Conditions: Chronic Obstructive Pulmonary Disease
Keywords: COPD Smokers Ex-smokers
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 31
Healthy volunteers: no

Brief summary:
The purpose of this study was to assess global ventilated lung volume in moderate to severe COPD patients using MRI lung imaging after treatment with QVA149 compared to placebo.

Detailed description:
The MRI approach represented an opportunity to better understand the impact of a potent dual bronchodilator on the small and central airways and thereby increasing ventilated lung volume, gas exchange, and ventilation-perfusion deficits.

The study investigated the effect of QVA149 on global and regional lung ventilation using MRI lung imaging to enhance the understanding of QVA pharmacology in COPD patients.

Arms:
arm 1: Single daily dose of 110/50 μg QVA149 for 8-10 days. arm 2: Single daily dose of matching placebo for 8-10 days.

Interventions: intervention 1: QVA149 intervention 2: Placebo
Intervention descriptions: intervention 1: QVA149 110/50 μg o.d. capsules for inhalation, supplied in blisters via the Concept 1 inhalation device, a single dose dry powder inhaler. intervention 2: Matching placebo

Protocol document:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
QVA149
CQVA149A2325
A randomized, double-blind, placebo-controlled, two-period 
crossover study to assess the effect of inhaled QVA149 on 
global and regional lung function and gas exchange in 
patients with moderate to severe COPD
Authors:
 
Document type:
Amended Protocol Version
EUDRACT number:
2013-004461-13
Versionnumber:
v02(Clean)
Development phase:
IV
Release date:
17-Feb-2017
Personal Data
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents.................................................................................................................3
List of tables........................................................................................................................6
List of abbreviations............................................................................................................7
Protocol synopsis...............................................................................................................13
1 Introduction.......................................................................................................................16
1.1
Background............................................................................................................16
1.1.1
Relevant data summary.........................................................................17
1.2
Study purpose........................................................................................................20
2 Study objectives.................................................................................................................21
2.1
Primary objective(s)...............................................................................................21
2.2
Secondary objective(s)...........................................................................................21
3 Investigational plan...........................................................................................................22
3.1
Study design...........................................................................................................22
3.2
Rationale of study design.......................................................................................23
3.3
Rationale of dose/regimen, duration of treatment.................................................24
3.4
Rationale for choice of comparator.......................................................................24
3.5
Purpose and timing of interim analyses/design adaptations..................................24
3.6
Risks and benefits..................................................................................................24
4 Population..........................................................................................................................27
4.1
Inclusion criteria....................................................................................................27
4.2
Exclusion criteria...................................................................................................27
5 Restrictions for Study Subjects.........................................................................................30
5.1
Contraception requirements...................................................................................30
6 Treatment...........................................................................................................................33
6.1
Study treatment......................................................................................................33
6.1.1
Investigational treatment.......................................................................33
6.1.2
Additional study treatment....................................................................33
6.2
Treatment arms......................................................................................................
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6.3
Permitted dose adjustments and interruptions of study treatment.........................33
6.4
Treatment assignment............................................................................................34
6.5
Treatment blinding.................................................................................................34
6.6
Emergency breaking of assigned treatment code ..................................................34
6.7
Treatment exposure and compliance .....................................................................35
6.8
Recommended treatment of adverse events ..........................................................35
6.9
Rescue medication.................................................................................................35
6.10
Concomitant treatment...........................................................................................36
7
Discontinuation and study completion ..............................................................................36
7.1
Discontinuation of study treatment........................................................................36
7.2
Study completion and post-study treatment ..........................................................37
7.2.1
Lost to follow-up...................................................................................37
7.3
Withdrawal of consent...........................................................................................37
7.4
Study Stopping rules..............................................................................................37
7.5
Early study termination..........................................................................................38
8
Procedures and assessments ..............................................................................................39
8.1
Informed consent procedures.................................................................................41
8.2
Subject demographics/other baseline characteristics.............................................41
8.3
Efficacy / Pharmacodynamics ...............................................................................42
8.3.1
MRI .......................................................................................................42
8.3.2
Spirometry.............................................................................................42
8.3.3
Multiple Breath Nitrogen Washout.......................................................43
8.3.4
DLCO and Lung Volumes Assessment ................................................43
8.3.5
Patient diary ..........................................................................................43
8.4
Safety.....................................................................................................................43
8.4.1
Physical examination ............................................................................43
8.4.2
Vital signs..............................................................................................44
8.4.3
Height and weight .................................................................................44
8.4.4
Local Laboratory evaluations................................................................44
8.4.5
Electrocardiogram (ECG) .....................................................................45
8.4.6
Pregnancy and assessments of fertility .................................................45
8.5
High Resolution CT...............................................................................................45
9
Safety monitoring..............................................................................................................45
9.1
Adverse events.......................................................................................................45
9.2
Serious adverse event reporting.............................................................................47
9.2.1
Definition of SAE .................................................................................47


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9.2.2
SAE reporting........................................................................................48
9.3
Liver safety monitoring .........................................................................................48
9.4
Renal safety monitoring.........................................................................................48
9.5
Pregnancy reporting...............................................................................................49
10 Data review and database management.............................................................................49
10.1
Site monitoring ......................................................................................................49
10.2
Data collection.......................................................................................................50
10.3
Database management and quality control............................................................50
11 Data analysis......................................................................................................................51
11.1
Analysis sets ..........................................................................................................51
11.2
Subject demographics and other baseline characteristics......................................51
11.3
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................51
11.4
Analysis of the primary variable(s) .......................................................................51
11.4.1
Variable(s).............................................................................................51
11.4.2
Statistical model, hypothesis, and method of analysis..........................51
11.4.3
Handling of missing values/censoring/discontinuations.......................52
11.4.4
Summary statistics of pharmacokinetics...............................................52
11.4.5
Supportive analyses...............................................................................52
11.5
Analysis of secondary and exploratory variables ..................................................52
11.5.1
Efficacy / Pharmacodynamics...............................................................52
11.5.2
Safety.....................................................................................................53
11.5.3
Pharmacokinetics ..................................................................................54
11.5.4
Pharmacokinetic / pharmacodynamic interactions................................54
11.5.5
Other assessments .................................................................................54
11.6
Sample size calculation..........................................................................................54
11.7
Power for analysis of key secondary variables......................................................54
11.8
Interim analyses.....................................................................................................55
12 Ethical considerations........................................................................................................55
12.1
Regulatory and ethical compliance........................................................................55
12.2
Responsibilities of the investigator and IRB/IEC..................................................55
12.3
Publication of study protocol and results...............................................................55
13 Protocol adherence ............................................................................................................55
13.1
Protocol Amendments ...........................................................................................56
14 References .........................................................................................................................57


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List of tables
Table 5-1
Prohibited Medications.........................................................................30
Table 6-1
Definition of treatment sequences.........................................................33
Table 8-1
Assessment Schedule............................................................................
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List of abbreviations
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AUC
area under the concentration time curve
AST
aspartate aminotransferase
BMI
Body Mass Index
BUN
blood urea nitrogen
CD-ROM
compact disc – read only memory
CFR
Code of Federal Regulation
CK
creatinine kinase
CO2
carbon dioxide
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CV
coefficient of variation
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
FDA
Food and Drug Administration
FEF
Forced expiratory flow
FEV1
Forced expiratory volume in one second
GCP
Good Clinical Practice
h
hour
HRCT
High Resolution Computed Tomography 
HIV
human immunodeficiency virus
i.v.
intravenous
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee


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IRB
Institutional Review Board
IRT
Interactive Response Technology
LDH
lactate dehydrogenase
LLN
lower limit of normal
LLQ
lower limit of quantification
MRI
Magnetic Resonance Imaging 
mg
milligram(s)
ml
milliliter(s)
o.d.
once a day
p.o.
oral
PA
posteroanterior
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
RBC
red blood cell(s)
REB
Research Ethics Board
s.c.
subcutaneous
SAE
serious adverse event
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
TBL
total bilirubin
ULN
upper limit of normal
ULQ
upper limit of quantification
WBC
white blood cell(s)


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Protocol synopsis
Protocol number
QVA149A2325
Title
A randomized, double-blind, placebo-controlled, two-period crossover study to 
assess the effect of inhaled QVA149 on global and regional lung function and 
gas exchange in patients with moderate to severe COPD
Brief title
Imaging study of inhaled QVA149 on lung function and gas exchange in 
patients with moderate to severe COPD 
Sponsor and 
Clinical Phase
Novartis
Phase IV
Intervention type
Drug
Study type
Interventional 
Purpose and 
rationale
This study will investigate the effect of QVA149 on global and regional lung 
ventilation using MRI hyperpolarized gas lung imaging to enhance the 
understanding of QVA pharmacology in COPD patients.
The assessment of regional ventilation measures can be combined with a MRI 
perfusion evaluation of the lung to visualize ventilation-perfusion mismatches 
which will also be evaluated in response to QVA149 treatment compared to 
placebo. Current physiological measures of small airway dysfunction are limited, 
subject to a high degree of variability and do not allow a quantitative 
assessment of global and regional ventilation defects. The MRI approach 
represents an opportunity to better understand the impact of a potent dual 
bronchodilator on the small and central airways and thereby increasing
ventilated lung volume, gas exchange, and ventilation-perfusion deficits.
Primary 
Objective(s)
To assess global ventilated lung volume in moderate to severe COPD patients 
using hyperpolarized gas lung imaging after 7 days of treatment with QVA149 
compared to placebo.
Secondary 
Objectives
To assess regional lung ventilated volume in moderate to severe COPD 
patients using hyperpolarized gas lung imaging after 7 days of treatment with 
QVA149 compared to placebo.
Study design
A double-blind, randomized, placebo-controlled, two-period, cross-over study in 
patients with moderate to severe COPD.
The study will consist of a 2-week screening period, a 7-9 day run-in, baseline, 
a double-blind 8-day (up to 10 day) treatment Period 1 followed by a washout 
period before crossing over to a double-blind 8-day (up to 10 day) treatment 
Period 2, and an end-of-study visit up to one week after the last MRI 
assessments.
Population
The study population consists of approximately 34 male and female moderate to 
severe COPD patients aged 40 years and above.


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Inclusion criteria

Writteninformed consent must be obtained before any assessment is 
performed.

Male and female with COPD aged 40 years and above.

Smokers and ex-smokers who have a smoking history of at least10 pack 
years. Smokers will be defined as any patient who reports tobacco use 
within the last month.

