Clinical trial NCT02927366
Conditions: Pulmonary Arterial Hypertension
Keywords: Pulmonary hypertension (PH), Increase blood pressure in the pulmonary artery Increased blood pressure in the pulmonary vein Increased blood pressure in the lung vasculature Shortness of breath Dizziness Fainting Leg swelling Cough QCC374
Sponsor: Novartis Pharmaceuticals
Start date: 2017-09-19; Completion date: 2018-06-07
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a non-confirmatory, randomized, placebo controlled, subject and investigator blinded study of QCC374 in PAH subjects. The study was planned to have 2 Parts: Part 1, an initial safety cohort with a 0.03 mg bid starting dose, and Part 2, a larger cohort with a 0.06 mg bid starting dose. However, due to early study termination following Part 1, Part 2 was not completed. Both study parts were comprised of four phases: a screening period for up to 28 days, a titration period of 2 weeks, a stable dose period of 14 weeks and safety follow-up period for 28 days. At the end of the treatment period of 16 weeks, eligible patients were given the option to participate in a separate long-term extension study (CQCC374X2201E1 (NCT02939599)), where all patients were treated with an individual optimal dose of QCC374.

Detailed description:
The decision for early termination was based on changes in Novartis strategy, and was not based on any safety concerns regarding QCC374. Only Part 1 of the study was completed.

Arms: arm 1: Adult patients with pulmonary arterial hypertension (PAH) on QCC374. All patients were initiated at 0.03 mg BID (Day 1-3), and were up-titrated to next higher dose 0.06 mg BID (Day 4) and increased to 0.12 mg BID (Day 7-14). arm 2: Adult patients with pulmonary arterial hypertension (PAH) on placebo matching to QCC374 doses (0.03 mg BID (Day 1-3), 0.06 mg BID (Day 4) and 0.12 mg BID (Day 7-14)).
Interventions: intervention 1: QCC374 intervention 2: Placebo Matching
Intervention descriptions: intervention 1: 0.03 mg (2 capsules of 0.015 mg) BID 0.06 mg (1 capsule of 0.06 mg) BID 0.12 mg (2 capsules of 0.06 mg) BID intervention 2: Placebo matching to QCC374:

0.03 mg BID, 0.06 mg BID and 0.12 mg BID

Protocol documents:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
QCC374
Clinical Trial Protocol CQCC374X2201
A randomized, parallel-group, placebo-controlled subject 
and investigator blinded study to assess the safety, 
tolerability, pharmacokinetics and efficacy of QCC374 in 
the treatment of pulmonary arterial hypertension 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2016-001412-38 
Version number: 
v02 (Clean) 
Clinical Trial Phase: 
II 
Release date: 
07-May-2018 
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


 
 
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Site Operations Manual (SOM) 
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. 
Notification of serious adverse events 
Refer to Section  9.2 of the protocol for definitions and reporting requirements for Serious 
Adverse Events (within 24 hours after awareness of the SAE to the local Novartis Chief 
Medical Office and Patient Safety Department and notify the Clinical Trial Leader.). 
Contact information is listed in the Site Operations Manual. 


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Table of contents 
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................7
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Pharmacokinetic definitions and symbols.........................................................................11
Glossary of terms...............................................................................................................13
Protocol synopsis...............................................................................................................20
1 Introduction .......................................................................................................................23
1.1 
Background............................................................................................................23
1.4 
Study purpose ........................................................................................................30
2 Study objectives and endpoints.........................................................................................30
2.1 
Primary objective(s)...............................................................................................30
2.2 
Secondary objective(s)...........................................................................................31
3 Investigational plan ...........................................................................................................32
3.1 
Study design...........................................................................................................32
3.1.1 
Part 1 .....................................................................................................33
3.1.2 
Part 2 .....................................................................................................35
3.2 
Rationale of study design.......................................................................................35
3.4  Rationale for choice of comparator .......................................................................37
3.5 
Rationale for choice of background therapy..........................................................3
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3.7 
Risks and benefits..................................................................................................38
3.7.1 
Hypotension ..........................................................................................38
3.7.2 
Prostacyclin Associated Adverse Events..............................................38
3.7.3 
Risk of Bronchospasm or Cough ..........................................................39
3.7.4 
Hemostasis ............................................................................................39
3.7.5 
Phototoxicity.........................................................................................40
3.7.6  
Women of child bearing potential.........................................................40
3.7.7 
Blood sample volumes..........................................................................40
4 Population..........................................................................................................................40
4.1 
Inclusion criteria....................................................................................................40
4.2 
Exclusion criteria...................................................................................................41
5 Restrictions for Study Subjects .........................................................................................43
5.1 
Contraception requirements...................................................................................43
5.2 
Prohibited treatment...............................................................................................43
5.3 
Dietary restrictions and smoking...........................................................................44
5.4  Other restrictions ...................................................................................................44
6 Treatment...........................................................................................................................44
6.1 
Study treatment......................................................................................................44
6.1.1 
Investigational treatment and control drugs..........................................44
6.2 
Treatment arms......................................................................................................44
6.3  Treatment assignment and randomization 
.............................................................44
6.4 
Treatment blinding.................................................................................................45
6.5 
Treating the subject................................................................................................46
6.6 
Permitted dose adjustments and interruptions of study treatment 
.........................46
6.7 
Emergency breaking of assigned treatment code ..................................................47
6.8 
Treatment exposure and compliance.....................................................................47
6.9 
Recommended treatment of adverse events ..........................................................47
6.10  Rescue medication 
................................ 
................................ 
.................................47
6.11 Concomitant treatment...........................................................................................48
7 Study completion and discontinuation 
..............................................................................48
7.1 
Study completion and post-study treatment ..........................................................48
7.2 
Discontinuation of study treatment........................................................................49
7.3 
Withdrawal of informed consent...........................................................................50
7.4 
Lost to follow-up ...................................................................................................50
7.5 
Study Stopping rules..............................................................................................51
7.6 
Early study termination by the sponsor.................................................................5
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Procedures and assessments ................................ ..............................................................52
8.1 
Assessment schedule .............................................................................................52
8.2 
Informed consent procedures.................................................................................62
8.3  Subject screening 
................................ 
................................ 
...................................62
8.4  Subject demographics/other baseline characteristics.............................................62
8.5 
Efficacy / Pharmacodynamics ...............................................................................63
8.5.1  
Right Heart Catheterization...................................................................63
8.5.2 
Echocardiography .................................................................................64
8.5.3  
6-Minute Walk Test ..............................................................................64
8.6 
Safety 
................................ 
................................ 
.....................................................65
8.6.1 
Spirometry.............................................................................................65
8.6.2 
Chest X-ray ...........................................................................................65
8.6.3 
Physical examination ............................................................................65
8.6.4 
Vital signs..............................................................................................65
8.6.5 
Pulse oximetry.......................................................................................65
8.6.6 
Height and weight.................................................................................65
8.6.7 
Laboratory evaluations..........................................................................65
8.6.8 
Pregnancy and assessments of fertility .................................................66
8.6.9 
Lung Volumes and DLCO....................................................................66
8.6.10 
ECG.......................................................................................................66
8.7 
Pharmacokinetics...................................................................................................66
8.7.1 
PK Sample Collection...........................................................................67
8.7.2 
Bioanalytical Method............................................................................67
8.7.3 
Calculation of PK Parameters...............................................................67
Safety monitoring..............................................................................................................69
9.1 
Adverse events.......................................................................................................69
9.2 
Serious adverse event reporting.............................................................................71
9.2.1 
Definition of SAE .................................................................................71
9.2.2 
SAE reporting........................................................................................72
9.3 
Liver safety monitoring 
.........................................................................................72
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9.4 
Renal safety monitoring.........................................................................................73
9.5 
Reporting Medication errors including misuse/abuse ...........................................74
9.6 
Pregnancy reporting...............................................................................................74
9.7 
Early phase safety monitoring...............................................................................75
10 Data review and database management.............................................................................75
10.1 Site monitoring ......................................................................................................75
10.2  Data collection 
................................ 
................................ 
.......................................75
10.3 Database management and quality control............................................................76
10.4 Data Monitoring Committee..................................................................................77
10.5 Adjudication Committee........................................................................................77
11 Data analysis......................................................................................................................77
11.1 Analysis sets ..........................................................................................................77
11.2  Subject demographics and other baseline characteristics......................................77
11.3 Treatments .............................................................................................................77
11.4 Analysis of the primary variable(s) .......................................................................78
11.4.1 
Variable(s).............................................................................................78
11.4.2 
Statistical model, hypothesis, and method of analysis..........................78
11.4.3 
Handling of missing values/censoring/discontinuations.......................78
11.4.4 
Sensitivity analyses...............................................................................78
11.5 Analysis of secondary variable(s)..........................................................................79
11.5.1 
Efficacy / Pharmacodynamics...............................................................79
11.5.2 
Safety.....................................................................................................79
11.5.3 
Pharmacokinetic / pharmacodynamic interactions................................80
11.5.4 
Other assessments .................................................................................80
11.7  Sample size calculation..........................................................................................81
11.8 Power for analysis of key secondary variables......................................................81
12  Ethical considerations........................................................................................................82
12.1 Regulatory and ethical compliance........................................................................82
12.2 Responsibilities of the investigator and IRB/IEC..................................................82
12.3 Publication of study protocol and results...............................................................83
13 Protocol adherence ............................................................................................................83
13.1 Protocol Amendments ...........................................................................................83
14 References .........................................................................................................................84
15 Appendix 1: Liver Event Definitions and Follow-up Requirements.................................8
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16 Appendix 2: Specific Renal Alert Criteria and Actions....................................................88
List of tables 
Table 8-1 
Part 1 Assessment Schedule..................................................................52
Table 8-2  
Part 1 PK blood collection 
................................
....................................56
Table 8-3 
Part 2 Assessment Schedule..................................................................57
Table 8-4  
Part 2 PK blood collection 
................................
....................................61
Table 9-1 
Summary of reporting requirements for medication errors...................74
Table 15-1  
Liver Event Definitions.........................................................................86
Table 15-2 
Actions required for Liver Events.........................................................86
Table 15-3 
Exclusion of underlying liver disease ...................................................87
Table 16-1 
Specific Renal Alert Criteria and Actions.............................................88
Table 16-2 
Follow-up of renal events......................................................................89
List of figures
Figure 3-1 
Study Periods ........................................................................................33
Figure 3-2 
Part 1 and Part 2 Dose Evaluation and Titration...................................3
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List of abbreviations 
6MWD 
Six Minute Walk Distance 
6MWT 
Six Minute Walk Test 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
bid 
twice a day 
BMI 
body mass index 
BUN 
blood urea nitrogen 
cAMP 
cyclic adenosine 3
'5
' monophosphate 
CAMPHOR 
Cambridge Pulmonary Hypertension Outcome Review 
CD-ROM 
compact disc – read only memory 
CFR 
Code of Federal Regulation 
CK 
creatinine kinase 
CNS 
central nervous system 
CO 
cardiac output 
CO2 
carbon dioxide 
CRF 
case report/record form (paper or electronic) 
CRO 
contract research organization 
CV 
coefficient of variation 
CXR 
chest x-ray 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
FEV 
forced expiratory volume 
FIH 
first in human 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GINA 
Global Initiative for Asthma 
GLP 
Good Laboratory Practice 
h 
Hour 


  
 
 
 
 
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HIV 
hPaSMc 
HR 
HV 
Hx/Su 
i.t. 
i.v. 
ICH 
IEC 
IPR 
IRB 
IRT 
LDH 
LLOQ 
LV 
MAD 
MCT 
mg 
ml 
mPAP 
MTD 
NOAEL 
NT-proBNP 
NYHA 
PA 
PAH 
PCWP 
PD 
PG 
PH 
PK 
human immunodeficiency virus 
human pulmonary artery smooth muscle cell 
heart rate 
healthy volunteer 
Hypoxia/Sugen 
intra-tracheal 
Intravenous 
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
Independent Ethics Committee 
prostacyclin receptor 
Institutional Review Board 
Interactive Response Technology 
lactate dehydrogenase 
lower limit of quantification 
left ventricular 
multiple ascending dose 
Monocrotaline 
milligram(s) 
milliliter(s) 
mean pulmonary artery pressure 
maximum tolerated dose 
no observed adverse effect level 
N-terminal prohormone of brain natriuretic peptide 
New York Heart Association 
pulmonary artery 
pulmonary arterial hypertension 
Pulmonary Capillary Wedge Pressure 
pharmacodynamic(s) 
Pharmacogenetics 
pulmonary hypertension 
pharmacokinetic(s) 


 
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PVR 
pulmonary vascular resistance 
RA 
right atrium 
REB 
Research Ethics Board 
RHC 
right heart catheterization 
RV 
right ventricular 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOM 
Site Operations Manual 
SVR 
systemic vascular resistance 
TBL 
total bilirubin 
ULN 
upper limit of normal 
WHO 
World Health Organization 


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Pharmacokinetic definitions and symbols 
AUC0-t 
AUClast 
AUCtau 
AUCtau,ss 
Cav,ss 
CL/F 
CLr 
Cmax 
Cmax,ss 
Cmin,ss 
F 
T1/2 
T1/2,acc 
Tmax 
Vss 
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to time 't
' where t is a defined time point after 
administration [mass x time / volume] 
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to the time of the last quantifiable concentration [mass x 
time / volume] 
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to the end of the dosing interval tau [mass x time / volume] 
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to the end of the dosing interval tau at steady state [mass x 
time / volume] 
The average steady state plasma (or serum or blood) concentration during 
multiple dosing 
The systemic (or total body) clearance from plasma (or serum or blood) 
following intravenous administration [volume / time] 
The apparent systemic (or total body) clearance from plasma (or serum or 
blood) following extravascular administration [volume / time] 
The renal clearance from plasma (or serum or blood) [volume / time] 
The observed maximum plasma (or serum or blood)  concentration 
following drug administration [mass / volume] 
The observed maximum plasma (or serum or blood) concentration 
following drug administration at steady state [mass / volume] 
The lowest plasma (or serum or blood) concentration observed during a 
dosing interval at steady state [mass / volume] 
Bioavailability of a compound. Fabs is the absolute bioavailability, i.e. the 
fraction (or percentage) of the administered extravascular  dose 
systemically available. Frel is the relative bioavailability, i.e. the 
bioavailability relative to a reference 
The terminal elimination half-life [time] 
The effective half-life based on drug accumulation at steady state [time] 
The time to reach the maximum concentration after drug administration 
[time] 
The volume of distribution at steady state following intravenous 
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The volume of distribution during the terminal elimination phase following 
Vz 
intravenous administration [volume]
The apparent volume of distribution during the terminal elimination phase 
Vz/F 
following extravascular administration [volume] 


