Conditions: Asthma
Keywords: CSJ117 uncontrolled asthma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 335
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the efficacy and safety of multiple CSJ117 doses (0.5; 1; 2; 4 and 8 mg) inhaled once daily compared with placebo, when added to standard-of-care (SoC) asthma therapy in adult patients with uncontrolled asthma with respect to change from baseline in FEV1 at the end of 12 weeks of treatment.

Detailed description:
This was a randomized, multicenter, multi-national, double-blind, placebo-controlled, parallel-arm study evaluating the effect of 5 dose levels of CSJ117 in adult subjects with inadequately controlled asthma despite medium to high dose inhaled corticosteroid (ICS) plus long-acting beta agonist (LABA).

Subjects were assigned to one of the following six treatment arms/groups in a ratio of 2:1:1:1:2:2:

* Placebo inhaled once daily
* CSJ117 0.5 mg inhaled once daily
* CSJ117 1.0 mg inhaled once daily
* CSJ117 2.0 mg inhaled once daily
* CSJ117 4.0 mg inhaled once daily
* CSJ117 8.0 mg inhaled once daily

The study included:

* A screening period of approximately 2 weeks
* A single blinded placebo run-in period of 4 weeks (extended to 8 weeks for subjects experiencing an asthma exacerbation or respiratory tract infection during the run-in period)
* A double blinded treatment period of 12 weeks
* A follow-up period of up to 12 weeks, study drug free, following the last dose of study treatment.

Patients who successfully completed 12 weeks of treatment in this study could be offered participation in the Safety Extension Study CCSJ117A12201E1 (NCT04946318).

Arms:
arm 1: CSJ117 0.5 mg inhaled once daily arm 2: CSJ117 1 mg inhaled once daily arm 3: CSJ117 2 mg inhaled once daily arm 4: CSJ117 4 mg inhaled once daily arm 5: CSJ117 8 mg inhaled once daily arm 6: Placebo inhaled once daily

Interventions: intervention 1: CSJ117 intervention 2: Placebo
Intervention descriptions: intervention 1: CSJ117 inhaled once daily (in the morning) for 12 weeks. Delivered via Concept1 device.

CSJ117 = inhaled monoclonal antibody fragment intervention 2: Run-in period (all arms): Placebo inhaled once daily (in the morning) for 4 weeks. Placebo dosing extended to 8 weeks in case of asthma exacerbation or respiratory tract infection during this period.

Treatment period (Placebo arm only): Placebo inhaled once daily (in the morning) for 12 weeks. Delivered via Concept1 device.

Protocol document:
Prot_000.pdf: 
Novartis Research and Development 
CSJ117 
Clinical Trial Protocol CCSJ117A12201C / NCT04410523
A 12-week, multicenter, randomized, double-blind, parallel-
arm, placebo-controlled study to assess the efficacy and 
safety of CSJ117, when added to existing asthma therapy 
in patients ≥18 years of age with severe uncontrolled 
asthma. 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2019-004905-29 
Version number: 
03 (Track Changes) 
Clinical Trial Phase: 
IIb 
Release date: 
21-Jan-2022
Property of Novartis Pharma AG 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 2.0 (01-Aug-2018) 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 12 
Amendment 3 .................................................................................................................... 14 
Amendment 2 (22-Jan-2021) ............................................................................................. 16 
Amendment 1 (26-Mar-2020) ........................................................................................... 18 
Protocol summary .............................................................................................................. 21 
1 
Introduction ....................................................................................................................... 25 
1.1 
Background ............................................................................................................ 25 
1.2 
Purpose .................................................................................................................. 26 
2 
Objectives and endpoints ................................................................................................... 26 
3 
Study design ...................................................................................................................... 28 
4 
Rationale ............................................................................................................................ 30 
4.1 
Rationale for study design ..................................................................................... 30 
4.1.1 
Rationale for choice of background therapy ......................................... 30 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 31 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 32 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 32 
4.5 
Risks and benefits .................................................................................................. 32 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 35 
5 
Population .......................................................................................................................... 36 
5.1 
Inclusion criteria .................................................................................................... 36 
5.2 
Exclusion criteria ................................................................................................... 37 
6 
Treatment ........................................................................................................................... 41 
6.1 
Study treatment ...................................................................................................... 41 
6.1.1 
Investigational and control drugs .......................................................... 41 
6.1.2 
Additional study treatments .................................................................. 42 
6.1.3 
Treatment arms/group ........................................................................... 43 
6.1.4 
Treatment duration ................................................................................ 43 
6.2 
Other treatment(s) .................................................................................................. 43 
6.2.1 
Concomitant therapy ............................................................................. 43 
6.2.2 
Prohibited medication ........................................................................... 46 
6.3 
Subject numbering, treatment assignment, randomization .................................... 47 


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6.3.1 
Subject numbering ................................................................................ 47 
6.3.2 
Treatment assignment, randomization .................................................. 47 
6.4 
Treatment blinding ................................................................................................. 48 
6.4.1 
Independent study-treatment administration site staff member ............ 48 
6.5 
Dose escalation and dose modification .................................................................. 49 
6.5.1 
Dose modifications ................................................................................ 49 
6.5.2 
Follow-up for toxicities ......................................................................... 49 
6.6 
Additional treatment guidance ............................................................................... 50 
6.6.1 
Treatment compliance ........................................................................... 50 
6.6.2 
Emergency breaking of assigned treatment code .................................. 51 
6.7 
Preparation and dispensation ................................................................................. 51 
6.7.1 
Handling of study treatment and additional treatment .......................... 52 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 53 
7 
Informed consent procedures ............................................................................................ 53 
8 
Visit schedule and assessments ......................................................................................... 54 
8.1 
Assessments order during randomization .............................................................. 60 
8.2 
Screening and re-screening .................................................................................... 61 
8.2.1 
Information to be collected on screening failures ................................. 61 
8.3 
Subject demographics/other baseline characteristics ............................................. 62 
8.4 
Efficacy .................................................................................................................. 62 
8.4.1 
Spirometry ............................................................................................. 62 
8.4.2 
Fractional exhaled Nitric Oxide (FeNO) ............................................... 63 
8.4.3 
eDiary/ePEF .......................................................................................... 63 
8.4.4 
Appropriateness of efficacy assessments .............................................. 66 
8.5 
Safety ..................................................................................................................... 66 
8.5.1 
Laboratory evaluations .......................................................................... 68 
8.5.2 
Electrocardiogram (ECG) ..................................................................... 69 
8.5.3 
Pregnancy and assessments of fertility ................................................. 70 
8.5.4 
Hepatitis and HIV screen ...................................................................... 70 
8.5.5 
Tuberculosis testing .............................................................................. 71 
8.6 
Additional assessments .......................................................................................... 71 
8.6.1 
Clinical Outcome Assessments (COAs) ............................................... 71 
8.6.2 
Pharmacokinetics .................................................................................. 74 
8.6.3 
Biomarkers ............................................................................................ 74 
8.6.4 
Asthma exacerbations ........................................................................... 75 
8.6.5 
Other Assessments ................................................................................ 76 
 
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9 
Study discontinuation and completion .............................................................................. 77 
9.1 
Discontinuation ...................................................................................................... 77 
9.1.1 
Discontinuation of study treatment ....................................................... 77 
9.1.2 
Withdrawal of informed consent/Opposition to use data/biological 
samples .................................................................................................. 78 
9.1.3 
Lost to follow-up ................................................................................... 79 
9.1.4 
Early study termination by the sponsor ................................................. 79 
9.2 
Study completion and post-study treatment .......................................................... 80 
10 Safety monitoring and reporting ........................................................................................ 80 
10.1 
Definition of adverse events and reporting requirements ...................................... 80 
10.1.1 
Adverse events ...................................................................................... 80 
10.1.2 
Serious adverse events .......................................................................... 82 
10.1.3 
SAE reporting........................................................................................ 83 
10.1.4 
Pregnancy reporting .............................................................................. 84 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 84 
10.1.6 
Concept1 related adverse events reporting ........................................... 85 
10.2 
Additional Safety Monitoring ................................................................................ 85 
10.2.1 
Liver safety monitoring ......................................................................... 85 
10.2.2 
Data Monitoring Committee ................................................................. 86 
11 Data Collection and Database management ...................................................................... 86 
11.1 
Data collection ....................................................................................................... 86 
11.2 
Database management and quality control ............................................................ 87 
11.3 
Site monitoring ...................................................................................................... 87 
12 Data analysis and statistical methods ................................................................................ 88 
12.1 
Analysis sets .......................................................................................................... 88 
12.2 
Subject demographics and other baseline characteristics ...................................... 88 
12.3 
Treatments ............................................................................................................. 88 
12.4 
Analysis of the primary endpoint(s) ...................................................................... 89 
12.4.1 
Definition of primary endpoint(s) ......................................................... 89 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 89 
12.4.3 
Handling of missing values/censoring/discontinuations ....................... 91 
12.4.4 
Sensitivity and Supportive analyses ...................................................... 91 
12.5 
Analysis of secondary endpoints ........................................................................... 92 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................... 92 
12.5.2 
Safety endpoints .................................................................................... 95 
12.5.3 
Pharmacokinetics .................................................................................. 96 
 
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12.7 
Interim analyses ..................................................................................................... 97 
12.8 
Sample size calculation .......................................................................................... 97 
12.8.1 
Primary endpoint(s) ............................................................................... 97 
12.8.2 
Sample size re-estimation ..................................................................... 97 
13 Ethical considerations and administrative procedures ...................................................... 98 
13.1 
Regulatory and ethical compliance ........................................................................ 98 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 98 
13.3 
Publication of study protocol and results............................................................... 99 
13.4 
Quality Control and Quality Assurance ................................................................. 99 
14 Protocol adherence ............................................................................................................ 99 
14.1 
Protocol amendments ............................................................................................. 99 
15 References ....................................................................................................................... 101 
16 Appendices ...................................................................................................................... 103 
16.1 
Clinically notable laboratory values and vital signs ............................................ 103 
16.2 
Liver event and Laboratory trigger Definitions and Follow-up Requirements ... 104 
16.3 
Spirometry Guidance ........................................................................................... 107 
16.4 
Repeat of the run in or end of run in visits .......................................................... 109 
16.4.1 
Run in visit .......................................................................................... 109 
16.4.2 
End of run in visit ................................................................................ 110 
16.5 
Asthma Control Questionnaire (ACQ-5) ............................................................. 110 
16.6 
Recommendation for FeNO Measurements ........................................................ 113 
16.7 
Asthma Quality of Life Questionnaire for 12 years and older (AQLQ+12) ....... 114 
16.8 
Timed assessment schedule ................................................................................. 120 
16.8.1 
Randomization visit: End of Run-In/Day 1 ........................................ 120 
16.8.2 
Weeks 2-24 .......................................................................................... 122 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 26 
Table 6-1 
Medications allowed under certain conditions ...................................... 45 
Table 6-2 
Medications to be withheld prior to spirometry .................................... 45 
Table 6-3 
Prohibited medication ........................................................................... 46 
Table 8-1 
Assessment Schedule ............................................................................ 56 
Table 8-2 
Assessments at randomization .............................................................. 60 
Table 8-3 
Assessments & Specifications ............................................................... 67 
Table 8-4 
Laboratory Evaluations ......................................................................... 69 


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Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 84 
Table 12-1 
Decision guidance on approximate sample size to ensure at least 
80% power to detect a dose-response signal ......................................... 98 
Table 16-1 
Liver event and laboratory trigger definitions .................................... 104 
Table 16-2 
Follow up requirements for liver events and laboratory triggers ........ 104 
Table 16-3 
Timed assessments for the randomization visit .................................. 120 
Table 16-4 
Timed assessments for visits week 2-12 ............................................. 122 
Table 16-5 
Timed assessments for visits week 14-24 ........................................... 124 
List of figures 
Figure 3-1 
Study Design ......................................................................................... 29 
Figure 12-1 
Candidate Dose Response Curves ......................................................... 90 
 
 
 


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List of abbreviations 
ACQ 
Asthma Control Questionnaire 
ADA 
Anti Drug Antibodies 
ADSD 
Asthma Daytime Symptom Diary 
AE 
Adverse event 
AIC 
Allergen inhalation challenge 
Alb 
Albumin 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AM 
Ante Meridiem (before midday) 
ANCOVA 
Analysis of covariance 
ANSD 
Asthma Nighttime Symptom Diary 
AQLQ 
Asthma Quality of Life Questionnaire 
AST 
Aspartate aminotransferase 
ATS 
American Thoracic Society 
AV 
Atrioventricular block  
b.i.d. 
Twice a day 
BD 
Bronchodilator 
BEV 
Back-extrapolated volume 
BfArM 
Bundesinstitut fuer Arzneimittel und Medizinprodukte (Federal Institute for Drugs 
and Medical Devices) 
BMI 
Body Mass Index 
BP 
Blood pressure 
BTPS 
Body temperature and pressure saturated  
BUN 
Blood urea nitrogen 
CABG 
Coronary artery bypass graft 
CE 
Conformité Européene mark 
CFR 
Code of Federal Regulation 
CMO & PS 
Chief Medical Office and Patient Safety 
CMV 
Cytomegalovirus 
COA 
Clinical Outcome Assessments 
COVID-19 
Corona Virus Disease 2019 
CRA 
Clinical research associate 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CT 
Computed tomography 
CTT 
Clinical Trial Team 
Ctrough 
Trough plasma concentration (measured concentration at the end of a dosing 
interval at steady state) 
CV 
Coefficient of variation 


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DBP 
Diastolic blood pressure 
DDE 
Direct data entry 
DILI 
Drug Induced Liver Injury 
DMC 
Data Monitoring Committee 
DMPK 
Drug Metabolism & PharmacoKinetics 
DNA 
Deoxyribonucleic acid 
DPI 
Dry powder inhaler 
DR 
Dose response 
EBV 
Epstein-Barr virus 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECLIA 
Electrochemiluminescence immunoassay 
eCRF 
Electronic case report forms 
EDC 
Electronic Data Capture 
EDD 
Expected delivery date 
eGFR 
Estimated Glomerular Filtration Rate 
EMA 
European Medicines Agency 
EOFE 
End of forced expiration 
EOS 
Eosinophils 
ePEF 
Electronic Peak Expiratory Flow 
ERS 
European Respiratory Society 
eSource 
Electronic source 
EU 
Europe 
Fab 
Fragment antigen binding 
FAS 
Full analysis set 
Fc 
Fragment crystallizable region 
FDA 
Food and Drug Administration 
FDC 
Fixed dose combination 
FeNO 
Fractional exhaled Nitric Oxide 
FEV1 
Forced expiratory volume in 1 second 
FIVC 
Forced inspiratory vital capacity 
FSH 
Follicle Stimulating Hormone 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GCS 
Global clinical supplies 
GGT 
Gamma-glutamyl transferase 
GINA 
Global Initiative for Asthma guidelines 
GLP 
Good laboratory practice 
HbA1c 
hemoglobin A1c  
HbcAb 
Hepatitis B core antibody  
HbsAb 
Hepatitis B surface antibody 
HbsAg 
Hepatitis B surface antigen 


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HBV 
Hepatitis B virus 
HBV-DNA 
Hepatitis B virus deoxyribonucleic acid  
HCV RNA 
Hepatitis C virus ribonucleic acid  
HCV RNA-
PCR  
Hepatitis C virus ribonucleic acid polymerase chain reaction  
HIV 
Human immunodeficiency virus 
HIV1/2-Ab 
HIV1/2 Antibodies 
hr 
Hour 
HRQOL 
Health related quality of Life 
HSV 
Herpes simplex virus 
i.v. 
Intravenous 
IB 
Investigators Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
ICS 
Inhaled corticosteroid 
IEC 
Independent Ethics Committee 
IG 
Immunogenicity 
IGRA 
Interferon Gamma Release Assay 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IMP 
Investigational Medicinal Product 
IN 
Investigator notification 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
J2R 
Jump to reference 
L 
Liter 
LABA 
Long acting beta-2 agonist 
LAR 
Late asthmatic response 
LAMA 
Long acting muscarinic antagonist 
LDH 
Lactate dehydrogenase 
LFT 
Liver function test 
LLOQ 
Lower Limit of Quantification 
LTRA 
Leukotriene receptor antagonists 
mAb 
Monoclonal antibody 
MAR 
Missing at random 
 
 
MCP-Mod 
Multiple comparison procedures modelling 
MDI 
Metered dose inhaler 
MDRD 
Modification of diet in renal disease 
MedDRA 
Medical dictionary for regulatory activities 


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mg 
milligram(s) 
MI 
Myocardial Infarction 
MID 
Minimally important difference 
mL 
Milliliter(s) 
MMRM 
Mixed effects model for repeated measures 
NA 
Not applicable 
ng/mL 
Mass per volume units 
NO 
Nitric oxide 
NRS 
Numeric rating scale 
NYHA 
New York Heart Association 
o.d. 
Once a day 
OCS 
Oral corticosteroid 
OHP 
Offsite healthcare professional 
p 
Probability value 
PD 
Pharmacodynamic(s) 
PEF 
Peak expiratory flow 
 
 
 
 
PK 
Pharmacokinetic(s) 
PM 
Post meridiem (after midday) 
Pre-BD 
Pre-bronchodilator 
PRN 
Pro re nata (as needed) 
PRO 
Patient reported outcome 
PSW 
Premature subject withdrawal 
PT/INR 
Prothrombin time international normalized ratio 
Q4W 
Every 4 weeks 
QMS 
Quality management system 
QoL 
Quality of Life 
RAS 
Randomized analysis set 
Racc 
Accumulation ratio 
RTI 
Respiratory Tract Infection 
RoW 
Rest of world 
s 
Seconds 
s.c. 
Subcutaneous 
SABA 
Short acting beta-2 agonist 
SAE 
serious adverse event 
SAMA 
Short Acting Muscarinic Antagonists 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SMQ 
Standardized MedDRA query 
SoC 
Standard of Care 


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SOP 
Standard Operating Procedure 
Spool 
Standard deviation pooled 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
 
 
TB 
Tuberculosis 
TBL 
Total bilirubin 
Th2 
T helper type 2  
TSLP 
Thymic stromal lymphopoietin 
ULN 
Upper limit of normal 
US 
United States of America 
WHO 
World Health Organization 
WoC 
Withdrawal of Consent 
µg 
Microgram 
µl 
Microliters 


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Glossary of terms 
Additional treatment 
Medicinal products that may be used during the clinical trial as described in 
the protocol, but not as an investigational medicinal product (e.g. any 
background therapy) 
Assessment 
A procedure used to generate data required by the study 
Biological samples 
A biological specimen including for example, blood (plasma, serum), saliva, 
tissue, urine, stool etc taken from a study subject 
Cohort 
A specific group of subjects fulfilling certain criteria 
Control drug 
A study drug used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug. 
Dosage 
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture is the electronic acquisition of clinical study data 
using data collection systems such as web-based applications, interactive 
voice response systems, and clinical laboratory interfaces. EDC includes the 
use of electronic case report forms which are used to capture data 
transcribed from paper source forms used at the point of care. 
End of the clinical 
trial 
The end of the clinical trial is defined as the last visit of the last subject or at a 
later point in time as defined by the protocol. 
Enrollment 
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol) 
Healthy volunteer 
A person with no known significant health problems who volunteers to be a 
study participant  
Investigational drug 
The study drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product”. 
Investigational 
treatment 
All investigational drug(s) whose properties are being tested in the study as 
well as their associated treatment controls. This includes any placebos, any 
active controls, as well as approved drugs used outside of their 
indication/approved dosage or tested in a fixed combination. Investigational 
treatment generally does not include other treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used within approved indication/dosage. 
Medication pack 
number 
A unique identifier on the label of each drug package in studies that dispense 
study treatment using an IRT system 
Mis-randomized 
subjects  
Mis-randomized subjects are those who were not qualified for randomization 
and who did not take study treatment, but have been inadvertently 
randomized into the study 
Non-investigational 
medicinal Product 
(NIMP) 
Products which are not the object of investigation (e.g. any background 
therapy administered to each of the clinical trial subjects, regardless of 
randomization group, rescue medication, active drug run-ins etc.) 
Off-site 
Describes trial activities that are performed at a remote location by an off-
site healthcare professional, such as procedures performed at the patient’s 
home.  
Off-site healthcare 
professional 
A qualified healthcare professional, such as a Nurse, who 
performs certain protocol procedures for the participant in an off-
site location such as a participant’s home.  
 


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Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy) 
Patient 
An individual with the condition of interest 
Period 
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc. 
Personal Data 
Subject information collected by the investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples. 
Premature subject 
withdrawal 
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned. 
Randomization 
number 
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment 
Screen Failure 
A subject who is screened but is not treated or randomized 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource 
Start of the clinical 
trial 
The start of the clinical trial is defined as the signature of the informed 
consent by the first subject. 
Study completion 
Point/time at which the subject came in for a final evaluation visit or when 
study was discontinued whichever is later. 
Study drug 
discontinuation 
Point/time when subject permanently stops taking study drug for any reason; 
may or may not also be the point/time of premature subject withdrawal. 
Study treatment 
discontinuation 
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date 
Subject 
A trial participant (can be a healthy volunteer or a patient) 
Subject number 
A number assigned to each subject who enrolls in the study. When combined 
with the center number, a unique identifier is created for each subject in the 
study. 
Tele-visit 
Procedures or communications conducted using technology such as 
telephone or video-conference, whereby the patient is not at the investigative 
site where the investigator will conduct the trial.  
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts. 
Variable 
Information used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints. 
Withdrawal of 
consent (WoC) 
Withdrawal of consent from the study is defined as when a subject does not 
want to participate in the study any longer, and does not allow any further 
collection of personal data 
 
 
 


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Protocol summary 
Protocol number 
CCSJ117A12201C 
Full Title 
A 12-week, multicenter, randomized, double-blind, parallel-arm, placebo-
controlled study to assess the efficacy and safety of CSJ117, when added to 
existing asthma therapy in patients ≥ 18 years of age with severe 
uncontrolled asthma. 
Brief title 
Study of efficacy and safety of CSJ117 in patients with severe uncontrolled 
asthma 
Sponsor and 
Clinical Phase 
Novartis Pharma AG 
Phase IIb 
Investigation type 
Drug; Biological 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this study is to determine the efficacy and safety of multiple 
CSJ117 doses (0.5; 1; 2; 4 and 8 mg) inhaled once daily compared with 
placebo, when added to standard-of-care (SoC) asthma therapy in adult 
patients with uncontrolled asthma with respect to change from baseline in 
FEV1 at the end of 12 weeks of treatment. 
Primary 
Objective(s)  
To characterize the dose-response relationship of five doses of CSJ117 
inhaled daily on lung function, compared with placebo, at the end of the 12-
week active-treatment period. 
Secondary 
Objectives 
1. To characterize the dose-response relationship of five doses of CSJ117 
inhaled daily on FeNO compared with placebo, during the 12-week 
active-treatment period 
2. To assess immunogenicity of five doses of CSJ117 during the study 
3. To characterize the systemic pharmacokinetic (PK) profile of multiple 
inhaled daily doses of CSJ117 during the 12 week, active treatment 
period and the 12 week, follow-up period 
4. To characterize the efficacy of five doses of CSJ117 once daily, 
compared with placebo, on peak expiratory flow (PEF; AM and PM), as 
assessed by mean morning and mean evening PEF over the 12-week 
active-treatment period 
5. To characterize the efficacy of five doses of CSJ117 once daily, 
compared with placebo, on Asthma Control Questionnaire (ACQ-5) over 
the 12-week active-treatment period. 
6. To characterize the efficacy of five doses of CSJ117 once daily, 
compared with placebo, on change from baseline in Asthma Quality of 
Life Questionnaire (AQLQ) score at the end of the 12-week active-
treatment period 
7. To characterize the efficacy of five doses of CSJ117 once daily, 
compared with placebo, on daytime and nighttime asthma symptoms 
over the 12-week active-treatment period 
8. To characterize the efficacy of five doses of CSJ117 once daily, 
compared with placebo, on daily short-acting β-agonist (SABA) use over 
the 12-week active-treatment period 
9. To assess the safety of five doses of CSJ117 once daily, compared with 
placebo, with respect to adverse events (AE), electrocardiograms 
(ECGs), vital signs and laboratory tests 


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Study design 
This study uses a randomized, multicenter, double-blind, placebo-controlled, 
parallel-group study design.  
Population 
The study population will include: 
• 
Males and females aged ≥ 18 and < 75 years. 
• 
Asthma patients who are already receiving ICS-LABA combination with 
up to two asthma controller medications (see Section 5.1, inclusion 
criterion 4 for allowed ICS doses and combinations) are the target 
population for this study. 
Key Inclusion 
criteria 
• 
Documented physician-diagnosed asthma (according to GINA 2019) for 
at least 12 months prior to screening. 
• 
Patients who have been treated with medium or high dose ICS plus 
LABA, alone or with up to two additional asthma controllers (allowed 
only: LTRA, theophylline or its derivatives, and LAMA) in a stable dose 
for at least 1 month, i.e. 30 days, prior to Screening 
• 
Subjects must have all morning pre-BD FEV1 values of ≥ 40% and ≤ 
85% of the predicted normal after withholding bronchodilators at the start 
and the end of run-in.  
• 
Subjects must perform a reversibility test at the run-in visit. Reversibility 
is demonstrated by a Post-BD reversibility of FEV1 ≥ 12% and ≥ 200 mL 
within 30 minutes after administration of 400 μg salbutamol/albuterol (or 
equivalent dose). If reversibility is not demonstrated at the run-in visit and 
up to two unscheduled visits the following historical information may be 
used: documented evidence of reversibility that was performed according 
to American Thoracic Society (ATS)/European Respiratory Society (ERS) 
Standardization of Spirometry (Graham et al 2019).  (ATS/ERS 2019)  
within the 1 year prior to Screening. 
• 
Subjects must have an ACQ-5 score of ≥ 1.5 at screening and end of 
run-in visits. 
• 
 
• 
Subjects must meet all of the following criteria at end of run-in visit prior 
to randomization:  
• 
Subjects must demonstrate acceptable inhaler, peak flow meter, and 
spirometry techniques during the run-in period 
(from beginning to end of run in). 
• 
Subjects must demonstrate ≥ 70% compliance with the asthma 
controller ICS-LABA during the run-in period based on their inhaler 
use count. 
• 
Subjects must demonstrate ≥ 70% compliance with the CSJ117 
placebo/Concept1 during the run-in period based on capsule use 
count. 
• 
Subjects must demonstrate ≥ 70% compliance with required use of 
the eDiary during the last 2 weeks of the run-in period. 70% 
compliance is defined as completing the daily eDiary for 70% of the 
days (either morning or evening, including at least 7 morning and 7 
evening eDiaries) in the last 2 weeks of the run in. 
 
