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
Phase: PHASE4
Conditions: Pulmonary Hypertension
Sponsor: University of Pennsylvania

 
CLINICAL RESEARCH PROTOCOL 
 
 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED, MULTI-CENTER STUDY TO ASSESS 
THE EFFECTS OF RANOLAZINE IN SUBJECTS WITH PULMONARY HYPERTENSION AND RIGHT 
VENTRICULAR DYSFUNCTION ACCOMPANIED BY  A COMPARATIVE STUDY OF CELLULAR 
METABOLISM INSUBJECTS WITH PULMONARY HYPERTENSION WITH AND WITHOUT RIGHT 
VENTRICULAR DYSFUNCTION  
 
 
 
 
Funding Sponsor: 
 
Cardiovascular Medical Research and Education Fund  
Gilead Science Inc  
 
Study Product: 
 
Ranolazine   
 
 
 
 
 
Initial version:  v1 May 29, 2013 
Amended: 
 v2 September 16, 2013 
Amended:         v3 January 15, 2014 
Amended:         v4 April 8, 2014 
Amended:         v5 February 4, 2015 
Amended:         v6 December 16, 2015 
 
 

Targeting RV in PAH 
 
Page 2 
Version6  
 
 
Table of Contents 
 
1 
STUDY FLOWCHART FOR ARM 1 .................................................................................................... 6 
2 
INTRODUCTION ................................................................................................................................ 10 
2.1 
BACKGROUND .............................................................................................................................. 10 
2.2 
INVESTIGATIONAL AGENT .............................................................................................................. 11 
2.2.1 
Ranolazine ............................................................................................................................. 11 
2.3 
PRECLINICAL DATA ...................................................................................................................... 12 
2.4 
CLINICAL DATA TO DATE............................................................................................................... 12 
2.4.1 
Ranolazine ............................................................................................................................. 12 
2.5 
DOSE RATIONALE AND RISK/BENEFITS .......................................................................................... 13 
3 
STUDY OBJECTIVES ....................................................................................................................... 13 
4 
STUDY DESIGN ................................................................................................................................. 13 
4.1 
GENERAL DESIGN ........................................................................................................................ 13 
4.2 
PRIMARY STUDY ENDPOINTS ........................................................................................................ 14 
4.3 
EXPLORATORY ENDPOINTS ........................................................................................................... 14 
4.3.1 
Outcomes .............................................................................................................................. 14 
4.3.2 
Health outcomeSF-36 ........................................................................................................... 15 
4.3.3 
microRNA and iPS ................................................................................................................ 15 
4.4 
PRIMARY SAFETY ENDPOINTS ....................................................................................................... 15 
5 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................. 15 
5.1 
INCLUSION CRITERIA .................................................................................................................... 15 
5.2 
EXCLUSION CRITERIA ................................................................................................................... 16 
5.3 
EARLY WITHDRAWAL OF SUBJECTS .............................................................................................. 17 
5.3.1 
When and How to Withdraw Subjects ................................................................................... 17 
6 
STUDY DRUG .................................................................................................................................... 18 
6.1 
DESCRIPTION ............................................................................................................................... 18 
6.2 
TREATMENT REGIMEN .................................................................................................................. 18 
6.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ....................................................... 18 
6.4 
PREPARATION, PACKAGING AND ADMINISTRATION OF STUDY DRUG ............................................... 19 
6.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................. 19 
6.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................. 19 
6.7 
BLINDING OF STUDY DRUG ........................................................................................................... 19 
6.8 
RECEIVING, STORAGE, DISPENSING AND RETURN .......................................................................... 20 
6.8.1 
Receipt of Drug Supplies ....................................................................................................... 20 
6.8.2 
Storage .................................................................................................................................. 20 
6.8.3 
Dispensing of Study Drug ...................................................................................................... 20 
6.8.4 
Return or Destruction of Study Drug ..................................................................................... 20 
7 
STUDY PROCEDURES ..................................................................................................................... 20 
7.1 
INFORMED CONSENT .................................................................................................................... 20 
7.2 
SCREENING PROCEDURES ............................................................................................................ 20 
7.3 
TREATMENT PERIOD .................................................................................................................... 21 
7.4 
CONCLUSION OF TREATMENT PERIOD ........................................................................................... 22 
7.5 
LONG TERM FOLLOW-UP .............................................................................................................. 22 
8 
METHODS .......................................................................................................................................... 22 
8.1 
CMR IMAGING ............................................................................................................................. 22 
8.1.1 
CMR Imaging Protocol .......................................................................................................... 22 
8.1.2 
Analysis of CMR data ............................................................................................................ 22 

Targeting RV in PAH 
 
Page 3 
Version6  
 
8.2 
METABOLON/MICRORNA/IPS ....................................................................................................... 22 
8.2.1 
Procedure .............................................................................................................................. 22 
8.2.2 
Analysis of Metabolon data ................................................................................................... 23 
8.2.3 
Analysis of MicroRNA data .................................................................................................... 23 
8.2.4 
Analysis of iPS ....................................................................................................................... 23 
8.3 
HEALTH OUTCOMES ASSESSMENT ................................................................................................ 23 
8.4 
LABORATORY DETERMINATIONS .................................................................................................... 23 
9 
STATISTICAL PLAN ......................................................................................................................... 24 
9.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 24 
9.2 
STATISTICAL METHODS ................................................................................................................ 24 
9.2.1 
General Considerations ......................................................................................................... 24 
9.2.2 
Background Characteristics .................................................................................................. 24 
9.2.3 
Efficacy Analysis.................................................................................................................... 25 
9.2.4 
Safety Analysis ...................................................................................................................... 26 
9.3 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 27 
10 
SAFETY AND ADVERSE EVENTS ................................................................................................... 27 
10.1 
DEFINITIONS ................................................................................................................................ 27 
10.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 29 
10.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................. 29 
10.3.1 
Investigator reporting: notifying the Penn IRB .................................................................. 30 
10.3.2 
Investigator reporting: Notifying a non-Penn IRB ............................................................. 31 
10.4 
MEDICAL MONITORING ................................................................................................................. 31 
10.5 
DATA AND SAFETY MONITORING BOARD ....................................................................................... 32 
11 
DATA HANDLING AND RECORD KEEPING ................................................................................... 32 
11.1 
CONFIDENTIALITY ......................................................................................................................... 32 
11.2 
SOURCE DOCUMENTS .................................................................................................................. 32 
11.3 
DATA MANAGEMENT PLAN ............................................................................................................ 32 
11.4 
DATA SHARING PLAN ............................................................................................................... 3332 
11.5 
RECORDS RETENTION .................................................................................................................. 33 
11.6 
MANAGEMENT OF INFORMATION FOR MULTI-CENTER RESEARCH ................................................... 33 
12 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 33 
12.1 
STUDY MONITORING PLAN ............................................................................................................ 33 
12.2 
REGULATORY DOCUMENTS REVIEWED .......................................................................................... 33 
12.3 
AUDITING AND INSPECTING ........................................................................................................... 33 
13 
ETHICAL CONSIDERATIONS .......................................................................................................... 34 
14 
STUDY FINANCES ............................................................................................................................ 34 
14.1 
FUNDING SOURCE ........................................................................................................................ 34 
14.2 
CONFLICT OF INTEREST ................................................................................................................ 34 
14.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................... 34 
15 
PUBLICATION PLAN ........................................................................................................................ 34 
16 
REFERENCES ............................................................................................................................... 3534 
 
 
 

Targeting RV in PAH 
 
Page 4 
Version6  
 
 
List of Abbreviations and Definitions 
 
 
 
AE 
Adverse event 
BID 
Twice a day 
BWH 
Brigham and Woman’s Hospital 
CMR 
cardiovascular MRI 
ECG  
Electrocardiography 
Echo 
echocardiography 
HRCT 
High resolution CT 
IDS 
Investigational drug service 
iPS 
Induced pluripotent stem cell 
LV 
Left ventricle 
UMD 
University of Maryland 
UPenn / Penn 
University of Pennsylvania 
PAH  
Pulmonary hypertension 
PAP 
Pulmonary artery pressure 
PCWP 
pulmonary capillary wedge pressure 
PET 
positron emission tomography 
PO 
To take orally 
PVR 
Pulmonary vascular resistance 
RHC 
Right heart catheterization  
RV 
Right ventricle 
RVEF 
Right ventricle ejection fraction 
WHO 
World Health Organization 
6MWT 
eCRF 
6 minute walk test 
Electronic case report form 
Evaluable population 
The evaluable population is defined as all subjects who have no protocol 
violations that could confound the interpretation of study results, receive at 
least 3 months of the test article. If the subject discontinues due to side 
effect or disease progression, clinical assessment of disease progression is 
adequate.   
Protocol violation 
Departure from the protocol that has a significant effect on the subject’s 
rights, safety, or welfare, and/or the integrity of the resultant study data 
(i.e., the sponsor’s ability to use the data in support of the product). 
Prospective waivers for deviations from the eligibility criteria will not be 
granted.  
Regulation 
The term regulation refers to all applicable regulations, laws, and 
guidelines.  The regulations may be international, national, or local and 
may include but are not limited to the US Code of Federal Regulations; the 
European Clinical Trials Directive; the Good Clinical Practice: Consolidated 
Guideline (Canada); the International Conference on Harmonisation 
Guideline for Good Clinical Practice; the Pharmaceutical Affairs Law and 
Good Clinical Practice (Japan); the Therapeutic Goods Administration 
Annotated 
International 
Conference 
on 
Harmonization 
Guidelines 
(Australia); and the World Medical Association Declaration of Helsinki: 
Ethical Principles for Medical Research Involving Human Subjects. 
Regulatory agency 
The term regulatory agency refers to all health and regulatory agencies 
with oversight responsibility for the study.  These may be international, 
national, or local and may include but are not limited to the Australian 
Therapeutic Goods Administration (TGA); the Canadian Health Products 
and Food Branch (HPFB); the European Medicines Agency (EMEA); the 
Japanese Ministry of Health, Labor, and Welfare (MHLW); the Japanese 
Pharmaceuticals and Medical Devices Agency (PMDA); the US Food and 

