A Randomized, Double-blind, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of Inhaled QBW276 in Patients With Cystic Fibrosis
Phase: PHASE1
Conditions: Pulmonary Cystic Fibrosis
Sponsor: Novartis Pharmaceuticals

Novartis Institutes for BioMedical Research
QBW276
Clinical Trial Protocol CQBW276X2201
A randomized, double blind,placebo-controlled study to 
assess the safety, tolerability, pharmacokinetics, and 
pharmacodynamics of multiple doses of inhaled QBW276 
in patients with cystic fibrosis
Document type:
Amended ProtocolVersion
EUDRACT number:
2014-004915-35
Version number:
v04(Clean)
Development phase:
Ib/IIa
Release date:
28-Jun-2018
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis

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ite perations Manual (
M)
A ite perations Manual (
M) accompanies this protocol, providing the operational details 
for study conduct
Notification of serious adverse events
Refer to ection 92of the protocol for definitions and reporting reuirements for erious 
Adverse Events (within 24 hours after awarenessof the AEto the local Novartis Chief Medical 
ffice  Patient afetyDepartmentand notify the Clinical Trial eader) 
Contact information islisted in the 
M 

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Table of contents
ite perations Manual (
M)
2
Notification of serious adverse events
2
Table of contents
3
ist of tables
6
ist of figures
6
ist of abbreviations
7
Pharmacokinetic definitions and symbols
10
Protocol synopsis
19
1 Introduction
23
11
Background
23
12
tudy purpose
28
2
tudy obectives
28
21
Primary obective(s)
28
22
econdary obective(s)
29
3 Investigational plan
30
31
tudy design
30
32
Rationale for study design
35
33
Rationale of dose/regimen, duration of treatment
35
34 Rationale for choice of comparator
37
36
Risks and benefits
37
4 Population
38
41
Inclusion criteria
38
42
Eclusion criteria
39
5 Restrictionsfor tudyPatients
41
51
Contraception reuirements
41
52
Prohibited treatment and rescreening
41
53
Dietary restrictions and smoking
42
6 Treatment
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61
tudy treatment
42
611 
Investigational treatment
43
612 
Additional study treatment
43
62
Treatment arms
43
63
Permitted dose adustments and interruptions of study treatment
44
64
Treatment assignment
44
65
Treatment blinding
44
66
Emergency breaking of assigned treatment code
45
67
Treatment eposure and compliance
45
68
Recommended treatment of adverse events
45
69
Rescue and bronchodilator medication
45
610 Concomitant treatment
46
7 Discontinuation and study completion
46
71
Discontinuation of study treatment
46
72
tudy completion and post-study treatment
47
73
ost to follow-up
47
74
Withdrawal of consent
48
75
tudy topping rules
49
76
Early study termination
49
8 Procedures and assessments
50
81
Informed consent procedures
60
82
Patient demographics/other baseline characteristics
60
83
Efficacy / Pharmacodynamics
61
831 
ung Clearance Inde ( CI)
61
832 
ung volumes
61
833 
pirometry
61
84
afety
62
841 
Physical eamination
62
842 
Vital signs
62
843 
eight and weight
62
844 
aboratory evaluations
62
845 
Electrocardiogram (EC)
63
846 
pirometry
64
847 
Pregnancy and assessments of fertility
64
85
Pharmacokinetics
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9
afety monitoring
67
91
Adverse events
67
92
erious adverse event reporting
68
921 
Definition of AE
68
922 
AE reporting
69
93
iver safety monitoring
70
94
Renal safety monitoring
73
95
Pregnancy reporting
74
96
Early phase safety monitoring
75
10 Data review and database management
75
101
ite monitoring
75
102 Data collection
76
11 Data analysis
77
111 Analysis sets
77
112 Patient demographics and other baseline characteristics
77
113 Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)
77
114 Analysis of the primary variable(s)
78
1141
Variable(s)
78
1142
tatistical model, hypothesis, and method of analysis
78
1143
andling of missing values/censoring/discontinuations
79
1144
upportive analyses
79
115 Analysis of secondary and eploratory variables
80
1152
afety
80
1153
Pharmacokinetics
81
1155
ther assessments
81
116
ample size calculation
82
117 Power for analysis of key secondary variables
82
12 Ethical considerations
83
121 Regulatory and ethical compliance
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122 Responsibilities of the investigator and IRB/IEC
83
123 Publication of study protocol and results
83
13 Protocol adherence
84
131 Protocol Amendments
84
14 References
85
ist of tables
Table 8-1 
Assessment schedules
50
Table 9-1 
iver Event and aboratory Trigger Definitions
71
Table 9-2 
ollow Up Reuirements for iver Events and aboratory Triggers 72
Table 9-3 
pecific Renal Alert Criteria and Actions
74
ist of figures
igure 3-1 
chematic for study design
30
igure 3-2 
chematic for Cohort 3 study design
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ist of abbreviations
AE
adverse event
A T 
alanine aminotransferase
A P 
alkaline phosphatase
ANC VA 
analysis of covariance
A T 
aspartate aminotransferase
bid
twice a day
BMI 
Body Mass Inde
BUN 
blood urea nitrogen
CD-R M 
compact disc read only memory
C
Cystic ibrosis
C Q-R 
Cystic ibrosis Questionnaire-Revised
C R 
Code of ederal Regulations
C
creatinine kinase
CM  P
Chief Medical ffice  Patient afety
CR
Case Report/Record orm (paper or electronic)
C 2
carbon dioide
CR
Contract Research rganization
CTCAE  
Common terminology criteria for adverse events
CTRD 
Clinical Trial Results Database
CV
coefficient of variation
EC
Ethics committee
EC
Electrocardiogram
EDC 
Electronic Data Capture
EI A 
Enzyme-linked immunosorbent assay
DMC 
Data Monitoring Committee
DA 
ood and Drug Administration
EV1
orced Epiratory Volume in 1 second
CP 
ood Clinical Practice
-T 
amma-glutamyl transferase
h
hour
IV 
human immunodeficiency virus

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IC
International Conference on armonization of Technical Reuirements for 
Registration of Pharmaceuticals for uman Use
IEC 
Independent Ethics Committee
iv
intravenous
IRB 
Institutional Review Board
IRT 
Interactive Response Technology
CI 
ung Clearance Inde
T 
iver function test
D
lactate dehydrogenase
N 
lower limit of normal
MedDRA 
Medical dictionary for regulatory activities 
NCD
Novartis Clinical Data tandards
N VDD 
Novartis Data Dictionary
C/RDC 
racleClinical/Remote Data Capture
PA
posteroanterior
PD
pharmacodynamic(s)
P
pharmacokinetic(s)
PR
Patient Reported utcome
RBC 
red blood cell(s)
REB 
Research Ethics Board
RV
Residual Volume
AE 
serious adverse event
sc
subcutaneous
T  
serum glutamic oaloacetic transaminase
PT 
serum glutamic pyruvic transaminase
D
standard deviation
M 
site operations manual
U AR 
uspected Unepected erious Adverse Reactions
TB
total bilirubin
T C 
Total ung Capacity

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U N 
upper limit of normal
U Q 
upper limit of uantification
WBC 
white blood cell(s)
W
World ealth rganization

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Pharmacokinetic definitions and symbols
AUClast 
Area under the blood concentration-time curve from time zero to the last 
sampling time with a uantifiable concentration
AUCtau 
Area under the blood concentration-time curve from time zero to the end of 
the dosing interval tau
Cma
Maimum blood concentration
Clast 
The last measurable concentration
Racc 
The accumulation ratio
T1/2 
alf-life
Tma
Time postdose when maimum concentrationoccurs
Tlast 
Time of last measurable concentration (when Clastoccurs)

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Protocol synopsis
Protocol number
CQBW276X2201
Title
A randomized, double-blind,placebo-controlled study to assess the safety, 
tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of 
inhaled QBW276 in patients with cystic fibrosis
Brief title
afety, pharmacokinetics and pharmacodynamics study of inhaled QBW276 
in patients with cystic fibrosis
ponsor and 
Clinical Phase
Novartis 
Phase Ib/IIa(non-confirmatory)
Intervention type
Drug 
tudy type
Interventional 
Purpose and 
rationale
To assess the clinical profile including safety, tolerability, pharmacokinetics 
of multiple doses of inhaledQBW276 in patients 
with cystic fibrosis to support potential clinical development in this 
indication
Primary 
bective(s)
Cohorts 1 and 2: To assess the safety, tolerability, and pharmacokinetics 
(P) of multiple doses of inhaled QBW276 and its metabolites, over 1 or 
2weeks of treatment in patients with cystic fibrosis regardless of the
underlying mutation 
Cohort 3: To evaluate the pharmacodynamic (PD) response to multiple 
doses of inhaled QBW276 in lung function (percent of predicted EV
1) over 
4weeks of treatment compared with placebo in patients with cystic fibrosis 
that are homozygous for the 508del mutation 
econdary 
bectives
Cohorts 1 and 2: To evaluate the PD response to multiple doses of inhaled 
QBW276 on change in lung function over 1 or 2 weeks of treatment from 
baseline compared with placeboin patients with cystic fibrosis
Cohort 3: To assess the safety, tolerability, P, and PD of multiple doses of 
inhaled 
QBW276 and its metabolites over 4 weeks of treatment per period in 
patients with cystic fibrosis who are homozygous for the 508del mutation
tudy design
Cohorts 1 and 2: Randomized, double-blind, placebo-controlled, multi-
cohort, parallel arm, multiple dose study of inhaled QBW276 to assess its 
safety, tolerability, pharmacokinetics, and pharmacodynamics in patients 
with cystic fibrosis over one or two weeks of therapy
Cohort 3: Randomized, double-blind, placebo-controlled, cross-over study of 
inhaled QB
W276 over 4 weeks of therapy to assess its pharmacodynamics, 
safety, tolerability, and pharmacokinetics in patients with cystic fibrosis who 
are homozygous for the 508del mutation
Population
Cohorts 1 and 2: 8 adults ( 18 years old) per cohort (N  16), male and 
female patients with a diagnosis of cystic fibrosis, on standard of care 
treatment, regardless of their genotype
Cohort 3: 24 adult ( 18 years old) male and female patients who are 
homozygous for the 508del mutation, on standard of care treatment (Up to 
40 may be randomized to ensure 24 completers)

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Inclusion criteria
1 Written informed consent must be obtained before any assessment is 
performed
2 Male and female patients of age 18 and above with a confirmed diagnosis 
of cystic fibrosis as per the Cystic ibrosis oundation consensus 
guidelines (arrelletal2008)
3
or Cohort 3, male and female patients of age 18 andabove with a 
confirmed diagnosis of cystic fibrosis, who are homozygous for the 
508del mutation
4
hould be on stable medical regimen in the 4 weeks prior to screening
and baseline visits(Cohorts 1  2: creening Cohort 3: creening (v1) 
and Baseline (v2))
5
hould be established as clinically stable to participate in the study in 
the udgment of a site investigator at the screening and baseline visits
6
EV1 must be between 40 and 100  predicted (inclusive) by 
N ANE/ ankinson standards at screeningandbaseline visits(may be 
repeated once at screening and once at baseline)(Cohorts 1  2: 
creening Cohort 3: creening (v1) and Baseline (v2))
7
CI25  8 at screening if EV1  80  of predicted(Cohorts 1  2 only)
8 Must pass the metabolite screening assay prior to baseline visit
9 Must demonstrate ability to communicate well with the investigator, to 
understand and comply with the reuirements of the study
Eclusion criteria
1
Use of other investigational drugs at the time of enrollment, or within 5 
half-lives 
of enrollment, or within 30 days, whichever is 
longer 
or longer 
if reuired by local regulations The only eception to this is QBW276 
If a patient has participated in 
cohort 1of CQBW276X2201, he/she may
ualify to participate in cohort 2contingent upon approval from the 
sponsor, as long as he/she has been through a 4 week wash-out 
between dosing in the two cohorts, and has not eperienced any 
significant AEssince enrollmentin cohort1 This will ensure that no 
patient receives more than 4 weeksof the investigational 
drug QBW276 
in his/herlifetime until further supportive toicology studies are 
conducted in the drugs development program Note that patients who 
participate in cohorts 1 or 2 cannot participate in cohort 3
2
istory of significantly uncontrolled or untreatedcardiovascular,adrenal 
or electrolyte abnormalities
3
istory of malignancy of any organ system (other than localized basal 
cell carcinoma of the skin), treated or untreated, within the past 5 years, 
regardless of whether there is evidence of local recurrence or 
metastases
4
istory of lung transplant
5
Pregnant or nursing (lactating) women, where pregnancy is defined as 
the state of afemale after conception and until the termination of 
gestation
6
A history of clinically significant EC abnormalities, or any of the 
following EC abnormalities at screening or baselinevisits:
PR  200 msec
QR comple  120 msec
QTc  450 msec (males)
QTc  460 msec (females)