Key Exclusion 
criteria 
• 
Patients, who cannot sustain washout of controllers additional to ICS-
LABA before beginning of run-in. 
• 
Any oral corticosteroids as a maintenance treatment within 6 weeks, or 
any use of short-acting, intra-articular, intramuscular, or intravenous 


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corticosteroid within 1 month, or any use of long acting, intra-articular or 
intramuscular corticosteroids within 3 months prior to Screening 
• 
Patients who have a cigarette smoking history of greater than 10 pack 
years or current smokers. 
• 
Pregnant or nursing (lactating) women 
• 
Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using specified methods 
of contraception during dosing of study drug and until 12 weeks after last 
study drug treatment (end of follow up) 
Patients with a history of immunodeficiency disease, or hepatitis B, 
untreated and not cured hepatitis C or HIV. 
Study treatment 
CSJ117 (0.5; 1; 2; 4 and 8 mg) inhaled once daily 
Placebo inhaled once daily 
Efficacy 
assessments 
• 
Lung function (FEV1) 
• 
FeNO 
• 
Asthma symptoms 
• 
ACQ-5 
• 
AQLQ 
• 
PEF 
• 
SABA use 
Pharmacokinetic 
assessments  
• 
Total CSJ117 serum concentration 
• 
Ctrough 
• 
Racc  
• 
T1/2 
Key safety 
assessments 
• 
Adverse event monitoring 
• 
Physical examinations 
• 
Vital signs  
• 
Laboratory examinations of blood and urine 
• 
12-lead ECG 
Other 
assessments  
• 
ADSD and ANSD 
 
 
 
 
 
 
 
 
 
 
Data analysis 
Primary objective: The MCP-Mod methodology will be used on the primary 
endpoint of the average change from baseline in pre-dose FEV1 at Week 8 
and Week 12 to address the primary objective. 
1. The adjusted mean responses at each individual dose will be estimated by 
modeling the primary endpoint using a mixed-effect linear model for repeated 
measures (MMRM). The null hypothesis of flat dose-response (DR) 
relationship will be tested at a two-sided significance level of 5% against the 
alternative hypothesis of a non-constant DR curve using a multiple contrast 
test, taking model uncertainty into account by considering a wide range of 
possible DR relationships. 


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2. Once the DR signal is declared, the final DR curve and the target dose(s) of 
interest will be estimated by model averaging. Corresponding 95% confidence 
intervals are obtained using bootstrapping. 
Secondary objectives: The following secondary endpoints will be analyzed 
using a MMRM - average change from baseline in FeNO, ACQ-5, AQLQ+12, 
ADSD, and ANSD at Week 8 and Week 12, weekly mean morning and evening 
PEF, mean number of puffs of SABA taken per day in each week. Treatment-
emergent adverse events will be summarized. Summary statistics will be 
provided by treatment and visit/time for each lab, vital signs, ECG, and 
pharmacokinetics variable. 
Key words 
CSJ117, uncontrolled asthma 
 


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1 
Introduction 
1.1 
Background 
Asthma is a chronic inflammatory disease of the airways characterized by reversible 
bronchoconstriction and an exaggerated airways response to bronchoconstrictor stimuli. 
Asthma presents a major global health burden. Despite existing therapies, there is still 
significant unmet medical need in asthma, with an estimated 300 million people affected 
worldwide. The World Health Organization estimates that 15 million disability–adjusted life 
years are lost annually due to asthma, representing 1% of the total global burden. Annual 
worldwide deaths have been estimated at 250,000 (Masoli et al 2004). Uncontrolled asthma has 
a prevalence of greater than 6 million patients worldwide. 
In the case of allergic asthma, characterized by eosinophilic inflammation and evidence of atopy, 
T helper type 2 (Th2) immune pathway elements are crucial in the development and 
maintenance of airway inflammation and airway hyper responsiveness. A key upstream 
regulator of the Th2 response is Thymic stromal lymphopoietin (TSLP) (He and Geha 2010). 
TSLP is an epithelial-cell derived cytokine produced in response to environmental and pro-
inflammatory stimuli. It is upstream and central to the regulation of type-2 immunity through 
its activity on dendritic, T cells, B cells and innate immune cells. Additionally TSLP stimulates 
production of cytokines by antigen-specific Th2 cells. 
In asthma patients, an increase in TSLP protein levels has been observed in both lung tissue and 
bronchial alveolar lavage fluid. Moreover TSLP has been shown to correlate with disease 
severity (Ying et al 2005, Ying et al 2008) and TSLP gene polymorphism is associated with a 
significant risk of childhood asthma (Biagini Myers et al 2014). 
Repression of upstream TSLP is expected to reduce Th2 inflammation through inhibition of 
multiple pro-inflammatory cytokines simultaneously e.g. IL-5 and IL-13. Thus, reduction of 
TSLP activity might provide a significant advantage to therapies targeting only individual 
cytokines, or their receptors, involved in asthma pathogenesis. 
CSJ117 is a potent neutralizing antibody fragment (fragment antigen-binding, Fab) directed 
against human TSLP. CSJ117 is formulated as a PulmoSol™ engineered powder in hard 
capsules for delivery to the lungs via dry powder inhaler (DPI). Compared to a full length 
antibody, CSJ117 does not have the Fc region and only contains the antigen binding region. 
Consequently the molecular weight of CSJ117, 46.6 kDa, is smaller than the molecular weight 
of a full length antibody, ~150 kDa. Once absorbed into the systemic circulation, the Fab 
molecule is expected to be cleared faster than a full length antibody, due to the smaller size of 
the Fab and the lack of neonatal Fc receptor binding. In the absence of target-mediated 
disposition, the systemic terminal elimination half-life (T½) in humans for a Fab typically 
ranges from 14 to 25 hours (Schaumann et al 1986, Czock et al 2012, Morris et al 2012 ) versus 
approximately 23 days for a full length IgG monoclonal antibody (mAb) (Lobo et al 2004). 
The use of an anti-TSLP Fab molecule with a DPI formulation is expected to result in improved 
lung distribution and tissue penetration as compared to a full length systemically delivered 
antibody, due to the smaller size of the Fab and targeted delivery to the lung. CSJ117, as an 
inhaled Fab targeting TSLP, offers the potential to be an efficacious therapy for moderate to 
severe asthma with a favorable safety and tolerability profile. 


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The aim of the study is to investigate the efficacy and safety of multiple doses of CSJ117, 
inhaled daily, in uncontrolled asthma patients treated with a medium or high dose of an inhaled 
corticosteroid (ICS) in combination with a long-acting beta agonist (LABA). Tezepelumab, a 
human IgG2 monoclonal antibody against TSLP, has demonstrated the validity of targeting 
TSLP in asthma by showing significant improvements across a wide range of endpoints 
including asthma exacerbations, lung function, and asthma control (Corren et al 2017). While 
tezepelumab demonstrated clinical benefits such as decreased rate of exacerbations in patients 
with low blood eosinophils at baseline, the improvement in lung function (forced expiratory 
volume in one second; FEV1) was greater in patients with higher blood eosinophil (EOS) counts. 
Therefore, in this study, at randomization, patients will be stratified based on their blood 
eosinophil count with approximately 70% of patients recruited to the stratum with higher counts 
(≥ 300 cells/µl). This overall % of high eosinophil patients may be lower depending on whether 
sample size is decreased after blinded re-assessment (See Section 12.8.2). 
1.2 
Purpose 
The purpose of this study is to determine the efficacy and safety of multiple CSJ117 doses (0.5; 
1; 2; 4 and 8 mg) inhaled once daily compared with placebo, when added to standard-of-care 
(SoC) asthma therapy in adult patients with uncontrolled asthma with respect to change from 
baseline in pre-dose, pre-bronchodilator FEV1 at the end of 12 weeks of treatment. 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To characterize the dose-response 
relationship of five doses of CSJ117 
inhaled daily on lung function, compared 
with placebo, at the end of the 12-week 
active-treatment period. 
• 
Average change from baseline in pre-dose 
FEV1 (L) at Week 8 and Week 12. 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To characterize the dose-response 
relationship of five doses of CSJ117 
inhaled daily on FeNO compared with 
placebo, during the 12-week active-
treatment period 
• 
Average change from baseline in FeNO at 
Week 8 and Week 12. 
• 
To assess immunogenicity of five doses of 
CSJ117 during the study 
• 
Measurement of Anti-Drug Antibodies (ADA) 
titers at baseline and during the study (Week 
0 [Day 1] to Week 24)  
• 
To characterize the systemic 
pharmacokinetic (PK) profile of multiple 
inhaled daily doses of CSJ117 during 
the 12 week, active treatment period and 
the 12 week, follow-up period 
• 
Measurement of total CSJ117 serum 
concentration during the study (Week 0 [Day 
1] to Week 24) and calculation of PK 
parameters (e.g., Ctrough, Racc, T½). 
• 
To characterize the efficacy of five doses 
of CSJ117 once daily, compared with 
• 
Change from baseline in peak expiratory flow 
(PEF; am and pm), as assessed by mean 


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Objective(s) 
Endpoint(s) 
placebo, on peak expiratory flow (PEF; AM 
and PM), as assessed by mean morning 
and mean evening PEF over the 12-week 
active-treatment period 
morning and mean evening PEF in each week 
(average over 7 days) during 12 weeks of 
treatment. 
• 
To characterize the efficacy of five doses 
of CSJ117 once daily, compared with 
placebo, on ACQ-5 over the 12-week 
active-treatment period. 
• 
Average change from baseline in ACQ-5 
score at Week 8 and Week 12. 
• 
To characterize the efficacy of five doses 
of CSJ117 once daily, compared with 
placebo, on change from baseline in 
Asthma Quality of Life Questionnaire 
(AQLQ) score at the end of the 12-week 
active-treatment period 
• 
Average change from baseline in AQLQ+12 
score at Week 8 and Week 12 
• 
To characterize the efficacy of five doses 
of CSJ117 once daily, compared with 
placebo, on daytime and nighttime asthma 
symptoms over the 12-week active-
treatment period 
• 
Average change from baseline in ADSD and 
ANSD score at Week 8 and Week 12. 
• 
To characterize the efficacy of five doses 
of CSJ117 once daily, compared with 
placebo, on daily short-acting β-agonist 
(SABA) use over the 12-week active-
treatment period 
• 
Change from baseline in number of puffs of 
SABA taken per day in each week (average 
over 7 days) during 12 weeks active-treatment 
period 
• 
To assess the safety of five doses of 
CSJ117 once daily, compared with 
placebo, with respect to adverse events 
(AE), electrocardiograms (ECGs), vital 
signs and laboratory tests 
• 
Summaries of treatment-emergent adverse 
events, systolic and diastolic blood pressure, 
pulse rate, body weight, ventricular rate, RR 
interval, PR interval, QRS duration, heart rate, 
and Fridericia’s QTc, laboratory values and 
change from baseline for continuous 
laboratory values. 


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The primary estimand of this trial is defined below. 
• Population: adult patients with inadequately controlled asthma on medium or high dose 
ICS/LABA, alone or with up to two additional asthma controllers (LTRA, LAMA or 
theophylline) 
• Variable: Average change from baseline in pre-dose FEV1 after 8 and 12 weeks of 
treatment 
• Treatment: CSJ117 or placebo 
• Intervention effect of interest: Effect of interventions initiated at randomization during 
stable periods (i.e. outside of periods of acute disease worsening requiring additional 
asthma medications) and that would have been observed had all patients remained on their 
assigned treatment for 12 weeks, with the following post-randomization events accounted 
for by assessing:  
• Intake of non-study drug with effect on FEV1: the effect outside of periods of 
worsening disease that necessitate rescue medication 
• Discontinuation of study treatment due to any reason: hypothetical value of the 
average between Week 8 and Week 12 pre-dose FEV1 had the patients not stopped 
the study treatment 
• The case where patient received treatment different from the assigned treatment: 
hypothetical value of the average between Week 8 and Week 12 pre-dose FEV1 had 
the patient remained on the assigned treatment for 12 weeks 
• Summary measure: mean difference between CSJ117 and placebo 
This estimand is considered appropriate for a dose finding trial in order to obtain a clear dose 
response signal and understand the maximum potential effect of the drug. 
3 
Study design 
This study is a phase IIb, multicenter, multi-national, double-blind, randomized, parallel-arm, 
placebo-controlled study to evaluate the effect of 5 dose levels of CSJ117 in adult subjects with 
inadequately controlled asthma despite medium to high dose ICS plus LABA. Approximately 
625 patients will be randomized into this study. A sample size re-estimation might be performed 
strictly using the blinded data after approximately 150 high eosinophils subjects completed the 
week 8 visit. 
 
The study will include: 
• A screening period of approximately 2 weeks, or shorter, to assess eligibility and baseline 
EOS count. Screening may optionally be split across 2 days to allow the collection of 
laboratory samples and the laboratory evaluations including the blood eosinophil (EOS) 
counts first. Patients will replace their current rescue medication with SABA provided by 


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Novartis, wash out prohibited medications (see Table 6-3) and practice the electronic peak 
expiratory flow (ePEF) and eDiary device. Screening must not end before confirmation of 
EOS count. If the results of EOS count or other laboratory assessments are not available at 
the end of the 2-week screening period or reversibility was not demonstrated at the run in 
visit the screening period will be extended.  
• A single blinded placebo run-in, i.e. Baseline, period of approximately 4 weeks, to collect 
baseline data for efficacy variables and compliance with the ePEF and eDiary device as well 
as to assess adherence with placebo and standardized maintenance medication, fluticasone 
propionate/salmeterol xinafoate 250/50 µg or 500/50 µg b.i.d.. If a patient experiences an 
asthma exacerbation or respiratory tract infection (RTI) during the run-in period, the run-in 
period must be extended to 8 weeks to allow for resolution of the asthma exacerbation or 
respiratory tract infection before randomization. Eligibility for randomization will be 
determined at the end of the placebo run-in period. Site staff should not inform patients that 
during run-in they will receive placebo. 
• A double blinded treatment period of 12 weeks. 
• A follow-up period of 12 weeks, study drug free, following the last dose of study drug. 
At randomization, subjects will be stratified by their blood eosinophil count (EOS) (≥ 300 or < 
300 cells/µl), measured at the screening visit. Approximately 70% of the total study population 
will be enrolled in the high EOS stratum. The proportion of subjects with high eosinophil counts 
at screening (% of overall population) may vary depending on whether the sample size is 
decreased after blinded re-assessment. If recruitment for one EOS stratum is completed, only 
patients with screening visit EOS count allowing randomization to the other stratum will be 
eligible. Subjects will be randomized in a 2:1:1:1:2:2 ratio to receive placebo or one of 5 doses 
of CSJ117 (0.5, 1, 2, 4, 8 mg) once daily for 12 weeks. All arms will have the same stratification 
ratio.  
 
  Figure 3-1 
Study Design 
 
 


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At the investigator’s direction based on benefit-risk considerations of the participant’s clinical 
condition, qualifying participants may be offered the option to have certain clinical trial 
procedures according to Table 8-1 performed at a remote location such as the patient’s home, 
in the event that the patient cannot attend site during a public health emergency as stated in 
section 4.6.  Procedures will be performed remotely under the oversight of the Investigator, who 
retains accountability for oversight and all efficacy and safety decisions with delegation of tasks 
to a mobile, offsite healthcare professional (OHP). The remote procedures will be offered in 
certain countries and sites as determined by Novartis based on national and local 
regulations.   The OHPs will be arranged in agreement with Novartis for example by a third-
party vendor. Where a site wishes to use OHPs that are not provided by Novartis this must be 
agreed with Novartis in advance. 
4 
Rationale 
4.1 
Rationale for study design 
This randomized, double-blind, parallel-group, placebo-controlled, design supports the 
assessment of efficacy as well as safety of CSJ117 as add-on treatment for patients with asthma 
inadequately controlled on medium or high dose ICS plus LABA. According to Global 
Initiative for Asthma (GINA, 2019) guidelines, the goals of asthma therapy are to attain asthma 
control and reduce future risk of asthma worsening while maintaining minimal side effects of 
therapy. By maintaining good asthma control in patients with appropriate use of therapies, 
potential future risk to patients may be reduced. The endpoints included in this study measure 
objective and symptomatic parameters of asthma control (objective: lung function [FEV1]; 
symptomatic parameters: daytime and nighttime asthma symptoms, SABA use, quality of life 
[QoL], ACQ scores) in patients over 12 weeks of therapy.  
4.1.1 
Rationale for choice of background therapy 
The most common use of biologic medications for asthma are currently in severe asthma 
patients who remain uncontrolled despite GINA Step 4 and 5 therapy. This trial aims to examine 
the biological effect of CSJ117 on lung function as assessed by change from baseline in pre-
dose, pre-BD FEV1 after 12 weeks of treatment in severe persistent asthmatic population. 
Preferred step 4 and step 5 treatment of choice in GINA guidelines are medium and high dose 
ICS-LABA combinations, respectively. Subjects in the study will be severe asthma patients 
inadequately controlled on medium or high dose ICS-LABA. Subjects who enter the study with 
medium dose ICS-LABA will receive a fixed dose combination (FDC) of fluticasone 
propionate/salmeterol 250/50 μg b.i.d., while subjects who enter with high dose ICS-LABA 
will receive a FDC of fluticasone propionate/salmeterol 500/50 μg b.i.d. from the start of 
placebo run-in and throughout the study period. If subjects have been using controller 
medications in addition to ICS-LABA, all additional controllers will be discontinued post the 
Screening visit with instructions to use SABA as needed and to monitor their symptoms and 
lung function daily with the eDiary/ePEF device. Other changes to subjects' asthma SoC 
background treatment will be forbidden during the screening, run-in and active treatment 
periods. CSJ117 or placebo will be administered as add-on therapy to medium or high dose 
fluticasone propionate/salmeterol. All patients will be allowed to use SABA as rescue 
medication when required, throughout the trial. 


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For patients who do not enter a separate safety extension study (see Section 9.2) after 
completing the treatment period, investigators will be allowed to modify patients' background 
asthma therapy after they enter the follow-up period. However, it is forbidden to add during the 
follow up period any of the following: 
• Oral, injectable or systemic corticosteroid (with exception as treatment of asthma 
exacerbations when necessary)  
• Biologic drugs 
4.2 
Rationale for dose/regimen and duration of treatment 
CSJ117 was designed for inhaled delivery. CSJ117 is formulated as a PulmoSol™ engineered 
powder in hard capsules for delivery to the lungs via dry powder inhaler (DPI; Concept1). Total 
duration of treatment with CSJ117 is 12 weeks. Total duration of treatment with placebo for all 
patients is from approximately 4 to 20 weeks, depending on randomization.  
This dose range finding study includes 5 active doses of CSJ117 (0.5; 1; 2; 4 and 8 mg) and 
matching placebo for once daily inhaled delivery via Concept1 device. Based on modelling 
predictions of the CSJ117 clinical efficacious dose range and PK profile after repeated 
administration, once daily dosing over 12 weeks is expected to provide adequate pulmonary 
exposure in order to assess pharmacodynamics (PD) effects (i.e. change in lung function 
parameters: FEV1, FVC, PEF etc.), change in FeNO, asthma control, and quality of life. The 
chosen dose range is expected to identify the most appropriate CSJ117 dosing regimen to carry 
forward to a phase 3 program. 
The CSJ117 doses selected for testing are 0.5, 1, 2, 4, and 8 mg o.d and the planned dose range 
is expected to adequately describe dose-response for CSJ117. The 4 mg o.d. dose is selected 
because of its demonstrated efficacy after 12 weeks of administration in a bronchoprovocation 
study (CCSJ117X2201) in mild atopic asthmatics. The efficacy profile of 4 mg o.d. CSJ117 in 
CCSJ117X2201 was similar to the results published for tezepelumab (700 mg i.v. every 4 weeks 
(Q4W) for 12 weeks) (Gauvreau et al 2014). The 4 mg inhaled o.d. dose of CSJ117 is also 
predicted to show similar efficacy as the 210 mg s.c. Q4W dose of tezepelumab, which had a 
demonstrated efficacy in a Phase 2b study in severe uncontrolled asthmatics. The lowest dose, 
0.5 mg o.d., is intended to capture the slope of the dose-response curve (e.g., around the 
predicted ED50). The top dose of 8 mg o.d. is selected to determine if the 4 mg dose has reached 
a plateau for efficacy and 1 and 2 mg doses are included to adequately describe the efficacy 
dose-response. 
CSJ117 doses in this trial were selected based on the safety, tolerability and pharmacokinetics 
of CSJ117 evaluated in a non-clinical good laboratory practice (GLP) toxicity study as well as 
in three studies mentioned below. 
• CSJ117X2101: 49 healthy volunteers, CSJ117 single inhaled dose via the Concept1 
device: 1 mg, 3 mg, 9 mg, 32 mg, 64 mg and 160 mg 
• CSJ117X1101: 24 adult Japanese male healthy volunteers, CSJ117 single inhaled dose via 
the Concept1 device: 9 mg, 16 mg and 32 mg 
• CSJ117X2201: 28 asthma patients, CSJ117 multiple 4 mg inhaled doses via the Concept1 
device. 


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The final analysis in both studies demonstrated that all doses were well-tolerated with no safety 
concerns. 
The totality of the non-clinical data and clinical data indicates that CSJ117 has a favorable 
safety profile and supports exposure in humans using inhaled delivery for up to 13 
weeks. Please refer to the Investigator Brochure (IB) for additional details on safety margin 
calculations. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Placebo was chosen as the comparator as it will permit the assessment of improvement in terms 
of pre-dose FEV1 for patients with uncontrolled disease who are treated with CSJ117 plus SoC 
asthma therapy, in comparison to those solely on SoC asthma therapy.  Additionally, the use of 
placebo will permit a controlled evaluation of the safety of CSJ117 plus SoC asthma therapy, 
compared with SoC asthma therapy in these patients. As mentioned above, all patients will be 
treated with SoC as background medication in line with GINA guideline recommendations and 
all patients will be allowed the use of SABAs as rescue medication when required.  
4.4 
Purpose and timing of interim analyses/design adaptations 
One or more interim analyses may be conducted to support decision-making in relation to the 
current clinical study, or the future of the sponsor’s clinical development plan or in case of any 
safety concerns from this study or ongoing clinical studies. 
4.5 
Risks and benefits 
CSJ117 is a potent and highly selective inhaled anti-TSLP Fab antibody fragment being 
developed as a potential therapy treatment for patients with asthma. TSLP is an epithelial-cell 
derived cytokine produced in response to environmental and pro-inflammatory stimuli. TSLP 
is a master regulator of the allergic immune response, and inhibition of TSLP has the potential 
to modulate multiple arms of the allergic immune response simultaneously. 
The potential benefits of CSJ117 therapy need to be balanced against its potential risks. The 
risk to patients in this study will be minimized by compliance with the inclusion/exclusion 
criteria and close clinical monitoring. Although altering current asthma medication regimens in 
some patients during the trial carries an inherent risk of a decline in lung function and/or a 
worsening of symptoms, providing patients with rescue medication (salbutamol/albuterol) and 
requiring them to take background ICS-LABA (fluticasone propionate/salmeterol b.i.d.) 
throughout the trial mitigates this risk. Compliance with the background therapy will be 
monitored at each clinic visit. All patients at screening will receive an eDiary/ePEF for daily 
monitoring their asthma symptoms and peak expiratory flow. eDiary/ePEF will need to be 
completed twice daily i.e. in the morning and in the evening. Investigators and their teams will 
be able to remotely monitor patients’ symptoms and lung functions. Additionally eDiary/ePEF 
device automatically generates alarms when the PEF performance drops down, SABA use 
increases and when patients wake up due to asthma symptoms. Furthermore, patients will be 
instructed how to react to worsening of asthma symptoms so patients can be managed 
appropriately. The Investigators might adjust patient’s therapy by adding controllers (allowed: 


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LAMA, LTRAs, theophylline and its derivatives) during the follow-up period once the active 
treatment period is completed. 
The overall clinical experience with CSJ117 includes 3 studies: 2 completed phase 1 studies in 
healthy volunteers and one phase 2 proof-of-concept bronchoprovocation trial in mild asthma 
patients. Overall, the safety profile of CSJ117 has been favorable across studies. As of 31-Dec-
2019, 70 subjects have been exposed to CSJ117. CSJ117 has been well tolerated in these 
subjects, studied at daily doses up to 160 mg. 
In two completed phase 1 studies in healthy volunteers (CSJ117X2101 and CSJ117X1101), no 
patients reported serious adverse events (SAEs), no deaths due to SAEs were reported, and no 
discontinuations due to SAEs were reported. In the CSJ117X2101 study, CSJ117 treated 
subjects did not experience a greater number of AEs compared to placebo and all of the AEs 
were mild except for two moderate AEs: (1) toothache requiring extraction in the 160 mg cohort 
on day 16, and (2) headache in the placebo group on day 1. In the CSJ117X1101 study, there 
was only one AE (increased blood triglycerides) reported in one subject in the placebo group. 
There were no SAEs with a suspected causal relationship to CSJ117. There have been no 
adverse events of idiopathic drug reactions. 
Two Phase 1 studies with healthy volunteers treated with CSJ117 were conducted i.e. Studies 
CSJ117X2101 and CSJ117X1101. In addition, study CSJ117X2201 in mild asthma patients 
was completed. Below is a summary of efficacy and safety data from these three completed 
studies. For detailed information on these studies, please refer to the Investigators Brochure. 
Study CSJ117X2101  
Study CSJ117X2101 was a first-in-human, randomized, subject-blind, placebo controlled, 
single ascending dose study to assess the safety, tolerability and pharmacokinetics of CSJ117 
in 51 adult healthy subjects. Tested inhaled CSJ117 doses included 1, 3, 9, 32, 64 and 160 mg. 
The primary objective of the study was to evaluate the safety and tolerability of single ascending 
doses of inhaled CSJ117 measured by adverse events, serious adverse events and all other safety 
assessments, up to and including the study completion visit. 
Results showed that CSJ117 was found to be safe and well-tolerated at single inhaled doses of 
1 mg, 3 mg, 9 mg, 32 mg, 64 mg, and 160 mg. There were no SAEs, deaths, and discontinuations 
due to AEs. CSJ117 subjects did not experience a greater number of AEs compared to placebo 
and the majority of AEs were mild. The most common AE was mild upper respiratory tract 
infection, which occurred in 8% of CSJ117 subjects and 8% of placebo subjects. Additionally 
CSJ117 serum exposure increased in a dose-dependent manner in the dose range of 1-160 mg 
following single inhaled doses of CSJ117 via the Concept1 device. There was no apparent 
impact of anti-CSJ117 antibodies on CSJ117 PK or safety. Pre-existing anti-CSJ117 antibodies 
were detected in 11 subjects. The detection of pre-existing anti-CSJ117 antibodies was not 
expected to increase the risk of clinically significant antidrug antibodies. 
Study CSJ117X1101  
Study CSJ117X1101 was a randomized, subject-blinded, placebo-controlled, and single 
ascending dose study to assess the safety, tolerability and pharmacokinetics of a single inhaled 
CSJ117 dose i.e. 9 or 16 or 32 mg in 24 Japanese healthy male subjects. The primary objective 


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was to evaluate the safety and tolerability of single ascending doses of inhaled CSJ117 
compared with placebo, as measured by all safety endpoints [i.e., physical exam, vital signs, 
electrocardiogram (ECG) parameters, spirometry parameters, clinical laboratories, and adverse 
events, including serious AEs (Serious Adverse Event (SAEs)] up to and including the End of 
Study visit. 
Overall, CSJ117 was found to be safe and well-tolerated at single inhaled doses of 9 mg, 16 mg 
and 32 mg. There were no SAEs, deaths, and discontinuations due to AEs. There was only one 
AE (blood triglycerides increased) reported in one subject in the placebo group. CSJ117 serum 
exposure increased in a dose-dependent manner in the dose range of 9-32 mg following single 
inhaled doses of CSJ117 via the Concept1 device.  Pre-existing ADAs were detected in 2 
subjects. There was no apparent impact of ADAs on CSJ117 PK or safety. No increase in 
antibody titers was observed. The detection of pre-existing anti-CSJ117 antibodies is not 
expected to increase the risk of clinically significant antidrug antibodies. 
Study CSJ117X2201  
Study CSJ117X2201 was a randomized, double-blinded, placebo-controlled, parallel-design, 
broncho-provocation study to evaluate the safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple doses of inhaled CSJ117 in adult subjects with mild atopic 
asthma.  
The primary objective was to evaluate the safety and tolerability of multiple dose 
administrations of CSJ117 over 12 weeks in subjects with mild atopic asthma, and to evaluate 
the late asthmatic response (LAR) after an allergen inhalation challenge (AIC) on Day 84. There 
was one active dose used in the study, i.e. CSJ117 4 mg.  
Overall, CSJ117 was generally safe and well-tolerated. The number, incidence, and severity 
of treatment-emergent adverse events were comparable between the two treatment 
groups, although more subjects receiving placebo (92.3%) developed at least one adverse 
event compared with those receiving CSJ117 (66.7%). No deaths or serious adverse events 
occurred, and no subject discontinued study drug due to an adverse event. No clinically relevant 
changes were noted in the hematology, chemistry, urinalysis, and ECG. In the study, 
no spirometry assessments suggested any untoward effect of CSJ117 on lung function. 
Although the majority of subjects (13/15) treated with CSJ117 developed CSJ117 anti-drug 
antibodies, no impact on pharmacodynamics or safety was noted by the last study visit. 
Major risks of CSJ117 are listed as follows: 
Hypersensitivity reactions 
The administration of any foreign protein can cause a hypersensitivity reaction. 
No hypersensitivity reactions were noted in cynomolgus monkeys administered CSJ117. 
Patients will be monitored for symptoms and signs consistent with such reactions, including 
shortness of breath, wheezing, coughing or hypoxemia given the inhaled route of administration. 
If anaphylaxis or other significant hypersensitivity reactions occur, then dosing must be 
permanently discontinued and appropriate medications and supportive care provided. 