Targeting RV in PAH 
 
Page 5 
Version6  
 
Drug Administration (FDA), etc. 
Sponsor 
The term sponsor refers but is not limited to the sponsors listed in the front 
of this document and any contract research organization that is being used 
for the study. 
Subject 
A participant in a clinical study.  A subject may be healthy or have a 
disease.  For obtaining informed consent, this term also includes legally 
acceptable representative where applicable. 
Test article 
For test article accountability, this term applies to such test articles as 
required by this protocol and supplied (shipped) by the sponsor. In this 
study, the term test article refers to ranolazine or placebo. 
Woman of childbearing 
potential 
A woman of childbearing potential is defined as one who is biologically 
capable of becoming pregnant. This includes women who are using 
contraceptives or whose sexual partners are either sterile or using 
contraceptives. 
 
 
 
 
 

Targeting RV in PAH 
 
Page 6 
Version6  
 
1 
Study Flowchart for ARM 1 
 
Treatment Period b 
 
Study Procedure 
Screening a 
Interim visit  
End of 
Treatment Visit  
4 Week Post 
Ranolazine 
Follow-up  
 
-4 to 0 
1 to 4 months post 
randomization 
    wk26 
(+/-1 
month) or earlier if 
endpoint occurs 
4 weeks post 
end of 
treatment 
visit(+2 
weeks) 
Informed consent 
X 
 
 
 
Demographic data 
X 
 
 
 
Medical History 
X 
 
 
 
Cardiac & Pulmonary History 
X 
 
 
 
Inclusion & exclusion criteria 
X 
 
 
 
Randomization 
X 
 
 
 
Plasma samples for biomarker 
analysis 
X 
 
X  
 
iPS and miRNAg 
X 
 
 
 
Clinic visit  
X d 
X d 
X d 
 
Physical exam/6MWT  
X d 
X d 
X d 
 
Vital signs  
X d 
X d 
X d 
 
Borg dyspnea index 
X d 
X d 
X d 
 
WHO functional class 
X d 
X d 
X d 
 
Health outcome 
       X  
X  
X  
 
Medications  
 
Continually (reported every 4 Weeks) 
X 
Adverse event monitoring  
 
Continually (reported every 4 Weeks) 
X 
ECG  
X d 
X d 
X d 
 
ECHO  
X d 
 
X d 
 
CMR  
X d 
 
X 
 
Liver function tests  
X d 
X d 
X d 
 
CBC with differential  
X d 
X d 
X d 
 
Chemistry 10  
X d 
X d 
X d 
 
Coagulation tests  
X d 
X d 
X d 
 
Uric acid, CRP, ANA, NT-
proBNP, total protein, albumin 
X d 
X d 
X d 
 
Pregnancy test (β-HCG)  
X d 
X d 
X d 
 
Right Heart Catheterization 
X d 
 
 
 
Drug dispense/reconciliation 
X f 
X  
X 
 

Targeting RV in PAH 
 
Page 7 
Version6  
 
Footnotes to Study Flowchart: 
 
a. The screening evaluation must be completed within 28 days before enrollment unless otherwise 
noted. AE/SAE data collection begins when the informed consent form is signed. 
b. The treatment period is defined as the period of time from the start of treatment until there is 
evidence of disease progression, or the subject is withdrawn from treatment, and includes the 2 
days after the last dose of test article. 
c. Vital signs include pulse, blood pressure, and O2 saturation.  Oral, tympanic, axillary, or core 
temperature will also be collected if done per routine clinical care. 
d. Indicates done standard of care. Results from clinic visit/procedure will be used for research data.  
Procedures and tests not done per standard of care will not be considered protocol deviations.  
These may be performed as research tests at the discretion of the Investigator (excluding right 
heart catheterization).  Right heart catheterization is not required, only performed on clinical 
indication prior to randomization will be used for research data.  
e. Randomization to ranolazine or placebo occurs on Day 1 
f. 
Drug is dispensed at randomization and 3 months later.  Drug reconciliation is performed at 3 
months clinical visit and at 6 month end of treatment visit.  
g. Participation in iPS and miRNA is optional. Samples can be collected any time prior to 
randomization. 
 
 

Targeting RV in PAH 
 
Page 8 
Version6  
 
Study Summary 
Title 
A randomized, double-blind, placebo controlled, multi-center study to assess 
the effect of ranolazine 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 
Short Title 
Targeting RV in PAH 
Study Design 
This study is a randomized, double-blind, placebo controlled, multi-center 
proof-of-concept study in 30 male or female subjects with pulmonary 
hypertension (PAH) and RV dysfunction (Arm 1) accompanied by an 
observational arm of 10 subjects without RV dysfunction (Arm 2).  
 
 
Arm 1: Incident (Stratum I) and prevalent (Stratum P) subjects with 
clinically indicated CMR RVEF < 45% who will be randomized to 
placebo (10 subjects) and ranolazine (20 subjects).  
 
 
Arm 2: Incident (Stratum I) and prevalent (Stratum P) subjects with 
clinically indicated CMR RVEF ≥ 45% who are RV controls (Arm 2 = 
10 subjects).   These “good RV” subjects will be followed in the 
observational arm and will be reevaluated in 6 months (optional).  
 
Stratum I refers to incident subjects. Stratum P refers to prevalent subjects. 
Each subject will be in the study for up to 46 weeks. The study includes a 
screening period, a treatment period, and a follow-up period. The screening 
period will be up to 4 weeks in length, the treatment period will be up to 26 
weeks, and follow-up period will be 4 weeks.  For incident patients, this means 
12 weeks of stable therapy prior to screening and up to 4 weeks before 
enrollment and 30 weeks of follow up.  For prevalent patients, this means 4 
weeks of screening and 30 weeks of follow up.  The follow-up period is 
optional for subjects in Arm 2.  Participation in the study is defined as the 
whole time period from signing and dating the informed consent form until 
study completion (or withdrawal of consent) or early discontinuation from the 
study.  
Subjects in Arm1 will receive ranolazine or placebo at 500mg PO BID and after 
two weeks will increase to 1000mg PO BID.  Subjects will continue at 1000mg 
BID for the duration of the study.  Subjects with adverse reactions that are 
difficult to tolerate will be down titrated to 500mg BID. Subjects on moderate 
CYP3A inhibitors will be limited to 500mg BID. 
Subjects in Arm 2 will have baseline studies performed and be observed over 
6 month (optional) and have 6-month studies performed (optional).  
Subjects who meet all entry criteria will be scheduled to return to the clinic for 
the startup visit.   After the start up visit, subjects will be seen as per standard 
clinical practice.   We will conduct a check in by telephone q4 weeks and see 
patients more frequently as clinically indicated.  
At baseline (week 0), interim (at drug reconciliation visit) and the conclusion of 
the treatment period (week 26) subjects will be assessed for functional class, 
6- MWD, and health outcome based on SF-36 tool. Peripheral blood will be 
obtained for metabolic profiling at baseline and the conclusion of the treatment 
period.  Subjects will have baseline CMR done per standard of care or may 
enroll in a separate imaging protocol and undergo the baseline CMR as a 
research scan. 

Targeting RV in PAH 
 
Page 9 
Version6  
 
Study Center(s) 
Multicenter, 4 sites: 
University of Pennsylvania  
Brigham and Women’s Hospital  
University of Maryland 
Washington University 
Primary Objective 
1. To demonstrate that there are differences in metabolism between 
subjects with normal RV function and persistent RV dysfunction as 
defined by CMR RVEF of <45%.  
2. To demonstrate that treatment with ranolazine improves RV energetic 
and contractility in the subjects with persistent RV dysfunction as 
measured by imaging.   
Exploratory Objective 
To evaluate the effects of ranolazine in subjects with PAH on stable 
background therapy and persistent RV dysfunction. 
Number of Subjects 
Approximately 40 subjects will participate in this study (account 20% early 
withdrawal) 
Diagnosis and Main 
Inclusion Criteria 
Planned enrollment will include up to 40 NYHA class II/III/IV PAH subjects. For 
incident subjects, they will have a clinical right heart catheterization (RHC) 
which must document a mean PAP ≥25 mmHg, PVR >3WU (>240 dyne⋅
sec/cm5), and pulmonary capillary wedge pressure (PCWP) or LV end 
diastolic pressure ≤15 mmHg. These subjects will have to be on stable therapy 
with no medication change for at least 12 weeks before screening. For 
prevalent subjects, they need to have a prior RHC that documented the 
criteria. 
Study Product, Dose, 
Route, 
Regimen, 
Duration 
Subjects in Arm1 will receive ranolazine or placebo at 500mg PO BID and after 
two weeks will increase to 1000mg PO BID and continue for a total of 26 
weeks.   
Reference therapy 
Placebo    
Statistical 
Methodology 
This trial is designed to understand the the impact of ranolazine on RV 
function. We’ll be examining different imaging markers as continuous variables 
comparing the difference pre and post drug treatment. 
 