 
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Glossary of terms 
Control drug 
Enrollment 
Investigational drug 
Investigational 
treatment 
Medication number 
Period 
Premature subject 
withdrawal 
Randomization 
number 
Stage 
Study completion 
Study drug 
discontinuation 
Study 
drug/treatment 
A study drug used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug. 
Point/time of subject entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol). 
The study drug  whose properties are being tested in the study; this 
definition is consistent with US CFR  21 Section 312.3 and is 
synonymous with “investigational new drug” or “investigational 
medicinal product”. 
All investigational drug(s) whose properties are being tested in the 
study as well as their associated treatment controls. This includes any 
placebos, any active controls, as well as approved drugs used outside 
of their indication/approved dosage or tested in a fixed combination. 
Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed 
by the protocol when used within approved indication/dosage. 
A unique identifier on the label of each study drug package in studies 
that dispense study drug using an IRT system. 
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc. 
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and assessments; at this 
time all study drug administration is discontinued and no further 
assessments are planned. 
A unique identifier assigned to each randomized subject, 
corresponding to a specific treatment arm assignment 
A major subdivision of the study timeline; begins and ends with major 
study milestones such as enrollment, randomization, completion of 
treatment, etc. 
Point/time at which the subject came in for a final evaluation visit or 
when study drug was discontinued whichever is later. 
Point/time when subject permanently stops taking study drug for any 
reason; may or may not also be the point/time of premature subject 
withdrawal. 
Any drug (or combination of drugs) administered to the subject as part 
of the required study procedures; includes investigational drug, active 
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An individual who has consented to participate in this study. The term 
Subject 
Subject may be used to describe either a healthy volunteer or a patient. 
A number assigned to each  subject who enrolls in the study. When 
Subject number 
combined with the center number, a unique identifier is created for 
each subject in the study. 
Information used in the data analysis; derived directly or indirectly 
Variable 
from data collected using specified assessments at specified 
timepoints. 


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Protocol synopsis 
Protocol number [CQCC374X2201] 
Title 
A randomized, parallel-group, placebo-controlled subject and investigator 
blinded study to assess the safety, tolerability, pharmacokinetics and efficacy of 
QCC374 in the treatment of pulmonary arterial hypertension (PAH) 
Brief title 
Safety, pharmacokinetics and efficacy study of QCC374 in PAH patients 
Sponsor and
Clinical Phase 
Novartis 
Phase II (non-confirmatory) 
Intervention type Drug 
Study type 
Interventional 
Purpose and 
This study is designed as a proof of concept study for QCC374, an inhaled 
rationale 
prostacyclin receptor (IPR) agonist for the treatment of PAH. The purpose of this 
study is to assess the safety, tolerability, pharmacokinetics and efficacy of 
QCC374 in adult patients with PAH to determine if QCC374 has an adequate 
clinical profile to warrant further clinical development in this indication. 
Primary
Objective(s) 
To assess the efficacy of 16 weeks of QCC374 administration in patients with 
PAH by measuring the change from baseline in pulmonary vascular resistance 
(PVR). 
Secondary
Objectives 

To evaluate the safety and tolerability of multiple doses of QCC374 in 
patients with PAH 

To evaluate the preliminary efficacy of 16 weeks of QCC374 administration 
in patients with PAH by measuring changes from baseline in: 

Six minute walk distance (6MWD) 

Hemodynamic parameters other than PVR 

Right ventricular function with echocardiography 

To evaluate the pharmacokinetics of QCC374 and its metabolite QCM441 in 
patients with PAH 
Study design 
This is a non-confirmatory, randomized, subject and investigator blinded, 
placebo controlled study of QCC374 in PAH patients. The study will have 
2 parts. In Part 1, an initial safety cohort, 8 subjects will be randomized in a 6:2 
ratio and the starting dose will be 0.03 mg bid. In Part 2, ~ 30 subjects will be 
randomized in a 2:1 ratio, with a starting dose of 0.03 mg bid. In Part 1, subjects 
will be  up-titrated during the first two weeks of the study to 0.12 mg bid, or to 
their maximum tolerated dose (MTD) if their individual MTD is below 0.12 mg bid 
during the first two weeks of the study. 
In Part 2, subjects will be up-titrated during the first two weeks of the study to 
0.06 mg bid, or will remain at the starting dose of 0.03 mg bid if the investigator 
believes, based on their medical judgement,  that the dose should not be 
increased. 
The treatment duration is 16 weeks. 
Population 
The study population for Parts 1 and 2 will be comprised of male and female 
adults with symptomatic PAH. A total of approximately 38 patients are planned 
to be enrolled and randomized, with approximately 30 patients expected to 
complete the study. The sample size will be re-estimated at the interim analysis 
and number of randomized patients may be increased up to a maximum of 60. 


    
  
  
  
   
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Inclusion criteria Male and female patients 18 years of age or older with symptomatic PAH. 
Subjects with PAH belonging to one of the following subgroups of the Updated 
Clinical Classification Group 1 (Nice, 2013): 

idiopathic PAH 

familial PAH 

PAH associated with connective tissue disease, congenital heart disease 
(surgically repaired at least 12 months prior to screening) or drug or toxin 
induced (for example, anorexigen use). 
Subjects must have persistent symptoms due to PAH despite therapy with at 
least one of the following PAH medications: an endothelin receptor antagonist, a 
soluble guanylate cyclase stimulator or a phosphodiesterase inhibitor. 
The subjects
' PAH medication regimen, with typical medications including 
endothelin receptor antagonists, soluble guanylate cyclase stimulators and/or 
phosphodiesterase inhibitors, must have been used at a stable dose and 
frequency for at least 12 weeks before the screening visit and during the 
screening period. 
Diagnosis of PAH established according to the standard criteria before the 
screening visit: 

Resting mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg 

PVR > 240 dyn·s/cm5 

Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic 
pressure ≤ 15 mmHg 
PVR > 400 dyn·s/cm5 at the time of the baseline right heart catheterization 
(RHC) (if a RHC was completed within one month of the screening visit, that 
result may be used for inclusion, if data meets criteria outlined in Section 8.5.1). 
6MWD greater than 150 meters at screening. This distance must be confirmed 
by a second 6MWT prior to randomization. The value of the second 6MWD 
should be within ± 15% of the value obtained at screening. 
Exclusion 
Subjects with  clinically unstable right heart failure within the last three months 
criteria 
(New York Heart Association (NYHA) Class IV). 
Subjects with 
PAH associated with 
portal hypertension, Human 
Immunodeficiency Virus (HIV) infection or unrepaired congenital systemic to 
pulmonary shunts 
Subjects who have received or have been scheduled to receive long-term 
treatment with epoprostenol or any prostacyclin within the three months prior to 
the screening visit or during the screening period. 
Hypotensive subjects (systemic systolic blood pressure < 85 mmHg) 
Subjects with three or more of the following left ventricular disease/dysfunction 
risk factors: Body mass index (BMI) > 30 kg/m2 at the screening visit (BMI = 
Body weight (kg) / [Height (m)]
2); History of Essential Hypertension; Diabetes 
Mellitus – any type; Medical history of significant coronary artery disease (CAD). 
Subjects with left sided heart disease, chronic left sided heart failure, congenital 
or acquired valvular disease and/or pulmonary venous hypertension. 
Subjects with obstructive (FEV1/FVC < 70% and FEV1 < 70% predicted) or 
restrictive (total lung capacity < 65% predicted and/or clinically significant 
abnormality on CXR) lung disease at screening. 


 
 
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Investigational
and reference 
therapy 

QCC374 0.015 mg 

QCC374 0.06 mg 
Efficacy/PD 

PVR 
assessments 

6MWD 

mPAP, PCWP, Cardiac Output (CO), Systemic Vascular Resistance (SVR) 

Right Ventricular (RV) function with echocardiography 
Safety 

Spirometry 
assessments 

Electrocardiogram (ECG) 

Chest X-ray (CXR) 

Blood Chemistries, Hematology and Urinalysis 
Other 

Pharmacokinetics (PK) 
assessments 
Data analysis 
Data from the two parts of the study will be pooled for the statistical analysis. 
The primary variable is PVR. The log transformed PVR is expected to be 
approximately normally distributed. The change from baseline (on log 
transformed values) will be analyzed using an Analysis of Covariance 
(ANCOVA) model with treatment as a factor and log transformed baseline PVR 
as a covariate. Likelihood based posterior distributions will be derived to assess 
the probability that QCC374 is better than placebo and the probability that the 
reduction vs placebo is at least 15%. 
The efficacy criteria at the end of the study is as follows: 

If there is at least 90% probability that the treatment effect of QCC374 is 
better than placebo in PVR and 

If there is at least 50% probability that the reduction in PVR is at least 15% 
in favor of QCC374 compared to placebo. 
Key words 
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Pulmonary Arterial Hypertension, Prostacyclin 


    
 
 
 
 
  
 
 
 
   
 
     
 
 
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1 
Introduction 
1.1 
Background 
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by chronic 
elevation of mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance 
(PVR), defined as a mPAP ≥  25 mmHg at rest, a PVR > 240 dyn.s.cm-5, and pulmonary 
capillary wedge pressure (PCWP) ≤  15 mmHg (Galie et  al 2015).  The Updated Clinical 
Classification of Pulmonary Hypertension (Simonneau et  al 2013) classifies pulmonary 
hypertension (PH) into five groups, based on similarities in clinical presentation, 
pathophysiology, prognosis and therapeutic approach. Within this classification, PAH is 
classified as Group 1 PH. Most cases of Group 1 PAH are idiopathic (i.e., not associated with 
known risk factors or conditions), but PAH also occurs in a heritable form and in association 
with other disorders, including collagen vascular diseases, congenital systemic-to-pulmonary 
shunts, ingestion of drugs/toxins or other systemic conditions such as HIV infection or portal 
hypertension. 
A variety of arterial abnormalities characterize the pathology of PAH, including intimal 
hyperplasia, medial hypertrophy, adventitial proliferation, thrombosis in situ, varying degrees 
of inflammation, and plexiform arteriopathy. These remodeling changes are paramount in the 
pathogenesis of PAH, resulting in loss of luminal cross-section and increased PVR 
(Schermuly et  al 2011), with only <20% of PAH patients demonstrating a dynamic 
vasoconstrictive component of their disease (McLaughlin et  al 2009). Progressive vascular 
remodeling and increased PVR results in increased workload for the right ventricle and right 
ventricular failure, which is the major cause of PAH associated mortality. 
Over the last 20 years, significant advances have occurred in the treatment of PAH with the 
development of marketed therapies targeting three pathways: the endothelin, nitric oxide and 
prostacyclin pathways. Therapies targeting the prostacyclin pathway include the synthetic 
prostacyclin epoprostenol, prostacyclin analogs such as iloprost and treprostinil, and the IPR 
agonist selexipag. Prostacyclins are available via intravenous (epoprostenol, treprostinil), 
subcutaneous (treprostinil), inhaled (nebulized treprostinil and iloprost) and oral routes 
(treprostinil,  beraprost (Japan only), selexipag). Despite these  therapies, however, PAH 
remains a fatal disease with a median survival from diagnosis of 7 years (Benza et al 2012). 
Prostacyclin (Prostaglandin I2, PGI2) is primarily produced by endothelial cells, formed from 
arachidonic acid via the cyclooxygenase pathway. The prostacyclin receptor (IPR) is widely 
expressed on multiple cell types, including vascular smooth muscle, fibroblasts, endothelium 
and various inflammatory cells (Woodward et  al 2011). The vasodilatory action of 
prostacyclins is well validated in the clinic, and there is also growing non-clinical evidence 
that prostacyclins will impact upon the underlying structural changes that lead to increased 
vascular resistance, reversing the remodeling of pulmonary vessels. Inhaled iloprost has been 
shown to reverse vascular remodeling in a monocrotaline (MCT) induced PAH model in the 
rat (Schermuly et al 2005). In addition to normalization of PVR, iloprost reduced right heart 
hypertrophy and pulmonary vascular thickening. In another study using the MCT model, 
selexipag was also able to prevent vascular remodeling (Kuwano et  al 2008). 


 
 
    
 
    
  
 
 
  
 
 
  
 
 
 
 
    
 
 
 
  
    
 
     
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Prostacyclins have also been associated with anti-inflammatory (Hayashi et  al 2010) and 
anti-fibrotic effects (Zhu et al 2010). 
Prostacyclins (e.g. epoprostenol, treprostinil, iloprost, selexipag) have  been associated with 
improvements in pulmonary hemodynamics in PAH patients both acutely and following short 
term chronic dosing (e.g., 12-17 weeks) (Barst el  al 1996; McLaughlin et al 2010; 
Simonneau et al 2002; Simonneau et  al 2012).  These chronic effects are associated with 
improvement in exercise capacity (e.g., 6MWD) and functional status. In a 12  week open 
randomized study, epoprostenol was associated with improved  survival in naive, severe 
Functional Class III/IV patients  (Barst et  al 1996). Most recently, in a time to clinical 
worsening (Phase 3 study with 1156 PAH patients treated for up to 4.2 years, selexipag 
decreased the risk of a worsening event versus placebo by 39%. Currently the effect of 
prostacyclins (and other PAH therapies) on chronic pulmonary vascular remodeling in the 
clinic is poorly characterized, in part due to the lack of validated endpoints/biomarkers to 
represent this process. 
All prostacyclins have limitations impacting their safety and potential efficacy profile. 
Parenteral and oral IPR agonists are associated with on-target dose-limiting adverse events, 
including headache, jaw pain, nausea, diarrhea and hypotension, and require titration to an 
individual maximum tolerable dose. Nebulized iloprost and treprostinil are also dose limited 
by systemic adverse effects and have a relatively short duration of action, with both factors 
likely contributing to modest efficacy of these agents. As a result of these shortcomings, the 
initiation of prostacyclin therapy is delayed in some  PAH patients, with a clear subsequent 
negative effect on prognosis (Badagliacca et al 2012). 
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To address these shortcomings, QCC374 has been designed as a chemically stable, selective 
inhaled IPR agonist for dry powder inhalation, with long duration of action (via optimized cell 
membrane affinity) and low systemic exposure (high plasma protein binding, rapid clearance). 
These characteristics are expected to lead to a considerably improved safety and tolerability 
profile and potentially increased efficacy compared to other members of the prostacyclin class. 