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7
istory of adverse reaction or hypersensitivity to any of the study drugs, 
ecipients (eg lactose)or to drugs of similar chemical classes, such as 
amiloride
8
Any upper respiratory tract infection (eg common cold, influenza, 
sinusitis) or signs or symptoms thereof within 4weeks prior to dosing 
that, inthe opinion of the investigator, may eopardize the patientor the 
study data in case of the patients participation in the study
9
Clinical evidence of liver disease or liver inury as indicated by clinically 
significant abnormal liver function tests as udged by the investigator, 
such as 
T, 
PT, 
T, alkaline phosphatase, or serum bilirubin
at screening or baseline visits
10 Clinical evidence of significantly impaired renal function (ie, Cr 30 
m /min) as indicated by abnormal creatinine or BUN values or clinically 
significant abnormal urinary constituents (eg albuminuria)at screening 
or baseline visits
11 Women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, unless they are using 
highly effective methods of contraception for the duration of the study
and for at least 3 days after the last dose of the study drug or untilthe 
end-of-study visit, whichever occurs later
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(eg age appropriate, 
history of vasomotor symptoms) or have had surgical bilateral
oophorectomy (with or without hysterectomy) or tubal ligation at least 
si weeks priorto enrollment In the case of oophorectomy alone, the 
reproductive status ofthe woman must havebeen confirmed by follow 
up hormone level assessment to be considered not of child-bearing 
potential
12
mokers (use of inhaled tobacco products in the previous 3 months) 
Urine cotinine levels will be measured during screening and at baseline 
for all patients mokers will be defined as any patientwho reports 
inhaled tobacco use in the previous 3 months and/or who has a urine 
cotinine  500 ng/m (E-cigarettes and nicotine patches are permitted 
concomitant medications)
13
eually active males unless they agree to use a condom during 
intercourse 
for the duration of the studyand for at least 3 days afterthe 
last dose of the study drug or until the end-of-study visit, whichever 
occurs later,and agree to not father achild in this period A condom is 
reuired to be used also by vasectomized men inorder to prevent 
delivery of drug or its metabolites via seminal fluid
14 Recent (within the last one year) and/or recurrent history of autonomic 
dysfunction(eg recurrent episodes of fainting, palpitations, etc)
15 A positive IV, epatitis B Ag or epatitis C Ab test result (unless 
previously treated andconfirmed epatitis C cleared)
16
istory of drug or alcohol abuse within the 12 months prior to dosing, 
or evidence ofsuch abuse as indicated by the laboratory assays 
conducted during screening andbaselinevisits
17 Any changes in concomitant medications during the 4weeks prior to 
screening and baseline visits ver-the-counter oral and topical 
medications, such as paracetamol/acetaminophen,antihistamines, etc
may be used in line with the product labels

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18 Patients on Prohibited medications as listed in ection52of the study 
protocol, and in the
uidance on Prohibited and Concomitant 
Medications provided in the site operations manual (
M), will be 
ecluded from the study 
Investigational and 
reference therapy
QBW276 or placebo in multiple inhaled doses
Efficacy/PD
assessments
Percent predicted forced epiratory volume in 1 second ( EV1) 
assessed by spirometry
ung Clearance Inde ( CI) assessed by Multiple Breath Nitrogen 
Washout(Cohorts 1  2 only)
Air trapping (RV/T C) assessed by lung volume measurement(Cohorts 
afety assessments
Vital signs
Physical eam
afety laboratory tests 
Pregnancy tests in women of child bearing potential
EC
Metabolite screening assay
AE and AE reporting
ther assessments
Drug and metabolite pharmacokinetics
Data analysis
Cohorts 1 and 2:Adverse events will be counted within each cohort/dose-
level by treatment received and corresponding percentages tabulated Data 
from subects receiving placebo may be pooled for cohorts 1 and 2of the 
study The numbers and percentages will be tabulated by system organ 
class, preferred term and severity A patient with multiple adverse events 
within a body system is only counted once towards the total of this body 
system
Cohort 3: The percent of predicted EV1measured on Days7, 14, 21and 
28 of each treatment period at the study site will be analyzed using mi ed 
effects modelfor repeated measurements The model will include fied 
effects for period, time (Days 7, 14, 21, 28), hypertonic salineuse,treatment 
and treatment by timeinteraction term ubectwill be included as a random 
effect and time will be repeated within each patient by period interaction
ubect average baseline and period adusted baseline will be fitted as 
covariates The difference in adusted means along with 80  two-sided 
confidence intervals together with standard error ( E) and P-value will be 
calculated for the contrast of QBW276 vs Placebo These will be calculated 
at all time-points, and specifically at the primary time-point of interest (Day 
28) using Placebo as the reference treatment
ey words
Cystic fibrosis, inflammation, Percent of predicted EV1, CI, C Q-R 
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1 
Introduction
11 
Background
Cystic fibrosis (C) is the most common lethal autosomal recessive hereditary disease of 
Caucasians, caused by mutations in the gene encoding the cystic fibrosis transmembrane 
conductance regulator (C TR), a chloride channel resident on the surface of epithelial cells in 
several body organs such as the airways, intestine, pancreas, bile ducts, and kidney 
( ullivanandreedman2009) With an incidence of 1 in 2,500 live births in Caucasians, C 
is estimated to affect approimately 30,000 patients in the U and 70,000 patients worldwide 
(Cysticibrosis oundation2012a) Despite a consistent increase in the life epectancy of C 
patients over the last three decades, predominantly due to the implementation of symptomatic 
therapies, the median predicted survival in the U is still only 35-40 years of age 
(Cysticibrosis oundation2012b) Although C is a chronic disorder affecting the epithelial 
cells of multiple organs (eg lung, gastrointestinal tract, pancreas), 90 of morbidity and 
mortality in 
C 
is currently 
associated with 
severe lung disease 
(Cysticibrosis oundation2012b) Inthe lungs, C reduces the clearance of mucus which 
leads to an increased risk of bacterial and viral infections In addition to the increased risk and 
therefore freuency of respiratory infections, C airways are characterized by an eaggerated 
inflammatory response that eventually leads to the destruction of lung tissue and a progressive 
decline in lung function There is no cure for C tandard of care therapies include mucolytics, 
antibiotics, and anti-inflammatory agents that treat the downstream disease processes that are 
secondary to the genetic defect Ivacaftor, a specific C TR potentiator, has been approved by 
health authorities for a small group of patients ( 10 ) with one of 10 rare C mutations 
Combination therapy of Ivacaftor with umacaftor, a C TR corrector, has recently been 
approved by some health authorities for patients with two copies of the 508del mutation 
(approimately 48 of all C patients) It provides modest clinical benefit, but is ineffective in 
patients who carry only one copy of the 508del mutation (approimately 40 of all C 
patients) ence, there continues to be an unmet medical need for additional interventional 
agents to treat the maority of patients with C
It is now widely accepted that the defect in C TR function leads to a dehydration of respiratory 
secretions (DonaldsonandBoucher 2007) Normal C TR protein function promotes anion and 
therefore fluid secretion into the airway lumen, a process that is balanced by the active 
absorption of Na and therefore fluid by the epithelial sodium channel, ENaC Theseion 
transport processes maintain an adeuate volume of airway surface liuid (A ) in non-C 
lungs to ensure the effective hydration and clearance of mucus by both mucociliary clearance 
(MCC) and cough clearance (CC) (DonaldsonandBoucher 2007) In C, C TR-mediated 
anion secretion is impaired, thereby limiting the ability of the airway epithelium to secrete fluid 
into the airway lumen Additionally, 
ENaC-mediated Na absorption is enhanced in C, leading
to an accelerated rate of fluid absorption The net effect of the imbalance inthese ion and fluid 
transport processes in C is to reduce the volume of A
 available for the hydration of secreted 
mucus and conseuently impairment in MCC (DonaldsonandBoucher2007)
A therapy designed to improve the hydration of respiratory secretions by blocking sodium 
reabsorption through durable attenuation of ENaC function is predicted to produce a sustained 
enhancement of mucociliary clearance, thereby reducing the freuency of respiratory infections 

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and slowing the decline in lung function (irsh2002) This rehydration approach has been 
tested clinically in C using inhaled amiloride, a direct blocker of the epithelial sodium channel 
(ENaC) Inhaled amiloride produced an enhancement of mucociliary clearance (Appet al 1990), 
and initial promising reports regarding improvement in lungfunction (nowlesetal1990) 
however with a prohibitively short duration of action in the airways and an estimated 
elimination half-life of around 23 minutes (ofmannetal1997) this compound lacked any 
robust clinical benefit (Pons et al 2000) Inhaled hypertonic saline, which increases A
 volume 
in vitro(Donaldson et al 2006), has been demonstrated to accelerate muco-ciliary clearance 
(MCC), reduce thefreuency of pulmonary eacerbations, and improve lung function in C 
(Elkinsetal 2006and Donaldsonetal2006) an early indication that an enhancement of MCC 
will be of clinical benefit in the disease Unfortunately, hypertonic saline is often poorly 
tolerated in the clinic due to cough and bronchospasm, and thus there is a need for novel 
therapies targeting ENaC in the airway (DonaldsonandBoucher2007
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A potential conseuence of an inhaled ENaC inhibitor is systemic eposure resulting in ENaC 
inhibition in the kidney ENaC inhibition in the kidney can lead to hyperkalemia, hyponatremia, 
volume depletion, and a compensatory increase in aldosterone 
 