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Immunomodulation 
Consistent with mechanism of action of TSLP as an upstream regulator of the immune response, 
blocking TSLP by CSJ117 may indicate a potential for immunomodulation and possible 
immunosuppression. In the 13-week GLP toxicity study, CSJ117 was not correlated with 
lymphocyte subset changes or alterations in lymphoid tissue histology. Also, no increased 
incidence of infections was seen. In the reported bronchoprovocation study with the systemic 
anti-TSLP mAb, an increase in the incidence of infection was not observed 
(Gauvreau et al 2014). Given the mild findings in the 13-week toxicity study and the published 
results with the systemic anti-TSLP mAb, the overall risk for clinically significant 
immunosuppression is considered low. Clinical monitoring for evidence of infection is included 
in this study. Patients with evidence of active infection, including bacterial, viral, parasitic or 
fungal, will be excluded. 
Coughing or bronchoconstriction 
Because CSJ117 is administered via inhalation, there is a risk that CSJ117 will result in local 
irritation within the airways, manifested as coughing or bronchospasm, even in the absence of 
local inflammation or a hypersensitivity reaction. Subjects with a history of reactive airway 
disease or abnormal pulmonary function tests beyond these observed in asthma will be excluded 
from the study. In this clinical study, patients will undergo several assessments of pulmonary 
function, including spirometry and daily PEF. In the event of clinically apparent airway 
reactivity or irritation, with possible symptoms including coughing, wheezing or shortness of 
breath, then appropriate medication and supportive care should be provided (i.e. SABA). 
The investigator must discontinue study treatment for a given patient and/or withdraw the 
patient from the study if, he/she believes that continuation would be detrimental to the patient’s 
well-being. Patients are also instructed that they can withdraw from the study at any time, and 
for any reason. 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and must agree that in 
order to participate in the study they must adhere to the contraception requirements outlined in 
the exclusion criteria (see Section 5.2). If there is any question that the subject will not reliably 
comply, they should not be entered or continue in the study. 
Safety data will be subjected to Data Monitoring Committee review. 
4.6 
Rationale for Public Health Emergency mitigation procedures 
During a Public Health Emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate. 
 


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5 
Population 
This study population will consist of male and female adult asthma patients treated with medium 
or high dose ICS plus LABA alone or with up to two additional asthma controllers (LTRA, 
LAMA or theophylline). Approximately 70% of the total study population will be enrolled in 
the high EOS stratum (EOS > 300 cells/µl). The proportion of patients with high eosinophil 
counts at screening (% of overall population) may vary depending on whether the sample size 
is decreased after blinded re-assessment. If recruitment for one EOS stratum completes first, 
only patients with screening visit EOS count applicable to the other stratum will be eligible. It 
is anticipated that approximately 3125 patients will need to be screened to randomize 
approximately 625 patients in a 2:1:1:1:2:2 (0 : 0.5 : 1 : 2 : 4 : 8 mg CSJ117) ratio into the study 
worldwide. The number of screened patients may vary depending on sample size re-estimation. 
An estimated 15% of patients will discontinue their study drug during the treatment period; 
these patients will not be replaced. 
5.1 
Inclusion criteria 
Subjects eligible for inclusion in this study must meet all of the following criteria: 
1. Written informed consent and any locally required authorization obtained from the 
subject/legal representative prior to performing any protocol-related procedures, including 
screening evaluations 
2. Documented physician-diagnosed asthma (according to GINA 2019) for at least 12 months 
prior to Screening. 
3. Male and female patients aged >18 and <75 years, inclusive at the time of screening. 
4. Patients who have been treated with medium or high dose ICS plus LABA*, alone or with 
up to two additional asthma controllers (allowed only: LTRA, theophylline or its derivatives, 
and LAMA**) at label approved dosage. The ICS dose and dose of other controllers must 
be  stable  for at least 1 month, i.e. 30 days, prior to Screening***.  
• To be classified as being on high-dose ICS, the subjects will be on a total daily dose 
(sum of all ICS) of > 500 μg fluticasone dry powder inhaler (DPI) or metered dose 
inhaler (MDI) or equivalent. 
• To be classified as being on medium-dose ICS, the subjects will be on a total daily 
dose (sum of all ICS) of 250 to 500 μg fluticasone DPI or MDI or equivalent. 
*ICS-LABA can be a fixed dose combination or separate inhalers 
**LAMA can be a separate to ICS-LABA* inhaler or a single FDC ICS-LABA-LAMA 
inhaler 
***If patients use a low dose ICS-Formoterol as a reliever, PRN, on the top of maintenance 
medium or high dose ICS-LABA combination, the ICS dose of ICS-Formoterol should not 
be added to the total dose calculation of maintenance ICS. GINA 2019 patients steps 1, 2 
and 3 are not eligible for this trial. 
5. Subjects must have all morning pre-BD FEV1 values of ≥ 40% and ≤85% of the predicted 
normal after withholding bronchodilators at the run-in and the end of run-in visits. At the 
run-in visit all lung function tests must be confirmed acceptable by central spirometry over 
read. At the end of run-in visit at least one lung function test (-2 hr 45 min and/or -2 hr 15 
min) must be confirmed acceptable by central spirometry over read. 


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6. Subjects must perform a reversibility test at the run-in visit. Reversibility is demonstrated 
by a Post-BD reversibility of FEV1 ≥ 12% and ≥ 200 mL within 30 minutes after 
administration of 400 μg salbutamol/albuterol (or equivalent dose). If reversibility is not 
demonstrated at the run-in visit (FEV1 increase was lower than 12% and 200 mL or pre-BD 
or post-BD spirometry tests were assessed by the central over reader as unacceptable) 
reversibility will be attempted at up to two ad hoc, unscheduled separate visits (the second 
ad hoc visit is allowed only for patients who failed to show positive reversibility during the 
first ad hoc visit).  
If reversibility is not demonstrated at run-in visit nor the unscheduled separate visits, but 
both pre and post-BD efforts within the same run-in or permitted unscheduled session are 
confirmed acceptable by central spirometry overread, the following historical information 
may be used:  
• Documented evidence of reversibility that was performed according to ATS/ERS 
guidelines (ATS/ERS 2019) within the 1 year prior to Screening.  Where a patient is 
assessed as eligible based on historical evidence of reversibility, a copy of the original 
printed spirometry report with relevant spirometry tracings must be available as 
source documentation. 
Until reversibility is demonstrated patient must continue the screening period or be run in 
failed, if they do not wish to continue the trial. Use of a spacer device is allowed ONLY for 
reversibility testing (See section 6.1.2.1).  
7. Subjects must have an ACQ-5 score of ≥ 1.5 at screening and end of run-in visits. 
 
9. Subjects must meet all of the following criteria at end of run-in visit (Week 0, Day1) prior 
to randomization:  
1. Subjects must demonstrate acceptable inhaler, peak flow meter, and spirometry 
techniques during the run-in period (from beginning to end of run in) as judged by the 
investigator. 
2. Subjects must demonstrate ≥ 70% compliance with the asthma controller fluticasone 
propionate/salmeterol during the run-in period based on their inhaler use count. 70% 
compliance is defined as at least one dose of medication i.e. morning or evening dose, 
taken in 70% of the days spent in the run-in period. 
3. Subjects must demonstrate ≥ 70% compliance with the CSJ117 placebo/Concept1 
during the run-in period based on capsule use count. 70% compliance is defined as 
medication taken in 70% of the days spent in the run-in period. 
4. Subjects must demonstrate ≥ 70% compliance with required use of the eDiary during 
the last 2 weeks of the run-in period. 70% compliance is defined as completing the daily 
eDiary for 70% of the days (either morning or evening, including at least 7 morning and 
7 evening eDiaries) in the last 2 weeks. 
5.2 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this study. 
1. Patients receiving any other asthma treatment that is not stipulated in Inclusion Criterion. 


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3. Patients who have had an asthma exacerbation requiring systemic corticosteroids, 
hospitalization, or emergency room visit within 4 weeks prior to Screening.  Patients may 
be re-screened 4 weeks after complete recovery from the exacerbation. 
4. Patients who have an asthma exacerbation requiring systemic corticosteroids, 
hospitalization or emergency room visit during the screening. Patients experiencing an 
asthma exacerbation during the screening period may be re-screened 4 weeks after complete 
recovery from the exacerbation. 
5. Patients with any chronic condition of the respiratory tract, which in the opinion of the 
investigator may interfere with study evaluation or optimal participation in the study. 
6. Patients, who cannot sustain washout of additional controllers (such as LTRA, theophylline 
or its derivatives, and LAMA) * 
*If subjects have been using other controllers in addition to ICS-LABA prior to screening, 
additional to ICS-LABA controllers must be discontinued before run-in. Patients must be 
instructed to use SABA as needed and to monitor their PEF daily with an eDiary/ePEF 
device provided by the sponsor. Investigator will have access to patients’ daily SABA use, 
symptoms and daily PEF data. 
If upon discontinuation of the additional controllers (on top of ICS-LABA) patients have 
excessive SABA use compared to patient's regular rescue medication use, and/or enduring 
significant daily PEF decrease and/or in the investigator's opinion patients fail to sustain the 
wash out during the run-in, the additional controllers should be reinstated and patients must 
not be randomized 
7. Patients, who show an absolute  difference of 15% in  FEV1 predicted value between the 
beginning and the end of run-in.* 
* In the situation when patients show an absolute >15% difference in FEV1 predicted value 
at the end of run-in, investigator must investigate the potential cause(s) and a repeat test 
should be scheduled to the next day or as soon as possible. If the repeated spirometry still 
shows a difference >15%, the patient must be excluded from the study.  
8. Any oral corticosteroids as a maintenance treatment within 4 weeks, or any use of short-
acting, intra-articular, intramuscular, or intravenous corticosteroid within 4 weeks, or any 
use of long acting, intra-articular or intramuscular corticosteroids within 3 months prior to 
Screening. See Table 6-3. 
9. Patients who have a cigarette smoking history of greater than 10 pack years or current 
smokers or vapers. 
10. Use of other investigational drugs within 5 half-lives or 30 days prior to Screening, 
whichever is longer. 
11. History of hypersensitivity to any ingredients of the study drug formulation or to drugs of 
similar classes to CSJ117. 
12. Patients with a history or current diagnosis of ECG abnormalities indicating significant risk 
of safety for patients participating in the study at screening or end of run in. 
13. Use of agents known to significantly prolong the QT interval unless it can be permanently 
discontinued for the duration of the study. 
14. Patients with a resting QTcF (Fridericia) ≥450 msec (male) or ≥460 msec (female) at 
screening or at end of run in, or inability to determine the QTcF interval. 
15. Cardiac or cardiac repolarization abnormality, including any of the following: 


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• History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft 
(CABG) within 6 months prior to starting study treatment 
• Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left 
bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and 
third degree AV block)  
16. Patients with a history of malignancy of any organ system (other than localized basal cell 
carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, 
regardless of whether there is evidence of local recurrence or metastases. 
17. Pregnant or nursing (lactating) women 
18. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using specified methods of contraception during dosing 
of study drug and 12 weeks after last study drug treatment (end of follow-up).  
Only the following highly effective contraception methods are permitted: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject) if allowed as effective method of contraception according to local regulations. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) 
and withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks before 
taking study treatment. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment. 
• Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate < 1%), for 
example hormone vaginal ring or transdermal hormone contraception.  In case of use 
of oral contraception women should have been stable on the same pill for a minimum 
of 3 months before randomization/start of treatment period. 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS).  
Women are considered post-menopausal and not of child-bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow-up hormone level assessment is she considered not of child-bearing potential. 
If local regulations deviate from the contraception methods listed above and require more 
extensive measures to prevent pregnancy, local regulations apply and will be described in 
the Informed Consent Form (ICF). 
19. Patients who have had a respiratory tract infection within 4 weeks prior to Screening or 
during the Screening. Patients may be re-screened 4 weeks after recovery. 
20. Patients with a history of chronic lung disease other than asthma, including (but not limited 
to) chronic obstructive pulmonary disease, bronchiectasis, (non-clinically significant 
bronchiectasis may be allowed provided recent [within 3 months prior to run-in visit] 
computed tomography (CT) scan proof is available), sarcoidosis, interstitial lung disease 
and cystic fibrosis. 


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21. Patients with a known history of active or latent tuberculosis (TB) or currently experiencing 
any TB symptom: productive, prolonged cough (> 3 weeks); coughing up blood; fever; night 
sweats; unexplained appetite loss; unintentional weight loss at screening. 
If requested by local regulations, an Interferon Gamma Release Assay (IGRA) test, e.g. 
QuantiFERON-TB® Gold test, will be used locally at screening to detect patients with TB.  
• Patients with a positive TB test result must be excluded from the trial prior to 
randomization.  
• 
Patients with an indeterminate TB test result may be enrolled if the repeated TB test 
is negative prior to randomization. Patients with the repeated indeterminate or 
positive TB test result must be excluded from the trial prior to randomization. 
Addition of TB testing at screening, where applicable, will be included in the ICF. 
22. Patients with a history of conditions other than asthma or allergic rhinitis that could result 
in elevated eosinophils (e.g., hypereosinophilic syndromes, Churg-Strauss Syndrome, 
eosinophilic esophagitis). Patients with known parasitic infestation within 6 months prior to 
screening are also excluded. 
23. Patients with uncontrolled diabetes having a glycosylated hemoglobin A1c (HbA1c) test 
result ≥8% at the screening visit laboratory test. 
24. Patients who have a clinically significant laboratory abnormality at screening in hematology, 
clinical chemistry, or urinalysis, which in the opinion of the investigator, may put the subject 
at risk during the study period. The laboratory test including (but not limited to): 
• Total white blood cell count <2500 cells/µL; 
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.0 X upper 
limit of normal (ULN) or total bilirubin >1.3 X ULN; 
• Estimated Glomerular Filtration Rate (eGFR) by the modification of diet in renal 
disease study (MDRD) equation.  
25. Patients who in the judgment of the investigator have a clinically significant condition such 
as (but not limited to) unstable ischemic heart disease, New York Heart Association 
(NYHA) Class III/IV left ventricular failure, arrhythmia, uncontrolled hypertension, 
cerebrovascular disease, neurodegenerative diseases, or other neurological disease, 
uncontrolled hypo- and hyperthyroidism and other autoimmune diseases, hypokalemia, 
hyperadrenergic state, or ophthalmologic disorder or patients with a medical condition that 
might compromise patient safety or compliance, interfere with evaluation, or preclude 
completion of the study. 
26. Patients with serious co-morbidities including, but not limited to, neurodegenerative 
diseases, rheumatoid arthritis and other autoimmune diseases. 
27. Patients with a history of alcohol or drug abuse within 12 months prior to Screening. 
28. Patients with a weight <30 kg at Screening. 
29. Patients who started immunotherapy or desensitization for allergies, within 3 months prior 
to Screening, or where the maintenance dose is expected to change during the study. 
30. Patients with a known history of non-compliance to medication or who are unable or 
unwilling to complete an electronic patient diary or who are unable or unwilling to use the 
Electronic Peak Expiratory Flow (ePEF) with eDiary device or who are unable to 
demonstrate good eDiary compliance during the screening period. 


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31. Patients with any medical or psychological condition that, in the investigator’s opinion, 
renders the patient unable to understand the nature, scope, and possible consequences of the 
study. 
32. Patients who have a history of or current treatment for hepatic disease including but not 
limited to acute or chronic hepatitis, liver steatosis, cirrhosis or hepatic failure. 
33. Patients with a history of immunodeficiency disease or hepatitis B, untreated and not cured 
hepatitis C or HIV. Patients who have completed hepatitis C treatment at least 12 weeks 
before, and Hepatitis C virus ribonucleic acid  (HCV-RNA) levels at screening are 
undetectable are considered cured and can be included in the study. 
34. No person directly associated with the conductance of the study is allowed to participate as 
a study subject. 
35. No family member of the investigational study staff is allowed to participate in this study. 
36. Patients who used other anti-TSLP drugs (investigational or approved). 
37. Patients unable to use the Concept1 dry powder inhaler, Discus®/Accuhaler® or a metered 
dose inhaler. Spacer devices are not permitted for rescue medication with the exception of 
reversibility testing (See section 6.1.2.1). 
38. Patients who are serving a custodial sentence, do not have a permanent residence or who 
are detained under local mental health legislation/regulations. 
39. Patients who discontinued monoclonal antibodies (investigational or approved) for asthma 
due to lack of efficacy. 
6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
The Investigational treatments are as follows: 
• CSJ117 0.5 mg capsules for inhalation, delivered via Concept1 
• CSJ117 1.0 mg capsules for inhalation, delivered via Concept1 
• CSJ117 2.0 mg capsules for inhalation, delivered via Concept1 
• CSJ117 4.0 mg capsules for inhalation, delivered via Concept1 
• CSJ117 8.0 mg capsules for inhalation, delivered via Concept1 
CSJ117 and matching placebo will be provided as powder filled capsules with a Concept1 
inhalation device. 
All CSJ117 doses and matching Placebo are prepared for a single inhalation. 
Under no circumstances is an alternative inhalation device to be used for the 
administration of investigational treatment capsules during the treatment period. 
All doses of CSJ117 and matching placebo will be supplied by Novartis Global Clinical Supply 
in blister packs, providing sufficient quantity of medication to last each patient between visits. 
Patients will be instructed by study personnel on the correct technique and dosing instructions 
for the device. Dispensation instructions are provided in Section 6.7.  


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Instructions for use of the Concept1 device are provided in a separate document. 
6.1.2 
Additional study treatments 
Additional study treatments include: 
• Asthma rescue medication i.e. salbutamol or albuterol 
• Standardized background ICS-LABA treatment i.e. a fixed dose combination of 
fluticasone propionate/salmeterol (allowed only Diskus®/Accuhaler®) in one of two doses 
i.e. either 250/50 µg b.i.d. or 500/50 µg b.i.d. 
6.1.2.1 
Asthma rescue medication 
At Screening all patients will be provided with a SABA (such as salbutamol [100 μg] or 
albuterol [90 μg], all other regular asthma rescue medication must be discontinued at screening 
visit) which they will be instructed to use throughout the study as asthma rescue medication on 
an ‘as needed basis’. Patients will be advised that between visits they can take their rescue 
medication for symptoms of asthma. Rescue medication (i.e. SABAs) will either be supplied to 
the study sites locally by Novartis or provided by the study site to the patient and reimbursed 
by Novartis. 
Nebulized salbutamol/albuterol is not allowed as rescue medication and will not be supplied. 
No other “at home use” asthma rescue treatment PRN is permitted and use of a spacer for rescue 
medication is not allowed at any time throughout the study, with the exception of reversibility 
testing. 
To standardize measurements, patients will be instructed not to use their rescue medication 
upon rising in the morning on days requiring spirometric assessments as indicated in Table 6-2, 
unless absolutely necessary. If rescue medication is taken within 6 hours prior to spirometry at 
any of the scheduled visits, this information will be recorded by the study site staff using the 
equipment provided by the central spirometry vendor. Additionally, the spirometry test must be 
rescheduled to the next possible day. 
Daily use of rescue medication (the number of puffs taken in the previous 12 hours) will be 
recorded (once in the morning and once in the evening) by the patient using ePEF/ eDiary. 
6.1.2.2 
Standardized background ICS-LABA treatment 
(fluticasone/salmeterol) 
All patients will be supplied with a fluticasone propionate/salmeterol xinafonate inhaler 
(Diskus®/Accuhaler®) at the run in visit. The fluticasone/salmeterol inhaler will replace patients 
regular ICS-LABA which they have been using until the run-in visit. Patients who were enrolled 
to the study with medium dose ICS-LABA at screening will receive a fixed dose combination 
(FDC) of fluticasone propionate/salmeterol 250/50 μg b.i.d., while patients who were enrolled 
at 
screening 
with 
high 
dose 
ICS-LABA 
will 
receive 
a 
FDC 
of fluticasone 
propionate/salmeterol 500/50 μg b.i.d. from the start of run-in and throughout the study 
treatment period. This standardized background medication will either be supplied to the study 
sites locally by Novartis or provided by the study site to the patient and reimbursed by Novartis. 


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Patients must be instructed not to use their standardized background medication i.e FDC of 
fluticasone/salmeterol, one day (24 hours) before all visits with spirometry assessments, as 
indicated in the Table 6-2. If FDC of fluticasone/salmeterol has been taken within 24 hours 
prior to spirometry at any of the scheduled visits with spirometry assessments, this information 
will be recorded by the study site staff using the equipment provided by the central spirometry 
vendor. Additionally, the visit must be rescheduled to the next possible day. 
Daily use of FDC of fluticasone/salmeterol will be recorded (once in the morning and once in 
the evening) by the patient using ePEF/ eDiary. Additionally adherence to the standardized 
background therapy i.e. FDC of fluticasone/salmeterol will be checked at each visit. 
6.1.3 
Treatment arms/group 
Subjects will be assigned at Randomization visit to one of the following six treatment 
arms/groups in a ratio of 2:1:1:1:2:2 
• Placebo o.d. delivered by Concept1 inhaler (in the morning) 
• CSJ117 0.5 mg o.d. delivered by Concept1 inhaler (in the morning) 
• CSJ117 1.0 mg o.d. delivered by Concept1 inhaler (in the morning) 
• CSJ117 2.0 mg o.d. delivered by Concept1 inhaler (in the morning) 
• CSJ117 4.0 mg o.d. delivered by Concept1 inhaler (in the morning) 
• CSJ117 8.0 mg o.d. delivered by Concept1 inhaler (in the morning) 
6.1.4 
Treatment duration 
For subjects who in the opinion of the investigator are still deriving clinical benefit from CSJ117, 
every effort will be made to continue provision of study treatment. The planned duration of 
treatment is 84 days (12 weeks). Subjects may be discontinued from treatment earlier due to 
unacceptable toxicity, disease progression and/or at the discretion of the investigator or the 
subject. Subjects who are discontinued from treatment earlier should remain in the study and 
finish the study visits as planned. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the patient is enrolled into the study. All medications, procedures, and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the subject is enrolled into the study must be recorded on the appropriate Case Report 
Forms (CRFs). 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a subject or allowing a new medication to be started. If the subject is already 
enrolled, contact Novartis to determine if the subject should continue his/her participation in 
the study. 


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6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “prohibited” as 
listed in Table 6-3. Specifically, subjects should receive full supportive care during the study, 
including treatment with antibiotics, anti-emetics, anti-diarrheals, analgesics, and other care as 
deemed appropriate, and in accordance with their institutional guidelines. In addition to the 
background asthma medications and rescue medications described in Section 6.1.2, the 
following concomitant medications related to asthma/allergy treatment are permitted from 
screening through the follow-up period. 
 
 


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Table 6-1 
Medications allowed under certain conditions 
Class of medication 
Condition 
Topical corticosteroids for the treatment of 
eczema 
In recommended doses and dosage regimens 
Intra-nasal corticosteroids 
Stable dose for at least 1 month prior to 
Screening. In the case of as needed, provided 
an established pattern of use has been 
documented. 
Systemic corticosteroids 
To treat asthma exacerbations 
Topical antihistamines 
In recommended doses and dosage regimens 
Oral antihistamines 
Stable dose for at least 1 month prior to 
Screening and throughout the trial. 
In the case of as needed, provided an 
established pattern of use has been 
documented 
Topical, nasal, and/or ocular formulations of 
cromones 
In recommended doses and dosage regimens 
Maintenance immunotherapy for allergies 
Stable dose for at least 3 months prior to run-in 
visit and unchanged throughout study treatment. 
COVID-19 vaccination 
At least one week before an in-clinic visit 
Table 6-2 
Medications to be withheld prior to spirometry 
Class of medication 
Last dose prior to spirometry 
Short-acting β2-agonists (SABA) 
≥ 6 hours 
Long-acting β2-agonists (LABAs) given twice 
daily 
≥ 24 hours 
ICS-Formoterol given PRN 
≥ 24 hours 
LABAs given once daily (e.g. vilanterol, 
indacaterol) 
≥ 36 hours 
Long-acting muscarinic antagonists (LAMAs e.g. 
tiotropium) 
≥ 7 days 
Fixed-dose combinations of LABA and ICS 
given twice daily 
≥ 24 hours 
Fixed-dose combinations of LABA and ICS 
given once daily 
≥ 36 hours 
Fixed-dose combinations of LABA and LAMA 
and ICS given once daily or twice daily. 
≥ 2 days 
The treatment of asthma exacerbations including the initiation of systemic corticosteroids 
should be done according to investigator’s or treating physician’s medical judgement and 
should be in line with their institutional, national and international recommendations. If 
systemic corticosteroids are required, a patient may return to the study assessments after 
successfully completing an Oral Corticosteroid (OCS) taper. If patients require treatment with 
systemic steroids longer than 3 weeks, including taper, or chronic systemic steroid 
administration, they must be discontinued from treatment. 