Targeting RV in PAH 
 
Page 10 
Version6  
 
2 
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.  
2.1 
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 dysfunction and PAH, and could be readily “re-purposed” as an already FDA-approved 
medication.  
 
In addition to PDH, other metabolic factors likely exist that are dysregulated in RV failure and primarily 
drive pathogenesis. 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. While deficiencies in BMPR219-23 or ALK124 predispose to the development of PAH and 
theoretically could affect RV function, such mutations are unlikely to be the only genetic factors involved. 
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 metabolism25 and known alterations in right ventricular failure26, changes in 
microRNA (miRNA) expression, which are small, non-coding RNA that negatively regulate gene 
expression, could also underlie such a predisposition to metabolic dysfunction of the RV. Furthermore, 
similar to secreted metabolites, miRNA could be released from injured myocardium27 and could thus 
serve as disease biomarkers. However, the lack of a clear familial pattern of inheritance of RV 

Targeting RV in PAH 
 
Page 11 
Version6  
 
dysfunction, accompanied by the relatively small PAH patient population, limits the utility of large scale 
genomic sequencing or genome wide association study alone to identify the existence of these factors. 
On the other hand, inducible pluripotent stem cell (iPSC) technology (whereby patient-specific fibroblasts 
are reprogrammed into iPSCs and are re-differentiated into cardiomyocytes)28-35 presents a viable 
opportunity to explore the genetic deficiencies of RV failure through the in vitro study of patient-specific 
deficiencies in cardiomyocyte metabolism.  
 
2.2 
Investigational Agent 
2.2.1 
Ranolazine 
2.2.1.1 
Description 
Ranexa™ (ranolazine) is available as an extended-release tablet for oral administration. 
Ranolazine is a racemic mixture and chemically described as 1-piperazineacetamide, N -(2,6-
dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-, (±)-. It has an empirical formula of 
C24H33N3O4, a molecular weight of 427.54 g/mole, and the following structural formula: 
 
Ranolazine is a white to off-white solid. Ranolazine is soluble in dichloromethane and methanol; sparingly 
soluble in tetrahydrofuran, ethanol, acetonitrile, and acetone; slightly soluble in ethyl acetate, isopropanol, 
toluene, and ethyl ether; and very slightly soluble in water. 
Ranexa is available for oral administration as film-coated, extended-release tablets containing 500 mg of 
ranolazine. Inactive ingredients of the 500 mg tablet include carnauba wax, hypromellose, magnesium 
stearate, methacrylic acid copolymer (Type C), microcrystalline cellulose, polyethylene glycol, polysorbate 
80, sodium hydroxide, titanium dioxide, and FD&C Yellow #6 Lake. 
2.2.1.2 
Mechanism of Action 
Ranexa has antianginal and anti-ischemic effects that do not depend upon reductions in heart rate or 
blood pressure. The mechanism of action of ranolazine is unknown. It does not increase the rate-
pressure product, a measure of myocardial work, at maximal exercise. 
2.2.1.3 
Pharmacokinetics 
Ranolazine is extensively metabolized in gut and liver and its absorption is highly variable. For example, 
at a dose of 1000 mg b.i.d., the mean steady state Cmax was 2569 ng/mL; 95% of Cmax values were 
between 420 and 6080 ng/mL. The pharmacokinetics of the (+) R and (-) S-enantiomers of ranolazine are 
similar in healthy volunteers. The apparent terminal half-life of ranolazine is 7 hours. Steady-state is 
generally achieved within 3 days of b.i.d. dosing with Ranexa. At steady-state over the dose range 500 to 
1000 mg b.i.d., Cmax and AUC0-τ increase slightly more than proportionally to dose, 2.2- and 2.4-fold, 
respectively. With twice daily dosing, the peak/trough ratio of the ranolazine plasma concentration is 1.6 
to 3.0. 

Targeting RV in PAH 
 
Page 12 
Version6  
 
2.2.1.4 
Absorption and Distribution 
After oral administration of Ranexa peak plasma concentrations of ranolazine are reached between 2 and 
5 hours. After oral administration of 14C-ranolazine as a solution, 73% of the dose is systemically 
available as ranolazine or metabolites. The bioavailability of ranolazine from Ranexa relative to that from 
a solution of ranolazine is 76%. Because ranolazine is a substrate of P-glycoprotein (P-gp), inhibitors of 
P-gp may increase the absorption of ranolazine. 
 
Food (high fat breakfast) has no important effect on the Cmax and AUC of ranolazine. Therefore, Ranexa 
may be taken without regard to meals. Over the concentration range of 0.25 to 10 µg/mL, ranolazine is 
approximately 62% bound to human plasma proteins. 
2.2.1.5 
Metabolism and Excretion 
Following a single oral dose of ranolazine solution, approximately 75% of the dose is excreted in urine 
and 25% in feces. Ranolazine is metabolized rapidly and extensively in the liver and intestine; less than 
5% is excreted unchanged in urine and feces. The pharmacologic activity of the metabolites has not been 
well characterized. After dosing to steady-state with 500 mg to 1500 mg b.i.d., the four most abundant 
metabolites in plasma have AUC values ranging from about 5 to 33% that of ranolazine, and display 
apparent half-lives ranging from 6 to 22 hours. Ranolazine is metabolized mainly by CYP3A and to a 
lesser extent by CYP2D6. 
 
2.3 
Preclinical Data 
 
2.3.1. 
Ranolazine 
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.  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 overload17. Recently, in a rodent model of RVH, ranolazine was 
reported to successfully reverse metabolic dysfunction and improve cardiac output and exercise 
capacity16.  
 
2.4 
Clinical Data to Date 
2.4.1 
Ranolazine 
Ranolazine has been evaluated in patients with chronic angina who remained symptomatic despite 
treatment with the maximum dose of an antianginal agent. In the ERICA 36(Efficacy of Ranolazine In 
Chronic Angina) trial, 565 patients were randomized to receive an initial dose of ranolazine 500 mg b.i.d. 
or placebo for 1 week, followed by 6 weeks of treatment with ranolazine 1000 mg b.i.d. or placebo, in 
addition to concomitant treatment with amlodipine 10 mg q.d. In addition, 45% of the study population 
also received long acting nitrates. Sublingual nitrates were used as needed to treat angina episodes. 
Statistically significant decreases in angina attack frequency (p = 0.028) and nitroglycerin use (p = 0.014) 
were observed with ranolazine compared to placebo. These treatment effects appeared consistent across 
age and use of long acting nitrates.  
CARISA37 was a study in 823 chronic angina patients randomized to receive 12 weeks of treatment with 
twice-daily ranolazine 750 mg, 1000 mg, or placebo who also continued on daily doses of atenolol 50 mg, 
amlodipine 5 mg, or diltiazem CD 180 mg. Sublingual nitrates were used in this study as needed. In this 
trial, statistically significant (p < 0.05) increases in modified Bruce treadmill exercise duration and time to 
angina were observed for each ranolazine dose versus placebo, at both trough (12 hours after dosing) 
and peak (4 hours after dosing) plasma levels, with minimal effects on blood pressure and heart rate. 

Targeting RV in PAH 
 
Page 13 
Version6  
 
Exercise treadmill results showed no increase in effect on exercise at the 1000 mg dose compared to the 
750 mg dose. 
There is no clinical data on the use of ranolazine in this study patient population. However, there is a 
clinical trial (NCT01174173) ongoing. The group of PAH subjects targeted in the cited trial must have 
angina or angina equivalent, and the trial primarily focuses on exercise capacity and hemodynamic 
assessment. The cited trial has a duration of 3 months with estimated enrollment is 25 subjects without a 
control group and is a single center open label study. 
 
2.5 
Dose Rationale and Risk/Benefits 
 
2.5.1. 
Ranolazine 
Subjects in Arm1 will receive ranolazine or placebo at 500mg PO BID and after two weeks will increase to 
1000mg PO BID and continue for a total of 26 weeks.  The most common reported adverse reactions 
during treatment with ranolazine (>4% and more common than with placebo) were dizziness (6.2%), 
headache (5.5%), constipation (4.5%), and nausea (4.4%).   Dizziness appeared to be dose related in 
clinical trials.  Subjects with persistent adverse reactions will be down titrated to 500mg BID. Subjects on 
moderate CYP3A inhibitors will be limited to 500mg BID.  For detailed safety information on ranolazine, 
refer to the most recent version from the manufacture website (Gilead).  The route of administration, 
dosage, and dosage regimen are per manufacturer label for chronic angina.  1000 mg twice a day is the 
maximum tolerated dose. The dosage period is longer than what has been tested for angina because we 
hypothesize that ranolazine’s effect on RV metabolism will result in improvement in RV function and 
therefore patient symptoms will take longer than angina symptom relief due to time required for RV 
remodeling.  The maximum tolerated dose is targeted in order to derive the maximum benefit if there is 
any benefit to the patients. The risks of exposure as related to adverse reactions is uncommon and are 
reasonable given that RV is a novel therapeutic target and current PAH therapies do not address RV 
dysfunction.   
 
3 
Study Objectives 
 
Primary Objectives:  
1. To demonstrate that there are differences in metabolism between subjects with normal RV function and 
persistent RV dysfunction as defined by CMR RVEF of <45%.   
2. To demonstrate that treatment with ranolazine improves RV energetic and contractility in the subjects 
with persistent RV dysfunction as measured by imaging.   
 