 
 
 
n this 
basis, QBW276 represents a noveltherapy with a potential for being disease-modifying in C 
while avoiding the potential complications of hyperkalemia, hyponatremia, volume disturbance, 
and compensatory aldosterone elevation
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12 
tudy purpose
The purpose of the study is to assess safety, tolerability, pharmacokinetics  
 
 of multiple doses of inhaled QBW276 in patients with C to support 
potential clinical development in this indication
2 
tudy obectives
21 
Primary obective(s)
Primary bective:  Cohorts 1 and 2 
Endpoints 
To assess the safety, tolerabilityand P 
of multiple doses of inhaled QBW276 
and its metabolites over1 or2 weeksof 
treatment in patients with C
All safety assessments during the cohort 
period, including:
Physical eamination
ematology
Blood chemistry (central and local 
labs)
Urinalysis
EC evaluation
Vital igns
AEs and AEs
P measurements
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Primary bective:  Cohort 3
Endpoints
To evaluate the pharmacodynamic 
response to multiple doses of inhaled 
QBW276 in lung function (percent of 
predicted EV1) over 4 weeks of 
treatment compared with placebo in 
patients with C that are homozygous 
for the 508del mutation
 
predicted 
EV1
(assessed by 
spirometry)
22 
econdary obective(s)
econdary bective:  Cohorts 1 and 2 
Endpoints
To evaluate the pharmacodynamic 
response to  multiple doses of inhaled 
QBW276 on change in lung function 
(percent of predicted EV
1and CI) in 
patients with C
 predicted EV1(assessed by 
spirometry)
CI
25(assessed by Multiple Breath 
Nitrogen Washout MBNW) if EV1at 
screening is  80 of predicted
econdary bective:  Cohort 3
Endpoints
To assess the safety, tolerability, P and 
PD of multiple doses of inhaled 
QBW276 and its metabolites over 4 
weeks of treatment in patients with C 
who are homozygous for the 508del 
mutation
All safety assessments during the cohort 
period, including:
Physical eamination
ematology
Blood chemistry
Urinalysis
EC evaluation
Vital igns
AEs and AEs
P measurements
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3 
Investigational plan
31 
tudy design
This is a study of multiple doses of inhaled QBW276 in patients with C on top of tandard of 
Care,including hypertonic saline, C TR potentiators and correctors, if applicable Thestudy 
will be divided into three cohortsCohorts 1 and 2 are designed to be a randomized, double-
blind, placebo-controlled, parallel armmultiple ascending dose study of the safety, tolerability, 
P and preliminary efficacy of inhaled QBW276 over 1 week (cohort 1) and 2weeks (cohort2) 
in patientswith C regardless of their genotype The primary rationale for cohorts1 and 2 will 
be to assess P, safety and tolerability inC Cohort 3 is a randomized, double-blind, placebo-
controlled, cross-over designmultiple dose study of the efficacy,safety, tolerability, andP of 
inhaled QBW276 over 4 weeks in patientswith C who are homozygous for the 508del 
mutation The primary rationale for cohort 3 will be to assess efficacy in a high unmet need C 
patient population 
igure 3-1  
chematic for study design 
Cohort 1will receive 3 mg bid dose (6 mg/day) or placebo over 1 week This dose selection is
based on safety and tolerability data obtained from healthy volunteers in the first-in-human 
CQBW276X2101 study Upward, downward, orrepeat dosing will continue in cohorts 2 and 3, 
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as long as the systemic eposure cap based on pre-clinical data or a clinical maimum tolerated 
dose(MTD)is not eceeded Cohorts 1 and 2 will enroll 8 patients each, with 6 patients 
randomized to receive active drug and 2 patients randomized to receive matching placebo 
Cohort 1 will be dosed for 1 week while cohort 2 will bedosed for 2weeks Cohort 2 will be 
initiated only after cohort 1 has completed dosing Cohort 2 may be skipped if safety, 
tolerability, P and PD data from cohort 1 are found favorable to proceed directly to cohort 3 
In cohorts 1 and 2, patients may be replaced if they do not complete the study duration for 
reasons other than safety to obtain 8 completers in each cohort If a patienthas participated in 
cohort 1, he/she may ualify to participate in cohort 2contingent upon approval from the 
sponsor, as long as he/she has been through a 4 week wash-out between dosing in the two 
cohorts, and has not eperienced any significant AEssince enrollmentin cohort1 This will 
ensure that no patient receives more than 4 weeks of the investigational drug QBW276 in his/her
lifetime until further supportive toicology studies are conducted in the drugs development 
program
N TE: No patient randomized to cohort 1 or 2will be eligible for cohort 3
Cohort 1 and 2
Cohorts 1 and 2 will consist of a21 dayscreening period followed by a baseline visit anda 7 
or 14 day Treatment Period in cohort 1 and 2, respectively Adeuate windows will be provided 
for patients convenience QBW276 will be administered on top of the patients usual standard 
of care medications
tudy inclusion/eclusion criteria as well as medication use will be assessed at screening 
Patients who meet the inclusion/eclusion criteria at screening will report to the study site on 
Day -1 at a time specified by the investigator, for the baseline assessments All baseline safety 
evaluation results must be available prior to dosing on Day 1, hence, Day -1 assessments can 
be carried out up to 72 hours prior to Day 1 dosing 
Patients who meet all of the inclusion and none of the eclusion criteria at baseline will then 
report to the study site on Day 1 and will remain in the clinic until at least 6 hours after the first 
dose in the morning
n Day 1, pre-dose safety, biomarker, P blood draw,and urine collection will be performed 
ollowing the pre-dose procedures,subects will be randomized Post-dose evaluations will 
include routine safety evaluations and blood for P assessments The patients will be asked to 
return to the study site for follow-up visits as specified on the respective assessment schedules 
(ection8)
afety will be monitored by assessment of vital signs, physical eamination, EC, clinical 
laboratory evaluations (hematology, blood chemistry, and urinalysis), urine electrolytes, 
aldosterone in plasma, lung function, and monitoring of adverse events (AEs) throughout the 
study P (drug and metabolites) and safety biomarkers (blood and urine electrolytes and 
plasma aldosterone) measured in cohorts1and 2will be compared withdata from the healthy 
volunteer study
A blindedreviewof datawill be conducted after completion of each cohort prior to initiation 
of the net cohort The ponsor (medically ualified representative) in conunction with the
designated site Investigator(s) will review blinded data (including lung function, AEs, vital 

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signs, safety laboratory parametersincluding aldosterone values, and P) An eternal data 
monitoring committee (DMC) will also be assembled to monitor study safety data as per an 
approved charter After the first 4 patients in Cohort 1 have completed the Day 7 study 
assessments, the P data may be reviewed by the study pharmacokineticist to compare eposure 
levels with previously observed data in healthy patients
Cohort 3
Dosing in cohort3 will not commence until the ponsor (medically ualified representative) in 
conunction with the designated site Investigator(s) have reviewed all available safety, 
tolerability, P, and PD data from cohorts 1 and/or 2 Endorsement for the dose selected for 
cohort 3 will also be sought from the DMC members perthe DMC charter

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igure 3-2 
chematic for Cohort 3 study design

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or Cohort 3, patients will be randomized to one of two treatment seuences: QBW276 in 
Period 1 and Placebo in Period 2 or Placebo in Period 1 and QBW276 in Period 2 Based on 
drop-out rates observed during conduct of the study, up to 40 patients will be randomized to 
ensure that at least 24 patients complete the study After a 45 dayscreening period, patients 
who meet all inclusion and eclusion criteria will receive drug for 4 weeks and placebo for 4 
weeks, separated by a washout period of approimately 3 to 4 weeks in patients who cycle 
inhaled antibiotics Washout period may be shortened to 2 weeks in patients who do not cycle 
inhaled antibioticsQBW276 will be administered on top of the patients usual standard of care 
medications or patients on cyclic inhaled antibiotics,baseline for periods 1 and 2 will 
commence on approimately day7(0/3) of the patients standard of care cyclic inhaled 
antibiotic regimen  Patients who use the same inhaled antibiotic throughout the year may start 
the study on any antibiotic day
creening and baseline visits for cohort 3 will be similar to the respective visits in cohorts1 and 
2 n Day 1 of cohort 3, pre-dose safety, efficacy 
 will be performed 
ollowing the pre-dose procedures eligible patients will be dosed for up to 28days Post-dose 
evaluations will include routine safety evaluations and blood for P assessments The patients 
will be asked to return to the study site for follow-up visits on Days7, 14, 21, and 28 after which 
they will undergo an approimately 3 to4 week wash-out period (may be shortened to 2 weeks 
in patients whodonot cycle inhaled antibiotics) prior to cross-over to the opposite arm, and 
follow a similar visit schedule until End of tudy assessment approimately 7 days after the last 
visit in the second period All patients will undergo the same assessments regardless of their 
dose 
Efficacy will be evaluated by spirometry and responses to the respiratory domain of the C Q-
R afety will be monitored by assessment of vital signs, physical eamination, EC, clinical 
laboratory evaluations (hematology, blood chemistry, and urinalysis), urine electrolytes, 
aldosterone in plasma, and monitoring of adverse events (AEs) throughout the study
If a maimum tolerated dose for patients with C (MTD) is identified in cohorts 1 or 2on the 
basis of dose-limiting toicity, the predicted eposure at the maimum planned dose in cohort3 
shall not eceed the eposure at the MTD If an MTD is not defined in cohorts1 and2, the 
maimum planned dose in cohort 3 shall not eceed the systemic eposure capbased on pre-
clinical data
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32 
Rationale for study design
Cohort 3 is designed as a cross-over study which is a more powerful design reuiring fewer 
patients than a parallel group design Parallel group designs have significant between patient 
variability in percent of predicted EV1(primary outcome) hence, a cross-over design will 
allow for each patient to be his/her own control 
The use of a placebo arm in both parts of the study is to provide a comparison group for an 
unbiased collection of safety, tolerability, P/ , and efficacy data in a blinded manner
The rationale to allow C TR modulators (correctors, potentiators, etc), chronic inhaled and 
systemic antibiotics 
 during the studyis related to the fact that many 
patients are/will betreated with these drugs as routine standard of care ome C patients 
standard of care regimen may include treatment with systemic antibiotics on a chronic basis 
ome C patients with chronic respiratory infections are prescribed inhaled antibiotics (for 
instance Tobramycin or vancomycin) which are alternately cycledafter 4 weeks of therapy, or 
patients may have a 4 week antibiotic holiday between two 4 week antibiotic cycles  
 
33 
Rationale of dose/regimen, duration of treatment
Cohorts 1 and 2: Up to 16 patients with C (8 patients in each cohort, regardless of genotype) 
will complete 7 to 14 days of inhaled QBW276 or placebo via the concept 1 inhaler Cohort1 
will receive 3 mg bid dose, which is based on safety, tolerability, P and adverse event data 
obtained from the CQBW276X2101 healthy volunteer study
Cohort 3: Cohort 3 will be restricted to C patients who are homozygous for the 508del 
mutation, 
This may also help reducevariability in baseline characteristics of patients in this small study
Patients will receive 4 weeks of drug and 4 weeks of placebo, separated by a washout period of 
approimately 3 to 4weeksin patients who cycle inhaled antibiotics Washout period may be 
shortened to 2 weeks in patients who do not cycle inhaled antibiotics or patients on cyclic 
inhaled antibiotics, the baseline visitwill be on approimately the 7th
Corporate Confidential Information
day (0/3days) of inhaled 
antibiotic use during their28 day antibiotic cycle Patients who use the same inhaled antibiotic 
throughout the year may start the study on any antibiotic dayPatients will take their inhaled 
antibiotic therapy at approimately the same time during the study as they would usually at 
home
 
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Cohort 1 -The first cohort will be dosed at 3 mg bid to begin assessment of safety and 
tolerability in C because this dose has been 
 
 and found to be safe and well tolerated 
 
 
 The dose and freuency will 
be proposed by the sponsor at the data review, and will reuire approval from the designated 
site Investigator(s) and endorsement from the independent DMC The maimum dose in cohort
3will be epected to not eceed 6 mg bid 
 
 
 
 
 
 
 
 P data will be assessed after each dose cohort completes the study to confirm 
that an appropriate eposure margin eists before escalating to the net dose level
Cohort 3 The dose selected for cohort 3 will be one that is epected to be safe and well-
tolerated over 4 weeks of treatment based on blinded data obtained from cohorts 1 and 2after 
7 to 14 days of treatment If a maimum tolerated dose for patients with C (MTD) is identified 
in cohorts 1 or 2on the basis of dose-limiting toicity, the predicted eposure at the maimum 
planned dose in cohort 3shall not eceed the eposure at the MTD If an MTD is not defined 
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Information

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in cohorts 1 or 2, the maimum planned dose in cohort 3shall not eceed the systemic eposure 
cap based on pre-clinical data The efficacy of the proposed dose will be ustified by the lung 
function measurements which will be conducted during cohorts 1 and 2 
 