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If indicated for the treatment of an adverse event, including asthma exacerbation, any treatment 
(including medications in Table 6-3) deemed necessary by treating physician for the safety of 
the patient is allowed from the start of the event until the event is resolved. If it is transitioning 
to chronic treatment, the investigator should discuss with Novartis Medical Monitor. Patients 
may NOT self-medicate (other than administration of rescue medication) or adjust therapy 
without permission/guidance from treating physician. 
6.2.2 
Prohibited medication 
The specified minimum washout periods prior to the run-in are described in Table 6-3. Use of 
the treatments displayed in Table 6-3 is NOT allowed after the beginning of run-in (unless for 
the treatment of adverse events and asthma exacerbations). Each concomitant drug must be 
individually assessed against all exclusion criteria and the tables below to see if it is allowed. If 
in doubt, the investigator must contact the Novartis medical monitor or designee before 
randomizing a patient or allowing a new medication to be started. Medications must be assessed 
for adherence to the indication and other inclusion/exclusion criteria. 
Table 6-3 
Prohibited medication  
Class of medication 
Minimum cessation prior to Run-In1,2 
Other investigational drugs 
30 days or 5 half-lives, whichever is longer  
Live attenuated vaccine* 
2 days 
Inactivated influenza vaccination, pneumococcal 
vaccination or any other inactivated vaccine* 
2 days 
Short-acting anticholinergics (SAMA)  
6 hours 
Long acting muscarinic antagonists (LAMAs)* 
7 days 
Fixed combinations of short-acting β2 agonists 
and short-acting anticholinergics (SABA/SAMA) 
12 hours 
Xanthines* 
7 days 
Leucotriene Receptor Antagonists (LTRAs) and 
leucotriene synthesis inhibitors* 
7 days 
Systemic mast cell stabilizers (e.g., 
cromoglycate, nedocromil, ketotifen)* 
7 days 
Oral corticosteroids 
6 weeks 
Short-acting, intra-articular, intramuscular, 
intravenous corticosteroid 
6 weeks 
Long acting, intra-articular, intramuscular depot 
corticosteroids 
3 months and 2 weeks 
Monoclonal antibodies for the treatment of 
asthma (e.g. omalizumab, mepolizumab, 
benralizumab etc.) (investigational or approved) 
5 half-lives or 6 months, whatever is longer 
Other anti-TSLP drugs (investigational or 
approved) 
Not permitted 
Methotrexate, gold salts, cyclosporine, 
troleandomycin, azathioprine, other 
immunomodulator drugs or immunomodulatory 
monoclonal antibodies 
6 months 


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1 This table is not considered all-inclusive. Medications should be assessed for adherence to the 
indication and other inclusion/exclusion criteria 
2 These medications are also prohibited if administered for other indications 
*these medications can be used again in the follow up period 
 
6.3 
Subject numbering, treatment assignment, randomization 
6.3.1 
Subject numbering 
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the subject is assigned to the next sequential Subject 
No. available. 
6.3.2 
Treatment assignment, randomization 
At the end of run-in, prior to the first dosing of the Investigational Medicinal Product (IMP), all 
patients will have 2 spirometry assessments done i.e. at -2h45min and -2h15min timepoints. 
Prior to randomization the patient’s spirometry assessments will be evaluated by a Central 
overreader and site staff will be informed if both spirometry assessments are acceptable. 
Subjects must have an FEV1 value of ≥ 40% and ≤85% of the predicted normal shown in both 
spirometry assessments in order to be randomized. If both spirometry assessments of a patient 
are evaluated by the overreader as unacceptable or the average FEV1 predicted value from both 
spirometry assessments differs >15% (absolute value) from the beginning of run-in FEV1 
predicted value, the randomization visit must be stopped and the patient must not be randomized 
on that day. The patient should return for an ad hoc randomization visit on the following day or 
as soon as possible and complete all assessments/procedures foreseen for the randomization 
visit with exception of eCOA assessments. If the difference in FEV1 predicted value between 
the beginning of Run-in and this ad hoc randomization visit is still > 15%, this patient must be 
excluded from the study. This patient is not allowed rescreening. 
At the end of run-in visit, all eligible subjects will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The investigator or his/her delegate will contact 
the IRT after confirming that the subject fulfills all the inclusion/exclusion criteria. The IRT 
will assign a randomization number to the subject, which will be used to link the subject to a 
treatment arm and will specify a unique medication number for the first package of study 
treatment to be dispensed to the subject. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 


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Global Clinical Supply (GCS) using a validated system that automates the random assignment 
of medication numbers to packs containing the study treatment. 
Randomization will be stratified by peripheral blood eosinophil counts at the screening visit (< 
300 cells/μl or > 300 cells/μl). Treatment randomization will also be stratified at the regional 
level. 
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office. 
6.4 
Treatment blinding 
This study consists of a single-blind run-in period (i.e., only patients will be blinded to the 
identity of the treatment) followed by a double-blind randomized treatment period. 
Subjects, investigator staff, persons performing the assessments, and CTT will remain blind to 
the identity of the treatment from the time of randomization until database lock, using the 
following methods: 
(1) Randomization data are kept strictly confidential until the time of unblinding and will not 
be accessible by anyone else involved in the study with the following exceptions: independent 
statistician and programmer supporting the DMC and, if deemed necessary by the DMC, the 
DMC members. 
(2) the identity of the treatments will be concealed by the use of study treatment that are all 
identical in packaging, labeling, schedule of administration, appearance, taste, and odor. 
The randomization codes associated with subjects from whom PK samples are taken will be 
disclosed to PK analysts who will keep PK results confidential until database lock. 
Unblinding will occur in the case of subject emergencies, in case of a DMC request as an 
outcome of their evaluation and at the conclusion of the study. 
If sponsor decides to conduct an unblinded interim analysis for internal decision making 
(Section 4.4), unblinding of predetermined CTT members may occur at the time of interim 
analyses. The study may then continue under the management of a separate blinded team. In 
order to maintain the integrity of the study data, separate blinded team members will not have 
access to any unblinded data. The detailed procedures will be described in a separate charter. 
The remainder of the members including clinical study team, subjects, investigator staff, 
persons performing the assessments will also remain blinded. 
 
6.4.1 
Independent study-treatment administration site staff member 
Owing to a slight difference in capsule powder fill volume between CSJ117 doses and placebo, 
none of the site staff including the OHP, apart from the independent study-treatment 
administration site staff member should handle or see the Investigational Medicinal Product 
(IMP) capsules when assisting patient with administration.  An independent study-treatment 
administration site staff member familiar with the correct inhalation technique will be the only 
person responsible for assisting patients with removing capsules from their blisters and placing 
them in the Concept1 inhaler if required and for the onsite IMP administration. The training kit 


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can be handled by the assigned study site staff for patient training purposes. The OHP must be 
familiar with the correct inhalation technique, observe the patient inhalation and if necessary 
retrain the patient on correct inhalation technique but must not directly handle or see the IMP 
capsules. 
Appropriate measures must be taken by the independent study-treatment administration staff to 
ensure that no information regarding the IMP capsules is discussed with the site staff or OHP 
and that the site staff do not come into direct contact with the IMP capsules. The independent 
study‑treatment administration staff will not perform any other study related duties 
(including assessments, procedures, documentation, data collection or record keeping for the 
study). 
Note: the risk of subject unblinding due to the different appearance of capsules is negligible as 
it is not expected subjects will see other individuals' patient kits. Besides the independent study-
treatment administration site staff member, other team members are not allowed to handle or 
see the IMP capsules directly. 
6.5 
Dose escalation and dose modification 
Investigational or other study treatment dose adjustments and/or interruptions are not permitted. 
6.5.1 
Dose modifications 
Dose adjustments and/or interruptions of a subject's study treatment are not permitted. 
The discontinuation of study treatment rules (Section 9.1.1) must be adhered to if a subject 
cannot complete inhalation of the required capsules per the study protocol.  
Any dose interruption must be recorded on the Dosage Administration Record CRF. 
6.5.2 
Follow-up for toxicities 
Not applicable. 
6.5.2.1 
Follow up on potential drug-induced liver injury (DILI) cases 
Subjects with transaminase increase combined with total bilirubin (TBL) increase may be 
indicative of potential DILI and should be considered as clinically important events. 
The threshold for potential DILI may depend on the subject’s baseline AST/ALT and TBL 
value; subjects meeting any of the following criteria will require further follow-up as outlined 
below: 
• For subjects with normal ALT and AST and TBL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBL > 2.0 x ULN 
• For subjects with elevated AST or ALT or TBL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBL > 2 x 
baseline AND > 2.0 x ULN] 
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in subjects without bone metastasis, or elevation 
of ALP liver fraction in subjects with bone metastasis. 


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Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. 
In the absence of cholestasis, these subjects should be immediately discontinued from study 
treatment, and repeat Liver function test (LFT) testing as soon as possible, preferably within 48 
hours from the awareness of the abnormal results. The evaluation should include laboratory 
tests, detailed history, physical assessment, and the possibility of liver metastasis or new liver 
lesions, obstructions/compressions, etc. 
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR, and alkaline phosphatase. 
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, and history of any pre-existing liver 
conditions or risk factors, should be collected. 
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary tract) 
may be warranted. 
4. Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is performed 
in the study. 
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), autoimmune 
hepatitis or liver biopsy may be considered as clinically indicated or after consultation with 
specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant,” and thus, meet the definition of SAE and should be reported as SAE using the term 
“potential drug-induced liver injury.” All events should be followed up with the outcome clearly 
documented. 
Please refer to Section 16.2 for complete definitions of liver laboratory triggers and liver events. 
Every liver event defined in Table 16-1 should be followed up by the investigator or designated 
personnel at the trial site. Additional details on actions required in case of liver events are 
outlined in Table 16-2. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
The time of study treatment administration at each dosing visit will be collected on the eCRF 
as well as any dosing interruptions. For visits where spirometry is performed, time of dose 
should be taken from the spirometer. While at home administration of study medication and 
background treatment will be recorded by eDiary during the placebo run-in period and the 
treatment period. The data from the eDiary will be reviewed at each visit.  
Study treatment compliance should be assessed by the investigator and/or center personnel at 
least for all visits. Where necessary, the Investigator will discuss compliance/documentation 
issues with the patient. The Investigator or designee, including OHP, will collect the 


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used/unused study medication and packaging (unused capsules/blister strips DPIs) at all  
visits. Study treatment compliance will be assessed based on the capsule count from the blisters 
dispensed at the previous visit. 
 
6.6.2 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide the 
requested subject identifying information and confirm the necessity to break the treatment code 
for the subject. The investigator will then receive details of the investigational drug treatment 
for the specified subject and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the study team that the code has been 
broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide: 
• protocol number 
• name (if available) 
• subject number 
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
Study drug must be discontinued after emergency unblinding. Study drug must also be 
discontinued for any patient whose treatment code has been inadvertently broken or for any 
other non-emergency reason. 
These patients will be not allowed to participate in a separate safety extension study with 
CSJ117. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section (see Section 6.1.1). 
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s). The study medication has a 2-part label (base 
plus tear-off label). Before dispensing the medication kit to the subject, site personnel will 
detach the outer part of the label from the packaging and affix it to the source document. 
Before dispensing to the patient, the medication kits are stored in the refrigerator, at 2-8°C. 
Prior to first dosing from the individual kit (opening of the blisters and use of the device), the 
medication kit will need to equilibrate to room temperature for a minimum of 1 hour. 


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As per section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
delivery of IMP directly to a participant’s home may be permitted (if allowed by Local or 
Regional Health Authorities and Ethics Committees as appropriate) in the event the Investigator 
has decided that an on-site visit by the participant is no longer appropriate or possible, and that 
it is in the interest of the participant’s health to continue in the study even without performing 
an on-site visit. Implementation will need to be discussed with Novartis. The dispatch of IMP 
from the site to the participant’s home remains under the accountability of the Investigator. 
Each shipment/provisioning will be discussed with Novartis and for a maximum of 1 kit supply 
to last until the next scheduled dispensing visit. In this case, regular phone calls or virtual 
contacts (every 2 weeks or more frequently if needed) will occur between the site and the 
participant for instructional purposes, safety monitoring, investigation of any adverse events, 
ensuring participants continue to benefit from continued participation, drug accountability and 
discussion of the participant´s health status until the participants can again visit the site. 
 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure. Clinical supplies are to 
be dispensed only in accordance with the protocol. Technical deficiencies related to the study 
treatment e.g. Concept1 inhaler, blisters or capsules are to be reported to the respective Novartis 
Country Organization Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Subjects will be asked 
to return all unused study treatment and packaging at least at the end of the study or at the time 
of discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
 
6.7.1.2 
Handling of additional treatment 
The following non-study treatment has to be monitored specifically: 
• SABA (such as salbutamol 100 μg or albuterol 90 μg) 


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• FDC of fluticasone propionate/salmeterol 250/50 μg 
• FDC of fluticasone propionate/salmeterol 500/50 μg 
The non-study treatment must be handled and stored according to label, kept in a secured 
location and dispensed only in accordance with the protocol. 
If possible, the investigator shall maintain an accurate record of dispensing of the above-
mentioned treatment in a drug accountability log / inventory log / source document. Monitoring 
of drug accountability will be performed by monitors during site visits and at the completion of 
the study. Patients will be asked to return all unused SABA and FDC of fluticasone/salmeterol 
treatments and their packaging at least at the end of the study or at the time of discontinuation 
from the study. 
6.7.2 
Instruction for prescribing and taking study treatment 
The instructions for the investigational drug (CSJ117/placebo) are as follows: 
• CSJ117 PulmoSol powder / placebo is provided in a hard capsule to be inhaled via the 
Concept1 device 
• CSJ117/placebo should be taken by patient once a day at approximately the same time 
each morning together with his/her maintenance ICS/LABA treatment (Fluticasone 
propionate/salmeterol) 
Instructions for fluticasone propionate/salmeterol and rescue medication should be according 
to the respective product label. 
On the run-in visit a medication kit with placebo capsules and a Concept1 inhalation device will 
be provided for demonstration and training purposes. On this visit, all patients will be fully 
trained in the correct use of the Concept1 devices used to administer study medication. Patients 
who are unable to use the device correctly at the end of run-in visit (Day 1) will not be eligible 
to enter the treatment epoch. 
On study visit days, patients should be reminded not to take the investigational drug 
(CSJ117/placebo) prior to the visit to ensure compliance with the pre-dose PK sampling 
procedure. 
On the day prior to and on days of visits, with the study drug administration, patients should be 
reminded not to take fluticasone/salmeterol in order to ensure compliance with the spirometry 
pre-dose measurements. 
The morning dose of fluticasone/salmeterol on the visit days should be taken after spirometry 
assessments and the pre-dose PK sampling have been both completed. The evening dose of 
fluticasone/salmeterol on visit days should be taken as usual. 
7 
Informed consent procedures 
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 


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his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the subject. 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
Male subjects must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information. 
The study includes optional sub studies/
 component which 
requires a separate signature if the subject agrees to participate. It is required as part of this 
protocol that the Investigator presents this option to the subjects, as permitted by local 
governing regulations. The process for obtaining consent should be exactly the same as 
described above for the main informed consent. 
Declining to participate in these optional assessments 
Sub Studies) will in no way affect 
the subject’s ability to participate in the main research study. 
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval. 
Where off-site visits are implemented, a separate Home Nursing consent document must be 
used in addition to the main ICF. The process for obtaining consent should be exactly the 
same as described above for the main informed consent. 
 
8 
Visit schedule and assessments 
Assessment schedule (Table 8-1) lists all of the assessments when they are performed. All data 
obtained from these assessments must be supported in the subject’s source documentation. 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule (Table 
8-1) or as close to the protocol schedule designated day/time as possible. Missed or rescheduled 


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visits should not lead to automatic discontinuation. Subjects who discontinue study treatment 
should NOT be considered withdrawn from the study UNLESS they withdraw their consent 
(see 'Withdrawal of Informed Consent' Section 9.1.2). Where possible, they should complete 
the assessments indicated in the Assessment Schedule.  
Subjects who prematurely discontinue the study for any reason should be scheduled for a visit 
as soon as possible, at which time all of the assessments listed for the Premature Subject 
Withdrawal (PSW) visit will be performed. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowable by a local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g. tele consult) or visits by site staff/ home nursing 
staff to the participant´s home, can replace selected on-site study visits as specified in Table 8-1, 
for the duration of the disruption until it is safe for the participant to visit the site again. 


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Table 8-1 
Assessment Schedule 
Period Screenin
g 
Baseline 
Treatment 
Follow up 
PS
W1* 
Visit Name Screenin
g17 
Run-
In 
Phon
e 
visit 
End 
of 
Run
-In 
Day 1 Wee
k 2* 
Wee
k 4* 
Wee
k 8 
Wee
k 12 
Week 
14* 
Wee
k 16* 
Wee
k 20* 
Wee
k 24 
Days 
-42 
-28 
-14 
1 
1 
15 
29 
57 
85 
99 
113 
141 
169 
- 
Informed 
consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
Pharmacogene
tic Informed 
Consent2 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
Demography 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
Inclusion / 
Exclusion 
criteria 
X 
X 
  
X 
  
  
  
  
  
  
  
  
  
 
Smoking 
history 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
Asthma 
exacerbation 
history 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
Prior asthma 
medication 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
AEs/SAEs 
assessment 
X 
X 
X 
X 
X3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review and 
record 
surgeries and 
procedures 
X 
X 
X 
X 
X3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical 
history/current 
medical 
conditions 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
Body Height 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
Body Weight 
X 
  
  
  
  
  
  
  
X 
  
  
  
X 
X 
Physical 
Examination 
S 
  
  
S 
S3 
  
  
  
S 
  
  
  
S 
S 
Vital Signs 
X 
X 
  
X 
X3 
  
  
  
X 
X 
  
X 
X 
X 
Abbreviated 
Physical 
Examination 
  
  
  
  
  
S 
S 
S 
  
  
S 
  
  
 
Alcohol Test, 
Drug Screen, 
and Cotinine 
Test 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
Pregnancy test 
(serum) for 
women of 
childbearing 
potential 
X 
  
  
  
  
  
X 
X 
X 
  
  
  
X 
X 


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Period Screenin
g 
Baseline 
Treatment 
Follow up 
PS
W1* 
Visit Name Screenin
g17 
Run-
In 
Phon
e 
visit 
End 
of 
Run
-In 
Day 1 Wee
k 2* 
Wee
k 4* 
Wee
k 8 
Wee
k 12 
Week 
14* 
Wee
k 16* 
Wee
k 20* 
Wee
k 24 
Days 
-42 
-28 
-14 
1 
1 
15 
29 
57 
85 
99 
113 
141 
169 
- 
Pregnancy test 
(urine) for 
women of 
childbearing 
potential 
  
S 
  
S 
  
  
  
  
  
  
S 
S 
  
 
Dispensation of 
rescue 
medication 
S 
S 
  
  
S 
  
S 
S 
S 
  
S 
S 
  
 
Washout of 
controllers 
additional to 
ICS/LABA 
S 
  
  
  
  
  
  
  
  
  
  
  
  
 
Standardization 
of background 
ICS/LABA 
treatment 
  
X 
  
  
  
  
  
  
  
  
  
  
  
 
Dispensation of 
background 
ICS/LABA 
treatment 
  
S 
  
  
S 
  
S 
S 
S 
  
S 
S 
  
 
Dispensation of 
eDiary/ePEF 
S 
  
  
  
  
  
  
  
  
  
  
  
  
 
Compliance 
with 
eDiary/ePEF 
  
S 
S 
S 
  
S 
S 
S 
S 
S 
S 
S 
S 
 
Training 
eDiary/ePEF 
S 
S2 
  
S2 
  
  
  
  
  
  
  
  
  
 
Inhaler devices 
training 
  
S 
  
S2 
  
S2 
S2 
S2 
S2 
  
  
  
  
 
Dispensation of 
IMP training kit 
  
S 
  
  
  
  
  
  
  
  
  
  
  
 
Dispensation of 
Run-In kit 
  
S 
  
  
  
  
  
  
  
  
  
  
  
 
Dispensation of 
study drug 
  
  
  
  
S 
  
S 
S 
  
  
  
  
  
 
Dispense & 
attach 
Concept1 add-
on sensor4 
 
 
 
 
S 
 
 
 
 
 
 
 
 
 
Upload data 
from the 
Concept1 add-
on sensor/re-
attach the 
sensor4 
  
  
  
  
 
  
S 
S 
S 
  
  
  
  
S 
IMP 
administration 
  
  
  
  
X5 
X 
X 
X 
X 
  
  
  
  
 


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Period Screenin
g 
Baseline 
Treatment 
Follow up 
PS
W1* 
Visit Name Screenin
g17 
Run-
In 
Phon
e 
visit 
End 
of 
Run
-In 
Day 1 Wee
k 2* 
Wee
k 4* 
Wee
k 8 
Wee
k 12 
Week 
14* 
Wee
k 16* 
Wee
k 20* 
Wee
k 24 
Days 
-42 
-28 
-14 
1 
1 
15 
29 
57 
85 
99 
113 
141 
169 
- 
fluticasone/sal
meterol 
administration 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Compliance 
with Concept1 
  
  
S 
S 
  
S 
S 
S 
S 
  
  
  
  
S 
ACQ 
X 
  
  
X 
  
  
X 
X 
X 
  
  
  
X 
X 
AQLQ 
  
  
  
X 
  
  
X 
X 
X 
  
  
  
X 
X 
FeNO pre-dose 
at site 
  
  
  
 X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Peak 
Inspiratory 
Flow training  
 
S 
  
  
  
  
  
  
  
  
  
  
  
 
Spirometry 
training2,16 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spirometry 
Reversibility 
Test 
  
X6 
  
  
  
  
  
  
  
  
  
  
  
 
-2hr45min Pre-
dose 
spirometry 
  
  
  
X 
  
  
  
  
  
  
  
  
  
 
-2hr15min Pre-
dose 
spirometry 
  
  
  
X 
  
  
  
  
  
  
  
  
  
 
-45min Pre-
dose 
spirometry 
  
 
  
  
  
X 
X 
X 
X 
  
X7 
X7 
X7 
X 
-15min Pre-
dose 
spirometry 
  
 
  
  
  
X 
X 
X 
X 
  
X7 
X7 
X7 
X 
Electrocardiogr
am (ECG) - 
triplicate 
  
  
  
X8 
X9 
  
  
  
X  
  
  
  
 
X 
Electrocardiogr
am (ECG) - 
Single10 
X 
  
  
  
  
  
X 
X 
 
  
X 
  
 X 
 
ImmunoCAP 
test 
  
  
  
X 
  
  
  
  
  
  
  
  
  
 
Hepatitis 
screen 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
HIV Screen11 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
Urinalysis 
X 
  
  
X 
  
X 
X 
X 
X 
  
X 
  
X 
X 
Hematology 
X 
  
  
X8 
  
X8 
X8 
X8 
X8 
  
X 
  
X 
X 
Clinical 
Chemistry 
X 
  
  
X8 
  
X8 
X8 
X8 
X8 
  
X 
  
X 
X 


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Period Screenin
g 
Baseline 
Treatment 
Follow up 
PS
W1* 
Visit Name Screenin
g17 
Run-
In 
Phon
e 
visit 
End 
of 
Run
-In 
Day 1 Wee
k 2* 
Wee
k 4* 
Wee
k 8 
Wee
k 12 
Week 
14* 
Wee
k 16* 
Wee
k 20* 
Wee
k 24 
Days 
-42 
-28 
-14 
1 
1 
15 
29 
57 
85 
99 
113 
141 
169 
- 
Blood collection 
for ADA 
  
  
  
X8 
  
X8 
X8 
X8 
X8 
X 
X 
X 
X 
X 
PK Blood 
collection Pre-
Dose 
  
  
  
X8 
  
X8 
X8 
X8 
X8 
X 
X 
X 
X 
X 
PK Blood 
collection Post-
Dose 2hr14 
  
  
  
  
X18 
X18 
X18 
X18 
X18 
  
  
  
  
 
PK Blood 
collection Post-
Dose 4hr14 
  
  
  
  
X18 
  
  
  
X18 
  
  
  
  
 
Contact IRT 
S 
S 
  
S 
S 
  
S 
S 
S 
  
  
  
  
S 
CSJ117 Safety 
Extension 
Study 
participation 
discussion 
  
  
  
  
  
  
  
S13 
  
  
  
  
  
 
TB testing15 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Premature Subject Withdrawal, no on site drug administration 
2 Optional, if needed 
3 Only if Day 1 visit was postponed, due to repetition of spirometry or operational issue 
4 Only for participating countries/sites 
5 Patient has to be observed for at least 4 hours post-administration 
6 If not achieved during the Run In visit, up to two additional attempts are allowed at separately scheduled visits 
before the End of Run in Visit. If reversibility is not demonstrated at Run in Visit and the two additional attempts, 
historical information may be used (Documented evidence of reversibility that was performed according to 
ATS/ERS guidelines (ATS/ERS 2019) within the 1 year prior to Screening).  
7 Pre-dose regarding fluticasone/salmeterol 
9 3 hours post-dose 
10 If ECG results are clinically abnormal, site has to repeat it twice and submit to the central reviewer 
11 To be confirmed by central lab if positive or indeterminate. 
12 Optional, only for consented patients 
13 Latest at day 84. It can be conducted earlier. 
14 In case a patient prematurely discontinued treatment but continued participation in the study, these PK samples 
will not be collected. 


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15 Where applicable by local regulations 
16 Medication washout prior to spirometry training is not required 
17 Screening visit can be optionally conducted across 2 days to collect laboratory samples and allow the laboratory 
evaluations including the blood eosinophil (EOS) counts first. 
*Selected assessments for these visits could be performed off site 
18 Within +/-15 minutes of specified sample collection time. 
 
8.1 
Assessments order during randomization 
During the end of run-in/Randomization visits (see Table 8-2)  suggested order of assessments 
outlined below should be followed (if possible). The randomization visit should be planned in 
the morning. This table is not exhaustive, for complete details on recommended timing and 
ordering of assessments see Section 16.8. Similar assessments order should be followed where 
these assessments are performed at other visits. 
Table 8-2 
Assessments at randomization 
Order of assessments 
Assessment 
1 
Question on medication withholding for 
spirometry/check the eDiary entry for the current 
day and one day before 
2 
Inclusion/exclusion criteria 
3 
Patient Reported Outcome instruments to be 
completed in the following order: ACQ-5, AQLQ 
4 
Pre-dose ECG triplicate 
5 
Vital signs 
6 
Full physical examination 
7 
Fractional exhaled nitric oxide (FeNO) 
8 
First pre-dose spirometry assessment: 
approximately 2hr45 min prior to the dosing of 
study drug at the clinic visit. 
9 
Second pre-dose spirometry assessment: 
approximately 2hr15 min prior to the dosing of 
study drug at the clinic visit. 
10 
Confirm acceptable spirometry results with an 
overread report and FEV1 difference with the 
run-in visit* 
11 
Samples for urine/hematology/blood 
chemistry/ImmunoCAP (including pregnancy 
test) 
12 
In-clinic witnessed dosing of the study drug 
13 
Samples for PK at 2 hour post-dose 
14 
ECG triplicate at 3 hour post-dose 
15 
In clinic administration of fluticasone/salmeterol 
background treatment 


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16 
Samples for PK at 4 hour post-dose 
*if overread indicates unacceptable spirometry results or an absolute FEV1 difference is >15%, a 
patient has to inhale a dose of fluticasone/salmeterol and the randomization visit has to be postponed 
to another ad hoc visit. There must be a minimum withholding time > 24 hr between dosing of 
fluticasone/salmeterol and the next spirometry. First dosing of the study medication should take place 
only at the ad hoc scheduled randomization visit. 
  