Exploratory Objective: 
To evaluate the effects of ranolazine in subjects with PAH on stable background therapy and persistent 
RV dysfunction 
 
4 
Study Design 
4.1 
General Design 
This study is a randomized double-blind, placebo controlled (2 drug to 1 placebo), multi-center proof-of-
concept study in 30 male or female subjects with pulmonary hypertension (PAH) and RV dysfunction 
(Arm 1) accompanied by an observational arm of 10 subjects without RV dysfunction (Arm 2).  
 
 
Arm 1: Incident (Stratum I) and prevalent (Stratum P) subjects with clinically indicated CMR 
RVEF <45% who will be randomized to placebo (10 subjects) and ranolazine (20 subjects).  
 

Targeting RV in PAH 
 
Page 14 
Version6  
 
 
Arm 2: Incident (Stratum I) and prevalent (Stratum P) subjects with clinically indicated CMR 
RVEF >= 45 % who are RV controls (Arm 2 = 10 subjects).   These “good RV” subjects will be 
followed in the observational arm and will be reevaluated in 6 months (optional).  
 
Stratum I refers to incident subjects. Stratum P refers to prevalent subjects. Each subject will be in the 
study for up to 46 weeks. The study includes a screening period, a treatment period, and a follow-up 
period. The screening period will be up to 4 weeks in length, the treatment period will be up to 26 weeks, 
and follow-up period will be 4 weeks.  For incident patients, this means 12 weeks of stable therapy prior 
to screening and up to 4 weeks before enrollment and 30 weeks of follow up.  For prevalent patients, this 
means 4 weeks of screening and 30 weeks of follow up.  Participation in the study is defined as the whole 
time period from signing and dating the informed consent form until study completion (or withdrawal of 
consent) or early discontinuation from the study.  
 
Subjects in Arm1 will receive ranolazine or placebo at 500mg PO BID and after two weeks will increase to 
1000mg PO BID.  Subjects will continue at 1000mg BID for the duration of the study.  Subjects with 
adverse reactions that are difficult to tolerate will be down titrated to 500mg BID. Subjects on moderate 
CYP3A inhibitors will be limited to 500mg BID. 
 
Subjects in Arm 2 will have baseline studies performed and be observed over 6 month (optional) and 
have 6-month studies performed (optional).  
 
Subjects who meet all entry criteria will be scheduled to return to the clinic for the startup visit.   After the 
startup visit, subjects will be seen as per standard clinical practice.   We will conduct a check in by 
telephone q4 weeks and see patients more frequently as clinically indicated.  
 
At baseline (week 0), interim (1 to 4 months post randomization) and the conclusion of the treatment 
period (week 26) subjects will be assessed for functional class, 6- MWD, and HEALTH OUTCOME based 
on SF-36 tool. Peripheral blood will be obtained for metabolic profiling at baseline and the conclusion of 
the treatment period.  Subjects will have baseline CMR done per standard of care or may enroll in a 
separate imaging protocol and undergo the baseline CMR as a research scan at Penn. 
 
4.2 
Primary Study Endpoints 
Compare metabolism at baseline for subjects with normal RV function (Arm 2) and those with persistent 
RV dysfunction (Arm 1). 
To demonstrate that treatment with ranolazine improves RV energetic and contractility in the subjects with 
persistent RV dysfunction as measured by imaging.   
 
4.3 
Exploratory Endpoints 
4.3.1 Outcomes 
Number and percentage of subjects with high risk profile at Week 26.  
Patients with high risk profile are defined as patients with clinical worsening events or lack of clinical 
improvement at Week 26.  
 
 
Clinical improvement is defined as an increase in 6MWD >or= 15% or more from baseline AND 
an improvement (decrease) in functional class by at least 1 class by end of treatment visit, week 
26. 
 
 
Clinical worsening event (adjudicated), as defined by at least one of the events listed below: 
         Death (all causes)  
         Hospitalization due to worsening PAH defined as: 

Targeting RV in PAH 
 
Page 15 
Version6  
 
o 
Non-elective hospitalization lasting at least 24 hours in duration caused by clinical 
conditions directly related to PAH and/or right heart failure; or 
o 
Lung or heart / lung transplantation; or 
o 
Atrial septostomy 
         Initiation of a prostacyclin for the treatment of worsening PAH 
         Disease progression (all criteria required): 
o 
A decrease in 6MWD of at least 15% from Baseline (or too ill to walk) directly related 
to PAH progression with other co-morbidities ruled out, confirmed by 2 6MWTs 
performed on different days. 
o 
Worsening of PAH symptoms, which must include either 
An increase in functional class or 
New onset of at least one symptom what did not respond to oral diuretic therapy (syncope, 
near syncope, chest pain, chest discomfort, orthopnea and dizziness)*  
 
 
4.3.2 
Health outcomeSF-36 
The objective is to assess the improvement in quality of life of the subjects after being treated with 
ranolazine. SF-36 is a short-form health survey with 36 questions.  The endpoint is the 8-scale profile of 
functional health and well-being scores.   
4.3.3 
microRNA and iPS 
Arm 1 and Arm 2 comparisons will also be made in changes of microRNA and directed studies on iPS 
cells derived from peripheral blood in a subset of subjects.  
 
4.4 
Primary Safety Endpoints 
Adverse Events 
5 
Subject Selection and Withdrawal 
5.1 
Inclusion Criteria 
 
1) Have a current diagnosis of symptomatic PAH based on one of the following criteria: 
a) Idiopathic pulmonary arterial hypertension 
b) Familial pulmonary arterial hypertension 
c) PAH associated with connective tissue disease 
i) 
Systemic sclerosis 
ii) CREST 
iii) Mixed connective tissue disease 
iv) Systemic lupus erythematosus 
d) CTEPH-nonsurgical/distal vessel disease or CTEPH patients who are reluctant to go to surgery 
within a 6-month period and are willing to participate 
e) Simple congenital such as repaired ASD/VSD or unrepaired small ASD/VSD with persistent and 
out of proportion PAH 
f) 
Group 3 patients who have a component of PAH and do not meet exclusion criteria (5) in 5.2.  

Targeting RV in PAH 
 
Page 16 
Version6  
 
g) PAH caused by conditions affect the veins and small vessels of the lungs, sickle cell disease.  
h) Group 5 PH such as polycythemia vera, essential thrombocythemia, sarcoidosis, or vasculitis, or 
metabolic disorder.  Sarcoid with known cardiac involvement (LV and/or RV) will be excluded.  
2) WHO functional class II, III, or IV 
3) Age >18 and < 80 years of age  
4) For incident cases a right heart catheterization performed within 100-days prior to enrollment (defined 
as randomization for Arm 1 and baseline imaging procedures for Arm 2) that shows the following 
(prevalent cases require a historical RHC within the past 60-months): 
a) Mean pulmonary artery pressure >25 mmHg at rest 
b) Pulmonary capillary wedge pressure or left ventricular end diastolic pressure < 15 mmHg. If the 
PCWP is >15 but < 20 mmHg then the Transpulmonary Gradient must be greater than 25. 
c) Pulmonary vascular resistance > 3 mmHg/L/min 
5) CMR RVEF < 45% obtained from a clinically indicate CMR  done within 28 days of entry (defined as 
randomization for Arm 1) (Subjects with CMR RVEF ≥ 45% will be given opportunity to go into the 
observational control arm; Subjects with CMR RVEF <45% who do not want to start 
ranolazine/placebo may be enrolled in Arm 2; Subjects who enroll in the observational arm will be 
allowed to re-enroll in the treatment arm if end of study imaging shows CMR RVEF <45%)  
6) 6-minute walk test distance > 50 meters within 90 days prior to enrollment (defined as randomization 
for Arm 1 and baseline imaging procedures for Arm 2) 
7) No dual up-front therapies permitted for Stratum I (incident) patients.   
8) No addition or discontinuation of PAH specific medication within 90 days and no change in PAH 
specific medication dose within 28 days prior to baseline imaging procedures. Note:  Adjustment of 
diuretic dose (increase or decrease of 100% or less) is permissible. Switches from same class of 
medication may only require a stable dose 28 days prior to baseline imaging procedures at the 
discretion of the Investigator.   
9) Participation in the companion imaging protocol “Evaluation of RV function and metabolism  in 
patients with pulmonary hypertension using combined [11C]Acetate and [18F]Fluorodeoxyglucose 
(FDG) PET/CT and Cardiovascular MR (CMR)” defined as:Subject must be willing to participate in the 
companion imaging protocol.  Note: Does not apply to subjects from UMD site.  
10) Subjects must be capable of giving informed consent 
 
5.2 
Exclusion Criteria 
1) Previous treatment with or prior sensitivity to any formulation of ranolazine (does not apply to 
observational arm). 
2) Any family history of QTc prolongation, congenital long QT syndrome, or receiving drugs that prolong 
the QTc interval such as Class Ia (e.g., quinidine) or Class III (e.g., dofetilide, sotalol, amiodarone) 
antiarrhythmic agents, erythromycin, and certain antipsychotics (e.g. thioridazine, ziprasidone) (does 
not apply to observational arm). 
3) For patients who have a prolonged QTc of >480 ms that is not due to the above exclusion #2 AND an 
increased QRS duration of >120 ms, QTrr,qrs formula38 will be used to calculate an adjusted QTc. 
Patient will be excluded if an adjusted QTc is >460 ms (does not apply to observational arm). 
4) Subject receiving IV inotropes within 2 weeks prior to the baseline imaging procedures 
5) Parenchymal lung disease based on pulmonary function testing within the past 12-months prior to 
baseline imaging procedures showing any of the following: 

