Conditions: Pulmonary Arterial Hypertension
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
The main objective of this study is to evaluate the safety and tolerability of 12-week oral CXA-10 therapy in subjects with pulmonary arterial hypertension, with additional evaluation on the clinical efficacy of oral CXA-10 on changes in hemodynamics, exercise capacity, cardiovascular function and patient reported outcomes.

Detailed description:
This is a single-center, one-arm, open-label proof of concept safety study and a phase 2a proof of efficacy pre- and post-assessment study of oral CXA-10 for the treatment of pulmonary arterial hypertension.

The investigators hypothesize that administration of CXA-10 for 12 weeks will improves exercise capacity, cardiovascular function and health related quality of life in pulmonary arterial hypertension patients with limited toxicity.

Subjects who meet the inclusion criteria and none of the exclusion criteria will be scheduled within 4 weeks of screening to receive oral CXA-10 at the dose of 300 mg once daily followed by 12 weeks of open-label CXA-10 treatment and then a 4-week safety follow-up. Additional follow-up assessments by telephone will occur in between each outpatient clinic visit.

Arms:
arm 1: Oral CXA-10 300 mg once daily for 12 weeks

Interventions: intervention 1: CXA-10
Intervention descriptions: intervention 1: Each subject will receive oral CXA-10 at the dose of 300 mg once daily for 12 weeks

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
CLINICAL PROTOCOL 
 
 
 
 
 
 
Phase 2 Open-Label Study of Safety and Efficacy Trial of CXA-10 in 
Pulmonary Arterial Hypertension 
 
 
 
 
 
IND 140685 
 
IND Sponsor: Mark Gladwin, MD 
 
Principal Investigator: Marc Simon, MD 
Co-Principal Investigator: Belinda Rivera-Lebron, MD 
 
 
 
University of Pittsburgh  
School of Medicine 
 
 
 
 
Version 1.4 
March 4, 2020 
 
 
 


Oral CXA-10 in PAH                                                                                     
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS………………………………………………………………………………...3 
 
1. 
STUDY OBJECTIVE, SPECIFIC AIMS, BACKGROUND AND SIGNIFICANCE….........9 
 
1.1 OBJECTIVE………………………………………………………………………………...10 
 
1.2 SPECIFIC AIMS……………………………………………………………………………10 
 
1.3 BACKGROUND AND RATIONALE……………………………………………………...10 
 
1.4 SIGNIFICANCE…………………………………………………………………………….15 
 
2. 
RESEARCH DESIGN AND METHODS……………………………………………………..16 
 
2.1 CLASSIFICATION AND METHODOLOGICAL DESIGN……………………………...15 
 
2.2 DETAILED DESCRIPTION OF STUDY DESIGN………………………….................16 
 
2.3 STUDY DRUG(S)………………………………………………………………................25 
 
2.4 STUDY ENDPOINTS……………………………………………………………………...27 
 
2.5 STATISTICAL ANALYSIS………………………………………………………………...28 
 
3. 
HUMAN SUBJECTS…………………………………………………………………………..30 
 
3.1 SUBJECT POPULATION………………………………………………………………....30 
 
3.2 INCLUSION CRITERIA…………………………………………………………………...31 
 
3.3 EXCLUSION CRITERIA…………………………………………………………………..31 
           3.4 PRECAUTIONARY AND PROHIBITED MEDICATIONS………………………………33 
 
4. 
IRB APPROVAL AND FDA AMMENDMENTS ……………………………………………36 
 
5. 
RECRUITMENT AND INFORMED CONSENT PROCEDURES………………………….36 
5.1 RECRUITMENT METHODS……………………………………………………………...36 
 
5.2 INFORMED CONSENT PROCEDURES………………………………………………..38 
 
6. 
POTENTIAL RISKS AND BENEFITS……………………………………………………….38 
 
6.1 POTENTIAL RISKS………………………………………………………………………..38 
 
6.2 ALTERNATIVE TREATMENTS…………………………………………………………..42 
 
6.3 POTENTIAL BENEFITS…………………………………………………………………..42 
 
6.4 DATA SAFETY MONITORING ……..……………………………………………………42 
 
6.5 RISK MANAGEMENT PROCEDURES………………………………………………….47 
 
7. 
COSTS AND PAYMENTS…………………………………………………………………….49 
 
7.1 COSTS……………………………………………………………………………………...49 
 
7.2 PAYMENTS………………………………………………………………………………...49 
 
8. 
QUALIFICATIONS AND SOURCE OF SUPPORT………………………………………...49 
 
8.1 QUALIFICATIONS OF THE INVESTIGATORS………………………………………..49 
 
8.2 SOURCE OF SUPPORT………………………………………………………………….51 
 
9. 
REFERENCES……………………………………………………………………………….…51 
 
 
 


Oral CXA-10 in PAH                                                                                     
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PROTOCOL SYNOPSIS 
 
Protocol Title: 
Phase 2 Open-Label Study of Safety and Efficacy Trial of CXA-
10 in Pulmonary Arterial Hypertension 
 
Protocol Number: 
STUDY19010004 
 
NCT Number: 
NCT04125745 
 
Version # and Date: 
Version 1.4/March 4, 2020 
 
Clinical Phase: 
 
Phase II Clinical Trial 
Investigational 
Product: 
CXA-10 
Trial Site: 
Single-Center Trial 
 
IND Sponsor 
Mark Gladwin, MD 
University of Pittsburgh, School of Medicine 
 
Principal Investigator: 
Marc Simon, MD 
 
 
Co-Principal 
Investigator: 
Belinda Rivera-Lebron, MD 
 
Sub-Investigators: 
Mark Gladwin, MD 
Bruce Freeman, PhD 
Alison Morris, MD 
Nicole Helbling, DNP, RN, 
CRNP 
 
Frederico Toledo, MD 
Stacy Wendell, PhD 
 
Study Monitor: 
Mark Gladwin, MD, IND Sponsor-Investigator 
 
Research Facilities: 
UPMC Montefiore Hospital, UPMC Presbyterian, CLC at Falk 
Clinic, Kaufman Medical Building 
 
 
Clinical Laboratories: 
UPMC Presbyterian Hospital, Shadyside CP PUH, UPMC 
Clinical Laboratory Building, 3477 Euler Way, Pgh, PA 15213  
 
Study Rationale: 
 
 
 
 
 
To date, current therapies for pulmonary arterial hypertension 
(PAH) are vasodilatory and reduce the symptoms associated 
with pulmonary artery (PA) vasoconstriction. The ability to modify 
the underlying disease (re-establish the normal architecture of 
the pulmonary vessels and cardiac muscle and improve right 
ventricular (RV) function to reduce morbidity and mortality) will 


Oral CXA-10 in PAH                                                                                     
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be the most important treatment goal for the next generation of 
therapies, ultimately translating to better outcomes.  
 
CXA-10 has the potential to be differentiating as a “disease 
modifying” therapy in PAH.  CXA-10 targets the oxidative stress, 
inflammatory and metabolic pathways shown to be important 
causes in this disease. Its ability to affect multiple targets is key 
to improving both the pulmonary vasculature and cardiac 
abnormalities of PAH. 
 
Study Objectives: 
The main objective of this study is to evaluate the safety and 
tolerability of 12-week oral CXA-10 therapy in subjects with 
pulmonary arterial hypertension (PAH), with preliminary 
evaluation on the clinical efficacy of oral CXA-10 on changes in 
hemodynamics, exercise capacity, cardiovascular function and 
patient reported outcomes. 
  
Study Hypothesis: 
We hypothesize that administration of CXA-10 for 12 weeks will 
decrease pulmonary vascular resistance (PVR) as measured by 
right heart catheterization (RHC), improve exercise capacity, 
cardiovascular function and health related quality of life in PAH 
patients with limited toxicity. 
 
Study Aims: 
Aim 1: To determine the safety and tolerability of oral CXA-10 
administered for 12 weeks in PAH subjects. 
 
Aim 2: To characterize the efficacy of CXA-10 administered for 
12 weeks in PAH subjects assessed by pulmonary vascular 
resistance (PVR) as measured by right heart catheterization 
(RHC). 
 
Aim 3: To characterize the efficacy of CXA-10 administered for 
12 weeks in PAH subjects on exercise capacity assessed by 6 
minute walk distance and home accelerometry, cardiovascular 
function assessed by RHC and echocardiogram, and patient 
reported outcomes assessed by disease specific health related 
quality of life questionnaire. 
 
Aim 4: To explore the pharmacokinetic-pharmacodynamic 
relationships of CXA-10 using sparse blood measures of drug 
concentrations and biomarkers associated with mechanism of 
action (MOA) of CXA-10 and PAH disease as endpoints in PAH 
subjects, if the data warrant such an analysis. 
 
Study Design: 
This is an open-label safety study and a phase 2a pre- and post-
assessment study aimed to evaluate the efficacy and safety of 
12-week oral CXA-10 therapy on the changes in hemodynamics 
and exercise capacity in PAH patients. 


Oral CXA-10 in PAH                                                                                     
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Potential subjects will undergo a screening visit to determine that 
eligibility requirements are met. Subjects who meet the inclusion 
criteria and none of the exclusion criteria will receive oral CXA-
10 at the dose of 300 mg once daily for 12 weeks. 
 
The first 10 subjects enrolled will receive the first dose of the 
study drug in the cardiac catheterization laboratory to evaluate 
acute pharmacological responses during the screening RHC 
(Visit1). This will be repeated at the end of the 12-week study 
RHC (Visit 7). Hemodynamic measures such as pulmonary 
vascular resistance (PVR), mean pulmonary artery pressure 
(mPAP) and left and right ventricular filling pressures, will be 
measured at baseline and 30 minutes post drug dose and CXA 
10 metabolites will be measured with pharmacokinetics 
sampling time points at baseline and 2-6 hours post drug. Food 
will be given prior to dosing. Subjects will have 6-minute walk 
distance with Borg dyspnea scale assessments. Plasma NT-
proBNP level, the World Health Organization (WHO) Functional 
Class assessment, and a health related quality of life 
questionnaire will also be collected. To evaluate in vivo insulin 
action in stimulating glucose disposal, oxidation, and 
nonoxidative disposal. An intravenous glucose tolerance test 
(IVGTT) will be performed before and after 12 weeks of CXA-10 
treatment. 
 
Subjects will be evaluated at 4-week intervals for occurrences of 
adverse events, laboratory test abnormalities, and evaluations of 
NT-proBNP plasma levels, six-minute walk distance with Borg 
dyspnea scale assessments, WHO functional classification and 
health related quality of life questionnaire recorded.  Additional 
blood samples will be obtained for biomarkers and cytokines 
analysis, and physical activities will be monitored using a 
noninvasive accelerometer before and after study drug 
treatment. 
 
Planned Sample Size:  
27 completed subjects 
 
Duration of Treatment: 
12 weeks 
 
Major Inclusion 
Criteria:  
• 
Male or female between 18-80 years of age inclusive at 
screening 
• 
Weight ≥ 40 kg or 88 lbs. 
• 
Have a WHO Classification of Functional Status Class II or III 
• 
Must meet all of the following hemodynamic criteria by means 
of a right heart catheterization: mPAP of ≥25 mmHg, PVR ≥ 


Oral CXA-10 in PAH                                                                                     
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3 wood units, PAWP of ≤15 mmHg. A clinical RHC done 
within 2 months may be acceptable to determine eligibility. 
• 
Meet all of the following pulmonary function test parameters, 
completed no more than 12 months before Screening or at 
screening: forced expiratory volume in one second (FEV1) > 
60% of predicted normal and forced vital capacity (FVC) ≥ 
60%  
• 
A 6 MWD test of ≥ 100 m and ≤ 600 m at Screening  
• 
Participants enrolled in an exercise program for pulmonary 
rehabilitation must be in a stable program 1 month prior to 
Screening and must agree to maintain their current level of 
rehabilitation throughout the study. If subjects are not 
enrolled in an exercise training program for pulmonary 
rehabilitation 
they 
cannot 
enroll 
during 
the 
screening/baseline period or throughout the study 
• 
If receiving HMG-CoA reductase inhibitors (i.e., statins) 
subjects must not have changed their dose <4 weeks prior to 
Screening 
• 
If receiving simvastatin-containing products: simvastatin 
(Zocor), Vytorin, or any other combination therapy containing 
simvastatin, the subject’s simvastatin dose should not 
exceed 20 mg/day. Note: Subjects using a simvastatin 
product at dose > 20 mg/day may be rescreened if their dose 
has been adjusted to < 20 mg/day, at least 4 weeks prior to 
Screening with no dose or regimen changes within 4 weeks 
prior to Baseline 
• 
Subjects must be receiving one or more of the following 
previously approved PAH therapies: phosphodiesterase type 
5 inhibitors (PDE5), endothelin receptor antagonist (ERA), 
soluble guanylate cyclase (sGC) stimulator, prostanoids, 
prostacyclin receptor agonists and must be on stable doses 
(> 3 months) with no dose adjustment within 1 month of 
Screening  
• 
Ability to provide written informed consent 
 
Major Exclusion 
Criteria: 
• 
Portopulmonary hypertension and pulmonary veno-
occlusive diseases  
• 
Congenital heart defects  (i.e., atrial septal defects, 
ventricular septal defects, and patent ductus arteriosus)  
repaired less than 1 year prior to Screening (Group 1 
classification of Pulmonary Hypertension)  
• 
Systolic blood pressure > 160 or < 90 mmHg or diastolic 
blood pressure > 110 mmHg at Screening 
• 
QTcF interval of >500 msec on triplicate supine ECGs 
Screening (Visit 1) 
• 
Acute myocardial infarction or acute coronary syndrome 
(ST-Elevation Myocardial Infarction (STEMI), Non STEMI 


Oral CXA-10 in PAH                                                                                     
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(NSTEMI) and/or unstable angina) within the last 90 days 
prior to Screening 
• 
Recent cerebrovascular accident/transient ischemic 
attack (CVA/TIA) within the last 90 days prior to 
Screening 
• 
Recent hospitalization for left heart failure within the last 
90 days prior to Screening 
• 
Clinically significant aortic or mitral valve disease defined 
as greater than moderate regurgitation or moderate 
stenosis; 
pericardial 
constriction; 
restrictive 
or 
constrictive cardiomyopathy; left ventricular dysfunction 
(LVEF < 50%); left ventricular outflow obstruction; 
symptomatic 
coronary 
artery 
disease; 
autonomic 
hypotension; or fluid depletion in the opinion of the 
investigator  
• 
Evidence of a life-threatening cardiac arrhythmias on 
ECG at Screening as determined by the physician 
investigator 
• 
Personal or family history of congenital prolonged QTc 
syndrome or sudden unexpected death due to a cardiac 
reason 
• 
Receiving 
intravenous 
inotropes 
(e.g. 
dopamine, 
dobutamine) within 2 weeks prior to Screening 
• 
History of angina pectoris or other condition that was 
treated with long or short acting nitrates <12 weeks of 
Screening 
• 
History of herbal or natural medication use (including fish 
oil) within 2 weeks or 5 half-lives, whichever is longer, 
prior to Baseline 
• 
Subject has taken prednisone at doses > 15 mg/day; if 
immunosuppressive medications are used the dose must 
be stable within 12 weeks prior to Screening and 
throughout the study 
• 
The subject is currently taking a drug that may affect the 
assay measurement of serum creatinine (e.g. cimetidine, 
Bactrim, Pyridium) 
• 
Newly prescribed drug or increased dose of an existing 
drug that is known to prolong the QTc interval and has 
been associated with Torsades de Pointes Note: Stable 
doses of these drugs are permitted (i.e., subject has 
received the same dose and regimen for at least 30 days 
prior to Screening with no anticipated changes to the 
dose or regimen during the course of the study) 


Oral CXA-10 in PAH                                                                                     
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• 
The subject is currently taking dimethyl fumarate 
(Tecfidera™) 
• 
Females with a positive urine pregnancy test at 
Screening or prior to dosing or who are pregnant or 
breastfeeding or who are trying to conceive. 
• 
Recent (within 6 months) history of abusing alcohol or 
illicit drugs 
• 
History of any primary malignancy, including a history of 
melanoma or suspicious undiagnosed skin lesions, with 
the exception of basal cell or squamous cell carcinomas 
of the skin or cervical carcinoma in situ or other 
malignancies curatively treated and with no evidence of 
disease for at least 5 years or prostate cancer who is not 
currently or expected, during the study, to undergo 
radiation 
therapy, 
chemotherapy, 
and/or 
surgical 
intervention, or to initiate hormonal treatment 
• 
Cardiovascular, 
liver, 
renal, 
hematologic, 
gastrointestinal, immunologic, endocrine, metabolic, 
central nervous system or psychiatric disease that, in the 
opinion of the investigator, may adversely affect the 
safety of the subject and/or efficacy of the investigational 
product or severely limit the lifespan of the subject other 
than the condition being studied 
• 
Clinically significant hyperthyroidism or hypothyroidism 
not adequately treated  
• 
Any other condition and/or situation that causes the 
Investigator to deem a subject unsuitable for the study 
(e.g., due to expected study medication non-compliance, 
inability to medically tolerate the study procedures, or a 
subject’s unwillingness to comply with study-related 
procedures) 
• 
The subject has known hypersensitivity to the CXA-10, 
the metabolites, or formulation excipients 
• 
The subject has had treatment with any investigational 
drug within 30 days or 5 half-lives (whichever is longer) 
prior to Screening or plans to participate in an 
investigational drug study at any time during this study 
 
Study Endpoints: 
Primary Endpoint:  
The primary endpoint measures the incidences of treatment-
emergent adverse events. 
 
Secondary Endpoints: 


Oral CXA-10 in PAH                                                                                     
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The primary efficacy endpoint measures the change from 
baseline in Pulmonary Vascular Resistance (PVR) assessed by 
Right Heart Catheterization at 12 weeks. 
 
Other secondary endpoints measure: 
• 
Change from baseline in hemodynamic parameters 
including Cardiac Output (CO), Cardiac index (CI), mean 
Pulmonary Artery Pressure (mPAP), Pulmonary Artery 
Wedge Pressure (PAWP), Mean Right Atrial Pressure 
(mRAP), and compliance (SV/ (sPAP-dPAP) at 12 weeks 
• 
Change from baseline in RV function including tricuspid 
annular plane systolic excursion (TAPSE) and tissue 
Doppler of the lateral tricuspid valve anulus (S’) as 
assessed by echocardiograms at 12 weeks 
• 
Change from baseline in functional exercise capacity by 
assessing 6 minute walk distance test with Modified Borg 
Dyspnea Scale at 12 weeks 
• 
Change from baseline in the levels of serum NT-proBNP 
at 12 weeks 
• 
Change from baseline in WHO Functional Class at 12 
weeks 
• 
Change from baseline in patient reported outcomes 
measured by PAH-SYMPACT® questionnaire at 12 
weeks 
• 
Change from baseline in daily physical activity assessed 
by personalized activity monitor at 12 weeks 
• 
Pharmacokinetic 
endpoint: 
CXA-10 
parent 
and 
metabolites 
 
Exploratory Endpoints: 
• 
Change in insulin sensitivity by intravenous glucose 
tolerance test at 12 weeks 
• 
Pharmacodynamic endpoint:  change from baseline in 
serum biomarkers, leptin, inflammatory cytokines (IL-17, 
IL-6, TNFα, MCP-1) and hsCRP at 12 weeks 
• 
Pharmacokinetic - Pharmacodynamic relationship of 
CXA-10 on relevant efficacy, safety and biomarkers 
endpoints 
• 
Epidemiological relationships of oral and gut microbiome 
and PAH 
 
 
1. OBJECTIVE, SPECIFIC AIMS, BACKGROUND, AND SIGNIFICANCE 
 
1.1 OBJECTIVE 
 
The main objective of this study is to evaluate the safety and tolerability of 12-week oral CXA-10 
therapy in subjects with pulmonary arterial hypertension (PAH), with additional evaluation on the 


Oral CXA-10 in PAH                                                                                     
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clinical efficacy of oral CXA-10 on changes in hemodynamics, exercise capacity, cardiovascular 
function and patient reported outcomes. 
 
 
1.2 SPECIFIC AIMS 
 
Hypothesis: 
 
We hypothesize that administration of CXA-10 for 12 weeks will decrease pulmonary vascular 
resistance (PVR) as measured by right heart catheterization (RHC), and improves exercise 
capacity, cardiovascular function and health related quality of life in PAH patients with limited 
toxicity.  
 
Specific Aims: 
 
Aim 1: To determine the safety and tolerability of oral CXA-10 administered for 12 weeks in PAH 
subjects. 
 
Aim 2: To characterize the efficacy of CXA-10 administered for 12 weeks in PAH subjects 
assessed by PVR as measured by RHC. 
 
Aim 3: To characterize the efficacy of CXA-10 administered for 12 weeks in PAH subjects on 
exercise capacity assessed by 6 minute walk distance and home accelerometry, cardiovascular 
function assessed by RHC and echocardiogram, and patient reported outcomes assessed by 
disease specific health related quality of life questionnaire. 
 
Aim 4: To explore the pharmacokinetic-pharmacodynamic relationships of CXA-10 using sparse 
blood measures of drug concentrations and biomarkers associated with mechanism of action 
(MOA) of CXA-10 and PAH disease as endpoints in PAH subjects, if the data warrant such an 
analysis. 
 