8.2 
Screening and re-screening 
Re-screening is allowed once, if a patient fails to meet the eligibility criteria during the 
screening period or at the run-in visit, before first placebo dosing. This includes: 
• Pre-BD FEV1 predicted value at the run-in visit falls within the margin of +/-2.0% 
allowed for re-screening (i.e. 38 and 87% predicted)  
• Asthma exacerbation requiring systemic corticosteroids, hospitalization or emergency. 
room visit during the screening period or within 4 weeks prior to screening. Patients may 
be re-screened 4 weeks after complete recovery from the exacerbation. 
• 
When the low EOS strata (blood EOS count at screening <300 cells/µL) is closed for 
recruitment, patients who failed due to low eosinophils may be re-screened once. If these 
patients have an EOS count >300 cells/µL at screening visit when re-screened, and they 
meet all other eligibility criteria, they can move to run-in and ultimately be randomized. 
Re-screening is NOT allowed in any of the following situations: 
• Subject fails to show reversibility in three allowed attempts and has no documented 
evidence of reversibility that was performed within the 1 year prior to Screening as 
specified in the inclusion criterion 6 (see Section 5.1) and the assessment schedule (see 
Table 8-1). 
A new patient number will be assigned and the site must record the re-screening information in 
the corresponding eCRF and in IRT. Rescreened patients must undergo all protocol defined 
assessment, as for newly screened patients. 
Patients who were dosed run-in IMP and were run-in failed are not eligible for re-screening, 
unless they were run-in failed due to not meeting the spirometry acceptability criteria at the run-
in visit and took less than 7 doses of run-in IMP and have met all other eligibility criteria. 
8.2.1 
Information to be collected on screening failures 
Subjects who sign an informed consent form and are subsequently found to be ineligible prior 
to randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate Case Report Form. The demographic information, informed 
consent, and Inclusion/Exclusion pages must also be completed for screen failure subjects. No 
other data will be entered into the clinical database for subjects who are screen failures, unless 
the subject experienced a serious adverse event during the screening phase (see SAE 
Section 10.1.3 for reporting details). If the subject fails to be randomized, the IRT must be 
notified within 2 days of the screen fail that the subject was not randomized. Adverse events 
that are not SAEs will be followed by the investigator and collected only in the source data. 


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Subjects who are randomized and fail to start treatment, e.g. subjects randomized in error, will 
be considered an early terminator. The reason for early termination should be recorded on the 
appropriate Case Report Form. 
8.3 
Subject demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF. 
• Age 
• Sex 
• Race and ethnicity 
• Height 
• Weight 
• Body mass index (BMI) 
• Duration of asthma 
• Number of exacerbations in the prior year 
• Atopic status (Yes/No) (ImmunoCAP) 
• Smoking history 
• Baseline Spirometry (FEV1, FVC, FEV1/FVC) 
• Reversibility (demonstrated) 
• Baseline ADSD/ANSD score 
• Baseline ACQ-5 
• Baseline AQLQ-12 
 
 
• Baseline FeNO 
• Baseline PEF 
• Baseline ICS dose level 
• Peripheral blood eosinophils at screening 
 
 
• Relevant medical history/current medical condition present before signing informed 
consent. Where possible, diagnoses and not symptoms will be recorded. 
8.4 
Efficacy 
The efficacy assessments selected are standard for this indication/subject population. 
8.4.1 
Spirometry 
All visits with spirometry testing (excluding screening visit) must occur in the morning. Please 
refer to the Table 8-1 for full details of the scheduling of spirometry measurements. 
Equipment for spirometry assessments will be provided for all study visits by a Central 
Spirometry vendor, and overread of spirometry assessments will be performed by trained 


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spirometry overreaders at the central vendor. The final spirometry assessments will be those 
provided by the spirometry overreaders of the central spirometry vendor. 
Please refer to the Spirometry Guidance, in (section 16.3 Spirometry Guidance), for full details 
on scheduling and performing spirometry. Reversibility testing must be conducted in the 
morning. 
Variability of FEV1 will be monitored in this study. Any unusual FEV1 difference will require 
the investigator or delegate to examine potential causes for the difference.   
8.4.2 
Fractional exhaled Nitric Oxide (FeNO) 
To ensure consistency in the measurement of FeNO, all sites participating in this study will be 
provided with a NIOX FeNO machine. FeNO measurements should be done at all on-site 
treatment and follow up visits (see Table 8-1). 
Several publications reported high fractional concentrations of orally exhaled Nitric Oxide 
(FeNO) in subjects with asthma as compared with unaffected subjects, and a fall after treatment. 
The measurement of exhaled nitric oxide is widely accepted as a non-invasive marker of airway 
inflammation and, amongst other uses, has been proposed to monitor the response to anti-
inflammatory medications. 
In this study, fractional exhaled nitric oxide will be measured following the published guidelines 
on standardized techniques (see section 16.6) including calibration of equipment as appropriate 
for measuring exhaled Nitric Oxide by ATS and ERS (ATS/ERS 2005). 
8.4.3 
eDiary/ePEF 
At screening all patients will be provided with a patient electronic diary (referred to as eDiary 
or eDiary/ePEF) to record daily asthma symptoms and rescue medication (salbutamol/albuterol) 
use. The eDiary has automated reminders to remind the patient to inhale the study medication 
and background therapy i.e. fluticasone propionate/salmeterol. Patients will be instructed to 
routinely complete the patient diary twice daily – at about the same time each morning and each 
evening, approximately 12 hours apart. The eDiary/ePEF recordings are to be reviewed at the 
visits as detailed in Table 8-1 until study completion. Sites and patients will receive appropriate 
training and guidance on the use of the eDiary device. 
8.4.3.1 
Asthma Daytime Symptom Diary (ADSD) and Asthma Nighttime 
Symptom Diary (ANSD) 
Asthma Daytime Symptom Diary (ADSD) and Asthma Nighttime Symptom Diary (ANSD) are 
self-administered patient reported outcome measures of asthma symptom severity designed for 
use with adolescents and adults with mild to severe persistent asthma. They were developed in 
accordance with the US Food and Drug Administration’s (FDA) PRO guidance. 
ADSD and ANSD will be part of the eDiary. 
Both diaries are comprised of 6 items assessing breathing symptoms (difficulty breathing, 
wheezing, and shortness of breath), chest symptoms (chest tightness and chest pain), and cough 
symptoms (cough). All items are assessed using an 11-point numeric rating scale (NRS) ranging 
from 0 (‘None’) to 10 (‘As bad as you can imagine’) 


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8.4.3.2 
Peak Expiratory Flow (PEF) 
PEF will be measured at consistent times for a patient, in the morning and evening each day 
during the study from the beginning of run-in visit to study completion. The measurements will 
be performed using an eDiary/ePEF provided to the patients. 
Patients should be encouraged to perform morning and evening PEF measurements BEFORE 
the use of any rescue medication and BEFORE the use of fluticasone/salmeterol medication. 
Patients will be asked to record if they have taken their rescue medication 6 hours prior to the 
peak flow assessment. 
At each time point, the patient will be instructed to perform 3 consecutive maneuvers within 
approximately 10 minutes. These PEF values are captured in the eDiary /ePEF.  
8.4.3.3 
Number of inhalations of Rescue Medication 
The total number of inhalations used of rescue medication (number of puffs taken in the 
previous 12 hours) will be recorded every morning and evening by the patient, in the 
eDiary/ePEF.  


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8.4.3.4 
Worsening of asthma (and related eDiary alerts) 
Asthma worsening criteria will be programmed into the eDiary/ePEF apart from criterion 5 
below. 
The data captured in the eDiary/ePEF will be used to alert the patient and/or investigator to 
possible signs of worsening asthma. 
The investigator should instruct the patient to contact the investigator if the patient 
develops one or more of the following asthma worsening criteria at any time during the 
trial from the screening onwards. Patients may also receive an alert via their eDiary 
requesting them to contact their investigator: 
• >50% increase in SABA use on 2 out of any 3 consecutive days compared to baseline 
and/or >8 puffs on 2 out of any 3 consecutive days *. For screening phase only: >8 puffs 
on 2 out of any 3 consecutive days  
• ≥20% decrease in AM or PM PEF from baseline on 2 out of any 3 consecutive days 
compared to baseline*.  
• <60% of PEF compared to baseline*, 
• Night time awakenings requiring SABA use on at least 2 out of any 3 consecutive nights; 
or 
• Urgent unscheduled clinic visit due to asthma-related deterioration. 
*Note: 
• The baseline for the run-in period is set at the run-in visit. 
• The baseline during the treatment is set at the beginning of treatment (end of run-in visit, 
Day 1).  
• Automated eDiary/ePEF PEF alerts will be implemented from the run-in visit until the study 
completion visit. During screening patients will be informed to monitor their PEF daily. At 
each morning and evening sessions they will be reminded to contact the PI in case of PEF 
decrease. 
If a patient develops any of the above criteria while he or she is in the screening (apart from 
>50% change in SABA use and PEF related criteria), run-in or treatment period, the investigator 
should assess the patient condition. If this occurs during screening, and it is considered a 
clinically significant worsening in the investigator’s opinion, the patient must be treated as 
appropriate and discontinued prior to run-in. Once the condition is resolved, if eligibility criteria 
are met, the patient may be reconsidered for rescreening. 
The alerts which are triggered by above criteria are in place to detect early onset of asthma 
worsening at any time during the study to help direct early intervention. Therefore, the 
investigator should do the following when alerts are received: 
• Review alert trends over time, in particular PEF decreases 
• Call the patient promptly when any one specific alert type (e.g. PEF<60%) is received on 
consecutive days to further assess the clinical status. This may include urgent clinic visits 
as appropriate and/or immediate treatment. 
• Implement prompt treatment as necessary 
• Report all types of events in the CRF 


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If patients believe their symptoms are worsening and/or receive alerts as outlined above, the 
patient should also notify the investigator and be evaluated by the investigator and treated as 
clinically appropriate. 
Investigator and the site study team must check and encourage patients' compliance with study 
medications and the eDiary/ePEF device. Should there be any compliance issue on study drug 
or e-diary completion potentially putting the patient’s safety at risk, Investigator must consider 
temporary or permanent discontinuation of study drug. 
Worsening of asthma symptoms may require unscheduled evaluation between visits. Study site 
personnel must be available to monitor and document the patient’s progress until the asthma 
worsening has resolved. 
8.4.4 
Appropriateness of efficacy assessments 
The efficacy assessments selected are standard for this indication/patient population. 
8.5 
Safety 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
For details on AE collection and reporting, refer to AE section. 
Spirometry will be used to monitor the safety of patients during the study. Patients will also be 
provided with an eDiary/ePEF. The data captured in the eDiary/ePEF will be used to alert the 
patient and/or investigator to possible signs of worsening asthma. 
A central laboratory will be used to analyze and report blood chemistry/hematology/urinalysis.  
Where required by local regulations TB testing will be done at screening. A local laboratory 
will be used to analyze and report TB testing. 
A central ECG vendor will be used to collect, assess and report ECGs. 
A Data Monitoring Committee will be set up to overview safety. See Section 10.2.2 for details. 
Physical assessments are defined in below table. 
 
 


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Table 8-3 
Assessments & Specifications 
Assessment 
Specification 
Physical 
A complete physical examination 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 will be performed. 
An abbreviated physical examination will include 
the examination of general appearance and vital 
signs (blood pressure [SBP and DBP] and 
pulse).  
Information for all physical examinations must be 
included in the source documentation at the 
study site. Clinically relevant findings that are 
present prior to signing informed consent must 
be recorded on the appropriate CRF that 
captures medical history. Significant findings 
made after signing informed consent which meet 
the definition of an Adverse Event must be 
recorded as an adverse event. 
Vital signs 
Vital signs include BP and pulse measurements. 
After the subject has been sitting for five 
minutes, with back supported and both feet 
placed on the floor, systolic and diastolic blood 
pressure will be measured three times using an 
automated validated device, e.g. OMRON, with 
an appropriately sized cuff. The repeat sitting 
measurements will be made at 1 - 2 minute 
intervals and the mean of the three 
measurements will be used. In case the cuff 
sizes available are not large enough for the 
subject's arm circumference, a 
sphygmomanometer with an appropriately sized 
cuff may be used. 
 
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 as specified 
in Table 8-1. 
 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
regular phone or virtual calls will occur aligned with the visit schedule for safety monitoring 
and discussion of the participant´s health status until it is safe for the participant to visit the site 
again.  
If participants cannot visit the site to have serum pregnancy tests, urine pregnancy test kits may 
be used. Relevant participants can perform the urine pregnancy test at home and report the result 


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to the site. It is important that participants are instructed to perform the urine pregnancy test 
first and only if the test result is negative proceed with the administration of the study treatment. 
A communication process should be established with the participant so that the Site is informed 
and can verify the pregnancy test results (e.g., following country specific measures). 
 
8.5.1 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens detailed in this section with the 
exception of urine pregnancy test and TB test. Details on the collections, shipment of samples 
and reporting of results by the central laboratory are provided to investigators in the laboratory 
manual. As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, or in the event of other conditions, that 
delays or prevents laboratory samples reaching the analysis laboratory within sample stability 
or acceptable timeframe, exceptionally local laboratory analysis may be implemented. Prior to 
implementation, this mitigation must be discussed and agreed with Novartis and 
permitted/approved by local or regional Health Authorities and Ethics Committees as 
appropriate. 
 
 


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Table 8-4 
Laboratory Evaluations 
Test Category 
Test Name 
Hematology 
Hemoglobin, Platelets, Red blood cells, White 
blood cells, Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils, Other) , 
HbA1C 
Chemistry 
Albumin, Alkaline phosphatase, ALT, AST, GGT, 
Lactate dehydrogenase (LDH), Calcium, 
Magnesium, Phosphorus, Chloride, Sodium, 
Potassium, Creatinine, Indirect Bilirubin, Direct 
Bilirubin, Total Bilirubin, Blood Urea Nitrogen 
(BUN) or Urea, Uric Acid, Amylase, Lipase, 
Glucose 
Urinalysis 
Microscopic Panel (Red Blood Cells, White 
Blood Cells, Casts, Crystals, Bacteria, Epithelial 
cells), Macroscopic Panel (pH, specific gravity, 
blood, protein). 
Hepatitis markers 
HBV-DNA, HbsAg, HbsAb, HbcAb, HCV RNA-
PCR, Hepatitis C Virus Antibody  
Screening for HIV 
HIV1/2-Ab  
 
 
Pregnancy Test 
Serum pregnancy test, urine pregnancy test 
Atopic status 
Tuberculosis test 
ImmunoCAP test 
IGRA test 
8.5.2 
Electrocardiogram (ECG) 
Timing and type of electrocardiograms (ECGs) is indicated in the Table 8-1. ECG must be 
recorded after 10 minutes rest in the supine position to ensure a stable baseline according to the 
ECG investigator manual. The preferred sequence of cardiovascular data collection during 
study visits is ECG collection first, followed by vital signs, blood sampling and spirometry. The 
Fridericia QT correction formula (QTcF) should be used for clinical decisions. 
Triplicate 12 lead ECGs are to be collected at visits specified in the Table 8-1 with ECG 
machines supplied by the central laboratory. Full details of all procedures relating to the ECG 
collection and reporting will be contained in an investigator manual to be provided to each 
investigator site. 
Single 12 lead ECGs are collected at visits specified in the Table 8-1 with ECG 
machines supplied by the central laboratory. 
For any single ECGs with subject safety concerns, two additional ECGs must be performed to 
confirm the safety finding and copies forwarded to the central ECG laboratory for assessment. 
A monitoring or review process should be in place for clinically significant ECG findings 
throughout the study and especially at baseline before administration of study treatment. 
Any identifier details must be redacted e.g. subject initials, date of birth. 
In the event that a clinically significant ECG abnormality is identified (e.g. severe arrhythmia, 
conduction abnormality of QTcF > 500 ms), a copy of the assessment is sent to the central 


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laboratory for expedited review if applicable, and the ECG is repeated to confirm the diagnosis. 
If the subject is hemodynamically compromised, the investigator or a medically qualified 
person must initiate appropriate safety procedures without delay (for example cardioversion). 
The original ECGs appropriately signed, must be collected and archived at the study site. 
Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or adverse events as appropriate. 
8.5.3 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have serum pregnancy or urine 
pregnancy testing at visits specified in the assessment schedule Table 8.1. Additional serum 
pregnancy testing might be performed if requested by local requirements or if urine pregnancy 
test is positive. 
A positive serum pregnancy test requires immediate discontinuation from study drug. 
A positive urine test requires interruption of study treatment until serum test is done.  If the 
serum test is negative, study treatment should continue.  
The patient must be followed to understand the outcome of the pregnancy. 
If the result of urine pregnancy test at the end of run-in visit is positive, the patient must not be 
randomized until the results is confirmed by a serum pregnancy test. 
Assessments of Fertility 
Medical documentation of oophorectomy, hysterectomy, or bilateral tubal ligation must be 
retained as source documents. Subsequent hormone level assessment to confirm the woman is 
not of child-bearing potential must also be available as source documentation in the following 
cases: 
• Surgical bilateral oophorectomy without a hysterectomy 
• Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 
In the absence of the above medical documentation, FSH (Follicle Stimulating Hormone) 
testing is required of any female subject regardless of reported reproductive/menopausal status 
at screening/baseline. 
8.5.4 
Hepatitis and HIV screen 
All subjects will be screened for Hepatitis B markers, i.e. HBsAg, HbsAb and HbcAb. 
Patients with a positive HBsAg and/or positive HbcAb are excluded. Patients who are 
vaccinated for Hepatitis B (HbsAb positive, both HBsAg and HbcAb negative) can participate 
in the study.  
Screening for Hepatitis C will be based on HCV antibodies and if positive, or indeterminate, 
HCV RNA levels must be determined. Patients who have completed Hepatitis C treatment at 
least 12 weeks before, and HCV-RNA levels at screening are undetectable are considered cured 
and can be included in the study.   


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Evaluation for HIV seropositivity will be performed, and, if positive, or indeterminate, 
confirmation by a second technique e.g. Western blot.  
Appropriate counseling will be made available by the site Investigator in the event of a positive 
finding.  
Notification of state and federal authorities, as required by local law, will be the responsibility 
of the site Investigator. 
8.5.5 
Tuberculosis testing 
Per exclusion criteria all patients with history of active or latent tuberculosis or experiencing 
any TB symptom, defined in the exclusion criteria, at screening must be excluded from the trial.  
In addition if required by local regulations laboratory TB testing will be done at the screening 
visit. Recommended IGRA test is the QuantiFERON-TB® Gold test. Patients with a positive 
TB test result will be excluded from the trial prior to randomization. Patients with an 
indeterminate TB test result may be enrolled if the repeated TB test is negative prior to 
randomization. Patients with the repeated indeterminate or positive TB test result will be 
excluded from the trial prior to randomization. 
8.6 
Additional assessments 
No additional tests will be performed on subjects entered into this study.  
8.6.1 
Clinical Outcome Assessments (COAs) 
Patient reported outcomes (PRO) 
The impact of CSJ117 on various aspects of patient’s health status will be assessed by the 
following measures: 
• Asthma Control Questionnaire-5 (ACQ-5) to assess improvement in asthma symptom 
control; 
• Asthma Quality of Life Questionnaire+12 (AQLQ+12) to measure health-related quality 
of life (HRQOL); 
 
 
 
 
All patients will complete the PRO questions via a handheld electronic device or an electronic 
tablet as specified in the assessment schedule in clinic visits (Table 8-1). Available training 
materials related to the administrative procedures of the questionnaires will be provided to the 
sites. 
The subject should be given the PRO measure(s) to be completed at the scheduled visit 
before any clinical assessments are conducted. Subject’s refusal to complete all or any part 
of a PRO measure should be documented in the study data capture system and should not be 
captured as a protocol deviation.  
Subject questionnaires should be completed in the language most familiar to the subject. The 
subject should be given sufficient space and time to complete the PRO measure(s). The site 


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personnel or OHP should check PRO measure(s) for completeness and ask the subject to 
complete any missing responses. The responses stored electronically on the database will be 
considered the source file. 
Completed measure(s) and any unsolicited comments written by the subject should be reviewed 
and assessed by the investigator for responses which may indicate potential AEs or SAEs before 
any clinical study examinations. This assessment should be documented in study source records. 
If AEs or SAEs are confirmed, study investigators should not encourage the subject to change 
responses reported in the completed questionnaires. Study investigators must follow reporting 
instructions outlined in Section 10.1.1 of the study protocol. 
As per section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
COA data may be collected remotely depending on local regulations, technical capabilities, and 
following any applicable training in the required process.  
 
8.6.1.1 
Asthma Control Questionnaire-5 (ACQ-5) 
In this study, the ACQ-5 will be used to assess improvements in asthma symptom control. The 
ACQ-5 will be collected in an electronic format. 
The original ACQ consists of 7 items: 5 items on symptom assessment, 1 item on rescue 
bronchodilator use, and 1 item on airway caliber (% FEV1 predicted). The rescue 
bronchodilator use and % FEV1 predicted items are not included in the ACQ-5. The ACQ is 
validated in patients with asthma over 17 years (Juniper et al. 1999, Juniper et al. 2006), and is 
one of several asthma control measures recommended by the GINA Guidelines. The ACQ has 
been fully validated, including patients aged from 6 to 16 years (Juniper et al. 2010) and 
including a minimal important difference (MID) or smallest change that can be considered 
clinically important (0.5). 
The ACQ-5 (see Section 16.5) only takes a few minutes to complete. Patients will be asked to 
recall how their asthma has been during the previous week and to respond to the symptom 
questions on a 7-point scale (0=no impairment, 6=maximum impairment). The questions are 
equally weighted and the ACQ-5 score is the mean of the 5 questions: therefore, between 0 
(totally controlled) and 6 (severely uncontrolled) (Juniper et al. 1999; Juniper et al. 
2005; Juniper et al. 2006). 
The ACQ will be completed by patients at the visits specified in the table of assessments 
(See Table 8-1). The questionnaire should be completed before the AQLQ and before any other 
assessments (see Section 8) 
. The appropriate language version(s) of the 
questionnaire will be used in each participating country. The same language version of the 
questionnaire should be used by a particular patient throughout the study.  
The study coordinator or OHP should be familiar with the instrument and the associated user 
guides and training materials provided. Patients should complete the questionnaire in a quiet 
area and are allowed to ask questions; however the site staff/OHP should take care not to 
influence the patient’s response. In response to a question, patients should be instructed to 
provide the truest or best response for them. 


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Missing data should be avoided; therefore, the study coordinator/OHP will check the 
questionnaire for completeness before the patient's next assessment in the clinic, and if 
necessary, encourage the patient to complete any missing responses. At later visits patients are 
not allowed to review their previous responses. 
Completed questionnaires will be reviewed by the investigator for responses which may 
indicate potential AEs or SAEs. The investigator should review not only the responses to the 
questions in the questionnaire but also for any unsolicited comments written by the patient. If 
AEs or SAEs are confirmed then the physician must record the events as per instructions given 
in Section 10.1.1 and Section 10.1.2 of the protocol. Investigators should not encourage the 
patients to change the responses reported in the completed questionnaires. 
8.6.1.2 
Asthma Quality of Life Questionnaire (AQLQ) 
In this study, the disease-specific AQLQ+12 will be used to measure health-related quality of 
life in patients. The measure was originally validated for use in patients with asthma aged “12 
to 80 years" (Juniper, et al. 2005). The AQLQ+12 will be collected in an electronic format. 
The AQLQ+12 comprises a total of 32 individual questions that span a total of four domains: 
symptoms, activity limitation, emotional function, and environmental stimuli. Test-retest 
reliability, construct validity (cross-sectional and longitudinal), and responsiveness have been 
demonstrated (See Section 16.7). 
The AQLQ+12 takes about 4 to 5 minutes to complete. Patients are asked to recall their 
experiences during the previous 2 weeks and to score each item on a 7-point scale (7 = not at 
all impaired to 1 = severely impaired). The AQLQ+12 yields individual domain scores, which 
is the mean of all items in each domain, and an overall score, which is the mean of all 32 
individual responses. Higher scores indicate less impairment in Health Related Quality of Life 
(HRQOL). 
The questionnaire will be completed by patients at the visits specified in the table of assessments 
(See Table 8-1). 
The appropriate language version(s) of the questionnaire will be used in each participating 
country. The same language version of the questionnaire should be used by a particular patient 
throughout the study.  
The study coordinator/OHP should be familiar with the instrument and the associated user 
guides and training materials provided. The patient should complete the questionnaire in a quiet 
area and be allowed to ask questions; however site staff/OHP should not influence patient’s 
responses. The patient will be instructed to provide the truest and best response for them. 
Missing data should be avoided, therefore, the study coordinator/OHP will check the 
questionnaire for completeness before the patient's next in clinic assessment, and if necessary, 
encourage the patient to complete any missing responses. At later visits patients are not allowed 
to review their previous responses. 
Completed questionnaires will be reviewed by the investigator for responses which may 
indicate potential AEs or SAEs. The investigator should review not only the responses to the 
questions in the questionnaire but also for any unsolicited comments written by the patient. If 
AEs or SAEs are confirmed then the physician must record the events as per instructions given 


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in Section 10.1.1 and Section 10.1.2 of the protocol. Investigators should not encourage the 
patients to change the responses reported in the completed questionnaires. 
 
 
 
 
 
 
8.6.2 
Pharmacokinetics 
PK samples will be collected at the visits defined in the assessment schedule (Table 8-1). Follow 
instructions outlined in the laboratory manual regarding sample collection, numbering, 
processing, and shipment. 
 
 
The number of samples/blood draws collected will not exceed those stated in the protocol. 
Pharmacokinetic (PK) samples will be obtained but only evaluated in all subjects at all dose 
levels except the placebo group. 
Total CSJ117 will be determined by a validated immunoassay method; the anticipated Lower 
Limit of Quantification (LLOQ) is 3 ng/mL. 
 
 
Concentrations will be expressed in mass per volume units (ng/mL) 
Concentrations below the LLOQ will be reported as “zero” and missing data will be labeled as 
such in the Bioanalytical Data Report. 
The following pharmacokinetic parameters will be determined using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 6.4 or 
higher): Ctrough, Racc, and T1/2 from the serum concentration-time data. Additional 
pharmacokinetic parameters may be calculated as necessary. 
8.6.3 
Biomarkers 
  
 
 
 
 
 
 
 


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 Pharmacogenetics 
The study includes an optional genetic research component which requires a separate informed 
consent signature if the subject agrees to participate. As permitted by local governing 
regulations and by IRB/EC, it is required as part of this protocol that the Investigator presents 
these options to the subject. 
The purpose of genetic research may be to better understand the safety and efficacy of CSJ117, 
or to learn more about human diseases, or to help develop ways to detect, monitor and treat 
diseases. 
 
 
Laboratory manuals will be provided with detailed information on sample collection, handling, 
and shipment.  
 
 
 
 
 
 
 
 
 
 
 
8.6.4 
Asthma exacerbations 
The following definitions of exacerbations are used in this study. 
A moderate asthma exacerbation is defined as treatment with ‘rescue’ systemic 
corticosteroids for at least 3 days either as an outpatient or in emergency department visits 
(Emergency department visit less < 24 hours). 
A severe asthma exacerbation is defined as treatment with ‘rescue’ systemic 
corticosteroids for at least 3 days and hospitalization; or 
• treatment with ‘rescue’ systemic corticosteroids for at least 3 days and emergency 
department visit (> 24 hours*); or 
• death due to asthma.  
*An emergency room visit greater than 24 hours is considered to be a hospitalization 
A single depo-injectable dose of corticosteroid will be considered the equivalent to a 3-day 
course of systemic steroids (Reddel, et al 2009). 


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Scheduled spirometry should not be performed during an exacerbation until it has completely 
resolved.  
The first day of treatment with systemic corticosteroid will determine the onset date of the 
exacerbation while the last day of treatment will define the stop date. If the second exacerbation 
episode starts within the 7 days after the end of the first exacerbation episode, it should be 
counted as a single exacerbation. 
If a patient experiences an asthma exacerbation during the screening period, the patient may be 
re-screened 4 weeks after complete recovery from the exacerbation. If a patient experiences an 
asthma exacerbation during the run-in period, the run-in period must be extended to 8 weeks in 
order to allow for resolution of the asthma exacerbation before randomization. An additional 
run-in medication kit should be dispensed in this case. 
8.6.5 
Other Assessments 
8.6.5.1 
Immunogenicity 
Immunogenicity (IG) blood samples for ADA will be obtained and evaluated in all subjects at 
all dose levels, including the placebo group, at the timepoints defined in the Assessment 
schedule (Table 8-1). In case of positive immunogenicity, backup of previous pre-dose PK 
samples could be used to better characterize the onset of immunogenicity response. 
 