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1.4 
Study purpose 
This study is designed as a proof of concept study for QCC374, an inhaled IPR agonist for the 
treatment of PAH. The purpose of this study is to assess the safety, tolerability, PK and 
efficacy of QCC374 in adult patients with PAH and determine if QCC374 has an adequate 
clinical profile to warrant further clinical development in this indication. 
2 
Study objectives and endpoints 
2.1 
Primary objective(s) 
Primary objective(s) 
Endpoints related to primary 
objective(s) 
To assess the efficacy of 16 weeks of QCC374 
administration in adult patients with PAH 

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Percentage of the baseline 
PVR at week 16. 


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2.2 
Secondary objective(s) 
Secondary objective(s) 
Endpoints related to secondary objective(s) 
To evaluate the safety and tolerability of 
multiple doses of QCC374 in patients with 
PAH 
AEs, SAEs and all safety assessments 
To evaluate the preliminary efficacy of 16 
weeks of QCC374 administration in 
patients with PAH by measuring changes 
from baseline in: 
Six minute walk distance (6MWD) 
Hemodynamic parameters other than 
PVR 
Right ventricular (RV) function with 
echocardiography 
6MWD 
mPAP, PCWP, CO, SVR 
Key RV function endpoints with 
echocardiography including but not 
limited to tricuspid annular peak systolic 
velocity (TA S
'), RV Tei index and RV 
fractional area change. 
To evaluate the pharmacokinetics of 
QCC374 and its metabolite QCM441 in 
patients with PAH 

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PK parameters of primary interest (Cmax 
Tmax, AUClast, AUCtau) of QCC374 
and QCM441 in plasma. 


 
 
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3 
Investigational plan 
3.1 
Study design 
This is a non-confirmatory, randomized, subject and investigator blinded, placebo controlled 
study of QCC374 in PAH patients. The study will have 2 parts: Part 1, an initial safety cohort 
with a 0.03 mg bid starting dose, and Part 2, a larger cohort with a 0.03 mg bid starting dose. 
An unblinded review of all available safety data will be reviewed prior to starting Part 2. 
The treatment duration is 16 weeks for both parts. 
Study flow and procedures (common to all parts, Figure 3-1): 
Screening Period (up to 28 days) 
During this period eligibility will be confirmed. During  
the screening phase subjects do not 
receive any study medication. 
Titration Period (2 weeks) 
The study dose can be titrated during the initial two week period, as described below for Parts 
1 and 2. 
Stable Dose Follow-up (14 weeks) 
No further adjustments in dose should occur unless a dose reduction for tolerability or safety 
reasons is indicated. In the event of a dose reduction, the subject could subsequently be 
increased back to the dose achieved at the end of the Titration Period, but increases above the 
dose level reached at the end of the Titration Period are not allowed. 
Safety Follow-up Period: 
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For all patients stopping study treatment prematurely at any time of the study or who decide 
not to participate in the long term extension phase study, a safety follow-up visit 28 days after 
the stop of study medication intake should be performed. 


 
  
 
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Figure 3-1 
Study Periods 
Screening Period: up to 28 days 
Titration Period: 2 weeks 
Stable Dose Follow-up Period: 14 weeks 
Safety Follow-up Period: 4 weeks* 
*only for patients who do not enter the open label extension trial (there will be a separate 
protocol for QCC374X2201E1 study) or who stop the study medication prematurely 
General Notes: 
QCC374 will be administered via inhalation using the Concept1 dry powder inhaler 
At the end of the treatment period of 16 weeks, eligible patients will be given the option to 
participate in a separate long term extension study, where all patients will be treated with 
an individual optimal dose of QCC374. 
Patients who complete Visit 108 (Day 111) and do not wish to enroll in the extension 
study will receive study drug on the morning of Visit 109 (Day 112) and complete PK and 
indicated safety assessments. These patients will not receive the pm dose of study drug. 
The last visit for these patients is the End of Study Visit (Visit 202), 28 days after 
receiving last dose of study drug. 
3.1.1 
Part 1 
Part 1 (Figure 3-2) will consist of 8 subjects, randomized in a 6:2 ratio to QCC374 or placebo. 
The planned bid dose levels in Part 1 are 0.03 mg, 0.06 mg and 0.12 mg. Subjects will begin 
dosing at 0.03 mg bid. 
On Day 4 the investigator will assess an individual subject
's clinical status and reported 
adverse events and confirm that an individual subject can be up-titrated to 0.06 mg bid. 
This decision, made individually for every subject, will be based on the investigator’s 
assessment of the severity of any adverse events, including adverse events typical of 
prostacyclins (e.g. headache, jaw pain, myalgia, flushing and nausea). 
On Day 7 the investigator will assess an individual subject
's clinical status and reported 
adverse events and confirm that an individual subject can be up-titrated to the next 
planned dose level. This decision, made individually for every subject, will be based on 
the investigator’s assessment of the severity of any adverse events, including adverse 
events typical of prostacyclins. 
On Day 14 the investigator will assess the patient
's clinical status and reported adverse 
events. If the patient is not already receiving the maximum dose of 0.12 mg bid, the 
investigator will determine whether an individual subject can be up-titrated one dose level.  


 
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This decision, made individually for every subject, will be based on the investigator’s 
assessment of the severity of any adverse events, including adverse events typical of 
prostacyclins. 
Following the Day 14 visit no further up-titrations are allowed. Subjects are allowed to 
continue in the trial even if their final dose after titration on Day 14 is not 0.12 mg. 
On Day 21, if the subject’s dose was up-titrated on Day 14, a follow-up phone call visit 
will occur to review safety and tolerability. 
At any point during the 16 week treatment period, if the investigator believes, based on 
their medical judgement, that the dose should be reduced due to the severity of adverse 
events, the investigator will reduce the dose to the previous tolerated dose. A follow-up 
phone call should be scheduled 7 days after dose adjustment to review safety and 
tolerability of adjustment. 
Figure 3-2 
Part 1 and Part 2 Dose Evaluation and Titration 
When the 8 subjects in Part 1 have been randomized, and completed 2 weeks of dosing 
(or discontinued), the sponsor will review all available unblinded safety data for these subjects, 
including adverse event listings, vital signs, spirometry and  ECG data. After receiving 
feedback from all investigators, and if in the opinion of the sponsor
's medical professional 
there is no evidence of a significant safety finding, dosing in Part 2 will proceed with a 0.06 
mg starting dose as described below. If a safety concern is identified by the sponsor
's medical 
physician or by an investigator, or if the sponsor
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proposed dosing schedule for Part 2 may not be well-tolerated, the sponsor may decide to 
adjust the dosing regimen for Part 2, either decreasing the final dose or increasing the interval 
between up-titrations. There is no plan to pause enrollment between Part 1 and Part 2, but a 
pause may be implemented if required. 
3.1.2 
Part 2 
Part 2 (Figure 3-2) will consist of approximately 30 subjects who will be randomized in a 2:1 
ratio, QCC374 or placebo. The planned dose levels in Part 2 are 0.03 mg and 0.06 mg. 
Subjects will begin dosing at 0.03 mg bid. 
On Day 7 the investigator will assess an individual subject
's clinical status and reported 
adverse events and confirm that an individual subject can be up-titrated to 0.06 mg bid. 
This decision, made individually for every subject, will be based on the investigator’s 
assessment of the severity of any adverse events, including adverse events typical of 
prostacyclins (e.g. headache, jaw pain, myalgia, flushing and nausea). 
On Day 14 the investigator will assess the patient
's clinical status and reported adverse 
events. If the patient is not already receiving the maximum dose of 0.06 mg bid, the 
investigator will determine whether an individual subject can be up-titrated to 0.06 mg, 
unless the investigator believes, based on their medical judgement, that the dose should 
not be increased due to the severity of adverse events. If this dosing scenario occurs, the 
subject is allowed to continue in the trial, and will continue to receive 0.03 mg bid. 
This decision, made individually for every subject, will be based on the investigator’s 
assessment of the severity of any adverse events, including adverse events typical of 
prostacyclins. 
Following the Day 14 visit no further up-titrations are allowed. Subjects are allowed to 
continue in the trial even if their final dose after titration on Day 14 is not 0.06mg. 
On Day 21, if the subject was up-titrated on Day 14, a follow-up phone call visit will 
occur to review safety and tolerability. 
At any point during the 16 week treatment period, if the investigator believes, based on 
their medical judgement, that the dose should be reduced due to the severity of adverse 
events, the investigator will reduce the dose to the previous tolerated dose. A follow-up 
phone call should be scheduled 7 days after dose adjustment to review safety and 
tolerability of adjustment. 
3.2 
Rationale of study design 
This study is designed as a  randomized, parallel group, placebo-controlled, subject and 
investigator blinded study, to assess the effect of a 16 week course QCC374 on the change 
from baseline in PVR as compared to placebo in patients with PAH. The rationales for key 
elements of the study design are as follows: 
Randomization: Decreases the chance of an imbalance in subject characteristics between 
treatment groups 
Subject and Investigator Blinding: Decreases the risk of bias of investigators or subjects in 
assessing subjective readouts such as adverse events* 


 
 
 
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Placebo controlled: Provides a comparison group for efficacy and safety/tolerability 
assessments. The placebo group will receive the standard of care therapy for PAH, as 
QCC374 and placebo are being studied in addition to standard of care therapy. 
Dose Titration Design: All current marketed prostacyclins have an up-titration dosing 
strategy to increase prostacyclin tolerability. With up-titration significantly higher 
prostacyclin doses can be tolerated as compared to single dose administration. 
 
 
Lower starting dose for 8 subjects in Part 1: Because QCC374 has not previously been 
tested in PAH patients, a lower starting dose is proposed for the first 8 subjects to monitor 
for any signals suggesting unanticipated, acute hemodynamic effects. 
Part 2 starting dose: As a result of the Safety Review of the 8 patients enrolled in Part 1, 
the starting dose of 0.03 mg was maintained for subjects enrolling in Part 2. 
Endpoints: PVR has been used by clinical studies in PAH previously to assess the 
pharmacodynamic effect of therapies on pulmonary pressures. In addition to PVR, several 
complementary endpoints will be used to assess efficacy, including additional pulmonary 
hemodynamic measurements, the 6MWD and echocardiographic assessments. 
Together these assessments are anticipated to provide a comprehensive view of the effect 
of QCC374 on PAH and inform future, larger studies. 
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*If a patient is considering enrollment in the separate long-term extension study 
(QCC374X2201E1), then the investigators may be unblinded only after all of the assessments 
on Day 111 (Visit 108) are completed; unblinding is necessary so that the appropriate dosing 
regimen can be selected for the extension study – either maintenance of the individual 
QCC374 dose for subjects randomized to QCC374 in this study, or initiation of QCC374 
titration for subjects randomized to placebo. 
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3.4 
Rationale for choice of comparator 
Placebo will be used as a comparator to QCC374 to provide an unbiased control for assessing 
and interpreting safety data as well as clinical efficacy data generated from patients exposed 
to QCC374. 
3.5 
Rationale for choice of background therapy 
QCC374 will be studied on top of standard of care therapy (endothelin receptor 
antagonist/soluble guanylate cyclase stimulator AND/OR a phosphodiesterase inhibitor) for 
PAH. Subjects will continue on their stable background therapy as established prior to study 
entry (Section 6.11
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), thereby justifying potential treatment with placebo. In addition, subjects 
will be maintained on their pre-existing stable medical  regiment for treatment of any 
additional pre-existing medical conditions. 
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3.7 
Risks and benefits 
Preclinical studies suggest that QCC374 may be of benefit for patients with PAH. 
However, QCC374 has not been studied previously in PAH patients and as such, the benefit 
for subjects participating in the study is unknown. 
Prostacyclins, including the synthetic prostacyclin epoprostenol, the prostacyclin analogs 
treprostinil and iloprost, and the IPR agonist selexipag, have  been associated a number of 
unwanted effects, including hypotension, jaw pain, flushing, headaches, an increased risk of 
bleeding, and gastrointestinal symptoms (nausea, vomiting, abdominal cramps and diarrhea). 
In addition, inhaled prostacyclin analogs have been associated with an increased risk of 
bronchospasm. As an inhaled IPR agonist, the potential risks of QCC374 are informed by 
prostacyclin adverse effects and some of these adverse events (headache, jaw pain, flushing) 
were observed in the FIH study, as described below. However, due to the QCC374’s mode of 
administration, its high plasma-protein-binding (99.9% in humans) and its fast clearance, the 
systemic exposure to free QCC374 is very low, which is expected to minimize unwanted 
effects at the anticipated clinical  doses. Furthermore, the data gained  from the safety 
pharmacology and repeated dose toxicity studies, as well as FIH study, suggest a favorable 
safety and tolerability profile for QCC374. 
The risk to subjects in this trial will be minimized by adherence to the eligibility criteria, close 
clinical monitoring, data review prior to beginning Part 2 and study stopping rules. 
There may be unknown risks of QCC374 which may be serious and unforeseen. 
3.7.1 
Hypotension 
In contrast to currently marketed prostacyclin analogs, QCC374 exerts its hemodynamic 
effects (on pulmonary as well as systemic vasculature) only at considerably higher doses than 
its antiproliferative effects. Thus, in animal studies considerable reversal of pulmonary 
vasculature remodeling was achieved in the absence of systemic hypotension. 
3.7.2 
Prostacyclin Associated Adverse Events 
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As discussed above, all marketed prostacyclins (synthetic prostacyclins, prostacyclin analogs 
and IPR agonists) are associated with on-target systemic adverse events, including headache, 
jaw pain, flushing, nausea and diarrhea. Headache, jaw pain and flushing were reported in the 
FIH study with QCC374. The risk of these adverse events is minimized in early clinical 
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MTD, and the overall systemic exposure is minimized due to inhaled delivery, rapid systemic 
clearance and high protein binding of QCC374. If a prostacyclin associated adverse event 
does occur, it is expected to be mild-to-moderate in severity and transient, and the subject will 
be treated with standard of care (e.g. acetaminophen or ibuprofen analgesia for headache). 
3.7.3 
Risk of Bronchospasm or Cough 
No compound-driven changes in the lung or effects on respiratory function were observed in 
the animal studies. Reversible alterations of the laryngeal epithelium were seen in the rat 
inhalation studies; however, similar findings are often observed in rodent inhalation studies 
and are considered adaptive to extended particle exposure and not test article-specific. 
Increased risk of bronchospasm, wheezing and worsening of  pre-existing pulmonary edema 
were reported with the inhaled prostacyclin analogs treprostinil and iloprost. 
 