 
1.3. BACKGROUND and RATIONALE 
 
1.3.1 Epidemiology and Pathophysiology 
Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries, 
characterized by vasoconstriction, vascular proliferation and remodeling. It is defined by an 
increase in the mean pulmonary artery pressure (mPAP) > 25 mmHg at rest and normal left 
ventricular filling pressures in the absence of diseases that could ‘‘mimic’’ this hemodynamic 
profile such as chronic obstructive pulmonary disease, interstitial lung disease, or 
thromboembolic lung disease.1 Patients usually present with exertional dyspnea, reduced 
exercise tolerance and fatigue. Overt symptoms of right heart failure emerge relatively late in 
the disease. The 5-year survival rate for patients with PAH is 57%.2 With a USA population 
incidence of 2 cases/million and a prevalence of approximately 12.4 cases/million based on data 
from the REVEAL registry3, PAH is an orphan disease characterized by very high unmet medical 
need.2 
PAH is a pulmonary vasculopathy characterized by chronic vasoconstriction, aberrant cellular 
proliferation and dysfunction and thrombosis leading to complex lesions called plexiform lesions. 
Vascular processes that take place include endothelial cell dysfunction, muscularization of 
normally non-muscular arteries, proliferation of vascular smooth muscle cells and increased 


Oral CXA-10 in PAH                                                                                     
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extracellular matrix deposition and fibrosis. All these features act in concert to raise PVR and 
right ventricular (RV) afterload. Consequent rises in RV pressure lead to RV hypertrophy (RVH) 
and eventual maladaptive cardiac remodeling and death.4 Although changes in the pulmonary 
vasculature are the primary cause of PAH, severity of symptoms and survival are strongly 
associated with right ventricular function. Despite the fact that medical therapies improve PVR, 
the prognosis for patients with PAH is still poor with the primary cause of death due to RV 
dysfunction and, ultimately, RV failure. 
Although the pathophysiology of PAH is not well understood, excessive production of reactive 
oxygen species (ROS), that can lead to damage of the vasculature, may play a significant role 
in the disease process.5-7 The damage to the vasculature induces excessive cellular 
inflammatory responses, with increased production of cytokines, chemokines, adipokines and 
growth factors as well as an increase in WBC infiltration and activity, fibrosis and cell death.4, 8, 9 
In the right ventricle, there is a transition from an adaptive pressure-overloaded RV to a 
maladaptive response. Causes may be due to insufficient RV contractility, myocardial fibrosis, 
capillary rarefaction and disturbed metabolism.4 Many of these pathways are the major targets 
for CXA-10 activity. 
Currently available treatment options promote vasodilation or inhibit vasoconstriction, thus 
decreasing pressure in the pulmonary arteries. These therapies include: endothelin receptor 
antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5Is), soluble guanylate cyclase 
(sGC) stimulators and prostacyclin analogues or receptor agonists. Although these therapies 
have been shown to have a positive effect on symptoms, they have little improvement in 
modifying the course of disease or in significantly prolonging survival.  Intravenous 
epoprostenol, was the only controlled study in PAH shown to improve survival with treatment.10 
 
1.3.2 CXA-10 Mechanism of Action 
CXA-10 (10-nitrooctadec-9(E)-enoic acid), an oral formulation of an endogenous compound, is 
a specific isomer of nitrated oleic acid (OA-NO2) with unique electrophilic properties that facilitate 
rapid and reversible protein adduction reactions with cysteine and, to a lesser extent, histidine 
residues11, but not DNA bases. Nitro fatty acids are a novel class of drugs which are endogenous 
mediators of signaling pathways that respond to cellular stress and damage. The mechanisms 
of action of CXA-10 are through post-translational signal modification by protein adduction of 
key signaling molecules. These signaling molecules are specifically involved in modulating 
metabolic and inflammatory activity leading to tissue protection and anti-oxidant, anti-
inflammatory and anti-fibrotic activity. While the actions of CXA-10, as an inducer of cell-
protective mechanisms, are multifaceted, they are also discriminate and specific, and have been 
characterized in in vitro and in vivo studies.12-15 
Major actions of CXA-10 are: 
1) to selectively adduct key cysteine residues (Cys273 and 288) of Kelch-like ECH- associated 
protein (Keap 1) to release and stabilize the nuclear factor E2-related factor 2 (Nrf2) and 
heme oxygenase-1 (HO-1), to upregulate antioxidant and detoxifying gene expression and 
effector protein production, and 
2) to selectively adduct Cys38 of the p65 subunit of nuclear factor κB (NF-κB) and to disrupt 
Toll-like receptor 4 (TLR4) signaling complex to prevent the elaboration of pro- 
inflammatory mediators such as cytokines and chemokines, pro-fibrotic agents, and 
adhesion molecules, and 
3) to bind to heat shock response elements and drive the expression of heat shock proteins 
(HSPs) which act as chaperones during cellular stress, and 


Oral CXA-10 in PAH                                                                                     
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4) to inhibit xanthine oxidoreductase (XOR) (IC50 = 0.6 μM in vitro, Kelly 2008) which is one 
of the major enzymes involved in the production of ROSs, agents that cause much of the 
damage associated with oxidative stress pathology. 
CXA-10 has been evaluated in vitro and in animal models.9, 16-19  The models have specifically 
demonstrated CXA-10’s ability to: 
1) Inhibit disease-associated oxidative stress and NF-ĸB/TLR4 induced inflammation 
(including cytokines, chemokines, inflammatory white blood cells, etc.) in pulmonary 
arterioles and RV muscle 
2) Improve PA structure (reverse remodeling) 
3) Reduce PA pressure 
4) Improve RV function 
5) Improve abnormal metabolic pathways that have been associated with obesity-induced PAH 
6) In vitro - Restore impaired bone morphogenetic protein receptor Type 2 (BMPR2) function 
which is genetically impaired in patients with heritable PAH and affects the pulmonary 
vasculature 
 
Many of the key pharmacological actions of CXA-10 underlying improvements in animal disease 
models have been demonstrated in humans in Complexa’s Phase 1 studies. These studies were 
conducted in subjects with renal disease and obesity. Administration of CXA-10 specifically: 
 
• 
Increased expression of Nrf2 and heat shock-related genes in whole blood and urinary 
exosomes in a dose-related fashion 
• 
Inhibited NF-κB pro-inflammatory activity (decreased cytokine levels) in blood 
• 
Improved abnormal metabolic pathways (decreased leptin and lipid concentrations) in blood 
 
1.3.3 Safety in Humans 
 
To date, three (3) studies using the oral formulation of CXA-10 have been conducted (Studies 
CXA-10-201, CXA-10-202 and CXA-10-203). Study CXA-10-201 was a single dose escalation 
study in 30 healthy volunteers. CXA-10 was administered at doses ranging from 150 mg to 1200 
mg once daily and 1800 mg as two divided doses of 900 mg. Study CXA-10-202 was a multiple 
dose escalation study in 42 obese subjects (3 cohorts of 14: 10 subjects treated with CXA-10 at 
each dose level, and 4 subjects treated with placebo). CXA-10 was administered at doses of 25 
mg and 150 mg once daily for 14 days and at 600 mg once followed by 450 mg daily for a total of 
14 days. Subjects in the last cohort receiving CXA-10 450 mg daily were fed a high fat (50%) diet 
on Day 15 followed by a single dose of CXA-10 or placebo. CXA-10-203 was an exploratory drug-
drug interaction study in 10 healthy male volunteers to investigate the effect of CXA-10 on the 
pharmacokinetics (PK) profiles of pravastatin and the two components of Vytorin® (combination 
of simvastatin and ezetimibe). Subjects received single doses of pravastatin (40 mg) and Vytorin® 
(ezetimibe/simvastatin 10 mg/20 mg/day) alone and after the administration of CXA-10 150 mg 
daily with food (standard meal of approximately 30% fat) for 8 and 9 days respectively. 
 
Study CXA-10-201 
Oral doses of CXA-10 and matched placebo at all doses administered were observed to be safe 
and well tolerated. There were no clinically significant abnormalities reported on physical 
examination, vital signs or routine electrocardiogram (ECG) evaluation. CXA 10 at any dose had 
no clinically relevant effect on ECG parameters (i.e., heart rate [HR], QTcF [QT corrected for HR 
based on Fridericia formula], PR, and QRS intervals). There were no clinically significant findings 


Oral CXA-10 in PAH                                                                                     
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in clinical laboratory evaluations including creatine phosphokinase (CPK), magnesium (Mg), 
creatinine levels, or liver function tests (LFTs). There were no significant findings in white blood 
cells (WBCs) including lymphocyte and monocyte counts. There were no serious adverse events 
(SAEs), withdrawals due to adverse events (AEs), or deaths. 
 
A total of 25 subjects (CXA-10, n=23; placebo, n=2) reported AEs. The most common AEs (>20%) 
were gastrointestinal (GI) AEs of diarrhea, nausea, and abdominal pain or discomfort. All reported 
AEs were mild to moderate in intensity and all resolved without sequelae. There appeared to be 
a dose response relationship with respect to the GI related AEs. As the dose increased, the 
number of subjects and number of GI AEs increased. Diarrhea was reported in the majority of 
subjects (5 of 6) in cohorts 4 (1200 mg) and 5 (1800 mg), which did not worsen with increasing 
dose. 
 
Study CXA-10-202 
Oral administration of CXA-10 and placebo, at all doses, were safe and tolerated. There were no 
clinically significant abnormalities reported on physical examination, vital signs or routine ECG 
evaluation. CXA-10 at any dose had no clinically relevant effect on ECG parameters (i.e., HR, 
QTcF, PR, and QRS intervals) based on serial ECGs extracted from continuous 12-lead ECG 
recording (Holter monitoring). There were no clinically significant findings in clinical laboratory 
evaluations including CPK, Mg, creatinine levels, or LFTs. There were no significant findings in 
WBC counts including lymphocyte and monocyte counts. There was a slight decrease in 
hemoglobin and red blood cell (RBC) counts during treatment on Days 8 and 15 at the highest 
dose (450 mg) compared to placebo. There were no SAEs, withdrawals due to AEs, or deaths 
during the study. 
 
A total of 26 out of 43 subjects who received CXA-10 across all dose groups or placebo reported 
AEs. The most commonly reported AEs (> 20%) were diarrhea, nausea, presyncope, fatigue and 
back pain. More subjects in the 450-mg dose group (cohort 3) reported AEs of diarrhea and 
nausea. The Investigator considered AEs of diarrhea, nausea, presyncope, and fatigue as 
possibly or definitely related to study medication. The AEs of back pain were considered unrelated 
by the Investigator. All reported AEs were mild to moderate in intensity and all resolved without 
sequelae. 
 
Study CXA-10-203 
Oral doses of 150 mg CXA-10 were observed to be safe and well tolerated. There were no 
clinically significant abnormalities reported on physical examination, vital signs, or routine ECG 
evaluation. CXA-10 had no clinically relevant effect on ECG parameters (i.e., HR, QTcF, PR, and 
QRS intervals). There were no clinically significant findings in clinical laboratory evaluations 
including CPK, Mg, creatinine levels, or LFTs. There were no significant findings in WBC counts 
including lymphocyte and monocyte counts.  
 
A total of 3 of 10 subjects reported AEs. One subject had nasopharyngitis, 1 subject had 
abdominal discomfort after the administration of pravastatin, and 1 subject had 7 AEs that may 
have been attributed to Norovirus infection (abdominal discomfort, diarrhea, nausea, vomiting, 
feeling of body temperature change, and decreased appetite). GI AEs related to CXA-10 observed 
in previous studies were not observed in this study. Thus, these events may have been prevented 
by administering CXA-10 with food. All reported AEs were mild to moderate in intensity and all 
resolved without sequelae. There were no serious AEs, withdrawals due to AEs or deaths during 
the reporting period. 
 


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Overall, oral administration of CXA-10 at single doses ranging from 150 to 1800 mg (900 mg 
administered twice approximately 6 hours apart) and in multiple doses ranging from 25 to 
450 mg was safe and generally well tolerated. There were no serious adverse events AEs 
(SAEs), withdrawals due to adverse events (AEs), or deaths in any of the studies. The most 
commonly reported AEs were GI-related. A dose dependent increase in the incidence of 
diarrhea and nausea was observed after oral administration in the fasted state (studies CXA-10-
201 and CXA-10-202). However, the severity of these events did not increase with increasing 
dose. All diarrhea AEs were Grade 1 or 2 in intensity (Common Terminology Criteria for 
Adverse Events v4.0) and began as loose stools that became watery over time. Across the four 
Phase 1 oral administration studies, diarrhea was reported by 31 of 80 subjects (39%) and 
nausea was reported by 12 of 80 subjects (15%). The incidence of GI events was lower when 
CXA-10 was administrated orally with food compared with the fasted state. In Study CXA-10-
202, 9 of 10 subjects (90%) experienced diarrhea who received oral administration of 450 mg 
CXA-10 fasted on Days 1 to 14 compared with 3 of 9 subjects (33.3%) who received 450 mg 
CXA-10 fed (50% fat) on Day 15. In Study CXA-10-203, the 150 mg dose was administered for 
9 days in the fed state (30% fat), and only 1 of 10 subjects (10%) experienced diarrhea. The 
diarrhea in this subject was attributed to a norovirus infection and was not considered treatment-
related by the Investigator. A similar trend was observed with nausea AEs. There were no 
clinically significant abnormalities reported on electrocardiogram (ECG) parameters, and no 
apparent effect of study drug treatment on cardiac conduction intervals, including no effect on 
QT/QTc calculated using the Fridericia correction (QTcF). Additionally, there were no clinically 
relevant findings in clinical laboratory evaluations or vital signs. 
 
Study CXA-10-204 
In the ongoing Phase 2 clinical study CXA-10-204 (called FIRSTx; patients with primary FSGS), 
patients are dosed in the fed state with CXA-10 at doses up to 300 mg once daily in a 90 day 
open-label study. To date, 18 FSGS patients have been treated for up to 90 days at 150 mg/day 
and 7 FSGS patients have been treated for up to 90 days with 300 mg/day.  There have been 
no deaths and none of the subjects have experienced a treatment-related SAEs. The most 
common treatment-related AEs have been GI in nature (mild diarrhea and moderate abdominal 
pain and nausea). These events were of limited duration and were ameliorated when CXA-10 
was administered with food.  
 
Pharmacokinetic Results 
Based on the results of the CXA-10-203 exploratory drug-drug interaction study, there is a 
potential for a drug-drug interaction with CXA-10 and simvastatin. This interaction results in 
increased exposure of the metabolite of simvastatin (simvastatin hydroxy acid), indicating that 
OATP1B1 may be inhibited by CXA-10. Simvastatin hydroxy acid is more potent than parent 
simvastatin. As a result, co-administration of CXA-10 and simvastatin could result in greater risk 
for side effects commonly associated with statins, including increased CPK, muscle toxicity, and 
liver function test elevation. In the absence of a definitive drug-drug interaction study, clinical 
studies involving CXA-10 will not allow the concomitant use of simvastatin at doses exceeding 20 
mg daily. 
 
1.3.4 In vivo finding in animal models 
In obese mice with pulmonary hypertension (PH)16, administration of OA-NO2 (CXA-10 isomer) 
improved PA function and structure (reverse remodeling) to reduce PA pressure. OA-NO2 
significantly reduced PA smooth muscle (PASM) thickening and macrophage infiltrations and 
significantly decreased pulmonary vascular resistance (PVR) and mean PA pressure (mPAP). 
Cardiac function and structure were also markedly improved. OA-NO2 significantly decreased 


Oral CXA-10 in PAH                                                                                     
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high fat diet-induced RV end systolic pressure (RVESP), improved cardiac contractility and 
reduced RVH.  Cytokine levels (MCP-1, IL-6) and XO activity, a measure of oxidative stress, were 
also significantly reduced in whole lungs of OA-NO2 treated mice. Glucose tolerance and plasma 
leptin levels were also significantly improved with OA-NO2 treatment in this model of obesity-
induced PH. 
 
In a hypoxia-induced mouse model of PH17, OA-NO2 significantly decreased RV systolic pressure 
(RVSP) and attenuated RVH and fibrosis.  OA-NO2 also improved pulmonary structure. OA-NO2 
significantly limited PA smooth muscle thickness and significantly diminished macrophage 
infiltration and superoxide production in lung of treated mice. In a recent study, Koudelka et al 20 
showed that OA-NO2 prevented hypoxia induced endothelial dysfunction in vitro via the 
STAT3/HIF-1a cascade. This study is the first to show the link between OA-NO2 and its role in 
preventing the pathological progression of PH.  
 
Although, not specific models of PAH, two (2) animal models of induced cardiac hypertrophy and 
fibrosis, the Angiotensin II and Transverse Aortic Constriction models, evaluated the effects of 
OA-NO2 on reducing cardiac hypertrophy and fibrosis.  Rudolph et al19 showed that OA-NO2 
suppressed the development of atrial (cardiac) fibrosis and the vulnerability to atrial fibrillation 
(AF) in a murine model of angiotensin II-induced AF. OA-NO2 significantly reduced myofibroblast 
formation, superoxide levels and macrophage concentrations in cardiac tissue which are critical 
in preventing or suppressing fibrosis. Villacorta et al18 showed that OA-NO2 reduced cardiac 
hypertrophy and significantly reduced cardiac fibrosis in a pressure overloaded mouse model 
induced by transverse aortic constriction. Despite persistent pressure overload, OA-NO2 also 
improved cardiac function (ejection fraction and fractional shortening). Multiple animal models 
have shown significant impact in all major aspects of disease progression, therefore, unlike 
current therapies, CXA-10 has the potential to modify disease progression in humans.   
 
1.3.5 CXA-10 effects in humans 
CXA-10 has also been shown to target the oxidative stress, inflammatory and metabolic pathways 
in humans.  These pathways have been implicated in the pathogenesis of PAH. CXA-10 
administration to patients with chronic renal disease (Study CXA-10-002) increased the 
expression of Nrf2 related genes, NQO1 and hemoxygenase 1 (HMOX-1, HO-1), and heat shock 
response (HSR)- related genes, HSPA1A/B, in both the blood and in the kidney (urinary 
exosomes). Activation of these genes protect cells from oxidative stress. 
  
CXA-10 inhibited NF-κB induced pro-inflammatory serum cytokines (MCP-1, IL-6) in obese 
humans after two weeks of dosing (Study CXA-10-202).  The changes in serum MCP-1 was both 
statistically and clinically significant. (MCP-1 Overall; LS mean difference: -228.5 (95% CI -387.2, 
-69.77). 
 
CXA-10 effects on metabolic pathways were also demonstrated in obese subjects (Study CXA-
10-202). CXA-10 reduced serum leptin levels (LS mean difference: -2640 (95% CI -6170, 890) 
equivalent to a 30 lb. reduction in weight and significantly inhibited serum triglyceride 
concentrations (LS mean difference: -59.60 (95% CI -102.3, -16.91).  The reduction in serum 
cholesterol levels, while not statistically significant, was clinically relevant as it approximated the 
effects of low dose statins (LS mean difference: 9.52 (95% CI -27.60, 8.57). 
Supportive biomarker engagement (NF-κB related proteins, Nrf2 protection, HSR repair) in 
Complexa’s Phase 1 strongly support efficacy of CXA-10 in the treatment of patients with PAH. 
 


Oral CXA-10 in PAH                                                                                     
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1.4 SIGNIFICANCE  
 
To date, current therapies for PAH are vasodilatory and reduce the symptoms associated with PA 
vasoconstriction. The ability to modify the underlying disease (re-establish the normal architecture 
of the pulmonary vessels and cardiac muscle and improve RV function to reduce morbidity and 
mortality) will be the most important treatment goal for the next generation products, ultimately 
translating to better outcomes.  
 
CXA-10 has the potential to be differentiating as a “disease modifying” therapy in PAH.  CXA-10 
targets the oxidative stress, inflammatory and metabolic pathways shown to be important causes 
in this disease. Its ability to affect multiple targets is key to improving both the pulmonary 
vasculature and cardiac abnormalities of PAH. CXA-10 has also been shown to reduce PA 
pressure, limit PA remodeling, improve RV function and reduce cardiac hypertrophy as well as 
attenuate cardiac fibrosis in animal models.16-19  
 
The information gained from the study will be important for better understanding the clinical effects 
and signaling mechanisms of CXA-10 on hemodynamics and exercise capacity in PAH patients. 
CXA-10 is not approved by the FDA. We anticipated the findings of the proposed clinical trial will 
contribute to the development of a precision medicine approach to the diagnosis and 
management of novel endophenotypes of PAH.  
 
2.   RESEARCH DESIGN AND METHODS 
 
2.1 CLASSIFICATION AND METHODOLOGICAL DESIGNS 
The clinical investigation is a single-center, one-arm, open-label proof of concept safety study and 
a phase 2a proof of efficacy pre- and post-assessment study of oral CXA-10 for the treatment of 
PAH. The study aims at assessing the safety and efficacy of 12-week oral CXA-10 therapy on the 
changes in hemodynamics and exercise capacity in PAH patients. Approximately 30 subjects will 
be enrolled to ensure at least 27 subjects complete the study.  
 
2.2 DETAILED DESCRIPTION OF STUDY DESIGN 
 
 
2.2.1. Study Design Overview 
The study consists of a screening period, a 12-week open-label treatment period, and a follow-up 
period of 4 weeks post treatment. Potential subjects will undergo a screening visit to determine 
that eligibility requirements are met. Subjects who meet the inclusion criteria and none of the 
exclusion criteria will be scheduled within 4 weeks of screening to receive oral CXA-10 at the 
dose of 300 mg once daily followed by 12 weeks of open-label CXA-10 treatment and then a 4-
week safety follow-up. The overall study design is depicted in Figure 1 below. 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Schematic Diagram of Study Design 
Safety F/U 
Week 16 
Baseline measurements 
prior to receiving study drug 
Clinic Visit 
Week 0 
Clinic Visit 
Week 4 
Clinic Visit 
Week 8 
Clinic Visit 
Week 12 
Telephone assessment at Weeks 2, 6, 10 
Screening 
12-Week Open-Label Treatment of Oral CXA-10 


Oral CXA-10 in PAH                                                                                     
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Noninvasive transthoracic echocardiograms will be performed to assess RV function before and 
after the 12-week study treatment period. The first 10 subjects enrolled will receive the first dose 
of the study drug in the cardiac catheterization laboratory to evaluate acute pharmacological 
responses during the screening RHC (Visit1). This will be repeated at the end of the 12-week 
study RHC (Visit 7). Hemodynamic measures such as pulmonary vascular resistance (PVR), 
mean pulmonary artery pressure (mPAP) and left and right ventricular filling pressures, will be 
measured at baseline and 30 minutes post drug dose and CXA 10 metabolites will be measured 
with pharmacokinetics sampling time points at baseline and 2-6 hours post drug as outlined in 
PK sampling window table in Section 2.2.3.. Food will be given prior to dosing.  
Subjects will have 6-minute walk distance with Borg dyspnea scale assessments during the 
screening visits. Plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) level, the World 
Health Organization (WHO) Functional Class assessment, and health related quality of life 
questionnaire will also be collected.  
 
Subject will continue the oral CXA-10 300 mg once daily in the morning with food at home for 12 
weeks. Throughout the outpatient study treatment period, subjects will be asked to remain diligent 
in recording the exact date and time of CXA-10 dosing with any associated symptoms. Subjects 
will be evaluated at 4-week intervals for occurrences of adverse events, laboratory test 
abnormalities, and evaluations of NT-proBNP plasma levels, six-minute walk distance with Borg 
dyspnea scale assessments, and WHO functional classification and health related quality of life 
questionnaire recorded.  Additional blood samples will be obtained for biomarkers and cytokines 
analysis before and after study drug treatment. An IVGTT will be performed before and after 12 
weeks of CXA-10 treatment to measure insulin secretion and sensitivity. 
 
To quantify physical activities, a noninvasive accelerometer will be used for physical activity 
monitoring. The device must be worn for a minimum of 7 days at home prior to receiving the first 
dose of CXA-10 and prior to the end of study drug treatment visit (Week 12). Measurements will 
include sleep and wake activity over the entire 24-hour period each day it is worn.  
 
After 12 weeks of study treatment, subjects will return for a repeat right heart catheterization, in 
addition to all study endpoints.  PK samples and plasma NT-proBNP will be collected. All subjects, 
regardless of whether they completed study treatment or discontinued study treatment 
prematurely, will be asked to return for a safety follow-up visit (4 weeks after stop of study 
medication intake).  Additional follow-up assessments by telephone will occur in between each 
outpatient clinic visit at Weeks 2, 6 and 10.  
 
Throughout the study, subjects will be monitored carefully for occurrences of adverse events, 
laboratory test abnormalities, and changes in vital signs. The expected duration of each subject’s 
participation in this proposed clinical investigation is approximately 5 months. 
2.2.2 Study Visits and Assessments 
 
Outlined below are study procedures that will be performed at screening, during the study 
treatments, and at follow-up.  See Appendix A for the complete study assessment and 
procedures.  
 
Visit 1 (Screening) 
Screening assessment will be performed within about 4 weeks prior to baseline testing (Visit 2) 
and will take place on two (2) separate days if a screening right heart catheterization (RHC) is 
needed. Subjects will be asked to fast a minimum of 8 hours prior to each visit.  
 