 
  
Immunogenicity analytical method(s) 
A validated bridging electrochemiluminescence immunoassay (ECLIA) will be used for the 
detection of potential anti-CSJ117 antibodies in serum, including 3 tiers of screening, 
confirmation and titration.
 
 
8.6.5.2 
Concept1 add on sensor (only in selected countries) 
The add on sensor detects and records the Concept1 inhaler use from randomization. Recorded 
use of the inhaler is transferred through Bluetooth wireless technology to a vendor provided 
tablet at the clinical site. Data is then uploaded to the propeller server.  
The sensor stores and transfers inhaler use data i.e. Date / Time and Sensor Technical events.  
The sensor does not interfere with the use or drug delivery of the inhaler and the patient is never 
prevented from taking a dose due to the add-on sensor. 
 
 
 


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8.6.5.5 
Peak Inspiratory Flow training 
At selected visits (see Table 8-1) patients will be trained on generating optimal inspiration flow 
for their inhalers i.e. Concept1 and Diskus®/Accuhaler® inhalers using In-Check device. This 
training should assure proper drug delivery into lungs during the trial. 
 
 
 
 
  
 
 
9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration and can be initiated by either the subject or the investigator. 
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being. 
Study treatment must be discontinued under the following circumstances: 
• Subject/guardian decision 
• Pregnancy 
• Permanent use of prohibited treatment as per recommendations in the prohibited treatment 
section 
• Any situation in which study participation might result in a safety risk to the subject 
• Female patients non-compliant with the chosen effective method of contraception during 
the study. The investigator must provide appropriate advice on the continued use of 


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effective contraception for at least 12 weeks (at least 5 half-lives of CSJ117) after study 
drug discontinuation and follow up with the subject as appropriate at least to the end of 
this period 
• Following emergency or accidental unblinding 
• Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the subject’s overall status, prevents the subject from continuing 
participation in the study 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information. 
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see 'Withdrawal of Informed Consent' section 9.1.2). Where possible, they 
should complete the assessments indicated in the Assessment Schedule. If they fail to return 
for these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should 
be made to contact the subject/pre-designated contact as specified in the lost to follow-up 
section. This contact should preferably be done according to the study visit schedule. 
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule. 
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment. 
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section (see Section 6.6.2). 
9.1.2 
Withdrawal of informed consent/Opposition to use data/biological 
samples 
Withdrawal of consent/opposition to use of data/ and/or biological samples occurs when a 
subject: 
• Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples) 
 and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts)  


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This request should be in writing (depending on local regulations (e.g. in writing) and recorded 
in the source documentation. 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw their consent/opposition 
to use data/biological samples and record this information. 
Where consent to the use of Personal and Coded Data is not required in a certain country's legal 
framework, the subject therefore cannot withdraw consent. However, they still retain the right 
to object to the further collection or use of their Personal Data. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
If the subject agrees, a final evaluation at the time of the subject’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
table (refer to Section 8). 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition. 
9.1.3 
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 must 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 considered as lost to follow-up until due 
diligence has been completed or until the end of the study. 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. Reasons for early 
termination: 
• Unexpected, significant, or unacceptable safety risk to subjects enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data  
• Discontinuation of study drug development 
In taking the decision to terminate, Novartis will always consider the subject welfare and safety. 
Should early termination be necessary, subjects must be seen as soon as possible and treated as 
a prematurely withdrawn subject. The investigator may be informed of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection of the 
subject’s interests. The investigator or sponsor depending on the local regulation will be 
responsible for informing IRBs/IECs of the early termination of the trial. 


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9.2 
Study completion and post-study treatment 
Study completion is defined as when the last subject finishes their Study Completion 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. For patients not entering a safety extension study after treatment period the 
Study Completion Visit is the last follow up visit i.e. Week 24 visit. For patients who enter the 
safety extension study after treatment period the Study Completion Visit is the Week 12 visit. 
Patients will be allowed to continue study participation if eligible, if they have already entered 
run-in period when enrolment target for a particular EOS stratum, or for the entire study, have 
been met. 
 At sites participating in the Safety Extension Study (CSJ117A12201E1), patients who 
successfully complete 12 weeks of treatment in this study (Study CCSJ117A12201C) may be 
offered participation in the Safety Extension Study; patient participation in the Safety Extension 
Study will be optional. Patients not entering the safety extension study directly after the 
treatment period will complete the 12 week follow-up period. Patients not entering the extension 
study will not be given further access to study drug because the risk/benefit ratio will not yet 
have been substantiated and there are already other marketed therapeutic alternatives available 
to treat these patients. At the time of study completion or early termination, all patients will be 
placed on the appropriate asthma treatment as prescribed by the investigator. 
The investigator must provide appropriate advice on the continued use of effective 
contraception for at least 12 weeks after the last study drug treatment and follow up with the 
subject as appropriate at least to the end of this period. 
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. 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 investigator has the responsibility for managing the safety of individual subjects and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must 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 


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the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments. 
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms, or 
diagnosis associated with them, accompanied by the following information (as far as possible) 
(if the event is serious refer to Section 10.1.2): 
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 and other investigational treatment (if any). If the 
event is due to lack of efficacy or progression of underlying illness (i.e. progression of the 
study indication) the assessment of causality will usually be ‘Not suspected.’ The rationale 
for this guidance is that the symptoms of a lack of efficacy or progression of underlying 
illness are not caused by the trial drug, they happen in spite of its administration and/or 
both lack of efficacy and progression of underlying disease can only be evaluated 
meaningfully by an analysis of cohorts, not on a single subject 
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported 
4. whether it constitutes a serious adverse event (SAE) (see Section 10.1.2 for definition of 
SAE) and which seriousness criteria have been met 
5. action taken regarding study treatment 
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving; 
recovered/resolved with sequelae; fatal; or unknown) 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:  
• Investigational treatment interrupted/withdrawn 
• Concomitant medication or non-drug therapy given 
• Patient hospitalized/hospitalization prolonged 
• No action taken (i.e. further observation only) 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
To ensure patient safety, every adverse event, occurring after the patient has provided informed 
consent and until end of the trial for each patient must be reported. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Information about adverse drug reactions that are already known for the investigational drug 
can be found in the Investigator's Brochure (IB). This information will be included in the patient 


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informed consent and should be discussed with the patient during the study as needed. Any new 
information regarding the safety profile of the investigational product that is identified between 
IB updates will be communicated as appropriate, for example, via an Investigator Notification 
or an Aggregate Safety Finding. New information might require an update to the informed 
consent and has then to be discussed with the patient. 
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 must 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 subjects with 
the underlying disease. Alert ranges for laboratory and other test abnormalities are included in 
Section 16.2. 
10.1.2 
Serious adverse events 
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. 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 it were more severe (please refer to 
the ICH-E2D Guidelines). 
• 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 (specify what this includes) 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• 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 
• is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
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 subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 


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considered as “medically significant”. 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 (please refer to the ICH-
E2D Guidelines). 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred (see Section 10.1.5). 
10.1.3 
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until end of the trial for each individual patient, must be reported 
to Novartis safety immediately, without undue delay, but under no circumstances later than 
within 24 hours of obtaining knowledge of the events (Note: If more stringent, local regulations 
regarding reporting timelines prevail). Detailed instructions regarding the submission process 
and requirements are to be found in the investigator folder provided to each site. 
For patients NOT participating in the separate CSJ117A12201E1 safety extension study: 
Any SAEs experienced after the 30 day period after end of the trial for each patient should only 
be reported to Novartis if the investigator suspects a causal relationship to study treatment. 
For patients participating in the separate CSJ117A12201E1 safety extension study: 
Any SAEs experienced after the patient’s last visit in the CSJ117A12201C study should ONLY 
be assigned to safety extension study and be reported to Novartis regardless of suspected causal 
relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information. (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 
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 study treatment, a Novartis Chief Medical Office 
and Patient Safety (CMO & PS) 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 study 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. 


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10.1.4 
Pregnancy reporting 
To ensure subject safety, each pregnancy occurring after signing the informed consent 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. 
Pregnancy should be recorded on a Pharmacovigilance Pregnancy Form, and reported by the 
investigator to CMO&PS. Pregnancy follow-up should be recorded on the same form and 
should include an assessment of the possible relationship to the study treatment. Any SAE 
experienced during pregnancy must be reported. 
Tracking of pregnancy cases occurs until after Expected Delivery Date (EDD) for all 
prospective pregnancy cases received from clinical studies 
• EDD +1 month (mandatory for all cases). Requesting the pregnancy outcome and other 
clinically relevant pregnancy data or changes in data 
• EDD+2 month (mandatory if no answer is obtained after request at EDD+1 month). A 
reminder letter for the outcome 
• The follow up at EDD+3 and EDD+12 months is mandatory for all cases of live birth and 
unknown outcome. Information on the status of the baby 3 months after delivery and 
information on any development issue or abnormality that would not be seen at birth must 
be collected. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 


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For more information on AE and SAE definition and reporting requirements, please see the 
respective Section 10. 
10.1.6 
Concept1 related adverse events reporting 
Any Concept1 device related adverse events must be reported to Novartis within 24 hours of 
learning of its occurrence. Concept1 device related adverse events must be recorded on the 
relevant device-related pages of the CRF. Country regulations have to be followed for the 
Concept1 device related adverse events reporting to Health Authorities and/or Ethics 
Committees. 
The investigator has the responsibility for managing the safety of individual subjects. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE): 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring and contributing 
factors are recorded on the appropriate CRFs 
Please refer to Section 16.2 for complete definitions of liver laboratory triggers and liver events. 
Every liver event defined in Table 16-1 should be followed up by the investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case 
of liver events are outlined in Table 16-2. Repeat liver chemistry tests (i.e. ALT, AST, TBL, 
PT/INR, ALP and GGT) to confirm elevation. 
• These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the subject. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results recorded on the appropriate CRF. 
• If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
Section 9.1.1), if appropriate 
• Hospitalization of the subject if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include investigations (can include based on 
investigator’s discretion): serology tests, imaging and pathology assessments, 


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hepatologist’s consultancy; obtaining more detailed history of symptoms and prior or 
concurrent diseases, history of concomitant drug use, exclusion of underlying liver disease 
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF. 
10.2.2 
Data Monitoring Committee 
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess at defined intervals the progress 
of the clinical trial, safety data and recommend to the sponsor whether to continue, modify, or 
terminate a trial. 
Specific details regarding composition, responsibilities, data monitoring, meeting frequency, 
and documentation of DMC reports, minutes, and recommendations will be described in a 
separate charter that is established between the sponsor and the DMC. 
11 
Data Collection and Database management 
11.1 
Data collection 
Data not requiring a separate written record will be defined in the protocol and the Assessment 
Schedule (Table 8-1) and can be recorded directly on the CRFs. All other data captured for this 
study will have an external originating source (either written or electronic) with the CRF not 
being considered as source. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate 
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site. 
Automatic validation programs check for data discrepancies and, by generating appropriate 
error messages, allow the data to be confirmed or corrected before transfer of the data to the 
vendor working on behalf of Novartis. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 


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11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis. 
ECG, spirometry and Concept1 add on sensor readings will be processed centrally and the 
results will be sent electronically to Novartis. 
Diary data will be entered into an electronic diary by the patient. The system will be supplied 
by a vendor(s), who will also manage the database. The database will be sent electronically to 
Novartis. 
Randomization codes and data about all study treatment (s) dispensed to the subject and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
eCRFs) 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 field monitor will visit the site to check the completeness of subject records, the accuracy 
of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis/CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight. 


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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 data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary 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. 
12 
Data analysis and statistical methods 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
The Randomized Analysis Set (RAS) consists of all randomized subjects. Subjects will be 
analyzed according to the treatment they were assigned to at randomization. Demographics and 
baseline characteristics will be summarized using the RAS. 
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned 
and who received at least one dose of study treatment. Subjects will be analyzed according to 
the treatment they have been assigned to during the randomization procedure. The FAS will be 
used for the analysis of all efficacy variables. 
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment received. The Safety Set will be used for the 
analysis of all safety variables. 
12.2 
Subject demographics and other baseline characteristics 
Demographic and other baseline data, including disease characteristics will be summarized 
descriptively by treatment group for the RAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term by treatment group. 
12.3 
Treatments 
The duration of exposure in days to each treatment group (CSJ117 dose or placebo) will be 
summarized by means of descriptive statistics. 


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Asthma-related medications will be summarized separately for medications prior to the start of 
randomized treatment and for concomitant medications (medications which were taken anytime 
between the first dose and last dose of randomized treatment, inclusive) by pre-defined 
categories, route of administration, preferred term, and treatment group. Non-asthma related 
medication prior to and after the start of randomized treatment will also be summarized by ATC 
classification system, preferred term, and treatment group. More than one ATC class per 
medication is possible and the medication will be reported under all applicable classes. 
The number of patients who permanently discontinued from double blind treatment and the 
reasons will be summarized by treatment group. 
Treatment compliance with study medication over the entire study will be summarized by 
treatment group. 
12.4 
Analysis of the primary endpoint(s) 
The primary objective of this study is to characterize the DR (dose response) efficacy 
relationship among CSJ117 doses (0.5, 1, 2, 4, and 8 mg daily) and placebo with regards to the 
average change from baseline in pre-dose FEV1 (L) at Week 8 and Week 12. The goals 
associated with this objective are below. 
• To confirm an overall drug response signal 
• To estimate the dose(s) that corresponds to the target effect (e.g., 120 mL) over placebo 
based on the estimated DR curve 
12.4.1 
Definition of primary endpoint(s) 
The primary endpoint for this study is the average change from baseline in pre-dose FEV1 (L) 
at Week 8 and Week 12. 
The baseline value is defined as the average of the values taken approximately 2 hours 45 
minutes and 2 hours 15 minutes prior to first dose of randomized drug at Day 1. If one of the 
two values is missing or unacceptable per the central spirometry overreader (or is not confirmed 
to be pre-dose) then the remaining non-missing value will be taken as the baseline. If both 
values are missing (or are not confirmed to be pre-dose), then the measurements taken at the 
run-in visit will be used as the baseline. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The Multiple Comparison Procedure – Modelling (MCP-Mod) methodology (see 
Bretz et al 2005 and Pinheiro et al 2014) will be employed to assess the primary objective. An 
overview of the steps for the MCP-Mod methodology is given below. Further details will be 
provided in the Statistical Analysis Plan (SAP). 
Step 1 (Testing an overall dose-response signal - MCP part): 
The covariate adjusted least-squares means averaged across Week 8 and Week 12 visits for 
each individual dose group and the corresponding variance-covariance matrix will be obtained 
from a linear mixed effects model for repeated measures (MMRM) with terms for baseline 
FEV1, visit, treatment, randomization strata – eosinophil count (EOS) (≥ 300 or < 300 cells/µl) 
and region, treatment-by-visit interaction, and baseline FEV1-by-visit interaction, FEV1 prior 


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to inhalation, and FEV1 within 30 min post inhalation of salbutamol/albuterol (components of 
SABA reversibility) as fixed effects. To allow adjustment for correlations between time points 
within patients, an unstructured variance-covariance structure will be used. 
The adjusted treatment means from the MMRM will be used to test the null hypothesis of a flat 
DR relationship for the primary efficacy endpoint at a two-sided significance level of 5% 
against the alternative hypothesis of a non-constant DR curve. Two one-sided tests will be 
performed to obtain the two-sided test. The testing will be performed with a multiple contrast 
test described in the MCP-Mod methodology. 
A wide range of possible dose response relationship will be considered to take model 
uncertainty into account (Figure 12-1). Based on inputs from Drug Metabolism & 
PharmacoKinetics (DMPK) and Clinical, nine candidate DR curves (4 Emax, 4 Sigmoid Emax, 
and 1 Quadratic) will be used to derive the optimal model contrasts for the multiple contrast 
tests. The ED50 (the dose at which half of the maximum effect is reached) values for the Emax 
models will be 0.5, 1, 2 and 4. The parameters of the sigmoidal Emax models (ED50, h) will be 
(0.5, 3), (1, 3), (2, 3) and (4, 3) where h is the Hill parameter that determines the steepness of 
the dose-response shape. A quadratic model is considered to capture a possible non-monotonic 
DR curve. The discriminant parameter of the Quadratic model will be -0.1. 
For each of the 9 candidate DR curves, a contrast test statistic will be derived that maximizes 
the power assuming the true mean response is the one assumed by the candidate DR curve. The 
detection of a significant DR signal is based on the maximum of the 9 contrast test statistics. 
The overall null hypothesis of no DR relationship is rejected if the multiplicity adjusted p-value 
for at least one contrast test is less than 0.05 (two sided). 
Figure 12-1 
Candidate Dose Response Curves 
  
Step 2 (Estimation of the dose-response curve and target dose – Mod part): 
Once the DR signal is tested, the DR curve and the target dose(s) of interest will be estimated. 


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A large number of bootstrap samples from the multivariate normal distribution will be drawn 
with adjusted means from the MMRM and corresponding covariance matrix. For each sample: 
• DR models from the candidate families (Emax, Sigmoid Emax, Quadratic) will be fitted to 
the data and the best model according to the generalized Akaike information criterion will 
be chosen. 
• The predictions for dose response will be obtained from the best model. 
The median of the predicted differences to placebo for each dose based on the selected model 
for each sample will be used as the estimated dose response curve. Bootstrap pointwise 95% 
confidence intervals will also be provided. This bootstrap model averaging approach reflects 
model uncertainty in the inference and typically leads to more reliable confidence intervals as 
well as more precise estimates of the dose-response curve compared to selection of a single 
model (Bornkamp 2015; Schorning et al 2016). 
The target dose(s) that corresponds to a clinically relevant effect over placebo can be estimated 
using inverse regression techniques (Bretz et al 2005). 
12.4.3 
Handling of missing values/censoring/discontinuations 
Despite all attempts to ensure complete follow-up for all patients, some patients may not be 
followed for pre-dose FEV1 for the whole planned study duration. 
The FEV1 value analyzed at each post-baseline visit is based on the average of the two FEV1 
assessments taken at approximately 45 minutes and approximately 15 minutes prior to the 
dosing of study drug at clinic visits. Since the estimand is related to an effect outside of rescue 
med intake, spirometry measurements within 6 hours of rescue medication, within 7 days of 
intake of systemic corticosteroid use, or within 3 months of a single depot corticosteroid 
injection, or within 24 hours of background medication use, or within 48 hours of LAMA use 
will be set to missing. In cases where one of the two values is missing, the remaining non-
missing value will be taken as pre-dose FEV1. If both values are missing, then their pre-dose 
FEV1 will be regarded as missing at that visit. 
For the primary analysis, only on-treatment data (from date of first randomized dose up to 1 
day after date of last randomized dose) will be used as the estimand specifies a hypothetical on-
treatment effect. Missing on-treatment data will not be explicitly imputed as the MMRM 
implicitly imputes missing data assuming the missing at random (MAR) mechanism. 
The imputation procedures related to the pre-dose FEV1 supportive analyses (Section 12.4.4) 
are "jump-to-reference" (J2R) and MAR (Carpenter et al 2013). The imputations will be based 
on all available data (i.e. from all scheduled timepoints) using all covariates as specified in the 
MMRM. For J2R, only placebo (reference) data will be used. For MAR, data from the same 
treatment arm will be used for building the imputation model. Imputation of intermittent 
missing observations before treatment discontinuation will be carried out following a MAR 
mechanism for all treatment arms. Additional details will be available in the SAP. 
12.4.4 
Sensitivity and Supportive analyses 
Sensitivity analyses 
Sensitivity analysis will be outlined in the SAP as appropriate.  


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Supportive analyses 
A single supplementary analysis will be performed that quantifies the treatment effect in all 
randomized patients during stable periods (i.e. outside episodes of asthma worsening that 
require rescue medication) with an adherence to treatment like we would see in clinical practice 
in a world without COVID-19, with the following post-randomization events accounted for by 
assessing: 
a. Intake of non-study drug with effect on FEV1: the effect outside of periods of worsening 
disease that necessitate rescue medication. 
b. Discontinuation of study treatment due to any non-COVID-19 related reason: actual off-
treatment value. If no data was retrieved after study treatment discontinuation, missing data will 
be multiply imputed based on placebo arm data: J2R assumption for the CSJ117 arms and MAR 
assumption for placebo arm. 
c. Discontinuation of study treatment due to any COVID-19 related reason: hypothetical value 
of the average between Week 8 and Week 12 pre-dose FEV1 had the patients not stopped the 
study treatment 
  
Any additional supportive analysis will be outlined in the SAP. 
12.5 
Analysis of secondary endpoints 
No multiplicity adjustment will be carried out for secondary analyses described below. In 
addition, the treatment effect of CSJ117 compared to placebo that would have been observed 
had all patients remained on their assigned treatment will be estimated. Only data obtained 
while patient is on-treatment (from date of first randomized dose up to 1 day after date of last 
randomized dose) will be used. Missing data for any reason will not be explicitly imputed and 
will be handled by the respective mixed effects model which implicitly imputes missing data 
assuming MAR. 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
12.5.1.1 FeNO 
Fractional exhaled Nitric Oxide (FeNO) is a non-invasive marker for airway inflammation and 
is used to monitor the response to anti-inflammatory medications. Several publications reported 
high fractional concentrations of orally exhaled NO (FeNO) in subjects with asthma as 
compared with unaffected subjects, and a fall after treatment. It will be measured following the 
recently published guidelines (ATS/ERS) on standardized techniques. 
Repeated, reproducible exhalations should be performed to obtain two FeNO measurements 
within 10% of each other. Exhaled NO is the mean of these two values. 
The average change from baseline in FeNO at Week 8 and Week 12 will be analyzed using the 
same MCP-Mod approach described for the primary analysis of the primary variable. The 
change from baseline in FeNO will be analyzed using a similar MMRM (including all scheduled 
post-baseline visits with FeNO data) on the FAS as used for the primary analysis but will 
include baseline FeNO instead of baseline FEV1. The estimated treatment difference (CSJ117 


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– placebo) at each visit will be reported as well as the average between Week 8 and Week 12 
along with the associated 95% confidence interval. 
12.5.1.2 ACQ-5 
The ACQ-5 measures asthma symptom control and consists of 5 items (questions) on symptom 
assessment. Patient recall is one week. 
All 5 questions of the ACQ-5 are equally weighted. Items are scored along a 7-point response 
scale, where 0 = totally controlled and 6 = severely uncontrolled. 
The total score is calculated as the mean of all five questions. 
The average change from baseline in ACQ-5 at Week 8 and Week 12 will be analyzed using 
the same MMRM (including all scheduled visits with ACQ data) on the FAS as used for the 
primary analysis but will include baseline ACQ-5 instead of baseline FEV1. The estimated 
treatment difference (CSJ117 – placebo) at each visit as well as the average between Week 8 
and Week 12 will be reported along with the associated 95% confidence interval. 
The proportion of patients who achieve an improvement of at least 0.5 in ACQ-5 (i.e. decrease 
of ACQ-5 score of at least 0.5 from baseline) at post-baseline visits will be analyzed using a 
repeated measurements logistic regression. The model will include the same terms as for the 
MMRM analysis of the primary variable with baseline ACQ-5 instead of baseline FEV1. The 
estimated adjusted odds ratios will be displayed along with the associated 95% (two-sided) 
confidence intervals. 
12.5.1.3 Daytime and nighttime asthma symptoms 
The baseline of ADSD and ANSD will be defined as the average of the respective scores during 
the run-in period. 
The mean daily scores of ADSD and ANSD will be summarized by weekly intervals and 
analyzed using a similar MMRM as specified for the primary analysis but including the 
appropriate weeks and baseline as a covariate. The estimated treatment difference (CSJ117 – 
placebo) at each week as well as the average between Week 8 and Week 12 will be reported 
along with the associated 95% confidence interval. 
12.5.1.4 AQLQ+12 
AQLQ (Asthma Quality of Life Questionnaire) is a 32-item disease specific questionnaire 
designed to measure functional impairments that are most important to patients with asthma, 
with 7-point scale (1-totally limited/problems all the time, 7-not at all limited/no problems). It 
consists of 4 domains: symptoms, emotions, exposure to environmental stimuli and activity 
limitation. Mean score will be calculated for the four domains, as well as the overall quality-of-
life score defined as the mean score of all 32 items. 
The average change from baseline in AQLQ+12 (overall and by domain) at Week 8 and Week 
12 will be analyzed using the same MMRM model as specified for the primary efficacy variable 
with baseline AQLQ as covariate. The estimated adjusted treatment difference at each visit as 
well as the average between Week 8 and Week 12 will be reported along with the associated 
95% confidence interval. 


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The proportion of patients who achieve an improvement of at least 0.5 in the change from 
baseline in AQLQ (i.e. increase of AQLQ score of at least 0.5 from baseline) at post-baseline 
visits will be analyzed using the same repeated measurements logistic regression model for the 
ACQ-5 analysis except that baseline AQLQ will be used instead of the baseline ACQ-5. The 
estimated adjusted odds ratios will be displayed along with the associated 95% (two-sided) 
confidence intervals. 
12.5.1.5 Total daily use of SABA 
Total daily use of SABA (the number of puffs taken in the previous 24 hours) by the patient 
will be analyzed using ePEF/ eDiary data. The baseline of SABA use will be defined as the 
average of total daily SABA use during the run-in period. 
The mean of change from baseline in the total daily use of SABA over the 12 weeks of treatment 
will be analyzed using an ANCOVA model with factors for treatment group, randomization 
strata (eosinophil count ≥ 300 or < 300 cells/µl, region), as well as baseline total daily SABA 
use, and baseline pre-dose FEV1 as continuous linear covariates. The estimated treatment 
difference (CSJ117 – placebo) will be reported along with the associated 95% confidence 
interval. 
In addition, the mean daily use of SABA will be summarized by weekly intervals and analyzed 
using a similar MMRM as specified for the primary analysis but including the appropriate visits 
and baseline as a covariate. The estimated treatment difference (CSJ117 – placebo) at each 
week will be reported along with the associated 95% confidence interval. 
12.5.1.6 Peak Expiratory Flow Rate (PEF) 
All the patients are instructed to record PEF twice daily using a mini Peak Flow Meter device, 
once in the morning (before taking the morning dose of asthma medications) and once 
approximately 12 hr later in the evening (before taking the evening dose of asthma medications), 
from the beginning of screening period to study completion. 
The morning/evening PEF (liters/min) will be averaged over the whole 12 weeks. E-diary data 
recorded during the run-in period will be used to calculate the baseline value. 
Mean morning/evening PEF will be summarized by treatment. Between-treatment differences 
of the change from baseline in mean morning/evening PEF will be performed using the same 
ANCOVA models as specified for rescue medication data except that baseline rescue 
medication use will be replaced with baseline morning/evening PEF as the covariate. LS mean 
and associated 95% confidence intervals will be presented for treatments and treatment 
differences. 
In addition, the mean morning/evening PEF will be summarized by weekly intervals and 
analyzed using a similar MMRM model as specified for the primary analysis with baseline 
FEV1 value replaced with the appropriate baseline PEF. The estimated treatment difference 
(CSJ117 – placebo) at each week will be reported along with the associated 95% confidence 
interval. 