 
Subjects with a 
history of significant underlying obstructive lung disease will be excluded from early clinical 
development studies in PAH. Bronchospasm will be monitored by subjective clinical data (i.e., 
cough, shortness of breath, and chest tightness) and objective clinical data (i.e. spirometry). In 
the event of clinically apparent airway reactivity/irritation, subjects will be treated with 
standard of care (i.e., inhaled short acting beta agonist). 
3.7.4 
Hemostasis 
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Inhibition of platelet aggregation constitutes a major physiological effect of prostacyclin, 
mediated via the IP receptor and cyclic adenosine monophosphate. Systemic and inhaled 
prostacyclins are reported to increase the risk of bleeding, particularly in patients with other 
risk factors for bleeding. Increased bleeding therefore represents a potential risk for QCC374. 
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3.7.5 
Phototoxicity 
QCC374 absorbs UV radiation in the relevant wavelengths of natural sunlight. In vitro 
assessments measuring neutral red uptake in 3T3 cells indicate a possible phototoxic potential.   
However, given the low expected systemic exposures and lack of specific accumulation in 
organs associated with phototoxicity (i.e. skin, eyes), the phototoxicity risk is considered to be 
low under the conditions of intended use for QCC374. Normal precautions to minimize sun 
exposure should be used throughout the study. 
3.7.6 
Women of child bearing potential 
Women of child bearing potential should be informed that taking the study drug may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirement for the duration 
of the study. If there is any question that the subject will not reliably comply, they should not 
be entered in the study. 
3.7.7 
Blood sample volumes 
A maximum of 242 mL of blood (231,2 ml in South Korea and Taiwan) is planned to be 
collected over a period of 20 weeks, from each subject as part of the study. Additional 
samples for monitoring of any safety findings would be in addition to  this. This is not 
considered to be a risk for this population. 
4 
Population 
4.1 
Inclusion criteria 
Subjects eligible for inclusion in this study must fulfill allof the following criteria: 
1.Written informed consent must be obtained before any assessment is performed 
2.Able to communicate well with the investigator, to understand and comply with the 
requirements of the study. 
3.Male and female patients 18 years of age or older with symptomatic PAH 
(WHO Functional Class II or III). 
4.Subjects with PAH belonging to one of the following subgroups of the Updated Clinical 
Classification Group 1 (Nice, 2013): 
Idiopathic PAH 
familial PAH 
PAH associated with connective tissue disease, congenital heart disease (surgically 
repaired at least 12 months prior to screening) or drug or toxin induced (for example, 
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5.Subjects must have persistent symptoms due to PAH despite therapy with at least one of 
the following PAH medications: an endothelin receptor antagonist, a soluble guanylate 
cyclase stimulator or a phosphodiesterase inhibitor. The subjects
' PAH medication 
regimen, with typical medications including endothelin receptor antagonists, soluble 
guanylate cyclase stimulators and/or phosphodiesterase inhibitors, must have been used at 
a stable dose and frequency for at least 12 weeks before the screening visit and during the 
screening period. 
6.Diagnosis of PAH established according to the standard criteria before the screening visit: 
1.Resting mPAP ≥ 25 mmHg. 
2.PVR > 240 dyn·s/cm5. 
3.PCWP or left ventricular end diastolic pressure ≤15 mmHg 
7.A PVR > 400 dyn·s/cm5 at the time of the baseline RHC (if a RHC was completed within 
one month of the screening visit, that result may be used for inclusion if data meets criteria 
outlined in Section 8.5.1) 
8.6MWD greater than 150 meters at screening. This distance must be confirmed by a second 
6MWT prior to randomization. The value of the second 6MWD must be within ± 15% of 
the initial value. 
4.2 
Exclusion criteria 
Subjects fulfilling any of the following criteria are not eligible for inclusion in this study: 
1.Subjects with clinically unstable right heart failure (NYHA Class IV) or with more than 
one unplanned hospital admission for the treatment of PAH within the three months prior 
to screening. 
2.Subjects with PAH associated with portal hypertension, Human Immunodeficiency Virus 
(HIV) infection or unrepaired congenital systemic to pulmonary shunts, or subjects with 
PAH responsive to high dose calcium channel blockers. 
3.Subjects who have received or have been scheduled to receive treatment with a 
prostacyclin (prostacyclin analog or IPR agonist) within the three months prior to the 
screening visit or during the screening period. 
4.Hypotensive subjects (systemic systolic blood pressure < 85 mmHg) at the screening visit 
or at the baseline visit. 
5.Subjects with left sided heart disease, chronic left sided heart failure, congenital or 
acquired valvular disease and/or pulmonary venous hypertension, as determined by history 
or echocardiogram at baseline visit. 
6.Subjects with three or more of the following left ventricular disease/dysfunction risk factors: 
1.Body mass index (BMI) > 30 kg/m
2 at the screening visit. BMI = Body weight 
(kg) / [Height (m)]
2. 
2.History of Essential Hypertension 
3.Diabetes Mellitus – any type 
4.Medical history of significant coronary artery disease (CAD), including a 
history of myocardial infarction or chronic stable angina, a history of 
percutaneous intervention or coronary artery surgery, prior angiographic 
evidence of CAD, or a positive stress test with imaging. 


 
  
   
    
    
  
    
 
 
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7.Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test. 
8.Use of other investigational drugs at the time of enrollment, or within 5 half-lives of 
enrollment, or within 30 days, whichever is longer; or longer if required by local 
regulations. 
9.History of hypersensitivity to any of the study drugs or to drugs of similar chemical 
classes. 
10. History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such 
abuse as indicated by the laboratory assays conducted during screening. 
11. Subjects with a history of a ventilation-perfusion lung scan or pulmonary angiography 
indicative of thromboembolic disease 
12. Subjects with obstructive (FEV1/ FVC < 70% and FEV1 < 70% predicted) or restrictive 
(total lung capacity < 65% predicted and/or clinically significant abnormality on CXR) 
lung disease at screening. 
13. Subjects with moderate or severe hepatic impairment (Child-Pugh B and C) 
14. Subjects with clinically significant chronic renal insufficiency at screening visit 
(estimated creatinine clearance < 30 mL/minute, or serum creatinine > 2.5 mg/dL). 
15. Subjects unable to perform the 6MWT due to disability from another condition, 
e.g. musculoskeletal disorder or arthritis 
16. A history of immunodeficiency diseases, including a positive HIV test result. 
17. Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV) at screening.  A positive 
HBV surface antigen (HBsAg) test excludes a subject. Subjects with a positive HCV 
antibody test at screening should have HCV RNA levels measured and confirmed by the 
central lab prior to their baseline visit. Subjects with positive (detectable) HCV RNA 
should be excluded. 
18. Patients with a history of moderate or severe asthma (as diagnosed by the 
Global Initiative for Asthma (GINA) Guidelines 2016) 
19. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception during dosing of 
investigational drug. Basic contraception methods include: 
Total abstinence from heterosexual intercourse (when this is in line with the preferred 
and usual lifestyle of the subject). Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. For Korea: total abstinence is not an allowed form of basic contraception. 
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment 
Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject. 


 
 
 
  
      
    
     
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Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/vaginal 
suppository. For Korea: Double barrier method of contraception is required – for 
example, use of a cervical cap, or diaphragm along with a condom. 
Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS) 
In case of use of oral contraception women should be stable on the same pill for a minimum 
of 3 months before taking study drug. 
If local regulations deviate from the contraception methods listed above and require more extensive 
measures to prevent pregnancy, local regulations apply
 and will be described in the ICF. 
Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or 
without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of 
oophorectomy alone, only
 when the reproductive status of the woman has been confirmed by follow 
up hormone level assessment is she considered not of child bearing potential. 
Subjects who failed to meet inclusion/exclusion criteria for  temporary reasons can be 
rescreened once. Please refer to the Site Operations Manual for additional details. 
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
5 
Restrictions for Study Subjects 
During recruitment, screening/informed consent review, and baseline visit, the subjects must 
be informed and reminded of the following restrictions: 
5.1 
Contraception requirements 
Women of child bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study, and agree that 
in order to participate in the study they must adhere to the contraception requirement outlined 
in the Section 4.2 (Exclusion Criteria). If there is any question that the subject will not reliably 
comply, they should not be entered or continue in the study. 
5.2 
Prohibited treatment 
The use of inhaled, intravenous, subcutaneous or oral prostacyclins (e.g., epoprostenol, 
treprostinil, iloprost or selexipag) in the 3 months prior to screening, during the screening 
period or during the treatment period of the trial is not allowed. In the  event of a clinically 
relevant  deterioration of the patient
's signs or symptoms of PAH, the investigator may 
consider starting treatment with an alternative prostacyclin. The decision should be based on 
the investigator
's assessment of the patient
's well-being and safety, and should be documented 


 
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in the case report form (CRF). Patients who require prostacyclin therapy must discontinue 
study treatment. 
5.3 
Dietary restrictions and smoking 
No alcohol for 48 hours prior to all clinic visits and while in the clinic. 
On the days when PK is collected, to ensure standardized dosing conditions, compound 
administration will take place 30 min before or after food intake. 
5.4 
Other restrictions 
No significant change in physical exercise program from the beginning of the study until 
after the visit has been completed for Day 112. If a patient is participating in a pulmonary 
rehabilitation program at the time of screening, then participation may continue 
throughout the study period. 
Avoid direct sunlight exposure, or, in the event of unavoidable direct sunlight exposure, 
use topical sun blocking agents 
6 
Treatment 
6.1 
Study treatment 
Details on the storage and management of study medication, randomization and instructions 
for prescribing and taking study treatment are outlined in the SOM. 
6.1.1 
Investigational treatment and control drugs 
The investigational drug, QCC374 0.015 mg and 0.06 mg, and matching placebo will be 
prepared by Novartis and supplied to the Investigator in blinded subject packs. 
6.2 
Treatment arms 
Subjects will be assigned to either the QCC374 or Placebo treatment arms in a ratio of 3:1 in 
Part 1 and ratio of 2:1 in Part 2. Refer to Section 3.1 and Section  3.2 for information on 
dosing schedule and rationale. 
6.3 
Treatment assignment and randomization 
Randomized treatment will be assigned to individual subjects by way of a randomization 
number,  which will be in the range of 5101-5108 for Part 1 and 5201-5252 for Part 2. 
The availability of 60 randomization numbers is chosen here as the sample size may be 
increased at the IA. 
The randomization number is only used to identify which treatment the patients have been 
randomized to receive. The Subject number assigned to a subject at screening remains the 
unique identifier for the subject throughout the study. For information on subject numbering, 
please see ‘Subject numbering’ section in the SOM. 


    
         
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All eligible subjects will be randomized via Interactive Response Technology (IRT) to one of 
the treatment arms. The investigator or his/her delegate will use the IRT system after 
confirming that the subject fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the subject, which will be used to link the subject to a treatment arm, 
and will specify a unique medication number for the first package of investigational treatment 
to be dispensed to the subject. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. 
A subject randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of subject numbers to randomization numbers. 
These randomization numbers are linked to the different treatment arms, which in turn are 
linked to medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the investigational drug(s). 
The randomization  scheme for subjects will be reviewed and approved by a member of the 
Randomization Office. Follow the details outlined in the SOM regarding the process and 
timing of treatment assignment and randomization of subjects. 
6.4 
Treatment blinding 
This is a subject and investigator blinded study. Subjects and investigators will remain blinded 
to study treatment throughout the study, except where indicated below. If the subject is 
eligible for the optional extension study (QCC374X2201E1) and is considering participation, 
the blind for the investigator and subject can be broken only after all assessments on Day 111 
(Visit 108) have been completed. 
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, and odor. 
Unblinding a single subject at site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (see Section 6.7
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6.5 
Treating the subject 
QCC374 will be administered to the subject via inhaled administration with the Concept1 dry 
powder inhaler. Throughout the 16-week treatment period, the majority of administration will 
occur at home on an outpatient basis. See the SOM for further details. 
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems. 
6.6 
Permitted dose adjustments and interruptions of study treatment 
For patients who are unable to tolerate the preferred protocol-specified dosing scheme, dose 
adjustments are permitted. The guidelines found in Section 3.1 
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6.7 
Emergency breaking of assigned treatment code 
Emergency unblinding should only be undertaken when it is essential to treat the subject 
safely and efficaciously. Most often, study treatment discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study subject who presents with an 
emergency condition. Emergency treatment code breaks are performed using the IRT. 
When the investigator contacts the system to break a treatment code for a subject, he/she must 
provide the requested subject identifying information and confirm the necessity to break the 
treatment code for the subject. The investigator will then receive details of the investigational 
drug treatment for the specified subject and a fax or email confirming this information. 
The system will automatically inform the study monitor for the site and the study team that 
the code has been broken. The local Novartis CPO (or any entity to which there has been 
delegation for the emergency code breaks) needs to be contacted. It is the investigator’s 
responsibility to ensure that there is a procedure in place to allow access to the IRT in case of 
emergency. If appropriate, the investigator will inform the subject how to contact his/her 
backup in cases of emergency when he/she is unavailable. 
An assessment will be done by the appropriate site personnel and the sponsor  after an 
emergency unblinding to assess whether or not study drug should be discontinued for a given 
subject and, if applicable, whether the subject can continue into the next trial phase (e.g, the 
extension study). 
6.8 
Treatment exposure and compliance 
PK parameters (measures of treatment exposure) will be determined in all subjects treated 
with QCC374, as detailed in Section 8.7. 
6.9 
Recommended treatment of adverse events 
Since QCC374 is an inhaled prostacyclin receptor agonist, subjects enrolled in this study may 
experience typical prostacyclin-associated adverse events, including headache, jaw pain, and 
flushing. If a subject experiences these adverse events, the subject may use standard of care 
therapy, including non-opioid analgesics, to relieve any associated symptoms. 
In addition, given the inhaled route of administration, there is a risk of local irritation within 
the airway, including coughing or wheezing. If a subject experiences significant coughing or 
respiratory symptoms during the study period, the site Investigator should use standard of care 
therapy, including a short-acting beta-agonist, to relieve symptoms. 
Medication used to treat AEs must be recorded on the  Concomitant medications/Significant 
non-drug therapies CRF. 
6.10 
Rescue medication 
Rescue medication is defined as an additional medication, or change in the dose of an existing 
medication, for the treatment of PAH. A clinical worsening of PAH requiring a change in 
dose of an existing PAH specific  medication, or the addition of a new PAH specific 
medication, is criteria for discontinuation for study treatment as described in Section 7.2. PAH 
specific medications include: all endothelin receptor antagonists, phosphodiesterase 5 


