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 Angina pector
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 5
Healthy volunteers: no

Brief summary:
This is a long-term open-label safety extension to the Phase 2a study of inhaled QCC374 in adult patients with PAH. This study provides the patients who completed the QCC374X2201 study with the option to continue receiving QCC374. The study will monitor the long-term safety, tolerability and efficacy of QCC374 in patients with PAH.

Detailed description:

Arms:
arm 1: placebo patients from QCC374X2201 rolled into extension study will start at 0.03mg b.i.d. or 0.06mg b.i.d. and have the opportunity to up-titrate 0.12mg

-active patients will continue at the dose they finished on the QCC374X2201 study

Interventions: intervention 1: QCC374
Intervention descriptions: intervention 1: 0.015mg and 0.06mg

Protocol document:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
QCC374
Clinical Trial Protocol CQCC374X2201E1
Long-term, open label, multicenter, extension study to 
evaluate the safety and tolerability of QCC374 in 
patients with PAH
Document type:
Amended Protocol Version
EUDRACT number:
2016-001411-20
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


Novartis
Confidential
Page 2
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. Note: The SOM will not be part of the Clinical Study Report.
Notification of serious adverse events
Dear Investigator,
You must report a serious adverse event (SAE) (initial or follow-up) to Novartis as 
summarized below.  Refer to Section 9.2 of the protocol for SAE criteria and additional 
requirements.  See also page 2 of the Site Operations Manual for further details on the method 
of reporting a SAE.

Complete SAE report

Submit SAE report to Novartis Chief Medical Office and Patient Safety (CMO&PS) 
within 24 hours after awareness of the SAE

Notify the Novartis Medical Lead

The fax number(s) and email address(es) are located in the Site Operations Manual. 


Novartis
Confidential
Page 3
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
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 .......................................................................................................................22
1.1
Background............................................................................................................22
1.2
Nonclinical data.....................................................................................................23
1.3
Clinical data...........................................................................................................26
1.4
Study purpose ........................................................................................................29
2
Study objectives and endpoints .........................................................................................29
2.1
Primary objective(s)...............................................................................................29
2.2
Secondary objective(s)...........................................................................................30
3
Investigational plan ...........................................................................................................31
3.1
Study design...........................................................................................................31
3.1.1
Study Periods ........................................................................................32
3.2
Rationale of study design.......................................................................................34
3.3
Rationale for dose/regimen, route of administration and duration of treatment....35
3.4
Purpose and timing of interim analyses/design adaptations..................................35
3.5
Risks and benefits..................................................................................................36
3.5.1
Hypotension ..........................................................................................36
Corporate Confidential Information
Corporate Confidential Information
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 4
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
3.5.2
Prostacyclin Associated Adverse Events ..............................................37
3.5.3
Risk of Bronchospasm or Cough ..........................................................37
3.5.4
Hemostasis ............................................................................................37
3.5.5
Phototoxicity.........................................................................................38
3.5.6
Women of child bearing potential.........................................................38
3.5.7
Blood sample volumes..........................................................................38
4
Population..........................................................................................................................39
4.1
Inclusion criteria ....................................................................................................39
4.2
Exclusion criteria...................................................................................................39
5
Restrictions for Study Subjects .........................................................................................40
5.1
Contraception requirements...................................................................................40
5.2
Prohibited treatment...............................................................................................41
5.3
Dietary restrictions and smoking...........................................................................41
5.4
Other restrictions ...................................................................................................41
6
Treatment...........................................................................................................................41
6.1
Study treatment......................................................................................................41
6.1.1
Investigational treatment and control drugs..........................................41
6.2
Treatment arms......................................................................................................41
6.3
Treatment assignment and randomization.............................................................42
6.4
Treatment blinding.................................................................................................42
6.5
Treating the subject................................................................................................42
6.6
Permitted dose adjustments and interruptions of study treatment.........................42
6.7
Emergency breaking of assigned treatment code ..................................................42
6.8
Treatment exposure and compliance .....................................................................42
6.9
Recommended treatment of adverse events ..........................................................42
6.10
Rescue medication.................................................................................................43
6.11
Concomitant treatment...........................................................................................43
7
Study completion and discontinuation ..............................................................................43
7.1
Study completion and post-study treatment ..........................................................43
7.2
Discontinuation of study treatment........................................................................43
7.3
Withdrawal of informed consent ...........................................................................44
7.4
Lost to follow-up ...................................................................................................44
7.5
Study Stopping rules..............................................................................................45
7.6
Early study termination by the sponsor .................................................................45
8
Procedures and assessments ..............................................................................................46
8.1
Assessment schedule .............................................................................................46
8.2
Informed consent procedures.................................................................................55


Novartis
Confidential
Page 5
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
8.3
Subject screening...................................................................................................55
8.4
Subject demographics/other baseline characteristics.............................................55
8.5
Efficacy / Pharmacodynamics ...............................................................................55
8.5.1
Echocardiogram ....................................................................................56
8.5.2
6-Minute Walk Test ..............................................................................56
8.6
Safety.....................................................................................................................56
8.6.1
Spirometry.............................................................................................57
8.6.2
Physical Examination............................................................................57
8.6.3
Vital Signs.............................................................................................57
8.6.4
Pulse Oximetry......................................................................................57
8.6.5
Body weight ..........................................................................................57
8.6.6
Laboratory Evaluations .........................................................................57
8.6.7
Pregnancy and Assessment of Fertility.................................................58
8.6.8
ECG.......................................................................................................58
8.7
Pharmacokinetics...................................................................................................58
8.7.1
PK Sample Collection...........................................................................58
8.7.2
Bioanalytical Method............................................................................59
8.7.3
Calculation of PK Parameters...............................................................59
9
Safety monitoring..............................................................................................................61
9.1
Adverse events.......................................................................................................61
9.2
Serious adverse event reporting.............................................................................63
9.2.1
Definition of SAE .................................................................................63
9.2.2
SAE reporting........................................................................................64
9.3
Liver safety monitoring .........................................................................................65
9.4
Renal safety monitoring.........................................................................................66
9.5
Reporting Medication errors including misuse/abuse ...........................................66
9.6
Pregnancy reporting...............................................................................................66
9.7
Prospective suicidality assessment ........................................................................67
10 Data review and database management.............................................................................67
10.1
Site monitoring ......................................................................................................67
10.2
Data collection.......................................................................................................67
Corporate Confidential Information


Novartis
Confidential
Page 6
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
10.3
Database management and quality control............................................................68
10.4
Data Monitoring Committee..................................................................................69
10.5
Adjudication Committee........................................................................................69
11 Data analysis......................................................................................................................69
11.1
Analysis sets ..........................................................................................................69
11.2
Subject demographics and other baseline characteristics......................................69
11.3
Treatments .............................................................................................................69
11.4
Analysis of the primary variable(s) .......................................................................70
11.4.1
Variable(s).............................................................................................70
11.4.2
Statistical model, hypothesis, and method of analysis..........................70
11.4.3
Handling of missing values/censoring/discontinuations.......................70
11.4.4
Summary statistics of safety..................................................................70
11.4.5
Sensitivity analyses ...............................................................................71
11.5
Analysis of secondary variable(s)..........................................................................71
11.5.2
Pharmacokinetics ..................................................................................71
11.5.3
Pharmacokinetic / pharmacodynamic interactions................................71
11.5.4
Other assessments .................................................................................71
11.7
Sample size calculation..........................................................................................72
11.8
Power for analysis of key secondary variables......................................................72
12 Ethical considerations........................................................................................................72
12.1
Regulatory and ethical compliance........................................................................72
12.2
Responsibilities of the investigator and IRB/IEC..................................................72
12.3
Publication of study protocol and results...............................................................73
13 Protocol adherence ............................................................................................................73
13.1
Protocol Amendments ...........................................................................................73
14 References .........................................................................................................................74
15 Appendix 1: Liver Event Definitions and Follow-up Requirements.................................76
16 Appendix 2: Specific Renal Alert Criteria and Actions ....................................................78
Corporate Confidential Information
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 7
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
List of tables
Table 8-1
Arm 1 Assessment Schedule (Subjects who completed 
QCC374X2201 and received QCC374)................................................46
Table 8-2
Arm 2 Assessment Schedule (Subjects who completed 
QCC374X2201 and received placebo)..................................................50
Table 8-3
Arm 2 PK blood collection (Subjects who completed 
QCC374X2201 and received placebo)..................................................54
Table 9-1
Summary of reporting requirements for medication errors...................66
Table 15-1
Liver Event Definitions.........................................................................76
Table 15-2
Actions required for Liver Events.........................................................76
Table 15-3
Exclusion of underlying liver disease ...................................................77
Table 16-1
Specific Renal Alert Criteria and Actions.............................................78
Table 16-2
Follow-up of renal events......................................................................79
List of figures
Figure 3-1
QCC374X2201E1 Extension Study Design..........................................31