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• 
Obtain written informed consent. 
• 
Review Inclusion and Exclusion criteria 
• 
Medical history review and demographics 
• 
Complete physical exam 
• 
Weight, height 
• 
Electrocardiogram (ECG) 
• 
Vital signs (temperature, respiratory rate, blood pressure, heart rate) and pulse oximetry 
• 
Clinical lab testing and urinalysis (fasting glucose, comprehensive metabolic panel, fasting 
lipid profile, complete blood count, platelet and differential [CBC/Diff/Plt], uric acid, PT/INR 
and hemoglobin A1C).  
• 
RHC. This will be completed if not done within the prior 2 months to verify eligibility or may 
be repeated at study PI discretion. For a RHC to be considered eligible within 2 months, 
the subject must be stable on their medications and should not have started a new 
exercise program right before the prior cath or since the RHC within 2 months leading up 
to screening or baseline. Pulse oximetry and automated blood pressures will be measured 
at regular intervals.  
• 
Hemodynamic measures such as pulmonary vascular resistance (PVR), mean pulmonary 
artery pressure (mPAP) and left and right ventricular filling pressures, will be measured at 
baseline and 30 minutes post drug dose and CXA 10 metabolites will be measured with 
pharmacokinetics sampling time points at baseline and 2-4 hours post drug dose. Food 
will be given prior to dosing. Research blood samples for biomarkers, cytokines 
measurements (samples collected at the same times as PK samples) 
• 
NT Pro-BNP 
• 
Urine pregnancy test in women of childbearing potential (i.e. women who are not at least 
1 year post-menopausal or who have not undergone a surgical sterilization procedure) 
• 
Pulmonary function testing (PFT) must have been completed, no more than 12 months 
prior to the start of screening visit. If this has not been performed, a new PFT will be 
obtained. 
• 
6 minute walk test (6MWT) with Borg Dyspnea Scale 
• 
Oral (saliva, tongue scraping) and stool samples for microbiome analysis; subjects may 
be provided a stool collection kit and return the sample in a pre-paid envelope by USPS 
mail. 
• 
WHO Functional Class assessment 
• 
Concomitant medications assessment 
• 
AE assessment 
• 
Attach accelerometer to the subject’s non-dominant wrist after all assessments have been 
completed and all eligibility criteria are met. The device must be worn for at least 7 
consecutive days prior to receiving the first dose of study medication in order to collect 
baseline activity. Subjects will be instructed to return the accelerometer at the next visit. 
 
Visit 2 (Week 0- Baseline testing) 
This visit will take place at UPMC Montefiore. Subjects will be asked to fast a minimum of 12 
hours to perform the assessments listed below. 
 
• 
Brief physical exam with a body weight measurement and WHO Functional class assessment 
• 
Vital signs (temperature, blood pressure, respiratory rate, heart rate, and pulse oximetry 
measurements are taken). 
• 
ECG 
• 
Echocardiogram (this test may be completed at any visit prior to first dose of drug) 


Oral CXA-10 in PAH                                                                                     
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• 
Clinical laboratory tests and urinalysis (fasting glucose, comprehensive metabolic panel, 
fasting lipid profile, CBC/Diff/Plt, uric acid, PT/INR) 
• 
Research blood samples for biomarkers, cytokines measurements NT-proBNP 
• 
Urine pregnancy test for female child-bearing potential 
• 
IVGTT 
• 
Health related quality of life questionnaire - Pulmonary Arterial Hypertension-Symptoms and 
Impact (PAH-SYMPACT®)  
• 
Return accelerometer for data download 
• 
Concomitant medications assessment 
• 
AE assessment 
 
Visit 3 (Week 0 – First dose)   
This visit will take place at UPMC Montefiore. Subjects do not need to fast for this visit and this 
visit will last up to about 4 hours.  
 
• 
6MWT 
• 
Blood draw for Population PK sampling (pre-dose and 2-4 hours after taking the study drug) 
• 
Research blood samples for biomarkers, cytokines measurements (samples collected at the 
same times as PK samples) 
• 
Subjects will be instructed to take the first dose of study medication at the clinic after a 
breakfast/morning snack containing up to approximately 30% fat  
• 
Dispense study drugs 
• 
Concomitant medications assessment 
• 
AE assessment 
 
Visit 3a (Week 1: +3d)  
This visit will take place at UPMC Montefiore or UPMC Presbyterian. This visit will last 
approximately 30 minutes. Subjects who are on warfarin will be asked to return to the clinic one 
week after taking the study drug for a blood draw for PT/INR. If the INR value is > 2.5, the warfarin 
dose may be adjusted per the standard of care. Subjects do not need to fast for this visit. 
 
The rationale for PT/INR measurement in PAH patients on warfarin is that Warfarin is a substrate 
of CYP2C9. Although the concentrations of CXA-10 in vivo are significantly lower than the 
concentrations in vitro, CXA-10 has shown moderate in vitro inhibition of CYP2C9. The lowest 
IC50 value, based on in vitro inhibition for CYP2C9, was 2.2 μM. The peak plasma concentrations 
of CXA-10 in humans following oral administration of a 1200 mg dose were less than 10 ng/mL 
(< 30 nM). Modeling of CXA-10 direct CYP inhibition in vitro data for CYP2C9 is projected to yield 
an R1 value (R1 = 1+[I]/Ki) of 1.02 for CYP2C9, that is less than the R1 value of 1.1, as defined 
in FDA Guidance Industry February 2012. Therefore, CXA-10 is not expected to increase the 
exposure to concurrently administered drugs that are primarily cleared by CYP2C9-mediated 
elimination mechanisms. Even though the potential for a drug-drug interaction is low, we will 
measure PT/INR on Week 2 for subjects taking warfarin. CXA-10 must reach steady-state 
concentration before collecting blood for PT and steady state of CXA-10 is achieved by day 7. 
 
Visit 4 (Week 4; ± 5d) and Visit 5 (Week 8; ± 5d)  
 
Subjects will report to the clinic on the morning of Week 4 and Week 8 (Visit 4 and Visit 5) after a 
minimum 8-hour overnight fast.  Subjects should not take their study medication that morning, 
prior to arriving at the clinic for their pre-dose assessment.  
 


Oral CXA-10 in PAH                                                                                     
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• 
Brief physical exam 
• 
Body weight 
• 
ECG 
• 
Vital signs (temperature, blood pressure, respiratory rate, heart rate, and pulse oximetry 
measurements are taken). 
• 
Clinical laboratory testing and urinalysis (fasting glucose, comprehensive metabolic panel, 
fasting lipid profile, CBC/Diff/Plt, uric acid)NT Pro-BNP 
• 
Urine pregnancy test in women of childbearing potential 
• 
6MWT with Borg Dyspnea Scale 
• 
Health related quality of life questionnaire - PAH-SYMPACT® 
• 
WHO Functional Class assessment 
• 
Dispense study drugs. Subjects will be instructed to take the study medication at the clinic 
after a breakfast/morning snack containing up to approximately 30% fat 
• 
PK blood sampling (pre-dose and 2-4 hours post-dose) 
• 
Research blood samples for biomarkers, cytokines measurements (samples collected at the 
same times as PK samples) 
• 
Concomitant medications assessment 
• 
AE assessment 
• 
Provide accelerometer on week 8 only and instruct to wear the accelerometer for at least 7 
consecutive days prior to the next visit (Week 12). 
 
END OF TREATMENT: All end of treatment study procedures will take place over 3 visits 
and can be completed in any order to accommodate scheduling needs. 
 
Visit 6 (Week 12 ± 5d – End of treatment) 
 
This visit will take place at UPMC Montefiore. Subjects will be asked to fast a minimum of 12 
hours to perform the assessments listed below. The visit will last approximately 6 hours.  
 
• 
Brief physical exam with a body weight measurement and WHO Functional class assessment 
• 
Vital signs (temperature, blood pressure, respiratory rate, heart rate, and pulse oximetry 
measurements are taken). 
• 
ECG 
• 
Clinical laboratory tests and urinalysis (fasting glucose, comprehensive metabolic panel, 
fasting lipid profile, CBC/Diff/Plt, uric acid, PT/INR, hemoglobin A1c (this test is performed if 
subject has abnormal HbA1c)) 
• 
Research blood samples for biomarkers, cytokines measurements, NT-proBNP 
• 
Oral (saliva, tongue scraping) and stool samples for microbiome analysis; subjects may be 
provided a stool collection kit and return the sample in a pre-paid envelope by USPS mail. 
• 
Urine pregnancy test for female child-bearing potential 
• 
IVGTT 
• 
Health related quality of life questionnaire - Pulmonary Arterial Hypertension-Symptoms and 
Impact (PAH-SYMPACT®)  
• 
Return accelerometer for data download 
• 
Concomitant medications assessment 
• 
AE assessment 
 
 
 


Oral CXA-10 in PAH                                                                                     
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Visit 7 (Week 12– End of Treatment)  
 
Subjects will report to the clinic on the morning of Week 12 after a minimum 8-hour overnight fast.  
Subjects should not take their study medication that morning, prior to arriving at the clinic for their 
pre-dose assessment.  
 
• 
Brief physical exam  
• 
Echocardiogram (may be completed on a separate day if a scheduling conflict occurs) 
• 
RHC. Pulse oximetry and automated blood pressures will be measured at regular intervals.  
• 
Hemodynamic measures such as pulmonary vascular resistance (PVR), mean pulmonary 
artery pressure (mPAP) and left and right ventricular filling pressures, will be measured at 
baseline and 30 minutes post drug dose and CXA 10 metabolites will be measured with 
pharmacokinetics sampling time points at baseline and 4-6 hours post drug dose. Food will 
be given prior to dosing. Research blood samples for biomarkers, cytokines measurements 
(samples collected at the same times as PK samples) 
• 
Concomitant medications assessment 
• 
AE assessment 
 
Visit 8 (Week 12 – End of treatment) 
 
This visit will take place at UPMC Montefiore and the visit will last up to about 7 hours. The subject 
does not need to fast.  
•    6MWT 
• 
Blood draw for Population PK sampling (pre-dose and 4-6 hours after taking the study drug) 
Subjects will be instructed to take the study medication at the clinic after a breakfast/morning 
snack containing up to approximately 30% fat 
• 
Research blood samples for biomarkers, cytokines measurements (samples collected at the  
 
same times as PK samples) 
• 
Concomitant medications assessment 
• 
AE assessment 
• 
Dispense 1st month of open label CXA-10 after the completion of all end of treatment testing 
(optional) 
 
Following the completion of all end of treatment assessments, patients have the option to 
discontinue treatment and have a safety follow up at Visit 9 or patients may also choose to enter 
the open label extension for 6 months. If patients are in the open label extension, Visit 9 will be 
the month 1 follow up. If patients wish to enter the open label extension, the first month supply 
will be dispensed at the end of their final visit for end of treatment testing.  
Telephone Assessments 
 
Visit 3b (Week 2; ± 5d), Visit 4a (Week 6; ± 5d) and Visit 5a (Week 10; ± 5d) 
 
The study personnel will contact the subject by telephone to perform a safety evaluation and 
review concomitant medications approximately 2 weeks after Visit 3, Visit 4 and Visit 5.  The 
subject will be asked if there were any changes to their concomitant medications.  Subjects will 
also be reminded to bring any remaining medication to their next clinic visit. 
 
 
Visit 9 (Week 16;- ± 5d– Follow-Up Visit) 
 


Oral CXA-10 in PAH                                                                                     
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Visit 9 will take place approximately 4 weeks after the end of treatment. Subjects will report to the 
clinic on the morning of Week 16 after a minimum 8-hour overnight fast. 
 
• 
Brief physical exam 
• 
Body weight 
• 
Vital signs (temperature, blood pressure, respiratory rate, heart rate, and pulse oximetry 
measurements are taken). 
• 
Clinical laboratory testing (fasting glucose, comprehensive metabolic panel, fasting lipid 
profile, CBC/Diff/Plt, uric acid) 
• 
Research blood samples for biomarkers, cytokines measurements  
• 
Urinalysis 
• 
NT Pro-BNP 
• 
Urine pregnancy test in women of childbearing potential 
• 
6MWT with Borg Dyspnea Scale 
• 
WHO Functional Class assessment 
• 
Concomitant medications assessment 
• 
AE assessment 
• 
Dispense 2nd month of open label CXA-10 (optional) 
 
Open Label Period 
Upon completion of the end of treatment visits, subjects will be given the option to receive open-
label drug for 6 months. Subjects will be asked to return for in person visits at month 4 and month 
6 for vital signs (temperature, blood pressure, respiratory rate, heart rate, and pulse oximetry 
measurements are taken), WHO Functional Class assessment, completion of the PAH-
SYMPACT questionnaire, a six-minute walk test, a blood collection to measure NT-proBNP level, 
research samples for biomarkers, cytokines measurements, clinical laboratory testing (fasting 
glucose, comprehensive metabolic panel, fasting lipid profile, CBC/Diff/Plt, uric acid) and 
dispense study medication. The total amount of blood drawn is 30ml. Months 3 and 5 will be 
telephone assessments to perform a safety evaluation and review concomitant medications. 
 
To date, current therapies for pulmonary arterial hypertension (PAH) are vasodilatory and reduce 
the symptoms associated with pulmonary artery (PA) vasoconstriction. The ability to modify the 
underlying disease is the most important treatment goal for the next generation of therapies, 
ultimately translating to better outcomes. CXA-10 has the potential to be differentiating as a 
“disease modifying” therapy in PAH.  The main purpose of the open label period is to provide 
specific treatment to those patients that have a response during the trial. This can also be a benefit 
to the patients if they are getting relief from their symptoms from the CXA-10. It will also provide 
longer term safety data. Patient reported outcomes such as QOL are collected. 
 
 
2.2.3 Description of Study Procedures 
Subjects must present to all study visits in the morning.  Subjects must fast from all food and drink 
(except water) for a minimum of 12 hours prior to Visits 2 and 6 (12-hour fast is required for leptin 
analysis). Subjects must fast from all food and drink (except water) for a minimum of 8 hours prior 
to visits 1, 4, 5, 7, 9.  
 
During treatment visits (Visits 3 through 9), when at the study site, subjects will have access to 
breakfast, lunch and dinner if appropriate.  Subjects will eat breakfast or a morning snack 
(containing no more than 30% fat) after completion of all pre-dose assessments and just prior to 


Oral CXA-10 in PAH                                                                                     
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the time of dosing.  Subjects will be instructed to take their dose of study medication at the clinic 
at each scheduled office visit (Visits 3, 4, 5, 7, 8).  The date and time of dosing will be recorded 
at these visits. 
 
Safety Assessments 
 
Physical Examinations: Physical examinations will be performed by a physician, or nurse 
practitioner or a physician’s assistant. A complete physical examination will be performed at 
Screening (Visit 1).  Genital, rectal, and breast examination may be excluded if not clinically 
indicated. Height and weight obtained at Screening (Visit 1) will be used to determine the BMI 
throughout the rest of the study.  Weight will be collected at all other visits, excluding the phone 
call visits. A brief physical exam will be performed during Visit 2 to Visit 9, except for visit 3a. 
 
Vital Signs: Vital sign measurements will include temperature, systolic and diastolic BP, heart rate 
(HR), respiratory rate (RR), and peripheral oxygen saturation (SpO2) after the subject has rested 
in a sitting position for at least 5 minutes.  Vital sign measurements will be repeated if clinically 
significant or should machine/equipment errors occur.  Out of range vital signs measurements will 
be repeated at the Investigator’s discretion and documented in the case report form (CRF).  Any 
confirmed, clinically significant, abnormal vital sign measurements must be recorded as adverse 
events. 
 
12-Lead Electrocardiograms (ECG): An ECG machine with an automatic QTcF reporting feature 
will be utilized. 12-lead ECG will be obtained after the subject has rested in a fully supine position 
for at least 5 minutes. Because food can prolong QTc intervals which may be incorrectly attributed 
to CXA-10, subjects must refrain from eating or drinking for approximately 2 hours prior to 
obtaining ECGs except at screening. ECGs will be performed to determine eligibility to participate 
in the trial at Screening, and all other scheduled times prior to dosing. ECGs will be interpreted 
by a physician investigator experienced in interpreting ECGs. Additional ECGs may be performed 
if deemed medically appropriate. 
 
Clinical Laboratory Tests: Clinical lab tests evaluation will include fasting glucose, comprehensive 
metabolic panel, fasting lipid profile, complete blood count, platelet and differential, and uric acid. 
In addition, HbA1C levels will be collected at Screening (Visit 1) on all subjects.  Subjects with 
abnormal HbA1C at screening, will have blood collected for HbA1C levels at the end of the 
treatment period (Visit 6). PT/INR will be evaluated on all subjects as this is standard of care for 
anyone having a RHC. Patients who are on warfarin will return approximately one week after 
starting study drug to re-check PT/INR (Visit 3a). 
 
Pulmonary Function Test (PFT): PFTs must be completed no more than 12 months before 
Screening or at Screening if outside the 12-month window.  FEV1 and FVC parameters will be 
collected to determine eligibility to participate in the trial.  Pulmonary function testing will be 
performed as per clinical standard of care.  
Efficacy Assessments 
Right Heart Catheterization (RHC): RHC is performed routinely as a clinical standard of care 
procedure for diagnostic purposes in this population.  RHC will be performed at Screening and at 
the end of the treatment (Visit 6 – Week 12).   
 
Briefly, RHC will be performed with a balloon tipped, flow-directed, pulmonary artery catheter (e.g. 
7F Swan Ganz catheter) inserted through a sheath in the internal jugular vein under continuous 


Oral CXA-10 in PAH                                                                                     
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ECG monitoring.  An alternate vein may be used at the physician’s discretion.  All measurements 
will be recorded with the subject in a supine position, at rest, breathing room air or with 
supplementary oxygen to obtain peripheral saturations above 90%.  Hemodynamic recording of 
right atrial, right ventricular, pulmonary artery pressures, pulmonary artery wedge pressure and 
cardiac output will be made. Parameters for analysis will include: Mean RAP, RVSP, RVDP, 
PASP, PADP, Mean PAP, Mean PAWP, Thermodilution Cardiac Output, PVR, Cardiac Index, 
and Pulmonary Vascular Compliance. Mixed venous oxygen saturation (SvO2) will be determined 
from a sample drawn from the Swan-Ganz catheter. Other parameters may be obtained as data 
permit.  
 
Echocardiogram: Noninvasive transthoracic echocardiograms will be completed to assess RV 
function by measures such as tricuspid annular plane systolic excursion (TAPSE) as well as tissue 
Doppler of the lateral tricuspid valve anulus (S’). 
 
Six Minute Walk Distance Test and Borg Dyspnea Scale: The 6MWD test will be performed 
according to a protocol-specific modification of the American Thoracic Society guidelines.21  The 
6MWD test measures the distance an individual is able to walk over a total of six minutes on a 
hard, flat surface. The Borg Scale is a method of rating perceived exertion during exercise. It 
should be performed immediately after the 6MWD test. 
 
Physical Activity: Continuous physical activity monitoring will be conducted using a noninvasive 
accelerometer (Actigraph, Pensacola, FL). All subjects will be instructed to use a noninvasive 
accelerometer at home during waking hours to quantify physical activities for 8 days to achieve a 
full 7 wear days, and to take it off only when showering. Measurements will include sleep and 
wake activity over the entire 24-hour period each day it is worn. The device must be worn for a 
minimum of 7 consecutive days at home prior to: (1) receiving the first dose of study medication 
(Visit 3 - Week 0) in order to collect baseline activity, and (2) prior to conducting end of study drug 
treatment assessments at Visit 6 (Week 12). The study staff will remove the accelerometer when 
the subject returns for Visit 3 and Visit 6.  The study staff will download the data, visually screen 
the raw accelerometer file for spurious data, perform a battery check, and allocate the unit for 
redeployment. 
 
N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP): Blood samples for determination of NT-
proBNP serum concentrations will be collected at Screening and at 4-week intervals throughout 
the study. 
 
WHO Functional Class: The World Health Organization (WHO) Classification of Functional Status 
of Patients with PH will be used to classify disease severity in PAH. It places patients in one of 
four categories based on how much they are limited during physical activity.22 
 
Class 
Patient Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea (shortness of breath). 


Oral CXA-10 in PAH                                                                                     
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III 
Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity 
causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of dyspnea at 
rest. If any physical activity is undertaken, discomfort increases. 
  
Health Related Quality of Life Questionnaire: The PAH-SYMPACT®23 will be utilized for 
measuring patient reported outcomes (PROs) for subjects with PAH. The PAH-SYMPACT® is a 
PRO instrument consisting of 12 symptoms and 11 impact items developed based on interviews 
of PAH patients and following FDA PRO guidance.  
Other Assessments 
Intravenous glucose tolerance test (IVGTT): The IVGTT is considered a gold-standard test to 
measure insulin secretion and sensitivity. It has been standardized and used worldwide for more 
than 20 years. In our study, the expected duration is 180 mins after the test is started with an IV 
glucose bolus of 0.3g/kg. After the glucose bolus, a small dose of human regular insulin is given 
IV to moderate the plasma glucose rise. The insulin dose is 25 mUnits/Kg body weight. Patients 
taking oral hypoglycemics may be asked to hold those medications the morning of the IVGTT but 
can resume taking them following the completion of the IVGTT the same day. 
 
Pharmacokinetics: Blood samples (approximately 5 mL each) will be collected during each visit 
as outlined below in    Table 1 to determine the concentrations of CXA-10 and two major 
metabolites (10-NO2-octadec-8-enoic acid [8, 9 alkene] and 10-nitro-octadecanoic acid 
[NO2-stearic acid]).  Other metabolite concentrations may be determined as appropriate in 
compliance with regulatory guidance.  Samples will be analyzed using a validated high 
performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) assay. One 
aliquot will be used for identification of the distribution of CXA-10 and metabolites in lipoproteins. 
 
Table 1. Population PK/PD Blood Sampling Windows 
 
Visit 1 
Visit 3* 
Visit 4 
Visit 5 
Visit 7 
Visit 8* 
 
(screening) 
(If RHC 
needed) 
(Week 0) 
(Week 4) 
(Week 8) 
(Week 12) 
(Week 12) 
PK/PD 
Sampling 
Window 
 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
 
Pre-dose 
Pre-dose 
PK/PD 
Sampling 
Window 
2-4 hours 
post-dose 
2-4 hours 
post-dose 
2-4 hours 
post-dose 
2-4 hours 
post-dose 
4-6 hours 
post-dose 
4-6 hours 
post-dose 
* Blood samples for both PK/PD studies will be collected at Visit 3 (Week 0) and Visit 8 (Week 12). 
 
Every effort should be made to collect samples at times spread throughout the time 
window (i.e., avoid collections from all subjects at the same time within a window or only at the 
extremes of a time window; e.g. 2-4 hrs time window-not all samples at 2.5 hours). The actual 
time at which the subject is dosed prior to the PK sample must be recorded, and the exact time 
at which the PK sample is drawn must be documented in the CRF. 
 
Pharmacodynamics: Coupled with PK studies, blood samples will be collected as the same times 
as PK samples at Weeks 0 and 12 to measure cytokines reflective of NFkB inhibition via IL-17, 


Oral CXA-10 in PAH                                                                                     
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IL-6, TNFa, MCP-1; Nrf2 activation via NQ01/HO-1; key PAH/metabolic syndrome biomarkers – 
ET-1, BMPR-1, leptin, CRP; F2a-isoprostane as an oxidative stress biomarker. A minimum 12 
hour fast prior to the collection of the leptin sample will be required.  
 