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inhibitors, soluble guanylate cyclase inhibitors and oral, intravenous or subcutaneous 
prostacyclins. 
Use of rescue medication must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF after signing the informed consent. 
6.11 
Concomitant treatment 
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the 
timeframe defined in the entry criteria prior to the start of the study and during the study, must be 
recorded on the Concomitant medications/Significant non-drug therapies section of the CRF. 
Medication entries should be specific to trade name, the single dose and unit, the frequency 
and route of administration, the start and discontinuation date and the reason for therapy. 
If present for at least 3 months before screening and during the screening period, at a stable dose, 
which should remain unchanged during the study, the following treatments for PAH are allowed: 
Oral phosphodiesterase inhibitors (e.g., sildenafil) or soluble guanylate cyclase inhibitor 
(riociguat) 
Endothelin receptor antagonists 
It is not allowed to modify the dose or type of concomitant PAH therapy during the screening 
period or treatment period of the study. In the event of a clinically relevant deterioration of the 
patient
's signs or symptoms of PAH, the investigator should determine whether a change to 
the concomitant PAH therapy is indicated based on the patient
's well-being and safety. If so, 
the reason for this decision should be documented in the CRF. An adjustment in the dose of a 
diuretic is allowed and should be documented as described in Section 6.10. Calcium channel 
blockers are allowed, but patients with PAH responsive to high dose calcium channel blockers 
should not be enrolled as described in exclusion criterion  #2. Patients who require a 
modification of their concomitant PAH therapy during the screening or treatment period must 
discontinue study treatment. 
7 
Study completion and discontinuation 
7.1 
Study completion and post-study treatment 
Each subject will be required to complete the study in its entirety and thereafter the subject 
will have the opportunity to enroll in the QCC374X2201E1  extension study protocol. 
Study completion for this trial is defined as when the last subject completes their end of study 
(EOS) visit, and any repeat assessments associated with this visit have been documented and 
followed-up appropriately by the Investigator, or in the event of an early study termination 
decision, the date of that decision. If the subject wishes to continue into the extension study, 
the subject
's last visit is on Day 112. 
Patients who agree to participate in the extension study may be unblinded on Study Day 111. 
For those patients who are on placebo, the completion of PK assessment on Study Day 112 is 
required in order to conduct bioanalysis to confirm lack of drug exposure and also have 
exposure data to explain if there are any drug-related safety findings in the subject 


 
 
  
     
 
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For subjects who do not wish to participate in the extension study protocol, at a minimum, 
they will be contacted for safety evaluations during the 30 days following the Study 
Completion visit, including a final post-study safety contact at the 30-day point. 
Documentation of attempts to contact the subject should be recorded in the source 
documentation. All SAEs reported during this time period must be reported as described in 
the SOM. 
7.2 
Discontinuation of study treatment 
Subjects may voluntarily discontinue study treatment for any reason at any time. 
The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would be detrimental to the subject
's well-being. 
Study treatment mustbe discontinued under any of the following circumstances and the 
reason for discontinuation must be indicated on the CRF: 
Subjects withdraws consent 
Pregnancy (see Section 8.6 (Safety) and Section 9.6 (Pregnancy reporting)) 
Clinically significant bronchospasm reflected in spirometry assessments believed to be 
related to study drug 
Occurrence of adverse events which the investigator or sponsor judges unacceptable for 
continuation of participation in the study 
Non-compliance with the conditions of the trial and/or instructions by the investigator 
which could jeopardize the subject
's safety or integrity of study results 
Use of prohibited treatment as per Section 5.2. 
Clinical worsening of PAH: 
A persistent decrease in 6MWD of more than 15% from baseline, confirmed by two 
tests on different days, believed to be due to worsening of underlying PAH* 
Hospitalization due to persistent worsening of PAH* 
The need for new PAH specific treatment or an adjustment in dose or type of an 
existing specific PAH treatment (PAH specific medications include: all endothelin 
receptor antagonists, phosphodiesterase 5 inhibitors, soluble guanylate cyclase 
inhibitors and oral, intravenous or subcutaneous prostacyclins.)* 
*In the event of clinical deterioration the investigator must carefully assess if the deterioration 
of the subject
's condition is related to the underlying pulmonary hypertension or can be 
explained by an  alternative cause (e.g. transient infection, surgical or medical intervention 
other than PH related, musculoskeletal disease) and document this determination in the CRF. 
The appropriate personnel from the site and Novartis will assess whether study treatment 
should be discontinued for any patient whose treatment code has been  broken inadvertently 
for any reason. 


 
 
 
 
   
 
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Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 7.3). If they fail to return for these assessments for unknown 
reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact them as 
specified in Section 7.4. 
7.3 
Withdrawal of informed consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject: 
Does not want to participate in the study anymore, and 
Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, 
letter) to understand the primary reason for the subject’s decision to withdraw his/her consent 
and record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their time of withdrawal) according to 
applicable law. 
For US: All biological samples not yet analyzed at the time of withdrawal may still be used 
for further testing/analysis in accordance with the terms of this protocol and of the informed 
consent form. 
For EU ans ROW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to 
applicable legal requirements. 
7.4 
Lost to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered  
letters, etc. A subject should not be formally considered lost to 
follow-up until his/her scheduled end of study visit would have occurred. 


 
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7.5 
Study Stopping rules 
The study will be placed on hold and no further enrollment of subjects will occur pending a 
full safety review if any of the following criteria are met: 
The principal investigator (or his designee) and the sponsor consider that the number 
and/or severity of adverse events may justify discontinuation of the study 
A safety concern is identified, either during the ongoing safety review conducted by the 
sponsor of this study or for the extension study QCC374X2201E1, which may justify 
discontinuation of the study 
The sponsor unilaterally requests it 
Any subjects currently being dosed in QCC374X2201 or QCC374X2201E1 will be allowed to 
continue dosing during the safety review,  as long as they have not met an individual 
discontinuation rule. 
7.6 
Early study termination by the sponsor 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
subjects should be seen as soon as possible and treated as a prematurely withdrawn subject. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the subject’s interests. 
The investigator will be responsible for informing IRBs/IECs of the early termination of the 
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8 
Procedures and assessments 
8.1 
Assessment schedule 
Table 8-1 
Part 1 Assessment Schedule 
Epoch 
Screening 
Treatment4 
Post Treatment Follow Up 
Visit Name Screening Baseline 
Titration 
Stable Dose Follow Up 
Termination 
Visit 
EOS Visit (28 days post 
last treatment) 
Visit Numbers1 
1 
22 
1012 
102 103 1043 105 106 107 1082 
1092,5 
2016 
2027 
Study Day(s) -28 to -2 
-1 
1 
4 
7 
±1 
14 
±1 
28 
±2 
56 
±2 
84 
±2 
111 
±2 
112 
±2 
113 
140 
Time (post-dose) 
-
-
0m 15m 30m 2h 4h -
-
-
-
-
-
-
0m 12h 
-
-
Informed consent 
X 
X 
Medical history/current medical 
conditions 
X 
Demography 
X 
Inclusion / Exclusion criteria 
X 
X 
X 
Randomization 
X 
Physical examination 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetry 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body height 
X 
Body weight 
X 
X 
X 
Hepatitis screen 
S8 
HIV screen 
S8 
Alcohol Test, Drug Screen, 
and Cotinine Test 
S
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8 


 
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Epoch 
Screening 
Treatment4 
Post Treatment Follow Up 
Visit Name Screening Baseline 
Titration 
Stable Dose Follow Up 
Termination 
Visit 
EOS Visit (28 days post 
last treatment) 
Visit Numbers1 
1 
22 
1012 
102 103 1043 105 106 107 1082 
1092,5 
2016 
2027 
Study Day(s) -28 to -2 
-1 
1 
4 
7 
±1 
14 
±1 
28 
±2 
56 
±2 
84 
±2 
111 
±2 
112 
±2 
113 
140 
Time (post-dose) 
-
-
0m 15m 30m 2h 4h -
-
-
-
-
-
-
0m 12h 
-
-
Pregnancy test 
X9 
X10 
X10 
Blood chemistry 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
Spirometry 
X 
X 
X11 X X 
X 
X 
X 
X 
X 
X 
X 
X 
Lung Volumes/DLCO 
X 
ECG evaluation 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
6-Minute Walk Test 
X12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest X-ray 
X13 
X14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Echocardiogram 
X15 
X 
X 
Right heart catheterization 
X16 
X 
Drug dispensation 
X 
X 
X 
X 
X 
X 
X 
Study drug administration 
Study Drug Administration will be bid -refer to Section 3.1 
Corporate Confidential 
Information
and Site 
Operations Manual 
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Information
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Epoch 
Screening 
Treatment4 
Post Treatment Follow Up 
Visit Name Screening Baseline 
Titration 
Stable Dose Follow Up 
Termination 
Visit 
EOS Visit (28 days post 
last treatment) 
Visit Numbers1 
1 
22 
1012 
102 103 1043 105 106 107 1082 
1092,5 
2016 
2027 
Study Day(s) -28 to -2 
-1 
1 
4 
7 
±1 
14 
±1 
28 
±2 
56 
±2 
84 
±2 
111 
±2 
112 
±2 
113 
140 
Time (post-dose) 
-
-
0m 15m 30m 2h 4h -
-
-
-
-
-
-
0m 12h 
-
-
X17 
PK blood collection18 
See Table 8-2 below 
Study/Epoch completion 
information 
X 
X 
X 
Concomitant medications 
As Required 
Adverse events 
As Required 
Serious adverse events 
As Required 
Comments 
Corporate Confidential 
Information
As Required 


  
  
  
  
  
  
      
    
  
  
 
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1 Visit structure given for internal programming purpose only
2 Domiciled in Clinic (optional)
3 If the subject was up-titrated at the Day 14 visit, a phone call for follow-up on subject safety and tolerability should be conducted 7 days later. 
4 If a patient needs to stop study medication prematurely (for example, due to worsening of underlying PAH), then an attempt should be made to complete the Day 113 
assessments, including a Blood Chemistry, Blood Hematology and Echocardiogram (unless these assessments were completed on Day 111). The investigator is 
responsible for making determination of what is safe and feasible. At a minimum, a safety evaluation must be completed. 
5 Visit 109 (Day 112) must occur 1 day after Visit 108 (Day 111)
6 This visit is only for subjects who have completed the study treatment (Day 112) and do not wish to participate in Extension Study, or for subjects who discontinue study 
treatment early.
7 This 28 days post last treatment follow up visit is for those subjects who have either prematurely stopped study treatment, or those subjects who completed the study 
treatment, but do not wish to participate in the extension study. 
8 The results of this assessment will only be recorded in the source data 
9 Serum Pregnancy Test
10 Urine Pregnancy Test
11 Within 2 hours after dose. 
12 During screening at least two 6MWT must be performed at least 2 hours apart. The two values must be within 15% of one another. Additional 6MWT may be performed 
until two consecutive 6MWDs are within 15% of on another (maximum of 4 tests performed). 
13 Chest X-ray needs to be completed prior to randomization, but Chest X-ray post RHC can be used (if part of standard of care follow-up) 
14 This to be completed post RHC
15 Echocardiogram can be completed any time during Day -21 to Day -1 
16 The baseline RHC can be completed any time from Day -28 to Day -1. If the subject has a historical RHC within one month of the screening visit, this result can be used 
Corporate Confidential Information
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Table 8-2 
Part 1 PK blood collection 
Epoch 
Visit Name 
Visit Numbers 
Day 
Time (post-dose) 
PK blood collection 
Treatment 
Titration 
101 
1 
0m 
X 
5m 
X 
15m 
X 
30m 
X 
1h 
X 
2h 
X 
4h 
X 
8h 
X 
12h 
X 
Stable Dose Follow Up 
109 
112 
-2 +2 
0m 
X 
5m 
X 
15m 
X 
30m 
X 
1h 
X 
2h 
X 
4h 
X 
8h 
X 
12h 
X 
NOTE: Additional visit information can be found in Table 8-1 


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Table 8-3 
Part 2 Assessment Schedule 
Epoch 
Screening 
Treatment4 
Post Treatment Follow Up 
Visit Name Screening Baseline 
Titration 
Stable Dose Follow Up 
Termination 
Visit 
EOS Visit (28 days post 
last treatment) 
Visit Numbers1 
1 
22 
1012 
103 1043 105 106 107 1082 1092,5 
2016 
2027 
Study Day(s) -28 to -2 
-1 
1 
7 
±1 
14 
±1 
28 
±2 
56 
±2 
84 
±2 
111 
±2 
112 
±2 
113 
140 
Time (post-dose) 
-
-
0m 15m 30m 2h 4h -
-
-
-
-
-
0m 
-
-
Informed consent 
X 
X 
Medical history/current medical 
conditions 
X 
Demography 
X 
Inclusion / Exclusion criteria 
X 
X 
X 
Randomization 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X19 X19 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body height 
X 
Body weight 
X 
X 
X 
X 
Hepatitis screen 
S8 
HIV screen 
S8 
Alcohol Test, Drug Screen, and 
Cotinine Test 
S8 
Pregnancy test 
X9 
X10 
X10 
X10 
Blood chemistry 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
Spirometry 
X 
X 
X11 X 
X 
X 
X 
X 
X 
X 
X 
Corporate Confidential 
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X 


 
 