Targeting RV in PAH 
 
Page 17 
Version6  
 
a) Total lung capacity < 50% of predicted and a HRCT that does not demonstrate clinically severe 
interstitial lung disease based on the discretion of the Investigator 
b) FEV1/FVC < 50% 
6) Subjects currently on a strong CYP3A inhibitor or inducer, or hepatic enzymes > 3x ULN, or moderate 
to severe liver disease at the Screening Visit (does not apply to observational arm)   
7) Portal hypertension associated with either cirrhotic or non-cirrhotic chronic liver disease (does not 
apply to observational arm).  
8) Left sided heart disease including any of the following: 
a) Moderate or greater aortic or mitral valve disease  
a) Any LV cardiomyopathy (including but not limited to restrictive, amyloid, hypertrophic) 
b) Left ventricular systolic dysfunction defined as an ejection fraction < 50% by echocardiography 
c) Symptomatic coronary artery disease 
9) Uncontrolled systemic hypertension (systolic BP > 160 mmHg or diastolic >100 mmHg) with or 
without treatment.  
10) Uncontrolled diabetes mellitus with fasting glucose > 150 mg/dL within 28 days of enrollment .  
11) Inability to perform a 6-minute walk test because of a mechanical problem such as arthritis, morbid 
obesity, or musculoskeletal problem 
12) The subject has the presence, or history, of malignancy that required significant medical intervention 
within the preceding 3 months and/or is likely to result in death within the next 2 years (exception of 
basal cell or non-metastatic squamous cell carcinoma of the skin, and carcinoma in-situ of the cervix) 
(does not apply to observational arm).   
13) The receipt of any investigational medication within 14 days prior to screening or the need for another 
investigational drug during the course of this study. Note: Subjects on an investigational medication 
may enroll if they meet inclusion criteria #8 and they are anticipated to remain on the investigational 
medication for the duration of the trial (26 weeks). 
14) Pregnancy or lactation: Women of childbearing potential and non-vasectomized men must agree to 
use a barrier method of contraception during screening and for the entire Study Period 
15) Psychiatric disorder that compromises the ability to provide informed consent 
16) ICD, Pacemaker, hazardous metallic implants or any other contraindication to MRI. 
 
5.3 
Early Withdrawal of Subjects 
5.3.1 
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 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: 
 
 
Progressive disease as determined by the investigator  
 
Use of unapproved concomitant medications (initiation of a strong CYP3A inhibitor or inducer without 
any alternative therapies; initiation of a moderate CYP3A inhibitor would warrant dose reduction), 

Targeting RV in PAH 
 
Page 18 
Version6  
 
 
Occurrence of intolerable AEs 
 
Withdrawal of consent by subject 
 
Noncompliance with protocol, e.g., the subject fails to appear at one or more visits 
 
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 electronic 
CRF (eCRF). 
 
6 
Study Drug  
6.1 
Description 
Ranolazine is a racemic mixture and chemically described as 1-piperazineacetamide, N -(2,6-
dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-, (±)-. It has an empirical formula of 
C24H33N3O4, a molecular weight of 427.54 g/mole. Ranexa is available for oral administration as film-
coated, extended-release tablets containing 500 mg of ranolazine.  
6.2 
Treatment Regimen 
All subjects will receive ranolazine or placebo at 500mg PO BID and after two weeks will increase to 
1000mg PO BID.  Subjects will continue at 1000mg BID for the duration of the treatment period (26 
weeks total).  Subjects with persistent adverse reactions will be down titrated to 500mg BID. Subjects on 
moderate CYP3A inhibitors will be limited to 500mg BID. 
6.3 
Method for Assigning Subjects to Treatment Groups 
This is a double blind study with an observational arm.  Subjects in Arm 1 will be randomized in a 2:1 
fashion to ranolazine or placebo by the University of Pennsylvania Investigational Drug Service (IDS).  
Subjects in the observational arm (Arm 2) will not receive treatment.   
 
A subject number will be assigned to an individual at the screening visit. Randomization of the subject will 
proceed through the use of a randomization table at Penn IDS. The Investigational Drug Service will 
prepare a randomization table which is stratified by site, using random blocks of 6 and 3, at a 2:1 ratio of 
active to placebo.  The table will be computer-generated prior to the start of the trial and maintained 
securely within the Investigational Drug Service (IDS), which is not accessible to the rest of the study 
team.  Subjects will be assigned to treatment in sequential order (lowest to highest) after stratification by 
site.  For emergency unmasking, the IDS will upload the randomization table into a secure web portal and 
issue an account for the study principal investigator.  The account will permit access from any internet-
enabled computer and will collect information on the reason for unmasking (such as whether there is a 
serious adverse event) before revealing the treatment assignment for one individual subject.  All use of 
the emergency unmasking system is logged and reviewed periodically by IDS personnel. 

Targeting RV in PAH 
 
Page 19 
Version6  
 
After a subject is screened and determined to be eligible for the study, the site personnel (the investigator 
or his/her designee) will contact Penn IDS and get a randomization number. The randomization number 
and the date the randomization number is assigned will be recorded in the eCRF. Once randomization 
numbers and registration numbers have been assigned, they cannot be reassigned.  
When a subject discontinues treatment, the investigator or his or her designee will enter date of 
discontinuation on the eCRF and the date when the last dose of test article was received by the subject.  
6.4 
Preparation, Packaging and Administration of Study Drug 
Ranolazine and placebo will be shipped directly from Gilead to Penn’s Investigational Drug Service (IDS). 
IDS will be coordinating the randomization process. The IDS will package blinded study medications 
according to the Hospital of the University of Pennsylvania’s Pharmacy Policy and Procedures. Labeling 
will be done by the IDS, and each packet will include the subject’s registration number, name, date 
dispensed, storage conditions and directions for use. Penn IDS will ship to research pharmacy or 
investigator at each institution once the subject is enrolled and randomization procedure is performed.  
6.5 
Subject Compliance Monitoring 
At each study visit, compliance with study drug will be reinforced. When study drug is returned, 
compliance will be assessed by pill count. Study medication dispensed or returned to IDS must be 
recorded for Drug Accountability and Reconciliation at each visit. Study drug bottles will be required to be 
returned at applicable visits throughout the study.  
6.6 
Prior and Concomitant Therapy 
Use of medications not excluded in the entry criteria will be permitted at the discretion of the investigator.  
Any medication, including over-the-counter medications, used during the course of the study will be 
documented.   
 
Eligible subjects may be receiving one of the following treatment regimens at screening:  
 
 
Monotherapy with an endothelin receptor antagonist (ERA: e.g., ambrisentan, or bosentan), a 
phosphodiesterase type-5 inhibitor (PDE5i: e.g., sildenafil, tadalafil),  a parenteral prostanoid 
(intravenous [iv] epoprostenol, iv or subcutaneous Treprostinil), or an inhaled prostanoid (inhaled 
iloprost or treprostinil) that is approved for the treatment of PAH  
 
 
Patient might be on chronic therapy for PAH including but not limited to digoxin and/or  
amlodipine.  
 
 
Combination therapy with eligible PAH treatments (any combination of two or three of ERA, 
PDE5i, or prostanoid).  
 
 
Other new PAH specific therapies at the discretion of the Investigator 
6.7 
Blinding of Study Drug 
This is a double blind study with an observational arm. Only the pharmacy at the University of 
Pennsylvania IDS will know if the subject is receiving active or placebo ranolazine.  Neither the study 
investigators nor the rest of the research team will know which subjects receive active versus placebo 
until the data base is locked.   
 
Unblinding a subject's treatment assignment may be done only for reasons related to subject safety. All 
efforts will be made to keep the investigator team blinded, such as having IDS send the unblinding 
information directly to the treating physician without involving the Investigator. If the investigator is the 
treating physician, then they will be involved in the unblinding.  Unblinding reasons, date, and time will be 
documented in the subject research record. The DSMB may also request for unblinding to occur through 
concerns over subject safety. 

Targeting RV in PAH 
 
Page 20 
Version6  
 
 
 
6.8 
Receiving, Storage, Dispensing and Return 
6.8.1 
Receipt of Drug Supplies 
Upon receipt of the of the study treatment supplies, an inventory must be performed and a drug receipt 
log filled out and signed by the person accepting the shipment.  It is important that the designated study 
staff counts and verifies that the shipment contains all the items noted in the shipment inventory.  Any 
damaged or unusable study drug in a given shipment (active drug or comparator) will be documented in 
the study files.  The investigator must notify study sponsor of any damaged or unusable study treatments 
that were supplied to the investigator’s site. 
 
6.8.2 
Storage 
The investigational pharmacist at the IDS will ensure that all study drug is stored in a secured area, under 
recommended storage conditions and in accordance with applicable regulatory requirements, and will be 
dispensed by qualified staff members. The pharmacist will maintain accurate records regarding study 
drug administration and return. 
 
6.8.3 
Dispensing of Study Drug 
The IDS service will maintain accurate logs of study drug dispensing, and will conduct regular drug 
reconciliation checks to document drug assigned, drug consumed, and drug remaining. This reconciliation 
will be logged on the drug reconciliation form, and signed and dated by the service.   
 
6.8.4 
Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and 
drug remaining.  This reconciliation will be logged on the drug reconciliation form, signed and dated.  Any 
discrepancies noted will be investigated, resolved, and documented prior to return or destruction of 
unused study drug.  Drug destroyed on site will be documented in the study files. 
 
