the various entities to which they are 
responsible, but at a minimum those events that must be reported are those that are: 
 related to study participation, 
 unexpected, and  
 serious or involve risks to subjects or others  
(see definitions, section 8.1).   
 


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If the report is supplied as a narrative, the minimum necessary information to be 
provided at the time of the initial report includes: 
 Study identifier 
 Subject number 
 A description of the event 
 Date of onset 
 Current status 
 Whether study was discontinued 
 The reason why the event is classified as 
serious 
 Investigator 
assessment 
of 
the 
association between the event and study 
drug  
 
9.3.1 Investigator reporting: notifying the study sponsor 
Any study-related unanticipated problem posing risk of harm to subjects or others, and 
any type of serious adverse event, must be reported to the study investigators. Imaging 
related unanticipated problems posing risk of harm to subjects or others, and any type 
of serious adverse event, must be reported to the imaging study sponsor (The 
Department of Radiology) by email within 24 hours of the event.  To report such events, 
a Serious Adverse Event (SAE) form must be completed by the investigator and 
emailed to the study sponsor within 24 hours.  The investigator will keep a copy of this 
SAE form on file at the study site.  Report serious adverse events related to imaging by 
email to the Radiology IND Office Manager. 
 
Within the following 48 hours, the investigator must provide further information on the 
serious adverse event or the unanticipated problem in the form of a written narrative.  
This should include a copy of the completed Serious Adverse Event form, and any other 
diagnostic information that will assist the understanding of the event.  Significant new 
information on ongoing serious adverse events should be provided promptly to the 
study sponsor. 
 
9.3.2 Investigator reporting: notifying the Penn IRB 
This section describes the requirements for safety reporting by investigators who are 
Penn faculty, affiliated with a Penn research site, or otherwise responsible for safety 
reporting to the Penn IRB. The University of Pennsylvania IRB (Penn IRB) requires 
expedited reporting of those events related to study participation that are unforeseen 
and indicate that participants or others are at increased risk of harm.  The Penn IRB will 
not acknowledge safety reports or bulk adverse event submissions that do not meet the 
criteria outlined below.  The Penn IRB requires researchers to submit reports of the 
following problems within 10 working days from the time the investigator becomes 
aware of the event: 
 Any adverse event (regardless of whether the event is serious or non-serious, on-
site or off-site) that occurs any time during or after the research study, which in 
the opinion of the principal investigator is: 


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Unexpected (An event is “unexpected” when its specificity and severity are not 
accurately reflected in the protocol-related documents, such as the IRB-approved 
research protocol, any applicable investigator brochure, and the current IRB-
approved informed consent document and other relevant sources of information, 
such as product labeling and package inserts.) 
AND 
Related to the research procedures (An event is “related to the research 
procedures” if in the opinion of the principal investigator or sponsor, the event was 
more likely than not to be caused by the research procedures.) 
 
Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be 
reported to the Penn IRB using the form: “Unanticipated Problems Posing Risks to 
Subjects or Others Including Reportable Adverse Events” or as a written report of the 
event (including a description of the event with information regarding its fulfillment of the 
above criteria, follow-up/resolution and need for revision to consent form and/or other 
study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in 
the Clinical Investigator’s study file. 
 
Other Reportable events: 
For clinical drug trials, the following events are also reportable to the Penn IRB: 
 Any adverse experience that, even without detailed analysis, represents a serious 
unexpected adverse event that is rare in the absence of drug exposure (such as 
agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome). 
 Any adverse event that would cause the sponsor to modify the protocol or 
informed consent form, or would prompt other action by the IRB to assure 
protection of human subjects. 
 Information that indicates a change to the risks or potential benefits of the 
research, in terms of severity or frequency. For example:  
– An interim analysis indicates that participants have a lower rate of response to 
treatment than initially expected. 
– Safety monitoring indicates that a particular side effect is more severe, or 
more frequent than initially expected. 
– A paper is published from another study that shows that an arm of your 
research study is of no therapeutic value. 
 Change in FDA safety labeling or withdrawal from marketing of a drug, device, or 
biologic used in a research protocol. 
 Breach of confidentiality 
 Change to the protocol taken without prior IRB review to eliminate apparent 
immediate hazard to a research participant. 


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 Incarceration of a participant when the research was not previously approved 
under Subpart C and the investigator believes it is in the best interest of the 
subject to remain on the study. 
 Complaint of a participant when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team. 
 Protocol violation (meaning an accidental or unintentional deviation from the IRB 
approved protocol) that in the opinion of the investigator placed one or more 
participants at increased risk, or affects the rights or welfare of subjects. 
9.3.3 Investigator reporting: Notifying a non-Penn IRB 
Investigators who are not Penn faculty or affiliated with a Penn research site are 
responsible for safety reporting to their local IRB.  Investigators are responsible for 
complying with their local IRB’s reporting requirements, though must submit the 
required reports to their IRB no later than 10 working days.  Copies of each report and 
documentation of IRB notification and receipt will be kept in the investigator’s study file. 
 