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Epoch 
Screening 
Treatment4 
Post Treatment Follow Up 
Visit Name Screening Baseline 
Titration 
Stable Dose Follow Up 
Termination 
Visit 
EOS Visit (28 days post 
last treatment) 
Visit Numbers1 
1 
22 
1012 
103 1043 105 106 107 1082 1092,5 
2016 
2027 
Study Day(s) -28 to -2 
-1 
1 
7 
±1 
14 
±1 
28 
±2 
56 
±2 
84 
±2 
111 
±2 
112 
±2 
113 
140 
Time (post-dose) 
-
-
0m 15m 30m 2h 4h -
-
-
-
-
-
0m 
-
-
Lung Volumes/DLCO 
X 
ECG evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6-Minute Walk Test 
X12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest X-ray 
X13 
X14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Echocardiogram 
X15 
X 
X 
Right heart catheterization 
X16 
X 
Drug dispensation 
X 
X 
X 
X 
X 
X 
Study drug administration20 
Study Drug Administration will be bid -refer to Section 3.1 and Site 
Operations Manual 
X17 
PK blood collection18 
See Table 8-4 
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Information
below 
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Information
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Corporate Confidential 
Information


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Protocol No. CQCC374X2201
Epoch 
Screening 
Treatment4 
Post Treatment Follow Up 
Visit Name Screening Baseline 
Titration 
Stable Dose Follow Up 
Termination 
Visit 
EOS Visit (28 days post 
last treatment) 
Visit Numbers1 
1 
22 
1012 
103 1043 105 106 107 1082 1092,5 
2016 
2027 
Study Day(s) -28 to -2 
-1 
1 
7 
±1 
14 
±1 
28 
±2 
56 
±2 
84 
±2 
111 
±2 
112 
±2 
113 
140 
Time (post-dose) 
-
-
0m 15m 30m 2h 4h -
-
-
-
-
-
0m 
-
-
Study/Epoch completion 
information 
X 
X 
X 
Concomitant medications 
As required 
Adverse events 
As required 
Serious adverse events 
As required 
Comments 
As required 


  
   
  
  
  
  
      
    
  
  
 
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1 Visit structure given for internal programming purpose only
2 Domiciled in Clinic (optional)
3 If the subject was up-titrated at the Day 14 visit, a phone call for follow-up on subject safety and tolerability should be conducted 7 days later. 
4 If a patient needs to stop study medication prematurely (for example, due to worsening of underlying PAH), then an attempt should be made to complete the Day 113 
assessments, including a Blood Chemistry, Blood Hematology and Echocardiogram (unless these assessments were completed on Day 111). The investigator is 
responsible for making determination of what is safe and feasible. At a minimum, a safety evaluation must be completed.
5 Visit 109 (Day 112) must occur 1 day after Visit 108 (Day 111)
6 This visit is only for subjects who discontinue study 
treatment early.
7 This 28 days post last treatment follow up visit is for those subjects who have either prematurely stopped study treatment, or those subjects who completed the study 
treatment, but do not wish to participate in the extension study. 
8 The results of this assessment will only be recorded in the source data 
9 Serum Pregnancy Test
10 Urine Pregnancy Test
11 Within 2 hours after dose. 
12 During screening at least two 6MWT must be performed at least 2 hours apart. The two values must be within 15% of one another. Additional 6MWT may be performed 
until two consecutive 6MWDs are within 15% of on another (maximum of 4 tests performed). 
13 Chest X-ray needs to be completed prior to randomization, but Chest X-ray post RHC can be used (if part of standard of care follow-up) 
14 This to be completed post RHC
15 Echocardiogram can be completed any time during Day -21 to Day -1 
16 The baseline RHC can be completed any time from Day -28 to Day -1. If the subject has a historical RHC within one month of the screening visit, this result can be used 
For all follow-up visits, the PK sample collection will take place during the visit, but the subject must record time of morning dose. 
19 Blood pressure should be collected in the sitting position and then repeated after 3 minutes in the standing position. 
20 For patients who performed Visit 108 (Day 111) and do not wish to continue into the extension study, the last dose administration will be the morning dose on Visit 109, 
Corporate Confidential Information
with no dose administration in the afternoon. 


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Table 8-4 
Part 2 PK blood collection 
Epoch 
Visit Name 
Visit Numbers 
Day 
Time (post-dose) 
PK blood collection 
Treatment 
Titration 
101 
1 
0m 
X 
5m 
X 
15m 
X 
30m 
X 
1h 
X 
2h 
X 
4h 
X 
8h 
X 
Stable Dose Follow Up 
109 
112 
-2 +2 
0m 
X 
5m 
X 
15m 
X 
30m 
X 
1h 
X 
2h 
X 
4h 
X 
8h 
X 
NOTE: Additional visit information can be found in Table 8-3 


 
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8.2 
Informed consent procedures 
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
The date of signing of informed consent  (and withdrawal, if later withdrawn) should be 
documented in the CRF. 
Novartis will provide to investigators a proposed informed  consent form that complies with 
the ICH Good Clinical Practice  (GCP) guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC. 
In the event that Novartis wants to perform testing on the samples that are not described in 
this protocol, additional Institutional Review Board and/or Ethics Committee approval will be 
obtained. 
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval. 
8.3 
Subject screening 
Information on screening procedures and data collected for Screen Failures can be found in 
the Study Operational Manual. In general it may be allowed to re-screen a subject once if s/he 
fails the initial screening; however, each case must be discussed and agreed with the Sponsor 
on a case-by-case basis. 
8.4 
Subject demographics/other baseline characteristics 
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Subject demographic and baseline characteristic data will be collected on all subjects. 
Relevant medical history/current medical conditions data includes data until signature of 
informed consent. Details are outlined in the SOM. When possible, diagnoses and not 
symptoms should be recorded. Investigators have the discretion to record abnormal test 
findings on the medical history CRF whenever in their judgment, the test abnormality 
occurred prior to the informed consent signature. 


 
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8.5 
Efficacy / Pharmacodynamics 
Pharmacodynamic assessments are specified below, with the methods for assessment and 
recording specified in the SOM. Assessments will be performed/samples collected at the time 
point(s) defined in the Assessment schedule (Section 8.1). 
In order to better define the PD profile, the timing of the sample collection may be altered 
based on  emergent data. The number of samples/blood draws and total blood volume 
collected will not exceed those stated in the protocol. 
8.5.1 
Right Heart Catheterization 
The RHC assessment is performed to assess several hemodynamic variables in pulmonary 
hypertension, including mPAP, PCWP, CO, PVR and Systemic Vascular Resistance (SVR). 
RHC will be performed according to the local hospital procedures. 
Concomitant PAH medications that could affect hemodynamic measurements, including 
endothelin receptor antagonists, phosphodiesterase inhibitors, soluble guanylate cyclase 
inhibitors and diuretics, will be taken on a standard schedule relative to the timing of the 
RHC. When possible, these medications should be taken at least 60 minutes prior to the 
start of the procedure. Exact timing of dosing should be recorded in the source document 
for catheterization. The timing of a patient’s concomitant medication relative to 
catheterization should be the same for the subsequent catheterization. 
The Week 16 RHC should occur after the QCC374 morning dose (2-4 hours post dose) 
The following hemodynamic parameters will be assessed when the patient is in a stable 
hemodynamic rest state (as demonstrated by three consecutive CO measurements within 
10% of each other) while the patient is breathing ambient air or oxygen:
RA, mPAP, PCWP, systolic and diastolic blood pressure, HR
CO (measured in triplicate by the thermodilution technique)
Mixed venous blood gas measurement 
Thermodilution is the preferred technique for measurement of hemodynamic parameters. 
The direct Fick technique may be used only with prior discussion and written approval 
from the Sponsor. In all cases, the same technique must be used for the baseline and week 
16 RHC measurements. 
The following parameters will be derived from the CO measurement: 
SVR in dyn·s/cm5 
PVR in dyn·s/cm5 
Additional instructions for RHC procedures can be found in the SOM. 


 
 
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8.5.2 
Echocardiography 
For the assessment of the impact of QCC374 on right and left heart structure and function, 
echocardiography will be performed based on the clinical practice and local regulation. 
The duration between an acceptable baseline scan and initiation of dosing will be less than 21 
days. In all  patients, the baseline and follow-up imaging will be performed where possible 
using the same ultrasound scanner. The methods for assessment and recording are specified in 
the imaging manual/charter. 
The coded medical images will be used primarily for analysis as described in this protocol; 
however, the images may also be used for the development and evaluation of new analysis 
methods directly related to the area of research that this study covers. 
8.5.3 
6-Minute Walk Test 
A standardized 6MWT will be performed in accordance with ATS guidelines  
(ATS 2002). 
The 6MWT measures how many meters a person can walk in 6 minutes. Repeated 
measurement of the 6MWT over time has been used in studying numerous musculoskeletal, 
pulmonary, and cardiovascular conditions and is a validated outcome in investigational drug 
trials. 
For the Borg score component, the patient will answer questions on a scale of one to ten in 
order to determine the patient
's shortness of breath during the 6MWT. During the 6MWT the 
patient will be connected to a portable pulse oximeter via a finger probe and oximetry results 
will be monitored. As soon as the test is complete, the patient will be asked to sit down and 
the SaO2, HR and Borg score values will be recorded. 
Patients resting values of oxygen saturation (%), heart rate (b/min), blood pressure and Borg 
score will be recorded in the CRF before the test, at the end of the test and two minutes after 
the end of the test. Total distance walked (meters), the number and duration of any stops and 
whether the patient completed the test will also be recorded in the CRF. 
Requirement of rescue medication including oxygen therapy and any adverse events occurring 
during the 6MWT will be recorded. If the patient is on chronic oxygen therapy, oxygen 
should be given at the standard rate (and at the same rate during each 6MWT procedure) or as 
directed by the investigator. 
During screening at least two 6MWT must be performed at least 2 hours apart. The two 
values must be within 15% of one another. Additional 6MWT may be performed until two 
consecutive 6MWDs are within 15% of on another (maximum of 4 tests performed). 
The site should record the values of both qualifying 6MWT in the CRF. The average of the 
two consecutive qualifying tests will be used as the baseline. 
After screening, single 6MWTs will be performed according the Assessment schedule 
(Section 8.1). Every attempt should be made to conduct the 6MWT at about the same time of 
day. 
Additional information on this assessment can be found in the SOM. 


 
 
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8.6 
Safety 
Safety assessments are specified below; methods for assessment and recording are specified in 
the SOM, with the Assessment Schedule (Section 8.1) detailing when each assessment is to be 
performed. 
8.6.1 
Spirometry 
Spirometry testing will be performed according to the American Thoracic Society guidelines 
(Miller et al 2005) at screening to assess patients’ eligibility for the study and as detailed in 
the Assessment schedule (Section 8.1). 
The spirometry equipment will be supplied for the study. The same spirometry equipment 
should be used for all assessments performed by a subject.  A limited number of staff, as 
designated by the investigator, will evaluate all patients at all visits throughout the entire trial. 
Where possible the same technician should perform all maneuvers for an individual subject. 
All staff conducting the spirometry tests must have received appropriate training which must 
be documented. Information on the procedures can be found in the SOM. 
8.6.2 
Chest X-ray 
Standard CXR will be performed except for those who have had a valid X-ray done within 
6 months of the screening visit to confirm eligibility. During the trial, there may be standard 
CXRs completed at the time of the RHC (if part of site’s standard of care follow-up). 
8.6.3 
Physical examination 
Information can be found in the SOM. 
8.6.4 
Vital signs 
At multiple time points referenced in the Assessment Schedule (Section 8.1), Blood Pressure, 
Pulse and Body Temperature will need to be recorded. 
8.6.5 
Pulse oximetry 
Oxygen saturations (%) will be measured by pulse oximetry using a SpO2 finger sensor. 
The timing of the assessments can be found in the Assessment Schedule (Section  8.1) and 
results will be recorded in the CRFs. 
8.6.6 
Height and weight 
Height and weight will need to be recorded as referenced in  the Assessment Schedule 
(Section 8.1). 
8.6.7 
Laboratory evaluations 
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and discussed with Novartis personnel. The results should be 
evaluated for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted. 


 
 
 
 
    
    
    
     
 
 
 
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Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential and 
platelet count will be measured. In addition, aPTT and PT and INR will be assessed. 
Clinical chemistry 
Sodium, potassium, creatinine, urea, uric acid, chloride, albumin, calcium, alkaline 
phosphatase, total bilirubin, LDH, GGT, AST, ALT, CK, glucose, total cholesterol, 
triglycerides. If the total bilirubin concentration is increased above 1.5 times the upper limit of 
normal, direct and indirect reacting bilirubin should be differentiated. 
Urinalysis 
Urine test by dipstick e.g. Combur9: leucocytes, nitrite, pH, protein, glucose, ketones, 
urobilinogen, bilirubin, hemoglobin 
If the dipstick result is positive for protein, nitrite, leucocytes and/or blood, the sample will be 
sent for microscopic analysis of white blood cells, red blood cells and casts. 
8.6.8 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have pregnancy testing.  
See the Assessment  schedule (Section 8.1), for timing of the protocol required pregnancy 
testing; additional pregnancy testing may be performed to meet local requirements.   
A positive urine pregnancy test must be immediately confirmed with a serum β-hCG, and if 
the serum β-hCG is found to be positive, study treatment must be discontinued. 
Refer to Section 9.6 for details on Reporting Pregnancy. 
8.6.9 
Lung Volumes and DLCO 
Lung volumes and DLCO measurements will be determined according to ATS guidelines 
(Wanger et al 2005, MacIntyre et al 2005). Detailed procedures for lung volume and DLCO 
acquisition are provided in the SOM. 
8.6.10 ECG 
ECGs will be assessed locally. Full details of all procedures relating to the ECG collection 
and reporting are contained in the SOM. 
8.7 
Pharmacokinetics 
All subjects who receive QCC374 (or matching placebo) will have blood samples collected as 
outlined in Table 8-2 and Table 8-4 (Section 8.1). Blood sampling times need to be adhered to 
sampling schedules. 
In order to better define the PK profile, the timing of the PK sample collection may be altered 
based on  emergent data. The number of samples/blood draws and total blood volume 
collected will not exceed those stated in the protocol. 