7 
Study Procedures 
7.1 
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.) 
7.2 
Screening Procedures 
The following procedures will be performed during the screening visit.  The screening visit can be one 
visit, or several visits occurring over 28 days.  All assessments must be completed within 28 days before 

Targeting RV in PAH 
 
Page 21 
Version6  
 
enrollment unless otherwise noted.  Enrollment is defined as randomization for Arm 1 (treatment arm) and 
as completing baseline imaging procedures for Arm 2 (observational arm). 
The following must be done within 90 days prior to enrollment: 
 
Informed consent: a signed and dated institutional review board (IRB) or independent ethics 
committee (IEC) approved ICF. This has to be clearly documented in the subject’s source 
documents.   
 
Demography: including gender, date of birth, and race 
 
6MWD  
 
Borg dyspnea index 
 
Medical history: including collection of the subject’s past and present medical history 
 
The following must be done within 28 days prior to enrollment: 
 
Prior and current medications  
 
HEALTH OUTCOMESF-36 assessment  
 
Screening CMR  
 
Baseline labs LFTs and ECG (does not apply to observational arm).  
 
The most recent data will be collected for the following: 
 
Baseline labs will include CBC, Chem10, LFTs, ANA, CRP, uric acid, total protein, albumin, 
Pro-NT BNP and coagulation analysis  
 
Physical examination  
 
ECG 
 
Echocardiography  
 
 
Adverse events will be recorded starting from the time informed consent is obtained. 
Pregnancy test (serum or urine; for women of childbearing potential) will be done at the baseline CMR 
and PET/CT procedures.  
 
Subjects will have baseline CMR done per standard of care or may enroll in a separate imaging protocol 
and undergo the baseline CMR as a research scan at Penn.   
 
Samples for miRNA and iPS may be obtained from Tissue Registry or BioBank protocols and used for 
this study.  This will be described in the site-specific IRB application. 
7.3 
Treatment Period 
On Study Day 1 subjects in Arm1 will be randomized 2:1 to ranolazine or placebo.  After randomization, 
subjects must initiate treatment within 14 business days at the investigator’s site and will continue 
treatment for up to 26 weeks. The “treatment period” is defined as the period from the start of treatment 
until end of treatment or end of study page is completed.   
The following may be done during the treatment period as clinical standard of care clinic visits: 
  
 
Physical examination  at 1 to 4 months post randomization   

Targeting RV in PAH 
 
Page 22 
Version6  
 
 
Borg dyspnea score and 6MWD at 1 to 4 months post randomization 
 
WHO and HEALTH OUTCOME assessment at 1 to 4 months post randomization 
 
Laboratory testing at 1 to 4 months post randomization  
 
Recording of AEs and concomitant medications in source documents will be done regularly 
throughout the treatment period  
  
7.4 
Conclusion of Treatment Period 
Subjects will complete the treatment period at week 26  (or earlier if endpoint criteria are met) and will 
come in for the following procedures: 
 
 
Physical examination, including weight, and assessment of the Borg dyspnea score 
 
Vital signs  
 
6MWD 
 
WHO and HEALTH OUTCOME 
 
ECG  
 
Laboratory testing 
 
AE and concomitant medication assessment 
7.5 
Long Term Follow-up 
Subjects in Arm 1 will be followed for 4 weeks after stopping ranolazine for adverse events only.  
8 
Methods 
 
8.1 
CMR Imaging  
8.1.1 
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.  
  
8.1.2 
Analysis of CMR data 
 
From the cine images, RV ventricular size, volumes, mass, and function are analyzed using Qmass 
(Medis) and then indexed to body surface area.  PC images will be processed using software tools. 
Echocardiography 
 
Echocardiography will be performed per clinical routine and include 3D volume and RV strain when 
possible.  Images will be anonymized and copied to CD/DVDs and analyzed of echo parameters.  
 
8.2 
Metabolon/MicroRNA/iPS 
8.2.1 
Procedure 
Peripheral blood at the baseline and end of treatment visit will be obtained from subjects to send for 
Metabolon analysis.  For the subjects who have a clinically indicated right heart catheterization during 

Targeting RV in PAH 
 
Page 23 
Version6  
 
screening, plasma may be drawn during the procedure for microRNA analysis.  Peripheral blood at 
baseline visit may also be sent for inducible pluripotent stem cells (iPSC) only if subject consents to it 
(optional).   
8.2.2 
Analysis of Metabolon data 
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 of disease. Following peak identification and quality control filtering, integrated peak ion 
counts for each compound in each sample are used for statistical analysis. 
8.2.3 
Analysis of MicroRNA data 
MiRNA will be quantified by standard RT-PCR. Exploratory correlational analysis will be performed 
among the various imaging parameters and biomarkers using Spearman rank correlation coefficients. 
8.2.4 
Analysis of iPS 
In cultured iPSC-derived cardiomyocytes (from blood) under both resting and injury-specific conditions, 
alterations in the utilization of glycolysis and oxidative phosphorylation will be assessed, along with known 
metabolic factors (e.g., protein-coding genes and microRNA) that control these processes. Downstream 
molecular signaling pathways that respond to such metabolic changes and directly influence RV 
contractility will also be assayed, including dynamic alterations in fetal contractile and angiogenic factors 
as well as cardiomyocyte calcium signaling and action potential. Quantitative differences in these 
parameters will then be correlated with individualized manifestations of clinical RV failure. 
!
8.3 
Health Outcomes Assessment 
The SF-36 health outcomes assessment surveys are for the purpose of exploring the subject’s own 
perceptions about his or her quality of life.  The investigator must not influence the subject’s 
assessments.  Every effort should be made to maintain an unbiased assessment. Refer to the flowchart 
for time points. We will be using the SF-36 tool, which is a short-form health survey with 36 questions. 
The endpoint is the 8-scale profile of functional health and well-being scores. 
 
8.4 
Laboratory Determinations 
Refer to the Flowchart for specifics and time points. 
 
Local laboratories will be used to process blood specimens for complete blood cell counts, 
coagulation tests, chemistry, and urinalysis. 
 
The complete blood cell count includes white blood cell count (WBC) with differential, platelet count, 
red blood cell count (RBC), hemoglobin (Hgb), and hematocrit (Hct). 
 
The chemistry panel includes levels of sodium, potassium, chloride, BUN (or urea), creatinine, 
glucose, calcium, magnesium, phosphorus, AST, ALT, albumin, total protein, uric acid, CRP, ANA, 
NT-proBNP. 
 
Coagulation tests include prothrombin time (PT, which may be expressed as INR), and partial 
thromboplastin time (PTT). 
 
Pregnancy tests (serum or urine) must be done at screening and before CMR in women of child 
bearing potential.   
 
Blood samples may be taken and used for purposes related to this research.  The samples will be stored 
for up to 15 years after the end of the study and then destroyed.  In addition, identifiable samples can be 
destroyed at any time at the request of the subject. 
 

Targeting RV in PAH 
 
Page 24 
Version6  
 
9 
Statistical Plan 
9.1 
Sample Size Determination 
Approximately 30 subjects with PAH and RV dysfunction will be randomized in 2:1 ratio to ranolazine or 
placebo group in Arm 1, with 16 evaluable subjects for ranolazine and 8 for placebo, after accounting for 
20 percent dropout/nonevaluable.  
 
This trial is designed to understand the difference between the 2 groups using ranolazine as a tool. The 
study is not powered to accomplish the primary study point comparisons due to difficulty in recruitment to 
achieve sufficient sample size. We will be examining different imaging markers as continuous variables 
comparing the difference pre and post drug treatment. With 16 treated patients and 16 untreated patients 
(8 in the randomized group and 8 in the observational group), we’ll have 76% of power to detect an 
improvement of 35% with a 50% coefficient of variation. Assuming the effect size is 40% with a standard 
deviation of 50%, we will have 89% power to detect the difference between groups with a sample size of 
16. The power would increase to 85% if we have 20 patients in the treated and 20 patients in the 
untreated arm with an effect size of 35%. Two reasons for the unequal randomization; one is to ensure 
minimum number of subjects are exposed to the treatment to provide sufficient information for the study, 
and the other is for ethical consideration. Additionally, we have control patients in the observational arm 
who also have longitudinal data.   
.  
9.2 
Statistical Methods 
9.2.1 
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.  
Unscheduled Visits: Subject data obtained during unscheduled visits will not be summarized but 
included in subject data listings only. Unscheduled visit values will not be used to impute missing 
scheduled visit values. 
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.   
9.2.2 
Background Characteristics  
9.2.2.1 
 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 
randomized population. 

Targeting RV in PAH 
 
Page 25 
Version6  
 
9.2.2.2 
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 randomized population.  
9.2.2.3 
 Prior and Concomitant Medications  
All medications will be coded using the World Health Organization Drug Dictionary Enhanced 
(WHODDE), March 2012 version. Medications used in the study will be summarized in 2 parts:  
 
Prior medication: medication taken before the initial dosing of study drug in the current study, 
regardless of when the medication administration ended. 
 