Patients with a diagnosis of moderate to severe COPD according to 
GOLD2015criteria. Patients with airflow limitation indicated by a post-
bronchodilator FEV1/FVC < 0.70 and by a post-bronchodilator FEV1 ≥ 30 % 
and <80 %.
o
Post-bronchodilator refers to 1 hr(+/-5 minutes)after sequential 
inhalation of 84 µg ipratropium bromide (or equivalent dose) and 
400 µg salbutamol/360 µg albuterol (or equivalent dose) Spacer 
devices are not permitted during reversibility testing.

Patientsmust weigh ≥45 kg and ≤100 kg to participate in the study.

Ableto communicate well with the investigator, to understand and comply 
with the requirements of the study.
Exclusion criteria

Historyof hypersensitivity to any of the study drugs or to drugs of similar 
chemical classes.

Anysignificant medical condition that in the opinion of the Investigator may 
compromise patient safety, patient compliance, interfere with evaluations, or 
preclude completion of the trial. For example, COPD exacerbations within 
the 6 weeks prior to screeningrequiring oral steroids and/or antibiotics

Patientswith concomitant pulmonary disease, e.g., pulmonary tuberculosis 
(unless confirmed by chest x-ray to be no longer active) or clinically 
significant bronchiectasis.

Patients with a history of asthma

Womenof child-bearing potential, defined as all women physiologically 
capable of becoming pregnant.

Patients unable to successfully use a dry powder inhaler device or perform 
spirometry, MBNW/Lung Volumes,and DLCO  measurements

Subjects with contraindications to MRI.
Investigational 
and reference 
therapy
QVA149 110/50 μg o.d. capsules for inhalation, supplied in blisters via Novartis 
single dose dry powder inhaler (SDDPI).
Efficacy/PD 
assessments

MRI lung imaging

Spirometry

MBNW
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Safety 
assessments

Adverse events and serious adverse events

Vital signs

ECG
Other 
assessments
Not applicable
Data analysis
The number and percentage of subjects with adverse events will be tabulated 
by body system and preferred term with a breakdown by treatment.
A patient with multiple adverse events within a body system and treatment 
period is only counted once towards the total of this body system and treatment.
The percent of global ventilated volume on Day 7 of each treatment period at 
the study site will be analyzed using mixed effects model. The model will include 
fixed effects for sequence, treatment and period. Patient factor will be
included as a random effect. An unstructured covariance matrix will be applied.
Confidence intervals together with standard error (SE) and P-value will be 
calculated for the contrast QVA149 vs Placebo.
Key words
Chronic Obstructive Pulmonary Disease, COPD, Glycopyrronium bromide, 
Indacaterol maleate, small airways, Helium-3 MRI, 


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1
Introduction
1.1
Background
Chronic obstructive pulmonary disease (COPD) is a disease of progressive airflow obstruction 
involving airways of all sizes, ultimately leading to alveolar destruction and loss of 
gas-exchange capacity resulting in disability and death. Worldwide, COPD is projected to 
rank fifth in burden of disease and third with respect to mortality by 2020 (Buist et al 2007). 
It affects approximately 20% of chronic cigarette smokers. There is a high level of unmet 
medical need in the management of COPD patients, including effective symptomatic relief or 
treatment of dyspnoea, limited exercise tolerance, mucus hyper-secretion, cough and poor 
quality of life (GOLD 2015).
Current treatment guidelines for COPD recommend the use of bronchodilators for all 
severities, either on an as-required (pro re nata: prn) basis, or on a regular basis (GOLD 2015). 
Inhaled long-acting bronchodilators such as β2-adrenergic agonists (LABAs) and muscarinic 
antagonists (LAMAs) are recommended as a monotherapy or in combination (LABA+LAMA) 
(in GOLD B, C and D patients) for treatment of COPD patients.
Though COPD is considered to be a progressive disease of airways of all sizes, there is 
emerging evidence that the small airways (i.e. bronchioles < 2mm in diameter) are the site of 
early and the major site of obstructive pathology in COPD and that the disease may be 
reversible  (McDonough et al 2011). However, as the disease progresses, there is incremental 
large airway involvement though there is considerable phenotypic, physiologic and anatomic 
heterogeneity. This study focuses primarily on a panel of endpoints that investigate small 
airway function. The assessment and potential improvement of both the ventilation and 
perfusion deficit resulting from smaller airway dysfunction could be important in preventing 
further deterioration or clinical improvement in longer studies manifested by fewer 
exacerbations.
Due to the heterogeneity of the COPD patient population, this study will apply non-invasive 
imaging technology to assess both the structural and functional responses of the small airways 
to treatment with QVA. Hyperpolarized gas imaging is a methodology that utilizes helium-3 
(He-3) gas that is polarized outside of the MRI scanner and then delivered to the patient 
(via inhalation) while in the scanner. The resulting MR images generated from the 
hyperpolarized helium gas within the lung produce high resolution volumetric images of the 
ventilatory (both static and dynamic) distribution of the inhaled gas. The extent of the 
ventilation defects observed in COPD by He-3 MRI has been established to correlate with 
both age and disease severity (Kirby et al 2010).
The intent of this study is to evaluate the impact of a dual, potent bronchodilator treatment on 
ventilation defects assessed by hyperpolarized helium MRI. By combining the ventilation 
imaging with standard dynamic gadolinium contrast-enhanced 1H MR imaging that reflects 
the lung perfusion, an estimate of the ventilation/perfusion mismatch can be determined. 
An additional opportunity with the He-3 MRI method is to assess the apparent diffusion 
coefficient of the helium that has very high sensitivity to emphysematous destruction and 
airspace size thus providing additional validation of the traditional high resolution 


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CT imaging that will be applied at screening to optimize patient selection regarding extent of 
emphysema. Thus, the goals of the non-invasive imaging modalities in this study are for the 
purposes of assessment of small airway responses by determining global and regional 
ventilation defect scores, changes in subsequent lung tissue perfusion, and functional 
improvements in gas trapping.
QVA149 is a fixed combination of a long-acting β2-agonist (Indacaterol maleate – QAB149) 
and a long-acting muscarinic antagonist (Glycopyrronium bromide – NVA237) that has been 
recently approved in Europe, Japan and several other countries worldwide for the 
maintenance treatment of COPD. QVA149 has been evaluated in a comprehensive Phase III 
development program comprising more than 11,000 COPD patients across 47 countries. 
Available data has demonstrated improvement in lung function, health-related quality of life, 
decrease in COPD symptoms and decrease in use of short-acting β2-adrenergic agonist 
(SABA) with a safety profile similar to the individual monotherapy components 
(Dahl et al 2013; Bateman et al 2013; Mahler et al 2014).
1.1.1
Relevant data summary
Detailed background information on the chemistry, pharmacology, toxicology and 
pharmacokinetics of QVA149 are given in the Investigator’s Brochure and in the package 
insert of marketed QVA149 (Ultibro Breezhaler® Package Insert 2013), respectively.
The most relevant data for the present study are summarized in the sections below.
1.1.1.1
Preclinical data
QVA149 is a combination of QAB149 and NVA237 ligands which bind to β2 and muscarinic 
receptors, respectively. The in vitro activity cellular activity and selectivity profile for the 
combination drug QVA149 is an additive profile of the individual components.
1.1.1.2
Toxicology data including teratogenicity and reproductive toxicity 
data
The non-clinical safety program for QVA149 is based upon the complete toxicology programs 
conducted for both individual active drugs which included chronic, reproductive, genotoxicity 
and carcinogenicity studies.
A bridging toxicology program was performed for QVA149 that included in vitro and in vivo 
safety pharmacology assessments, 2-week inhalation toxicity studies in rats and dogs, a 
13-week inhalation toxicity study in dogs as the most sensitive species and an inhalation 
embryo-fetal development study in rats. No new toxicological findings were observed. 
The effects seen in the QVA149 inhalation toxicity studies and the safety pharmacology 
studies are consistent with the known effects of indacaterol (tachycardia, shortened ECG 
intervals, ischemic heart damage) and glycopyrronium (tachycardia, shortened ECG intervals) 
and relate to the exaggerated pharmacological effects of high-dose β2-adrenergic receptor 
agonists and muscarinic receptor antagonists, respectively. In the 14-day and 13-week 
inhalation dog studies, the QVA149 mid- and high-dose groups and also the dose groups in 
the cardiovascular inhalation safety pharmacology study in telemetered dogs showed 
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In addition, investigations with the components of QVA149, indacaterol maleate and 
glycopyrronium bromide have shown that the conducted preclinical experiments do not 
provide any evidence that the drugs have the potential to influence (induce or inhibit) each 
other’s pharmacokinetics (PK) via pathways of metabolism. Toxicokinetic data for the 
co-administration of indacaterol and glycopyrronium in inhalation toxicology studies in rats 
and dogs showed no apparent PK interaction.
1.1.1.3
Human safety and tolerability data
QVA149 was studied in clinical trials with the approved 110/50µg o.d. and was found safe 
and well tolerated based on a safety profile that is comparable to its monotherapy components 
and is consistent with other products in the class. The safety database includes patients treated 
with QVA149 up to 64 weeks. The safety profile for QVA149 in COPD patients is 
characterized by typical β2-adrenergic agonist and anticholinergic symptoms related to the 
individual monotherapy components.
The totality of the safety data in the QVA149 programs, show that adverse events were 
consistent with those expected for the LAMA and LABA classes of drugs in COPD patients; 
there was no clinically meaningful difference in frequencies of AEs by preferred term, 
severity, relatedness, or SAEs between QVA149 and placebo or the monotherapy components 
QAB149 and NVA237.
The most common events (>5%) occurred in the respiratory, thoracic and mediastinal disorders and 
infections and infestations system organ classes. Most common adverse drug reactions related to the 
combination (reported >3% and higher than placebo) were COPD and nasopharyngitis.
The overall incidence of death was comparable to placebo and the active comparators. 
Causes of death were consistent with those expected in the studied patient population.
The incidence of adverse events of interest including CCV events (including MACE and atrial 
fibrillation events), and events due to anti-cholinergic and β-adrenergic effects were all 
comparable to placebo and the monotherapy components.
QVA149 showed clinically insignificant systemic effects of β-adrenergic stimulation at 
therapeutic doses. Mean heart rate changes were less than one beat per min, and tachycardia 
was infrequent and reported at a lower rate than with placebo. Relevant prolongations of 
QTcF were not detectable compared to placebo. The frequency of notable QTcF intervals 
(>450 ms) and reports of hypokalemia were similar to placebo.
The frequencies of clinically notable laboratory abnormalities were comparable for QVA149, 
placebo and the monotherapy components with the exception of a slight imbalance in glucose 
abnormalities that were higher for QVA149 compared to placebo, but comparable to the 
active comparators.
Subgroup analyses on all safety topics did not reveal conclusive evidence for a particular sub 
population who was at risk of adverse outcomes, or revealed a relevant difference in AE profile.
Other safety parameters did not show clinically meaningful changes from baseline and were 
balanced across treatment groups.