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12.5.2 
Safety endpoints 
Safety summaries include only data from the on-treatment period with the exception of baseline 
data which will also be summarized where appropriate (e.g. change from baseline summaries). 
In addition, a separate summary for death including on treatment and post treatment deaths will 
be provided. 
Adverse events  
For patients not entering the safety extension study directly after the treatment period or not 
participating in the safety extension study, the on-treatment period for adverse events (AEs) 
lasts from the time of first administration of double-blind study treatment to 30 days after the 
time of the last administration of randomized study treatment. For patients entering the safety 
extension study directly after the treatment period, the on-treatment period lasts from the time 
of first administration of double-blind study treatment to the time of the last actual 
administration of randomized study treatment. Summary tables for AEs will summarize only 
on-treatment events (also known as treatment-emergent AEs). 
All information obtained on adverse events will be summarized by treatment group. 
The number (and percentage) of subjects with treatment emergent adverse events will be 
summarized separately for the treatment period and the follow-up period (30 days after the last 
time of the last administration of randomized study treatment) in the following ways:  
• by treatment, primary system organ class and preferred term. 
• by treatment, primary system organ class, preferred term and maximum severity. 
• by treatment, Standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation separately for the 
treatment period and the follow-up period (30 days after the last time of the last actual 
administration of randomized study treatment). 
A subject with multiple adverse events within a primary system organ class or preferred term 
is only counted once towards the total of the primary system organ class or preferred term. 
Vital signs 
Summary statistics will be provided by treatment and visit/time for each vital signs variable. 
Notable values (to be defined in the SAP) and change from baseline will also be summarized. 
The baseline value is the last value prior to first dose of double-blind treatment. 
12-lead ECG 
Summary statistics will be provided by treatment and visit/time for each ECG variable. 
Categorical analysis of QTc interval data based on the number of subjects meeting or exceeding 
predefined limits (to be defined in the SAP) in terms of absolute QTc intervals or changes from 
baseline will be presented. The baseline value is the last value prior to first dose of double-blind 
treatment. 


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Clinical laboratory evaluations 
Summary statistics will be provided by treatment and visit/time by each lab variable.  
For selected laboratory tests, the number and percentage of patients with newly occurring or 
worsening laboratory abnormalities meeting the clinically notable criteria (to be defined in the 
SAP) will be summarized by laboratory parameter. Change from baseline will also be 
summarized. The baseline value is the last value prior to first dose of double-blind treatment. 
Immunogenicity  
Results of the anti-CSJ117 antibodies (anti-drug antibodies, ADA) will be listed by treatment 
group, subject and visit/time. 
12.5.3 
Pharmacokinetics 
CSJ117 plasma concentration data will be listed by treatment, subject, and visit/sampling time 
point. Descriptive summary statistics will be provided by treatment and visit/sampling time 
point, including the frequency (n%) of concentrations below the LLOQ and reported as zero. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum, and maximum. Concentrations below LLOQ will be treated as 
zero in summary statistics and for PK parameter calculations. If at a single time point a 
substantial number of concentrations are below LLOQ, they may be substituted with a pre-
defined value, such as ½ LLOQ for calculation of PK parameters. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12.7 
Interim analyses 
DMC analyses are planned for the monitoring of safety data, and details will be provided in the 
DMC charter. Such safety analyses do not inflate the type I error for the primary efficacy 
hypothesis testing and thus no adjustment for multiplicity is required. 
A blinded sample size re-estimation might be performed when approximately 150 high 
eosinophil subjects completed week 8 visit (see Section 12.8.2). 
One or more interim analyses may be conducted to support decision-making in relation to the 
current clinical study, or the future of the sponsor’s clinical development plan or in case of any 
safety concerns from this study or ongoing clinical studies. 
12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
For the primary endpoint pre-dose FEV1, we assume a variance of 0.1461 L at week 8, 0.1456 
L at week 12, and a covariance of 0.1163 between the week 8 and 12 assessments (based on a 
recent asthma dose ranging study (Bateman et al 2017) and literature data (Corren et al 2017). 
On this basis, the average of the week 8 and 12 assessments has a standard deviation of 0.3622 
L. 
We assume 2:1:1:1:2:2 randomization to placebo, CSJ117 0.5 mg o.d., CSJ117 1 mg o.d., 
CSJ117 2 mg o.d., CSJ117 4 mg o.d. and CSJ117 8 mg o.d.. 
With these assumptions 531 patients result in above 80% power (on average across dose 
response shapes) to have a significant contrast test at the one-sided 2.5% significance level for 
a maximum treatment effect over placebo of 0.120 L in the absence of missing data. If we 
assume that 15% of patients will have missing data and if we conservatively assume that these 
patients will not contribute any information to the primary analysis, 625 patients are needed for 
the dose response part of the trial. These calculations were performed using ADDPLAN DF 
4.0.9. 
The precision of the DR curve estimation were obtained from simulations. Specifically, the 
average half-length of 95% confidence interval of the estimated DR curve is 57.61 mL, and that 
of the estimated placebo-adjusted DR curve is 76.93 mL. 
12.8.2 
Sample size re-estimation 
A sample size re-estimation might be performed strictly using the blinded data when 
approximately 150 high eosinophil subjects completed week 8 visit. No treatment information 
would be used for sample size re-estimation, thus there would be no inflation of type I error 
rate. 
  
Let Spool be the pooled standard deviation of the primary endpoint. The decision on the final 
sample size will be based on the decision guidance specified in the following Table 12-1.  
 


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Table 12-1 
Decision guidance on approximate sample size to ensure at least 80% power to 
detect a dose-response signal
Estimated Spool 
Approximate final sample size 
Spool ≤ 315 ml 
466 
315 ml < Spool ≤ 320 ml 
480 
320 ml < Spool ≤ 325 ml 
495 
325 ml < Spool ≤ 330 ml 
509 
330 ml < Spool ≤ 335 ml 
523 
335 ml < Spool ≤ 340 ml 
540 
340 ml < Spool ≤ 345 ml 
555 
Spool > 345 ml 
Keep original sample size 
When 315 ml < Spool ≤ 345 ml, the proposed total sample size will assure at least 80% power 
(on average across dose response shapes) to have a significant contrast test at the one-sided 
2.5% significance level for a maximum treatment effect over placebo of 0.120 L assuming 15% 
drop-out rate. 
 
Based on findings from sample size re-estimation, the overall sample size for the study may be 
reduced accordingly. 
 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines 
for Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC, US CFR 21), and with the ethical principles laid down in the Declaration of 
Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g. 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and 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. 


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13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.) . 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal Standard Operating Procedures (SOPs), and are performed according to 
written Novartis processes. 
14 
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 including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be implemented. 
14.1 
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. 


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Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
References are available upon request 
ATS/ERS (2005) Recommendations for standardized procedures for the online and offline 
measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am. J. 
Respir. Crit. Care Med; p. 912-30. 
Bateman ED, Guerreros AG, Brockhaus F, et al (2017) Fevipiprant, an oral prostaglandin 
DP2 receptor (CRTh2) antagonist, in allergic asthma uncontrolled on low-dose inhaled 
corticosteroids. Eur. Respir. J.;50(2). 
Biagini Myers JM, Martin LJ, Kovacic MB, et al (2014) Epistasis between serine protease 
inhibitor Kazal-type 5 (SPINK5) and thymic stromal lymphopoietin (TSLP) genes contributes 
to childhood asthma. J. Allergy Clin. Immunol; 134(4):891-9. 
Bornkamp B (2015) Viewpoint: model selection uncertainty, pre-specification, and model 
averaging. Pharm Stat; 14(2):79-81. 
Bretz F, Pinheiro JC, Branson M (2005) Combining multiple comparisons and modeling 
techniques in dose-response studies. Biometrics; 61:738-48. 
Carpenter JR, Roger JH, Kenward MG (2013) Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible assumptions, and inference via multiple 
imputation. J Biopharm Stat; 23(6):1352-71. 
Corren J, Lemanske R, Hanania N, et al (2011) Lebrikizumab Treatment in adults with 
Asthma. N. Engl. J. Med; 365 (12):1088-98. 
Corren J, Parnes JR, Wang L, et al (2017) Tezepelumab in Adults with Uncontrolled Asthma. 
N. Engl. J. Med; 377:936-46. 
Czock D, Keller F, Seidling HM (2012) Pharmacokinetic predictions for patients with renal 
impairment: focus on peptides and protein drugs. Br J Clin Pharmacol; 74(1):66-74. 
Gauvreau GM, O'Byrne PM, Boulet LP, et al (2014) Effects of an anti-TSLP antibody on 
allergen-induced asthmatic responses. N. Engl. J. Med;370(22):2102-10. 
Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma 
(GINA) 2019. Available from http://www.ginasthma.org/ 
Graham BL, Steenbruggen I, Miller MR, et al (2019) Standardization of Spirometry 2019 
Update. An Official American Thoracic Society and European Respiratory Society Technical 
Statement. Am. J. Respir. Crit. Care Med;200(8):e70-e88. 
He R, Geha RS (2010) Thymic stromal lymphopoietin. Ann. N. Y. Acad. Sci; 1183:13-24. 
Hurst H, Bolton J (2004) Assessing the clinical significance of change scores recorded on 
subjective outcome measures. J Manipulative Physiol Ther; 27(1):26-35. 
Juniper EF, Bousquet J, Abetz L, et al. (2006) Identifying 'well-controlled' and 'not well-
controlled' asthma using the Asthma Control Questionnaire. Respir Med; 100(4):616-21. 


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Juniper EF, Gruffydd-Jones K, Ward S, et al (2010) Asthma Control Questionnaire in 
children: validation, measurement properties, interpretation. Eur. Respir. J; 36:1410-6.  
Juniper EF, O'Byrne PM, Guyatt GH et al. (1999) Development and validation of a 
questionnaire to measure asthma control. Eur. Respir. J; 14(4):902-7. 
Juniper EF, Svensson K, Mörk AC, et al (2005) Modification of the asthma quality of life 
questionnaire (standardised) for patients 12 years and older. Health Qual Life Outcomes; 3:58. 
Kubota M, Kobayashi H, Quanjer PH, et al (2014) Reference values for spirometry, including 
vital capacity, in Japanese adults calculated with the LMS method and compared with 
previous values. Respir Investig p. 242-50. 
Lobo ED, Hansen RJ, Balthasar JP (2004) Antibody pharmacokinetics and 
pharmacodynamics. J Pharm Sci; 93(11):2645-68. 
Masoli M, Fabian D, Holt S, et al (2004) The global burden of asthma: executive summary of 
the GINA Dissemination Committee report. Allergy; 59(5):469-78.  
Morris PE, Zeno B, Bernard AC, et al (2012) A placebo-controlled, double-blind, dose-
escalation study to assess the safety, tolerability and pharmacokinetics/pharmacodynamics of 
single and multiple intravenous infusions of AZD9773 in patients with severe sepsis and 
septic shock. Crit Care; 16(1):R31. 
Pinheiro J, Bornkamp B, Glimm E, et al (2014) Model-based dose finding under model 
uncertainty using general parametric models. Stat Med; 33(10):1646-61. 
Reddel HK, Taylor DR, Bateman ED et al. (2009) An official American Thoracic 
Society/European Respiratory Society statement: asthma control and exacerbations: 
standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care 
Med; 180: 59-99. 
Quanjer PH, Stanojevic S, Cole TJ, et al (2012) Multi-ethnic reference values for spirometry 
for the 3-95-yr age range: the global lung function 2012 equations. Eur. Respir J;40(6):1324-
43. 
Schaumann W, Kaufmann B, Neubert P, et al (1986) Kinetics of the Fab fragments of digoxin 
antibodies and of bound digoxin in patients with severe digoxin intoxication. Eur. J. Clin. 
Pharmacol; 30(5):527-33. 
Schorning K, Bornkamp B, Bretz F, et al (2016) Model selection versus model averaging in 
dose finding studies. Stat Med; 35(22):4021-40. 
Ying S, O'Connor B, Ratoff J, et al (2005) Thymic stromal lymphopoietin expression is 
increased in asthmatic airways and correlates with expression of Th2-attracting chemokines 
and disease severity. J. Immunol; 174(12):8183-90. 
Ying S, O'Connor B, Ratoff J, et al (2008) Expression and cellular provenance of thymic 
stromal lymphopoietin and chemokines in patients with severe asthma and chronic obstructive 
pulmonary disease. J. Immunol; 181(4):2790-8. 


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16 
Appendices 
16.1 
Clinically notable laboratory values and vital signs 
The central laboratory will flag laboratory values falling outside of the normal ranges on the 
central laboratory reports. Investigators are responsible for reviewing these abnormal values for 
clinical significance, signing the laboratory reports to indicate their review, and reporting values 
considered clinically significant in the appropriate electronic case report form (eCRF).  
Any clinically significant abnormal laboratory value should be evaluated and followed-up by 
the investigator until normal or a cause for the abnormality is determined. 
See Section 16.2 for specific liver event and laboratory test trigger definitions and follow-
up requirements. 


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16.2 
Liver event and Laboratory trigger Definitions and Follow-up 
Requirements 
Table 16-1 
Liver event and laboratory trigger definitions 
  
Definition/ threshold 
LIVER LABORATORY TRIGGERS 
• 
3 x ULN < ALT / AST ≤ 5 x ULN 
• 
1.5 x ULN < TBL ≤ 2 x ULN 
LIVER EVENTS 
• 
ALT or AST > 5 × ULN 
  
• 
ALP > 2 × ULN (in the absence of known 
bone pathology) 
  
• 
TBL > 2 × ULN (in the absence of known 
Gilbert syndrome) 
  
• 
ALT or AST > 3 × ULN and INR > 1.5 
  
• 
Potential Hy’s Law cases (defined as ALT or 
AST > 3 × ULN and TBL > 2 × ULN [mainly 
conjugated fraction] without notable increase 
in ALP to > 2 × ULN) 
  
• 
Any clinical event of jaundice (or equivalent 
term) 
  
• 
ALT or AST > 3 × ULN accompanied by 
(general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with 
eosinophilia 
  
• 
Any adverse event potentially indicative of a 
liver toxicity* 
*These events cover the following: Hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms TBL: total bilirubin; ULN: upper limit of normal 
Table 16-2 
Follow up requirements for liver events and laboratory triggers 
Criteria 
Actions required 
Follow-up monitoring 
Potential Hy’s Law casea 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize, if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
ALT or AST 
> 8 × ULN 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 


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Criteria 
Actions required 
Follow-up monitoring 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
> 3 × ULN and INR > 1.5 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize, if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
> 5 to ≤ 8 × ULN 
• 
Repeat LFT within 48 
hours 
• 
If elevation persists, 
continue follow-up 
monitoring 
• 
If elevation persists for 
more than 2 weeks, 
discontinue the study drug 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 × ULN accompanied by 
symptomsb 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 to ≤ 5 × ULN (patient is 
asymptomatic) 
• 
Repeat LFT within the next 
week 
• 
If elevation is confirmed, 
initiate close observation of 
the patient 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks 
ALP (isolated) 
  
  
> 2 × ULN (in the absence of 
known bone pathology) 
• 
Repeat LFT within 48 
hours 
• 
If elevation persists, 
establish causality 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 


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Criteria 
Actions required 
Follow-up monitoring 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
TBL (isolated) 
  
  
> 2 × ULN (in the absence of 
known Gilbert syndrome) 
• 
Repeat LFT within 48 
hours 
• 
If elevation persists, 
discontinue the study drug 
immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 1.5 to ≤ 2 × ULN (patient is 
asymptomatic) 
• 
Repeat LFT within the next 
week 
• 
If elevation is confirmed, 
initiate close observation of 
the patient 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
Jaundice 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize the patient 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
Any AE potentially indicative of 
a liver toxicity* 
• 
Consider study treatment 
interruption or 
discontinuation 
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
Investigator discretion 
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death. 


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Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease. 
16.3 
Spirometry Guidance 
Equipment 
Spirometers must meet the accuracy specifications according to the American Thoracic Society 
(ATS)/European Respiratory Society (ERS) Standardization of Spirometry (Graham et al 2019). 
Spirometers must have the capacity to print forced vital capacity (FVC) tracings. All spirometry 
values should be reported at body temperature and pressure saturated (BTPS) by the method 
established by the manufacturer. 
Calibration 
The spirometer should be calibrated every morning before any spirometric measurements for 
the study are performed. Calibration reports should be printed and stored as source data at the 
site. 
Preparing the test subject 
On study days when spirometry will be performed, patients should refrain from the following: 
• Coffee, tea, chocolate, cola and other caffeine-containing beverages and foods and ice-
cold beverages for 4 hours prior to spirometry 
• Alcohol for 8 hours prior to spirometry 
• Strenuous activity for 1 hour prior to spirometry 
• Exposure to environmental smoke, dust or areas with strong odors 
• Wearing clothing that substantially restricts full chest and abdominal expansion 
Every effort should be made to assure consistent testing conditions throughout the study. A 
seated position with nose clips is recommended to reduce risks related to dizziness or syncope. 
When possible, spirometry should be conducted by the same technician using the same 
spirometer. To minimize the effects of diurnal variation on lung function, spirometry visits 
should start at approximately the same time of day at each visit.  
Performing Spirometry 
For full details on performing spirometry see Graham et al 2019.  
In summary the subject’s age, height and gender will be entered into the spirometer. It is 
important that the height is measured accurately at the study site. Spirometry, an effort-
dependent test, requires careful instruction and cooperation of the subject. The technician 
should ensure a good seal around the mouthpiece, and confirm that the subject’s posture is 
correct. The results of spirometry should meet the ATS/ERS criteria for acceptability and FEV1 
repeatability. Acceptability criteria should be applied before repeatability is determined.  


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FEV1 and FVC Maneuver 
The subject should be instructed to perform: 
1) Maximal inspiration 
2) A “blast” of expiration 
3) Continued complete expiration for a maximum of 15 seconds 
4) Inspiration at maximal flow back to maximum lung volume 
Number of trials 
A minimum of 3 maneuvers should be performed. If a subject is unable to perform a single 
acceptable maneuver after 8 attempts, testing should be discontinued. 
Acceptability 
• Must have BEV <5% of FVC or 0.100 L, whichever is greater  
• Must have no evidence of a faulty zero-flow setting  
• Must have no cough in the first second of expiration  
• Must have no glottic closure in the first second of expiration 
• Must have no glottic closure after 1 second (s) of expiration  
• Must achieve one of these three end of forced expiration (EOFE) indicators:  
1. Expiratory plateau (<0.025 L in the last 1 s of expiration) 
2. Expiratory time >15 s 
• Must have no evidence of obstructed mouthpiece or spirometer  
• Must have no evidence of a leak  
 
Overall acceptability will be determined by expert over-read by spirometry vendor.  
All spirometry assessments at the run in visit must be confirmed as acceptable by the central 
over read. At least one spirometry assessment, i.e. -2 hr 45 min or/and -2 hr 15 min, at the end 
of run in visit must be confirmed as acceptable by the central over read before randomization 
takes place. 
Repeatability 
 For acceptable spirometry the difference between the two largest FEV1 values must be 
<0.150 L. 
 
Recording of data 
The greatest FEV1 and FVC from any of the acceptable curves are recorded. (The greatest 
FEV1 and FVC may not necessarily result from the same acceptable curve).  


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Predicted normal 
For all patients, this study will utilize the global lung function 2012 equations (GLI2012) 
published by Quanjer et al 2012 or Japanese Respiratory Society (Kubota et al 2014). 
Reversibility 
All reversibility evaluations should follow the recommendations of the ATS/ERS Task force: 
Standardization of Lung Function Testing (Graham et al 2019). A pre-bronchodilator 
spirometry assessment should be performed after withholding of specified medications as 
specified in Table 6-2 “Medications to be withheld prior to spirometry”. 
Administer 400µg of salbutamol/albuterol (or equivalent) following the completion of the pre-
bronchodilator 
assessment. 
Spacers 
will 
be 
allowed 
for 
the 
administration of 
salbutamol/albuterol (or equivalent) for reversibility testing. Post-bronchodilator spirometry 
assessment is then performed within 30 minutes after administration of the salbumatol/albuterol. 
Reversibility is calculated as: 
100 x  FEV1 (post-bronchodilator) – FEV1 (pre-bronchodilator) 
FEV1 (pre-bronchodilator) 
Patients will be considered reversible if an increase of at least 12% and 200 mL is demonstrated 
after administration of the salbutamol/albuterol. 
16.4 
Repeat of the run in or end of run in visits 
16.4.1 
Run in visit 
The run in visit, with initiated spirometry, can be repeated twice.  
The visit must be repeated when:  
1. Central over read assessed pre- or post-SABA spirometry data as unacceptable 
2. FEV1 repeatability was not demonstrated at pre- or post-SABA spirometry 
3. Reversibility was not demonstrated  
If pre- or post-SABA spirometry test at the run in visit is assessed, by the central over read, as 
unacceptable, the visit must be repeated so that pre- AND post-SABA spirometry assessments 
at the repeated visit are assessed, by the central over read, as acceptable.  
Until all criteria for the run in visit are satisfied at a single visit i.e. both pre- and post-SABA 
spirometry are acceptable with FEV1 repeatability and reversibility met, site staff MUST NOT 
initiate the run in period, i.e. the site staff is NOT ALLOWED to: 
• Dispense to patients fluticasone-Salmeterol (SoC) 
• Dispense to patients the run in kit 
• Reprogram eDiary 
  


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16.4.2 
End of run in visit 
The visit must be repeated when:  
1. Central over read assessed both -2hr45min AND -2hr15min spirometry tests as 
unacceptable 
2. FEV1 repeatability was not demonstrated at both -2hr45min AND -2hr15min 
spirometry 
3. Absolute difference in FEV1 predicted value between the beginning and the end of run 
in is >15%  
If both -2hr45min AND -2hr15min spirometry test at the end run in visit are assessed, by the 
central over read, as unacceptable, the visit must be repeated so that at least one spirometry 
assessment at the repeated visit is assessed, by the central over read, as acceptable.  
Repetition of the visit is possible only if FEV1 measured on a previous visit were in range of 
40-85% predicted FEV1 for both -2hr45min and -2hr15min spirometry tests. 
 
16.5 
Asthma Control Questionnaire (ACQ-5) 
A SAMPLE of the Asthma Control Questionnaire – 5 is included below. The format of the 
administered test may vary. 


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16.6 
Recommendation for FeNO Measurements 
FeNO measurements should be performed PRIOR to spirometry assessments, as spirometric 
maneuvers have been shown to transiently reduce exhaled NO levels. FeNO measurements have 
to be performed within 4 hours of getting up from bed. 
Where possible, serial NO measurements should be performed in the same period of the day 
and the time should always be recorded. 
Repeated, reproducible exhalations should be performed to obtain two measurements within 
10% of each other. Exhaled NO is the mean of these two values. The duration of exhalation 
must be sufficient (up to 10 seconds) to achieve a stable NO plateau. Allow subjects at least 30 
seconds of relaxed tidal breathing to rest between repeated exhalations in order not to exhaust 
the patient. 
The patient should be seated comfortably with the equipment at the proper height and position. 
Patients should refrain from eating and drinking at least 2 hours before measurements. 
Patients should avoid strenuous exercise for 1 hour before measurements. 
The time of last bronchodilator should be noted, as FeNO levels may vary with the degree of 
airway obstruction or after bronchodilation. 
Respiratory tract infections may lead to increased levels of exhaled NO in asthma, therefore the 
measurements should be re-scheduled until recovery if possible, or the infection should be 
recorded in the patient’s medical file (and as an AE in the CRF). 
Holding breath results in NO accumulation which causes NO peaks in the exhalations profiles 
of NO versus time and should therefore be discouraged. 
 
 


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16.7 
Asthma Quality of Life Questionnaire for 12 years and older 
(AQLQ+12) 
A SAMPLE of the Asthma Quality of Life Questionnaire for 12 years and older is included 
below. The format of the administered test may vary. 
  