 
34 
Rationale for choice of comparator
This is a placebo controlled study The use of a double blind placebo arm as a comparator is to 
provide a comparison group for an unbiased collection of safety and tolerability data
36 
Risks and benefits
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While patients who participate in the study may notice an improvement in their symptoms 
and/or lung function, this is not epected because of the eploratory nature of this study 
QBW276 has been safe and well tolerated 
 at doses eamined and the 
risk/benefit assessment remains supportive for eamination in patients with C
 
 
 
 
 
The risk to patients in this trial will be minimized by adherence to the eligibility 
criteria, close clinical and laboratory monitoring, stopping rules and dosing well within the 
safety margins of the systemic eposure cap determined from pre-clinical toicity studies 
Patients will be closely monitored for changes in vital signs, serum electrolytes, EC intervals 
and lung function Plasma aldosterone will be monitored between cohorts during the study
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A maimum of 333 m  and 371 m  of blood is planned to be collected for Cohorts 1 and 2 
over a period of 18 (21) and 25(21) days, respectively A maimum of 421 m  of blood is 
planned to be collected over a period of 105 (16) days in cohort 3 Additional samples for 
clinical monitoring of any abnormal laboratory values may be collected This is not considered 
to be a risk for this population
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 pre-specified contraception reuirement for 
the duration of the studyand for at least 3 days after the last dose of the study drugor until the 
end-of-study visit, whichever occurs later If there is any uestion that the patientwill not 
reliably comply, they should not be randomizedin the study
Refer to eclusion criteria for further details in ection42
There may beunknown risks of QBW276which may be serious and unforeseen
4 
Population
The study population will be comprised of male and female patients aged 18 and above with a 
diagnosis of C Patients in cohort 3 will be restricted to those who are homozygous for the 
508del mutation
The investigator must ensure that all patientsbeing considered for the study meet the following 
eligibility criteria No additional criteria should be applied by the investigator, in order that the 
study population will be representative of all eligible patients
Patientselection is to be established by checking through all eligibilitycriteria at screening and 
baseline A relevant record (eg checklist) of the eligibility criteria must be stored with the 
source documentation at the study site
Deviation from any entry criterion ecludes a patientfrom enrollment into the study
41 
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1 Written informed consent must be obtained before any assessment is performed
2
Male and female patients of age 18 and above with a confirmed diagnosis of 
C , all 
mutations as per the Cystic ibrosis oundation consensus guidelines (arrelletal2008)
3
or Cohort 3, male and female patients of age 18 and above with a confirmed diagnosis of 
C , who are homozygous for the 508del mutation
4
hould be on stable medical regimen in the 4 weeks prior to screeningand baseline visits
(Cohorts 1  2: creening Cohort 3: creening (v1) and Baseline (v2))
5
hould be established as clinically stable to participate in the study in the udgment of a 
site investigator at the screening and baseline visit
6
EV1must be between 40 and 100 predicted (inclusive) by N ANE/ ankinson 
standards at screeningand baseline visits(may be repeated onceat screening and once at 
baseline)(Cohorts 1  2: creening Cohort 3: creening (v1) and Baseline (v2))
7
CI
25  8 at screening if EV1  80 (Cohorts 1  2 only)

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8 Must pass the metabolite screening assay prior to baseline visit
9 Must demonstrate abilityto communicate well with the investigator, to understand and 
comply with the reuirements of the study
42 
Eclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study 
Noadditional eclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients
1 Use of other investigational drugs at the time of enrollment, or within 5 half-lives of 
enrollment, or within 30 days, whichever is longer or longer if reuired by local regulations 
The only eception to this is QBW276 If a patient has participated in cohort 1 of 
CQBW276X2201, he or she will ualify to participate in cohort 2 contingent up on approval 
from the sponsor, as long as he/she has been though a 4 week wash-out between dosing in 
the two cohorts, and has not eperienced any significant AEs since enrollment in cohort 1 
This will ensure that no patient receives more than 4 weeks of the investigational drug 
QBW276 in his lifetime until further supportive toicology studies are conducted in the 
drugs development program Note that patients who participate in cohorts 1 or 2 cannot 
participate in cohort 3
2 istory of significantly uncontrolled or untreated cardiovascular, adrenal or electrolyte 
abnormalities
3 istory of malignancy of any organ system (other than localized basal cell carcinoma of the 
skin), treated or untreated, within the past 5 years, regardless of whether there is evidence 
of local recurrence or metastases
4 istory of lung transplant
5 Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation
6 A history ofclinically significant EC abnormalities, or any of the following EC 
abnormalities at screening or baselinevisits:
PR  200 msec
QR comple  120 msec
QTc  450 msec (males)
QTc  460 msec (females)
7 istory of adverse reaction or hypersensitivity toany of the study drugs, ecipients(eg 
lactose)or to drugs of similar chemical classes, such as amiloride
8 Any upper respiratory tract infection (eg common cold, influenza, sinusitis) or signs or 
symptoms thereof within 4weeks prior to dosing that, in the opinion of the investigator, 
may eopardize the patient or the study data in case of the patients participation in the study
9 Clinical evidence of liver disease or liver inury as indicated by clinically significant 
abnormal liver function tests as udged by the investigator, such as 
T, 
PT, 
T, 
alkaline phosphatase, or serum bilirubinat screening orbaselinevisits

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10Clinical evidence of significantly impaired renal function (ie, C r 30 m /min) as 
indicated by abnormal creatinine or BUN values or clinically significant abnormal urinary 
constituents (eg,albuminuria)at screening orbaselinevisits
11Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception for the 
duration of the study and for at least 3 days after the last dose of the study drugor until the 
end-of-study visit, whichever occurs later
ighly effective contraception methods include:
Total abstinence (when this is in line with the preferred and usual lifestyle of the patient 
Periodic abstinence (eg calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception
emale sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least si weeks before taking study treatment  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 m prior to screening) or female patients in the study, the 
vasectomized male partner should be the sole partner for that patient
Use of oral, inected or implanted combined hormonal methods of contraception or 
placement of an intrauterine device (IUD) or intrauterine system (IU)or other forms of 
hormonal contraception that have comparable efficacy (failure rate 1 ), for eample 
hormone vaginal ring or transdermal hormone contraception
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment
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 (eg age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy) or tubal ligation at least si weeks prior to enrollment 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
12 mokers (use of inhaled tobacco products in the previous 3 months) Urine cotinine levels 
will be measured during screening and at baseline for all patients mokers will be defined 
as any patient who reports inhaled tobacco use in the previous 3 months and/or who has a 
urine cotinine  500 ng/m  (E-cigarettes and nicotine patches are considered permitted 
concomitant medications)
13 eually active males unless they agree to use a condom during intercourse for the duration 
of the studyandfor at least 3 days after the last dose of the study drug or until the end-of-
study visit, whichever occurs later,and agree to not father a child in this period Acondom 
is reuired to be used also by vasectomized men in order to prevent delivery of drug via 
seminal fluid
14Recent (within the last one year) and/or recurrent history of autonomic dysfunction 
(eg,recurrent episodes of fainting, palpitations, etc)

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15A positive IV, epatitis B Ag or epatitis C Ab test result (Unless previously treated and
confirmed epatitis C cleared)
16 istory of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such 
abuse as indicated by the laboratory assays conducted during screening and baselinevisits
17Any changes in concomitant medications during the 4-weekprior to screening and baseline 
visits ver-the-counter oral and topical medications, such as paracetamol/acetaminophen, 
antihistamines, etc may be used in line with the product labels
18Patients on Prohibited medications as listed in ection 52of the study protocol and in the 
uidance for Prohibited and Concomitant Medications provided in the 
M, will be 
ecluded from the study
Note: In the case where a safetylaboratory assessmentat screening and/orinitial baselineis 
outside of the normal rangeand considered clinically significant, the assessment may be 
repeated once prior to randomizationNon-clinically significant abnormal values need not be 
repeated ifthis is deemed appropriate by the investigator
No additional eclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients
5  
Restrictionsfor tudyPatients
During recruitment,screening/informed consent review, and baseline visit, the patientsmustbe 
informed and reminded of the following restrictions:
51 
Contraception re uirements
Please refer to eclusion criteria (ection 4) for details of contraception reuirements for the 
study 
52 
Prohibited treatmentand rescreening
If a patient eperiences a respiratory infection or eacerbation which reuiressystemic 
antibiotics and/or systemic glucocorticoids at any time, he/she will be discontinued from the 
study e/she may be rescreened if he/she subseuently fulfills the reuired inclusion/eclusion 
criteria for the studyNote that chronic inhaled and/or systemic antibiotics are permitted as 
concomitant medications during the study, if they are considered the patients standard of care 
at screening and baselinevisits
If a patient is deemed a screened failure, he/she maybe rescreened once based on the 
investigators udgement
Patients who have failed to meet AT reuirements for acceptability/reproducibility for 
pirometry or MBNW(Cohorts 1  2), will be allowed one additional repeat testing session at 
creening and/orBaseline in order to meet inclusion criteria or additional details on 
rescreening and retesting, please refer to the site operations manual (
M) 
Patients should refrain from using their short and long acting bronchodilators for 6, 12 or 
24hours as described in the site operations manual (
M) to enable measurement of trough 

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lung function If the patient is not able to withhold rescue medications due to bothersome 
symptoms, the patient may be rescheduled if deemed appropriate by the investigative site
Butylcholinesterase and acetylcholinesterase inhibitorsare prohibited because QBW276 is 
hydrolyzed mainly by butylcholinesterase and acetylcholinesteraseenzymes Patients who are 
either on these inhibitors or patients who fail the butylcholinesterase screening assay will be 
ecluded from the study The following butylcholinesterase and acetylcholinesterase inhibitors 
are prohibited:
Aclidinium bromide
Amitriptyline
Citalopram
Donepezil
Ecothiopate
alantamine
ovastatin
Neostigmine
Rivastigmine
imvastatin
ertraline
Tacrine
Patients who are prescribed these medications during the course of the study should be 
immediately discontinued from the study and the ponsor must be informed  The list of 
prohibited medications is not inclusive and subects may be eposed to non-medicinal 
butyrylcholinesterase inhibitors, such as insecticides, which should be monitored
53 
Dietary restrictions and smoking 
mokers (use of inhaled tobacco products in the previous 3 months)will be ecluded from 
participating in the study Urine cotinine levels will be measured during screening and at 
baseline for all patients mokers will be defined as any patientwho reports inhaled 
tobacco use in the previous 3 months and/or who has a urine cotinine  500ng/m 
(E-cigarettes and nicotine patches are permitted concomitant medications)
No alcohol for 48 hours prior to all clinic visits and while in the clinic During the 
treatment phase of the study, alcohol consumption is restricted to no more than 2 regular 
drinks/day
Caffeine restriction should apply for 4 hours prior to the start of lung function testing 
Patients should refrain from drinking caffeine for 4 hours prior to the start of these tests
6 
Treatment
61 
tudy treatment
Details on the storage and management of study medication, randomization,and instructions 
for prescribing and taking study treatmentare outlined in the M