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The safety data shows that QVA149 has an acceptable safety profile comparable to its 
monotherapy components and to placebo.
1.1.1.4
Human pharmacokinetic data
The steady-state exposure to indacaterol after QVA149 110/50 µg o.d. was either similar or 
slightly lower than systemic exposure after QAB149 150 µg (monotherapy product 
inhalation). Based on the in vitro performance data, the dose of indacaterol delivered to the 
lung is expected to be similar for QVA149 110/50 µg and QAB149 150 µg. The steady-state 
exposure to glycopyrronium after QVA149 110/50 µg o.d. was similar to systemic exposure 
after NVA237 50 µg o.d. (monotherapy product inhalation). 
There was no pharmacokinetic drug-drug interaction resulting from the concomitant 
administration of glycopyrronium and indacaterol based on steady state exposure data. 
Following inhalation of QVA149 110/50 µg o.d. the median time to reach peak plasma 
concentrations of indacaterol and glycopyrronium was approximately 15 minutes and 
5 minutes, respectively.
There were no relevant differences in systemic exposure to indacaterol or glycopyrronium 
following QVA149 administration between healthy subjects and patients with COPD. 
There was no clinically relevant covariate effect of body weight, age, gender, or baseline 
FEV1 on the pharmacokinetics of indacaterol or glycopyrronium following QVA149 
administration. There was no relevant ethnic/race effect (across Caucasian, Chinese, and 
Japanese subjects) on systemic exposure to indacaterol and glycopyrronium. QVA149 can be 
used at the recommended dose in patients with mild and moderate hepatic or renal impairment. 
In patients with severe renal impairment or end-stage renal disease requiring dialysis, 
QVA149 should only be used if the expected benefit outweighs the potential risk.
1.1.1.5
Human pharmacodynamic data
The totality of the human pharmacodynamic and efficacy data from the clinical studies 
(spirometry, exacerbations and patient-reported outcomes, use of rescue medication) reflect a 
clinically relevant benefit in COPD patients for treatment with QVA149 110/50 µg 
administered. A summary of the results for the QVA149 programs are:
QVA149 110/50 µg administered once daily demonstrated clinically meaningful efficacy: 

Improvements in lung function (an increase in the primary endpoint, trough FEV1) which 
was statistically significantly superior to placebo (above the MCID), the monotherapy 
components QAB149 and NVA237, and the active comparator, tiotropium.

Improvement in lung function, standardized FEV1 AUC (0-12h), which was statistically 
significantly superior to the active comparator fluticasone/salmeterol.

Rapid onset of action and significantly improved peak FEV1 versus all comparators 
studied.

Sustained bronchodilation (pre-dose FEV1) over 64 weeks of treatment.

Clinically meaningful and statistically significant versus NVA237 in reducing the rate of 
moderate or severe COPD exacerbations in severe to very severe patients over 64 weeks 
of treatment.


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
Provided consistent symptomatic benefit to patients with improvements in TDI, SGRQ 
and symptoms over time compared to placebo.

Reduced use of rescue medication compared to placebo, individual monotherapy 
components (QAB149 and NVA237), tiotropium and fluticasone/salmeterol. 

Showed a statistically significant increase in exercise endurance in patients treated with 
QVA149 compared to placebo.

Clinically meaningful and statistically significant bronchodilator response in terms of lung 
function and physiological markers of hyperinflation compared to placebo.

QVA149 was safe and well tolerated, providing effective bronchodilation and 
improvement in disease-specific QOL in Japanese patients with moderate to severe COPD 
for 52 weeks of treatment.

QVA149 provided clinically meaningful improvements in lung function after six weeks of 
treatment, with corresponding significant improvements in patient-reported dyspnea, 
compared with blinded tiotropium and placebo.
1.2
Study purpose
This study will investigate the effect of QVA149 on global and regional lung ventilation using 
MRI hyperpolarized gas imaging to enhance the understanding of QVA149 pharmacology in 
COPD patients.
The assessment of regional ventilation measures can then be combined with a MRI perfusion 
evaluation of the lung to visualize ventilation-perfusion mismatches. The reduction of 
ventilation-perfusion mismatch will also be evaluated in response to QVA149 treatment 
compared to placebo. Current physiological measures of small airway dysfunction are limited, 
subject to a high degree of variability and do not allow a quantitative assessment of global and 
regional ventilation defects. The MRI approach represents an opportunity to better understand 
the impact of a potent dual bronchodilator on the small and central airways and thereby 
measure the increases in ventilated lung volume, gas exchange, and reduction of 
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2
Study objectives
2.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary objective(s)
To assess global ventilated lung volume 
after treatment with  QVA149 
compared toplacebo
Global lung ventilation volume as expressed 
in percentage (%VV) of total lung volume 
using hyperpolarized helium (3He) lung MRI
2.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)
To assess regional lung ventilated 
volume after treatment with QVA149 
compared to placebo
MRI using hyperpolarized helium (3He) to 
assess regional ventilation defects as 
expressed in percentage (% VDV) of total 
lung volume for each lobar region
Standard 1H MRI with gadolinium 
enhancement tomeasure pulmonary 
perfusion(ml/g/min)
To evaluate physiologic measures of 
lung function after treatment with 
QVA149 compared to placebo to 
provide a measure of assay sensitivity 
for this study
Spirometry to assess FEV
1, FVC, FEV
1/FVC 
ratio
To assess small airway function after 
treatment with QVA149 compared to 
placebo
Lung Clearance Index by Multiple Breath 
Nitrogen Washout (MBNW)
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3
Investigational plan
3.1
Study design
This is a double-blind, randomized, placebo-controlled, two-period, cross-over study in 
patients with moderate to severe COPD.
The study will consist of a 2-week screening period, a 7-9 day run-in, a baseline visit, a 
double-blind up to 10 day treatment Period 1 followed by a washout period before crossing 
over to a double-blind up to 10-day treatment Period 2, and an end-of-study visit. At the 
Run-In visit study subjects will be taken off medications specified in Table 5-2 and will 
receive rescue medication. The investigator will need to assess whether subjects can tolerate 
being off long-acting bronchodilators prior to baseline assessments.
To minimize patient burden, MRI and lung function assessments (spirometry, MBNW/lung 
volumes, DLCO) will not be scheduled for the same day. Subjects will have two MRI 
sessions – approximately 20 mins for He3 MRI and 10 mins for proton MRI for a total of 
30-45 mins per session that includes the setup and completion of 4-5 sequences. Actual MRI 
assessments will commence 2 hours after subject dosing at the site. Assessments for 
evaluation of MRI endpoints will be done on Day 7 and all other assessments, in particular 
spirometry, MBNW/lung volumes, and DLCO will be done on the day following MRI 
assessments i.e. Day 8 of treatment during Period 1 and Period 2.
If for important operational reasons MRI assessments cannot be performed on Day 7 of the 
respective treatment period, treatment in this period may be extended by up to 3 days. If MRI 
assessments cannot be performed on Day 7, then Day 7 and Day 8 assessments can be flexibly 
scheduled in any order (i.e. Day 7 assessments can be performed before or after Day 8 
assessments and vice-versa) between Day 7 and Day 10, with all efforts made to minimize 
total days of treatment. 
If the Day 7 or Day 8 assessments are scheduled on Day 8, 9 or 10 the subject will continue 
dosing until the day of the last assessment with a maximum 10 day dosing period. Sites will 
be requested to maintain the same sequence of MRI and lung function assessments for both 
treatment periods.
Study drug should be taken on each assessment day in the presence of and under the guidance 
of study site personnel. The assessment days are Day 1, Day 7 (MRI) and Day 8 
(lung function tests) for each treatment period. Deviations within the time-frame given above 
are permissible. At all other times the subjects will take the drug at home and note date and 
time in the provided patient diary along with information about rescue medication use. 
Randomization takes place on Day 1 of Treatment Period 1. Each treatment period consists of 
a once daily dose of QVA149 or placebo over 8 days (dosing is allowed for up to 10 days). 
The treatment will be administered by oral inhalation using the Concept 1 inhalation device.
A wash-out period of at least 7 days, but no more than 14 days, will separate the two 
treatment periods.


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Safety assessments will include physical examinations, ECGs, vital signs, standard clinical 
laboratory evaluations (hematology, blood chemistry and urinalysis), adverse event and 
serious adverse event monitoring.
3.2
Rationale of study design
The study is a randomized, double-blind, placebo controlled, two arm cross over study.  
The crossover design is being used to evaluate the effect of the global endpoints of imaging 
following bronchodilation with QVA149 compared to placebo without any prior knowledge 
or data.
The 7-9 day run-in period will determine whether screened COPD patients can tolerate being 
off long-acting bronchodilators for the duration of the study. Withholding long-acting 
β2-agonists (LABAs)/long-acting muscarinic antagonists (LAMAs) and providing rescue 
medication only is common practice in short-term lung function trials in COPD patients. 
Patients who would find it hard to abstain from long-acting bronchodilators during the study 
will be identified during this run-in period and will not be randomized. Therefore, this is 
expected to reduce the number of patients dropping out of the study after randomization by 
excluding patients who can't tolerate the use of rescue medication only.
The washout period between the two treatment periods is of one to two weeks duration in 
order to ensure that there is no carry over pharmacodynamic effect of the study medications 
between treatment periods. The half-life of the bronchodilatory effect of QVA149, although 
not formally investigated, is, based on 24 hour spirometry data estimated to be < 1 day. 
Therefore no QVA149 PD effect is expected 13 days after last dosing when the next MRI 
assessment is scheduled to be conducted (1 week of washout plus 1 week of treatment in 
period 2). The helium gas does not stay in the lungs as it is washed out in a few breaths, 
within minutes of being administered.