Novartis
Confidential
Page 8
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
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
ATS
American Thoracic Society
bid
twice a day
BUN
blood urea nitrogen
C-SSRS
Columbia Suicide Severity Rating Scale
cAMP
cyclic adenosine 3'5' monophosphate
CD-ROM
compact disc – read only memory
CDS
Core Data Sheet (for marketed drugs)
CFR
Code of Federal Regulation
CK
creatinine kinase
CNS
central nervous system
CO
cardiac output
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CV
coefficient of variation
CXR
chest x-ray
DMC
Data Monitoring Committee
ECG
Electrocardiogram
FDA
Food and Drug Administration
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


Novartis
Confidential
Page 9
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
GLP
Good Laboratory Practice
h
hour
HIV
human immunodeficiency virus
hPaSMc
human pulmonary artery smooth muscle cell
HR
heart rate
HV
healthy volunteer
Hx/Su
Hypoxia/Sugen
i.t.
intra-tracheal
i.v.
intravenous
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IPR
prostacyclin receptor
IRB
Institutional Review Board
IRT
Interactive Response Technology
LDH
lactate dehydrogenase
LLOQ
lower limit of quantification
LV
left ventricular
MAD
multiple ascending dose
MCT
monocrotaline
mg
milligram(s)
mL
milliliter(s)
mPAP
mean pulmonary artery pressure
MTD
maximum tolerated dose
NOAEL
no observed adverse effect level
NT-proBNP
N-terminal prohormone of brain natriuretic peptide
NYHA
New York Heart Association
PA
pulmonary artery
PAH
pulmonary arterial hypertension
PCWP
Pulmonary Capillary Wedge Pressure
PD
pharmacodynamic(s)
PG
pharmacogenetic


Novartis
Confidential
Page 10
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
PH
pulmonary hypertension
PK
pharmacokinetic(s)
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
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
ULN
upper limit of normal
WHO
World Health Organization


Novartis
Confidential
Page 11
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Pharmacokinetic definitions and symbols
Ae0-t
Amount of drug (or defined metabolite) excreted into the urine from time 
zero to time 't' where t is a defined time point after administration [mass 
units or % of dose]
AUC0-t
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]
AUCinf
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to infinity [mass x time / volume]
AUClast
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]
AUCtau
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]
AUCtau,ss
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]
Cav,ss
The average steady state plasma (or serum or blood) concentration during 
multiple dosing
CL
The systemic (or total body) clearance from plasma (or serum or blood) 
following intravenous administration [volume / time]
CL/F
The apparent systemic (or total body) clearance from plasma (or serum or 
blood) following extravascular administration [volume / time]
CLr
The renal clearance from plasma (or serum or blood) [volume / time]
Cmax
The observed maximum plasma (or serum or blood) concentration following 
drug administration [mass / volume]
Cmax,ss
The observed maximum plasma (or serum or blood) concentration following 
drug administration at steady state [mass / volume]
Cmin,ss
The lowest plasma (or serum or blood) concentration observed during a 
dosing interval at steady state [mass / volume]
F
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
MRT
Mean residence time determined as AUMCinf/AUCinf following 
intravenous administration [time]
Racc
The accumulation ratio
T1/2
The terminal elimination half-life [time]


Novartis
Confidential
Page 12
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
T1/2,acc
The effective half-life based on drug accumulation at steady state [time]
Tmax
The time to reach the maximum concentration after drug administration 
[time]
Vss
The volume of distribution at steady state following intravenous 
administration [volume]
Vz
The volume of distribution during the terminal elimination phase following 
intravenous administration [volume]
Vz/F
The apparent volume of distribution during the terminal elimination phase 
following extravascular administration [volume]


Novartis
Confidential
Page 13
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) which 
is used as a comparator to the investigational drug being tested in the 
trial
Dosage
Dose of the study treatment given to the subject in a time unit 
(e.g. 100 mg once a day, 75 mg twice a day)
Enrollment
Point/time of subject entry into the study at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described 
in the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is 
associated with a purpose (e.g. screening, randomization, treatment, 
follow-up), which applies across all arms of a study.
Healthy volunteer
A person with no known significant health problems who volunteers to 
be a study participant 
Investigational drug
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and Directive 
2001/20/EC and is synonymous with “investigational new drug” or 
“test substance”
Investigational 
treatment
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.
Medication number
A unique identifier on the label of each study drug package in studies 
that dispense study drug using an IRT system.
Medication pack 
number
A unique identifier on the label of each drug package in studies that 
dispense study treatment using an IRT system
Non-investigational 
medicinal Product 
(NIMP)
Products which are not the object of investigation (e.g. any background 
therapy administered to each of the clinical trial subjects, regardless of 
randomization group, rescue medication, active drug run-ins etc.)
Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: 
a single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease.
Patient
An individual with the condition of interest


Novartis
Confidential
Page 14
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Period
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc.
Premature subject 
withdrawal
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.
Randomization 
number
A 
unique 
identifier 
assigned 
to 
each 
randomized 
subject, 
corresponding to a specific treatment arm assignment
Screen Failure
A subject who is screened but is not treated or randomized
Stage
A major subdivision of the study timeline; begins and ends with major 
study milestones such as enrollment, randomization, completion of 
treatment, etc.
Study completion
Point/time at which the subject came in for a final evaluation visit or 
when study drug was discontinued whichever is later.
Study drug 
discontinuation
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.
Study 
drug/treatment
Any drug (or combination of drugs) administered to the subject as part 
of the required study procedures; includes investigational drug, active 
drug run-ins or background therapy.
Study treatment
Any drug administered to the study participants as part of the required 
study procedures; includes investigational drug (s), control(s) or non-
investigational medicinal product(s)
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject 
and should be used to identify the subject throughout the study for all 
data collected, sample labels, etc.
Treatment number
A unique identifier assigned in non-randomized studies to each dosed 
subject, corresponding to a specific treatment arm 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested 
in the study
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study is defined as when a subject 
does not want to participate in the study any longer, and does not want 
any further visits or assessments, and does not want any further study 
related contact, and does not allow analysis of already obtained 
biologic material


Novartis
Confidential
Page 15
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Corporate Confidential Information


Novartis
Confidential
Page 16
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Corporate Confidential Information


Novartis
Confidential
Page 17
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Corporate Confidential Information


Novartis
Confidential
Page 18
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Corporate Confidential Information


Novartis
Confidential
Page 19
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Corporate Confidential Information


Novartis
Confidential
Page 20
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Protocol synopsis
Protocol 
number
CQCC374X2201E1
Title
Long-term, open label, multicenter, extension study to evaluate the safety and 
tolerability of QCC374 in patients with pulmonary arterial hypertension (PAH)
Brief title
Long-term extension study of the safety and pharmacokinetics of QCC374 in PAH
patients
Sponsor and 
Clinical Trial 
Phase
Novartis
Phase 2 (Extension Study)
Intervention 
type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study, as a long-term open-label safety extension to the 
Phase 2a study of inhaled QCC374 in adult patients with PAH, is to provide 
patients with the option to continue receiving QCC374 after completion of the 
QCC374X2201 trial, and monitor the long-term safety, tolerability and efficacy of 
QCC374 in patients with PAH.
Primary 
Objective(s)
To evaluate the safety and tolerability of QCC374 in patients with PAH over a two 
year period
Secondary 
Objectives

To assess the treatment effect of QCC374 in PAH patients not previously
dosed with QCC374 (i.e., those subjects previously in the placebo group of
QCC374X2201, Arm 2)

Six Minute Walk Distance (6MWD)

Right Ventricular (RV) function with echocardiography

To evaluate the pharmacokinetics of QCC374 and its metabolite QCM441 in
PAH patients not previously dosed with QCC374 (i.e., subjects previously in
the placebo group of QCC374X2201, Arm 2)
Study design
This is a multicenter, open label trial to assess the safety, tolerability 
pharmacokinetics and efficacy of inhaled QCC374 over a two year period in 
patients with PAH who have completed study QCC374X2201. This study will have 
two arms. In Arm 1, patients who had been randomized to active in the 
QCC374X2201 study will continue on QCC374 at their highest stable dose. In Arm 
2, the patients who had been randomized to placebo will complete a titration 
scheme similar to that of the active arm in QCC374X2201 protocol.
For both arms the study consists of a screening visit, a treatment period of 720 
days, and an EOS visit 30 days after treatment is completed. This study may be 
amended in the future to increase the treatment duration period, as additional data 
emerges for QCC374 in PAH.
All patients willing to participate in this trial will roll-over directly from the 
QCC374X2201 study after their 112 days of participation has been completed. 
The electrocardiogram (ECG), pulse oximetry, vital signs, weight, spirometry, 
6MWD, 
hematology, blood chemistry, body measurement and urinalysis results from the 
QCC374X2201 Visit Day 111 visit will be used as the baseline assessments for 
the extension study.
Corporate Confidential Information


Novartis
Confidential
Page 21
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Population
The study population will be comprised of male and female PAH patients who 
have completed the QCC374X2201 PoC study and wish to participate in the 
extension study. A total of approximately 38 subjects are planned to be enrolled 
and randomized in the QCC374X2201 study, with approximately 30 patients 
expected to complete the study.
Key Inclusion 
criteria

Written informed consent must be obtained before any assessment is
performed.