Concomitant medication: medication received at or after initial dosing of study drug, or those 
received before initial dosing with study drug that continued after initial dosing of study drug.  
If a medication start date is at or after the date of dosing of study drug, then the medication will be 
summarized as concomitant medication regardless of whether the medication end date is missing or not. 
If a medication end date is before the date of dosing of study drug, then the medication will be 
summarized as a prior medication regardless of whether the medication start date is missing or not. Note 
that medication taken before initial dosing of study drug and continued after initial dosing will be 
summarized as prior medication, and separately as concomitant medication. 
Concomitant medications will be assigned to each dosing period based on the start date of the 
medication and the study drug administration dates (concomitant medications taken during the first 
dosing period will be assigned to the first dosing period, and so forth). Note that a concomitant medication 
may be assigned to both dosing periods.  
Concomitant medications will be summarized by dosing period and overall, based on the FAS. Prior 
medications will only be listed. Summary will be based on the all randomized population.  
9.2.2.4 
 Study Drug Exposure  
Exposure (days) of study drug administration will be estimated as last dose date – first dose date + 1, 
where dose refers to a dose of study drug. 
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.  
9.2.3 
 Efficacy Analysis 
9.2.3.1 
Analysis of Primary Endpoint 
Cardiac Imaging studies performed in the companion study to assess RV function will be used 
as primary endpoint for assessment the treatment outcome.  
Metabolic profiling will be provided by Metabolon and will be further analyzed with collaborating 
scientists from the Broad Institute, Cambridge, Massachusetts.  
9.2.3.2 
Analysis of Exploratory Efficacy Variable 
The exploratory efficacy endpoint is the estimate and a confidence interval for the difference in 
proportions between the treatment groups. Number and percentage of subjects with high risk profile for 
each treatment group at Week 26 will be provided.  Fisher’s Exact test will be employed to detect the 
difference between Arm 1 Placebo vs Arm 1. Patients with high risk profile are defined as patients with 
clinical worsening events or lack of clinical improvement at the end of the study (week 26).  The primary 
efficacy analysis will be conducted on the all-randomized population.  
 
 

Targeting RV in PAH 
 
Page 26 
Version6  
 
 
Clinical worsening event (per independent clinical assessment), as defined by at least one of the 
events assessed by the independent clinician till end of treatment visit, week 26. 
 
Lack of clinical improvement. Clinical improvement is defined as an increase in 6MWD >or= 15% 
or more from baseline AND an improvement (decrease) in functional class by at least 1 class by 
end of treatment visit, week 26. 
 
Clinical worsening is evaluated by 2 independent clinicians at each visit, from date of first dose to end of 
treatment visit. To minimize investigator bias, the data manager will compare the assessed outcome 
between the 2 independent clinicians. Shall the assessment be different between the 2 independent 
clinicians, the 3rd clinician will be involved to adjudicate the case. The evaluation from the adjudicator will 
be used for analysis. At any given time the difference exceed more than 30%, the investigator will have a 
conversation with the 2 independent clinicians to narrow the difference.   
For subjects do not experience clinical worsening, the end of the treatment visit (week 26) with 6MWT 
and functional class assessment would determine if there is no clinical improvement or if there is clinical 
improvement. All efforts should be made to collect the death information in the follow up period. 
9.2.3.3 
Analysis of Other Exploratory Endpoints 
A. Quality of Life Health Outcome 
The objective is to assess the improvement in quality of life of the subjects after being treated with 
ranolazine. Ordinal regression will be employed using SF-36 responses to predict a general health 
perception variable (response options ‘Excellent’, 'Very good', 'Good', 'Fair', and 'Poor'). Items that 
significantly predicted this variable were candidates for inclusion in the utility exercise. The efficacy 
analysis will be conducted on the all-randomized 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. 
9.2.4 
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 treatment-emergent adverse events (TEAEs) 
 
Clinical laboratory values 
 
ECG outcomes 
 
Vital signs 
9.2.4.1 
Adverse Events 
AEs will be coded according to MedDRA (Version 15.1) and will be classified as pre-treatment or 
treatment-emergent.  
 
Pre-treatment adverse events are defined as AEs that developed or worsened after signing the 
informed consent before the start of study drug. 
 
Treatment-emergent adverse events (TEAEs) are defined as AEs with start date or increased 
severity on or after the first study drug dose through the Safety Follow-up Visit.  
9.2.4.2 
Clinical Laboratory 
All statistical analyses of laboratory values will be performed using international system (SI) units. 
Continuous hematology/coagulation and clinical chemistry results will be summarized (raw and change 
from baseline) at each scheduled time point. The number and percentage of subjects with shift changes 
from baseline based on the laboratory normal ranges will be tabulated at each scheduled time point.  

Targeting RV in PAH 
 
Page 27 
Version6  
 
9.2.4.3 
Electrocardiogram 
A summary of raw values and change from baseline values will be provided by dosing period at each 
scheduled time point for the following ECG measurements: heart rate, PR, RR, QRS, QT and QTc 
intervals (QTcB and QTcF). 
9.2.4.4 
Vital Signs 
The following vital signs (raw values and change from baseline) will be summarized by dosing period at 
each scheduled time point: systolic and diastolic blood pressure (mmHg), body temperature, pulse rate 
(beats per minute [bpm], oxygen saturation). 
9.3 
Subject Population(s) for Analysis 
All efficacy analyses will be performed using all-randomized population.  All safety (AE, lab, vital) 
analyses will be performed using all-treated population. Subject populations are specified within each of 
the analyses section.  
10 Safety and Adverse Events 
10.1 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. 
 
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:  

Targeting RV in PAH 
 
Page 28 
Version6  
 
 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 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.   They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
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 must be reported is normally defined as the period from 
the initiation of any study procedures to the end of the study treatment follow-up.  For this study, the study 
treatment follow-up is defined as 4 weeks following the last administration of study drug.  
 
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.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following 
conditions is met:  
 The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
 The abnormality suggests a disease and/or organ toxicity 
 The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic investigation, 
etc. 
 
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 

Targeting RV in PAH 
 
Page 29 
Version6  
 
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. 
10.2 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 study 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. 
10.3 Reporting of Serious Adverse Events and Unanticipated Problems 
Site investigators 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).   
 
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  
 
Any study-related unanticipated problem posing risk of harm to subjects or others, and any type of 
serious adverse event, must be reported to Penn principle investigator. To report such events, a Serious 
Adverse Event (SAE) form must be completed by the investigator and faxed or emailed to the study 
sponsor within 24 hours.  The investigator will keep a copy of this SAE form on file at the study site.   
 
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 Penn principle investigator.  

Targeting RV in PAH 
 
Page 30 
Version6  
 
 
Reporting Procedures for Potential Endpoints and Endpoints 
Events that are potential endpoints: hospitalization for PAH, death, worsening of PAH, lung or heart-lung 
transplant, atrial septostomy or other interventional procedure specifically for RH failure or PAH, decline 
of 6-MWD, increase in Borg Dyspnea Index and Increase in WHO-functional class initially will not be 
considered as serious adverse events but will be handled as efficacy endpoints.  They will not be subject 
to the immediate submission requirements for SAEs in this study and will not require the investigator’s 
causality assessment.  The site investigator will make the initial determination to classify these events as 
endpoints or SAEs.  Events that are equivocal will be adjudicated by the medical monitor in real time.  For 
these potential endpoints, an SAE eCRF will only be completed if the DSMB determines that a specific 
event does not meet the criteria for the relevant endpoint (ie, the potential endpoint is negatively 
adjudicated).  Once an investigator is notified of the negative adjudication, the investigator must complete 
and submit a SAE eCRF within 24 hours.  The DSMB will be requested to follow the occurrence of these 
events to see if specific action needs to be taken during the course of the study.   
 
In addition, the DSMB will review all fatal endpoints to evaluate whether the cause of death is due to a 
serious adverse event that is a specific concern for the study drug or which may be individually 
informative, such as an anaphylactic reaction, Hy’s Law, rhabdomyolysis, or Stevens-Johnson syndrome.  
If such an event is detected, the DSMB will notify the investigator to submit the SAE per local reporting 
requirements.   
10.3.1 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: 
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: 

Targeting RV in PAH 
 
Page 31 
Version6  
 
 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 investigators brochure, 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. 
 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. 
10.3.2 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. 
 
10.4 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above.  Medical monitoring will include a regular assessment of the number and type of serious adverse 
events.Safety will be closely monitored by the site investigators on an ongoing basis for subjects on both 
treatment and placebo arms. A Data and Safety Monitoring Committee (DSMB) is planned to monitor the 
safety of this study.   
Subjects receiving at least 1 dose of test article will be evaluable for safety. Safety will be assessed by 
telephone interview every 4 weeks during the study: concomitant medications for the management of 
adverse events (AEs), and serious adverse event (SAE) evaluations throughout the study. AEs will be 
graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.  
Additionally, subjects will be instructed to report all AEs that occur at any time during the study. The 
investigative team at the study site will be responsible for all physical and laboratory evaluations, as well 
as for the completion of the appropriate eCRFs.   
The eCRF data are stored in REDCap database and processed electronically.  The data are reviewed for 
completeness, and logical consistency.  Automated validation programs identify missing data, out-of-

Targeting RV in PAH 
 
Page 32 
Version6  
 
range data, and other data inconsistencies. Requests for data clarification are forwarded to the 
investigative site for resolution. Certain data (e.g. independent radiographic assessments, ECGs, 
biomarker data) will be transferred from external vendors to the investigators.   
10.5 Data and Safety Monitoring Board 
An independent DSMB will be established to assure the safety of participants in this trial as well as the 
validity and integrity of the data generated.  The DSMB will review the study for safety and overall study 
conduct.  At the end of the study they may adjudicate final outcome based on the clinical information.  
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.   
 
11 Data Handling and Record Keeping 
11.1 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 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. 
11.2 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. 
11.3 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 CRFs, 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.   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. 

Targeting RV in PAH 
 
Page 33 
Version6  
 
11.4 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 safeguards.  Image data will be shared between institutions through a secure file 
share.  Prior to sharing, all data and all images will be anonymized to strip all identifiers to protect the 
human participants.   
 