 
 
   
  
 
 
 
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8.7.1 
PK Sample Collection 
All samples will be given a unique sample number and a collection number (as listed in 
Table 8-2 and Table 8-4, Section  8.1). Each site is to ensure the correct sample number is 
reflected on the respective tube. The actual sample collection time will be entered on the PK 
blood collection page of the CRF. Any problems with sampling will be documented within 
the CRFs. 
Further details on sample collection, numbering, processing and shipment can be found in the SOM. 
8.7.2 
Bioanalytical Method 
QCC374 and QCM441 concentrations in plasma samples will be determined by a validated 
LC-MS/MS method; the Lower Limit of Quantification (LLOQ) is 5 pg/mL for QCC374 and 
20 pg/mL for QCM441. Biofluid concentrations will be expressed in mass per volume units 
and referring to the free base. Missing data will be labelled as such in the concentration data 
listings. Concentrations below LLOQ will be treated as zero in summary statistics for 
concentration data as well as for calculation of PK parameters. 
Untreated samples (placebo) will not be analyzed. 
PK samples remaining after completion of the determination of QCC374 and QCM441 may 
be used for exploratory assessment of metabolites or other bioanalytical purposes (e.g. cross 
check between different sites, stability assessment). Given the exploratory nature of the work, 
the analytical method used for those assessments will not be validated and results will not be 
reported in the clinical study report (CSR). 
8.7.3 
Calculation of PK Parameters 
For standard pharmacokinetic abbreviations and definitions see the list provided at the 
beginning of this protocol. 
The 
following pharmacokinetic 
parameters 
of 
QCC374 
and 
QCM441 
(where possible/applicable) will be determined using the actual recorded sampling times and 
non-compartmental method(s) with Phoenix WinNonlin (Version 6.2 or higher): 
Primary: Cmax, Tmax, AUClast, AUCtau for Day 1 and Day 112 
Secondary: Tlast, T1/2, Tmin, Cmin, fluctuation index, Cav, Vz/F (QCC374 only) and CL/F 
(QCC374 only) for Day 1 and Day 112. 
Additional parameters may be determined if appropriate. To denote parameters determined at 
steady state "ss" will be used. The parameters AUClast, AUCtau, and Cmax will be 
transferred into molar units using the molecular weight of QCC374 (443.58 g/mol) and 
QCM441 (415.23 g/mol) to enable the exposure comparison between the two analytes. 
The linear trapezoidal rule will be used for AUC calculation. Regression analysis of the 
terminal plasma elimination phase for the determination of T1/2 will include at least 3 data 
points after Cmax. If the adjusted R2 value of the regression analysis of the terminal phase 
will be less than 0.75 and the extrapolated AUC will be greater than 20%, no values will be 
reported for AUCtau, T1/2, CL/F, and Vz/F. 


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1


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9 
Safety monitoring 
9.1 
Adverse events 
An AE is any untoward medical occurrence (i.e., any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a subject or clinical 
investigation subject after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
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The occurrence of adverse events should be sought by non-directive questioning of the subject 
at each visit during the study. AEs also may be detected when they are volunteered by the 
subject during or between visits or  through physical examination, laboratory test, or other 
assessments. 


 
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Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:
they induce clinical signs or symptoms,
they are considered clinically significant,
they require therapy.
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for liver related events are included in 
Section 9.3.
Adverse events must be recorded on the Adverse Events CRF for subjects that have been 
randomized into the study. The adverse events should be reported according to the signs, 
symptoms or diagnosis associated with them, and accompanied by the following information:
1.The severity grade: 
mild: usually transient in nature and generally not interfering with normal activities 
moderate: sufficiently discomforting to interfere with normal activities 
severe: prevents normal activities 
2.Relationship to the study treatment 
3.Duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved should be reported. 
4.Whether it constitutes a serious adverse event (SAE). See Section 9.2 for definition of 
SAE. 
5.Action taken regarding study treatment. All adverse events should be treated appropriately. 
Treatment may include one or more of the following: 
no action taken (i.e. further observation only) 
study treatment dosage adjusted/temporarily interrupted 
study treatment permanently discontinued due to this adverse event 
concomitant medication given 
non-drug therapy given
subject hospitalized/subject’s hospitalization prolonged
6.Outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown). 
Once an adverse  event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications (IN). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. 


 
  
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The investigator should also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the  subject’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents, however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis. 
9.2 
Serious adverse event reporting 
9.2.1 
Definition of SAE 
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria: 
is fatal or life-threatening 
results in persistent or significant disability/incapacity 
constitutes a congenital anomaly/birth defect 
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
elective or pre-planned treatment for a pre-existing condition (that is unrelated to the 
indication under study) and has not worsened since the start of study drug 
treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
is medically significant, i.e. defined as an event that jeopardizes the subject or may require 
medical or surgical intervention. 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical  events that might not be 
immediately life threatening or result in death or hospitalization  but might jeopardize the 
patient or might require  intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse. 


   
 
  
   
 
 
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All AEs (serious and non-serious) are captured on the CRF and SAEs also require individual 
reporting to the Drug Safety and Epidemiology Department as per Section 9.2.2. 
9.2.2 
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence as described below. Any SAEs 
experienced after this should only be reported to Novartis if the investigator suspects a causal 
relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of  when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
SAEs (initial and follow-up) that are recorded electronically in the Electronic Data Capture 
system should be entered, saved  and e-signed within 24 hours of awareness of the SAE or 
changes to an existing SAE. These data will automatically be submitted to Novartis Drug 
Safety & Epidemiology  immediately after investigator signature or 24 hours after entry, 
whichever occurs first. Study site personnel must also inform the Clinical Trial Leader. 
Follow-up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. 
If the SAE is not previously documented in the Investigator’s Brochure and is thought to be 
related to the investigational treatment a Drug Safety and Epidemiology Department associate 
may urgently require further information from the investigator for Health Authority reporting. 
Novartis may need to issue an IN to inform all investigators involved in any study with the 
same investigational treatment that this SAE has been reported. Suspected Unexpected 
Serious Adverse Reactions (SUSARs) will be collected and reported  to the  competent 
authorities and relevant ethics committees in accordance with EU Guidance 2011/C 172/01 or 
as per national regulatory requirements in participating countries. 
Note: SAEs reported by subjects deemed to be screen failures must be reported to Novartis as 
outlined here, with appropriate information also captured in the CRFs as specified in the SOM. 
9.3 
Liver safety monitoring 
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification,  monitoring and evaluation of 
liver events has to be followed. 
Please refer to Table 15-1-Appendix 1 for complete definitions of liver events. 


 
 
 
 
  
 
        
  
    
   
   
  
 
  
  
    
   
 
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Follow-up of liver events 
Every liver event defined in Table 15-1-Appendix 1 should be followed up by the investigator 
or designated personnel at the trial site, as summarized below. Additional details on actions 
required in case of liver events are outlined in Table 15-2-Appendix 1. 
Repeating liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and γGT) to confirm 
elevation within 48-72 hours. 
These LFT repeats should be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory should then be performed at central laboratory as soon as possible. 
If a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event should be reported on the appropriate CRF pages. 
If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
Discontinuation of the investigational drug (refer to Section 7.2 Discontinuation of study 
treatment), if appropriate 
Hospitalization of the subject if appropriate 
Causality assessment of the liver event 
Thorough follow-up of the liver event should include 
Repeating liver chemistry tests two or three times weekly. Testing should include 
ALT, AST, ALP, PT/INR, and γGT. If total bilirubin is elevated > 2 x ULN, 
fractionation into direct and indirect bilirubin is required. To rule out muscular origin 
of transaminase elevations, CPK should be measured along with liver chemistry tests. 
Frequency of retesting can decrease to once a week or less if abnormalities stabilize 
or the study drug has been discontinued and the subject is asymptomatic. 
Retesting should be continued up to resolution. 
Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets. 
Exclusion of underlying liver disease, as specified in Table 15-3.
Imaging such as abdominal US, CT or MRI, as appropriate
Obtaining a history of exposure to environmental chemical agents. 
Considering gastroenterology or hepatology consultations. 
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. 
9.4 
Renal safety monitoring 
Every renal laboratory trigger or renal event must be followed up by the investigator or 
designated personnel at the trial site.  Recommended  follow-up assessments are listed in 
Appendix 2. 


  
 
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9.5 
Reporting Medication errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing,  administration or 
monitoring of a medicine while under the control of a healthcare  professional, subject or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic,  intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects but should not be 
applicable in this single dose study where treatment is administered under supervision of site 
staff. 
All study treatment errors and uses outside of what is foreseen in the protocol will be 
collected in the dose administration record. Study treatment errors are only to be reported to 
Novartis Drug Safety and Epidemiology department if the treatment error is associated with 
an SAE. 
All instances of misuse or abuse must be documented in the Adverse Event CRF irrespective 
of the misuse/abuse being associated with an AE/SAE. In addition, all instances of misuse or 
abuse must be reported to Novartis Drug Safety and Epidemiology. As such,  instances of 
misuse or abuse are also to be reported using the SAE form/CRF. Table 9-1 summarizes the 
reporting requirements. 
Table 9-1  
Summary of reporting requirements for medication errors 
Treatment error type 
Document in Dose 
Administration CRF 
Document in AE CRF 
Complete SAE form/CRF 
Unintentional study 
treatment error 
Yes 
Only if associated with an 
AE 
Only if associated with an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not associated with a 
SAE 
For more information on AE and SAE definition and reporting requirements, please 
see Section 9.1 and Section 9.2, respectively. 
9.6 
Pregnancy reporting 
To ensure patient safety, each pregnancy in a subject on study drug must be reported to 
Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up 
to determine outcome, including spontaneous or voluntary termination, details of the birth, 
and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. The study drug must be discontinued, though the subject may stay in 
the study, if she wishes to do so. All assessments that are considered as a risk during 
pregnancy must not be performed. The subject may continue all other protocol assessments. 
Pregnancy must be recorded on a Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the Novartis study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on an SAE Report Form. 


 
 
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9.7 
Early phase safety monitoring 
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. 
When two or more clinical site(s) are participating in the clinical study, the Sponsor will 
advise the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any 
new, clinically relevant safety information reported from another site during the conduct of 
the study in a timely manner. 
10 
Data review and database management 
10.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. 
During the study Novartis employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. The monitor will visit the site to check 
the completeness of subject records, the accuracy of entries on the CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
drug is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the monitor during these visits. 
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All  
information on CRFs must be traceable to these source documents in the 
subject
's file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the eligibility criteria, documentation of 
SAEs, and the recording of data that will be used for all primary and safety variables. 
Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about 
the identity of the subjects will be disclosed. 
10.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the CRF using 
fully validated software that conforms to 21 CFR Part 11 requirements. Designated 
investigator site staff will not be given access to the electronic data capture system until they 
have  been trained. Automatic validation programs check for data discrepancies and, by 
generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the contract research organization (CRO) working on behalf of Novartis. 
The Investigator must certify that the data entered into the CRFs are complete and accurate. 
After database lock, the investigator will receive a CD-ROM or paper copies of the subject 
data for archiving at the investigational site. 


 
 
   
 
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Data not requiring a separate written record  will be defined in the SOM and 
Assessment schedule (Section 8.1) and can be recorded directly on the CRFs. All other data 
captured for this study will have  an external originating source (either written or electronic) 
with the CRF not being considered as source. 
10.3 
Database management and quality control 
All data should be recorded, handled and stored  
in a way that allows its accurate reporting, 
interpretation and verification. 
The CRO working on behalf of Novartis will review the data entered into the CRFs by 
investigational staff for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to CRO working on behalf of Novartis who will make the correction to the database. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
Spirometry will be processed centrally and the results will be sent electronically to Novartis 
(or a designated CRO). 
Randomization codes and data in reference to dispensing of study drug(s) to the subject and 
all IRT recorded dosage changes will be tracked using  Interactive Response Technology 
(IRT). The system will be supplied by a vendor, who will also manage the database. 
The database will be sent electronically to Novartis (or a designated CRO). 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis. 
Corporate Confidential Information
The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked 
and the treatment codes will be unblinded and made available for data analysis. Any changes 
to the database  after that time can only be made by joint written agreement between the 
Global Head of Clinical Information Sciences and the Clinical Franchise Head. 


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10.4 
Data Monitoring Committee 
The study will be using a Data Monitoring Committee (DMC). A DMC is a group of 
professionals, experienced in clinical care and/or clinical research, assembled to provide 
additional safety oversight to a clinical study. The DMC will consist of four members, with 
one member being a statistician. The DMC will have a charter completed prior to FPFV and 
will meet on a regular basis to review safety. 
10.5 
Adjudication Committee 
Not required 
11 
Data analysis 
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation. 
11.1 
Analysis sets 
For all analysis sets, subjects will be analyzed according to the study treatment(s) received. 
The safety analysis set will include all subjects that received any study drug. 
The PK analysis set will include all subjects with available PK data and no protocol 
deviations with relevant impact on PK data. 
The PD analysis set will include all subjects who  received any study drug and have no 
protocol deviations with relevant impact on PD data. If retrospective review of RHC or 
echocardiogram data suggests inclusion/exclusion criteria may not have been met, additional 
subjects may be excluded from the PD analysis set. 
Data from the two parts of the study will be pooled for the statistical analysis and treatment 
groups will be defined as QCC374 and placebo. 
11.2 
Subject demographics and other baseline characteristics 
All data for background and demographic variables will be listed by treatment group and 
subject. Summary statistics will be provided by treatment group. 
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject. 
11.3 
Treatments 
Corporate Confidential Information
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment group and subject. 


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11.4 
Analysis of the primary variable(s) 
The primary objective of this study is to assess the efficacy of 16 weeks of QCC374 
administration in patients with PAH. The primary endpoint is the percentage of the baseline 
PVR at week 16. 
11.4.1 Variable(s) 
The primary variable is the PVR. The log transformed PVR is expected to be approximately 
normally distributed. 
11.4.2 Statistical model, hypothesis, and method of analysis 
The change from baseline (on log transformed values) will be analyzed using an ANCOVA 
model with treatment as a factor and log transformed baseline PVR as a covariate. Likelihood 
based posterior distributions will be derived to assess the probability that QCC374 is better 
than placebo and the probability that the reduction vs placebo is at least 15%. 
11.4.3 Handling of missing values/censoring/discontinuations 
The primary analysis of efficacy will be conducted only on complete cases (i.e. patients with 
baseline and week 16 PVR values), which is considered valid under the missing completely at 
random (MCAR) assumption. 
11.4.4 Sensitivity analyses 
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Sensitivity analyses will be carried out if the assumption of missing completely at random 
values is not appropriate. 