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611 
Investigational treatment
The investigational drug QBW276 15 mg strengths and matching placebo capsules, and if 
reuired, 03 mg strengths and matching placebo capsules) will be prepared by Novartis and 
supplied to the Investigator in blister packsNovartis willalso supply the Concept1 inhalation 
devices to the Investigator
612 
Additional study treatment
The patient or the Investigational site is responsible for sourcing all additional study treatments 
listed in the protocol, including but not limited to:
ypertonic aline
Inhaled antibiotics
Rescue inhalers
62 
Treatment arms
Cohort 1 and 2:
Patients will be assigned to one of the following 2 treatment arms in a ratio of 3:1 In each 
cohort (n8), there will be 6 patients randomized to receive QBW276 and 2 patients randomized 
to receive Placebo
tudy treatments are defined as:
Cohort 1:
QBW276 3mg bid
Placebo to QBW276 3mg bid
Cohort 2:
QBW276 Dose 6 mg bid 
Placebo to QBW276 Dose 6 mg bid 
Cohort 3:
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tudy treatments are defined as:
A:  QBW276 Dose B (no more than 6 mg bid)
B:  Placebo to QBW276 Dose B(no more than 6 mg bid)
63 
Permitted dose adustments and interruptions of study treatment
In case of notable adverse events, safety concerns and/or based on pharmacokinetic data during 
review of data at the end of a cohort, the following changes to the net planned dose level may 
be considered:
Administration of a dose below the starting dose
Administration of an intermediate dose between the current and preceding dose
Administration of an intermediate dose between the current and net planned dose
Repeated administration of the current dose
Termination of any further doses
These changes must be recorded on the Dosage Administration Record CR
64 
Treatment assignment
If a patient is deemed eligible for enrollment into the study, they will be randomized and 
treatment will be assigned via the IRT system
65 
Treatment blinding
This is a double blind study: Patients, investigator staff, and persons performing the assessments 
will remain blind to the identity of the treatment from the time ofrandomization until database 
lock, using the following methods: (1)Randomization dataare kept strictly confidential until 
the time of unblinding, and will not be accessible by anyone else involved in the study with the 
following eceptions: P bioanalyst, clinical pharmacologist, and persons involved in the 
interim analyses as specified in the 
M and (2) The identity of the treatments will be concealed 
by the use of study drugs that are all identical in packaging, schedule of administration, 
appearance, taste and odor
Unblinding will only occur in the case of patient emergencies (seeection66
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), at the time of 
the interim analysis and at the conclusion of the study
urther information regarding blinding (and unblinding) is presented in the 
M

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66 
Emergency breaking of assigned treatmentcode
Emergency unblinding should only be undertaken when it is essential to treat the patientsafely 
and efficaciously Most often, study treatment discontinuationand knowledge of the possible 
treatment assignments are sufficient to treat a study patientwho presents with an emergency 
condition Emergency code break canbe performed via theIRTsystemTheinvestigator must 
also immediately inform the Novartis local monitor that emergency unblinding has occurred 
via IRT
It is the investigators responsibility to ensure that there is a procedure in place to allow 
unblinding via the IRT systemin case of emergency If appropriate, the investigator will inform 
the patienthow to contact his/her backup in cases of emergency when he/she is unavailable
The appropriate site personnel and the sponsor will do an assessment after an emergency 
unblinding to assess whether or not study drug should be discontinued for a given patient
67 
Treatment e posure and compliance
As dose administration will occur in the research clinic and at home, compliance will be 
confirmed as fully as possible by site staff checking medication as it is returned by the patient
(any doses administered in the clinic will be checked by site staff)  The patient will inhale the 
first dose at the research clinic and receive training at the research clinic on the use of the inhaler 
and study medication
Patientswill also document their study drug administration time in the clinic and at home on a 
paper diary
The correctallocation of study drug and number of doses taken by the patientwill be confirmed 
via drug accountability procedures
ite staff will enter drug administration information (at least date/time/dose) into the eCR to 
ensure a complete record of dosing foreach patient
Pharmacokinetic parameters (measures of treatment eposure) will be determined in all patients
treated withQBW276, as detailed inection 85
68 
Recommended treatment of adverse events
There is no specific anti-dote for the compound In case of an overdose or other adverse events 
such as hyperkalemia, the patient should be monitored and managed at the discretion of the 
treating physician Medication used to treat AEs must be recorded on the Concomitant 
medications/ignificant non-drug therapies CR
69 
Rescue and bronchodilator medication
Patients should refrain from using their short and long acting bronchodilators for 6, 8, 12 or 
24hours as described in the 
M to enable measurement of trough lung function If the patient 
is not able to withhold rescue medications due to bothersome symptoms, the patient may be 
rescheduled if deemed appropriate by the investigative site If rescheduling the patient is not 
feasible, the visit may continue but the use of a bronchodilator during the restricted time prior 
to P T assessments must be noted in the CR, and captured in the nDD Easy ne Pro ab device 

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If this use occurs after the start of study treatment (ie after Visit 101), it also must be 
documented in the Concomitant medications/ignificant non-drug therapies CR
 
 
ence, patients are permittedto use their shortor long-acting bronchodilator 
immediately prior to administration of the study drug if they wish to, as long as pre-dose lung 
function measurements have been completedduring study visitsThe study staffwill have the 
opportunity to perform unscheduled spirometrymaneuvers if they wish to evaluate the patient 
for post-drugbronchospasm based on the patients signs and symptoms, and administer 
additional bronchodilator if needed These events may be captured as adverse events if 
appropriate
Patients who take multiple inhaled medications as part of their standard of care may continue 
to do so 
 
 
610 
Concomitant treatment
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the timeframe 
defined in the entry criteriaprior to the start of the study and during the study, must be recorded 
on the Concomitant medications/ ignificant non-drug therapies section of the CR
Medication entries should be specific to trade name, the single dose and unit, the freuency and 
route of administration, the start and discontinuation date and the reason for therapy
Please refer to ection 52and the 
M for permitted and prohibited concomitant medications 
for study participants
7 
Discontinuationand study completion
71 
Discontinuation of study treatment
Patientsmay voluntarily discontinuestudy treatment for any reason at any time
tudy treatment mustbe discontinued under the following circumstances: 
Patient withdraws consent
Pregnancy
A serious adverse event that is suspected of being related to study drug
Corporate Confidential Information
The site investigator udges that continuation would be detrimental to the patients well-being
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Emergence of the following adverse events: 
n-treatment increase in QTc  60 ms from baseline    
Clinically significant and/or persistent serum electrolyte or other laboratory 
abnormalities
If a patient has an eacerbation during the study, the patient should be discontinued and 
may be replaced
Use of prohibited treatment as per ection 52and the Prohibited and Concomitant 
Medication uidance provided in the 
M
Any other protocol deviation that results in a significant risk to the patients safety
Investigators discretion if the physician perceives a significant risk to the patients safety
or study data integrity
Cohorts 1 and 2: if a patient misses  4 doses, either between visitsor consecutive doses 
overall
Cohort 3: if a patient misses  8 doses, either between visits or consecutive doses overall
The appropriate personnel from the site and Novartis will assess whether treatment should be 
discontinued for any patientwhose treatment code has been broken inadvertently for any reason
The appropriate personnel from the site and Novartis will assess whether treatment should be 
discontinued for apatientwho hasbeen prescribed a new standard of care treatment or 
concomitant medication which may impact the integrity of study data 
Patientswho discontinue study treatment or who decide they do not wishto participate in the 
study further should N T be considered withdrawn from the study UN E  they withdraw 
their consent (see ection 74) Where possible, patientsshould return for theEnd of tudy 
assessments listed in the assessment table If they fail to return for these assessments for 
unknown reasons, every effort (eg telephone, e-mail, letter) should be made to contact them 
as specified inection 73 
72 
tudy completion and post-study treatment
Each patientwill be reuired to complete the study in its entirety and thereafter no further study 
treatment will be made available to them tudy completion is defined as when the last patient
completes their End of tudy visit, and any repeat assessments associated with this visit have 
been documented and followed-up appropriately by the Investigator, or in the event of an early 
study termination decision, the date of that decision
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them forappropriate ongoing care 
73 
ost to follow-up
or patientswhose 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 patient, eg dates of telephone 

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calls, registered letters, etc A patientshould not be formally considered lost to follow-up until 
his/her scheduled end of study visit would have occurred
74 
Withdrawal of consent
ubects may voluntarily withdraw consent to participate in the study for any reason at any 
time Withdrawal of consent occurs only when a subect:
 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 (eg telephone, e-mail, letter) 
to understand the primary reason for the subects decision to withdraw his/her consentand 
record this information
tudy treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subseuent visits will be considered missing
urther attempts to contact the subect are not allowed unless safety findings reuire 
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 subects 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 subects samples until their time of withdrawal) according to applicable 
law
or U and Japan: 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 andof the 
informed consent form
or 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 reuirements

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75 
tudy topping rules
The study will be placed on clinical hold, no dose escalation will occur in any subseuent 
cohorts and the current dose level will not be repeated if any one of the following occur:
(a) ne AEoccurs in a cohortthat issuspected of being related to study drugby the 
ponsor, pending full safety review
(b) Two similar AEs which are severe (rade 3 or greater) occur in two patients in the 
same cohort and are suspected of being related to study drug by the ponsor, pending 
full safety review
(c) If the mean systemic eposure for the parent drug or metabolites at the current or 
net dose level (using either non-compartmental or P modeling methods) is observed 
or predicted to eceed the eposure at the AUC0-24 at steady state at the N AE of 
504 mg/kg/day in the rat preclinical toicology study
76 
Early study termination
The study can be terminated at any time for any reason by Novartis hould this be necessary, 
patientsshould be seen as soon as possible and treated as a prematurely withdrawn patient End 
of study visit should be completed as soon as possible The investigator may be informed of 
additional procedures to be followed in order to ensure that adeuate consideration is given to 
the protection of the patients interests
The ealth Authorities andIRBs/IECs will beinformed in caseearly termination of the trial

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1Visit structure given for internal programming purpose only
2Early Termination/End of tudy completion (study/treatment discontinuation and premature subect withdrawal should complete all these assessments)
3Pre-dose
4May be completed any time betweenvisit 2 and 101after eligibility is confirmed
0m sample is taken pre-dose all post-dose samples (15 minutes 6 hours) are timed from the start of inhalation
7Central lab collection: odium, potassium, bicarbonate, creatinine, BUN, uric acid, chloride, albumin, calcium, alkaline phosphatase, total bilirubin, D, 
T, A T, 
A T, PT/INR, amylase, lipase, C, glucose, total cholesterol, and triglycerides
8 ocal lab collection: sodium, potassium, chloride, bicarbonate
9 nly to be performed if subects EV1 is 80  of predicted at creening
10 erum pregnancy test
11 Urine pregnancy test/dipstick
12 creening phase completion
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Cohort 1 -Details for highly repetitive assessments
EP C
Visit Name VisitNumber 
Day 
Time (post-dose) Vital igns
P blood collection 
ocal ab Blood Chemistry
CREENIN
creening 
1  
-28 to -7  
-
X
Baseline 
2
-1
-2 0
-
X
TREATMENT
Day 1 
101 
1
0m1
X
X
X
15m
X
30m
X
X
1h
X
X
X
2h
X
X
4h
X
X
6h
X
X
X
Day 2 
102
2
-0 1
0m1
X
X
Day 7 
103
7
-2 2
0m1
X
X
X
15m
X
30m
X
X
1h
X
X
X
2h
X
X
4h
X
X
6h
X
X
X
ET / E
2
199
11
-2 2
-
X
X
10minute (0m)sample is taken pre-dose all post-dose samples (15 minutes 6 hours
nhalationof the morning dose
2  Early termination/tudy completion (study/treatment discontinuation and premature subect withdrawal should complete all these assessments)
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Cohort 2 -Details for highly repetitive assessments
EP C
Visit Name VisitNumber 
Day 
Time (post-dose) Vital igns
P blood collection 
ocal ab Blood Chemistry
CREENIN
creening 
1  
-28 to -7  
-
X
Baseline 
2
-1
-2 0
-
X
TREATMENT
Day 1
101 
1
0m2
X
X
X
15m
X
30m
X
X
1h
X
X
X
2h
X
X
4h
X
X
6h
X
X
X
Day 2
102
2
-0 1
0m2
X
X
Day 7
103
7
-2 2
0m2
X
X
Day 14 
104
14
-2 2
0m2
X
X
X
15m
X
30m
X
X
1h
X
X
X
2h
X
X
4h
X
X
6h
X
X
X
ET/E
1
199
18
-2 2
-
X
X
1Early termination/tudy completion (study/treatment discontinuation and premature subect withdrawal should complete all these assessments)
20minute (0m)sample is taken pre-dose all post-dose samples (15 minutes 6 hours) are timed from the start of inhalationof the morning dose
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81 
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
reuired by law or regulation), IRB/IEC-approved informed consent
Informed consent must be obtained before conducting any study-specific procedures (ie all of 
the procedures described in the protocol) The process of obtaining informed consent should be 
documented in the patientsource documents
The date of signing of informed consent (and withdrawal, iflater withdrawn) should be 
documented in the CR
Novartis will provide to investigators a proposed informed consent form that complies with the 
IC CP guideline and regulatory reuirements 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
Novartis will review the Investigators proposed informed consent formto ensure itcomplies 
with the IC CP guideline and regulatory reuirements and is considered appropriate for this 
study Anyfurtherchanges to the proposed consent form suggested by the investigator must be 
agreed to by Novartis before submission to the IRB/IEC
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother 
In the event that Novartis wants to perform testing on the samples that are not described in this 
protocol, additional Institutional Review Board and/or Ethics Committee approval will be 
obtained
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval
82 
Patientdemographics/other baseline characteristics
Corporate Confidential Information
Patientdemographic and baseline characteristic data willbe collected on all patients
Relevant medical history/current medical conditions data includes data until signature of 
informed consent Where possible, diagnoses and not symptoms will be recorded
Investigators have the discretion to record abnormal test findings on the medical history CR 
whenever in their udgment, the test abnormality occurred prior to theinformed consent 
signature