Additional biomarkers appropriate to the disease or to the pharmacology of CXA-10 may be 
examined in these samples depending on emerging science.  It is possible that not all samples 
will be analyzed.  Subjects’ blood samples collected from baseline until the end of the study will 
be batched and stored at Dr. Bruce Freeman’s lab located at the University of Pittsburgh 
Biomedical Science Tower (BST) until analysis. 
 
Microbiome: Studies of the microbiome’s impact on the development of diseases such as PAH 
are in early stages, and much remains unknown. To explore the associations between oral and 
gut bacterial and cardiovascular disease, we will obtain oral (saliva, tongue scraping) and stool 
samples from each subject pre and post drug treatment. Unstimulated saliva will be collected in 
a sterile specimen cup. Tongue scraping will be collected with a sterile scraper over the dorsum 
of the tongue. Stool samples will be collected using a stool collection kit54. Participants will return 
their biospecimens in a pre-stamped envelope. Stool collection kit may be provided to subjects 
for home collection. Subjects may return their samples in a pre-stamped envelope by mail. 
Microbiome samples will be stored at Dr. Alison Morris’s lab in BST until analysis. 
 
Microbiome analyses will be performed to determine if oral and gut samples from PAH patients 
differ in overall bacterial community structure. We will compare functional properties of the oral 
and gut microbiomes in relate these findings to PAH clinical severity and outcomes using network 
analyses. 
 
2.3 INVESTIGATIONAL PRODUCT 
The drug product is a size ‘1’ white, opaque hydroxypropylmethyl cellulose capsule filled with a 
solution of CXA-10 (25% or 50% w/w) in medium chain triglyceride oil with 0.05% of butylated 
hydroxytoluene as an antioxidant.  Fumed silica may be added as a thickening agent.  Capsules 
are provided in the dose strength of 75 mg or 150 mg.  The filled capsules are packaged in white 
high-density polyethylene containers (18 capsules per bottle) with child resistant closures.  
 
Dosages: The dose for this study is 300 mg once daily (two 150 mg capsules daily) 
 
2.3.1. Investigational Product Preparation and Dispensing  
 
CXA-10 will be obtained from Complexa, Inc. The labeling and packaging will be conducted 
according to Good Clinical Practice and regulatory requirements. The University of Pittsburgh 
Medical Center Investigational Drug Services (UPMC-IDS) Pharmacy will be utilized for 
dispensing of the study drug. The study drug is administered only to subjects enrolled in the study 
and in accordance with the protocol. 
 
2.3.2. Administration of Investigational Product 
 
CXA-10 will be administered orally. Subjects will be instructed to take their CXA-10 dose once 
daily in the morning with food.  The food can contain up to approximately 30% of calories from 
fat.  A high fat meal must be avoided.  A list of recommended meals/snacks will be provided to 
subjects. 
 


Oral CXA-10 in PAH                                                                                     
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Dosing will begin on Visit 3 (Week 0) in the clinic where subjects will self-administer study 
medication. Dosing will then commence at home.  However, subjects should not take their 
morning dose of study medication at home when Visits 4, 5, 6, 7 and 8 are scheduled.  These 
doses will be administered in the clinic. 
 
 
2.3.3. Dose Selection 
 
The doses of CXA-10 for this study is 300 mg once daily (with food containing up to 
approximately 30% fat).  The highest repetitive dose administered in the Phase I, CXA-10-202 
study was 450 mg for 14 days in a fasted state.  Analysis of preclinical exposure response data 
predicted the human therapeutic dose at approximately 150 mg daily.  Subsequently, more data 
has been developed including data from the Phase 1 Multiple ascending dose (MAD) study and 
the Phase 2 FSGS Study (clinicaltrials.gov NCT02460146 and NCT03422510, respectively). 
The MAD data was used to select doses of 75, 150 and 300 mg QD for the FSGS study which 
is approved by the FDA and is currently ongoing.  An interim look by Complexa at the first 21 
subjects who completed 90 days of dosing in FSGS study suggests that the higher dose (300 
mg/day) may be more effective and no drug-related SAEs have been reported.  
 
In this study, dosing will take place in the fed state (food with up to approximately 30% fat).  This 
regimen has been shown to improve GI tolerability without impacting PK.  In Study CXA-10-202, 
healthy, obese, male subjects received CXA-10 once daily for 14 days in the fasting state.  Under 
the fasted dosing condition, mild to moderate, intermittent diarrhea of probable to definite causality 
was reported by 5 of 10 subjects (50%) at the 150 mg dose and by 9 of 10 subjects (90%) at the 
450 mg dose.  Subjects at the 450 mg dose level also received one CXA-10 dose with a high fat 
meal (50% fat) and the incidence of diarrhea decreased (3 of 10 subjects [30%]). While the high 
fat meal (50% fat) resulted in a lower incidence of diarrhea, CXA-10 exposure was increased 
compared with the fasting state (Cmax and AUC increased by 2.2-fold and 1.6-fold, respectively, 
after a high fat breakfast).  In Study CXA-10-203, a 150 mg dose of CXA-10 was administered to 
healthy, male subjects once daily on Days 4 to 12 of the study in the fed state (after a standard 
breakfast of approximately 30% fat). When CXA-10 was administered with a standard breakfast 
(30% fat), only 1 of 10 subjects (10%) experienced diarrhea.  This subject’s diarrhea was 
considered unlikely to be related to CXA-10 and was instead attributed to a Norovirus infection.  
CXA-10 PK after dosing with a meal of approximately 30% fat was similar to the PK after dosing 
in the fasting state. 
 
2.3.4. Overdose 
 
There is currently no information available on the medication effects of an overdose of oral CXA-
10, although a single dose of 1200 mg and a total daily dose of 1800 mg (900 mg twice within 6 
hours) was administered with the most notable effect of Grade 1 to Grade 2 diarrhea. 
 
If an overdose is suspected, the subject should be maintained under close medical observation 
and be intensively monitored for potential GI and cardiovascular events. Diarrhea has been the 
most obvious and consistent side effect thus far seen, and an overdose could possibly result in 
profound and persistent diarrhea. Subjects may experience vasovagal signs and symptoms, 
dehydration and electrolyte abnormalities should such an event occur due to an overdose. 
Medical intervention and subsequent care should be instituted as appropriate to the signs and 
symptoms of any AE. 
 
2.3.5. Treatment Period 


Oral CXA-10 in PAH                                                                                     
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Twelve weeks. 
 
2.3.6. Investigational Product Storage and Accountability 
 
Study drugs used during the trial will be stored at the UPMC-IDS in accordance with Good Clinical 
Practice (GCP) in a place accessible only to authorized personnel. CXA-10 capsules should be 
stored refrigerated between 2 and 8°C (35 to 46°F).  Brief excursions (for up to 48 hours) are 
permitted at room temperature (20 to 25°C [68 to 77°F]).  Storage in direct sunlight or at 
temperatures greater than 25°C (77°F) should be avoided.  
Adequate accountability records of study drug received, dispensed, used will be maintained 
throughout the course of the study.  The study investigators or the study coordinator will document 
the amount of study drug dispensed from UPMC-IDS. The study drug accountability records will 
be maintained at UPMC-IDS throughout the course of the clinical trial. 
 
2.3.7 Concomitant Medications 
 
Concomitant medication assessments will be conducted throughout the study.  While it is 
expected that subjects’ medication regimens remain stable over the course of the study, changes 
are permitted if medically indicated.  Subjects will be asked if they have had any change(s) to 
their medication regimen since their last visit, except for visit 3a.  Any medication regimen changes 
will be documented in the Concomitant Medication section of the CRF.  
 
Permitted Medications 
Any concomitant medication to treat adverse events will be recorded in the Concomitant 
Medication section of the CRF. All subjects are required to take their stable regimen of PAH 
therapy during the study, and no regimen changes will be permitted during the study (unless 
indicated for safety). 
 
Precautionary and Prohibited Medications 
During the study, subjects are not allowed to take the following medications:   
• 
Intravenous inotropes (e.g. dopamine, dobutamine) 
• 
Long or short acting nitrates 
• 
Newly prescribed drug or increased dose of an existing drug that is known to prolong QTc 
interval or has been associated with Torsades de Pointes.  Stable doses of these drugs are 
permitted (i.e., subject has received the same dose and regimen for at least 30 days prior to 
Screening (Visit 1) with no anticipated changes to the dose or regimen during the course of 
the study).   
• 
Herbals, natural medications and fish oil  
• 
Drugs that may affect the measurement of serum creatinine (e.g. cimetidine, Bactrim, 
Pyridium).  
• 
Dimethyl fumarate (Tecfidera™) 
• 
Simvastatin at doses greater than 20 mg (Zocor), Vytorin, or any other combination therapy 
containing simvastatin at doses greater than 20 mg.  
• 
Any other investigational drug regardless of route (topical, intranasal, etc.). 
 
 
2.4 STUDY ENDPOINTS 
 


Oral CXA-10 in PAH                                                                                     
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Primary Endpoint:  
 
The primary endpoint measures the incidences of treatment-emergent adverse events. 
 
Secondary Endpoints: 
 
The primary efficacy endpoint measures the change from baseline in Pulmonary Vascular 
Resistance (PVR) assessed by Right Heart Catheterization at 12 weeks. 
 
Other secondary endpoints measure: 
• 
Change from baseline in hemodynamic parameters including Cardiac Output (CO), Cardiac 
index (CI), mean Pulmonary Artery Pressure (mPAP), Pulmonary Artery Wedge Pressure 
(PAWP), Mean Right Atrial Pressure (mRAP), and compliance (SV/ (sPAP-dPAP) at 12 weeks 
• 
Change from baseline in RV function including tricuspid annular plane systolic excursion 
(TAPSE) and tissue Doppler of the lateral tricuspid valve anulus (S’) as assessed by 
echocardiograms at 12 weeks 
• 
Change from baseline in functional exercise capacity by assessing 6 minute walk distance 
test with Modified Borg Dyspnea Scale at 12 weeks 
• 
Change from baseline in the levels of serum NT-proBNP at 12 weeks 
• 
Change from baseline in WHO Functional Class at 12 weeks 
• 
Change from baseline in patient reported outcomes measured by PAH-SYMPACT® 
questionnaire at 12 weeks 
• 
Change from baseline in daily physical activity assessed by personalized activity monitor at 
12 weeks 
• 
Pharmacokinetic endpoint: CXA-10 parent and metabolites  
 
Exploratory Endpoints: 
• 
Change in insulin sensitivity by intravenous glucose tolerance test at 12 weeks 
• 
Pharmacodynamic endpoint:  change from baseline in serum biomarkers, leptin, 
inflammatory cytokines (IL-17, IL-6, TNFα, MCP-1) and hsCRP at 12 weeks 
• 
Pharmacokinetic - Pharmacodynamic relationship of CXA-10 on relevant efficacy, safety and 
biomarkers endpoints, if the data allow 
• 
Epidemiological relationships of oral and gut microbiome and PAH 
 
 
2.5 STATISTICAL ANALYSIS 
 
2.5.1 Sample Size Determination 
 
We plan to enroll 30 subjects with PAH, allowing for a conservative drop-out rate of 10%, in this 
open label trial of oral CXA-10.  We expect to see decrease in the PVR after 12 weeks of therapy. 
The intention to treat (ITT) population will consist of all subjects who have received at least one 
dose of study medication. To estimate our effect size for power calculations, we use data from 
the SUPER-1 sildenafil PAH trial (a randomized placebo control trial evaluating the effects of 20 
mg, 40 mg or 80 mg TID of sildenafil in subjects with PH).  Using the hemodynamic data from the 
80 mg arm of the SUPER-1 trial and making a conservative assumption that our therapy will only 
have an effect that is 70% of sildenafil (decrease in PVR of 2.3 woods units with SD of 4.1), the 
sample size required for 80% power and P = 0.05 is 27 subjects (Table 2). We anticipate more 
than sufficient power to detect vasodilatory effects of NO2-OA administration (decreased PVR) 
after 3 months of therapy. Based on our extensive phase 1 data with CXA-10 formulations, we 


Oral CXA-10 in PAH                                                                                     
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anticipate the drug will cause no systemic blood pressure changes and no increases in 
methemoglobin levels. 
 
 
Table 2 Required sample size for different effect, 
Power =0.8 , a=0.05, two sided test  
% of Sildenafil 
Mean (SD) PVR 
change, Woods unit 
N 
90 
3.0 (4.9) 
23 
80 
2.6 (4.2) 
23 
70 
2.3 (4.1) 
27 
 
With safety as the primary outcome measure, we use Fleming’s single stage phase II design with 
the following assumptions: α = 0.05, Power= 0.80, lower proportion for rejection 70% (with no 
SAEs), higher proportion of acceptance 90% (with no SAEs) with maximum recruited patients of 
27 patients resulting in a minimum number of success (with no SAEs to indicate that the treatment 
is safe) is 24. Thirty patients will be enrolled to compensate for up to 10% lost-to follow-up. 
 
2.5.2 Statistical Analysis 
 
Change of each outcome from baseline will be presented by median (IQR). Primary analysis will 
be performed by paired t-test comparing continuous outcome in 12-weeks vs. baseline. All data 
will be tested for normality, and non-normal data will be tested by Wilcoxon signed rank test. We 
will also use mixed effect models with restricted maximum likelihood estimation to test the change 
of outcome during the 12 weeks of intervention.  
 
Demographics and baseline characteristics will be listed and summarized descriptively. Safety 
will be evaluated via the incidence of AE’s, changes in clinical labs, and vital signs. AEs will be 
coded by system organ class and preferred term according to the most recent edition CTCAE. 
AEs will be summarized by frequency, severity, and relationship to study medication. Clinical labs 
will be compared to normal ranges and flagged if found to be of clinical concern. Results will be 
presented as observed changes and depicting changes from baseline to defined study 
timepoints.  
 
2.5.3 Pharmacokinetics Analyses 
 
Plasma concentration-time data of CXA-10 parent and metabolite(s) will be displayed in tables 
and/or graphs. Individual plasma concentration-time data will be pooled, and population 
pharmacokinetics will be performed using a currently acceptable method as permitted by the 
data. Population PK parameters such as Clearance (CL) and volume of distribution (V) will be 
determined, as the data allow. In addition, the influence of various covariates (e.g. BMI) of the 
PK parameters will be examined. 
 
2.5.4 Pharmacodynamics Analyses 
 
2.5.4.1 Biomarker Analyses 
PD endpoints will be listed and summarized descriptively by assessment time. Change from 
baseline in lipid profile (e.g. total cholesterol and triglycerides) will be separately analyzed using 
an appropriate model. Additional biomarkers (e.g. leptin, MCP-1, IL-6, etc.) may also be 
analyzed as appropriate. Relevant covariates (e.g. underlying disease) will be included. The 


Oral CXA-10 in PAH                                                                                     
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least square mean difference and associated 95% confidence intervals for each assessment 
time and across all assessment times will be obtained from the model. 
 
2.5.4.2 Pharmacokinetic/Pharmacodynamic Analyses 
PK/PD modeling will be conducted to better define exposure-response and dose determination 
for future studies, as appropriate. 
 
2.5.5 Handling Missing Data 
 
Every effort will be made to minimize the missing data in the study. We will record reasons for 
drop-out and compare baseline characteristics between participants who do and do not complete 
the study. A mixed effect model approach will be used to take into account missing data for the 
endpoints which are measured at more than just baseline (or screening) and Week 12. In the 
event of missing data, a complete-case analysis will be performed as a sensitivity analysis to 
assess the robustness of the treatment effect. In the event Week 12 data is missing for endpoints 
routinely collected only prior to the start of treatment and at Week 12, a mixed model approach 
will not be applicable. Accordingly, methods for assessing the impact of missing data on 
conclusions will be a function of several factors. These factors include: the extent of missing data 
at Week 12, the reasons data may be missing for individual subjects, and whether or not any post-
baseline are available, prior to Week 12 (e.g., at early discontinuation). We will also use multiple 
imputation approach to impute these values to perform a sensitivity analysis.  
 
2.5.6 Data Management 
 
The study forms will be paper-based in that the data will be first recorded on paper forms at the 
time of the study visits. A relational database will be constructed on a local server with daily 
backups where only select research team members will have access to the database. The 
database will include data entry forms with the same appearance as the paper forms to facilitate 
accurate data entry and routine data edit checks for consistency both within and between forms. 
After data entry, the paper forms will be archived in secure file cabinets. All study subjects will be 
assigned unique study identifiers that will appear on all data collection instruments, documents, 
and files used in the statistical analysis and manuscript preparation. The case report forms with 
study IDs will be housed in the same chart as personal identifier documents are while the subject 
is active in the protocol. Only limited team members will have access to charts and database. No 
personal information concerning study participants will be released without their written consent. 
Other data quality assurance measures will include verifying the data, out of range data checks, 
and repeated evaluation of the data process. A separate data management document including 
variable characteristics, codebooks, validation role for each variable, characteristics of database 
file will be created and archived with original data.  
 
3.  HUMAN SUBJECTS 
 
The proposed study population will consist of 27 subjects with PAH. In order to achieve this 
number, it is anticipated that approximately 30 participants may need to be enrolled into this study 
to account for subjects who may not qualify the eligibility criteria or are withdrawn for any reasons.  
 
3.1 SUBJECT POPULATION 
 
3.1.1 Inclusion of Women and Minorities 
 


Oral CXA-10 in PAH                                                                                     
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Women and individuals from minority groups who meet the inclusion criteria and have none of 
the exclusion criteria, will be enrolled without restriction as dictated by the study protocols.  Every 
effort will be made to enroll participants in this research in a distribution, which mirrors the study 
population of the Pittsburgh area.  
 
3.1.2 Inclusion of Children 
 
This investigation will not enroll children based upon lack of safety data in children with regards 
to the investigational product.  
 
3.1.3 Inclusion of Prisoners 
 
This investigation will not enroll prisoners. 
 
3.2  INCLUSION CRITERIA 
 
The following criteria will be required on ALL subjects: 
 
• 
Male or female between 18-80 years of age inclusive at Screening 
• 
Weight ≥ 40 kg or 88 lbs 
• 
Have a WHO Classification of Functional Status Class II or III 
• 
Must meet all of the following hemodynamic criteria by means of a right heart catheterization: 
mPAP of ≥25 mmHg, PVR ≥ 3 wood units, PAWP of ≤15 mmHg. A clinical RHC done within 
2 months is acceptable to determine eligibility 
• 
Meet all of the following pulmonary function test parameters, completed no more than 12 
months before Screening or at screening: forced expiratory volume in one second (FEV1) > 
60% of predicted normal and forced vital capacity (FVC) ≥ 60% 
• 
A 6 MWD test of ≥ 100 m and ≤ 600 m at Screening 
• 
Participants enrolled in an exercise program for pulmonary rehabilitation must be in a stable 
program 1 month prior to Screening and must agree to maintain their current level of 
rehabilitation throughout the study. If subjects are not enrolled in an exercise training program 
for pulmonary rehabilitation they cannot enroll during the Screening/Baseline Period or 
throughout the study 
• 
If receiving 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (i.e., 
statins) subjects must not have changed their dose <4 weeks prior to Screening 
• 
If receiving simvastatin-containing products: simvastatin (Zocor), Vytorin, or any other 
combination therapy containing simvastatin, the subject’s simvastatin dose should not exceed 
20 mg/day  
      Note: Subjects using a simvastatin product at dose > 20 mg/day may be rescreened if their 
dose has been adjusted to < 20 mg/day, at least 4 weeks prior to Screening with no dose or 
regimen changes within 4 weeks prior to Baseline 
• 
Subjects must be receiving one or more of the following previously approved PAH therapies: 
phosphodiesterase type 5 inhibitors (PDE5), endothelin receptor antagonist (ERA), soluble 
guanylate cyclase (sGC) stimulator, prostanoids, prostacyclin receptor agonists and must be 
on stable doses (> 3 months) with no dose adjustment within 1 month of Screening  
• 
Ability to provide written informed consent 
 
 


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3.3 EXCLUSION CRITERIA 
 
Subjects meeting any of the following exclusion criteria at baseline will be excluded from 
participating in study: 
 
• 
Portopulmonary hypertension and pulmonary veno-occlusive diseases  
• 
Congenital heart defects (i.e., atrial septal defects, ventricular septal defects, and patent 
ductus arteriosus) repaired less than 1 year prior to Screening (Group 1 classification of 
Pulmonary Hypertension)  
• 
Systolic blood pressure > 160 or < 90 mmHg or diastolic blood pressure > 110 mmHg at 
Screening 
• 
An average QTcF on supine triplicate ECGs at Screening (Visit 1) of  >500 msec Acute 
myocardial infarction or acute coronary syndrome (ST-Elevation Myocardial Infarction 
(STEMI), Non STEMI (NSTEMI) and/or unstable angina) within the last 90 days prior to 
Screening 
• 
Recent cerebrovascular accident/transient ischemic attack (CVA/TIA) within the last 90 days 
prior to Screening 
• 
Recent hospitalization for left heart failure within the last 90 days prior to Screening 
• 
Clinically significant aortic or mitral valve disease defined as greater than moderate 
regurgitation or moderate stenosis; pericardial constriction; restrictive or constrictive 
cardiomyopathy; left ventricular dysfunction (LVEF < 50%); left ventricular outflow obstruction; 
symptomatic coronary artery disease; autonomic hypotension; or fluid depletion in the opinion 
of the investigator  
• 
Evidence of a life-threatening cardiac arrhythmias on ECG at Screening as determined by 
the physician investigator 
• 
Personal or family history of congenital prolonged QTc syndrome or sudden unexpected death 
due to a cardiac reason 
• 
Receiving intravenous inotropes (e.g. dopamine, dobutamine) within 2 weeks prior to 
Screening 
• 
History of angina pectoris or other condition that was treated with long or short acting nitrates 
<12 weeks of Screening 
• 
The subject has a history of herbal or natural medication use (including fish oil) within 2 weeks 
or 5 half-lives, whichever is longer, prior to Baseline 
• 
Subject has taken prednisone at doses > 15 mg/day; if immunosuppressive medications are 
used the dose must be stable within 12 weeks prior to Screening and throughout the study 
• 
 The subject is currently taking a drug that may affect the assay measurement of serum 
creatinine (e.g. cimetidine, Bactrim, Pyridium) 
• 
Newly prescribed drug or increased dose of an existing drug that is known to prolong the QTc 
interval and has been associated with Torsades de Pointes  
 Note: Stable doses of these drugs are permitted (i.e., subject has received the same dose 
and regimen for at least 30 days prior to Screening with no anticipated changes to the dose 
or regimen during the course of the study) 
• 
The subject is currently taking dimethyl fumarate (Tecfidera™) 


Oral CXA-10 in PAH                                                                                     
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• 
Females with a positive urine pregnancy test at Screening or prior to dosing or who are 
pregnant or breastfeeding or who are trying to conceive 
• 
Recent (within 6 months) history of abusing alcohol or illicit drugs 
• 
History of any primary malignancy, including a history of melanoma or suspicious 
undiagnosed skin lesions, with the exception of basal cell or squamous cell carcinomas of the 
skin or cervical carcinoma in situ or other malignancies curatively treated and with no evidence 
of disease for at least 5 years or prostate cancer who is not currently or expected, during the 
study, to undergo radiation therapy, chemotherapy, and/or surgical intervention, or to initiate 
hormonal treatment 
• 
Cardiovascular, liver, renal, hematologic, gastrointestinal, immunologic, endocrine, metabolic, 
central nervous system or psychiatric disease that, in the opinion of the investigator, may 
adversely affect the safety of the subject and/or efficacy of the investigational product or 
severely limit the lifespan of the subject other than the condition being studied 
• 
Clinically significant hyperthyroidism or hypothyroidism not adequately treated 
• 
Any other condition and/or situation that causes the Investigator to deem a subject unsuitable 
for the study (e.g., due to expected study medication non-compliance, inability to medically 
tolerate the study procedures, or a subject’s unwillingness to comply with study-related 
procedures) 
• 
The subject has known hypersensitivity to the CXA-10, the metabolites, or formulation 
excipients 
• 
The subject has had treatment with any investigational drug within 30 days or 5 half-lives 
(whichever is longer) prior to Screening or plans to participate in an investigational drug study 
at any time during this study 
 
Subjects who fail inclusion/exclusion criteria may be re-screened once. 
 