Subject was enrolled in the QCC374X2201 study and completed per protocol
Key Exclusion 
criteria

Subjects who have started receiving prostacyclin (epoprostenol), prostacyclin
analogs (i.e. trepostinil, iloprost, beraprost) or prostacyclin receptor agonists
(i.e. selexipag) since the last study drug intake in the QCC374X2201 study.

Females who are pregnant, or who plan to become pregnant during the study,
or who are breastfeeding

Any known factor or disease that may interfere with treatment compliance or
study conduct (i.e. drug or alcohol dependence)

Subjects who withdrew consent from the study QCC374X2201
Study treatment

QCC374 0.015 mg

QCC374 0.06 mg
Efficacy/PD 
assessments

6MWD

RV function with echocardiography
Key safety 
assessments

Adverse event (AE) monitoring

Physical examinations

Spirometry

ECG

Blood Chemistries, Hematology and Urinalysis
Other 
assessments

PK - in those subjects who had not previously received QCC374 in the
QCC374X2201 trial
Data analysis
All data for vital signs, ECG evaluations and clinical laboratory evaluations will be 
listed by subject and visit/time and summarized by descriptive statistics.
All information obtained on AEs will be displayed by subject. The number and 
percentage of subjects with AEs will be tabulated by body system and preferred 
term and QCC374X2201 study treatment group (QCC374 or placebo). A subject 
with multiple AEs within a body system is only counted once towards the total of 
this body system.
Baseline and end of study assessments from QCC374X2201 study will be 
included in the summary tables.  Summary statistics will be presented by 
QCC374X2201 study treatment group.
No inferential statistical analysis will be performed.
Key words
Pulmonary Arterial Hypertension
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 22
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
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). 


Novartis
Confidential
Page 23
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
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).
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.
1.2
Nonclinical data
Corporate Confidential Information


Novartis
Confidential
Page 24
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Corporate Confidential Information


Novartis
Confidential
Page 25
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Corporate Confidential Information


Novartis
Confidential
Page 26
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
1.3
Clinical data
The safety, tolerability and pharmacokinetics of QCC374 was evaluated in healthy subjects in 
the QCC374X2101 study: Part 1 was a single ascending dose (SAD) study; Part 2 was a 
multiple ascending dose (MAD) study; and Part 3 was a within subject up-titration study in 
two cohorts. 
Corporate Confidential Information
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 27
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Corporate Confidential Information


Novartis
Confidential
Page 28
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Corporate Confidential Information


Novartis
Confidential
Page 29
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
1.3.3
Human pharmacodynamic data
There is no human pharmacodynamic data available.
1.4
Study purpose
The purpose of this study, as a long-term open-label safety extension to the Phase 2a study of 
inhaled QCC374 in adult patients with PAH, is to provide patients with the option to continue 
receiving QCC374 after completion of the QCC374X2201 trial, and monitor the long-term 
safety, tolerability and efficacy of QCC374 in patients with PAH.
2
Study objectives and endpoints
2.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary 
objective(s)

To evaluate the safety and tolerability of
QCC374 in patients with PAH over a two year
period

Adverse Events, Serious Adverse
Events and all safety assessments
Corporate Confidential Information


Novartis
Confidential
Page 30
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
2.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

To assess the treatment effect of QCC374
in PAH patients not previously dosed with
QCC374 (Arm 2: those subjects previously
in the placebo group of QCC374X2201)

6MWD

Key RV function endpoints with
echocardiography will include 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
PAH patients not previously dosed with
QCC374 (Arm 2: subjects previously in the
placebo group of QCC374X2201)

PK parameters (Cmax, AUClast,
AUCtau, Ctrough) of QCC374 and
QCM441in plasma
Corporate Confidential Information


Novartis
Confidential
Page 31
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
3
Investigational plan
3.1
Study design
This is a multicenter, open label trial to assess the safety, tolerability, pharmacokinetics and 
efficacy of inhaled QCC374 over a two year period, in subjects with PAH who have 
completed study QCC374X2201. This study will have two arms (Figure 3-1). In Arm 1, 
subjects randomized to active in the QCC374X2201 study will continue on QCC374 at their 
highest stable dose. In Arm 2, the subjects randomized to placebo in the QCC374X2201 study 
will complete a titration scheme similar to that of the active arm in QCC374X2201 protocol. 
For subjects in both Arms, the assessments obtained during the Day 111 visit for the 
companion QCC374X2201 study (including physical examination, vital signs, pulse oximetry, 
ECG, spirometry, 6MWD, 
 and laboratory data) will be used as the 
baseline values for this study. 
This study may be amended in the future to increase the treatment duration period, as 
additional data emerges for QCC374 in PAH.
Figure 3-1
QCC374X2201E1 Extension Study Design
Corporate Confidential 
Information


Novartis
Confidential
Page 32
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
3.1.1
Study Periods
3.1.1.1
Screening
Arm 1 (patients who received QCC374 in the companion QCC374X2201 study): 
The screening period (Day-8 to Day-1, max 8 days, min 1 day) may begin no earlier than 
Day 111 of the companion QCC374X2201 study. Subjects may be unblinded to the main 
study treatment allocation and provide informed consent for this study only after all of the 
Day 111 assessments have been completed for the QCC374X2201 study. Day -1 in the 
screening period may occur no earlier than Day 112 in the companion QCC374X2201 study.  
The goal is for patients to continue to receive QCC374 without interruption between the 
QCC374X2201 study and the extension study; no more than one week (7 days) can elapse 
between the last dose of study drug administered in the QCC374X2201 study and the first 
dose of study drug administered in the QCC374X2201E study. 
Arm 2 (patients who received placebo in the companion QCC374X2201 study):
The screening period (Day -8 to Day -1, max 8 days, min 1 day) may begin no earlier than 
Day 111 of the companion QCC374X2201 study. Subjects may be unblinded to the main 
study treatment allocation and provide informed consent for this study only after all of the 
Day 111 assessments have been completed for the QCC374X2201 study. Day -1 in the 
screening period may occur no earlier than Day 112 in the companion QCC374X2201 study. 
No more than one week (7 days) can elapse between the last dose of study drug administered 
in the QCC374X2201 study and the first dose of study drug administered in the 
QCC374X2201E study. 
3.1.1.2
Treatment Period
Arm 1 (patients who received QCC374 in the companion QCC374X2201 study): 
Arm 1 consists of a treatment period of 720 days. Subjects may be dispensed study drug for 
the extension study no earlier than Day -1. The first study drug administration for the 
QCC374X2201E extension study will occur on Day 1. The first study drug administration 
may occur at home if the patient was dispensed study drug on Day -1. 
Subjects will continue to receive QCC374 at the same dose that was administered during the 
proof of concept study (0.06 mg bid or lower if their individual maximum tolerated dose 
(MTD) if their individual MTD was below 0.06 mg bid). At any point during the treatment 
period, if a subject is on 0.06 mg and the investigator believes, based on their medical 
judgement, that the dose should be reduced due to the severity of adverse events, the 
investigator may reduce the dose to 0.03 mg. The investigator may subsequently increase the 
dose back to the 0.06 mg dose if the investigator believes this is appropriate based on their 
medical judgement. A follow-up phone call should be scheduled 7 days after adjustment to 
review safety and tolerability of the dose adjustment.