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The crossover design allows for a comparably small sample size since treatment effects are 
estimated per individual subject and intraindividual variability is inherently lower than 
inter-subject variability. In addition, the pharmacodynamic characteristics of QVA149, 
e.g. fast onset of bronchodilatory action, allow for a short study duration which also favors the 
use of a crossover study design. 
3.3
Rationale of dose/regimen, duration of treatment
QVA149 is a marketed product (Ultibro Breezhaler (R)) and the current recommended dose is 
110 mcg indacaterol / 50 mcg glycopyrronium once daily.
Based on data from previous lung function trials, the treatment duration of 7 days is expected 
to achieve clinically significant bronchodilation with QVA149. In addition, the duration of 
treatment is sufficiently short limiting the risk of patients dropping out during the study.
The use of a double-blind placebo arm as a comparator is to provide a comparison group to 
evaluate the direct effect of treatment in the investigated endpoints. This will require the 
subject to be without long-acting bronchodilators for a maximum of 33 days (i.e. 7-9 days of 
run-in, a maximum of 10 days during Period 1 (if randomized to placebo during Period 1) 
plus a maximum of 14 days of wash-out. To minimize any potential negative impact of this 
study on the participants, subjects will remain on their background inhaled corticosteroid (ICS)
therapy throughout the study if they were on ICS when entering the study. In addition, SABA 
rescue medication will be provided to be used as needed if required by subject symptoms. For 
subjects with moderate to severe COPD (very severe not included) this is considered an 
acceptable procedure.
3.4
Rationale for choice of comparator
The use of a double-blind placebo arm as a comparator is to provide a comparison group for 
an unbiased collection of lung function assessment data to allow for evaluation of the direct 
effect of QVA149 treatment in the primary and secondary endpoints.
3.5
Purpose and timing of interim analyses/design adaptations
Interim analyses may be conducted to support decision making concerning the current clinical 
study, the sponsor’s clinical development projects in general or in case of any safety concerns.
3.6
Risks and benefits
Altering the current COPD medication regimen of enrolled COPD patients carries a potential 
risk of de-stabilizing the patient. Patients who cannot tolerate the change in medication 
regimen are expected to be identified during the run-in period and if deemed intolerable of the 
change in medication not randomized. In randomized patients the short duration of the trial 
and the provision of rescue medication (SABA) for both treatment arms provides sufficient 
risk mitigation for changing the treatment of a patient and having an effective drug-free 
placebo and washout period.


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During the study, patients will be allowed to use inhaled corticosteroids if they were treated 
with them during screening and use their provided rescue medication (short-acting 
beta2-agonists provided at the end of Visit 2) until a window of 6 hours before lung 
function/MRI assessments.
Risk to subjects (COPD exacerbations, increase on symptoms or decrease in the lung function) 
will be minimized by compliance with the eligibility criteria, study procedures, close clinical 
monitoring and use of rescue medication for the relief of acute respiratory symptoms.
Similarly, repetitive lung function measurement maneuvers during the study can lead to cough, 
shortness of breath, dizziness, or exhaustion. Since the patient only carries out forced 
maneuvers during clinic visits (not at home), these are performed under medical supervision 
to ensure availability of immediate aid if required. The assessments are part of the regular 
medical assessments of this patient population.
The risks of side effects from the study medication are those known for QVA149 which is a 
licensed medication, marketed as Ultibro® Breezhaler®. The most frequently reported side 
effects with QVA149 aside COPD to date are nasopharyngitis, upper respiratory tract 
infection, cough, and headache. Further information can be obtained from the QVA149 
Investigator’s Brochure and the Summary of Product Characteristics for Ultibro Breezhaler.
The United States Food and Drug Administration (FDA) issued a warning concerning long 
acting beta-2 agonists (LABA). The warning states that LABAs may increase the chance of 
severe asthma episodes and asthma related death in patients with asthma. The warning was 
based on a study that evaluated the safety of salmeterol, which showed an increase in asthma 
related deaths in patients with asthma receiving salmeterol and their usual asthma medication
(Vogelmeier et al 2013).
Indacaterol, which is one part of the study medication QVA149, is a LABA. 
However, indacaterol and QVA149 are not indicated to treat asthma and studies have not been 
done that show whether or not indacaterol has the same risks as salmeterol when given to 
patients with asthma. There is also currently no data that show whether or not there is the 
same risk when given to patients with COPD. Per the eligibility criteria in Section 4, patients 
with a prior or current asthma diagnosis are excluded.
There may be unknown risks of QVA149 which may be serious and unforeseen.
A potential benefit for the patient lies in a thorough medical evaluation of the patients’ disease 
and close clinical monitoring for the duration of the study.
Potential risks associated with Hyperpolarized Helium-3 MRI and GD enhanced 
MRI
There have been no ill effects reported from exposure to the magnetism or radio waves used 
in MRI. A known risk of MRI is that the magnet could attract certain types of metal. 
Therefore, metal within the patient’s body will be evaluated (this includes pacemakers, 
defibrillators, vascular clips, prosthetic heart valves, metallic particles in the eye, non-fixed 
metallic particles, certain dyes found in tattoos, etc.) If there is any question about potentially 
hazardous metal within the patient’s body, they will be excluded from participation in this 


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study. There is a possibility of discomfort from lying still for protracted periods (45 mins) 
during examination inside the scanner.
The RF coil detector, which is necessary to obtain the MR images of the lungs with the 
hyperpolarized gas, transmits and receives radio waves at much lower power than used with 
most standard MRI techniques. The coil is considered by the manufacturer a non-significant 
risk device, but it has not been approved by the FDA.
Hyperpolarized Helium-3
Helium-3 is considered to be safe and well-tolerated as an inhaled MR contrast agent for lung 
imaging. The most common respiratory related symptoms include sore, dry or scratchy throat; 
tickle in throat; and cough. Additional non-respiratory related symptoms have also occurred 
and include headache and lightheadedness. Other respiratory related symptoms include 
wheezing, chest tightness or chest pain and a decrease >10% in %PO2. Patients with lung 
disease have not been shown to be at greater risk for experiencing an adverse event compared 
to those without lung disease. This also holds true for subjects with severely compromised 
lung function (FEV1 < 40% of predicted). Helium does not stay in the lungs. Helium is 
washed out in a few breaths, within minutes of being administered.
Gadolinium
The pulmonary imaging exam includes the use of an exogenous contrast agent gadolinium 
diethyltriaminepentaacetic acid (GdDTPA) to assess lung perfusion. As with the use of an 
intravenous contrast agent, as with any injected agent, there is a small risk of a serious allergic 
reaction. This dye may cause an allergic reaction with symptoms that include rash, itchiness, 
or hives. Serious reactions are rare, and there have been fewer than 10 cases of serious allergic 
reactions (called anaphylaxis) in over a million injections. Nephrogenic Systemic Fibrosis 
(NSF) is a serious malady that has been reported only in certain people who have renal 
insufficiency and which can also occur in patients with renal transplants or liver transplant.
To avoid the very low NSF risk, the calculated glomerular filtration rate (GFR) will be 
required to be greater than 30. This is the value below which NSF has not been reported.
High resolution CT
This use of HRCT involves minimal risk and is necessary to obtain the research information 
desired. The total amount of radiation for the HRCT scans will not exceed about 10.0 mSv or 
1000 mrem on most current HRCT scanner platforms, which is well within both US and EU 
guidelines for annual exposure limits for whole body radiation. Some people may have a 
‘closed in’ feeling while inside the CT machine.
Blood Sampling
A maximum of 15 mL of blood is planned to be collected over a period of approximately 
43 days, from each subject as part of the study. Additional samples for monitoring of any 
safety findings would be in addition to this. This is not considered to be a risk for this 
population.


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4
Population
The study population will be comprised of male and female moderate to severe COPD 
patients aged 40 years and above.
A total of approximately 34 subjects will be enrolled to participate in the study and 
randomized. At least 28 subjects are expected to complete the study. 
4.1
Inclusion criteria
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female with COPD aged 40 years and above.
3. Smokers and ex-smokers who have a smoking history of at least 10 pack years. 
Smokerswill be defined as any patient who reports tobacco use within the last month. 
4. Patients with a diagnosis of moderate to severe COPD according toGOLD 2015criteria. 
Patients with airflow limitation indicated by a post-bronchodilator FEV1/FVC < 0.70 and 
by a post-bronchodilator FEV1≥ 30 % and <80 %. 
Post-bronchodilator refers to 1 hr(+/-5 minutes)after sequential inhalation of 84 µg 
ipratropium bromide (or equivalent dose) and 400 µg salbutamol/360 µg albuterol 
(orequivalent dose).Spacer devices are not permitted during reversibility testing.
5. Patients must weigh ≥45 kg and ≤100 kg to participate in thestudy.
6. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.
4.2
Exclusion criteria
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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 required by local 
regulations
2. History of hypersensitivity to any of the study drugs or to drugs of similar chemical 
classes.
3. Any significant medical condition that in the opinion of the Investigator may compromise 
patient safety, patient compliance, interfere with evaluations, or preclude completion of 
the trial. For example, COPD exacerbations within the 6 weeks prior to screening
requiring oral steroids and/or antibiotics.


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10.Patients who have had a lower respiratory tract infection within 6 weeks prior to screening, 
or significant illness which has not resolved within two (2) weeks prior to initial dosing.
11.Patients with concomitant pulmonary disease, e.g., pulmonary tuberculosis (unless 
confirmed by chest x-ray to be no longer active) or clinically significant bronchiectasis.
12.Patients with a history of asthma, indicated by (but not limited to):
15.Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant.
19.Patients unable to successfully use a dry powder inhaler device or perform spirometry, 
MBNW/lung volumesand DLCO  measurements
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22.For a subject to be enrolled in the study the following exclusion criteria relating to MRI 
will apply.
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5
Restrictions for Study Subjects
During recruitment, screening/informed consent review, and baseline visit, the subjects must 
be informed and reminded of the following restrictions:
5.1
Contraception requirements
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Not applicable. Women of childbearing potential are excluded from the study.


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6
Treatment
6.1
Study treatment
Details on the storage and management of study medication, randomization and instructions 
for prescribing and taking study treatment are outlined in Section 3 of the Site Operations 
Manual.
6.1.1
Investigational treatment
QVA149 110/50 μg o.d. capsules for inhalation, supplied in blisters via the Concept 1 
inhalation device, a single dose dry powder inhaler (SDDPI).
The investigational drug, QVA149 and matching placebo will be prepared by Novartis and 
supplied to the Unblinded Pharmacist/Unblinded Personnel at Investigator site as single blind 
patient kits.
The inhaler is supplied by the Novartis Drug Supply Management. The handling and 
administration instruction will be provided and training on how to use the inhaler will be 
provided by Novartis or its designee as appropriate at the study initiation visit.
6.1.2
Additional study treatment
Please refer to Section 6.9 for more details regarding rescue medication.
6.2
Treatment arms
Subjects will be assigned to one of the following two treatment arms in a ratio of 1:1 
(active: placebo). Study treatments are defined as:

A:  single daily dose of 110/50 μg QVA149 for 8-10 days.

B:  single daily dose of matching placebo for 8-10 days.
Table 6-1
Definition of treatment sequences 
Sequence
Period 1
Period 2
1
A
B
2
B
A
6.3
Permitted dose adjustments and interruptions of study treatment
Study drug dose adjustments and/or interruptions are not permitted.