3.4 Precautionary and Prohibited Medications  
 
3.4.1. Table of Drug Classes  
 
Drug Class Category 
Intravenous inotropes 
(e.g. dopamine, 
dobutamine) 
No obvious mechanistic 
interaction, but would change 
the hemodynamics which are 
a primary endpoint 
If the subject needs IV 
inotropes, then the study team 
may stop the subject from taking 
CXA-10 and patient will receive 
treatment.  The subject may 
become sicker, if they now need 
this therapy. 
Long or short acting 
nitrates 
Both nitrates can affect 
hemodynamics (endpoint in 
study) and could impact 
If the subject uses the nitrates 
for short term and acutely (ie SL 
NTG for CP) then there are no 


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formation of endogenous 
nitro-fatty acids  
health issues. If the subject 
used the nitrates chronically, 
then the subject’s study results 
may not be interpretable. This 
may withdrawal the subject from 
the study.  
Newly prescribed drug or 
increased dose of an 
existing drug that is 
known to prolong QTc 
interval and has been 
associated with Torsades 
de Pointes (TdP) 
identified in the 
CredibleMeds.org 
website list as known risk 
(KR) of TdP. Stable 
doses of drugs classified 
as conditional risk (CR) of 
TdP or possible risk (PR) 
of TdP are permitted (i.e., 
subject has received the 
same dose and regimen 
for at least 30 days prior 
to Screening (Visit 1) with 
no anticipated changes to 
the dose or regimen 
during the course of the 
study). 
  
CXA-10 showed QT 
prolongation in dog toxicity 
study when the concentration 
was very high (much higher 
than levels seen in 
humans).  QT analysis in 
human studies did not reveal 
a QT issue.  However, in an 
abundance of caution, this 
exclusion was added. See IB 
for full QT analysis. 
  
As noted in the exclusion, if 
the subject is on stable doses 
of drug of PR and CR for TdP, 
and the subject’s QTc is 
acceptable, then the subject 
can continue. 
If there is no alternate therapy 
which does not cause QT 
prolongation to the subject, then 
it is a short term treatment. 
Therefore, the subject should 
stop taking CXA-10 during 
conmed use rather than 
restarting it. If it is not a short 
term treatment, then the subject 
should stop taking the CXA-10.  
  
[In the case of a subject taking 
antibiotics, often an alternate 
antibiotic can be used.  Also, 
many antibiotic treatment 
courses are short (single dose 
to 3-5 days, so the subject can 
stop taking CXA-10 for this 
period] 
   
Herbals, natural 
medications and fish oil 
These agents typically are of 
unknown composition and 
quality, so this exclusion is 
included in most clinical trial 
protocols.  
If the subjects are taking 
herbals, natural medications 
and fish oil, the subject should 
stop taking CXA-10 because 
there are typical risks of agents. 


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If there is an AE, the study team 
will not know if it is due to CXA-
10 or this herbals, natural 
medications and fish oil.  It is 
known that OTC products 
contain unexpected materials 
and/or have unexpected effects 
on prescribed drugs. 
Drugs that may affect the 
measurement of serum 
creatinine (e.g. 
cimetidine, Bactrim, 
Pyridium). 
The study team will monitor 
the subject’s renal function (a 
safety endpoint), so agents 
that affect the measure will 
confuse the interpretation of 
the safety signal. 
Often there are other 
therapeutic options which do not 
impact measurement of 
sCr.  Also, if the acute therapy 
and labs are not checked during 
the period of therapy, then it 
may not be a problem. 
Dimethyl fumarate 
(Tecfidera™) 
CXA-10 “like” drug which is an 
Nrf2 activator, so use will 
confuse interpretation of study 
results.  
Stop CXA-10 if the patient 
needs DMF. 
Simvastatin at doses 
greater than 20 mg 
(Zocor), Vytorin, or any 
other combination 
therapy containing 
simvastatin at doses 
greater than 20 mg. 
Drug-drug interaction study 
demonstrated that CXA-10 
could raise simvastatin acid 
level probably due to an effect 
on a transporter. 
Use alternate statin, since this 
interaction only is for 
simvastatin.  This is not a 
general statin interaction. 
Any other investigational 
drug regardless of route 
(topical, intranasal, etc). 
The study team will not allow 
2 investigational agents 
(which are not designed to be 
co-administered) be co-
administered. The study team 
will not know if CXA-10 drug 
or other investigational agent 
taken by patient caused an 
AE since there is not enough 
The subject can only participate 
in one clinical study at a time. 


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known about how CXA-10 
interacts with other 
investigational agents. 
 
 
 
 
 
4.   IRB APPROVAL AND FDA AMENDMENTS 
 
The Investigator will obtain, from the University of Pittsburgh Institutional Review Board (IRB), 
prospective approval of the clinical protocol and corresponding informed consent form(s); 
modifications to the clinical protocol and corresponding informed consent forms, and 
advertisements (i.e., directed at potential research subjects) for study recruitment.    
 
The only circumstance in which a deviation from the current IRB-approved clinical 
protocol/consent form(s) may be initiated in the absence of prospective IRB approval is to 
eliminate an apparent immediate hazard to the research subject(s).  In such circumstances, the 
Investigator will promptly notify the University of Pittsburgh IRB of the deviation. The Investigator 
should also notify the sponsor of this event.   
 
The University of Pittsburgh IRB operates in compliance with FDA regulations at 21 CFR Parts 
50 and 21 CFR 56, and in conformance with applicable International Conference on 
Harmonization (ICH) Guidelines on Good Clinical Practice (CGP).  
 
In the event that the University of Pittsburgh IRB requires, as a condition of approval, substantial 
changes to a clinical protocol submitted under an FDA-accepted IND application, or in the event 
of the Investigator’s decision to modify the previously accepted clinical protocol, the Sponsor will 
submit (i.e., in advance of implementing the change) a Protocol Amendment to the IND describing 
any change to a Phase 2 or Phase 3 protocol that significantly affects the safety of subjects, the 
scope of the investigation, or the scientific quality of the study.   
 
 
 
5. RECRUITMENT AND INFORMED CONSENT PROCEDURES 
 
5.1 RECRUITMENT METHODS 
 
The following recruitment methods will be used to identify potential subjects. All recruitment 
procedures and materials will be reviewed and approved by the IRB prior to their use. 
 
a. UPMC 
Pulmonary hypertension patients can be referred by their physician and/or cardiologist or 
pulmonologist from the UPMC Advanced Heart Failure Center, General Cardiology clinic, 
Benedum Geriatric Center, the Comprehensive Pulmonary Hypertension (PH) Program, 
internal medicine clinics, or other UPMC or community facilities. For UPMC 
Presbyterian/Montefiore-based clinics, we will obtain physician and HRPO approval for 
screening of subject medical records for identification of eligible candidates. Dr. Simon is a 


Oral CXA-10 in PAH                                                                                     
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part of the Advanced Heart Failure physician group so he may screen their patients. He will 
engage with additional cardiologists, pulmonologists, internal medicine physicians, and 
geriatricians for permission to screen from those clinics. Once identified as preliminarily 
eligible, the study coordinator/staff will reaffirm with the subject's physician that recruitment of 
the subject is medically appropriate. Staff will also request direction from the attending 
physician as to the timing of speaking to the subject, i.e., before or after the subject has seen 
the physician for their visit. This will be done on a case by case basis. The subject’s treating 
physician will obtain permission from the subject before the research team talks to the subject. 
Study staff will speak with candidates at clinic visits or by telephone call to assess interest and 
review medical history to assess eligibility.  
 
Subjects referred from facilities outside the UPMC Epic medical record system will be provided 
a medical record release for their physician to release needed documents to confirm eligibility. 
 
Subjects can also be identified from the inpatient Cardiology service. The study coordinator 
will follow the same procedure as for outpatients by screening the inpatient service for subjects 
admitted with heart failure symptomatology, check medical history for heart failure diagnoses, 
and engage the attending cardiologist as to appropriateness for the study. As noted, 
permission to speak with subject will be obtained from the Cardiology attending. 
 
b. Research Registry 
One research registry is available to the PI. The HRPO submission will include the request to 
use the Clinical Translational Science Institute’s Pitt+Me Research Registry, which includes 
a database of over 90,000 individuals who have indicated their interest in participating in 
research studies. The Pitt+Me initiative includes the use of social media to engage subjects. 
 
c. Advertisements 
An approved study flier and recruitment brochure will be placed in key places and/or be 
distributed to physician offices, related clinics, or on other occasions/venues that present as 
an opportunity to recruit (e.g., a PI speaking engagement or a community outreach event to 
reach minority subjects). Potential subjects can self-refer by contacting the study staff via a 
telephone number/email address that is provided on these advertisements. Study staff will 
utilize the approved phone screening script when responding to interested candidates. With 
subject permission, they will be screened on the phone to make a preliminary assessment of 
eligibility. We will obtain permission to access their medical records in the UPMC database or 
request records from their provider as needed to further document eligibility.  
 
Advertisements, such as on or print copy in newspapers, or bus signs, may also be utilized 
depending on recruitment rates.  
 
Once subjects have been determined to be eligible from medical record review and attending 
approval, recruitment and enrollment procedures will then follow, including: 
 
a) Confirmation of eligibility by study physician.  
 
b) Setting dates for patient visits will also occur prior to screening visit to maintain timeliness 
of visits per protocol. 
 


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c) Scheduling outpatient screening visit where study risks and potential benefits and rights 
as a research subject will be described in detail, informed consent will be obtained, and 
final eligibility will be confirmed. 
 
d) To minimize the possibility that subjects will feel obligated to participate, investigators will 
reinforce with their subjects that participation is voluntary, that they do not have to 
participate, and that the decision not to participate will not affect their care, now or in the 
future. The investigator will also allow subjects to make further inquiries if they are 
interested. 
 
5.2 INFORMED CONSENT PROCEDURES  
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of participation in this study will be provided to the subjects and their 
families.  Consent forms describing in detail the study procedures and risks are given to the 
subject and written documentation of informed consent is required prior to enrolling in the study.  
Consent forms will be IRB approved and the subject will be asked to read and review the 
document. Upon reviewing the document, the investigator will explain the research study to the 
subject and answer any questions that may arise.  The subjects will sign the informed consent 
document prior to being enrolled in the study.  The subjects should have the opportunity to discuss 
the study with their surrogates or think about it prior to agreeing to participate. The subjects may 
withdraw consent at any time throughout the course of the study. A copy of the informed consent 
document will be given to the subjects for their records. The rights and welfare of the subjects will 
be protected by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. 
Prior to performing any of the research study procedures or interventions, subjects must provide 
informed consent. The investigator will verbally explain the study to the potential subject in a 
language understandable to subjects, providing all pertinent information (purpose, procedures, 
risks, benefits, alternatives to participation, etc.), and will allow potential subjects ample 
opportunity to ask questions to elicit a better understanding of the study. Following this verbal 
explanation, potential subjects will be provided with a local IRB approved consent form and will 
be asked to read and review the document. Upon reviewing the document, the investigator will 
provide adequate opportunity for the subject to consider all options and answer any additional 
questions the potential subject may have. Every effort will be made to ensure that subjects have 
comprehended the study information prior to obtaining subject's voluntary agreement to 
participate. This interview will impose only minimal risk, since: the interview must stop after any 
question that determines the patient is not eligible; the answers to the interview of an ineligible 
patient will not be retained; and the answers of potentially eligible patients will be secured 
consistent with the confidentiality safeguards described at Risks and Benefits. 
In addition, older potential participants whose competency to consent is in question will be tested 
for sufficient comprehension and recall of the information presented. Prospective subjects who 
do not remember the important facts about participation in the research study after repeated 
testing will not be included in the study.  
The subjects may withdraw consent at any time throughout the course of the study. A copy of the 
informed consent document will be given to the subjects for their records. The rights and welfare 


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of the subjects will be protected by emphasizing to them that the quality of their medical care will 
not be adversely affected if they decline to participate in this study. 
 
 
6.  POTENTIAL RISKS AND BENEFITS 
 
6.1 POTENTIAL RISKS 
 
As with any experimental procedure, there may be adverse events or side effects that are 
currently unknown, and certain of these unknown risks could be permanent, severe or life 
threatening.  Every attempt will be taken to minimize these risks. 
 
Risks of CXA-10 
CXA-10 has been given to approximately 107 subjects, some healthy and some with kidney 
disease. Most of these subjects (97 subjects) received CXA-10 on an empty stomach.  When taken 
on an empty stomach, the most common side effects were: 
 
• 
Diarrhea  
• 
Nausea  
• 
Abdominal pain 
• 
Vomiting   
Other less common side effects included: 
• 
Abdominal discomfort 
• 
Dizziness  
• 
Fatigue  
• 
Lightheadedness  
• 
A metallic taste in the mouth.  
Uncommon (rare) side effects included: 
• 
Heart burn  
• 
Fainting  
• 
Indigestion  
• 
Headache  
• 
Rectal discomfort  
The side effects were mild to moderate.   
Nineteen subjects have received at least one dose of CXA-10 after eating breakfast. When taken 
with food, some subjects experienced: 
 
• 
Diarrhea  
• 
Nausea  
These side effects were less common than in subjects who took CXA-10 on an empty stomach. 
Subject may or may not experience similar side effects in this study. 
Allergic Reaction Risks 
As with taking any drug, there is a risk of allergic reaction including a serious allergic reaction that 
may be life-threatening or cause death. Some symptoms of allergic reactions are:   
• 
Rash 


Oral CXA-10 in PAH                                                                                     
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• 
Wheezing and difficulty breathing  
• 
Dizziness and fainting 
• 
Swelling around the mouth, throat or eyes 
• 
A fast pulse 
• 
Sweating 
 
Reproductive Risks   
It is not known if the study drug can affect an unborn baby so the subject should perform the 
appropriate methods to prevent pregnancy. The subject should not father a baby while on this 
study and the subject should perform the appropriate methods to prevent pregnancy..  If subjects 
are physically able to father a baby, subjects must use an effective method of birth control while 
on this study. If subjects become aware that they or their sexual partner is pregnant during the 
course of their participation in this research study, subjects must contact, as soon as possible, 
the study investigator.  
Risks of 6MWT 
The 6-Minute Walk Test, can cause muscle soreness or fatigue (occurs in 10-25% of people). 
Other changes include shortness of breath, abnormal blood pressure, or fainting (occurs in 10-
25% of people). Heart attack, stroke, or sudden death are rare (occur in <1% of people). Rarely, 
exercise may cause moderate to extreme pain which could be due to muscle sprains, muscle 
strains, broken bones, or chest pain. 
 
Risks of Blood Drawing 
Common risks include temporary discomfort, bruising which may last for several days, redness, 
swelling, lower hemoglobin level. Infrequent risks include a subject may feel lightheaded or faint 
when blood is drawn. This is usually due to nervousness and is not usually serious. Rare risks 
include infection and bleeding. 
Risks of ECG 
There are generally no risks associated with ECG. A subject may experience a mild skin rash 
from the ECG leads. 
Risks of Echocardiography 
This is a noninvasive procedure. There is no known risk associated with this procedure. Gel will 
be applied during the test which may cause coldness and/or irritation. 
Risks of Accelerometer Use 
Common risks associated with wearing the accelerometer are redness, irritation, and chaffing.  
 
Risks of Right Heart Catheterization 
Common risks: pain at the needle entry site and slight risk of bleeding around the site, bruising at 
site, lightheadedness or dizziness during the needle stick. 
Infrequent risks: puncturing the lung which would require a chest tube insertion, irregular 
heartbeats which usually stop when the long tube is removed from the heart. 
Very rare complications include cardiac arrhythmias, cardiac tamponade, low blood 
pressure, infection, or embolism caused by blood clots at the tip of the catheter. 
 
The additional time of the procedure for measurement of hemodynamics 30 minutes after giving 
study drug is not expected to incur any additional risk. 


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Risks of Medications used during Catheterization 
The medications used for sedation are relatively brief in duration and should wear off within 
several hours. The side effects are listed below for each drug. 
• 
1% Lidocaine: will be used to numb the area prior to the insertion of the cardiac catheter 
into either the arm, neck or groin vein. A common side effect is slight burning at the site 
which dissipates quickly.  
• 
Fentanyl: Common side effects include temporary light-headedness, dizziness, and 
nausea, vomiting or sweating.  
• 
Midazolam: Common side effect includes drowsiness. Infrequent side effects are nausea, 
vomiting. Breathing problems are rare.  Allergic reactions (e.g., hives, itching, etc.) to 
lidocaine, fentanyl, or midazolam are rare. 
Risks of Fluoroscopy during the Catheterization 
An x-ray may be done, if indicated, on participants whose neck vein is used for the catheterization. 
An X-ray performed for the purpose of this research study involves exposure to radiation. Each 
x-ray will result in a radiation dose of approximately 3 rems to the neck with minimal exposure of 
other body areas. A total of 6 rems if 2 RHCs are performed. For comparison, radiation workers 
are permitted, by Federal regulation, to receive a maximum annual radiation dose of 20 rems to 
the most sensitive organs of their body. There is no minimum amount of radiation exposure that 
is recognized as being totally free of the risk of causing genetic mutations (abnormal cells) or 
cancer. However, the risk associated with the amount of radiation exposure received from 
participation in this study is considered to be low and comparable to everyday risks.  
Risk of Pulmonary Function Test  
Pulmonary function test infrequently can make the chest tight or lead to shortness of breath. 
Albuterol will be available if this occurs. Rarely, a subject may have coughing or lightheadedness 
with spirometry. If Albuterol is given, the subject will get up to 4 puffs of albuterol with these tests. 
Albuterol may make a subject feel slightly jittery or nervous, but the feelings are temporary. 
 
Risk of IVGTT  
Common Risks: (occurring in less than 25% of people) include: phlebitis (inflammation of a vein), 
transient hyperglycemia (high blood sugar not requiring treatment). Rare side effects (occurring 
in less than 1% of people) include: Hypoglycemia (low blood sugar) which may cause symptoms 
such as shakiness, nervousness, sweatiness, hunger, dizziness, or fast heart rate. If severe, 
hypoglycemia can cause coma, seizure, or even death. 
 
Risks of Stool Collection 
There is no risk from stool collection. 
 
Risks of Oral Sample Collection (Saliva and Tongue Scrapings) 
There are no anticipated risks from saliva collection. Tongue scrapings might cause gagging or 
mild local irritation or a very small amount of bleeding that will resolve on its own. 
 
Risks of blood draw/intravenous line 
A common symptom of anemia is fatigue (feeling tired or weak). Common risks of blood sampling 
by venipuncture or intravenous line placement include temporary pain, bruising which may last 
for several days, redness, swelling and phlebitis. Infrequent risks include feeling lightheaded or 
faint when blood is drawn. This is usually due to nervousness (not due to the amount of blood 


Oral CXA-10 in PAH                                                                                     
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taken), and it is not usually serious. Infrequent risks for the intravenous line include infiltration (a 
leakage of anything that has been given through the vein (such as the saline, dextrose, insulin) 
into the arm tissue that surrounds the vein and holds the IV). Rare risks include infection and 
bleeding. 
 
Risk of Breach of Confidentiality 
Although we are taking many steps to protect the participants' information, there is always a 
chance that their information or identity could be disclosed. To protect their information, paper-
based records will be kept in a secure location and only be accessible to personnel involved in 
the study. Paper charts will contain subject identifiers but will be in locked cabinets within a locked 
office on a unit that has restricted access. Specimens will be stripped of subject identifiers and 
stored with a study ID only. These specimens will be stored safely in the custody of the 
Investigator responsible for the individual assays. 
 
 
6.2 ALTERNATIVE TREATMENTS 
 
If subjects choose not to participate in this study, they are to continue their medical care under 
the direction of their treating physicians. 
 
 
6.3 POTENTIAL BENEFITS 
 
There may or may not be direct benefits for the volunteer subjects participating in this study. 
However, there may be a potential future benefit to society as a whole, from the information 
obtained from the conduct of this study through the advancement of knowledge. The proposed 
clinical trial has the potential to profoundly affect current paradigms and treatment approaches to 
PAH, for which there is no available therapy. If novel treatments of PAH are discovered, this 
finding would benefit a large group of patients. 
 
Based on the preceding assessment of risks and potential benefits, the risks to subjects are 
reasonable in relation to anticipated benefits.  The research presents a balance of risks and 
expected direct benefits similar to that available in the clinical setting. 
 
6.4 DATA SAFETY MONITORING  
 
6.4.1 Data Safety Monitoring Board 
 
An Independent Data and Safety Monitoring Board (iDSMB) will be established; to be comprised 
of individuals who are not involved with this study protocol. The iDSMB will comprise of members 
including senior experts in PAH, clinical research and clinical trial design.  The members selected 
will be responsible for the monitoring of the CXA-10 Complexa Study only. All members of the 
DSMB are required to be independent of the studies being reviewed and need to certify this by 
signing a DSMB Conflict of Interest and Confidentiality statement. Dr. Freeman will disclose his 
SFI at the beginning of the DSMB meetings and that his SFI will be recorded in the meeting’s 
minutes and agenda.   
 
The iDSMB will conduct interim monitoring of accumulating data from research activities to assure 
the continue safety of human subjects, relevance and appropriateness of the study, and the 
integrity of research data.  
 


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6.4.2 Data Safety Monitoring Plan 
 
Before the start of the study, the DSMB will review the protocol for any major concern and the 
plans for data and safety monitoring to ensure that the frequency of monitoring is appropriate for 
the intervention. 
  
Once the study is implemented, the DSMB will convene as often as necessary, but not less than 
every 6 months, to examine the accumulated safety and enrollment data, review study progress, 
and discuss other factors (internal or external to the study) that might impact continuation of the 
study as designed. A DSMB meeting may be requested by DSMB members, the PO, IRB, or 
study PI at any time to discuss safety concerns. Meetings may be held by conference calls or 
videoconferences or as face-to-face meetings. 
 