Novartis
Confidential
Page 33
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Visits will occur every three months during the extension treatment period, but the subject 
may need to return for drug resupply on a monthly basis. The resupply plan is country and site 
specific, and the expectations for resupply should be reviewed with the subject prior to the 
first dispensing of study medication.
Arm 2 (patients who received placebo in the companion QCC374X2201 study): 
Arm 2 consists of a treatment period of 720 days, which is further divided into a Titration 
Period (Day 1 to Day 14), a Stable Dose Period (Day 15 to Day 112), and an Extension 
Treatment Period (Day 113 to Day 720) (Figure 3-1). Subjects in Arm 2 will be dispensed 
study drug on Day 1, and the first study drug administration for the QCC374X2201 extension 
study will occur on Day 1. This study drug administration must occur in the clinic. 
Arm 2 Titration Period: 
The starting dose of QCC734 for subjects in Arm 2 is 0.03 mg bid. 

On Day 7 the investigator will assess the subject's clinical status, and reported adverse
events. The subject's dose will be increased 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 typical pharmacological effects of IP-receptor agonists, such as headache, jaw pain,
myalgia, flushing and nausea.

On Day 14 the investigator will assess the subject's clinical status, and reported adverse
events. If the subject is not receiving the maximum 0.06 mg bid dose, the dose level will
be increased 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.

Following the Day 14 visit no further up-titrations above the Day 14 dose are allowed.
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.
Arm 2 Stable Dose Period: 
During the stable dose period (Day 15 to Day 112), subjects will continue to receive the 
QCC374 dose established during the Titration Period (0.06 mg or 0.03 mg). At any point 
during the stable dose period, if a subject is on 0.06 mg and the investigator believes, based on 
their medical judgement, that the dose should be reduced due to the severity of adverse events, 
the investigator may reduce the dose to 0.03 mg. The investigator may subsequently increase 
the dose back to the 0.06 mg dose if the investigator believes this is appropriate based on their 
medical judgement. A follow-up phone call should be scheduled 7 days after adjustment to 
review safety and tolerability of the dose adjustment. During the stable dose period the subject 
will return for safety assessments every 28 days. 


Novartis
Confidential
Page 34
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Arm 2 Extension Period: 
Once the stable dose period is complete (following Day 112), subjects will continue to receive 
the same dose of QCC374 throughout the extension treatment period. Visits will occur every 
three months during the extension treatment period, but the subject may need to return for 
drug resupply on a monthly basis. The resupply plan is country and site specific and the 
expectations should be reviewed with the subject prior to the first dispensing of study 
medication.
3.1.1.3
End of Study Visit
For both Arm 1 and Arm 2, an end of study visit will occur 30 days after the last treatment 
visit. If a patient stops study medication prematurely, at a minimum a safety evaluation must 
be completed, and an attempt should be made to complete all assessments indicated at the End 
of Study Visit. 
3.2
Rationale of study design
This open-label safety extension study will offer continuous QCC374 therapy to PAH patients 
who have completed the study QCC374X2201, and will provide long-term safety, tolerability 
and efficacy data.

Open-label: This is a long-term study designed to assess safety and all subjects will
receive active treatment

Dose-titration design: This applies only to subjects in Arm 2 (i.e. those who are initiating
treatment with QCC374 at the beginning of the study). 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

Starting dose: This applies only to subjects in Arm 2 (i.e. those who are initiating
treatment with QCC374 at the beginning of the study). The starting dose in Arm 2 is
0.03 mg, which is the same as the starting dose in the QCC374X2201 study.

Eligibility: All subjects who completed QCC374X2201 are eligible to enroll. At the time
of enrollment the efficacy of QCC374 in PAH patients will be unknown, as efficacy data
from QCC374X2201 will not yet be available. All subjects who completed
QCC374X2201 are eligible to enroll in the extension study in order to avoid an
interruption in prostacyclin therapy.

Endpoints: The primary endpoint of this study is the number of participants with adverse
events as a measure of safety and tolerability. In addition, there are secondary
 Together these assessments are 
anticipated to inform future, larger studies of QCC374 in PAH. 
Corporate Confidential Information


Novartis
Confidential
Page 35
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
There is no comparator in this open-labeled extension study.
3.4
Purpose and timing of interim analyses/design adaptations
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 36
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
3.5
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.
3.5.1
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.
To further 
minimize risk in the QCC374X220E1 study, any subjects enrolling in this extension study 
who are receiving QCC374 for the first time (Arm 2, QCC374X2201 placebo patients) will 
use the same starting dose as the current starting dose in QCC374X2201 study. In the event of 
symptomatic hypotension, subjects will be treated with standard of care. 
Corporate Confidential Information


Novartis
Confidential
Page 37
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
3.5.2
Prostacyclin Associated Adverse Events
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 
exploratory studies in PAH because subjects are not expected to be titrated to their individual 
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).
3.5.3
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).
3.5.4
Hemostasis
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. 
Corporate Confidential Information
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 38
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
 Throughout early clinical development studies, subjects will be monitored for 
evidence of increased bleeding or local pulmonary hemorrhage by subjective (shortness of 
breath, cough, hemoptysis) and objective clinical data (i.e. pulse oximetry, safety laboratory 
data). Any clinically significant findings are anticipated to be readily reversed with standard 
of care.
3.5.5
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.
3.5.6
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.
3.5.7
Blood sample volumes
A maximum of 194 mL of blood is planned to be collected over a period of 24 months, from 
each subject who was an active subject in the QCC374X2201 protocol. A maximum of 
331 mL of blood is planned to be collected over a period of 24 months, from each subject who 
was a placebo subject in the QCC374X2201 protocol. 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.
Timings of blood sample collection are outlined in the Assessment Schedule, Section 8.1.
A summary blood log is provided in the Site Operations Manual, together with instructions 
for all sample collection, processing, storage and shipment information. See Section 8.9
regarding the potential use of residual samples.


Novartis
Confidential
Page 39
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
4
Population
The study population will consist of male and female patients 18 years or older who have 
completed the study QCC374X2201. It is expected that all subjects who enrolled and 
completed the QCC374X2201 study will roll-over into QCC374X2201E1.
4.1
Inclusion criteria
Subjects eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Subject was enrolled in the QCC374X2201 study and completed per protocol.
3. For patients enrolling in Arm 2, the spirometry assessed at Visit 111 in the companion
QCC374X2201 study must meet ATS criteria for acceptability and reproducibility. If
necessary, this assessment can be repeated during the Screening Period.
4.2
Exclusion criteria
Subjects fulfilling any of the following criteria are not eligible for inclusion in this study:
1. Subjects who have started receiving prostacyclin (epoprostenol), prostacyclin analogs
(i.e. trepostinil, iloprost, beraprost) or prostacyclin receptor agonists (i.e. selexipag) since
the last study drug intake in the QCC374X2201 study.
2. Females who are pregnant, or who plan to become pregnant during the study, or who are
breastfeeding
3. Any known factor or disease that may interfere with treatment compliance or study
conduct (i.e. drug or alcohol dependence)
4. Subjects who withdrew consent from the study QCC374X2201
5. 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.

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.


Novartis
Confidential
Page 40
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1

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.
6. Subjects who demonstrated a serious protocol deviation, determined by the Sponsor or
Investigator, related to subject compliance in the study QCC374X2201.
No additional exclusions may be applied by the investigator, in order to ensure that the
study population will be representative of all eligible patients.
NOTE: Re-screening of subjects is not allowed for anything other than the Spirometry 
assessment for inclusion. This assessment will be over read by a central reader and results will 
need to be communicated from the vendor to the site staff prior to treatment for subjects in 
Arm 2 in the extension study. If the subject does not meet inclusion from the Day 111 
spirometry, the subject is allowed to repeat the assessment during the screening window. The 
repeat assessment will also need to be over read by the central vendor and the results will 
need to be confirmed to the site staff.
5
Restrictions for Study Subjects
During recruitment, screening/informed consent review, and baseline visit, the subjects must 
be informed and reminded of the restrictions outlined in this section.
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 enrolled or continue in the study.


Novartis
Confidential
Page 41
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
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 
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, ensure standardized dosing conditions, compound 
administration will take place 30 min before or after food intake.
5.4
Other restrictions

For those subjects who were randomized to placebo in the QCC374X2201, there should
be 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 subject is participating in a
pulmonary rehabilitation program at the time of screening, then participation may
continue throughout the study period.

All subjects should 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 requirements for storage and management of study treatment, and instructions 
to be followed for subject numbering, prescribing/dispensing 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 will be prepared by Novartis and 
supplied to the Investigator.
6.2
Treatment arms
All subjects will receive QCC374 during this extension study. Refer to Section 3.1 and 
Section 3.2 for information on dosing schedule and rationale. 