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831 
ung Clearance Inde ( CI) 
CI will be determined using MBNW according to AT guidelines (Robinsonetal2013)in 
Cohorts 1 and 2 only
CI represents the cumulative epired volume reuired to wash out nitrogen to 25 of the
starting concentration, normalized to the function residual capacity ( RC) of the lungs With
heterogeneous small airway obstruction, a greater epired volume is reuired for nitrogen
washout and the CI is increased Additional measurements provided by MBNW includecond 
and acin, which reflect ventilation heterogeneity in the conducting and acinar airways 
Detailed procedures for the CI acuisition are provided in the 
M
832 
ung volumes
ung volumes will be determined according to AT guidelines (Wanger etal2005)in Cohorts 
1 and 2 only
Measurements will include IC, RC, T C and RV Additional information for conduct of lung 
volume testing is provided in the 
M
833 
pirometry
All spirometry evaluations should follow the recommendations of the AT/ER 2005 
Task orce:  tandardization of pirometry (Milleretal2005)The spirometry euipment used 
during the trial must meet or eceed the minimal AT/ER recommendations for diagnostic 
spirometry euipment as defined in the guideline All patientspirometry reports should be 
stored as source data pirometric parameters for screening, baseline and subseuent 
assessments are pre bronchodilator, including  predicted EV1, VC, difference between 
VC and VC, EV1/ EV6, EV1/ VC ratio, E 25-75, EV3, 1-EV3, EV3/ VC ratio, 
1-EV3/ VC, EV6, EV3/ EV6 ratio, 1-EV3/ EV6 ratio (ansenetal2006
Corporate Confidential Information
)Additional 
information for conduct of spirometry evaluations is provided in the 
M
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84 
afety
afetyassessments are specifiedbelow methods for assessment and recording are specified in 
the 
M, with the Assessmentscheduledetailing when each assessment is to be performed
841 
Physical eamination
Physical eamination
842  Vital signs
Body temperature
Blood pressure (BP) 
Pulse 
Respiratory rate
Pulse oimetry
843 
eight and weight
eight
Body weight
Body mass inde (BMI) will be calculated (Body weight (kg) / eight (m)2)
844 
aboratory evaluations
Clinically significantdeviations of laboratory test results occurring at screening or baseline 
visits, or during or at completion of the study must be repeated, reported and/ordiscussed 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
ematology
Corporate Confidential Information
emoglobin, hematocrit, red blood cell count, white blood cell count with differential and 
platelet count will be measured

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Clinical chemistry
odium, potassium, bicarbonate,creatinine, blood urea nitrogen, uric acid, chloride, albumin, 
calcium, alkaline phosphatase, total bilirubin, D, 
T, A T, A T, PT/INR, amylase, lipase
C, glucose, total cholesterol, triglycerides If the total bilirubin concentration is increased 
above 15 times the upper limit of normal, direct and indirect reacting bilirubin should be 
differentiated
ocal blood chemistry (Cohorts 1 2 only)
odium, potassium, chloride, bicarbonatecollection to monitor for hyperkalemia
Urinalysis
Routine urinalysis and odium/potassium ratio measurement will be provided by the central lab
845 
Electrocardiogram (EC)
A standard EC will be performed Interpretation of the tracing must be made by aualified 
physician within 72 hours and documented on the EC section of the e(CR)
Thefollowing will be recorded in the e(CR ):
date and time ofEC
heart rate
PR interval
QT interval
QTc interval
QR duration
Each EC tracing should be labeled with the
study number
patient initials
patient number
Dateof assessment 
and kept in the source documents at the study sitePhotocopies of the EC tracings should be 
made to preserve the integrity of EC data nly clinically significant abnormalitiesshould be 
reported on this page Clinically significant abnormalities should also berecorded on the 
Relevant medical history/Current medical conditions e(CR) page Clinically significant 
findings must be discussed with the sponsor
The overall interpretation will be collected with a es/No statement to confirm if anyclinically 
significant abnormalities are present which need to be specified further
riginal EC tracings, appropriately signed, will be archived at study site
The ridericia QT correction formula (QTc) should be used for clinical decisions

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846 
pirometry
Besidesthe spirometry measurements reuired for the study as per the assessment table, 
additional pre-or post-dose spirometry may be conducted by the sites for safety reasons 
847 
Pregnancyand assessments of fertility
erum and urine pregnancy tests will be conducted per the assessment tables 
Allpre-menopausal women who are not surgically sterile will have regular pregnancy tests 
during the studyper protocol A positive urine pregnancy test reuires immediate interruption 
of study drug until serum -hC is performed and found to be negative
85 
Pharmacokinetics
Pharmacokinetic blood samples will be collected at the time points defined in the 
Assessmentschedule
Corporate Confidential Information
 In Cohorts 1 and 2 this consists of multiple samplesthrough 6 hours after 
inhalation on Days 1 and either 7 or 14 and predose concentrations on selected days InCohort 
3 this consists of a 15-minute sample after the start of inhalation of the morning dose on selected 
days Details on sample collection, numbering, processing and shipment are in the
M The 
customized tubes used for collection of P blood samples are not sterile and must N T be filled 
by direct phlebotomy the specific instructions on the use of these tubes, provided in the 
M, 
must be followed
 
 
 
Concentrations below the uantification 
limitwill be reported as 0 ng/m  Bloodremaining after completion of the bioanalytics 
described above may be used for eploratory assessment of metabolites or other bioanalytical 
purposes (eg cross check between different sites, stability assessment) 
Pharmacokinetic abbreviations and definitions are inthe list at the beginning of this protocol
The following pharmacokinetic parameters for all three analytes will be determined for Day1 
and Day 7 or 14 in Cohorts 1 and 2 using the actual recorded sampling times and 
noncompartmental methods: Cma, Tma, and AUCtau on Day 1 and Cma,ss, Tma,ss, and 
AUCtau,ss on Day 7 for cohort 1 and Day 14 for cohort 2 alf-lives will be calculated by log-
linear regression on the terminal portion of the concentration-time profile if enough 
concentrations are available (minimum3) Racc will be derived as the ratio of AUCtau,ss from 
Day 14 divided by the AUCtau from Day1 In cohort 3, eposure from 15-minute sample after 
start of inhalation of the morning dose on selected days will be monitored ther P parameters 
maybe calculated in all cohorts if deemed necessary
In order to avoid long clinical stays for patients in this study, the blood sampling for AUCs is 
terminated at 6 hours after inhalation 
 
 
 
 
 
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 No formal statistical comparison is foreseen as the intent of this 
comparison is to determine if eposure is similar in the two groups
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9 
afety monitoring
91 
Adverse events
An adverse event (AE) is any untoward medical occurrence (ie, any unfavorable and 
unintended sign including abnormal laboratory findings, symptom or disease) in a patientor 
clinical investigation patientafter providing written informed consentfor 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 uestioning of the patient
at each visit during the study Adverse events also may be detected when they are volunteered 
by the patientduring or between visits or through physical eamination, 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 reuire 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 patientswith 
underlying disease Investigators havethe responsibility for managing the safety of individual 
patientand identifying adverse events Alert ranges for liver related eventsare included in
ection93
Adverse events must be recorded on the Adverse Events CR for patients that pass screening 
and enter into the study The adverse events should be reported according to the signs, 
symptoms or diagnosis associated with them, and accompanied by the following information:
1 The Common Toicity Criteria (CTC) AE grade (version 403)  CTCAE 403 can be found 
at the following  Internet site:  http://evsncinihgov/ftp1/CTCAE/Abouthtml
mild: 
usually transient in nature and generally not interfering with normal 
activities
moderate: sufficiently discomforting to interfere with normal activities
severe: 
prevents normal activities
If CTC-AE grading does not eist for an adverse event, use:
1 mild, 
2 moderate, 
3severe 
4life threatening 
CTC-AE grade 5 (death) is not used, but is collected in other CRs (eg tudy Completion, 
Death/urvival)
2 its relationship to thestudy treatment (no/yes)

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3 its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported
4 whether it constitutes a serious adverse event ( AE) ee ection 92for definition of AE
5 action taken regarding study/investigational treatment(select as appropriate) 
All adverse events should be treated appropriately Treatment may include one or more of 
the following: 
no action taken (ie further observation only) 
study treatmentdosage adusted/temporarily interrupted 
study treatmentpermanently discontinued due to this adverse event 
concomitant medication given 
non-drug therapy given 
patienthospitalized/patientshospitalization prolonged 
6 its outcome (not recovered/not resolved recovered/resolved recovering/resolving, 
recovered/resolved with seuelae fatal or unknown)
nce an adverse event is detected, it should be followed until its resolution or until it is udged 
to be permanent, and assessment should be made at each visit (or more freuently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
reuired 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 Core Data heet (for marketed drugs) or will be 
communicated between IB updates in the form of Investigator Notifications This information 
will be included in the patientinformed consent and should be discussed with the patientduring 
the study as needed
The investigator should also instruct each patientto report any new adverse event (beyond the 
protocol observation period) that the patient, or the patientspersonal physician, believes might 
reasonably be related to study treatment This information should be recorded in the 
investigators source documents however, if the AE meets the criteria of an AE, it must be 
reported to Novartis
92 
erious adverse event reporting
921 
Definition of AE
An AE is defined as any adverse event (appearance of (or worsening of any pre-eisting) 
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

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reuires inpatient hospitalization or prolongation of eisting 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-eisting 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 AE given above and not resulting in hospital admission 
social reasons and respite care in the absence of any deterioration in the patients 
general condition
is medically significant, ie defined as an event that eopardizes the patientor may reuire 
medical or surgical intervention
ife-threatening in the contet of a AE refers to a reaction in which the patientwas 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 udgment should be eercised 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 eopardize the patient or might 
reuire intervention toprevent one of the other outcomes listed above Eamples 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 CR, AEs also reuire individual 
reporting to D
E as per ection 922
922 
AE reporting
To ensure patientsafety, every AE, regardless of causality, occurring after the patienthas 
provided informed consent and until 30 days after the last study visitmust be reported to 
Novartis within 24 hours of learning of its occurrenceas described below Any AEs 
eperienced after thisshould only be reported to Novartis if the investigator suspects a causal 
relationship to study treatment 
Recurrent episodes, complications, or progression of the initial AE 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 AE that is 
considered completely unrelated to a previously reported one should be reported separately as 
a new event