9.3.4 Sponsor reporting: Notifying the FDA 
The study sponsor is required to report certain study events in an expedited fashion to 
the FDA.  These written notifications of adverse events are referred to as IND safety 
reports. The following describes the safety reporting requirements by timeline for 
reporting and associated type of event: 
 
 Within 7 calendar days 
Any study event that is: 
– associated with the use of the study drug 
– unexpected,  
– fatal or life-threatening, and  
 
 Within 15 calendar days 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later 
found to fit the criteria for reporting (reporting within 15 calendar days from 
when event was deemed reportable). 
Any finding from tests in laboratory animals that:  
– suggest a significant risk for human subjects including reports of mutagenicity, 
teratogenicity, or carcinogenicity. 
 
Additional reporting requirements 


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Sponsors are also required to identify in IND safety reports all previous reports 
concerning similar adverse events and to analyze the significance of the current event 
in light of the previous reports. 
 
9.3.5 Sponsor reporting: Notifying participating investigators 
It is the responsibility of the study sponsor to notify all participating investigators, in a 
written IND safety report, of any adverse event associated with the use of the drug that 
is both serious and unexpected, as well as any finding from tests in laboratory animals 
that suggest a significant risk for human subjects.  Additionally, sponsors are also 
required to identify in IND safety reports all previous reports concerning similar adverse 
events and to analyze the significance of the current event in light of the previous 
reports. 
 
9.4 Safety Monitoring 
Subject safety will be monitored continuously by the Investigators.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events 
and a regular assessment of the number and type of serious adverse events. 
9.5 Data and Safety Monitoring Board 
An independent DSMB will be established to assure the safety of participants as well as 
the validity and integrity of the data generated in both this trial and the companion 
treatment study.  The DSMB will meet every 6 months to review the study for safety, 
progress towards completion and overall study conduct.  The membership of the DSMB 
as well as the responsibilities and procedures used to carry out these responsibilities 
are described separately in the DSMB charter.    
 
10 Data Handling and Record Keeping 
10.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a signed subject authorization informing the subject 
of the following:  
 What protected health information (PHI) will be collected from subjects in this 
study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use 


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PHI, attempts should be made to obtain permission to collect at least vital status (i.e. 
that the subject is alive) at the end of their scheduled study period. 
10.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents.  Examples of these original 
documents, and data records include: hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the 
clinical trial. 
 
Source documents for the imaging protocol will be kept in a secure location by the Penn 
principal investigator or her designee.  Source documents for the treatment protocol will 
be kept in a secure location at the site where the subject participates. 
10.3 Data Management Plan 
We will create a shared database with common data definitions.  This database will be 
programmed in REDCap (Research Electronic Data Capture).  REDCap is a secure, 
web-based application with the capacity for direct export to Excel and common 
statistical packages (SPSS, SAS, Strata, R).  REDCap has electronic CRF (eCRF)s, 
real-time data entry validation, audit trails, user authentication, data logging and 
encryption.  It is HIPAA compliant with mechanisms in place to ensure confidentiality. 
 
Specific forms will be used for each component of the subject’s progress.  The forms 
and data dictionary will be available online for all individuals who perform data entry.  
Research personnel, trained on data definitions, will enter data via web-based data 
forms after abstraction from the primary medical record and source documents.  The 
multisite feature of REDCap will be used to restrict data viewing by investigators. 
 REDCap allows double-data entry on some or all of the data elements. We will apply 
this feature to predefined “key” variables.  In addition, logical data checks will be used to 
assess data quality for mis-entry.  Suspect data entries will be flagged for re-review and 
confirmation by the investigative team at each site.  When data are complete and all 
suspect entries addressed for a time period, the database will be “locked” for analysis. 
 Analysis will use only this final locked version. 
 
10.4 Data Sharing Plan 
Clinical data will be exported from REDCap into proper statistical software format for 
analysis.   The final dataset will be provided in proper format to investigators 
participating in data analysis from each site.  The mode of data sharing will be by 
downloading from REDCap from secure accounts.  Data will be secured by electronic 


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safeguards.  Image data will be shared between two institutions, UPenn and BWH, 
through the BMIC Secure Computing Environment.  The BMIC Secure Computing 
Environment is used by a number of entities across the Perelman School of Medicine.   
Individual users of the system include investigators and research personnel using the 
secure file server and statisticians using high performance analytic servers.  The BMIC 
supplies individual accounts to all users and a basic online safety course to ensure that 
users know how to make use of the servers safely and securely. UMD will have access 
to the final result of the image data, but not the raw images.  Prior to sharing, all data 
and all images will be anonymized to strip all identifiers to protect the human 
participants.   
 