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6.4
Treatment assignment
Randomization numbers will be assigned in ascending, scrambled order to eligible subjects 
(see Site Operations Manual for details). The investigator will enter the randomization 
number on the CRF.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. 
A Randomization list/ Treatment Allocation Card will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of treatment arms to randomization numbers in the specified ratio. 
The randomization scheme for subjects will be reviewed and approved by a member of the 
Novartis IIS Randomization Group.
Patients must meet the inclusion/exclusion criteria to be randomized. If a randomization 
number is allocated to a patient who subsequently does not meet the study eligibility criteria, 
then the patient is a screen failure. The allocated randomization number will be reused in the 
study. The unblinded pharmacist should document that the treatment allocation card, if used,
was opened and dose was prepared, but no drug administration occurred. The allocation card 
will be re-used for the next available patient in the study.  
6.5
Treatment blinding
This is a double blind study: subjects, investigator staff, persons performing the assessments, 
and data analysts will remain blind to the identity of study treatments according to the 
specifications provided in the Site Operations Manual.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, and odor.
Randomization data are kept strictly confidential, and are accessible only to authorized 
personnel, until unblinding of the trial as described in the table in the Blinding levels table in 
the Site Operations Manual.
Unblinding will only occur in the case of patient emergencies (see Section 6.6) and at the 
conclusion of the study.
Further information regarding blinding (and unblinding) is presented in the Site Operations Manual.
6.6
Emergency breaking of assigned treatment code
Emergency unblinding should only be undertaken when it is essential to treat the subject 
safely and efficaciously. Most often, study treatment discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study subject who presents with an 
emergency condition. A complete set of emergency code break cards will be provided to the 
investigator site(s) and a complete set will be available at Novartis. All code break cards must 
be retained until the end of the study and returned to Novartis. They must be stored in a secure 
place but be accessible in case of emergency. The investigator will receive a blinded code 
break card for each subject, with the details of drug treatment covered by a removable, 
scratch-off cover. In an emergency, the scratch-off cover can be removed to determine the 
treatment. The scratch-off covers are not to be removed for any reason other than an 


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emergency. When the investigator removes the scratch-off cover he/she must note the date, 
time, and reason for removing it and retain this information with the case report form 
documentation. The unblinded treatment code should not be recorded on the CRF.
The investigator must also immediately inform the Novartis local monitor that the code has 
been broken.
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the code break cards in case of emergency. If appropriate, the investigator will inform the 
subject how to contact his/her backup in cases of emergency when he/she is unavailable.
6.7
Treatment exposure and compliance
As dose administration will occur in study site and at home, compliance will be confirmed as 
fully as possible by site staff checking medication as it is returned by the subject. 
Study treatment compliance is assessed by the investigator at all visits. The Investigator or 
designee collects, from the patient, the used/unused investigational medication and packaging 
(capsules/blister strips and SDDPIs) at all dispensing visits. Any doses administered in the 
clinic will be checked by site staff.
Study drug compliance is assessed from the capsule count and from information provided by 
the patient and/or caregiver.
The correct allocation of the study medications will be entered into the eCRF to ensure a 
complete record of dosing for each subject.
6.8
Recommended treatment of adverse events
In the event of paradoxical bronchospasm the subject should be treated with a rapidly-acting 
inhaled bronchodilator, with repeated doses as required and carefully monitored until recovery 
has been documented. Subjects will be withdrawn from the study and should be carefully 
advised on future exposure to inhaled medications.
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF.
6.9
Rescue medication
At the Run-In visit all subjects will be provided with a short acting β2-agonist 
(salbutamol/albuterol) inhaler which they will be instructed to use throughout the trial as 
rescue medication. Patients randomized will be provided with rescue medication for the entire 
duration of the trial.
No other rescue medication is permitted.
Subjects need to be instructed to abstain from rescue medication (salbutamol/albuterol) for at 
least 6 hours prior to Spirometry, DLCO, MBNW/Lung Volumes and MRI imaging 
assessments. Rescue medication can be taken within the 6 hours prior to testing if warranted 
by subject’s symptoms if absolutely necessary. If subject takes rescue medication within the 
6 hours prior to spirometry, PFT, MBNW, or imaging assessments, all attempts should be 
made to reschedule the visit, if possible. If rescheduling the visit is not possible, the subjects 


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with rescue medication use within 6 hours prior to said assessments should continue with their 
planned visit, but will be excluded from the PD analysis set. 
Patients are required to record information about rescue medication use in the patient diary 
provided.
Use of rescue medication must be recorded by site staff on the Concomitant 
medications/Significant non-drug therapies CRF after start of study drug.
6.10
Concomitant treatment
The investigator should instruct the patient to notify the study site about any new medications 
s/he takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and
blood transfusions) 
administered after the patient was enrolled into the study must be recorded.
Any medication not listed in the prohibited medication table that is required by the patient for 
a medical condition and does not affect the study endpoints is allowed.
7
Discontinuation and study completion
7.1
Discontinuation of study treatment
Subjects may withdraw from the study for any reason at any time. They may be considered 
withdrawn if they state an intention to withdraw, fail to return for visits, or become lost to 
follow-up for any other reason.
In addition, study treatment must be discontinued and the subject withdrawn from the trial 
under the following circumstances:

subject withdraws consent

adverse events for which continued inhalation of the study drug would be detrimental to 
the subject e.g. paradoxical bronchospasm

abnormal test procedure results indicating risk for the patient on continued inhalation of 
the study drug.

pregnancy.

deterioration in the patient’s health that requires alternative intervention not permitted per 
protocol.

deviations from the prescribed dose regimen for the study drug: more than 2 consecutive 
missed doses between days 2 and 10 of each treatment period.

use of prohibited treatment as per protocol.

any other protocol deviation that results in a significant risk to the subject’s safety.


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7.2
Study completion and post-study treatment
Each subject will be required to complete the study in its entirety and thereafter no further 
study treatment will be made available to them. Study completion is defined as when the last 
subject completes their End of Study 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.
7.2.1
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A subject should not be formally considered lost to 
follow-up until his/her scheduled end of study visit would have occurred.
7.3
Withdrawal of consent
Subjects may withdraw consent to participate in the study for any reason at any time.
Withdrawal of consent occurs only when a subject does not want to participate in the study 
anymore and does not want any further visits or assessments and does not want any further 
study related contact and does not allow analysis of already obtained biologic material.
If a subject withdraws consent, the investigator must make every effort to determine the 
primary reason for this decision and record this information. Study treatment must be 
discontinued and no further assessments conducted. All biological material that has not been 
analyzed at the time of withdrawal must not be used. Further attempts to contact the subject 
are not allowed unless safety findings require communicating or follow-up.
7.4
Study Stopping rules
Stopping rules for safety are listed below:
The Study may be put on hold and no further dosing or enrollment will take place pending a 
full safety review in case of any of the following:

Two SAEs of a similar nature in two different subjects that are suspected of being related 
to study drug

Two AEs of a similar nature in two different subjects which are severe in intensity and 
suspected of being related to study drug
Following the review a decision will be made to resume or stop the study.


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7.5
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
subjects should be seen as soon as possible and treated as a prematurely withdrawn subject. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the subject’s interests.
The investigator will be responsible for informing IRBs/IECs of the early termination of the 
trial.


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8
Procedures and assessments
Table 8-1
Assessment Schedule




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8.1
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the subject source documents.
The date of signing of informed consent (and withdrawal, if later withdrawn) should be 
documented in the CRF.
Novartis will provide to investigators a proposed informed consent form that complies with 
the ICH GCP guideline and regulatory requirements and is considered appropriate for this 
study. Any changes to the proposed consent form suggested by the investigator must be 
agreed to by Novartis before submission to the IRB/IEC. 
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
8.2
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects.
Relevant medical history/current medical conditions data includes data until signature of 
informed consent. Where possible, diagnoses and not symptoms will be recorded.
Investigators have the discretion to record abnormal test findings on the medical history CRF 
whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
Hepatitis screen, HIV screen
All subjects will be screened for Hepatitis B surface antigen (HBsAg). Screening for Hepatitis 
C will be based on HCV antibodies. Evaluation for HIV seropositivity will be performed, and, 
if positive, confirmation by a second technique available at the laboratory site, e.g., Western 
blot. Results will be available as source data and will not be recorded within the CRF.
Alcohol test, Drug screen
Subjects will be tested for substances of abuse (e.g. alcohol, amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, and opiates).
Results will be available as Source data and will not be recorded within the eCRF.
HbA1c diabetes 
All patients will be tested for poorly controlled Type I and Type II diabetes. Patients HbA1c 
levels should not be >8%.
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8.3
Efficacy / Pharmacodynamics
Pharmacodynamic assessments are specified below, with the methods for assessment and 
recording specified in the Site Operations Manual. Assessments will be performed/samples 
collected at the timepoint(s) defined in the Assessment Schedule.
8.3.1
MRI
Hyperpolarized Helium Lung Imaging: Using an inhaled gaseous contrast agent, 
hyperpolarized helium-3 (He-3), the regional distribution of inhaled gas within the lung can 
be assessed using MRI a method that does not involve the use of ionizing radiation. In young 
healthy subjects, inhaled helium-3 gas distributes evenly throughout the airspaces producing 
uniformly high signal throughout the lung on the MR images (Parragaetal2008, 
Altesetal2001). When there is focal reduction in airflow such as that present in COPD, the 
airspaces distal to the area of obstruction do not fill with the gas and appear dark on the 
images, depicted as a so-called “ventilation defect”. Multiple different factors such as mucus 
plugging, and airway narrowing and airway narrowing or closure from a variety of etiologies 
can cause ventilation defects on hyperpolarized gas MRI.
Lung Perfusion Imaging: MR perfusion imaging of the lung with gadolinium contrast agent 
will also be performed to determine whether vascular abnormalities producing perfusion 
deficits correspond to abnormalities in ventilation, so called hypoxic vasoconstriction.
The lung imaging methodology is limited to an expert imaging center with advanced 
pulmonary imaging experience and the dedicated MRI hardware necessary for hyperpolarized 
He-3. Adetailed Imaging Acquisition Guidelines will be developed for the study. All imaging 
analysis procedures applied to produce the quantitative assessments of regional ventilation 
defects will be in a separate manual and all image analysis results will be transferred from a 
commercial imaging CRO.
8.3.2
Spirometry
Spirometry will be performed at study visits as outlined inthe Assessment Schedule. 
Apre-dose assessment (-45 min and -15 min in relation to study drug administration) will be 
performed as well as post-dose assessments at 15 min, 1 hour and 2 hours following on-site 
administration of study medication.
Centralized spirometry will be provided by a vendor, and training and instructions will be 
provided. Spirometric parameters to be measured are:
Forced Expiratory Volume in 1 second (FEV
1)
Forced Vital Capacity (FVC)
FEV1
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/FVC ratio
Additional information for conduct of spirometric assessments will be provided in the Site 
Operations Manual.