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11.5 
Analysis of secondary variable(s) 
11.5.1 Efficacy / Pharmacodynamics 
For the 6MWD, mPAP, PCWP, CO, SVR, and RV function with echocardiography, the raw 
data  and change from baseline will be listed by treatment, subject and visit/time. Summary 
statistics will be provided by treatment and visit/time. 
For the 6MWD, change from baseline will be analyzed using a mixed effects model for 
repeated measures. The model will investigate effects for treatment by time interaction and 
baseline by time interaction. The outcome of interest will be the comparison of QCC374 
versus placebo after 16 weeks of treatment. 
The mPAP, PCWP, CO, SVR, and RV function parameters with echocardiography will be 
analyzed using ANCOVA model with treatment as a factor and baseline value as a covariate. 
If the distribution of a  variable cannot be assumed normal, log-transformation or a 
non-parametric test will be used. 
11.5.2 Safety 
Vital signs 
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time. 
ECG evaluations 
All ECG data will be listed by treatment, subject and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time. 
Clinical laboratory evaluations 
All laboratory data will be listed by treatment, subject, and visit/time and if normal ranges are 
available abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit/time. 
Adverse events 
All information obtained on AEs will be displayed by treatment and subject. 
The number and percentage of subjects with AEs will be tabulated by body system and 
preferred term with a breakdown by treatment. A subject with multiple adverse events within 
a body system is only counted once towards the total of this body system. 
Spirometry 
All spirometry data will be listed by treatment, subject and visit/time. Summary statistics will 
be provided by treatment and visit/time. 


 
 
 
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Pharmacokinetics 
QCC374 and QCM441 plasma concentration data will be listed by dose-level, subject, and 
visit/sampling timepoint. Missing data will be labeled as such in the concentration data 
listings. 
Descriptive summary statistics will be provided by dose-level and visit/sampling time point, 
including the frequency (n, %) of concentrations below the LLOQ and reported as zero. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. Concentrations below LLOQ will be treated as 
zero in summary statistics as well as for calculation of PK parameters. A geometric mean will 
not be reported if the dataset includes zero values. 
Pharmacokinetic parameters will be calculated as described in Section 8.7 and will be listed 
by dose-level, study day and subject.  Descriptive summary statistics will be provided 
including mean (arithmetic and geometric), SD, CV (arithmetic and geometric), median, 
minimum and maximum. An exception to this are Tmax, Tmin, and Tlast where only median, 
minimum and maximum will be presented. A geometric mean will not be reported if the 
dataset includes zero values. 
11.5.3 Pharmacokinetic / pharmacodynamic interactions 
Not applicable for this study. 
11.5.4 Other assessments 
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There will be no other assessments than what has been previously documented. 


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11.7 
Sample size calculation 
We assume around 20% dropout, which should provide complete PVR data from around 
30 patients (approximately 10  on  placebo and approximately 20 on QCC374), if 
approximately 38 patients are randomized. 
 
 
 
 
 
 
 
If the true effect is 20% over placebo, then the probability to meet the efficacy criteria is 80%. 
If the drug effect over placebo is 0, then there is 40% chance of declaring futility at the IA. 
If the drug effect over placebo is 0, then the chance of declaring efficacy is 9% at the end of 
the study. 
11.8 
Power for analysis of key secondary variables 
Corporate Confidential Information
Not applicable. 
Corporate Confidential Information
Corporate Confidential Information
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12 
Ethical considerations 
12.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki. 
12.2 
Responsibilities of the investigator and IRB/IEC 
Corporate Confidential Information
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g. advertisements) and any other written information to be provided to subjects. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 


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agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made. 
For multi-center trials, a Coordinating Investigator will be selected by Novartis around the 
time of Last Patient Last Visit to be a reviewer and signatory for the clinical study report. 
12.3 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 
13 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs. 
Investigators must apply due diligence to avoid protocol deviations. If the investigator feels a 
protocol deviation would improve the conduct of the study this must be considered a protocol 
amendment, and unless such an amendment is agreed upon by Novartis and approved by the 
IRB/IEC/REB it cannot be implemented. All significant protocol deviations will be recorded 
and reported in the CSR. 
13.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are intended to eliminate an apparent immediate hazard to subjects 
may be implemented, provided the Health Authorities and the reviewing IRB/IEC are 
subsequently notified by protocol amendment. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the clinical 
trial leader should be informed and (serious) adverse event reporting requirements (Section 9) 
followed as appropriate. 


 
 
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References 
ATS Statement: Guidelines for the Six-Minute Walk Test (2002) Am J Respir Crit Care Med 
166:111-117. 
Badagliacca R, Pezzuto B, Poscia R, et al (2012) Prognostic factors in severe pulmonary 
hypertension patients who need parenteral prostanoid therapy: The impact of late referral. 
J Heart Lung Transplant. 31: 364–72 
Barst RJ, Rubin LJ, Long WA, et al (1996) A comparison of continuous intravenous 
epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension: 
The Primary Pulmonary Hypertension Study Group. N Engl J Med; 334: 296-301. 
Benza R, Miller DP, Barst RJ, et al (2012) An evaluation of long-term survival from time of 
diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest; 142:448-56. 
Galie N, Humbert M, Vachiery JL, et al (2015) 2015 ESC/ERS Guidelines for the diagnosis 
and treatment of pulmonary hypertension. Eur Respir J; 46: 903-975. 
Global Initiative for Asthma (2016) Pocket Guide for the Diagnosis and Management of 
Asthma. www.ginaasthma.org, accessed 31 August 2016. 
Hayashi M, Koya T, Kawakami H, et al (2010) A prostacyclin agonist with thromboxane 
inhibitory activity for airway allergic inflammation in mice. Clin Exp Allergy; 40, 317-326. 
Kuwano K, Hashino A, Noda K, et al (2008) A long-acting and highly selective prostacyclin 
receptor agonist prodrug, 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-
(methylsulfonyl)acetamide (NS-304), ameliorates rat pulmonary hypertension with unique 
relaxant responses of its active form, {4-[(5,6-diphenylpyrazin-2-
yl)(isopropyl)amino]butoxy}acetic acid (MRE-269), on rat pulmonary artery. J Pharm Exp 
Ther; 326, 691-699. 
MacIntyre N, Crapo RO, Viegi G, et al (2005) Standardisation of the single-breath 
determination of carbon monoxide uptake in the lung. Eur Respir J; 26:720-735. 
McLaughlin VV, Archer SL, Badesh DB, et al (2009) 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; America 
Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 53: 
1573-1619. 
McLaughlin VV, Benza RL, Rubin LJ, et al (2010) Addition of inhaled treprostinil to oral 
therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll 
Cardiol; 55(18): 1915-22. 
Miller MR, Hankinson J, Brusasco V, et al (2005) Standardization of spirometry. Eur Respir J; 
26:319-338. 


 
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Schermuly RT, Yilmaz H, Ghofrani HA, et al (2005) Inhaled iloprost reverses vascular 
remodeling in chronic experimental pulmonary hypertension. Am J Resp Crit Care; 172, 358-63. 
Schermuly RT, Ghofrani HA, Wilkins MR, et al (2011) Mechanisms of disease: pulmonary 
arterial hypertension. Nat Rev Cardiol; 8(8): 443-55. 
Simonneau G, Barst RJ, Galie N, et al (2002) Continuous subcutaneous infusion of 
treprostinil, a prostacyclin analog, in patients with pulmonary arterial hypertension: a double-
blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med.; 165(6):800-4. 
Simonneau G, Torbicki A, Hoeper MM, et al (2012) Selexipag, an oral, selective IP receptor 
agonist for the treatment of pulmonary arterial hypertension. Eur Respir J; 40: 874–880. 
Simonneau G, Gatzoulis M, Adatia I, et al (2013) Updated Clinical Classification of 
Pulmonary Hypertension. J Am Coll Cardiol; 62:25_S. 
Wanger J, Clausen JL, Coates G, et al (2005) Standardization of the measurement of lung 
volumes. Eur Respir J; 26:511-522. 
Woodward DF, Jones RL, Narumiya S (2011) International Union of Basic and Clinical 
Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of 
Progress. Pharm Rev; 63, 471-538. 
Zhu Y, Liu Y, Zhou W, et al (2010) A prostacyclin analog, iloprost, protects from bleomycin-
induced pulmonary fibrosis in mice. Respir Res; 11:34. 


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Appendix 1: Liver Event Definitions and Follow-up 
Requirements 
Table 15-1 
Liver Event Definitions 
Definition 
Potential Hy’s law cases 
ALT or AST elevation with 
coagulopathy 
ALT or AST elevation 
accompanied by symptoms 
Isolated ALT or AST elevation 
Isolated ALP elevation 
Others 
Thresholds 
ALT or AST > 3 × ULN and TBL > 2 × ULN without initial increase 
in ALP to > 2 × ULN 
ALT or AST > 3 × ULN and INR > 1.5 (in the absence of 
anticoagulation) 
ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash, or
eosinophilia
ALT or AST > 8 × ULN
5 x ULN < ALT/AST 8 x ULN
3 x ULN < ALT/AST 5 x ULN
ALP > 2 × ULN (in the absence of known bone pathology)
Any clinical event of jaundice (or equivalent term)
Any adverse event potentially indicative of liver toxicity
Table 15-2 
Actions required for Liver Events 
Criteria 
Actions required 
Potential Hy’s Law case 
ALT or AST elevation with 
coagulopathy 
ALT or AST elevation 
accompanied by symptoms 
Isolated ALT or AST 
elevation > 8 × ULN 
Jaundice 
Discontinue the study treatment immediately 
Hospitalize, if clinically appropriate 
Establish causality 
Complete CRFs per liver event guidance 
Isolated ALT or AST 
If confirmed, consider interruption or discontinuation of study drug 
elevation > 5 to ≤ 8 × ULN 
If elevation persists for more than 2 weeks, discontinue the study 
drug 
Establish causality 
Complete CRFs per liver event guidance 
Isolated ALT or AST 
Monitor liver chemistry tests two or three times weekly 
elevation > 3 to ≤ 5 × ULN 
(patient is asymptomatic) 
Isolated ALP elevation 
Repeat liver chemistry tests within 48-72 hours 
If elevation is confirmed, measure fractionated ALP; if >50% is of 
liver origin, establish hepatic causality 
Complete CRFs per liver event guidance 
Any AE potentially 
Consider study treatment interruption or discontinuation
indicative of liver toxicity 
Hospitalize if clinically appropriate 
Complete CRFs per liver event guidance 


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Table 15-3 
Exclusion of underlying liver disease 
Disease 
Assessment 
Hepatitis A, B, C, E 
IgM anti-HAV; HBSAg, IgM anti-HBc, HBV DNA; anti-HCV, HCV 
RNA, IgM & IgG anti-HEV, HEV RNA 
CMV, HSV, EBV infection 
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV 
Autoimmune hepatitis 
ANA & ASMA titers, total IgM, IgG, IgE, IgA 
Alcoholic hepatitis 
Ethanol history, GGT, MCV, CD-transferrin 
Nonalcoholic steatohepatitis 
Ultrasound or MRI 
Hypoxic/ischemic hepatopathy Medical history: acute or chronic CHF, hypotension, hypoxia, 
hepatic venous occlusion. Ultrasound or MRI. 
Biliary tract disease 
Ultrasound or MRI, ERCP as appropriate. 
Wilson disease 
Caeruloplasmin 
Hemochromatosis 
Ferritin, transferrin 
Alpha-1-antitrypsin deficiency Alpha-1-antitrypsin 


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Appendix 2: Specific Renal Alert Criteria and Actions 
Table 16-1 
Specific Renal Alert Criteria and Actions 
Criteria 
Action required 
Serum creatinine (sCr) increase 
Consider causes and possible interventions
25 – 49% compared to baseline 
Follow up within 2-5 days 
Serum creatinine increase ≥50% 
Consider causes and possible interventions 
Repeat assessment within 24-48h if possible 
Consider drug interruption or discontinuation unless 
other causes are diagnosed and corrected 
Consider hospitalization and specialized treatment 
Protein-creatinine or albumin-creatinine 
Consider causes and possible interventions
ratio increase ≥ 2-fold 
Assess serum albumin & serum protein 
or 
Repeat assessment to confirm
new onset dipstick proteinuria ≥ 1+ 
Consider drug interruption or discontinuation unless 
or 
other causes are diagnosed and corrected 
Albumin-creatinine ratio (ACR) ≥ 30 
mg/g or ≥ 3 mg/mmol; 
or 
Protein-creatinine ratio (PCR )≥ 150 
mg/g or >15 mg/mmol 
New onset glucosuria on urine dipstick 
Assess & document: 
(unless related to concomitant treatment, Blood glucose (fasting) 
diabetes) 
Serum creatinine 
Urine albumin-creatinine ratio 
New hematuria on dipstick 
Assess & document: 
Urine sediment microscopy 
Assess sCr and urine albumin-creatinine ratio 
Exclude infection, trauma, bleeding from the distal 
urinary tract/bladder, menstruation 
Consider bleeding disorder 
Additional specialized assessments are available to assess renal function or renal pathology. 
Whenever a renal event is identified, a detailed subject history and examination are indicated 
to identify, document and potentially eliminate risk factors that may have initiated or 
contributed to the event:
Blood pressure assessment (after 5 min rest, with an appropriate cuff size)
Signs and symptoms such as fever, headache, shortness of breath, back or abdominal pain, 
dysuria, hematuria, dependent or periorbital edema 
hanges in blood pressure, body weight, fluid intake, voiding pattern, or urine output 
Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other potential 
causes of renal dysfunction, e.g., dehydration, hemorrhage, tumor lysis 


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Table 16-2 
Follow-up of renal events 
Action 
Follow up 
Assess*, document and record in the 
Case Report Form (CRF) or via 
electronic data load. Review and record 
possible contributing factors to the 
renal event (co-medications, other co-
morbid conditions) and additional 
diagnostic procedures (MRI etc) in the 
CRF. 
Urine dipstick and sediment microscopy 
Blood pressure and body weight 
Serum creatinine, electrolytes (sodium, potassium, 
phosphate, calcium), bicarbonate and uric acid 
Urine output 
Monitor subject regularly (frequency at 
Event resolution: (sCr within 10% of baseline or protein-
investigator’s discretion) until: 
creatinine ratio within 50% of baseline) 
or 
Event stabilization: sCr level with ±10% variability over 
last 6 months or protein-creatinine ratio stabilization at 
a new level with ±50% variability over last 6 months. 
* Urine osmolality: in the absence of diuretics or chronic kidney disease this can be a very 
sensitive metric for integrated kidney function that requires excellent tubular function. A high 
urinary osmolality in the setting of an increase in sCr will point toward a “pre-renal” cause 
rather than tubular toxicity. 

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