10.5 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 
years after the last approval of a marketing application in their country and until there 
are no pending or contemplated marketing applications in their country or at least 2 
years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  These documents should be retained for a longer period if 
required by an agreement with the sponsor.  In such an instance, it is the responsibility 
of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained.  
 
11 Study Monitoring, Auditing, and Inspecting 
11.1 Study Monitoring Plan 
The Principal Investigator is responsible for assigning staff for preliminary monitoring of 
study files.  Staff members are required to review all subject binders for completion and 
accuracy. This review will be documented.  The investigative team will meet after 
Subject 1 to review the study flow and to discuss any issues that occurred.  This 
meeting will be documented.   The Sponsor will also supply a monitor for the below 
plan. The investigator will allocate adequate time for such monitoring activities.  The 
Investigator will also ensure that the monitor or other compliance or quality assurance 
reviewer is given access to all requested study-related documents and facilities if 
necessary. 
Frequency 
Enrollment will be complete when up to 54 subjects are enrolled into the trial.   
Approximately 4 subjects will be enrolled per month.  Monitoring will be conducted 
periodically throughout the study as described below.   
 
 The first monitoring session will occur after the first two subjects have been 
enrolled. 
 


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 A second monitoring session will be conducted when approximately 25% of 
the subjects have been enrolled. 
 
 A third monitoring session will be conducted when approximately 50% of 
the subjects have been enrolled..  
 
 A fourth monitoring session will be conducted when approximately 75% of 
the subjects have been enrolled.  
 
 A fifth monitoring session will be conducted after 100% of the subjects 
have been enrolled.  This visit may be conducted after the subjects have 
completed the study and can also serve as the close-out monitoring visit. 
Data Review 
Enrollment will be complete when up to 54 subjects are enrolled into the trial.   
Approximately 4 subjects will be enrolled per month.  Monitoring will be conducted 
periodically throughout the study as described below.   
 
 Electronic CRFs for the first 2 subjects will be 100% source data verified.  In 
addition, the eCRF for at least an additional 4 randomly selected subjects will 
be 100% source data verified at each additional monitoring session.   
 
 If a greater than 10% error rate is noted during the data review, this 
monitoring plan may be revised and more subject files may be 100% source 
data verified.   
Additional subjects/events to be reviewed: 
All subjects who discontinued due to serious adverse events will be reviewed for key 
safety and efficacy data.  
 
11.2 Regulatory Documents Reviewed 
The Regulatory Documents will be maintained in the Regulatory Binder.  The 
Regulatory Binder may be reviewed by the monitor during any visit.  The monitor will 
review the regulatory binder for completeness and will assure that the eCRFs are being 
completed.      
11.3  Documentation of the Monitoring Visit 
All monitoring visits will be documented on the Monitor’s Report and Visit Checklist.    
The original report for each visit will be filed in the Sponsor section of the Regulatory 
Binder.  The Sponsor will also retain a copy of this report. 
 


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11.4 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the 
EC/IRB, the sponsor, government regulatory bodies, and University compliance and 
quality assurance groups of all study related documents (e.g. source documents, 
regulatory documents, data collection instruments, study data etc.).  The investigator 
will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection 
by government regulatory authorities and applicable University compliance and quality 
assurance offices. 
 
12 Ethical Considerations 
This study is to be conducted accordance with applicable US government regulations 
and international standards of Good Clinical Practice, and applicable institutional 
research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of the IRB concerning the conduct of the 
study will be made in writing to the investigator and a copy of this decision will be 
provided to the sponsor before commencement of this study.  The investigator should 
provide a list of IRB members and their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study.  This consent form will be submitted with the protocol for 
review and approval by the IRB for the study.  The formal consent of a subject, using 
the IRB-approved consent form, must be obtained before that subject undergoes any 
study procedure.  The consent form must be signed by the subject or legally acceptable 
surrogate, and the investigator-designated research professional obtaining the consent.  
13 Study Finances 
13.1 Funding Source 
 
Cardiovascular Medical Research and Education Fund 
 
13.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) 
must have the conflict reviewed by a properly constituted Conflict of Interest Committee 
with a Committee-sanctioned conflict management plan that has been reviewed and 


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approved by the study sponsor prior to participation in this study.  All University of 
Pennsylvania investigators will follow the applicable University conflict of interest 
policies. 
13.3 Subject Stipends or Payments 
 
Subjects will be compensated $100 at baseline imaging visits and at the completion of 
the study imaging visits. Therefore, subjects will receive a total of $200 if attending all 
the study imaging visits.  Transportation fees and overnight hotel for patients from 
University of Maryland will be reimbursed up to $400 per visit in addition to the $100 
subject stipend.  
 