11.5 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. 
11.6 Management of Information for Multi-Center Research 
University of Pennsylvania will be the coordinating center as well as a site for recruitment and data 
collection for the trial.  Brigham and Women’s Hospital, the University of Maryland and Washington 
University will be the other sites.  Dr. Han (Penn) and Dr. Waxman (BWH), the PIs of the grant together 
with the Project Manager at Penn will supervise all aspects of the project, including management of 
project timelines, management of data collected from each site, safety reporting, and submitting progress 
reports.  There will be regular, documented communication (e.g. teleconferences) with the participating 
sites to update and inform all participating sites about progress of the study.   As the lead investigator at 
the coordinating institution, Dr Han will receive data and reports from other sites in a timely manner and 
distribute them to the Penn IRB and other sites as required.  The PI for each site will be the regulatory 
sponsor for their site and will be responsible for enrollment, managing IRB communications and data 
quality.  The DSMB will also monitor participant safety, data quality and evaluate the progress of the 
study.   
 
12 Study Monitoring, Auditing, and Inspecting 
12.1 Study Monitoring Plan 
The Principal Investigator at each site is responsible for assigning staff for monitoring.  Enrollment will be 
complete when all subjects are enrolled into the trial across 3 sites.   The following will occur after the first 
subject is enrolled at each site, and throughout the trial:    
 
1) Informed consent documentation will be reviewed for all subjects 
2) Eligibility criteria 
3) Safety Monitoring (adverse event documentation and assessment) 
4) Regulatory documentation (IRB – amendments, continuing review and reportable events) 
 
12.2 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 CRFs are being completed.      
12.3  Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, government 
regulatory bodies, and University compliance and quality assurance groups of all study related 

Targeting RV in PAH 
 
Page 34 
Version6  
 
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. 
 
13 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 independent Ethics 
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of the EC/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 EC/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 EC/IRB for the study.  The formal 
consent of a subject, using the EC/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.  
14 Study Finances 
14.1 Funding Source 
 
Cardiovascular Medical Research and Education Fund 
Gilead Science Inc  
14.2 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 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. 
14.3 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 imaging study visits.   
 
15 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. 

Targeting RV in PAH 
 
Page 35 
Version6  
 
16 References 
 
1. 
Bogaard HJ, Abe K, Vonk Noordegraaf A, Voelkel NF. The right ventricle under pressure: Cellular 
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 
Physiol. 2004;286:H1185-1192 
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 
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 
patients with pulmonary hypertension and the effect of epoprostenol. J Am Coll Cardiol. 2005;45:1849-
1855 
11. 
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 
13. 
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 
14. 
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 
15. 
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 
16. 
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 
Cardiol. 2008;97:222-226 
18. 
van de Veerdonk MC, Kind T, Marcus JT, Mauritz GJ, Heymans MW, Bogaard HJ, Boonstra A, 
Marques KM, Westerhof N, Vonk-Noordegraaf A. Progressive right ventricular dysfunction in patients with 
pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol. 2011;58:2511-2519 

Targeting RV in PAH 
 
Page 36 
Version6  
 
19. 
Deng Z, Morse J, Slager S, Cuervo N, Moore K, Venetos G, Kalachikov S, Cayanis E, Fischer S, 
Barst R, Hodge S, Knowles J. Familial primary pulmonary hypertension (gene pph1) is caused by 
mutations in the bone morphogenetic protein receptor-ii gene. American Journal of Human Genetics. 
2000;67:737-744 
20. 
Lane K, Machado R, Pauciulo M, Thomson J, Phillips Jr, Loyd J, Nichols W, Trembath R. 
Heterozygous germline mutations in bmpr2, encoding a tgf-beta receptor, cause familial primary 
pulmonary hypertension. The international pph consortium. Nature Genetics. 2000;26:81-84 
21. 
Thomson J, Machado R, Pauciulo M, Morgan N, Humbert M, Elliott G, Ward K, Yacoub M, 
Mikhail G, Rogers P, Newman J, Wheeler L, Higenbottam T, Gibbs J, Egan J, Crozier A, Peacock A, 
Allcock R, Corris P, Loyd J, Trembath R, Nichols W. Sporadic primary pulmonary hypertension is 
associated with germline mutations of the gene encoding bmpr-ii, a receptor member of the tgf-beta 
family. Journal of Medical Genetics. 2000;37: 741-745 
22. 
Machado R, Pauciulo M, Thomson J, Lane K, Morgan N, Wheeler L, Phillips J, Newman J, 
Williams D, Galiè N, Manes A, McNeil K, Yacoub M, Mikhail G, Rogers P, Corris P, Humbert M, Donnai 
D, Martensson G, Tranebjaerg L, Loyd J, Trembath R, Nichols W. Bmpr2 haploinsufficiency as the 
inherited molecular mechanism for primary pulmonary hypertension. American Journal of Human 
Genetics. 2001;68:92-102 
23. 
Newman J, Wheeler L, Lane K, Loyd E, Gaddipati R, Phillips Jr, Loyd J. Mutation in the gene for 
bone morphogenetic protein receptor ii as a cause of primary pulmonary hypertension in a large kindred. 
New England Journal of Medicine. 2001;345:319-324. [Erratum, N Engl J Med 2001;2345:1506, 
2002;2346:1258.] 
24. 
Trembath R, Thomson J, Machado R, Morgan N, Atkinson C, Winship I, Simonneau G, Galie N, 
Loyd J, Humbert M, Nichols W, Morrell N, Berg J, Manes A, McGaughran J, Pauciulo M, Wheeler L. 
Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic 
telangiectasia. New England Journal of Medicine. 2001;345:325-334 
25. 
Small EM, Olson EN. Pervasive roles of micrornas in cardiovascular biology. Nature. 
2011;469:336-342 
26. 
Drake JI, Bogaard HJ, Mizuno S, Clifton B, Xie B, Gao Y, Dumur CI, Fawcett P, Voelkel NF, 
Natarajan R. Molecular signature of a right heart failure program in chronic severe pulmonary 
hypertension. Am J Respir Cell Mol Biol. 2011;45:1239-1247 
27. 
Creemers EE, Tijsen AJ, Pinto YM. Circulating micrornas: Novel biomarkers and extracellular 
communicators in cardiovascular disease? Circ Res. 2012;110:483-495 
28. 
Park IH, Zhao R, West JA, Yabuuchi A, Huo H, Ince TA, Lerou PH, Lensch MW, Daley GQ. 
Reprogramming of human somatic cells to pluripotency with defined factors. Nature. 2008;451:141-146 
29. 
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. Induction of 
pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861-872 
30. 
Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir 
GA, Ruotti V, Stewart R, Slukvin, II, Thomson JA. Induced pluripotent stem cell lines derived from human 
somatic cells. Science. 2007;318:1917-1920 
31. 
Ren Y, Lee MY, Schliffke S, Paavola J, Amos PJ, Ge X, Ye M, Zhu S, Senyei G, Lum L, Ehrlich 
BE, Qyang Y. Small molecule wnt inhibitors enhance the efficiency of bmp-4-directed cardiac 
differentiation of human pluripotent stem cells. J Mol Cell Cardiol. 2011;51:280-287 
32. 
Zhang J, Wilson GF, Soerens AG, Koonce CH, Yu J, Palecek SP, Thomson JA, Kamp TJ. 
Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res. 2009;104:e30-
41 
33. 
Itzhaki I, Maizels L, Huber I, Zwi-Dantsis L, Caspi O, Winterstern A, Feldman O, Gepstein A, 
Arbel G, Hammerman H, Boulos M, Gepstein L. Modelling the long qt syndrome with induced pluripotent 
stem cells. Nature. 2011;471:225-229 
34. 
Moretti A, Bellin M, Welling A, Jung CB, Lam JT, Bott-Flugel L, Dorn T, Goedel A, Hohnke C, 
Hofmann F, Seyfarth M, Sinnecker D, Schomig A, Laugwitz KL. Patient-specific induced pluripotent stem-
cell models for long-qt syndrome. N Engl J Med. 2010;363:1397-1409 
35. 
Carvajal-Vergara X, Sevilla A, D'Souza SL, Ang YS, Schaniel C, Lee DF, Yang L, Kaplan AD, 
Adler ED, Rozov R, Ge Y, Cohen N, Edelmann LJ, Chang B, Waghray A, Su J, Pardo S, Lichtenbelt KD, 
Tartaglia M, Gelb BD, Lemischka IR. Patient-specific induced pluripotent stem-cell-derived models of 
leopard syndrome. Nature. 2010;465:808-812 

Targeting RV in PAH 
 
Page 37 
Version6  
 
36. 
Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L. Antianginal efficacy of ranolazine when 
added to treatment with amlodipine: The erica (efficacy of ranolazine in chronic angina) trial. J Am Coll 
Cardiol. 2006;48:566-575 
37. 
Sendon JL, Lee S, Cheng ML, Ben-Yehuda O. Effects of ranolazine on exercise tolerance and 
angina frequency in patients with severe chronic angina receiving maximally-tolerated background 
therapy: Analysis from the combination assessment of ranolazine in stable angina (carisa) randomized 
trial. Eur J Prev Cardiol. 2012;19:952-959 
38. 
Rautaharju PM, Zhang ZM, Prineas R, Heiss G. Assessment of prolonged qt and jt intervals in 
ventricular conduction defects. Am J Cardiol. 2004;93:1017-1021