During the study, the DSMB will review cumulative study data to evaluate safety, study conduct, 
and scientific validity and integrity of the trial as well as to assess the performance of overall study 
operations and any other relevant issues, as necessary. The DSMB will conclude each review 
with their recommendations to NHLBI, IRB and other applicable oversight bodies as to whether 
the study should continue without change, be modified, or terminated 
 
The study PI will ensure that the DSMB is apprised of all new safety information relevant to the 
study product and the study, including all protocol revisions, summary safety and enrollment data 
and all safety reports. 
 
The IND Sponsor- will also submit annually an Annual Report to the FDA. The detailed written 
summary will be provided to the DSMB and the IRB. In addition, the DSMB Report will be 
submitted to the IRB at the time of continuing review annually or more often as required.  
 
Monitoring of safety and data quality in the proposed study will be the responsibility of all 
personnel on the project, with primary responsibility and supervision by the Investigator.  The 
Institutional Review Board will approve the Statement of Informed Consent for the study and 
provide institutional oversight of data and safety issues. The study protocol will be approved prior 
to recruiting or obtaining consent from any participants. Moreover, the study will be reviewed at a 
minimum of annual basis (or more frequently as deemed necessary) by the IRB committee. Each 
participant will sign the Informed Consent Form described above prior to participating in the study. 
To ensure participant safety, once participants are enrolled in the study, study staff will 
immediately report all adverse and serious adverse events to one of the Investigators. The 
Investigator will, per standardized procedures, report them to the IRB for their review. These 
events should also be communicated to the sponsor of the IND.   With regard to monitoring of 
data quality and protected health information, all required personnel proposed for this project will 
have the required human subjects and confidentiality training, which includes information about 
maintaining data integrity and security. Confidentiality will be guarded using established 
procedures such as storing data in locked cabinets within locked offices or locked data rooms, 
coding by study identification numbers rather than any personally identifying information to avoid 
revealing the identity of subjects, and aggregating data across participants. The key linking names 
and study identification numbers will be kept separately from the data sets with limited access by 
study personnel. Only study personnel will have access to the data sets on protected servers. 
Oversight of all aspects of data management will occur with the Investigator. 
 
Data Monitoring Plan. The proposed study will use the FDA definition of adverse events (AE) and 
serious adverse events (SAE). Any SAE, which is unexpected and related to study intervention, 
will be reported immediately to the IRB and Complexa Inc., and will be followed by an additional 


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letter detailing the nature of the SAE. In the event that a participant either withdraws from the 
study or the investigators decide to discontinue a participant due to a SAE, the participant will be 
monitored by the co-PIs until (a) a resolution is reached (e.g., the problem has resolved or 
stabilized with no further change expected), (b) the SAE is determined to be clearly unrelated to 
the study intervention, or (c) the SAE results in death. Outcomes of SAEs will be regularly reported 
to the IRB and Complexa Inc., and the IND sponsor. Dr. Freeman will not be involved in any 
decisions about adverse event reporting. A summary of the SAEs that occurred during the 
previous year will be included in the annual progress report as well as in the annual IRB renewal. 
 
6.4.3 Parameters to be monitored 
 
The following progress will be monitored throughout the course of the research to ensure the 
safety of subjects as well as the integrity and confidentiality of their data. 
 
• 
An evaluation of the progress of the research study, including subject recruitment and 
retention, and an assessment of the timeliness and quality of the data. 
 
• 
A review of collected data (including adverse events, unanticipated problems, and subject 
withdrawals) to determine whether there is a change to the anticipated benefit-to-risk 
assessment of study participation and whether the study should continue as originally 
designed, should be changed, or should be terminated. 
 
• 
An assessment of external factors or relevant information (eg. pertinent scientific literature 
reports or therapeutic development, results of related studies) that may have an impact on the 
safety and study participants or the ethics of the research study. 
 
• 
A review of study procedures designed to protect the privacy of the research subjects and the 
confidentiality of their research data. 
 
The severity of adverse changes in physical signs or symptoms will be classified as follows: 
 
• 
Grade 1 (Mild): asymptomatic or mild symptoms; clinical or diagnostic observation only; 
intervention not indicated. 
 
• 
Grade 2 (Moderate): minimal, local or noninvasive intervention indicated; limiting age-
appropriate ADL (Activities of Daily Living). 
 
• 
Grade 3 (Severe): medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care ADL. 
 
• 
Grade 4 (Life-threatening): consequences; urgent intervention indicated. 
 
• 
Grade 5 (Death): event is a direct cause of death. 
 
For AEs of Diarrhea: 
 
The severity of diarrhea will be graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03: 
 


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Grade 1: 
Increase of < 4 stools per day over baseline; mild increase in ostomy output 
compared with baseline 
 
Grade 2: 
Increase of 4 to 6 stools per day over baseline; moderate increase in ostomy output 
compared with baseline 
 
Grade 3: 
Increase of ≥ 7 stools per day over baseline; incontinence; hospitalization indicated; 
severe increase in ostomy output compared with baseline; limiting self-care 
activities of daily living 
 
Grade 4: 
Life-threatening consequences; urgent intervention indicated 
 
Grade 5: 
Death 
 
6.4.4 Frequency of Monitoring 
 
The Investigator will review subject safety data as it is generated. The Investigator, sub-
investigators, and the research staff will meet on an approximately monthly interval to re-evaluate 
study goals, subject recruitment, data coding and retention, documentation and identification of 
adverse events, complaints and confidentiality of subjects. There will be an evaluation of the 
progress of the research study, including assessments of data quality, time lines, participant 
recruitment, accrual, and retention. The Investigator will also review the outcome and adverse 
event data to determine whether there is any change to the anticipated benefit-to-risk ratio of 
study participation and whether the study should continue as originally designed or should it be 
re-evaluated and changed. 
 
The DSMB will also be expected to meet as needed, but not less than every six months to provide 
an overall summary status report to the regulatory agencies. Dr. Freeman will not be involved in 
those monthly reviews.  
 
6.4.5 Reportable Adverse Events 
 
For this study, a serious adverse event is any untoward clinical event that is thought by either the 
investigator or the sponsor to be related to the study and results in any of the following outcomes: 
that is also: 
 
1) Death 
2) A life threatening adverse event  
3) Inpatient hospitalization or prolongation of an existing hospitalization   
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
5) A congenital anomaly or birth defect 
6) Important medical events that may not result in death, be life threatening, or require 
7) hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient, or subject, and may require medical, or surgical intervention 
to prevent one of the serious outcomes listed above. 
 
If clinically important and unexpected adverse experiences or clinically important study-related 
adverse experiences occur, they will be recorded on the adverse event case report form.    
 


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6.4.6 Adverse Events Reporting Timeline 
 
Life-threatening or fatal unexpected adverse events associated with the use of the study drug or 
procedures must be reported to the IRB and Complexa Inc within 24 hours of discovery of the 
incident with subsequent follow-up submission of a detailed written report. 
 
The FDA will be notified by telephone or facsimile transmission of a human adverse event that is 
fatal or life-threatening no later than 7 calendar days after receiving the respective human adverse 
event information, followed by the subsequent submission of a written IND Safety Report. 
 
Serious and unexpected adverse events associated with the use of the study drug or procedures 
will be reported to the IRB and Complexa Inc. with subsequent follow-up submission of a detailed 
written report in accordance with the respective policies and procedures of the IRB. Written IND 
Safety Reports will be submitted to the FDA and Complexa Inc. as soon as possible and, in no 
event, later than 15 calendar days following the investigator-sponsor’s receipt of the respective 
adverse event information. 
 
The unexpected, life-threatening or fatal, suspected adverse reaction will be reported to the 
NHLBI within 7 calendar days. Unanticipated problems suggesting greater risk of harm to study 
participants than was previously known or recognized will be reported to NHLBI within 30 calendar 
days. Expedited SAE/UP reports to NHLBI will include the following elements: 
 
• 
Study title, grant/contract number, PI name 
• 
Description and date of the event or problem, including why it merits expedited reporting 
• 
When available, date(s) when the event was reported to applicable governing bodies (e.g., 
IRB, FDA) 
• 
Any corrective action planned or taken in response to the event or problem (e.g., study 
suspension, consent or protocol changes, additional training or security measures) 
 
Communications from other applicable oversight bodies (eg: IRB, FDA, iDSMB, Complexa Inc.) 
regarding any applicable SAE/UP will also be reported to NHLBI. 
 
6.4.7 Reporting of Changes to Protocol and Consent 
 
Any amendments or modifications to the protocol will be shared with Complexa, Inc. Modifications 
to the clinical protocol or consent will also be submitted to the IRB for review prior to 
implementation of the changes in study practice. In the event that the study is suspended or 
terminated by the IRB or by the DSMB, or for other reasons, the NHLBI will be notified in writing 
including details as to the reasons for suspension or termination and any recommendations made 
by the IRB or DSMB. The FDA and Complexa, Inc. will also be notified of any changes to the 
protocol, suspensions or termination. 
 
6.4.8. Withdrawal of Subjects and Stopping Criteria: 
 
STOPPING RULES: 
 
Dose Reduction: If subjects experience an increase of ≥ 7 stools/day over baseline or any 
serious AE believed to be possibly related to the study drug the dose of the study drug may be 
reduced to 150 mg/day or 75 mg/day at the discretion of the physician investigator. Subjects may 
be asked to return to the clinic for an unscheduled visit to assess their status if deemed necessary 


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based on the clinical judgement of the physician investigator. This unscheduled visit may require 
blood draws, vital signs and/or review of concomitant medication. 
 
Withdrawal of Subjects: Subjects must be withdrawn from the study for the following reasons: 
 
• 
Systolic BP < 80 mmHg 
• 
Liver function test abnormalities: if ALT and/or AST > 8X ULN, the subject should stop taking 
study drug immediately. Medical evaluation should be undertaken as appropriate to the signs 
and symptoms manifested by the subject 
• 
Positive pregnancy test 
 
Subjects may be withdrawn from the study for the following reasons: 
 
• 
At their own request 
• 
At the specific request of the Investigator (eg: detection of a new significant safety concern 
related to the study drug) 
• 
Occurrence of intercurrent diseases which in investigator's opinion, continuation of the study 
drug would be harmful to the subject's well-being 
• 
Pertinent non-compliance with the conditions for the trial or instructions by the investigator 
• 
Lost to follow up  
Any subject removed from the study will remain under medical supervision until the condition is 
medically acceptable. Study subjects removed from the study will replaced by enrolling another 
volunteer with similar demographics. 
 
Subjects not completing the entire study should be fully evaluated when possible according to 
the following schedule: 
 
• 
If study medication is discontinued on or prior to Week 4, complete all protocol required 
assessments scheduled for the End of Treatment visit excluding the RHC. 
• 
If study medication is discontinued after Week 4 but prior to Week 10, complete all protocol 
required assessments scheduled for the End of Treatment visit excluding the RHC. 
• 
If study medication is discontinued on or after Week 10 and prior to the start of the End of 
Treatment visit, complete all protocol required assessments scheduled for the End of 
Treatment Period. 
 
All withdrawn subjects will be asked to report to the clinic for a follow-up visit (Visit 9). 
 
Discontinuation of the Clinical Trial:  For safety reasons, we may discontinue the study if the 
first two subjects enrolled experience any unexpected fatal or life-threatening events that can be 
attributed to the study drug; the study will be halted until data review by investigators and the 
iDSMB has rendered a final recommendation about study continuation. 
 
 
6.5 RISKS MANAGEMENT PROCEDURES 
 
6.5.1  Protection Against Risks  
 
General Risks of Study Protocol and Procedures 


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• 
All research interventions/activities will be conducted in private patient care areas. The 
collection of sensitive information about subjects is limited to the amount necessary to achieve 
the aims of the research, so that no unneeded sensitive information is being collected. 
 
• 
All demographic and clinical information about the subject will be stored on a Case Report 
Form which will be completed for each subject enrolled into the clinical study. A relational 
database will be constructed on a local server with daily backups where only select research 
team members will have access to the database. The electronic data capture system being 
used for this clinical research study has not been fully certified as being compliant with the 
FDA regulations at 21 CFR Part 11 due to the limited scope of this clinical research study. 
Data will be entered on the server over an encrypted network connection and stored behind 
a secure firewall. The case report forms with study IDs will be housed in the same chart as 
personal identifier documents are while the subject is active in the protocol. Personal 
information documents will be stored separately once each subject’s participation is complete. 
Only limited team members will have access to charts and database. Other data quality 
assurance measures will include verifying the data, out of range data checks, and repeated 
evaluation of the data process. All members of the research team should receive appropriate 
training about securing and safeguarding research data.  
 
• 
Specimens will be stripped of subject identifiers and stored according to a similar coding 
protocol as described above. These specimens will be stored safely in the custody of the 
Investigator responsible for the individual assays. The Investigators will limit future access to 
any remaining sample to only those investigators with prior IRB approval for their studies. 
 
• 
All staff involved in this study are properly credentialed and instructed in the areas of testing, 
confidentiality, and safety.  
 
• 
The Investigator will retain the data for the entire period of this study and will retain the 
specified records and reports until two years after investigations under the IND have been 
discontinued and the FDA is notified. The Investigator may continue to use and disclose 
subjects’ de-identified information for the purpose of this study for a minimum of seven years 
after final reporting or publication of the study. If the subject decides to withdraw or be 
withdrawn from study participation, they may request that the study data and samples be 
destroyed. Subject names or other directly identifiable information will not appear on any 
reports, publications, or other disclosures of clinical study outcomes. 
 
6.5.2 Protection Against Potential Risks of Experimental Intervention 
 
Blood Draws: To minimize the risks of blood drawing, a licensed technician or registered nurse 
will perform the procedure and standard aseptic technique will be followed to avoid the very rare 
complication of infection.  
 
Echocardiography: There are no known risks from echocardiography. 
 
Right Heart Catheterization: The procedures will only be performed by trained and experienced 
clinicians.  Subjects will be closely monitored as is routinely done for such procedures.   
 
Six Minute Walk Test: Risks normally associated with 6 minute walk testing will be minimized by 
selecting study personnel who are experienced with these testing procedures and who have the 
facilities and equipment necessary to complete the testing. 


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IVGTT: To minimize the risk associated with the IVGTT, subjects will be closely monitored for 
signs and symptoms of hypoglycemia. 
 
Confidentiality:  Risk to confidentiality will be minimized by identifying data collected only by 
anonymous study number.  A confidential database linking subject identifying information with 
study ID number will be maintained in a password-protected computer, and access to the 
database will be limited to the research staff under the supervision of the PI. All data storage and 
transfer including imaging and physiology data will be secure and HIPAA compliant. At no time 
will human subjects be identified in data presentation, publications etc. Specimens will be stripped 
of subject identifiers and stored according to a similar coding protocol as described above. These 
specimens will be stored securely in the custody of the investigators responsible for the individual 
assays.  All staff involved in this study are properly credentialed and instructed in the areas of 
testing, confidentiality, and safety. 
 
Certificate of Confidentiality: To further protect the privacy of study participants, a Certificate of 
Confidentiality will be issued by the National Institutes of Health.  This certificate protects 
identifiable research information from forced disclosure. It allows the investigator and others who 
have access to research records to refuse to disclose identifying information on research 
participation in any civil, criminal, administrative, legislative, or other proceeding, whether at the 
federal, state, or local level. By protecting researchers and institutions from being compelled to 
disclose information that would identify research participants, Certificates of Confidentiality help 
achieve the research objectives and promote participation in studies by helping assure 
confidentiality and privacy to participants. 
 
Protection of Human Subjects Education: The PI, sub-investigators and all involved research staff 
are trained in human research protection issues and have completed the Collaborative 
Institutional Training Initiative (CITI) online courses including education in Human Subject 
Research and Responsible Conduct of Research. The courses consist of modules on Informed 
Consent, the Consent Process, Research Integrity and Conflict of Interests, Research and Health 
Insurance Portability and Accountability Act (HIPAA) Privacy Protections.  Any new research staff 
will be required to complete the CITI online courses before engaging in human subjects research 
and being added to a research protocol. In addition, all members of the research team must 
continue to supplement this training by completing a refresher course every three years. 
 
Safety Oversight: An external Data and Safety Monitoring Board will be established to monitor 
the study. 
 
7.  COSTS AND PAYMENTS 
 
7.1 COSTS 
 
Research subjects or their insurance providers will not be charged for any of the procedures 
performed for the purpose of this research study.  
 
7.2 PAYMENTS 
 
The subjects will receive the remuneration upon completion of the study. In the event that a 
subject drops out prior to completion of the study due to study related adverse events, the subject 


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will be reimbursed for the individual study visits that they completed. Travel expenses may also 
be reimbursed. 
 
8.  QUALIFICATIONS AND SOURCE OF SUPPORT 
 
8.1 QUALIFICATIONS OF THE INVESTIGATORS 
 
IND SPONSOR AND SUB-INVESTIGATOR: 
 
Mark Gladwin, M.D., is a Distinguished Professor of Medicine, University of Pittsburgh. Dr 
Gladwin is the Chair of the Department of Medicine and Director of the Vascular Medicine Institute 
at the University of Pittsburgh.  Dr. Gladwin is recognized internationally as an expert in pulmonary 
hypertension, having described the pathobiology and clinical characteristics of pulmonary 
hypertension in patients with sickle cell disease and other chronic hereditary and acquired 
hemolytic diseases. He has authored more than 10 textbook chapters on pulmonary vascular 
disease and has published 109 peer-reviewed manuscripts on the topic of pulmonary 
hypertension alone. Dr. Gladwin currently serves as the Associate Editor for the American Journal 
of Respiratory and Critical Care Medicine responsible for pulmonary vascular disease 
manuscripts, authored the ATS guidelines on PH management in sickle cell disease, and has 
served on a number of NHLBI workshops on pulmonary vascular disease. Dr. Gladwin has a long 
history of leadership of translational projects and programs, having served as a principal or 
associate investigator on more than 30 human subjects protocols and has three drugs developed 
at the NIH that are currently licensed and in phase I-II development. Additionally, as the IND 
Sponsor for this clinical investigation, Dr. Gladwin will ensure that effective IND application is 
maintained with respect to this clinical investigation. He will be responsible for taking all 
reasonable steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial 
compliance, integrity, and validity of the data collection. 
 
 
PRINCIPAL INVESTIGATOR: 
 
Marc Simon, MD: Dr. Simon is an Associate Professor of Medicine in the Heart Failure and 
Cardiac Transplantation Section at the University of Pittsburgh. Dr. Simon has been involved in 
many research projects. He will be responsible for the overall accrual of patients who are seen at 
the UPMC Heart and Vascular Institute on a regular basis as well as for performance of the 
cardiac catheterizations, analysis and reporting of all data. Dr. Simon will provide daily leadership 
and supervision to all aspects of the study execution.  
 
CO-PRINCIPAL INVESTIGATOR: 
 
Belinda River-Lebron, MD: Dr. Rivera-Lebron is an Assistant Professor in the Department of 
Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine. Dr. Rivera-Lebron’s clinical 
interests are primarily focused on the diagnosis, management and treatment of pulmonary 
hypertension. Together, both Drs. Rivera-Lebron and Simon will oversee the execution of the trial 
and ensure proper monitoring of this clinical investigation. 
 
SUB-INVESTIGATORS: 
 
Frederico Toledo, MD: Dr. Toledo is an Associate Professor of Medicine. Dr. Toledo is board-
certified in endocrinology and has been a clinical researcher for one and a half decades. He has 


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performed more than 500 euglycemic clamps/IVGTTs as part of his studies and as a collaborator 
in others. 
 
Bruce Freeman, PhD: Dr. Freeman is Professor and Chair of the Department of Pharmacology 
and Chemical Biology. Dr. Freeman studies the cell and tissue production and actions of reactive 
species, with the goal of understanding fundamental mechanisms of redox-mediated metabolic 
and inflammatory signaling. His discoveries have revealed new therapeutic strategies for treating 
acute and chronic inflammatory conditions, including metabolic, renal, cardiovascular and 
respiratory diseases. Drug candidates stemming from this work have led to >10 issued US and 
international patents and lead compounds having Investigative New Drug status from the FDA. 
These drug candidates are being evaluated in early stage human studies by Complexa, a 
biopharmaceutical company for which Freeman is the scientific founder. In recent years, his 
academic laboratory has revealed that a) nitric oxide signaling and pathogenic actions are 
modulated by a variety of secondary free radical and oxidant-mediated reactions, b) nitric oxide 
and nitrite-dependent reactions of unsaturated fatty acids yield nitroalkene products that potently 
regulate the activity of key inflammatory-related enzymes and transcription factors. Current focus 
is directed toward understanding inflammatory signaling reactions in asthma, pulmonary and 
systemic hypertension and metabolic syndrome. In particular, electrophilic nitro- and oxo-fatty 
acid-induced post-translational protein modification reactions are explored in the context of the 
regulation of cell and tissue inflammatory and metabolic responses. 
 
Stacy Gelhaus Wendell, PhD: Dr. Wendell is an Assistant Professor of the Department of 
Pharmacology and Chemical Biology. Dr. Wendell is the Director of Metabolomics for the 
Biomedical Mass Spectrometry Center at the University of Pittsburgh and has extensive 
experience and expertise in the development of liquid chromatography mass spectrometry (LC-
MS) methods for the analysis of fatty acids, exogenous and endogenous biomarkers of disease, 
and drug metabolites. Dr. Wendell has published several reviews and book chapters on 
metabolite identification by mass spectrometry and fatty acids in disease. The proposed aims of 
this study are focused on the formation, metabolism, and anti-inflammatory signaling actions of 
NO2-FA in PAH. Dr. Wendell’s research focus along with her LC-MS expertise make her the ideal 
investigator to conduct the analytical analyses of NO2-FA formation and metabolism in this 
proposal. 
 
Alison Morris, MD: Dr. Morris is a Professor of Medicine and Vice Chair for Clinical Research, 
Department of Medicine, and UPMC Chair of Translational Pulmonary and Critical Care Medicine. 
She is the Founder and co-Director of the University of Pittsburgh Center for Medicine and the 
Microbiome. Dr. Morris' research interests include HIV-associated lung disease as well as the role 
of the microbiome in disease. Her group works with large cohort epidemiologic studies of HIV and 
other diseases as well as in translational studies in which physiologic and molecular techniques 
are applied to patient populations. As part of her role in the Center for Medicine and the 
Microbiome, she works with collaborators in diverse areas studying the microbiome. 
 
Nicole Helbling, DNP, RN, CRNP: Nicole is a certified registered nurse practitioner with 
extensive clinical and translational research experience. She is well trained to review study 
consent, obtain medical histories, perform venipunctures and IV placements and assist with day-
to-day clinical trial execution. She is well trained to perform physical examinations on patients. 
 