14 Publication Plan 
A Publication Committee will include Drs. Han, Park, and Waxman, and will be open to 
co-investigators and collaborators.  The purpose of the Publication Committee is to 
effectively manage and oversee the primary, secondary and ancillary publications 
generated from the study while complying with all applicable guidelines and policies.  
This includes delivering high-quality publications that address the primary evidence 
needs identified and prioritized by any collaborators, co-investigators, and the 
Publication Committee. 
 
15 References 
 
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and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest. 2009;135:794-804 
2. 
Ryan J, Bloch K, Archer SL. Rodent models of pulmonary hypertension: Harmonisation with the 
world health organisation's categorisation of human ph. Int J Clin Pract Suppl. 2011:15-34 
3. 
Tuder RM, Davis LA, Graham BB. Targeting energetic metabolism: A new frontier in the 
pathogenesis and treatment of pulmonary hypertension. Am J Respir Crit Care Med. 2011;185:260-266 
4. 
Lee JK, Kodama I, Honjo H, Anno T, Kamiya K, Toyama J. Stage-dependent changes in 
membrane currents in rats with monocrotaline-induced right ventricular hypertrophy. Am J Physiol. 
1997;272:H2833-2842 
5. 
Sharma S, Taegtmeyer H, Adrogue J, Razeghi P, Sen S, Ngumbela K, Essop MF. Dynamic 
changes of gene expression in hypoxia-induced right ventricular hypertrophy. Am J Physiol Heart Circ 
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6. 
Kleiman RB, Houser SR. Outward currents in normal and hypertrophied feline ventricular 
myocytes. Am J Physiol. 1989;256:H1450-1461 
7. 
Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thebaud B, Haromy A, Harry G, 
Moudgil R, McMurtry MS, Weir EK, Archer SL. An abnormal mitochondrial-hypoxia inducible factor-
1alpha-kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn 
hooded rats: Similarities to human pulmonary arterial hypertension. Circulation. 2006;113:2630-2641 
8. 
Michelakis E, McMurtry M, Wu X, Dyck J, Moudgil R, Hopkins T, Lopaschuk G, Puttagunta L, 
Waite R, Archer S. Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic 
pulmonary hypertension in rats: Role of increased expression and activity of voltage-gated potassium 
channels. Circulation. 2002;105:244-250 
9. 
Piao L, Fang YH, Cadete VJ, Wietholt C, Urboniene D, Toth PT, Marsboom G, Zhang HJ, Haber 
I, Rehman J, Lopaschuk GD, Archer SL. The inhibition of pyruvate dehydrogenase kinase improves 


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impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: 
Resuscitating the hibernating right ventricle. J Mol Med (Berl). 2010;88:47-60 
10. 
Oikawa M, Kagaya Y, Otani H, Sakuma M, Demachi J, Suzuki J, Takahashi T, Nawata J, Ido T, 
Watanabe J, Shirato K. Increased [18f]fluorodeoxyglucose accumulation in right ventricular free wall in 
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Basu S, Alzeair S, Li G, Dadparvar S, Alavi A. Etiopathologies associated with intercostal muscle 
hypermetabolism and prominent right ventricle visualization on 2-deoxy-2[f-18]fluoro-d-glucose-positron 
emission tomography: Significance of an incidental finding and in the setting of a known pulmonary 
disease. Mol Imaging Biol. 2007;9:333-339 
12. 
Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J, Pepine CJ, Wang W, Nelson 
JJ, Hebert DA, Wolff AA. Anti-ischemic effects and long-term survival during ranolazine monotherapy in 
patients with chronic severe angina. J Am Coll Cardiol. 2004;43:1375-1382 
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Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, Wang W, Skettino SL, 
Wolff AA. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina 
frequency in patients with severe chronic angina: A randomized controlled trial. JAMA. 2004;291:309-316 
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Clarke B, Spedding M, Patmore L, McCormack JG. Protective effects of ranolazine in guinea-pig 
hearts during low-flow ischaemia and their association with increases in active pyruvate dehydrogenase. 
Br J Pharmacol. 1993;109:748-750 
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Clarke B, Wyatt KM, McCormack JG. Ranolazine increases active pyruvate dehydrogenase in 
perfused normoxic rat hearts: Evidence for an indirect mechanism. J Mol Cell Cardiol. 1996;28:341-350 
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Fang YH, Piao L, Hong Z, Toth PT, Marsboom G, Bache-Wiig P, Rehman J, Archer SL. 
Therapeutic inhibition of fatty acid oxidation in right ventricular hypertrophy: Exploiting randle's cycle. J 
Mol Med (Berl). 2012;90:31-43 
17. 
Hasenfuss G, Maier LS. Mechanism of action of the new anti-ischemia drug ranolazine. Clin Res 
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