Novartis
Confidential
Page 42
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
6.3
Treatment assignment and randomization
As this is an open-label extension trial, subjects will maintain the same subject number 
allocated 
in 
the 
QCC374X2201 
protocol. 
This 
is 
not 
a 
randomized 
trial. 
Additional information for the unblinding of subjects in the QCC374X2201 protocol can be 
found in the SOM.
6.4
Treatment blinding
As this is an open-label study design, blinding does not apply.
6.5
Treating the subject
QCC374 will be administered to the subject via inhaled administration with the Concept1 dry 
powder inhaler. Throughout the duration of the extension study, 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 should be followed. 
6.7
Emergency breaking of assigned treatment code
All subjects will receive QCC374 throughout this open label extension study.
6.8
Treatment exposure and compliance
PK parameters (measures of treatment exposure) will be determined in subjects who had not 
previously received QCC374 (placebo patients from the QCC374X2201 study), as detailed in 
Section 8.7.
6.9
Recommended treatment of adverse events
Because 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.


Novartis
Confidential
Page 43
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
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. 
Use of rescue medication must be recorded on the Concomitant medications/Significant non-
drug therapies CRF after start of study drug.
6.11
Concomitant treatment
All treatments for PAH are allowed, except for those mentioned in the prohibited treatment 
section. It is allowed to modify the type or dose of concomitant PAH therapy during the study 
and these changes should be document in the CRF. The reason for the decision should also be 
documented. 
7
Study completion and discontinuation
7.1
Study completion and post-study treatment
This study will enroll subjects for a planned period of two years. Study completion will either 
be defined as a voluntary withdrawal or the Sponsor termination of the trial.
All subjects should have a safety follow-up call conducted 30 days after the last clinic visit. 
The information collected is kept as source documentation.  All SAEs reported during this 
time period must be reported as described in Section 9.2 and the SOM. Documentation of 
attempts to contact the subject should be recorded in the source documentation.
7.2
Discontinuation of study treatment
Patients may voluntarily discontinue study treatment for any reason at any time. 
The investigator should discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would be detrimental to the patient’s well-being.
Study treatment must be discontinued under any of the following circumstances and the 
reason for discontinuation must be indicated on the CRF:

Patient 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 trial.

Any protocol deviation that results in a significant risk to the patient’s safety.

Use of prohibited treatment (referring to relevant section in the full protocol), including if
an investigator decides to initiate therapy with a different prostacyclin analogue or
prostacyclin receptor agonist


Novartis
Confidential
Page 44
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Patients 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. If they fail to return for these assessments for unknown reasons, every effort 
(e.g. telephone, e-mail, and letter) should be made to contact them.
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 and 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 cannot be formally considered lost to follow-
up until his/her scheduled end of study visit would have occurred.


Novartis
Confidential
Page 45
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
7.5
Study Stopping rules
The study will be placed on hold and no further enrollment of subjects on placebo in 
QCC374X2201 will occur pending a full safety review if any of the following criteria are met:

The principle 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 in the QCC374X2201 study or the ongoing safety review conducted by the 
sponsor in this study, which may justifies 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 by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons 
(including slow enrollment), or for regulatory or medical reasons. Should this be necessary, 
subjects must 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 
trial.


Novartis
Confidential
Page 46
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
8
Procedures and assessments
8.1
Assessment schedule
Table 8-1
Arm 1 Assessment Schedule (Subjects who completed QCC374X2201 and received QCC374)
Epoch
Extension Screening
Extension-Treatment5,6
Visit Name
Extension Screening
Visit Numbers1
301
401
406
408
410
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
Study Day(s)
-8 to -1
(max 8 days, min 1 day)
17
30
±5
60
±5
90
±5
120
±5
150
±5
180
±5
210
±5
240
±5
270
±5
300
±5
330
±5
360
±5
390
±5
420
±5
450
±5
480
±5
510
±5
540
±5
Time (post-dose)
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Informed consent
X2
Inclusion / Exclusion criteria
X
Physical examination
X
X
X
X
X
X
Pulse oximetry
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
Pregnancy test
X3
X3
X3
X3
X3
X3
X3
Body weight
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
X
X
X
X
ECG evaluation
X
X
X
X
X
X
6-Minute Walk Test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Corporate Confidential Information


Novartis
Confidential
Page 47
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Epoch
Extension Screening
Extension-Treatment5,6
Visit Name
Extension Screening
Visit Numbers1
301
401
406
408
410
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
Study Day(s)
-8 to -1
(max 8 days, min 1 day)
17
30
±5
60
±5
90
±5
120
±5
150
±5
180
±5
210
±5
240
±5
270
±5
300
±5
330
±5
360
±5
390
±5
420
±5
450
±5
480
±5
510
±5
540
±5
Time (post-dose)
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
X
Echocardiogram
X
Drug dispensation
X4
X4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug administration
Study drug administration will be bid - refer to Section 3.1 and Site Operational Manual7
Concomitant medications
As Required
Adverse events
As Required
Serious adverse events
As Required
Comments
As Required
Study/epoch completion information
X
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 48
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Epoch
Extension-Treatment5,6
Visit Name
EOS (30 days post last treatment)
Visit Numbers1
427
428
429
430
431
432
4335
Study Day(s)
570
±5
600
±5
630
±5
660
±5
690
±5
720
±5
750
±5
Time (post-dose)
-
-
-
-
-
-
-
Informed consent
Inclusion / Exclusion criteria
Physical examination
X
X
X
Pulse oximetry
X
X
X
Vital Signs
X
X
X
Pregnancy test
X3
X3
X3
Body weight
X
Blood chemistry
X
X
X
Hematology
X
X
X
Urinalysis
X
X
X
Spirometry
X
X
X
ECG evaluation
X
X
X
6-Minute Walk Test
X
X
X
X
X
X
X
X
X
X
X
Echocardiogram
X
Drug dispensation
X
X
X
X
X
X
Study drug administration
Study drug administration will be bid - refer to Section 3.1
and Site Operational Manual
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 49
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Epoch
Extension-Treatment5,6
Visit Name
EOS (30 days post last treatment)
Visit Numbers1
427
428
429
430
431
432
4335
Study Day(s)
570
±5
600
±5
630
±5
660
±5
690
±5
720
±5
750
±5
Time (post-dose)
-
-
-
-
-
-
-
Concomitant medications
As Required
Adverse events
As Required
Serious adverse events
As Required
Comments
As Required
Study/epoch completion information
X
1 Visit structure given for internal programming purpose only
2 The earliest that informed consent can occur is Day 111 in the companion QCC374X2201 study, and informed consent can occur no later than 7 days after Day 111. 
3 Urine Pregnancy Test (females only)
4 The first drug study dispensation may occur on Day -1 or Day 1.
5 If a patient stops study medication prematurely, at a minimum, a safety evaluation must be completed. Then an attempt should be made to complete all assessments
listed under Visit 433, with the investigator making the determination of what is safe and feasible to complete.
6 If the subject's dose was altered at any point during the extension treatment period, a follow-up phone call visit should be conducted 7 days post dose change for a
  review of safety and tolerability.
7 The goal is for subjects to continue to receive QCC374 without interruption from the QCC374X2201 study, so that no doses are missed. The first study drug 
administration must occur within 7 days of the last study drug administration in the QCC374X2201 study.  


Novartis
Confidential
Page 50
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Table 8-2
Arm 2 Assessment Schedule (Subjects who completed QCC374X2201 and received placebo)
Epoch Extension Screening
Extension-Treatment8,9
Visit Name Extension Screening
Titration
Stable Dose Follow Up
Long Term Follow Up
Visit Numbers1
301
4015
403
404
405
407
409
4115
413
414
415
416
417
418
Study Day(s)
-8 to -1
(max 8 days, min 1 
day)
1
7
±1
14
±1
28
±2
56
±2
84
±2
112
±2
150
±5
180
±5
210
±5
240
±5
270
±5
300
±5
Time (post-dose)
0m6
5m
15m 30m
2h
4h
-
-
-
-
-
-
-
-
-
-
-
-
-
Informed consent
X2
Inclusion / Exclusion criteria
X
Physical examination
X
X
X
X
X
X
X
X 
X
X
Pulse oximetry
X
X
X
X
X
X
X
X
X 
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test
X3
X3
X3
X3
Body weight
Blood chemistry
X7
X
X
X
X
X
X
Hematology
X7
X
X
X
X 
X
X
Urinalysis
X7
X
X
X
X
X
X
Spirometry
X4
X
X
X
X
X
X
X
X
X
X
ECG evaluation
X
X
X
X
X
X
X
X
X
X
6-Minute Walk Test
X
X
X
X 
X
X
X
X
X
X
X
X
X
X
X
X 
X
X
X
X
X
X
X 
X
X
Echocardiogram
X 
Corporate Confidential Information