 
 


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8.2 SOURCES OF SUPPORT 
 
National Institutes of Health 
 
 
 
9.  REFERENCES 
 
1. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, 
McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J, Harrington RA, 
Anderson JL, Bates ER, Bridges CR, Eisenberg MJ, Ferrari VA, Grines CL, Hlatky MA, Jacobs 
AK, Kaul S, Lichtenberg RC, Lindner JR, Moliterno DJ, Mukherjee D, Pohost GM, Rosenson 
RS, Schofield RS, Shubrooks SJ, Stein JH, Tracy CM, Weitz HH and Wesley DJ. ACCF/AHA 
2009 expert consensus document on pulmonary hypertension: a report of the American 
College of Cardiology Foundation Task Force on Expert Consensus Documents and the 
American Heart Association: developed in collaboration with the American College of Chest 
Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. 
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2. McGoon MD, Benza RL, Escribano-Subias P, Jiang X, Miller DP, Peacock AJ, Pepke-Zaba 
J, Pulido T, Rich S, Rosenkranz S, Suissa S and Humbert M. Pulmonary arterial hypertension: 
epidemiology and registries. Journal of the American College of Cardiology. 2013;62:D51-9. 
3. Ling Y. Demographics, Epidemiology and Prognostic Factors in Pulmonary Arterial 
Hypertension. 2014. 
4. van de Veerdonk MC, Bogaard HJ and Voelkel NF. The right ventricle and pulmonary 
hypertension. Heart failure reviews. 2016;21:259-71. 
5. Demarco VG, Whaley-Connell AT, Sowers JR, Habibi J and Dellsperger KC. Contribution of 
oxidative stress to pulmonary arterial hypertension. World journal of cardiology. 2010;2:316-
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6. Forstermann U. Oxidative stress in vascular disease: causes, defense mechanisms and 
potential therapies. Nature clinical practice Cardiovascular medicine. 2008;5:338-49. 
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8. Pugh ME, Robbins IM, Rice TW, West J, Newman JH and Hemnes AR. Unrecognized glucose 
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10. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, 
Bourge RC, Brundage BH, Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, 
Clayton LM, Jobsis MM, Blackburn SD, Shortino D and Crow JW. A comparison of continuous 
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11. Baker LM, Baker PR, Golin-Bisello F, Schopfer FJ, Fink M, Woodcock SR, Branchaud BP, 
Radi R and Freeman BA. Nitro-fatty acid reaction with glutathione and cysteine. Kinetic 
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12. AL KEaL. In vivo mouse dosing study. 2015. 


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13. Cui T, Schopfer FJ, Zhang J, Chen K, Ichikawa T, Baker PR, Batthyany C, Chacko BK, Feng 
X, Patel RP, Agarwal A, Freeman BA and Chen YE. Nitrated fatty acids: Endogenous anti-
inflammatory signaling mediators. The Journal of biological chemistry. 2006;281:35686-98. 
14. Kansanen E, Jyrkkanen HK, Volger OL, Leinonen H, Kivela AM, Hakkinen SK, Woodcock SR, 
Schopfer FJ, Horrevoets AJ, Yla-Herttuala S, Freeman BA and Levonen AL. Nrf2-dependent 
and -independent responses to nitro-fatty acids in human endothelial cells: identification of 
heat shock response as the major pathway activated by nitro-oleic acid. The Journal of 
biological chemistry. 2009;284:33233-41. 
15. Villacorta L, Chang L, Salvatore SR, Ichikawa T, Zhang J, Petrovic-Djergovic D, Jia L, Carlsen 
H, Schopfer FJ, Freeman BA and Chen YE. Electrophilic nitro-fatty acids inhibit vascular 
inflammation by disrupting LPS-dependent TLR4 signalling in lipid rafts. Cardiovascular 
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16. Kelley EE, Baust J, Bonacci G, Golin-Bisello F, Devlin JE, St Croix CM, Watkins SC, Gor S, 
Cantu-Medellin N, Weidert ER, Frisbee JC, Gladwin MT, Champion HC, Freeman BA and 
Khoo NK. Fatty acid nitroalkenes ameliorate glucose intolerance and pulmonary hypertension 
in high-fat diet-induced obesity. Cardiovascular research. 2014;101:352-63. 
17. Klinke A, Moller A, Pekarova M, Ravekes T, Friedrichs K, Berlin M, Scheu KM, Kubala L, 
Kolarova H, Ambrozova G, Schermuly RT, Woodcock SR, Freeman BA, Rosenkranz S, 
Baldus S, Rudolph V and Rudolph TK. Protective effects of 10-nitro-oleic acid in a hypoxia-
induced murine model of pulmonary hypertension. American journal of respiratory cell and 
molecular biology. 2014;51:155-62. 
18. Villacorta L, Guo Y, Zhang J, Converso-Baran K, Schopfer FJ, Freeman BA and Chen YE. 
Electrophilic Nitro-Fatty Acids Exert Cardioprotection against Hypertrophic Remodeling and 
Fibrosis in Pressure Overloaded Mice. The FASEB Journal. 2015;29:640.6. 
19. Rudolph TK, Ravekes T, Klinke A, Friedrichs K, Mollenhauer M, Pekarova M, Ambrozova G, 
Martiskova H, Kaur JJ, Matthes B, Schwoerer A, Woodcock SR, Kubala L, Freeman BA, 
Baldus S and Rudolph V. Nitrated fatty acids suppress angiotensin II-mediated fibrotic 
remodelling and atrial fibrillation. Cardiovascular research. 2016;109:174-84. 
20. Koudelka A, Ambrozova G, Klinke A, Fidlerova T, Martiskova H, Kuchta R, Rudolph TK, 
Kadlec J, Kuchtova Z, Woodcock SR, Freeman BA, Kubala L and Pekarova M. Nitro-Oleic 
Acid Prevents Hypoxia- and Asymmetric Dimethylarginine-Induced Pulmonary Endothelial 
Dysfunction. Cardiovascular drugs and therapy. 2016;30:579-586. 
21. ATS statement: guidelines for the six-minute walk test. American journal of respiratory and 
critical care medicine. 2002;166:111-7. 
22. Rich S. Primary pulmonary hypertension: executive summary from the World Symposium on 
Primary Pulmonary Hypertension. 1998. 
23. McCollister D, Shaffer S, Badesch DB, Filusch A, Hunsche E, Schuler R, Wiklund I and 
Peacock A. Development of the Pulmonary Arterial Hypertension-Symptoms and Impact 
(PAH-SYMPACT(R)) questionnaire: a new patient-reported outcome instrument for PAH. 
Respiratory research. 2016;17:72. 
 
 
 
 
 
 
 


Or al C X A -1 0 i n P A H                                                                                     
V er si o n 1. 4/ M ar c h 4, 2 0 2 0                           P a g e 5 5  of 5 6  
 
 
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Or al C X A -1 0 i n P A H                                                                                     
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ICF_001.pdf: 
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University of Pittsburgh
School of Medicine
                  UPMC Vascular Medicine Institute
CONSENT TO ACT AS A PARTICIPANT IN A RESEARCH STUDY
TITLE: Phase 2 Open-Label Study of Safety and Efficacy Trial of CXA-10 in
Pulmonary Arterial Hypertension 
 
Key Information
You are being asked to take part in the research study. Research studies include only people 
who choose to take part. The study team members will explain the study to you and will answer 
any questions that you may have. You should take your time to make your decision.

The purpose of this study is to see if the investigation drug CXA-10 helps patients with 
pulmonary arterial hypertension (PAH).
The study has 9 visits over the course of about 5 months.

Study procedures include blood draws, lung function test, questionnaires, 6-minute 
walking test (6MWT), activity monitors, intravenous glucose tolerance tests (IVGTT), 
electrocardiograms (ECG), right heart catheterizations (RHC) and echocardiogram tests.

You will be asked to take a pill once daily for the duration of the study.
Risks and side effects related to the study include those which are common while taking CXA-
10 - diarrhea, nausea and abdominal pain; those related to blood draw – bruising or swelling at 
the site; those related to right heart catheterization – bruising or swelling at the site; those 
related to confidentiality – small risk of information being disclosed. These risks will be reviewed 
PRINCIPAL INVESTIGATOR: 
Marc A. Simon, MD, MS, FACC
   Associate Professor of Medicine
                                                      Heart and Vascular Institute
                                                      Scaife Hall, S555
                                                      200 Lothrop Street
                                                      Pittsburgh, PA 15213
                                                      412-802-3131
CO-INVESTIGATORS:
Belinda N. Rivera-Lebron, MD, MSCE Associate 
Professor of Medicine Department of Medicine
Mark Gladwin, MD Professor of Medicine 
Chair, Department of Medicine
Nicole Helbling, DNP, RN, CRNP 
Vascular Medicine Institute 
412-692-2285
SOURCE OF SUPPORT: National Institutes of Health-tPPG Grant–Mark Gladwin, MD


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in much more detail below. 
You may feel better as a result of taking part in this study. There is, however, no guarantee that 
you will benefit from taking part in this study. Taking part in this study may help doctors learn 
more about CXA-10 and PAH. It is hoped that this information will help in the treatment of future 
patients with conditions like yours. 
If you decide not to participate in this research study, your other options are to continue to get 
regular care from your doctor and/or talk to your doctor about other medicines to treat PAH. 
We invite you to take part in the CXA-10 research study. We want you to know that taking part 
in this research study is completely voluntary. Your doctor may be involved as an investigator in 
this research study. Before agreeing to participate in this research study, or at any time during 
your study participation, you may discuss your care with another doctor who is not associated 
with this research study. You are not under any obligation to participate in any research study 
offered by your doctor. Please take your time to make your decision about taking part. 
A description of this clinical trial will be available on www.clinicaltrials.gov, as required by US 
law. This website will not include information that can identify you. At most, the website includes 
the summary of results. You can search this website any time.
One or more of the investigators conducting this research has a financial interest as an 
inventor/developer of the drug being evaluated/developed in this study. Furthermore, one or 
more of the investigators conducting this research has a financial interest in a company with 
intellectual property rights (property that result in patents, copyrights, and trademarks) the drug 
being evaluated/developed in this study. The University of Pittsburgh also has a financial 
interest in this company, has received charitable gifts from the company, and has sold and/or 
licensed intellectual property, including intellectual property being evaluated/developed in this 
study, to the company. This means that the results of this study could lead to personal profit for 
the individual investigator(s) or the University of Pittsburgh. Any questions you might have about 
this will be answered fully by the Human Subject Protection Advocate of the University of 
Pittsburgh at (866) 212-2668 or the Principal Investigator, Dr. Marc Simon (412) 802-3131, who 
has no financial conflict of interest with this research.
Why is this research being done? 
You are being asked to take part in this study because you have been diagnosed with 
Pulmonary Arterial Hypertension. PAH is a medical disease that affects your heart and lungs. 
Having PAH means that you have high blood pressure in your blood vessels that travel from 
your heart to your lungs. This happens because there is narrowing of the blood vessels which 
makes it is harder for your blood to pass through them. This causes your heart to overwork and 
can lead to a weakening of the heart. 
This study involves the use of an investigational drug called CXA-10. At low levels, CXA-10 is 
normally found in the human body. This naturally-occurring substance helps to decrease 
inflammation (the human body’s response to injury that results in swelling, redness, and heat) in 
the body. Inflammation is a body's healing response to injury, but sometimes inflammation plays 
as an important factor in certain diseases such as PAH. Researchers believe that CXA-10 plays 
a vital role in reducing inflammation, improving blood pressure in the blood vessels that travel 
from the heart to the lungs, and improves how the heart functions. 
Complexa, Inc. is the pharmaceutical company sponsoring CXA-10 and preparing the capsules. 


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CXA-10 is not FDA-approved for use in patients with PAH. However, the FDA does permit it to 
be used in experimental research studies like this, under strict regulations. 
Who is being asked to take part in this research study? 
A total of 30 participants ages 18-80 who have been diagnosed with PAH are expected to be 
enrolled in this study. 
What am I expected to do in this research study?
This study will last about 5 months. During this time, you will need to visit the study clinic on 
schedule (outlined below), take the study medication, get tests, and tell the study doctor or study 
staff about any changes in your health or the way you feel. You may have up to 9 visits to the 
outpatient clinic and will have multiple telephone calls from the study staff throughout your 
participation in the study treatment. 
What procedures will be performed for research purposes? 
You will visit the study clinic on scheduled dates, receive tests, and tell the study doctor or study 
staff about any changes in your health or the way you feel. The research study tests and 
procedures listed below are not part of your routine care. We will give you 300 mg of CXA-10 
once daily in the morning with food at home for 12 weeks. You will be asked to thoroughly 
record your exact date and time of your CXA-10 dosing and report any symptoms. There will be 
9 visits over about 5 months. During this 5 month period, we will be asking you to undergo 2 
RHC at visit 2 (week 0) and at visit 7 (week 12). The study personnel will contact you to review 
your medications and perform a safely evaluation approximately 2 weeks after certain visits. 
You will receive reminder calls or emails for appointments. 
The study visits will take place at the UPMC Heart and Vascular Institute (including the 
outpatient cardiology clinic and cardiac catheterization lab), the Comprehensive Lung Center at 
Falk Clinic, the Clinical Translational Research Center (CTRC) located on the 6th floor of UPMC 
Montefiore, and the Endocrinology and Metabolism Research Center (EMRC), which is located 
on the 8th floor of UPMC Montefiore and Pulmonary Physiology Laboratory on the 12th floor of 
the Kaufmann Medical Building.
SCREENING PROCEDURES: 
Procedures to determine if you are eligible to take part in a research study are called screening 
procedures. Your study coordinator will work with you to schedule your screening procedures 
for Visit 1. This Visit 1 will take place within 4 weeks prior to taking the study drug.
Visit 1- Screening 
This visit will take place in the UPMC Montefiore, Presbyterian Hospital and/or the Kaufmann 
Medical Building. The screening visit assessment will take place on (2) separate days if a 
screening right heart catheterization (RHC) is needed. You will need to fast a minimum of 8 
hours (plain water is ok) prior to each visit. For this research study, the screening procedures 
include:
1.
We will review the study with you again and review the study consent form, which you 
will need to sign with a study doctor to be a part of the study.
2.
Review your medical history, demographics and medications.
3.
Physical examination including measurement of your height, weight, vital signs, and the 
stage of your heart failure - this is also known as the World Health Organization (WHO) 
functional class assessment (based on symptoms related to heart failure).  A clip will also 
be placed on your finger to measure the oxygen in your blood.


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4.
We will draw a blood sample from a vein in one of your arms or hand to conduct routine 
laboratory tests to help evaluate your overall health such as fasting glucose, 
comprehensive metabolic panel (blood test that measures your glucose levels, 
electrolyte and fluid balance, liver function, and kidney function), fasting lipid profile 
(tests that measure fats in your blood) , CBC/Diff test (a test to make sure that you do 
not have few red blood cells, uric acid (a test to measure uric acid in the blood to test 
for gout), and a hemoglobin A1c (a test to measure your average blood sugar level in 
the last 2-3 months), NT-proBNP (marker for heart failure). We will collect blood to test 
your PT/INR. This test is to measure how long your blood takes to clot. 
5.
We will collect and test a small volume of your urine to check for infection.
6.
A urine pregnancy test is required if you are a woman of child-bearing potential.
7.
You will be asked to do an ECG test. Electrocardiogram measures your heart's 
electrical activity. This procedure is done by putting small sticky pads on your chest, 
ankles, and wrists while you lay down flat. It is important for you to relax while lying 
down for a few minutes before taking the reading because this allows the ECG to be 
more reliable.
8.
You will complete a lung function test. This test (spirometer that is a small machine with 
an attached mouthpiece) measures how well your lungs are working. If you completed a 
lung function test no more than 12 months prior to this screening visit, then we may use 
those results.
9.
You will complete a 6-minute walking test (6MWT). You will walk as quickly as possible 
for 6 minutes on a standard course. We will measure the distance and speed while you 
walk, and we will also ask you to rate (with a number) how hard you are working while 
you are walking. 
10. We will collect your saliva, tongue scrapings, and stool samples (you will have a kit to 
take home for stool collections). 
11.  On a separate day, the RHC will be performed if you have not had a RHC in the last 2 
months of enrollment based on your medical records. In order for a RHC from 2 months 
ago to be eligible, you must be on stable doses of your medications and should have not 
started an exercise program right before your RHC 2 months ago or started one within 2 
months prior to the screening visit. This RHC visit will take place in UPMC Presbyterian 
Hospital, 3rd FL Catheterization Laboratory, and may take up to 4 hours to complete. You 
will need to fast a minimum of 8 hours prior to this visit. You will be allowed to take 
necessary medication with sips of water as directed by the study doctor performing the 
procedure. You may be asked to hold anticoagulation therapy, oral hypoglycemics, and 
diuretics along with potassium, based on review of your case, as this is standard clinical 
care prior to RHC. We will provide you with specific instructions depending on the 
medications you are taking. The following procedures will be done at this visit:
a.
An IV will be placed into your vein. This IV will be used to give you medications for 
the right heart catheterization procedure and to draw blood if we need to do so. 
You may also receive medications to make you less nervous, such as midazolam 
and/or fentanyl intravenously.
b.
If you are a woman of child-bearing potential, a second urine pregnancy test will 
be performed.
c.
A clip will be placed on your finger to measure the oxygen in your blood, and a 
blood pressure machine will measure your blood pressure at regular intervals. 
d.
You will have an echocardiogram in a UPMC lab usually prior to the RHC. If there 


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is a scheduling issue, the echocardiogram can be performed at another visit prior 
to beginning the 12-week daily dosing of CXA-10. An echocardiogram is the same 
as an ultrasound of the heart. Most people who have heart failure are familiar with 
this test. During an echocardiogram, a health care professional will press a probe 
with gel on it against the left area of your chest. The professional can then view 
images of your beating heart. This test can give measurements of how strongly 
your heart can pump. 
e.
Right heart catheterization (RHC) involves placing a thin, flexible tube into a vein 
in your arm, neck, or groin and guiding the tube into your main lung artery, where 
it can be used to measure your blood flow and lung artery pressures. X-ray may 
be used to track the tube. RHC is performed under local anesthesia, usually 
lidocaine, which will eliminate any associated pain. Using a TV screen and x-rays, 
the doctor threads the catheter along the vein, through the heart, and into the blood 
vessels going to your lungs. As the catheter is advanced toward the pulmonary 
artery, a number of blood pressure and blood flow measurements are taken in 
different places in the heart and lungs. Indirect measurements of pressures on the 
left side of the heart are made, as well, by inflating a tiny balloon at the tip of the 
catheter once the catheter reaches the pulmonary artery. This pressure 
measurement is called the pulmonary capillary wedge pressure (PCWP). 
Hemodynamic measurements (measuring blood flow in your body) will be taken 
during the RHC. If the RHC shows that you are ineligible for the study, you will 
not receive the study medication, CXA-10, and will have no further procedures or 
testing. If you are one of the first 10 subjects enrolled in the study and are 
eligible, you will be given a single dose of CXA-10 after the baseline 
hemodynamic measurements have been captured to assess an acute dose of 
CXA-10. We will then take another series of hemodynamic measurements after 
the dose of CXA-10. Food will be given to you prior to dosing. You will not begin 
the daily dosing until all eligibility criteria have been met and after all baseline 
procedures have been completed. 
f.
Blood samples will be collected to study how much of the drug goes into your 
bloodstream and how long it stays there before and after you receive the CXA-
10.  Additional blood samples will be collected to perform a biomarker and 
cytokine measurements (measurements that provided information about 
presence or progress of a disease) at the same time points (if not collected 
during initial screening visit).  Approximately 1 ¾ tablespoons of blood may be 
collected throughout the entire procedure.
g.
You will be monitored closely and given something to eat after the procedure is 
over. You will not be discharged until all medications have worn off and your 
breathing and heart rate are normal. The study doctor will see you before you leave 
the hospital. You should avoid strenuous activity for the rest of the day and call the 
study doctor if you notice any symptoms you did not have before the test.
12. We will monitor you for any adverse events.
13. You will be given an activity monitor to wear after all of the eligibility requirements have 
been met. This device measures your body movement, activity, and sleep over the 
entire 24 hour period each day it is worn. You will be asked to wear the monitor on your 
non-dominant wrist for at least 7 consecutive days at home prior to receiving the first 
dose of the study drug on Visit 2.  You will wear it all hours of the day except when you 


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bathe. We will give you directions on how to wear it. You will be asked to return the 
monitor at the next visit.
The total amount of blood is approximately 5 tablespoons.
Visit 2 (Week 0-Baseline testing)
This visit will take place at UPMC Montefiore. You will be asked to fast a minimum of 12 hours 
prior to completing the tests listed below. 
1.
Brief physical exam with WHO Functional Class assessment and body weight 
measurement, vital signs (blood pressure, heart rate, respiratory rate, temperature, 
pulse oximetry) and review your medications 
2.
You will have an ECG performed.
3.
We will draw your blood samples for tests (e.g., fasting glucose, comprehensive 
metabolic panel, fasting lipid profile, CBC/Diff, and uric acid), PT/INR, NT-proBNP
4.
Blood samples will be collected to perform a biomarker and cytokine measurements
5.
Collect and test a small volume of your urine for a urinalysis
6.
A urine pregnancy test is required if you are a woman of child-bearing potential.
7.
Intravenous glucose tolerance test (IVGTT) is given to measure your sensitivity to insulin 
and your insulin’s secretion. We will give you glucose through an IV, then after we will 
give you insulin to control the glucose. If you are taking oral hypoglycemic, we may ask 
you to hold those medications during this test, but you can take those medications the 
same day following the completion of this test. This test will take 3 hours.
8.
We will have you complete the health related quality of life questionnaire-Pulmonary 
Arterial Hypertension-Symptoms and the Impact (PAH-SYMPACT) questionnaire. This 
questionnaire is used to assess your pulmonary arterial symptoms and the impact on 
your life.
9.
Return activity monitor
10. Monitor for any adverse events
The total amount of blood is approximately 20 tablespoons.
Visit 3 (Week 0 – First dose)  
This visit will take place at UPMC Montefiore. Subjects do not need to fast for this visit and 
this visit will last up to 4 hours. 
1.
You will complete the 6-minute walking test (6MWT) with Borg Dyspnea (how short of 
breath you are) questionnaire.
2.
We will draw your blood sample for the Population PK sampling (test is used to see how 
well the human body handles the study drug, CXA-10). We will draw your blood again 
for the PK sampling 2-4 hours after taking the study drug. 
3.
Blood samples will be collected to perform a biomarker and cytokine measurements 
which be collected at the same times as the PK sampling.
4.
Dispense study drug. You will be instructed to take the first dose of study medication at 
the clinic after a breakfast/morning snack (i.e. such as a granola bar)
5.
We will review your medications
6.
Monitor for any adverse events.
Visit 3a (Week 1)
1.
If you are on warfarin, you will be asked to return to the clinic for a blood draw one week 
after taking CXA-10, to check your PT/INR. You will not need to fast at this visit.