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8.3.3
Multiple Breath Nitrogen Washout
MBNW will be performed at visits as detailed in the Assessment Schedule using a multiple 
breath inert gas washout technique. The device provides the global index of ventilation 
inhomogeneity assessment (LCI = Cumulative Expired Volume/Functional Residual Capacity). 
Further information on this assessment can be found in the Site Operations Manual.
8.3.4
DLCO and Lung Volumes Assessment
Lung volumes and DLCO determinations will be performed at visits as outlined in the 
Assessment Schedule. Parameters measured will include DLCO, IC, FRC, TLC, RV and 
RV/TLC ratio. The parameters can be determined by the use of a conventional body 
plethysmograph or a device provided to the site. Additional information will be provided in 
the Site Operations Manual.
8.3.5
Patient diary
Subjects will be provided with individual diary cards to record each administration of study 
medication and information on use of rescue medication. This will be checked regularly by 
site staff.
8.4
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment Schedule detailing when each assessment is 
to be performed.
8.4.1
Physical examination
A physical examination will be performed at Screening and End of Study. It will include the 
examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, 
lungs, heart, abdomen, back, lymph nodes, extremities, vascular, and neurological. 
If indicated based on medical history and/or symptoms, rectal, external genitalia, breast, and 
pelvic exams are performed.
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to the start of study must be included in 
the Relevant Medical History/Current Medical Conditions screen on the patient’s eCRF. 
Significant findings made after the start of study which meet the definition of an 
Adverse Event must be recorded on the Adverse Event screen of the patient’s eCRF.


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8.4.2
Vital signs
Vital signs include temperature, pulse rate (measured for 60 seconds, if performed manually) 
and systolic and diastolic blood pressure. Pulse rate and blood pressure is assessed after the 
patient has rested in the sitting position for at least 3 minutes. If an automated blood pressure
device is used, it should be calibrated according to the manufacturer’s guidelines.
If vital signs are out-of-range in the opinion of the Investigator at screening or prior to initial 
dosing, the Investigator should obtain two additional readings, so that a total of up to three 
consecutive assessments are made, with the subject seated quietly for approximately five 
minutes preceding each repeat assessment. At least the last reading must be within an 
acceptable range in the opinion of the investigator in order for the subject to qualify.
8.4.3
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured. Body mass index (BMI) will be calculated 
using the following formula:
BMI = Body weight (kg) / [Height (m)]2
8.4.4
Local Laboratory evaluations
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and discussed with Novartis personnel. The results should be 
evaluated for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted.
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential and 
platelet count will be measured.
Clinical chemistry
Sodium, potassium, creatinine, urea, uric acid, chloride, albumin, calcium, alkaline 
phosphatase, total bilirubin, LDH, GGT, AST, ALT, aPTT, PT/INR, CK, HbA1c at screening, 
glucose, total cholesterol, triglycerides. If the total bilirubin concentration is increased above 
1.5 times the upper limit of normal, direct and indirect reacting bilirubin should be 
differentiated.
Urinalysis
Urine test by dipstick: leucocytes, nitrite, pH, protein, glucose, ketones, urobilinogen, 
bilirubin, blood/ hemoglobin
If the dipstick result is positive for protein, nitrite, leucocytes and/or blood, the sample will be 
sent for microscopic analysis of WBC, RBC and casts.


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8.4.5
Electrocardiogram (ECG)
A standard single 12 lead ECG is collected at Visit 1 and End of Study. ECGs must be 
recorded after 10 minutes rest in the supine position to ensure a stable baseline. The preferred 
sequence of cardiovascular data collection during study visits is ECG collection first, 
followed by vital signs, and spirometry. The Fridericia QT correction formula (QTcF) should 
be used for clinical decisions.
The original ECGs appropriately signed, should be collected and archived at the study site. 
Each ECG tracing should be labeled with study number, subject initials, subject number, date 
and time, and filed in the study site source documents.
QTcF, QT duration, heart rate, PR duration, and QRS complex duration will be recorded in 
the eCRF.
Clinically significant abnormalities are recorded on the relevant section of the medical 
history/Current medical conditions/AE eCRF page as appropriate.
8.4.6
Pregnancy and assessments of fertility
Women of child-bearing potential are excluded from this study.
Despite meeting the selection criterion of not being of child-bearing potential, all participating 
women will have regular urine pregnancy tests during the study. A positive urine pregnancy 
test requires immediate interruption of study drug until serum β-hCG is performed and found 
to be negative.
8.5
High Resolution CT
HRCT will be completed at screening for the purpose of fulfilling eligibility criteria. 
A historic HRCT performed within 6 months of the screening visit may be accepted as long as 
it is performed by a protocol approved by the Sponsor. The imaging acquisition guidelines for 
HRCT will include details of the protocol and machine settings and will be provided to all 
trial sites as part of the SOM.
9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The occurrence of adverse events should be sought by non-directive questioning of the subject 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the subject during or between visits or through physical examination, laboratory test, or 
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Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms,

they are considered clinically significant,

they require therapy.
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for liver related events are included in 
Section 9.3.
Adverse events must be recorded on the Adverse Events CRF for subjects that 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 severity grade

mild:  usually transient in nature and generally not interfering with normal  activities

moderate:  sufficiently discomforting to interfere with normal activities

severe:  prevents normal activities
2. its relationship to the study treatment (no/yes),
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 (SAE) See Section 9.2 for definition of SAE
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 (i.e. further observation only)

study treatment dosage adjusted/temporarily interrupted

study treatment permanently discontinued due to this adverse event

concomitant medication given

non-drug therapy given

subject hospitalized/subject’s hospitalization prolonged
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, 
if necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome.


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Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or Core Data Sheet (for marketed drugs) or will be 
communicated between IB updates in the form of Investigator Notifications. This information 
will be included in the subject informed consent and should be discussed with the subject 
during the study as needed.
The investigator should also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents, however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
9.2
Serious adverse event reporting
9.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition e.g. scheduled lung function or progression of disease 
assessments elective or pre-planned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since the start of study 
drug

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, i.e. defined as an event that jeopardizes the subject or may require 
medical or surgical intervention.
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
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Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse.
All AEs (serious and non-serious) are captured on the CRF, SAEs also require individual 
reporting to DS&E as per Section 9.2.2.
9.2.2
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence, if the investigator becomes aware, as 
described below. Any SAEs experienced after this should only be reported to Novartis if the 
investigator suspects a causal relationship to study treatment.
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event.
Follow- up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the investigational treatment a Drug Safety 
and Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 
investigational treatment that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with EU Guidance 2011/C 172/01 or as per national 
regulatory requirements in participating countries.
9.3
Liver safety monitoring
Not applicable in this COPD study.
9.4
Renal safety monitoring
Not applicable in this COPD study.


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9.5
Pregnancy reporting
To ensure patient safety, each pregnancy in a subject on study drug must be reported to 
Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up 
to determine outcome, including spontaneous or voluntary termination, details of the birth, 
and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. The study drug must be discontinued, though the subject may stay in 
the study, if she wishes to do so. All assessments that are considered as a risk during 
pregnancy must not be performed. The subject may continue all other protocol assessments. 
Pregnancy must be recorded on a Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. 
Pregnancy follow-up should be recorded on the same form and should include an assessment
of the possible relationship to the Novartis study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on an SAE Report Form.
10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. 
During the study Novartis employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. The monitor will visit the site to check 
the completeness of subject records, the accuracy of entries on the CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
drug is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the monitor during these visits.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject's file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the eligibility criteria, documentation of 
SAEs, and the recording of data that will be used for all primary and safety variables. 
Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about 
the identity of the subjects will be disclosed.


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10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the 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 corrected before 
transfer of the data to Novartis. The Investigator must certify that the data entered into the 
Electronic Case Report Forms are complete and accurate. After database lock, the investigator 
will receive a CD-ROM or paper copies of the subject data for archiving at the investigational 
site.
Data not requiring a separate written record will be defined in the Site Operations Manual and 
Assessment Schedule and can be recorded directly on the CRFs. All other data captured for 
this study will have an external originating source (either written or electronic) with the CRF 
not being considered as source.
10.3
Database management and quality control
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
Novartis staff review the data entered into the eCRFs by investigational staff for completeness 
and accuracy and instruct the site personnel to make any required corrections or additions. 
Queries are sent to the investigational site using an electronic data query. 
Designated investigator site staff is required to respond to the query and confirm or correct the 
data. If the electronic query system is not used, a paper Data Query Form will be faxed to the 
site. Site personnel will complete and sign the faxed copy and fax it back to Novartis staff 
who will make the correction to the database.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system.
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
HRCT and MRI readings as well as Spirometry, DLCO and MBNW/ Lung Volumes readings 
will be processed centrally and the results will be sent electronically to Novartis (or a 
designated CRO).
At the conclusion of a non-IRT study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to 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.
11.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The safety analysis set will include all subjects that received any study drug.
The primary population of interest is the PD population, all the patients with evaluable 
PD parameter data and no major protocol deviations impacting PD data will be included in the 
PD data analysis "PD population". Any PD data less than 6 hours after rescue medication use 
or within 7 days of systemic corticosteroid will be set to missing.
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment sequence and 
subject. Summary statistics will be provided for all subjects, as well as for each treatment 
sequence.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment sequence and subject.
11.3
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment sequence and subject.
11.4
Analysis of the primary variable(s)
11.4.1
Variable(s)
The primary variable is to evaluate the pharmacodynamics response as reflected by percent of 
global lung ventilation volume on day 7 after the treatment with QVA149 compared to 
placebo in moderate to severe COPD patients.
11.4.2
Statistical model, hypothesis, and method of analysis
The percent of global ventilation volume on day 7 will be analyzed using a mixed effects 
model. The model will include sequence, period and treatment as fixed effects. Patient factor 
will be included as a random effect. An unstructured covariance matrix will be applied.
The final model estimates will include the LSmean for each treatment (QVA149 and placebo) 
together with standard error (SE), the adjusted mean difference between QVA149 and placebo, 
and corresponding 90% two-sided confidence intervals and P-value for the differences using 
placebo as the reference treatment.