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Information about all AEs (either initial or follow up information)is collected and recorded 
on the paper erious Adverse Event Report orm The investigator must assess the relationship 
to each specific component of study treatment (if study treatment consists of several drugs)
complete the AE Report orm in English, and send the completed, signed form by fa within 
24 hours after awarenessof the AEto the local Novartis CM  P Department, notifying 
the Clinical Trial eader Contact information islisted in the 
M 
The original copy of the AE Report orm and the fa confirmation sheet must be kept with 
the sourcedocumentation at the study site ollow-up information should be provided using a 
new paper AE Report orm stating that this is a follow-up to a previously reported AE
AEs (initial and follow-up) that are recorded electronicallyin the ElectronicDataCapture 
system should be entered, saved and e-signed within 24 hours of awareness of the AE or 
changes to an eisting AE These data will automatically be submitted to Novartis CM  
P immediately after investigator signature or 24 hours after entry, whichever occurs first 
tudy site personnel must also informthe Clinical Trial eader
ollow-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 patient
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 AE is not previously documented in the Investigators Brochure or Package Insert (new 
occurrence) and is thought to be related to the investigational treatment a CM  P 
Departmentassociate may urgently reuire further information from the investigator for ealth 
Authority reporting Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same investigational treatment thatthis AE has 
been reported uspected Unepected erious Adverse Reactions ( U ARs) will be collected 
and reported to the competent authorities and relevant ethics committees in accordance with EU 
uidance 2011/C 172/01 or as per national regulatory reuirements in participating countries
93 
iver safety monitoring
To ensure patientsafety and enhance reliability in determining the hepatotoic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study:
iver laboratory triggers, which will reuire repeated assessments of the abnormal 
laboratory parameter
iver events, which will reuire close observation, follow-up monitoring and completion 
of the standard base liver CR pages
Please refer toTable 9-1and Table 9-2for complete definitions of liver laboratory triggers and 
liver events 
Every liver laboratory trigger or liver event should be followed up by the investigator or 
designated personal at the trial site, as summarized below and detailed in inTable 9-2

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or the liver laboratory trigger:
Repeating the T within the net week to confirm elevation
These 
T 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 subseuently reported, any local Ts previously conducted that are 
associated with this event should be reported on the iver CR pages
Repeat laboratory tests should be entered on the appropriate unscheduled local laboratory CR 
page
If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate
or the liver events:
Repeating the T to confirm elevation as appropriate
Discontinuation of the investigational drug(refer to ection 71,if appropriate
ospitalization of the patientif appropriate
A causality assessment of the liver event via eclusion of alternative causes (egdisease, 
co-medications)
An investigation of the liver event which needs to be followed until resolution 
These investigations can include serology tests, imaging and pathology assessments, 
hepatologists consultancy, based on investigators discretion All follow-up information, and 
the procedures performed should be recorded as appropriate in the CR , including the liver 
event overview CR pages
Table 9-1 
iver Event and aboratory Trigger Definitions
Definition/ threshold
iver laboratory triggers
3  U N  A T / A T 5  U N
15  U N  TB 2  U N
iver events
A T orA T  5  U N
A P  2  U N (in the absence of known bone pathology)
TB  2  U N (in the absence of known ilbert syndrome)
A T or A T  3  U N and INR  15 
Potential ys aw cases (defined as A T or A T  3  U N and 
TB  2  U N mainly conugated fraction without notable 
increase in A P to  2  U N)
Any clinical event of aundice (or euivalent term)
A T or A T  3  U N accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia
Any adverse event potentially indicative of a liver toicity  

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Table 9-2 
ollow Up Re uirements for iver Events and aboratory Triggers
Criteria
Actions re uired
ollow-upmonitoring
Potential ys aw casea
Discontinue the study drug 
immediately
ospitalize, if clinically 
appropriate
Establish causality
Complete liver CR
A T, A T, TB, Alb, PT/INR, 
A P and 
T until resolutionc
(freuency at investigator 
discretion)
A T or A T
 8 U N
Discontinue the study drug 
immediately
ospitalize if clinically appropriate
Establish causality
Complete liver CR
A T, A T, TB, Alb, PT/INR, 
A P and 
T until resolutionc
(freuency at investigator 
discretion)
 3  U N and INR  15
Discontinue the study drug 
immediately
ospitalize, if clinically 
appropriate
Establish causality
Complete liver CR
A T, A T, TB, Alb, PT/INR, 
A P and 
T until resolutionc
(freuency at investigator 
discretion)
 5 to  8 U N
Repeat T within 48hours
If elevation persists, continue 
follow-up monitoring
If elevation persists for more than 
2 weeks, discontinue the study 
drug
Establish causality
Complete liver CR
A T, A T, TB, Alb, PT/INR, 
A P and 
T until resolutionc
(freuency at investigator 
discretion)
 3 U Naccompanied 
by symptomsb
Discontinue the study drug 
immediately
ospitalize if clinically appropriate
Establish causality
Complete liver CR
A T, A T, TB, Alb, PT/INR, 
A P and 
T until resolutionc
(freuency at investigator 
discretion)
 3 to  5 U N 
(patient is asymptomatic)
Repeat T within the net week
If elevation is confirmed, initiate 
close observation of the patient
Investigator discretion
Monitor T within 1 to 4 weeks 
A P (isolated)
 2  U N (in the 
absence of known bone 
pathology)
Repeat T within 48 hours
If elevation persists, establish 
causality
Complete liver CR
Investigator discretion
Monitor T within 1 to 4 weeks 
or at net visit

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Criteria
Actions re uired
ollow-upmonitoring
TB (isolated)
 2  U N (in the 
absence of known ilbert 
syndrome)
Repeat T within 48 hours
If elevation persists, discontinue 
the study drug immediately
ospitalize if clinically appropriate
Establish causality
Complete liver CR
A T, A T, TB, Alb, PT/INR, 
A P and 
T until resolutionc
(freuency at investigator 
discretion)
Test for hemolysis (eg 
reticulocytes, haptoglobin, 
unconugated indirect bilirubin)
 15 to  2 U N
(patient is asymptomatic)
Repeat T within the net week
If elevation is confirmed, initiate 
close observation of the patient
Investigator discretion
Monitor T within 1 to 4 weeks 
or at net visit
Jaundice
Discontinue the study drug 
immediately
ospitalize the patient
Establish causality
Complete liver CR
A T, A T, TB, Alb, PT/INR, 
A P and 
T until resolution
c
(freuency at investigator 
discretion)
Any AE potentially 
indicative of a liver 
toicity
Consider study drug interruption 
or discontinuation 
ospitalization if clinically 
appropriate
Establish causality
Complete liver CR
Investigator discretion
These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions the non-infectious hepatitis the benign, malignant and unspecified liver 
neoplasms
aElevated A T/A T  3  U N and TB  2 U N but without notable increase in A P to  2  U N
b( eneral) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2)stable 
values at three subseuent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maimum of 6 months, (4) liver transplantation, and (5) death
94 
Renal safety monitoring
Renal events are defined as one of the following:
confirmed (after  24h) increase in serum creatinine of  25 compared withbaseline 
during normal hydration status
new onset (1) proteinuria, hematuria or glucosuria or as a
doubling in the urinary albumin-creatinine ratio (ACR) or urinary protein-creatinine ratio 
(PCR) (if applicable)
The following two categories of abnormalities/adverse events have to be considered during the 
course of the study:
erum creatinine triggers that will reuire follow up and repeat assessments of the 
abnormal laboratory parameter 

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Urine dipstick triggers that will reuire follow up and repeat assessments of the abnormal 
laboratory parameter
Table 9-3 
pecific Renal Alert Criteria and Actions
Renal Event
Actions
erum creatinine increase
25 49  compared withbaseline
Confirm 25  increase after 24-48h 
ollow up within 2-5 days
erum creatinine increase  50  
compared withbaseline
ollow up within 24-48h if possible
Consider drug interruption 
Consider patient hospitalization /specialized treatment
Albumin-or Protein-creatinine ratio 
increase  2-fold
Albumin-creatinine ratio (ACR)  30 
mg/g or  3 mg/mmol
New dipstick proteinuria  1
Protein-creatinine ratio (PCR) 150 
mg/g or 15 mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Consider drug interruption / discontinuation 
New dipstick glucosuria  1 not due to 
diabetes
Blood glucose (fasting)
Perform serum creatinine, ACR 
New dipstick hematuria not due to 
trauma
Urine sediment microscopy
Perform serum creatinine, ACR 
Document contributing factors: co-medication, other co-morbid conditions, and additional diagnostic 
procedures performed in the CR
Monitor patient regularly (freuency at investigators discretion) until one of the following:
Event resolution: (sCr within 10  of baseline or protein-creatinine ratio within 50  of baseline) 
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
95 
Pregnancy reporting
To ensure patient safety, each pregnancy in a patient 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 patient 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 patient may continue all other protocol assessments Pregnancymust be 
recorded on a Pharmacovigilance Pregnancy orm and reported by the investigator to the local 
Novartis CM  P Department Pregnancy follow-up should be recorded on the same form 
and should include an assessment of the possible relationship to the Novartis study drug of any 
pregnancy outcome Any AE eperienced during pregnancy must be reported on an AE 
Report orm
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatmentin this study Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother

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96 
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the ponsor of 
any clinically relevant observations Any reuired safety reviews will be made ointly between 
medically ualified personnel representing the ponsor and Investigator uchevaluations may 
occur verbally, 
but the outcome and key discussion points will be summarized in writing (e-mail) 
and made available to both ponsor and all Investigator(s) Criteria pertaining to stopping the 
study/treatment or adapting the study design are presented above
When two or more clinical site(s) are participating in the clinical study, the ponsor 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
101 
ite monitoring
Before study initiation, at a site initiation visit or at an investigators meeting, a Novartis 
representative will review the protocol and CRs with the investigators and their staff 
Duringthe studyNovartis employs several methods of ensuring protocol and CP compliance 
and the uality/integrity of the sites data Themonitor will visit the site to check the 
completeness of patientrecords, the accuracy of entries on the CRs, the adherence to the 
protocol and to ood Clinical Practice, the progress of enrollment, and to ensure that study drug 
is being stored, dispensed, and accounted for according to specifications ey study personnel 
must be available to assist the monitor during these visits
The investigator must maintain source documents for each patientin 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 CRs must be traceable to these source documents in the 
patients
 file The investigator must also keep the original informed consent form signed by the 
patient(a signed copy is given to the patient)
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CR entries Novartis monitoring standards reuire full verification forthe 
presence of informed consent, adherence to the eligibilitycriteria, documentation of AEs, 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 CRs are performed according to the study-
specific monitoring plan No information in source documents about the identity of the patients
will be disclosed

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102 
Data collection
Designated investigator staff will enter the data reuired by the protocol into the Electronic 
Case Report orms using fully validated software that conforms to 21 C R Part 11 reuirements 
Designated investigator site staff will not be given access to the EDC system until they have 
been trained Automatic validation programs check for data discrepancies and, by generating 
appropriate error messages, allow the data to be confirmed or correctedbefore transfer of the 
data to the CR working on behalf of Novartis TheInvestigator must certify that the data 
entered into the Electronic Case Report ormsare complete and accurate Afterdatabase lock, 
the investigator will receive a CD-R M or paper copies of the patientdata for archiving at the 
investigational site
Data not reuiring a separate written record will be defined in the Mand assessment schedule 
and canbe recorded directly on the CRs All other data captured for this study will have an 
eternal originating source (either written or electronic)withthe CR not being considered as 
source
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification
Novartis staff review the data entered into the eCRs by investigational staff for completeness 
and accuracy and instruct the site personnel to make any reuired corrections or additions 
Queries are sent to the investigational site using an electronic data uery 
Designatedinvestigator site staff is reuired to respond to the uery and confirm or correct the 
data If the electronic uery system is not used, a paper Data Query orm will be faed to the 
site ite personnel will complete and sign the faed copy and fa it back to Novartis staff who 
will make the correction to the database
Concomitant medications entered into the database will be coded using the W  Drug 
Reference ist, 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
aboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CR)
Randomization codes and data in reference to dispensing of study drug(s)to the patientand 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 Thedatabase will 
be sent electronically to Novartis (or a designated CR)
Each occurrence of a code break via IRT will be reported to the clinical team and monitor 
Thecode break functionality will remain available until study shut down or upon reuest of 
Novartis