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Visit 4 (Week 4) and Visit 5 (Week 8)-Study Drug
You will be asked to fast (no food and drinks, only water) for a minimum of 8 hours overnight 
prior to this visit. You should not take your study medication in the morning, prior to arriving for 
your visit. You will be asked to take 300 mg of CXA-10, by the study doctor or study coordinator 
after completing assessments and tests during the morning. This visit will take place in UPMC 
Montefiore and will last up to about 4 hours.
Procedures done before you take the study drug:
1.
Brief physical exam with WHO Functional Class assessment and body weight 
measurement, vital signs (blood pressure, heart rate, respiratory rate, temperature, 
pulse oximetry) and review your medications
2.
You will be asked to complete an ECG test.
3.
We will draw your blood samples for tests (e.g., fasting glucose, comprehensive 
metabolic panel, fasting lipid profile, complete blood count, and platelet and differential, 
uric acid and NT-proBNP).
4.
We will draw your blood sample for the Population PK sampling and blood samples will 
be collected to perform a biomarker and cytokine measurements.
5.
Collect and test a small volume of your urine.
6.
A urine pregnancy test is required if you are a woman of child-bearing potential.
7.
You will complete the 6-minute walking test (6MWT) with Borg Dyspnea questionnaire 
8.
You be asked to complete the health related quality of life-PAH-SYMPACT. 
.
Procedures done after you take the study drug: 
1.
You will be given a breakfast/snack with the 300 mg dose of CXA-10, during the 
morning. 
2.
We will draw a blood sample for Population PK sampling 2-4 hours after taking the study 
drug and blood samples will be collected to perform a biomarker and cytokine 
measurements.
3.
Monitor for any adverse events.
4.
Dispense study drugs
5.
At Visit 5, we will provide you an accelerometer and instruct you to wear this for at least 
7 consecutive days prior to the next visit (Week 12).
The total amount of blood is approximately 4 tablespoons for visits 3 and 3a. The total of blood 
is approximately 5 tablespoons for visit 4 and the total of blood is approximately 5tablespoons 
for visit 5.
Visits 6-8(Week 12)-End of Treatment
The visits listed above are repeated at the end of the study and will take about 3 days to complete. 
The tests are listed below and are done the same way as described above in Visits 1, 2 and 3. 
Visit 6 (Week 12)-End of Treatment
You will be asked to come to UPMC Montefiore for this visit. Subjects will be asked to fast a 
minimum of 12 hours to perform the assessments listed below. The visit will last approximately 
6 hours. 
1.
Brief physical exam with WHO Functional Class assessment and body weight 
measurement, vital signs (blood pressure, heart rate, respiratory rate, temperature, 
pulse oximetry) and review your medications
2.
You will be asked to complete an ECG test.


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3.
We will draw your blood samples for tests (e.g., fasting glucose, comprehensive 
metabolic panel, fasting lipid profile, complete blood count, and platelet and differential, 
uric acid, PT/INR, hemoglobin A1c (this test is performed if subject has abnormal 
HbA1c) NT-proBNP).
4.
Blood samples will be collected to perform a biomarker and cytokine measurements
5 Oral and stool samples will be collected.
6. You will have a IVGTT.
7. A PAH-SYMPACT questionnaire will be performed.
8. You will return the accelerometer for data download.
9. Review your medications.
10. Monitor for adverse events.
The total amount of blood is approximately 20 tablespoons.
Visit 7 (Week 12)-End of Treatment
You will report to the clinic on the morning of Week 12 after a minimum 8-hour overnight fast.  
You should not take their study medication that morning, prior to arriving at the clinic for your pre-
dose assessment. 
Procedures done before you take the study drug:
1.
Brief physical exam An echocardiogram will be performed.
2.
You will have a RHC.
3.
Hemodynamic measurements (measuring blood flow in your body) will be taken during 
the RHC.  You will be given a single dose of CXA-10 that you will take with food after the 
baseline hemodynamic measurements have been captured to assess an acute dose of 
CXA-10. We will then take another series of hemodynamic measurements after the dose 
of CXA-10. You will take food prior to dosing.
4.
We will draw your blood sample for the Population PK sampling 
5.
 Blood samples will be collected to perform a biomarker and cytokine measurements 
which these samples are collected at the same time as Population PK sampling.
Procedures done after you take the study drug: 
1.
 We will draw your blood sample for the Population PK sampling 
2.
 Blood samples will be collected to perform a biomarker and cytokine measurements 
which these samples are collected at the same time as Population PK sampling.
3.
Review your medications
4.
Monitor for adverse events
The total amount of blood is approximately 3.5 tablespoons.
Visit 8 (Week 12-End of Treatment)
You will be asked to come to UPMC Montefiore for this visit and this visit will last up to 6 hours. 
You will not need to fast for this visit. 
Procedures done before you take the study drug:
1.
You will complete the 6-minute walking test (6MWT) with Borg Dyspnea questionnaire 
2.
We will draw your blood sample for the Population PK sampling.


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3.
Blood samples will be collected to perform a biomarker and cytokine measurements 
which these samples are collected at the same time as Population PK sampling.
4.
You will be given a breakfast/snack with the 300mg dose of CXA-10, during the morning. 
Procedures done after you take the study drug: 
1.
We will draw your blood sample for the Population PK sampling.
2.
Blood samples will be collected to perform a biomarker and cytokine measurements
3.
We will review your medications
4.
Monitor for adverse events.
5.
Dispense 1st month supply of CXA-10 (optional).
The total amount of blood is approximately 3.5 tablespoons.
Open Label Period
Upon completion of the end of treatment visits, you will be given the option to receive a 6-month 
supply of CXA-10. If you decide to receive the CXA-10, we will follow up with you in the clinic at 
month 1, 2, 4 and 6 to monitor your vital signs, blood work, six-minute walk test, and 
questionnaires. Months 3 and 5 will be a phone call to perform a safety evaluation and to see if 
there are any changes in medications. The total amount of blood drawn at each visit is about 5 
tablespoons.
Visit 3b (Week 2), Visit 4a (Week 6), Visit 5a (Week 10)-Telephone Calls
A member from the study team will contact you by phone to perform a safety evaluation and ask 
if there were any changes in medications that you are currently taking approximately 2 weeks 
after Visit 2, Visit 3 and Visit 4. You will be reminded to bring any remaining medication to your 
next clinic visit.
Visit 9 (Week 16)-Follow-up Visit
This visit will take place approximately 4 weeks after the end of treatment. You will fast (no food 
and drink, except water) overnight for 8 hours prior to coming to this visit.  This visit will last 
about 1 hour. 
1.
Brief physical exam with WHO Functional Class assessment and body weight 
measurement, vital signs (blood pressure, heart rate, respiratory rate, temperature, 
pulse oximetry) and review your medications
2.
We will draw your blood samples for tests (e.g., fasting glucose, comprehensive 
metabolic panel, fasting lipid profile, complete blood count, and platelet and differential, 
uric acid and NT-proBNP).
3.
Blood samples will be collected to perform a biomarker and cytokine measurements
4.
Collect and test a small volume of your urine.
5.
A urine pregnancy test is required if you are a woman of child-bearing potential.
6.
You will complete the 6-minute walking test (6MWT) with Borg Dyspnea questionnaire 
7.
Monitor for adverse events. 
8.
Dispense 2nd month supply of CXA-10 (optional).
The total amount of blood is approximately 3.5 tablespoons.
What side effects or risks can I expect from being in this research study?
As with any experimental procedure, there may be adverse events or side effects that are 


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currently unknown and certain of these unknown risks could be permanent, severe, or even life 
threatening.
Risks of CXA-10
There are risks associated with the study drug, CXA-10. The most common side effects on an 
empty stomach were: diarrhea, nausea, abdominal pain, and vomiting. Other less common side 
effects were: abdominal discomfort, dizziness, tiredness, lightheadedness, and a metallic taste 
in the mouth. The rare side effects were: heart burn, fainting, indigestion, headache, and rectal 
discomfort. The side effects were mild to moderate. When CXA-10 is taken with food, some 
subjects experienced: diarrhea and nausea. 
Risks of blood draw/intravenous line:
A risk of drawing blood is anemia, which is a lower hemoglobin level. A common symptom of 
anemia is fatigue (feeling tired or weak). The amount of blood to be drawn over the course of 
this investigation could be a maximum of about 52 tablespoons among the blood draws, cardiac 
catheterizations and IVGTTs. This is about 4 cups which is a little more than what is taken at a 
blood donation. We encourage you not to give blood just before enrolling or during the time you 
are in the study, to minimize the risks of blood tests a RN, MD, technician or phlebotomist will 
draw your blood. Common risks of blood sampling by venipuncture or intravenous line 
placement include temporary pain, bruising which may last for several days, redness, swelling 
and phlebitis. Infrequent risks include feeling lightheaded or faint when blood is drawn. This is 
usually due to nervousness (not due to the amount of blood taken), and it is not usually serious. 
Infrequent risks for the intravenous line include infiltration (a leakage of anything that has been 
given through the vein (such as the saline, dextrose, insulin) into the arm tissue that surrounds 
the vein and holds the IV). Rare risks include infection and bleeding.
Allergic Reaction Risks
As with taking any drug, there is a risk of allergic reaction including serious reaction that may be 
life-threatening and cause death. Some allergic reactions risks: rash, wheezing and difficulty 
breathing, dizziness and fainting, swelling around the mouth and throat or eyes, a fast pulse, 
and sweating.
Reproductive Risks
It is not known if the study drug can affect an unborn baby. Therefore, you should not become 
pregnant and you should perform the appropriate methods to prevent pregnancy. You should not 
father a baby while on this study and you should perform the appropriate methods to prevent 
pregnancy. If you are physically able to father a baby, you must use an effective method of birth 
control while in this study. If you become aware that you or your sexual partner is pregnant during 
the course of your participation in this research study, you must contact, as soon as possible, the 
study doctor listed on the first page of this form. 
Risks of 6MWT
The 6-Minute Walk Test, can cause muscle soreness or fatigue (occurs in 10-25% of people). 
Other changes include shortness of breath, abnormal blood pressure, or fainting (occurs in 10-
25% of people). Heart attack, stroke, or sudden death are rare (occur in <1% of people). Rarely, 
exercise may cause moderate to extreme pain which could be due to muscle sprains, muscle 
strains, broken bones, or chest pain.
Electrocardiogram (ECG) Risks
There is no known risk associated with this procedure. You may develop a mild skin rash from 


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the ECG leads.
Echocardiography Risks
There is no known risks associated with this procedure. Gel will be applied during the test which 
may cause coldness and/or irritation.
Risks of Activity monitor/Accelerometer Use
Common risks associated with wearing the accelerometer are redness, irritation, and chaffing. 
Right Heart Catheterizations (RHC) Risks
The common risks of RHC are pain at the needle entry site and slight risk of bleeding around the 
site, bruising at site, lightheadedness or dizziness during the needle stick.
The uncommon risks are puncturing the lung which would require a chest tube insertion and/or 
having irregular heartbeats which usually stop when the long tube is removed from the heart.
The very rare complications include cardiac arrhythmias (irregular heartbeats), cardiac 
tamponade (blood or fluids build up in the space between the heart muscle and other outer 
covering sac of the heart which causes pressure on the heart), low blood pressure, infection, or 
embolism (blockage of material inside a blood vessel) caused by blood clots at the tip of the 
catheter.
There is no expected additional risk from the additional time of the procedure for measuring the 
hemodynamics (measuring blood flow in your body) 30 minutes after giving you the study drug.
Risks of Medications used during Catheterization
The medications used for sedation are used for a short period of time during the right heart 
catheterization. These medications should wear off within several hours. The side effects are 
listed below for each drug.

1% Lidocaine: Will be used to numb the area prior to the insertion of the cardiac catheter 
into either the arm, neck or groin vein. A common side effect is slight burning at the site 
which dissipates quickly. 

Fentanyl: Common side effects include temporary light-headedness, dizziness, and 
nausea, vomiting or sweating. 

Midazolam: Common side effect includes drowsiness. Infrequent side effects are nausea, 
vomiting. Breathing problems are rare.  Allergic reactions (e.g., hives, itching, etc.) to 
lidocaine, fentanyl, or midazolam are rare.
Risks of Lung Function Test (spirometry)
Spirometry can infrequently make the chest tight or short of breath. Albuterol will be available if 
this occurs. Rarely, you may have coughing or lightheadedness with this test. If Albuterol is 
needed, you will get up to 4 puffs of albuterol. Albuterol may make you feel slightly jittery or 
nervous, but the feelings are temporary.
Risks of IVGTT
Common risks include: phlebitis (inflammation of a vein), transient hyperglycemia (high blood 
sugar not requiring treatment). The risk of receiving insulin during the study is that it could cause 
a low blood sugar reaction (termed “hypoglycemia”). Hypoglycemia, which is rare (occurs in 
<1% of people), may cause symptoms such as shakiness, nervousness, sweating, hunger, 
dizziness, and a fast heart rate. If severe, hypoglycemia can cause coma, seizure, or even 


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death, all of which are rare (occurs in <1% of people). It is very unlikely that severe 
hypoglycemia will occur during the insulin infusion because the blood sugar will be monitored 
every few minutes by trained nursing staff. As an additional safety measure, you will be kept 
awake during the insulin infusion. This will allow the study team to be certain that you are not 
experiencing any kind of unusual or unexpected reaction to the insulin infusion.
Risks of X-ray used during the Catheterization
An x-ray may be done during the right heart catheterization. An X-ray performed for the purpose 
of this research study involves exposure to radiation. There is no minimum amount of radiation 
exposure that is recognized as being totally free of the risk of causing genetic mutations 
(abnormal cells) or cancer. However, the risk associated with the amount of radiation exposure 
received from participation in this study is considered to be low.
Risks of Stool Collection
There is no risks from stool collections.
Risks of oral sample collections (saliva and tongue scrapings)
There is no risks from oral sample collections. The tongue scrapings might cause gagging or 
mild local irritation or very small bleeding that will resolve on its own.
Risk of Breach of Confidentiality
Although we are taking many steps to protect your information, there is always a chance that your 
information or identity could be disclosed. We will continue to review and improve the ways we 
keep your information private. To protect your information, paper-based records will be kept in a 
secure location and only be accessible to personnel involved in the study. Paper charts will 
contain subject identifiers but will be in locked cabinets within a locked office on a unit that has 
restricted access.
Are there benefits to taking part in this research study? 
There may or may not be direct benefits for you participating in this study. However, there may 
be a potential future benefit to society as a whole, from the information obtained from the conduct 
of this study through the advancement of knowledge.
May I withdraw, at a future date, my consent for participation in this research study? 
You may withdraw, at any time, your consent for participation in this research study, to include 
the use and disclosure of your identifiable information for the purposes described above. (Note, 
however, that if you withdraw your consent for the use and disclosure of your identifiable 
medical record information for the purposes described above, you will also be withdrawn, in 
general, from further participation in this research study). Any identifiable research or medical 
information recorded from your participation in this research study prior to the date that you 
formally withdraw your participation may continue to be used and disclosed by the investigators 
for the purposes described above. 
Your data and biological samples will be stored indefinitely unless you request for the samples 
to be destroyed. Your samples will not be labeled with direct identifiers. Your identity on these 
samples and records will be indicated by a random case number, rather than by your name, 
social security number or any other label that could identify you. 
To formally withdraw your consent for participation in this research study, you should provide a 
written and dated notice of this decision to the principal investigator of this research study at the 
address listed on the first page of this form. 


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Your decision to withdraw your consent for participation in this research study will have no effect 
on your current or future medical care at a UPMC hospital or affiliated health care provider or your 
current or future relationship with a health care insurance provider.
If you are withdrawn from this study, you will be asked to report to visit 6. 
If I agree to take part in this research study, can I be removed from the study without my 
consent? 
You may be removed from the study by the investigators in the event that the investigators feel 
that the study drug adversely influence your health; if you don't comply with study requirements; 
if a pregnancy test proves positive; or other situation at Dr. Simon’s discretion.
Any identifiable research or medical information recorded for, or resulting from your participation 
in this research study prior to the date that you were withdrawn from participation may continue 
to be used and disclosed by the investigators for the purposes described. 
If I agree to take part in this research study, will I be told of any new risks that may be 
found during the course of the study? 
You will be promptly notified if any new information develops during the conduct of this research 
study that may cause you to change your mind about continuing to participate.
The study team will discuss any research results that would affect your health care with you; for 
example if any of your labs are abnormal.
Will this research study involve the use or disclosure of my identifiable medical record 
information? 
As part of this screening process, we will review your identifiable medical records to see if you 
are eligible for this study. We will protect your privacy and the confidentiality of your records, as 
described in this document, but cannot guarantee the confidentiality of your research records, 
including information placed in your medical records, once your personal information is disclosed 
to others outside UPMC or the University.
Will my information be kept private? 
Any information about you obtained from or for this research study will be kept as confidential 
(private) as possible. All records related to your involvement in this research study will be kept in 
a locked file cabinet or in a password protected computer database accessible only to study 
personnel. Your identity on these records will be indicated by a unique study number, rather 
than your name, and the information linking this study number with you identity will be kept 
separate from the research records. You or your family will not be identified in any publication of 
the research study. 
Who will have access to identifiable information related to my participation in this research 
study?
In addition to the investigators listed on the first page of this authorization (consent) form and their 
research staff, the following individuals will or may have access to identifiable information (which 
may include your identifiable medical information) related to your participation in this research 
study: 

Authorized representatives of the Office of Research Protections may review your 
identifiable research information (which may include your identifiable medical information) 
for the purpose of monitoring the appropriate conduct of this research study. 


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
Authorized representatives of the UPMC hospitals or other affiliated health care providers 
may have access to identifiable information (which may include your identifiable medical 
information) related to your participation in this research study for the purpose of (1) 
fulfilling orders, made by the investigators, for hospital and health care services (e.g., 
laboratory tests, diagnostic procedures) associated with research study participation; (2) 
addressing correct payment for tests and procedures ordered by the investigators; and/or 
(3) for internal hospital operations (i.e. quality assurance).

Authorized representatives of this research study (National Institute of Health (NIH) will 
review and/or obtain identifiable information; which may include the subject’s identifiable 
medical information related to participation in this research study for the purpose of 
monitoring the accuracy and completeness of the research data and for preparing 
required scientific analyses of the research data. Authorized representatives of the study 
sponsors may also be present during the subject’s participation in certain research 
procedures. While the study sponsor understands the importance of maintaining the 
confidentiality of your identifiable research and medical information, the UPMC and the 
University of Pittsburgh cannot guarantee the confidentiality of this information after it 
has been obtained by the study sponsor. 

Authorized representatives of the Food and Drug Administration and the study sponsor 
(the National Heart, Lung, and Blood Institute, a part of the National Institutes of Health), 
who may need to review the records for accuracy and completeness. Representatives of 
the study sponsor may also be present during your participation in the research study. 
While the study sponsor understands the importance of maintaining the confidentiality of 
your identifiable research and medical record information, UPMC and the University of 
Pittsburgh cannot guarantee the confidentiality of this information after it has been 
obtained by the study sponsor.

In unusual cases, the investigators may be required to release identifiable information 
(which may include your identifiable medical information) related to your participation in 
this research study in response to an order from a court of law. If the investigators learn 
that you or someone with whom you are involved is in serious danger or potential harm, 
they will need to inform, as required by Pennsylvania law, the appropriate agencies. 
This research is covered by a Certificate of Confidentiality from the National Institutes of Health. 
The researchers with this Certificate may not disclose or use information, documents, or 
biospecimens that may identify you in any federal, state, or local civil, criminal, administrative, 
legislative, or other action, suit, or proceeding, or be used as evidence, for example, if there is a 
court subpoena, unless you have consented for this use. Information, documents, or 
biospecimens protected by this Certificate cannot be disclosed to anyone else who is not 
connected with the research except, if there is a federal, state, or local law that requires disclosure 
(such as to report child abuse or communicable diseases but not for federal, state, or local civil, 
criminal, administrative, legislative, or other proceedings; if you have consented to the disclosure, 
including for your medical treatment; or if it is used for other scientific research, as allowed by 
federal regulations protecting research subjects.
The researchers may share your de-identified data with the maker of the drug, Complexa, Inc. 
We may also share de-identified data with other researchers in the future.


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Though none is planned at present, your samples, (blood, saliva, stool, tongue scrapings) may 
undergo genetic analysis in the future. This may include whole genome sequencing, which is 
identifying your entire, unique genetic code from your biological parents. Please ask the study 
team any questions you have about this.
Will I have to pay anything to be part of this study?
Neither you, nor your insurance provider, will be charged for the costs of any of the procedures 
performed for the purpose of this research study, i.e. study drugs and the tests performed on your 
body and your blood collected for the study. All laboratory, physician, and hospital costs not 
related to the research are considered to be “routine clinical services” that you would have 
received even if you were not participating in the research study. All costs of the study are covered 
by the National Institute of Health (NIH). If you receive a bill or believe that your health insurance 
has been billed for something that is part of the research study, immediately notify a member of 
the research team or UPMC Patient Billing Services.
Will I be paid if I take part in this research study?
You will be paid up to the total of $930 if you complete this study. Here is a breakdown of 
payments:
•
$20 for Visit 1
•
$150 for Visit 2
•
$100 for Visit 3
•
$10 for Visit 3a
•
$50 for Visit 4
•
$50 for Visit 5
•
$200 for Visit 6 
•
$200 for Visit 7
•
$100 for Visit 8
•
$50 for Visit 9
You will receive payment following the completion of all study visits. In order to be compensated 
for your participation in this study, you will have to provide your Social Security Number. If you 
receive more than $600 in a calendar year, it will be reported to the IRS as income. 
You will also be provided a ticket for outpatient parking costs at all visits. In the event that you 
do not complete the study due to study related adverse events, you will be reimbursed for the 
individual study visits that were completed to date per the above reimbursement schedule. 
Travel accommodations and travel reimbursement may be provided in certain circumstances. 
What happens if I am injured because I took part in this study?
If you believe that you are injured as a result of the research procedures being performed, please 
contact immediately the Principal Investigator or one of the co-investigators listed on the first page 
of this form. Emergency medical treatment for injuries solely and directly related to your 
participation in this research study will be provided to you by the hospitals of UPMC. It is possible 
that UPMC may bill your insurance provider for the costs of this emergency treatment, but none 
of these costs will be charged directly to you. If your research-related injury requires medical care 
beyond this emergency treatment, you will be responsible for the costs of this follow-up care 
unless otherwise specifically stated. There is no plan for monetary compensation. You do not, 
however, waive any legal rights by signing this form. University of Pittsburgh researchers and 
their associates who provide services at UPMC recognize the importance of your voluntary 
participation in their research studies. These individuals and their staffs will make reasonable 


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efforts to minimize, control, and treat any injuries that may arise as a result of this research.  
What are my rights if I take part in this study?
Taking part in this study is your choice. You may choose either to take part or not to take part in 
the study. If you decide to take part in this study, you may leave the study at any time. No matter 
what decision you make, there will be no penalty to you and you will not lose any of your regular 
benefits. 


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VOLUNTARY CONSENT
The above information has been explained to me and all of my current questions have been 
answered. I understand that I am encouraged to ask questions about any aspect of this 
research study during the course of this study, and that such future questions will be answered 
by a qualified individual or by the investigator(s) listed on the first page of this consent document 
at the telephone number(s) given. I understand that I may always request that my questions, 
concerns, or complaints be addressed by a listed investigator.  
I understand that I may contact the Human Subjects Protection Advocate of the IRB Office, 
University of Pittsburgh (1-866-212-2668) to discuss problems, concerns, and questions; obtain 
information; offer input; or discuss situations that have occurred during my participation.  
By signing this form, I consent to participate in this research study and provide my authorization 
to share my medical records with the research team. A copy of this consent form will be given to 
me.
________________________________
Printed Name of Participant 
_________________________________                 _______________________
Signature of Participant                                              Date 
CERTIFICATION of INFORMED CONSENT
I certify that I have explained the nature and purpose of this research study to the above-named 
individual(s), and I have discussed the potential benefits and possible risks of study 
participation. Any questions the individual(s) have about this study have been answered, and 
we will always be available to address future questions as they arise.
I further certify that no research component of this protocol was begun until after this consent 
form was signed.
Printed Name of Physician 
Obtaining Consent
Role in Research Study
Signature of Person 
Obtaining Consent
Date