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Percent of global ventilation volume will be listed by treatment, subject and visit/time and 
descriptive summary statistics will be provided by treatment, and visit/time. 
Summarystatistics will include arithmetic mean, SD, CV (arithmetic), median, minimum and 
maximum.
Graphical methods will be employed to show mean and individual figures for %global 
ventilation volume.
No adjustments for multiplicity will be applied for this exploratory study.
11.4.3
Handling of missing values/censoring/discontinuations
Subjects withdrawn for any reasons other than safety and tolerability may be replaced.
Where data has values below and above limits of quantification then the following rule will 
apply.
In the summary tables, the frequency (n, %) of values below the LLOQ and above the ULOQ,
respectively, will be included.
In case of censored values (values below the LLOQ and/or values above the ULOQ), the
summary statistics (arithmetic mean, standard deviation, geometric mean and CV% of
geometric mean) will be calculated as the maximum likelihood estimates using a parametric
model for data that can be right censored and left censored assuming the data being normally
or log-normally distributed.
Values BLQ that are statistically analyzed will be analyzed at half the LLOQ.
11.4.4
Summary statistics of pharmacokinetics
Not Applicable
11.4.5
Supportive analyses
Not Applicable
11.5
Analysis of secondary and exploratory variables
11.5.1
Efficacy / Pharmacodynamics
Secondary pharmacodynamic variables are Forced Expiratory Volume in 1 second (FEV1), 
Forced Vital Capacity (FVC), FEV1/FVC ratio measured by spirometry, Lung Clearance 
Index measured by Multiple Breath Nitrogen Washout, Percent of regional ventilation defects 
volume measured by MRI using hyperpolarizedhelium(
3He),Pulmonary perfusion (ml/g/min) 
using Standard 1
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H MRI with gadolinium enhancement, Collateral ventilation by 
hyperpolarized gas MRI lung imaging.


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The primary model described for percent of global ventilation volume in Section 11.4.2will 
be fit to all secondary and exploratory parameters of interest (separate model for each 
parameter). For spirometry parameters, the model may include fixed effects for time (15 min, 
1 hour and 2 hourspost dose) and treatment by time interaction term. Time will be repeated 
within each patient*period interaction and subject-average baseline and period-adjusted 
baselineas covariates in addition to the factors added to the primary analysis. An unstructured 
variance unstructured covariance matrix will be applied.
The subject average baseline will be derived as the average of their pre-dose assessments from 
each period.  Period adjusted baseline will be calculated for each subject and for each period, 
as the difference between the period baseline and the subject average baseline, i.e. value of 
period baseline –value of average baseline (Kenward and Roger1997).
Sensitivity analysis for LCI, Lung volumes and DLCOas described in Section 11.4.2may be 
repeated with a mixed effects model by using screening visit as covariate.
Correlations between MR imaging parameters, spirometry,MBNW/ lung volumesand DLCO 
at baseline and end of each period for QVA149 and Placebo will be presented, and all end 
points will be summarized graphically and in tables.
All MR imaging, spirometry,MBNW/lung volumesand DLCO parameters will be listed by 
treatment, subject and visit/time and descriptive summary statistics will be provided by 
treatment, and visit/time. Summary statistics will include arithmetic mean, SD, CV 
(arithmetic), median, minimum and maximum.
Graphical methods will be employed to show mean and individual figures for all parameters.
11.5.2
Safety
Vital signs
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will beflagged. Summary statistics 
will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment, subject and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
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All laboratory data will be listed by treatment, subject, and visit/time and if normal ranges are 
available abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit/time.


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Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
The number and percentage of subjects with 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 next period is counted only in the onset period. A subject with 
multiple adverse events within a body system and treatment period is only counted once 
towards the total of this body system and treatment.
11.5.3
Pharmacokinetics
Not Applicable. 
11.5.4
Pharmacokinetic / pharmacodynamic interactions
Not Applicable.
11.5.5
Other assessments
11.5.5.1Exploratory biomarkers
Not Applicable.
11.6
Sample size calculation
Allowing for a 20% dropout rate, a total sample size of 34 (17 per sequence) patients will be 
randomized to two treatment sequences.
11.7
Power for analysis of key secondary variables
The sample size of 28 (14 per sequence) completers is also sufficient to confirm an assay 
sensitivity for trough FEV1between QVA149 and Placebo. By examining several relevant 
crossover studies (QVA149A2303, NVA237A2205, NVA237A2208 and AC41113073 from 
Anoro PADAC Briefing Book), the within patient standard deviation for trough FEV1is 
estimated as 175 mL.  The estimate of the true drug effect on trough FEV1is likely to be at 
least 170 mL. This was derived from the lower 90% CI boundary on trough FEV1from 
QVA149A2303 study.
The study will also provide at least 80% power to detect a difference of 170 mL in trough 
FEV1
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using a 2-sided test at a significance level of 10%.
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Protocol No. CQVA149A2325
11.8
Interim analyses
Interim analyses may be conducted to support decision making concerning the current clinical 
study, the sponsor’s clinical development projects in general or in case of any safety concerns.
12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g. advertisements) and any other written information to be provided to subjects. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis around the 
time of Last Patient Last Visit to be a reviewer and signatory for the clinical study report.
12.3
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results.
13
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs.


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Protocol No. CQVA149A2325
Investigators must apply due diligence to avoid protocol deviations. If the investigator feels a 
protocol deviation would improve the conduct of the study this must be considered a protocol 
amendment, and unless such an amendment is agreed upon by Novartis and approved by the 
IRB/IEC/REB it cannot be implemented. All significant protocol deviations will be recorded 
and reported in the CSR.
13.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are intended to eliminate an apparent immediate hazard to subjects 
may be implemented, provided the Health Authorities and the reviewing IRB/IEC are 
subsequently notified by protocol amendment.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the CTL 
should be informed and (serious) adverse event reporting requirements (Section 9) followed 
as appropriate.


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Protocol No. CQVA149A2325
14
References
Altes TA, Powers PL, Knight-Scott J, et al (2001). Hyperpolarized 3He MR lung ventilation 
imaging in asthmatics: preliminary findings. J Magn Reson Imaging;13(3):378-384.
Bateman ED, Ferguson GT, Barnes N, et al (2013) Dual bronchodilation with QVA149 versus 
single bronchodilator therapy: the SHINE study. Eur Respir J 42(6):1484-94.
Buist AS, McBurnie MA, Vollmer WM, et al. (2007) International variation in the prevalence 
of COPD (the BOLD Study): a population-based prevalence study. Lancet 370(9589):741-50.
Dahl R, Chapman KR, Rudolf M, et al (2013) Safety and efficacy of dual bronchodilation 
with QVA149 in COPD patients: The ENLIGHTEN study. Respir Med 107(10):1558-67.
Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive 
Pulmonary Disease (COPD).From the Global Strategy for the Diagnosis, Management and 
Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2015. 
Available from: http://www.goldcopd.org/
Kenward MG and Roger JH (1997). Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics 53(3), 983–997.
Kirby M, Matthew L, Wheatly A, et al (2010) Chronic obstructive pulmonary disease: 
longitudinal hyperpolarized (3)He MR imaging. Radiology; 256(1): 280-9.
Mahler DA, Decramer M, D’Urzo, A, et al (2014) Dual bronchodilation with QVA149 
reduces patient-reported dyspnoea in COPD: the BLAZE study. Eur Respir J 43(6): 1599-609.
McDonough JE, Yuan R, Suzuki M, et al (2011) Small-airway obstruction and emphysema in 
chronic obstructive pulmonary disease. New England Journal of Medicine; 365(17):1567-75.
Parraga G, Mathew L, Etemad-Rezai R, et al (2008) Hyperpolarized 3He magnetic resonance 
imaging of ventilation defects in healthy elderly volunteers: initial findings at 3.0 Tesla. Acad 
Radiol;15(6):776-785.
Vogelmeier CF, Bateman ED, Pallante J, et al (2013) Efficacy and safety of once-daily 
QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic 
obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group 
study. Lancet Respir Med 1(1):51-60.

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
QVA149
CQVA149A2325
A randomized, double-blind, placebo-controlled, two-period crossover 
study to assess the effect of inhaled QVA149 on global and regional lung 
function and gas exchange in patients with moderate to severe COPD
Statistical Analysis Plan (SAP)
Author(s):
Document type: 
SAP Documentation –NIBR 
Document status:
Final
Release date:
13-May-2016
Number of pages:
13
Personal Data
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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CQVA149A2325
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SAP
CQVA149A2325
able of contents
able of contents
3
ist of tables
4
1 Introduction
5
11 Scope of document
5
12 Study reference documentation
5
13 Study obectives
5
131 
Primary obectives
5
132 
Secondary obective(s)
5
14 Study design and treatment
5
2 First interpretable results (FIR)
3 Interim analyses
4 Statistical methods: Analysis sets
5 Statistical methods for Pharmacoinetic (P) parameters
51 Variables
52 Descriptive analyses
53 
Statistical model, assumptions and hypotheses
9
531 
Model checing procedures
9
532 
raphicalpresentation of results
9
6 Statistical methods for Pharmacodynamic (PD) parameters
9
61 Primary obective
9
611 
Variables
9
612  
Descriptive analyses
9
613 
Statistical model, assumptions and hypotheses
9
62 Secondary obectives
10
621 
Variables
10
622 
Descriptive analyses
10
623 
Statistical model, assumptions and hypotheses
10
63 
xploratory obectives
11
631 
Variables
11
632 
Descriptive analyses
12
Statistical methods for safety and tolerability data
12
11 
Variables
12
12 
Descriptive analyses
12
13 
raphical presentation
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13


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SAP
CQVA149A2325
Statistical methods for Biomarer data
13
ist of tables
able4-1 
Protocol deviation codes and analysis sets