Novartis
Confidential
Page 51
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Epoch Extension Screening
Extension-Treatment8,9
Visit Name Extension Screening
Titration
Stable Dose Follow Up
Long Term Follow Up
Visit Numbers1
301
4015
403
404
405
407
409
4115
413
414
415
416
417
418
Study Day(s)
-8 to -1
(max 8 days, min 1 
day)
1
7
±1
14
±1
28
±2
56
±2
84
±2
112
±2
150
±5
180
±5
210
±5
240
±5
270
±5
300
±5
Time (post-dose)
0m6
5m
15m 30m
2h
4h
-
-
-
-
-
-
-
-
-
-
-
-
-
X
Drug dispensation
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug administration
Study drug administration will be bid - refer to Section 3.1 and Site Operations Manual 
PK blood collection
See table below
Concomitant medications
As required
Adverse events
As required
Serious adverse events
As required
Comments
As required
Study/epoch completion 
information
X
Corporate Confidential Information


Novartis
Confidential
Page 52
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Epoch
Extension-Treatment8,9
Visit Name
Long Term Follow Up
EOS (30 days post last treatment 
visit)
Visit Numbers1
419
420
421
422
423
424
425
426
427
428
429
430
431
432
4338
Study Day(s)
330
±5
360
±5
390
±5
420
±5
450
±5
480
±5
510
±5
540
±5
570
±5
600
±5
630
±5
660
±5
690
±5
720
±5
750
±5
Time (post-dose)
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Informed consent
Inclusion / Exclusion criteria
Physical examination
X
X
X
X
X
X
Pulse oximetry
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
Pregnancy test
X3
X3
X3
X3
X3
X3
Body weight
X
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
X
X
X
X
ECG evaluation
X
X
X
X
X
X
6-Minute Walk Test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Echocardiogram
X
Corporate Confidential Information
Corporate Confidential Information




Novartis
Confidential
Page 54
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Table 8-3
Arm 2 PK blood collection (Subjects who completed QCC374X2201 and received placebo)
Epoch
Visit Name
Visit Numbers
Day
Time (post-dose)
PK blood collection
Extension Screening
Extension Screening
301
1
0m
X
Extension-Treatment
Titration
401
1
5m
X
15m
X
30m
X
1h
X
2h
X
4h
X
8h
X
Stable Dose Follow Up
411
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 8-2


Novartis
Confidential
Page 55
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
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.
Novartis will provide to investigators a proposed informed consent form that complies with 
the ICHE6 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.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. 
Any new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification or an Aggregate Safety Finding. New information might require an update to the 
informed consent and then must be discussed with the subject.
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
Subjects are only allowed to participate in the trial if they have successfully completed the 
QCC374X2201 study and have signed consent for this trial. Additional information can be 
found in the SOM.
8.4
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects. 
Relevant medical history/current medical conditions data will also be collected until signature 
of informed consent.  Details are outlined in the SOM.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
8.5
Efficacy / Pharmacodynamics
Pharmacodynamic (PD) samples will be collected at the time points defined in the 
Assessment schedule, Section 8.1. Follow instructions outlined in the SOM regarding sample 
collection, numbering, processing and shipment.
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. PD samples will be obtained and 
evaluated in all subjects at all dose levels.
Corporate Confidential Information


Novartis
Confidential
Page 56
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
8.5.1
Echocardiogram
In this trial, this assessment will only be completed for subjects who were randomized to 
placebo in the QCC374X2201 study, (Arm 2). 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. All 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.
8.5.2
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.
Additional information on this assessment can be found in the SOM.
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.


Novartis
Confidential
Page 57
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
8.6.1
Spirometry
Spirometry testing will be performed according to the American Thoracic Society guidelines 
(Miller et al 2005) 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
Physical Examination
Information can be found in the SOM.
8.6.3
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.
8.6.4
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.
8.6.5
Body weight
Weight will need to be recorded as referenced in the Assessment Schedule (Section 8.1).
8.6.6
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.
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential and 
platelet count will be measured. In addition, aPTT and PT/INR will be assessed.
Clinical chemistry
Sodium, potassium, creatinine, urea, uric acid, chloride, albumin, calcium, alkaline 
phosphatase, total bilirubin, LDH, GGT, AST, ALT, aPTT, 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.


Novartis
Confidential
Page 58
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Urinalysis
Urine test by dipstick e.g. Combur9: leucocytes, nitrite, pH, protein, glucose, ketones, 
urobilinogen, bilirubin, blood/ hemoglobin
If the dipstick result is positive for protein, nitrite, leucocytes and/or blood, the sample will be 
sent for microscopic analysis of WBC, RBC and casts.
8.6.7
Pregnancy and Assessment 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.
8.6.8
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
Only those subjects who had been randomized to placebo in the PoC study (QCC374X2201) 
will have blood samples collected outlined in Table 8-3. 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.
Further details on sample collection, numbering, processing and shipment can be found in the 
SOM.
8.7.1
PK Sample Collection
All samples will be given a unique sample number and a collection number. 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. Sampling 
problems will be commented in the CRFs provided to the site. 
Further details on sample collection, numbering, processing and shipment can be found in the 
SOM.


Novartis
Confidential
Page 59
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
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.
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 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.


Novartis
Confidential
Page 60
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Corporate Confidential Information


Novartis
Confidential
Page 61
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
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.
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.
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.
Corporate Confidential Information


Novartis
Confidential
Page 62
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
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:

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

Relationship to the study treatment

Duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not
resolved should be reported.

Whether it constitutes a serious adverse event (SAE). See Section 9.2 for definition of
SAE.

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

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.
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.


Novartis
Confidential
Page 63
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
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.
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.


Novartis
Confidential
Page 64
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
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 or Package Insert 
(new occurrence) 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 Investigator 
Notification (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.


Novartis
Confidential
Page 65
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
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. 
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.


Novartis
Confidential
Page 66
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
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.
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, patient/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.
All study treatment errors and uses outside of what is foreseen in the protocol will be 
collected in the dose administration record (DAR) CRF.  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 (AE) 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 (DAR) 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 


Novartis
Confidential
Page 67
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
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 
9.7
Prospective suicidality assessment
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 Electronic 
Case Report Forms 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 


Novartis
Confidential
Page 68
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
or corrected before transfer of the data to the CRO working on behalf of Novartis. 
The Investigator must certify that the data entered into the Electronic Case Report Forms 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.
Data not requiring a separate written record will be defined
in the SOM
and 
Assessment Schedule 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 eCRFs 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).
ECG readings and Spirometry will be processed centrally and the results will be sent 
electronically to Novartis (or a designated CRO).
All 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).
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.


Novartis
Confidential
Page 69
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
10.4
Data Monitoring Committee
This study will not be using a Data Monitoring Committee (DMC), as this is an open label 
study. However, the QCC374X2201 trial will be using a DMC, which will have a charter 
completed prior to the FPFV and will meet on a regular basis. A Data Monitoring Committee 
(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 QCC374X2201 DMC 
will consist of four members, with one member being a statistician.
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 full analysis set will include all subjects that received any study drug.
The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact on PK data.
The PD analysis set will include all subjects with available PD data and no protocol 
deviations with relevant impact on PD data.
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by subject. 
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by subject.
11.3
Treatments
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by subject.


Novartis
Confidential
Page 70
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
11.4
Analysis of the primary variable(s)
The primary aim of the study is to evaluate safety and tolerability of QCC374 in patients with 
PAH over a two year period.
11.4.1
Variable(s)
Safety and tolerability assessments include vital signs, ECG evaluations, clinical laboratory 
evaluations and AEs.
11.4.2
Statistical model, hypothesis, and method of analysis
All data for vital signs, ECG evaluations and clinical laboratory evaluations will be listed by 
subject and visit/time and summarized by descriptive statistics.
All information obtained on AEs will be displayed by subject. The number and percentage of 
subjects with AEs will be tabulated by body system and preferred term and QCC374X2201 
study treatment group (QCC374 or placebo). A subject with multiple AEs within a body 
system is only counted once towards the total of this body system.
Baseline and end of study assessments from QCC374X2201 study will be included in the 
summary tables. Summary statistics will be presented by QCC374X2201 study treatment 
group.
No inferential statistical analysis will be performed.
11.4.3
Handling of missing values/censoring/discontinuations
All patients who received study drug will be included in the safety and tolerability evaluation.
11.4.4
Summary statistics of safety
Vital signs
All vital signs data will be listed by subject, and visit/time and if ranges are available 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by QCC374X2201 study treatment and visit/time.
ECG evaluations
All ECG data will be listed by subject and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by QCC374X2201 study treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by subject and visit/time and if normal ranges are available 
abnormalities will be flagged. Summary statistics will be provided by QCC374X2201 study 
treatment and visit/time.