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11 
Data analysis
Analysis of the data will be conducted under the direction of Novartis personnel in compliance 
with internal guidance documents and standards
111 
Analysis sets
or all analysis sets, patientswill be analyzed according to the study treatment(s) received
The safety analysis set will include all patientsthat received any study drug
The P analysis set will include all patients with at least one available valid (ie, not flagged 
for eclusion) P concentration measurement, who received study drug, and eperienced no 
protocol deviations with relevant impact on P data
112 
Patientdemographics and other baseline characteristics
All data for background and demographic variables will be listed by cohort, treatment and 
patient ummary statistics will be provided for all patients, as well as for each treatmentData 
from patients receiving placebo may be pooled only for cohort 1 and 2 of the study
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment (treatment seuence for cohort3) 
and patient
113 
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
Corporate Confidential Information
Use of rescue and/or concomitant medications and data on administration of study drug will be 
listed by cohort, treatment (treatment seuence for cohort 3), and patient
Corporate Confidential Information

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114 
Analysis of the primary variable(s)
1141
Variable(s)
The primary variable is occurrence of an adverse event for cohort 1 and cohort 2 and evaluate 
the pharmacodynamic response as reflected in percent of predicted EV1 for cohort 3 of 
multiple doses of inhaled QBW276 in C patients
1142
tatistical model, hypothesis,and method of analysis
Cohort 1 and Cohort 2:All information obtained on adverse events will be listed by cohort, 
treatment andpatient or each cohort, adverse events will be counted within each cohort/dose-
level, by treatment received and corresponding percentages will be tabulated 
Data from subects receiving placebo may be pooled for cohorts 1 and 2 of the study 
Thenumbers and percentages will be tabulated by body system, preferred term and severity A 
patient with multiple adverse events within a body system is only counted once towards the 
total of this body system
All other safety assessments including EC, vital signs and laboratory data will be listed by 
cohort, treatment, patient, and visit/time and if ranges are available abnormalities (and relevant 
orthostatic changes) will be flagged ummary statistics will be provided by treatment and 
visit/time
Drug concentrations will be listed by treatment, patientand visit/sampling time point 
Descriptive summary statistics will be provided by treatment and visit/sampling time point 
ummary statistics will include mean (arithmetic and geometric), D, CV (arithmetic and 
geometric), median, minimum and maimum Concentrations below the 
Q will be treated 
as zero in summary statistics A geometric mean will not be reported if the dataset includes zero 
values
Pharmacokinetic parametersin Cohorts 1 and 2will be calculated as described in ection85
and will be listed by treatment and patient Descriptive summary statistics will include mean 
(arithmetic and geometric), D, and CV (arithmetic and geometric), median, minimum and 
maimum An eception to this is Tma where median, minimum and maimum will be 
presented Individual concentration-time profiles and mean profiles with D bars will be 
presented for Day 1 and Day 7 or 14 in Cohorts 1 and 2 
Cohort 3:
Corporate Confidential 
Information
The percent of predicted EV1maybe put into a mied effects model Percent of predicted 
EV1 values measured on Day 7, 14,21and 28of each treatment period at the study site will 
be analyzedusing a mied effects model for repeated measurements The model will include 
fied effects for period, time (Days 7, 14, 21, 28), 
 treatment and treatment 
by time ubect will be included as a random effect and time will be repeated within each 
patient by periodinteraction term ubect-average baseline and period-adusted baseline will 
be fitted as covariatesAn unstructured covariance matri will be applied enward Roger 
options will be used to calculate the degrees of freedom in all Proc Mied analysis

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The subect average baseline will be derived as the average of their pre-dose assessments from 
each period  Period adusted baseline will be calculated for each subect andfor each period, 
as the difference between the period baseline and the subect average baseline, ie value of 
period baseline value of average baseline (enwardandRoger1997)
The final model estimates will include the mean for each treatment together with standard 
error (E), the adusted mean difference between treatments, and 80 two-sided confidence 
intervals and P-value for the differences These will be calculated at all time points, and 
specifically atthe primary time point of interest (Day 28) using Placebo as the reference 
treatment
The results of analysis will also be presented in a graphicalrepresentation showing the estimated 
mean differences to placebo and their confidence intervals per time point
ummary statistics and graphical representations of percent of predicted EV1will be 
presented by treatment group and time
No adustments for multiplicity will be applied for this eploratory study
Additional eploratory analyses such as responder analyses and analysis by gender may be 
performedDetailed statistical methods will be discussed in the tatistical Analysis Plan
1143
andling of missing values/censoring/discontinuations
Corporate Confidential Information
Cohorts 1 and 2: Patients withdrawn for reasons other than safety and tolerability prior to 
completion of the Day 7 or 14 assessments may be replacedto gather sufficient data to perform 
an informed decision on dose selected for the subseuent cohort
Cohort 3: The repeated measures analysis includes all available information in terms of 
measurements at all times If missing measurements are missing at random, an analysis of the 
available data provides consistent estimates of model parameters Alternative assumptions may 
beeplored to investigate the robustness of the results under plausible non-Missing at Random 
situations Reasons for dropouts will be eplored
Where data has values below and above limits of uantification then the following rule will 
apply
In the summary tables, the freuency (n, ) of values below the 
Q and above the U
Q,
respectively, will be included
Any values below the limit of uantification will be analyzed as 05the lower limit, both in the 
descriptive and the model analysis Any values above the limit of uantification will be 
analyzed as 10the upper limit, both in the descriptive and the model analysis 
No other imputation of missing data is allowed

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115 
Analysis of secondary and e ploratory variables
1152
afety
Vital signs
All vital signs data will be listed by cohort, treatment(treatment seuence for cohort 3), patient, 
and visit/time and if ranges are available abnormalities (and relevant orthostatic changes) will 
be flagged ummary statistics will be provided by treatment and visit/time
EC evaluations
All EC data will be listed by cohort, treatment(treatment seuence for cohort 3), patientand 
visit/time, abnormalities will be flagged ummary statistics will be provided by treatment and 
visit/time
Clinical laboratory evaluations
Corporate Confidential Information
All laboratory data will be listed by cohort, treatment(treatment seuence for cohort 3), patient, 
and visit/time and if normal ranges are available abnormalities will be flagged ummary 
statistics will be provided by treatment and visit/time
Corporate Confidential Information

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Adverse events
or cohort 3, all information obtained on adverse events will be displayed by cohort, treatment 
seuence andpatient
The number and percentage of patientswith adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment An adverse event starting in one period and 
continuing into the net period is counted only in the onset period A patientwith multiple 
adverseevents within a body system and treatment period is only counted once towards the 
total of this body system and treatment
1153
Pharmacokinetics
Corporate Confidential Information
The 15 minute post-dose concentrations in Cohort 3 will be listed bytreatment, patient and 
visit/sampling time point  Descriptive statistics will be provided by treatment and 
visit/sampling time point ummary statistics will include mean (arithmetic and geometric), D, 
and CV (arithmetic and geometric), median, minimum and maimum Concentrations below 
the 
Q will be treated as zero in summary statistics A geometric mean will not be reported 
if the dataset includes zero values 
Corporate Confidential Information

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116 
ample size calculation
Cohort 1 and 2:The first and second cohort will include 8 patients each, randomized 3:1 to 
drug: placebo The sample size of 8 patients per cohort was based on practical considerations 
and clinical udgment that the numbers of patientsare appropriate for the assessment of overall 
safety and tolerability and for providing adeuate confidence for dose escalation In cohort 1, 
for instance, an adverse event with an incidence of 235 will have a probability of 80 of 
occurring in at least one patientand a probability of 43 of occurring in two or more patients
Cohort 3:Based on drop-out rate during the study, up to 40 patients may
 be randomized to cohort 
3 to ensure that at least 24completeboth periods  
 
117 
Power for analysis of key secondary variables
Corporate Confidential Information
Not Applicable
C
o
 
 
Corporate Confidential Information
C
o
 
 
Corporate Confidential Information

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12 
Ethical considerations
121 
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with the 
IC armonized Tripartite uidelines for ood Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, U Code of ederal Regulations Title 
21, and Japanese Ministry of ealth, abor, and Welfare), and with the ethical principles laid 
down in the Declaration of elsinki
122 
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, patientrecruitment procedures 
(egadvertisements) and any other written information to be provided to patients Prior to study 
start, the investigator is reuired to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and allof the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as reuired If an inspection of the clinical site is 
reuested by a regulatory authority, the investigator must inform Novartis immediately that this 
reuest has been made
or multi-center trials, a Coordinating Investigator will be selected by Novartis around the time 
of ast Patient ast Visit to be a reviewer and signatory for the clinical study report 
123 
Publication of study protocol and results
Corporate Confidential Information
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrialsgov 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

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13 
Protocol adherence
This protocol defines the study obectives, the study procedures and the data to be collected on 
study participants Additional assessments reuired to ensure safety of patientsshould be 
administered as deemed necessary on a case by case basis Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research related 
purpose involving any investigational drugs
Investigators must apply due diligence to avoid protocol deviations If the investigator feels a 
protocol deviation would improve the conduct of the study this must be considered a protocol 
amendment, and unless such an amendment is agreed upon by Novartis and approved by the 
IRB/IEC/REB/regulatory authorityit cannot be implemented All significant protocol 
deviations will be recorded and reported in the C R
131 
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, ealth Authorities where reuired, and the IRB/IECprior to 
implementation 
nlyamendments that areintended to eliminate an apparent immediate hazard to patients may 
be implemented,provided the ealth Authorities and the reviewing IRB/IEC are subseuently 
notified by protocol amendment
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
epected to take any immediate action reuired for the safety of any patientincluded in this 
study, even if this action represents a deviation from the protocol Insuch cases, the CT should 
be informed and (serious) adverse event reporting reuirements (ection9) followed as 
appropriate

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14 
References
Available upon reuest
App EM, ing M, elfesrieder R, et al (1990) Acute and long-term amiloride inhalation in 
cystic fibrosis lung disease Am Rev Respir Dis 141:605-12
Cystic ibrosis oundation (2012a) About cystic fibrosis (Internet) Available from 
http://cfforg/ (Accessed 20 January 2012)
Cystic ibrosis oundation (2012b) Cystic ibrosis oundation Patient Registry 2009 Annual 
Data Report (Internet) Available from 
http://cfforg/ Uploadediles/research/ClinicalResearch/Patient-Registry-Report-2009pdf
(Accessed 20 January 2012)
Davies J, heridan , Bell N, et al (2013) Assessment of clinical response to ivacaftor with 
lung clearance inde in cystic fibrosis patients with a 551D-C TR mutation and preserved 
spirometry: a randomised controlled trial ancet Respir Med p 630-8
Donaldson , Bennett WD, eman , et al (2006) Mucus clearance and lung function in 
cystic fibrosis with hypertonic saline N Engl J Med 354:241-50
Donaldson , Boucher RC (2007) odium channels and cystic fibrosis Chest 132(5):
1631-6
Elkins MR, Robinson M, Rose BR, et al (2006)A controlled trial of long-term inhaled 
hypertonic saline in patients with cystic fibrosis N Engl J Med 354:229-40
arrell PM, Rosenstein BJ, White TB, et al (2008) uidelines for diagnosis of cystic fibrosis 
in newborns through older adults: Cystic ibrosis oundation consensus report J Pediatr 153, 
4-14
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