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SAP
CQVA149A2325
1 
Introduction 
11 
Scopeof document
he RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial CQVA149A2325
he Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol
12 
Study reference documentation
Final Study protocol is available at the time of finalization of this Statistical Analysis Plan
13 
Study obectives
131 
Primary obectives
o assess global ventilated lung volume after treatment with  QVA149 compared to 
placebo
132 
Secondary obective(s)
o assess regional lung ventilated volume after treatment with QVA149 compared to 
placebo
o evaluate physiologic measures of lung function after treatment with QVA149 
compared to placebo to provide a measure of assay sensitivity for this study
o assess small airway function after treatment with QVA149 compared to placebo
14 
Study design and treatment
his is a double-blind, randomized, placebo-controlled, two-period, cross-over study in 
patients with moderate to severe COPD
he study will consist of a 2-wee screening period, a -9 day run-in, a baseline visit, a 
double-blind up to 10 day treatment Period 1 followed by a washout period before crossing 
over to a double-blind up to 10-day treatment Period 2, and an end-of-study visit Atthe Run-
In visitstudy subects will be taen off medications (Refer protocol: section 52 of able 5-2
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SAP
CQVA149A2325
and will receive rescue medication he investigator will need to assess whether subects can 
tolerate being off long-acting bronchodilators prior to baseline assessments
o minimize patient burden, MRI and lung function assessments (spirometry, MBN /lung 
volumes, D CO) will not be scheduled for the same day Subects will have two MRI 
sessions –approximately 20 mins for e3MRI and 10 mins for proton MRI for a total of 30-
45 mins per session that includes the setup and completion of 4-5 seuences Actual MRI 
assessments will commence 2 hours after subect dosing at the site Assessments for 
evaluation of MRI endpoints will be done on Day  and all other assessments, in particular 
spirometry, MBN /lung volumes, and D CO will be done on theday following MRI 
assessments ie Day  of treatment during Period 1 and Period 2
If for important operational reasons MRI assessments cannot be performed on Day  of the 
respective treatment period, treatment in this period may be extended by up to 3 daysIf MRI 
assessments cannot be performed on Day , then Day  and Day  assessments can be flexibly 
scheduled in any order (ie Day  assessments can be performed before or after Day  
assessments and vice-versa) between Day  and Day 10, with all efforts made to minimize 
total days of treatment 
If the Day  or Day assessmentsarescheduled on Day , 9 or 10 the subect will continue 
dosing until the day of thelastassessment with a maximum 10 day dosing period Sites will 
be reuested to maintain the same seuence of MRI and lung function assessments for both 
treatment periods
Study drug should be taen on each assessment day in the presence of and under the guidance 
of study site personnel he assessment days are Day 1, Day  (MRI) and Day  (lung 
function tests) for each treatment period Deviations within the time-frame given above are 
permissible At all other times the subects will tae the drug at home and note date and time 
in the provided patient diary along with information aboutrescue medicationuse 
Randomization taes place on Day 1 of reatment Period 1 ach treatment period consists of 
a once daily dose of QVA149 or placebo over  days (dosing is allowed for up to 10 days) 
he treatment will be administered by oral inhalation using the Concept 1 inhalation device
A wash-out period of at least  days, but no more than 14 days, will separate the two 
treatment periods
Safety assessments will include physical examinations, Cs, vital signs, standard clinical 
laboratory evaluations (hematology, blood chemistry and urinalysis),adverse event and 
serious adverse event monitoring


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2 
First interpretable results (FIR)
First interpretable results (FIR) willbe provided for this trial
 
 
 
 
 
 
3  
Interim analyses 
Interim analyses may be conducted to support decision maing concerning the current clinical 
study, the sponsors clinical development proects in general or in case of any safety concerns 
In this case,thisinterim analysis maybe performed bythe study statistician he purpose of 
this IA is to confirm the sample size assumptions while assessing the variability in the 
primary end point in this population
here will be no pause in enrollment at the time of interim analysis
4 
Statistical methods: Analysis sets
For subects for which the actual treatment received does not match the randomized treatment 
the treatment actually received will be used for the analysis
For subects for which the actual seuence of treatments received does not match the 
randomized seuence of treatments, the actual seuence will be used for analysis involving a 
seuence component (eg ANOVAs with a seuence effect) if the actual seuence is one of 
the seuences planned in the study design If the actual seuence is not one of the seuences 
planned in the study design, the randomized seuence will be used for analysis involving a 
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CQVA149A2325
seuence component but data points from periods in which the subect has not received the 
randomized treatment will be excluded from the analysis 
he safety analysis set will include all subects that received any study drug
he primary population of interest is the PD population, all the patients with evaluable PD 
parameter data and no maor protocol deviations impacting PD data will be included in the PD 
data analysis PD population Any PD data less than 6 hours after rescue medication use or 
within  days of systemic corticosteroid will be set to missing
he analysis sets and protocol deviation codes are related as follows:
able 4-1 
Protocol deviation codes and analysis sets
Category
Deviation code
ext description of deviation
Data exclusion
Subects are excluded from all (safety)analysis in case of these 
PDs: 
xclude subect completely 
from all (safety)analysis 
sets
INC 01
Deviation from inclusion criteria: ritten
informed consent was not obtained before 
anystudy assessment was performed
es
Subects are excluded from PD analysis in case of these PDs:
xclude subect from PD 
analysis set
INC 01
Deviation from inclusion criteria: ritten
informed consent was not obtained before 
anystudy assessment was performed
es
Only PDs which impacts in subects exclusion are mentioned above
If updates to this table are needed,anamendment tothe SAP may need tobe implemented 
priortoDB
5 
Statistical methods for Pharmacoinetic (P) parameters
Not applicable
51 
Variables 
Not applicable
52 
Descriptive analyses
Not applicable


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53 
Statistical model, assumptions and hypotheses
Not applicable
531  Model checing procedures
Not applicable
532 
raphical presentation of results
Not applicable
6 
Statistical methods for Pharmacodynamic (PD) parameters
61 
Primary obective
611 
Variables 
he primary variable is the percent of global lung ventilation volume as determined by 3e 
lung MRI to evaluate the pharmacodynamic response on day  after once daily treatment with 
QVA149 compared to placebo
612 
Descriptive analyses
Results for percent of global lung ventilation volumewill be presented in summary table by 
treatment and time, and graphically as arithmetic mean and boxplots by treatment over time 
and as individual graphs (individual data for each patient over time, separate for each 
treatment) All results will also be listed by treatment group, subect, and time-point
613 
Statistical model, assumptions and hypotheses
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A comparison of QVA149 vs placebo on percent of global lung ventilation volumeis of 
primary interest to investigate the effect of QVA149 on global and regional lung ventilation 
using MRI hyperpolarized gas imaging to enhance the understanding of QVA149 
pharmacology in COPD patients
he percent of global ventilation volume on day  will be analyzed using a mixed effects 
model he model will include seuence, period and treatment as fixed effects Patient factor 
will be included as a random effect he within-patient correlation will be modeled using the 
unstructured covariance matrix Restricted maximum lielihood method will be used he 
enward-Roger approximation will be used to estimate denominator degrees of freedom In 
case of the analysis fails to converge, compound symmetric covariance structure will be used 
No adustment for multiplicity is planned
he final model estimates will include the Smean for each treatment (QVA149 and placebo) 
together with standard error (S), the adusted mean difference between QVA149 and placebo, 
and corresponding 90 two-sided confidence intervals and P-value for the differences using 
placebo as the reference treatment
 


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6131 Model checing procedures
Missing data will not be imputed for the primary analysisSubects withdrawn for any reason 
other than safety and tolerability maybe replaced
6132
raphical presentation of results
Refer section 612
62 
Secondary obectives
621 
Variables 
Secondary pharmacodynamicvariables are Forced xpiratory Volume in 1 second (F V1), 
Forced Vital Capacity (FVC), F V1/FVC ratio measured by spirometry, ung Clearance 
Index measured by Multiple Breath Nitrogen ashout, Percent of regional ventilation defects 
volume measured by MRI using hyperpolarized helium (
3 e), Pulmonary perfusion 
(ml/g/min) using Standard1 MRI with gadolinium enhancement
622 
Descriptive analyses
Results for all secondary parameters will be presented in summary tables by treatment and 
time, and graphically as mean plots and boxplots by treatment over time and as individual 
graphs (individual data for each patient over time, separate for each treatment)All results will 
also be listed by treatment seuence, subect, and time-pointSummary statistics will include 
arithmetic mean, SD, CV (arithmetic), median, minimum and maximum
623 
Statistical model, assumptions and hypotheses
he primary model described for percent of global ventilation volume in Section 613
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will be 
fit to all secondary parameters of interest (separate model for each parameter) For spirometry 
parameters, the model willinclude fixed effects for time (15 min, 1 hour and 2 hours post 
dose) and treatment by time interaction term ime will be repeated within each 
patientperiod interaction andsubect-average baseline and period-adusted baseline as 
covariates in addition to the factors added to the primary analysis An unstructured variance 
unstructured covariance matrix will be applied


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he 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 and for each period, 
as the difference between the period baseline and the subect average baseline, ie value of 
period baseline –value of average baseline
he baseline will be defined as the average of -45 min and -15 min pre-dose assessments 
his gives a more robust estimate of pre-dose valuesfor the calculation of subect average 
baseline 
Sensitivity analysis for CI, ung volumes andD CO as described in Section 613may be 
repeated with a mixed effects model as described for primary variable by addingscreening 
visit as covariate
 
            
6231 Model checing procedures
Refer section 6131
6232
raphical presentation of results
Refer section 622
63 
xploratory obectives
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631 
Variables 


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632 
Descriptive analyses
Results for all exploratory parameters will be presented in summary tables by treatment and 
time, and graphically as boxplots by treatment over time and as individual graphs (individual 
data for each patient over time, separate for each treatment)All results will also be listed by 
treatment seuence, subect, and time-pointSummary statistics will include arithmetic mean, 
SD, CV (arithmetic), median, minimum and maximum
Correlations between MR imaging parameters, spirometry, MBN / lung volumes and DCO 
at baseline and end of each period for QVA149 and Placebo will be presented, and all end 
points will be summarized graphically and in tables
RC results will be listed by subect and visit
Refer section 623for statisticalanalysis of the exploratory end points
 
 
Statistical methods for safety and tolerability data
11 
Variables 
Adverse events, vital signs (blood pressure, pulse rate, body temperature), C intervals, 
laboratory measurements, as well as subect demographics, baseline characteristics, and 
treatment information
12 
Descriptive analyses
Subect demographics and other baseline characteristics
All data for bacground and demographic variables will be listed by treatment seuence and 
subect Summary statistics will be provided for all subects, as well as for each treatment 
seuence
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment seuence and subect
reatment
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Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment seuence andsubect
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Vital signs
All vital signs data will be listed by treatmentseuence, subect, and visit/time and if ranges 
are available abnormalities (and relevant orthostatic changes) will be flagged Summary
statistics will be provided by treatment and visit/time
C evaluations
All C data will be listed by treatmentseuence, subect and visit/time, abnormalities will 
be flagged Summary statistics will be provided by treatment and visit/time
Clinical laboratory evaluations
All laboratory data will be listed by treatmentseuence, subect, and visit/time and if normal 
ranges are available abnormalities will be flagged A separate listing is provided presenting all 
parameters in a subect with any abnormalvalues Summary statistics will be provided by 
treatment and visit/time
Adverse events
All information obtained on adverse events will be displayed by treatment andsubect
he number and percentage of subects with adverse events will be tabulated by body system 
and preferred term with a breadown by treatment An adverse event starting in one period 
and continuing into the next period is counted only in the onset period A subect with 
multiple adverse events within a body system and treatment period is only counted once 
towards the total of this body system and treatment
he number and percentage of subects with adverse events by maximum severity of adverse 
events will be tabulated by body system and preferred term with a breadown by treatment
he number and percentage of subects with adverse events classified as related to study drug 
will be tabulated by body system and preferred term with a breadown by treatment
13 
raphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitalsigns) will be created
Statistical methods for Biomarer data
Not applicable