Novartis
Confidential
Page 71
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
Adverse events
All information obtained on adverse events will be displayed by subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by QCC374X2201 study treatment. A subject with 
multiple adverse events within a body system is only counted once towards the total of this 
body system.
Other safety evaluations
All spirometry data will be listed by subject and visit/time. Summary statistics will be 
provided by QCC374X2201 study treatment and visit/time.
11.4.5
Sensitivity analyses
Not applicable.
11.5
Analysis of secondary variable(s)
11.5.1
Efficacy / Pharmacodynamics
Data from 6MWD and RV structure and function with echocardiography will be listed by 
subject and visit/time and summarized descriptively. Baseline and end of study assessments 
from QCC374X2201 study will be included in the summary tables.
No inferential statistical analysis will be performed.
11.5.2
Pharmacokinetics
QCC374 and its metabolite QCM441 plasma concentration data will be listed by subject, and 
visit/sampling time point. Descriptive summary statistics will be provided by 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. An exception to this is Tmax where median, 
minimum and maximum will be presented. Concentrations below LLOQ will be treated as 
zero in summary statistics and for PK parameter calculations. 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 subject.
11.5.3
Pharmacokinetic / pharmacodynamic interactions
Not Applicable.
11.5.4
Other assessments
There will be no other assessments than what has been previously documented.


Novartis
Confidential
Page 72
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
11.7
Sample size calculation
As this is an open-label extension of a previous study (QCC374X2201), no sample size 
calculation is done.
11.8
Power for analysis of key secondary variables
Not applicable.
12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed 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
Before initiating a trial, the investigator/institution must 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 
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 73
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
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
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 is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
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 and health authorities, where required, it cannot be 
implemented.
13.1
Protocol Amendments
Any change 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.
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified.
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 reporting 
requirements identified in Section 9 (Safety Monitoring) must be followed and the Study Lead 
informed.


Novartis
Confidential
Page 74
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
14
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. 
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.
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.
Schermuly RT, Yilmaz H, Ghofrani HA, et al (2005) Inhaled iloprost reverses vascular 
remodelling 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.


Novartis
Confidential
Page 75
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
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. 
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.


Novartis
Confidential
Page 76
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
15
Appendix 1: Liver Event Definitions and Follow-up 
Requirements
Table 15-1
Liver Event Definitions
Definition
Thresholds
Potential Hy’s law cases

ALT or AST > 3 × ULN and TBL > 2 × ULN without initial increase 
in ALP to > 2 × ULN
ALT or AST elevation with 
coagulopathy

ALT or AST > 3 × ULN and INR > 1.5 (in the absence of 
anticoagulation)
ALT or AST elevation 
accompanied by symptoms

ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash, or eosinophilia
Isolated ALT or AST elevation

ALT or AST > 8 × ULN

5 x ULN < ALT/AST £ 8 x ULN

3 x ULN < ALT/AST £ 5 x ULN
Isolated ALP elevation

ALP > 2 × ULN (in the absence of known bone pathology)
Others

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

Discontinue the study treatment immediately

Hospitalize, if clinically appropriate

Establish causality

Complete CRFs per liver event guidance
ALT or AST elevation with 
coagulopathy
ALT or AST elevation accompanied by 
symptoms
Isolated ALT or AST elevation > 8 × 
ULN
Jaundice
Isolated ALT or AST elevation > 5 to ≤ 
8 × ULN

If confirmed, consider interruption or discontinuation of 
study drug

If elevation persists for more than 2 weeks, discontinue 
the study drug

Establish causality

Complete CRFs per liver event guidance
Isolated ALT or AST elevation > 3 to ≤ 
5 × ULN (patient is asymptomatic)

Monitor liver chemistry tests two or three times weekly
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 indicative of liver 
toxicity

Consider study treatment interruption or discontinuation

Hospitalize if clinically appropriate

Complete CRFs per liver event guidance


Novartis
Confidential
Page 77
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
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


Novartis
Confidential
Page 78
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
16
Appendix 2: Specific Renal Alert Criteria and Actions
Table 16-1
Specific Renal Alert Criteria and Actions
Criteria
Action required
Serum creatinine (sCr) increase
25 – 49% compared to baseline

Consider causes and possible interventions

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 
ratio increase ≥ 2-fold
or
new onset dipstick proteinuria ≥ 1+
or
Albumin-creatinine ratio (ACR) ≥ 30 mg/g or 
≥ 3 mg/mmol;
or
Protein-creatinine ratio (PCR )≥ 150 mg/g or 
>15 mg/mmol

Consider causes and possible interventions

Assess serum albumin & serum protein

Repeat assessment to confirm

Consider drug interruption or discontinuation 
unless other causes are diagnosed and corrected
New onset glucosuria on urine dipstick 
(unless related to concomitant treatment, 
diabetes)
Assess & document:

Blood glucose (fasting)

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. 
(Note: In exceptional cases when a nephrologist considers a renal biopsy, it is strongly 
recommended to make specimen slides available for evaluation by Novartis to potentially 
identify project-wide patterns of nephrotoxicity.)


Novartis
Confidential
Page 79
Amended Protocol Version v02 (Clean)
Protocol No. CQCC374X2201E1
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

Changes 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
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 
investigator’s discretion) until:

Event resolution: (sCr within 10% of baseline or 
protein-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.

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
QCC374
CQCC374X2201E1
Long-term, open label, multicenter, extension study to 
evaluate the safety and tolerability of QCC374 in patients 
with PAH
Statistical Analysis Plan (SAP)
Author(s):
Document type:
SAP Documentation – NIBR 
Document status:
Final
Release date:
04-Dec-2017
Number of pages:
14
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Personal Protected Data


Novartis
For business use only
Page 2
SAP 
CQCC374X2201E1
Corporate Confidential Data


Novartis
For business use only
Page 3
SAP 
CQCC374X2201E1
Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................3
1
Introduction .........................................................................................................................4
1.1
Scope of document ..................................................................................................4
1.2
Study reference documentation ...............................................................................4
1.3
Study objectives.......................................................................................................4
1.3.1. Primary objective(s).......................................................................................4
1.3.2. Secondary objective(s)...................................................................................4
1.4
Study design and treatment......................................................................................5
2
First interpretable results (FIR) ...........................................................................................6
4
Statistical methods: Analysis sets........................................................................................7
5
Statistical methods for Pharmacokinetic (PK) parameters..................................................8
5.1
Variables..................................................................................................................8
5.2
Descriptive analyses ................................................................................................8
6
Statistical methods for Pharmacodynamic (PD) parameters...............................................9
6.1
Secondary objectives ...............................................................................................9
6.1.1
Variables .................................................................................................9
6.1.2
Descriptive analyses..............................................................................10
7
Statistical methods for safety and tolerability data............................................................11
7.1
Variables................................................................................................................11
7.2
Descriptive analyses ..............................................................................................11
7.3
Graphical presentation...........................................................................................13
List of tables
Table 4-1
Protocol deviation codes and analysis sets..............................................7
Corporate Confidential Data
Corporate Confidential Data
Corporate Confidential Data
Corporate Confidential Data


Novartis
For business use only
Page 4
SAP 
CQCC374X2201E1
1
Introduction 
1.1
Scope of document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CQCC374X2201E1”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
Final study protocol (V01) is available at the time of finalization of Statistical Analysis Plan.
1.3
Study objectives
1.3.1. Primary objective(s)
Primary objective(s)
Endpoints related to primary objectives

To evaluate the safety and tolerability of
QCC374 in patients with PAH over a
two year period

Adverse Events, Serious Adverse Events
and all safety assessments
1.3.2. Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

To assess the treatment effect of
QCC374 in PAH patients not
previously dosed with QCC374
(Arm 2: those subjects previously in
the placebo group of
QCC374X2201)

6MWD

Key RV function endpoints with
echocardiography will include 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 PAH patients not previously dosed
with QCC374 (Arm 2: subjects
previously in the placebo group of
QCC374X2201)

PK parameters (Cmax, AUClast,
AUCtau, Ctrough) of QCC374 and
QCM441 in plasma.
Corporate Confidential Data


Novartis
For business use only
Page 5
SAP 
CQCC374X2201E1
1.4
Study design and treatment
This is a multicenter, open label trial to assess the safety, tolerability pharmacokinetics and 
efficacy of inhaled QCC374 over a two year period in patients with PAH who have completed 
study QCC374X2201. This study will have two arms. In Arm 1, patients who had been 
randomized to active in the QCC374X2201 study will continue on QCC374 at their highest 
stable dose. In Arm 2, the patients who had been randomized to placebo will complete a titration
scheme similar to that of the active arm in QCC374X2201 protocol.
For both arms the study consists of a Day 1 visit, a treatment period of 720 days, and an EOS 
visit 30 days after treatment is completed. This study may be amended in the future to increase 
the treatment duration period, as additional data emerges for QCC374 in PAH.
All patients willing to participate in this trial will roll-over directly from the QCC374X2201 
study after their 112 days of participation has been completed. The electrocardiogram (ECG), 
spirometry, 6MWD,
hematology, blood chemistry, body
measurement and urinalysis results from the 
QCC374X2201 Visit Day 112 visit will be used as the Day 1 assessments for the extension 
study.
Corporate Confidential Data
Corporate Confidential Data


Novartis
For business use only
Page 6
SAP 
CQCC374X2201E1
Figure 1-1: QCC374X2201E1 extension study design
2
First interpretable results (FIR)
First interpretable results (FIR) will be provided for this trial.
The study FIR template (mock slides) can be found in CREDI in the study RAP folder.
The template shows the analysis / results to be presented in the FIR. Study outputs required to 
be created at the time of the FIR will be highlighted in TFL shells document and marked as 
“Key” in the Programming Deliverables Tracker (PDT) output list. 
FIR will focus on the following analyses:

Analysis populations (if needed)

Subject disposition

Demographics and baseline characteristics. Baseline chracteristics will be presented
both at Core (QCC374X2201) and Extension study (QCC374X2201E1) baseline
(subject to data availability at baseline for each study) and will include, but are not
limited to:
o
Etiology of PAH
o
Time from PAH diagnosis
o
PVR
o
WHO FC
o
Borg Dyspnea Score
o
NT-proBNP level
o
Background PAH therapy
o
Smoking status
o
FEV1% predicted
o
Lung volumes (TLC % predicted)


Novartis
For business use only
Page 7
SAP 
CQCC374X2201E1
o
DLco
o
Historic right catheter vs catheter at baseline

Safety results
o
Number and percentage of subjects with adverse events by body system
o
Number and percentage of subjects on different dose levels during stable dose
treatment period (0.03, 0.06. 0.12)

Pharmacodynamic analyses will include, but are not limited to:
o
Raw arithmetic mean (SD) of 6MWD by arm over time
4
Statistical methods: Analysis sets
For subjects for which the actual treatment received in the Core study (QCC374X2201) does 
not match the Core study randomized treatment the treatment actually received will be used for 
the analysis.
The full analysis set will include all subjects that received any study drug.
The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and experienced 
no protocol deviations with relevant impact on PK data.
The PD analysis set will include all subjects with any available PD data, who received any study 
drug and experienced no protocol deviations with relevant impact on PD data.
The analysis sets and protocol deviation codes are related as follows:
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PK analysis in case of these PDs: 
Exclude subject from PK 
analysis set 
Subjects are excluded from PD analysis in case of these PDs:
Exclude subject from PD 
analysis set
Corporate Confidential Data


Novartis
For business use only
Page 8
SAP 
CQCC374X2201E1
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PK and PD analysis in case of these 
PDs:
Exclude subject from PK 
and PD analysis sets
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to
DBL.
5
Statistical methods for Pharmacokinetic (PK) parameters
All subjects within the PK analysis set will be included in the PK data analysis. Only subjects 
who had been randomized to placebo in the Core study (QCC374X2201) will have blood 
samples collected.
5.1
Variables 
Plasma concentrations of QCC374 and QCM441 will be expressed in the mass per volume unit 
ng/mL. The following pharmacokinetic parameters of both analytes (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, Racc 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 converted 
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 in terms of their ratio 
QCM441/QCC374.
5.2
Descriptive analyses
QCC374 and QCM441 plasma concentrations will be listed by dose-level, subject, and 
visit/sampling time point. 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. 
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 and for PK parameter calculations. A geometric mean will not be 
reported if the dataset includes zero values.


Novartis
For business use only
Page 9
SAP 
CQCC374X2201E1
Pharmacokinetic parameters for QCC374, QCM441 and their ratio will be listed by dose-level,
visit, and subject and summarized by dose-level with descriptive statistics as listed above. Since 
Tmax is generally evaluated by a nonparametric method, only median, minimum, and 
maximum will be reported. 
Graphical methods will be employed to show mean and individual concentration-time profiles.
6
Statistical methods for Pharmacodynamic (PD) parameters
All subjects within the PD analysis set will be included in the PD data analysis. 
6.1
Secondary objectives
The secondary objective of the study is to assess the treatment effect of QCC374 in PAH 
patients not previously dosed with QCC374 (Arm 2: those subjects previously in the placebo 
group).
6.1.1
Variables 
The secondary variables are:

6MWD

Right ventricular (RV) function with echocardiography, measured at baseline and at 16
weeks. See Table 6.1 for details.
Table 6-1   Imaging parameters (secondary endpoints)
Imaging parameter (name 
as in the dataset) 
Description
Unit
Directionality
Tvsa
Tricuspid annular peak systolic velocity
cm/sec 
Higher is better
tei index
RV Tei Index 
Unitless
Lower is better
Rvfac
RV fractional area change
%
Higher is better
Rvfwls
RV free wall average peak longitudinal 
strain
%
Lower is better
Tapse
Tricuspid 
annular 
plane 
systolic 
excursion
cm
Higher is better
The following two definitions of baseline will be used, and where change from baseline will be 
reported both definitions will used:
1. Core: Baseline is defined as the Core study (QCC374X2201) baseline visit.
2. Extension: Baseline will be defined as the Extension study (QCC374X2201E1) baseline.
The Extension baseline is defined as the Day 112 of the Core study.


Novartis
For business use only
Page 10
SAP 
CQCC374X2201E1
6.1.2
Descriptive analyses
The secondary variables (raw values primarily, and change from baseline where needed) will 
be listed by arm, subject and visit/time and descriptive statistics will be provided by arm and 
visit/time. Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic 
and geometric), median, minimum, maximum. A geometric mean will not be reported if the 
dataset includes zero values.
Graphical methods will be employed to show group summary and individual (spaghetti) plots 
over time by arm as required.
Corporate Confidential Data


Novartis
For business use only
Page 11
SAP 
CQCC374X2201E1
7
Statistical methods for safety and tolerability data
All subjects within the Safety analysis set will be included in the safety data analysis.
7.1
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as subject demographics, baseline characteristics, and 
treatment information.
7.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by arm and subject. Baseline 
chracteristics will be presented both at Core (QCC374X2201) and Extension study 
(QCC374X2201E1) baseline. The Extension baseline, is defined, as the Extension study 
screening visit where the respective measurements are available (as per the assessment schedule) 
and Day 112 of the Core study where they are not. Summary statistics will be provided by arm.
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.
Treatment
Data for study drug administration (rescue medication) and concomitant therapies will be listed 
by arm and subject.
Corporate Confidential Data


Novartis
For business use only
Page 12
SAP 
CQCC374X2201E1
Summary tables will be used to present the proportion of subjects who reached each QCC374 
dose, the proportion of subjects who had their dose reduced due to an adverse event, and the 
proportion of subjects who completed 16 weeks of treatment by dose subject received most 
from Day 15 to Day 112. Summary statistics for the number of days at each dose will be 
provided.
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 arm 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 arm 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. A separate listing is provided presenting all parameters 
in a subject with any abnormal values. Summary statistics will be provided by arm and visit/time.
Adverse events
All information obtained on adverse events will be displayed by arm and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by arm. A subject with multiple adverse events within a 
body system is only counted once towards the total of this body system and arm.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
5% and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date
of the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 


Novartis
For business use only
Page 13
SAP 
CQCC374X2201E1
Other safety evaluations
Spirometry
All spirometry data will be listed by subject and visit/time. Summary statistics (raw values 
primarily, and change from baseline) will be provided by QCC374X2201 study arm and 
visit/time.
Baseline is defined as the Day 112 of the Core study for the subjects who received QCC374 in 
the Core study, and the Screening visit of the Extension study for the subjects who received
placebo in the Core study.
7.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created. Mean (SD) plots will be used to visualize trends for spirometry.
Corporate Confidential Data


Novartis
For business use only
Page 14
SAP 
CQCC374X2201E1
Corporate Confidential Data