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16.8 
Timed assessment schedule 
16.8.1 
Randomization visit: End of Run-In/Day 1 
Table 16-3 
Timed assessments for the randomization visit 
Visit Name 
End of Run In 
Day 1 
Timepoint 
-3hr50min 
-2hr45min 
-2hr15min 
-1hr15min 
-1hr 
0 
2hr 
3hr 
4hr 
Review: 
1.Incl./Excl. Criteria 
✔ 
  
  
  
  
  
  
  
  
Review: 
1.AEs/SAEs assessment, 
2.Concomitant medications, 
3. Surgeries and procedures 
✔ 
  
  
  
  
  
  
  
  
1.ACQ 
2.AQLQ 
✔ 
  
  
  
  
  
  
  
  
ECG 
triplicate 
  
  
  
  
  
  
triplicate 
 
1.Vital signs  
2.Physical Examination (S) 
✔ 
  
  
  
  
  
  
  
  
FeNO pre-dose at site 
✔ 
  
  
  
  
  
  
  
  
-2hr45min  
Pre-dose spirometry 
  
✔ 
  
  
  
  
  
  
  
Urinalysis 
  
✔ 
  
  
  
  
  
  
  
Pregnancy test (Urine) 
  
S 
  
  
  
  
  
  
  
-2hr15min  
Pre-dose spirometry 
  
  -  
✔ 
  
  
  
  
  
  
Contact IRT upon feedback 
received from overreader  
  
  
  
S 
  
  
  
  
  
Equilibrate IMP 
  
  
  
  
S 
  
  
  
  
Dispensation of study drug 
  
  
  
  
S 
  
  
  
  


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Visit Name 
End of Run In 
Day 1 
Timepoint 
-3hr50min 
-2hr45min 
-2hr15min 
-1hr15min 
-1hr 
0 
2hr 
3hr 
4hr 
Inhaler Devices training** 
 
 
 
 
S 
 
 
 
 
Attach the add on sensor to the 
Concept1 inhaler 
  
  
  
  
S 
  
  
  
  
Blood sampling: 
1. Hematology 
2. Chemistry 
3. ADA 
 
6.ImmunoCAP 
 
 
 
 
✔ 
 
 
 
 
PK Blood collection  
Pre-Dose 
 
 
 
 
✔ 
 
 
 
 
On site IMP administration 
  
  
  
  
  
✔ 
  
  
  
Compliance with Concept1 
 
 
 
 
 
S 
 
 
 
PK Blood collection  
Post-Dose 2hr 
  
  
  
  
  
  
✔ 
  
  
eDiary/ 
ePEF training** 
  
  
  
  
  
  
S 
  
  
PK Blood collection  
Post-Dose 4hr 
  
  
  
  
  
  
  
  
✔ 
Dispensation of:  
1.Fluticasone/salmeterol 
2.SABA rescue 
  
  
  
  
  
  
  
  
S 
Inhale Fluticasone/salmeterol 
  
  
  
  
  
  
  
  
S 
*only for consented patients 
**optional if needed 
S source only 


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16.8.2 
Weeks 2-24 
Table 16-4 
Timed assessments for visits week 2-12 
Visit Name 
Week 2 
Week 4 
Week 8 
Week 12 
 
Timepoint 
-1hr15min 
-45min 
-15min 
0 
2hr 
-
1hr30mi
n 
-45min 
-15min 
0 
2hr 
-
1hr30mi
n 
-
45mi
n 
-
15mi
n 
0 
2hr 
-1hr30min 
-45min 
-15min 
0 
2hr 
4hr 
Before patient 
comes in: 
1.Contact IRT 
2.Equilibrate IMP 
  
  
  
  
  
S 
  
  
  
  
S 
  
  
  
  
S 
  
  
  
  
  
Review: 
1.AEs/SAEs 
assessment, 
2.Concomitant 
medications, 
3. Surgeries and 
procedures 
✔ 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
  
1.ACQ 
2.AQLQ 
  
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
  
ECG 
  
  
  
  
  
Single 
  
  
  
  
Single 
  
  
  
  
 
Triplicate 
  
  
  
  
  
Vital Signs 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
✔ 
  
  
  
  
  
1.Physical 
Examination (S) 
2.Body weight 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
✔ 
  
  
  
  
  
Abbreviated 
Physical 
Examination 
S 
  
  
  
  
S 
  
  
  
  
S 
  
  
  
  
  
  
  
  
  
  
FeNO pre-dose 
at site** 
✔ 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
  
-45min  
Pre-dose 
spirometry 
  
✔ 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
Urinalysis 
  
✔ 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  


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Visit Name 
Week 2 
Week 4 
Week 8 
Week 12 
 
Timepoint 
-1hr15min 
-45min 
-15min 
0 
2hr 
-
1hr30mi
n 
-45min 
-15min 
0 
2hr 
-
1hr30mi
n 
-
45mi
n 
-
15mi
n 
0 
2hr 
-1hr30min 
-45min 
-15min 
0 
2hr 
4hr 
Pregnancy test 
(urine) 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Blood sampling: 
1.Hematology 
2.Chemistry 
  
✔ 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
Blood sampling: 
1.ADA 
  
✔ 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
PK Blood 
collection  
Pre-Dose 
  
✔ 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
Pregnancy test 
(serum) 
  
  
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
-15min  
Pre-dose 
spirometry 
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
Dispensation of 
study drug 
  
  
  
  
  
  
  
S 
  
  
  
  
S 
  
  
  
  
  
  
  
  
Inhaler Devices 
Training*** 
 
 
 
S 
 
 
 
S 
 
 
 
 
S 
 
 
 
 
S 
 
 
 
Upload data from 
the Concept1 
add-on 
sensor/re-attach 
the sensor 
  
  
  
  
  
  
  
S 
  
  
  
  
S 
  
  
  
  
S 
  
  
  
Inhale IMP  
  
  
  
✔ 
  
  
  
  
✔   
  
  
  
✔   
  
  
  
✔   
  
Compliance with 
Concept1 
  
  
  
S 
  
  
  
  
S   
  
  
  
S 
  
  
  
  
S   
  


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Visit Name 
Week 2 
Week 4 
Week 8 
Week 12 
 
Timepoint 
-1hr15min 
-45min 
-15min 
0 
2hr 
-
1hr30mi
n 
-45min 
-15min 
0 
2hr 
-
1hr30mi
n 
-
45mi
n 
-
15mi
n 
0 
2hr 
-1hr30min 
-45min 
-15min 
0 
2hr 
4hr 
Compliance with 
eDiary/ePEF 
  
  
  
S 
  
  
  
  
S   
  
  
  
S 
  
  
  
  
S   
  
PK Blood 
collection  
Post-Dose 2hr 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
  
  
  
✔ 
  
Inhale 
Fluticasone/salm
eterol 
  
  
  
  
S 
  
  
  
  
S 
  
  
  
  
S 
  
  
  
  
S 
  
Dispensation of:  
1.Flutisacone/sal
meterol 
2.SABA rescue 
  
  
  
  
  
  
  
  
  
S 
  
  
  
  
S 
  
  
  
  
S 
  
PK Blood 
collection  
Post-Dose 4hr 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
✔ 
CSJ117 Safety 
Extension Study 
participation 
discussion 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
S 
  
  
  
  
  
  
*only for consented patients 
***optional if needed 
**only for onsite visits 
S source only 
Table 16-5 
Timed assessments for visits week 14-24 
Visit Name 
Week 
14 
 
 
Week 16 
 
 
Week 20 
 
 
Week 24 
Timepoint 
-1hr 
-1hr 
-45 
mi
n 
-30 
min 
-15 
min 
0 
-1hr 
-45 
mi
n 
-
30min 
-15 
min 
0 
-1hr20min 
-45 
min 
-
30min 
-15 
min 
0 
Before patient comes in: 
1.Contact IRT 
2.Equilibrate IMP 
  
  
 
  
 
  
  
 
  
 
  
  
 
  
 
  


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Visit Name 
Week 
14 
 
 
Week 16 
 
 
Week 20 
 
 
Week 24 
Timepoint 
-1hr 
-1hr 
-45 
mi
n 
-30 
min 
-15 
min 
0 
-1hr 
-45 
mi
n 
-
30min 
-15 
min 
0 
-1hr20min 
-45 
min 
-
30min 
-15 
min 
0 
Review: 
1.AEs/SAEs assessment, 
2.Concomitant 
medications, 
3. Surgeries and 
procedures 
✔ 
✔ 
 
  
 
  
✔ 
 
  
 
  
✔ 
 
  
 
  
1.ACQ 
2.AQLQ 
  
  
 
  
 
  
  
 
  
 
  
✔ 
 
  
 
  
ECG 
  
Single 
 
  
 
  
  
 
  
 
  
Single 
 
  
 
  
Vital Signs 
✔ 
  
 
  
 
  
✔ 
 
  
 
  
✔ 
 
  
 
  
1.Physical Examination 
(S) 
2.Body weight 
  
  
 
  
 
  
  
 
  
 
  
✔ 
 
  
 
  
Abbreviated Physical 
Examination 
  
S 
 
  
 
  
  
 
  
 
  
  
 
  
 
  
FeNO pre-dose at site** 
✔ 
✔ 
 
  
 
  
✔ 
 
  
 
  
✔ 
 
  
 
  
-45min  
Pre-dose spirometry 
  
  
✔ 
 
  
  
✔ 
 
  
  
✔ 
 
  
Urinalysis 
  
  
 
✔ 
 
  
  
 
  
 
  
  
 
✔ 
 
  
Pregnancy test (urine) 
  
  
 
✔ 
 
  
  
 
✔ 
 
  
  
 
  
 
  
Blood sampling: 
1.Hematology 
2.Chemistry 
  
  
 
✔ 
 
  
  
 
  
 
  
  
 
✔ 
 
  
Blood sampling: 
1.ADA 
 
✔ 
  
 
✔ 
 
  
  
 
✔ 
 
  
  
 
✔ 
 
  
PK Blood collection  
Pre-Dose 
✔ 
  
 
✔ 
 
  
  
 
✔ 
 
  
  
 
✔ 
 
  
Pregnancy test (serum) 
  
  
 
  
 
  
  
 
  
 
  
  
 
✔ 
 
  


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Visit Name 
Week 
14 
 
 
Week 16 
 
 
Week 20 
 
 
Week 24 
Timepoint 
-1hr 
-1hr 
-45 
mi
n 
-30 
min 
-15 
min 
0 
-1hr 
-45 
mi
n 
-
30min 
-15 
min 
0 
-1hr20min 
-45 
min 
-
30min 
-15 
min 
0 
-15min  
Pre-dose spirometry 
  
  
 
  
✔ 
  
 
  
✔ 
 
  
 
  
✔ 
Dispensation of study drug 
  
  
 
  
 
  
  
 
  
 
  
  
 
  
 
  
Upload data from the 
Concept1 add-on 
sensor/re-attach the 
sensor 
  
  
 
  
 
  
  
 
  
 
  
  
 
  
 
  
Compliance with Concept1 
  
  
 
  
 
  
  
 
  
 
  
  
 
  
 
  
Compliance with 
eDiary/ePEF 
S 
  
 
S 
 
  
  
 
S 
 
  
  
 
  
 
S 
Inhale 
Fluticasone/salmeterol 
S  
  
 
  
 
S  
  
 
  
 
S  
  
 
  
 
S  
Dispensation of:  
1.Flutisacone/salmeterol 
2.SABA rescue 
  
  
 
S 
 
  
  
 
S 
 
  
  
 
  
 
  
*only for consented patients 
**only for onsite visits 
S source only 

SAP_001.pdf: 


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
6
7
8
9
1
Introduction .......................................................................................................................10
1.1
Study design...........................................................................................................10
1.2
Study objectives and endpoints .............................................................................11
2
Statistical methods.............................................................................................................13
2.1
Data analysis general information .........................................................................13
2.1.1
General definitions................................................................................13
2.2
Analysis sets ..........................................................................................................14
2.2.1
Subgroup of interest ..............................................................................14
2.3
Patient disposition, demographics and other baseline characteristics ...................15
2.3.1
Patient disposition.................................................................................15
2.3.2
Patient demographics and other baseline characteristics ......................15
2.3.3
Medical history/current medical condition ...........................................16
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................16
2.4.1
Study treatment / compliance................................................................16
2.4.2
Prior, concomitant and post therapies...................................................17
2.5
Analysis of the primary objective..........................................................................17
2.5.1
Primary endpoint...................................................................................17
2.5.2
Statistical hypothesis, model, and method of analysis..........................18
2.5.3
Handling of missing values/censoring/discontinuations.......................20
2.5.4
Supportive analyses...............................................................................20
2.6
Analysis of the key secondary objective ...............................................................21
2.7
Analysis of secondary efficacy objective(s)..........................................................21
2.7.1
Secondary endpoints .............................................................................21
2.8
Safety analyses.......................................................................................................23
2.8.1
Adverse events (AEs)............................................................................23
2.8.2
Deaths....................................................................................................25
2.8.3
Laboratory data .....................................................................................25
2.8.4
Other safety data ...................................................................................25
2.8.5
Immunogenicity ....................................................................................26


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2.9
Pharmacokinetic endpoints....................................................................................29
30
2.11
Patient-reported outcomes .....................................................................................30
30
2.13
Interim analysis......................................................................................................30
2.13.1
Safety.....................................................................................................30
2.13.2
Efficacy .................................................................................................30
3
Sample size calculation .....................................................................................................31
4
Change to protocol specified analyses ..............................................................................31
5
Appendix ...........................................................................................................................32
5.1
Imputation rules.....................................................................................................32
5.1.1
Study drug.............................................................................................32
5.1.2
AE date imputation ...............................................................................32
5.1.3
Concomitant medication date imputation .............................................32
5.2
AEs coding/grading ...............................................................................................32
5.3
Laboratory parameters derivations ........................................................................33
5.4
Vital signs and ECG – definition of clinically notable values...............................36
5.5
Statistical models...................................................................................................37
Primary analysis.....................................................................................................37
Rule of exclusion criteria of analysis sets .........................................................................40
6
Reference...........................................................................................................................41


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List of abbreviations
ACQ
ADA
ADSD
AE
AESI
ANSD
AQLQ
ATC
BMI
CRF
CRS
CSR
DMC
DMS
DR
ECG
EOS
Asthma Control Questionnaire
Anti-Drug Antibodies
Asthma Daytime Symptom Diary
Adverse Event
Adverse Event of Special Interest
Asthma Nighttime Symptom Diary
Asthma Quality of Life Questionnaire
Anatomical Therapeutic Chemical
Body Mass Index
Case Report Form
Case Retrieval Strategy
Clinical Study Report
Data Monitoring Committee
Document Management System
Dose Response
Electrocardiograms
Eosinophil Count
FAS
FeNO
IA
Full Analysis Set
Fractional exhaled Nitric Oxide
Interim Analyses
J2R
Jump-to-reference
MAR
MCP-Mod
MedDRA
MMRM
PD
PEF
Missing at Random
Multiple Comparison Procedure – Modelling
Medical Dictionary for Drug Regulatory Affairs
Mixed effects Model for Repeated Measures
Protocol Deviation
Peak Expiratory Flow
PK
Pharmacokinetics
PRO
Patient-reported Outcomes
PT
RAS
Preferred Term
Randomized Analysis Set
SABA
SAP
SAS
Short-Acting β-agonist
Statistical Analysis Plan
Statistical Analysis System
SOC
Primary system organ class


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1
Introduction
This document contains details of the statistical methods that will be used in the phase IIb 
clinical trial CCSJ117A12201C. This study is designed to support the dose selection for future 
studies by evaluating the efficacy and safety of different CSJ117 doses in adult patients with 
severe uncontrolled asthma. The primary endpoint is the average change from baseline in pre-
dose FEV1 at Week 8 and Week 12.
Data will be analyzed according to Section 12 of the study protocol.
The following document was referred while writing the SAP:
CCSJ117A12201C Clinical Trial Protocol Final version 03 dated 21-Jan-2022.
Important information is given in the following sections and details are provided, as applicable, 
in Section 5: Appendix.
1.1
Study design
This study is a phase IIb, multicenter, multi-national, double-blind, randomized, parallel-arm, 
placebo-controlled study to evaluate the effect of 5 dose levels of CSJ117 in adult subjects with 
inadequately controlled asthma despite medium to high dose ICS plus LABA.
The study will include:

A screening period of approximately 2 weeks

A single blinded placebo run-in period of 4 weeks (must be extended to 8 weeks for 
patients experiencing an asthma exacerbation or respiratory tract infection during the 
run-in period)

A double blinded treatment period of 12 weeks

A follow-up period of 12 weeks, study drug free, following the last dose of study drug.
Or a follow-up period of 8 weeks for patients that discontinued the study due to early 
termination.
Figure 1-1
Study design




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Objective(s)
Endpoint(s)
inhaled daily on FeNO compared with 
placebo, during the 12-week active-
treatment period

To assess immunogenicity of five doses of 
CSJ117 during the study

Measurement of Anti-Drug Antibodies (ADA) 
titers at baseline and during the study (Week 
0 [Day 1] to Week 24)

To characterize the systemic 
pharmacokinetic (PK) profile of multiple 
inhaled daily doses of CSJ117 during 
the 12 week, active treatment period and 
the 12 week, follow-up period

Measurement of total CSJ117 serum 
concentration during the study (Week 0 [Day 
1] to Week 24) and calculation of PK 
parameters (e.g., Ctrough, Racc, T½).

To characterize the efficacy of five doses 
of CSJ117 once daily, compared with 
placebo, on peak expiratory flow (PEF; AM 
and PM), as assessed by mean morning 
and mean evening PEF over the 12-week 
active-treatment period

Change from baseline in peak expiratory flow 
(PEF; am and pm), as assessed by mean 
morning and mean evening PEF in each week 
(average over 7 days) during 12 weeks of 
treatment.

To characterize the efficacy of five doses 
of CSJ117 once daily, compared with 
placebo, on ACQ-5 over the 12-week 
active-treatment period.

Average change from baseline in ACQ-5 
score at Week 8 and Week 12.

To characterize the efficacy of five doses 
of CSJ117 once daily, compared with 
placebo, on change from baseline in 
Asthma Quality of Life Questionnaire 
(AQLQ) score at the end of the 12-week 
active-treatment period

Average change from baseline in AQLQ+12 
score at Week 8 and Week 12

To characterize the efficacy of five doses 
of CSJ117 once daily, compared with 
placebo, on daytime and nighttime asthma 
symptoms over the 12-week active-
treatment period

Average change from baseline in ADSD and 
ANSD score at Week 8 and Week 12.

To characterize the efficacy of five doses 
of CSJ117 once daily, compared with 
placebo, on daily short-acting β-agonist 
(SABA) use over the 12-week active-
treatment period

Change from baseline in number of puffs of 
SABA taken per day in each week (average 
over 7 days) during 12 weeks active-treatment 
period

To assess the safety of five doses of 
CSJ117 once daily, compared with 
placebo, with respect to adverse events 
(AE), electrocardiograms (ECGs), vital 
signs and laboratory tests

Summaries of treatment-emergent adverse 
events, systolic and diastolic blood pressure, 
pulse rate, body weight, ventricular rate, RR 
interval, PR interval, QRS duration, heart rate, 
and Fridericia’s QTc, laboratory values and 
change from baseline for continuous 
laboratory values.


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2
Statistical methods
2.1
Data analysis general information
The statistical analysis will be performed by Novartis. The most recent version of SAS® (SAS 
Institute Inc., Cary, NC, USA) available in the statistical programming environment of Novartis
will be used for the analysis. R version 3.6.1 may also be used as appropriate.
2.1.1
General definitions
The terms ‘double-blind treatment’ will be used in this document and refer to the double-blind 
CSJ117 doses and placebo.
2.1.1.1
Study day
Study day will be defined as the number of days since the date of first dose of double-blind 
treatment. The date of first dose of double-blind treatment will be defined as Day 1 and the day 
prior to first dose of double-blind treatment will be defined as Day -1.
Therefore, for a particular date, study day will be calculated as follows:
for dates on or after the date of first dose of double-blind treatment,
Study day = Assessment date – Day 1 + 1;
for dates prior to the date of first dose of double-blind treatment,
Study day = Assessment date – Day 1.
If a patient never received any double-blind treatment, the date of randomization will be used 
as Day 1.


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2.1.1.2
Baseline definition
In general, baseline is defined as the last measurement taken before the first dose of double-
blind treatment. Details on calculation of baseline will be provided in the latter sections.
For patients who never received any double-blind treatment, the baseline is the last 
measurement taken before randomization.
2.1.1.3
Post-baseline definition
All data collected after the start of double-blind treatment are defined as post-baseline. For 
patients who are not treated, the post-baseline is any assessments after randomization.
When change from baseline is of interest the following formula will be used for each scheduled 
visit and time-point where baseline and post-baseline values are both available:
Change from baseline = post-baseline value – baseline value.
If not stated otherwise for efficacy analyses, on-treatment values are defined as values taken 
post-baseline but no later than 1 day after last dose of double-blind treatment. Off-treatment 
values are defined as post-baseline values taken more than 1 day after last dose of double-blind 
treatment.
Details on calculation of post-baseline values are provided in the latter sections.
2.2
Analysis sets
The Randomized Analysis Set (RAS) consists of all randomized subjects. Subjects will be 
analyzed according to the treatment they were assigned to at randomization. Demographics and 
baseline characteristics will be summarized using the RAS.
The Full Analysis Set (FAS) comprises all subjects to whom double-blind treatment has been 
assigned and who received at least one dose of double-blind treatment. Subjects will be 
analyzed according to the treatment they have been assigned to during the randomization 
procedure. The FAS will be used for the analysis of all efficacy variables.
The Safety Set includes all subjects who received at least one dose of double-blind treatment. 
Subjects will be analyzed according to the treatment they received, where treatment received is 
defined as the randomized/assigned treatment if the participant took at least one dose of that 
treatment or the first treatment received if the randomized/assigned treatment was never 
received. The Safety Set will be used for the analysis of all safety variables.
The PK set will include all patients with at least one evaluable drug concentration data sample.
2.2.1
Subgroup of interest
Subgroup analyses are conducted to assess consistency of the treatment effect among the 
subgroups, without multiplicity adjustments. The following subgroups will be evaluated for the 
primary endpoint:

Age group (18 - < 40, 40 - < 65, ≥ 65 years)

Gender (male, female)

Race (White, Asian, Black, other)


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
Region

Body mass index (BMI) (≤ 30.0 kg/m2, > 30.0 kg/m2)

Duration of asthma (1 - 5 years, > 5 - 10 years, > 10 - 15 years, > 15 - 20 years, > 20 
years)

Pre-bronchodilator FEV1 in % of predicted FEV1 (<40%, 40 - < 50%, 50 - < 60%, 60% - < 
80%, 80 - 85%)

Use of medications at screening in addition to ICS/LABA controllers (Yes, No)

Prior asthma treatment (medium or high ICS/LABA)

Atopic asthma status (Yes, No)

Baseline FeNO (< 25 ppb, ≥ 25 ppb)

Number of exacerbations in the prior year (1, 2, ≥3

Baseline ACQ-5 (<1.5, 1.5 - < 2, 2 - < 2.5, ≥ 2.5)
2.3
Patient disposition, demographics and other baseline 
characteristics
No inferential testing on the differences in patient disposition, demographics and other baseline 
characteristics between treatment arms will be performed.
2.3.1
Patient disposition
The RAS will be used for the summary and listing of patient disposition. The screening 
disposition and the analysis sets table will be based on all screened patients.
The number of patients in the RAS will be summarized by region, country, center and treatment 
group. Further, the overall number of patients who entered completed, and discontinued study
will be summarized including the reasons for discontinuation for each period: pre-
randomization, double-blind treatment and follow-up. 
Number of patients with protocol deviations (PDs) and with Covid-19 related PDs will be 
tabulated by category (e.g., selection criteria not met, subject not withdrawn as per protocol, 
treatment deviation, prohibited concomitant medication, other) and deviation.
COVID-19 pandemic-related impact to protocol adherence captured as protocol deviations will 
be tabulated by Pandemic-related PD Relationship to COVID-19 by treatment and category.
The number of patients included in each analysis set will be tabulated. Patients exclusion from 
analysis sets will be listed for all patients with reasons for exclusion (i.e. including both protocol 
and non-protocol deviations).
2.3.2
Patient demographics and other baseline characteristics
Demographics and other baseline characteristics will be summarized and listed using the RAS.
Demographic characteristics, including age, gender, race, ethnicity, region, height, weight, and 
BMI will be summarized by treatment and overall.


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Baseline disease characteristics, including duration of asthma, run-in spirometry (FEV1, FVC, 
FEV1/FVC and % of predicted FEV1 pre- and post-bronchodilator, FEV1 reversibility), asthma 
exacerbation history, smoking history, atopic asthma status (Yes/No), baseline ACQ-5, baseline 
AQLQ+12, blood eosinophils at screening, prior asthma treatment (medium/high ICS/LABA)
will be summarized.
Summaries of continuous variables will include mean, standard deviation (SD), first and third
quartile, median, minimum and maximum. Summaries of categorical variables will show
absolute (n) and relative (%) frequencies including a category for missing data if any.
No statistical analyses will be provided for baseline comparability among the treatment groups.
In addition, the following categorizations of continuous variables will be done:

Age into 18 - < 40, 40 - < 65, and ≥ 65 years;

BMI into ≤30.0 kg/m2 and > 30.0 kg/m2;

Duration of asthma into < 1 year, 1 - 5 years, > 5 - 10 years, > 10 - 15 years, > 15 – 20 years, 
and > 20 years;

Severity of airflow limitation: pre-bronchodilator FEV1 % predicted values into 40 - < 50%, 
50 - < 60%, 60% - < 80%, and 80 - 85%

ACQ-5 into 1.5 - < 2, 2 - < 2.5, and ≥ 2.5
2.3.3
Medical history/current medical condition
Medical history will be coded with the Medical Dictionary for Regulatory Activities 
terminology (MedDRA) using the most recent version at the time of database lock. Relevant 
medical histories and current medical conditions, including pre-specified protocol solicited 
events, will be summarized for the RAS by primary system organ class and preferred term by 
treatment group. 
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
All summaries of treatments will be performed on the Safety Set.
2.4.1
Study treatment / compliance
The duration of exposure in days to each treatment group (CSJ117 doses or placebo) will be 
summarized by means of descriptive statistics. In addition, the duration of exposure will be 
summarized as a categorical variable classified into ≤ 2 weeks, > 2 – 4 weeks, > 4 – 6 weeks, > 
6 – 8 weeks, > 8 – 10 weeks, > 10 – 12 weeks, > 12  – 13 weeks, and > 13 weeks.
Duration of exposure to double-blind treatment will be calculated as the number of days
between the first dose date and the last dose date exposed to that treatment over the specified
period (expressed as: Duration of exposure = Date of last known dose of double-blind treatment
– Date of first dose of double-blind treatment + 1).
The number of patients who permanently discontinued from double-blind treatment and the 
reasons will be summarized by treatment group. Patients who permanently discontinued from 
double-blind treatment will be listed including reason and date of discontinuation.


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Compliance will be calculated as the percentage of the number of days where double-blind 
treatment was administered as per protocol divided by the duration of exposure (i.e., the number 
of days between first and last dose).
Compliance will be categorized by < 80 % and 80 % - 100 % and summarized by treatment
group.
2.4.2
Prior, concomitant and post therapies
Summaries for asthma-related medications will be performed separately for medications prior 
to the start of double-blind treatment (medications starting prior to Day 1) and for concomitant 
medications (medications which were taken anytime between the first dose and last dose of 
double-blind treatment, inclusive). Medications can be considered both prior and concomitant.
Asthma-related medications will be summarized by pre-specified drug categories, route of 
administration, preferred term, and treatment group.
Non-asthma related medication prior to and after the start of double-blind treatment will be 
summarized by the Anatomical Therapeutic Chemical (ATC) classification system, preferred 
term, and treatment group. More than one ATC class per medication is possible and the 
medication will be reported under all applicable classes.
Surgical and medical procedures (non-drug therapies) are coded using MedDRA. Presentations 
will be done by MedDRA primary system organ class and preferred term, separately for prior 
and concomitant procedures.
2.5
Analysis of the primary objective
The primary objective of this study is to characterize the DR (dose response) efficacy 
relationship among CSJ117 doses (0.5, 1, 2, 4, and 8 mg daily) and placebo with regards to the 
average change from baseline in pre-dose FEV1 (L) at Week 8 and Week 12. The goals 
associated with this objective are below.

To confirm an overall drug response signal

To estimate the dose(s) that corresponds to the target effect over placebo based on the 
estimated DR curve
2.5.1
Primary endpoint
The primary estimand, defined below, quantifies a hypothetical on-treatment effect during 
stable periods (i.e. outside of periods of acute disease worsening requiring additional asthma 
medications). This estimand targets the maximum treatment effect for CSJ117 and allows 
selection of the best dose for those who take it for 12 weeks.

Population: adult patients with inadequately controlled asthma on medium or high dose 
ICS/LABA, alone or with up to two additional asthma controllers (LTRA, LAMA or 
theophylline)

Variable: Average change from baseline in pre-dose FEV1 after 8 and 12 weeks of 
treatment

Treatment: CSJ117 or placebo




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Step 2 (Estimation of the dose-response curve and target dose – Mod part):
Once the DR signal is tested, the DR curve and the target dose(s) of interest will be estimated
by model averaging. A large number of bootstrap samples from the multivariate normal 
distribution will be drawn with adjusted means from the MMRM and corresponding covariance 
matrix. For each sample:

DR models from the candidate families 
 will be fitted to 
the data and the best model according to the generalized Akaike information criterion will 
be chosen.

The predictions for dose response will be obtained from the best model.
The final DR curve estimate is the median of these predictions while confidence intervals will 
be calculated from the quantiles. The final DR curve estimate with the model-based two-sided 


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95% confidence interval will be presented graphically. In addition, the plot will include the 
mean responses from the MMRM and the associated 95% confidence intervals for each of the 
studied dose groups. This bootstrap model averaging approach reflects model uncertainty in the 
inference and typically leads to more reliable confidence intervals as well as more precise 
estimates of the dose-response curve compared to selection of a single model (Bornkamp 2015; 
Schorning et al 2016).
2.5.3
Handling of missing values/censoring/discontinuations
Despite all attempts to ensure complete follow-up for all patients, some patients may not be 
followed for pre-dose FEV1 for the whole planned study duration.
The FEV1 value analyzed at each post-baseline visit is based on the average of the two FEV1
assessments taken at approximately 45 minutes and approximately 15 minutes prior to the 
dosing of study drug at clinic visits. Since the estimand is related to an effect outside of periods 
of acute disease worsening requiring additional asthma medications, spirometry measurements
taken within 6 hours of rescue medication, 7 days of intake of systemic corticosteroid use, 3 
months of a single depot corticosteroid injection, 24 hours of background medication use, 
and/or 48 hours of LAMA use will be set to missing. In cases where one of the two values is 
missing, the remaining non-missing value will be taken as pre-dose FEV1. If both values are 
missing, then their pre-dose FEV1 will be regarded as missing at that visit.
For the primary analysis, only on-treatment data (from date of first dose of double-blind 
treatment up to 1 day after date of last dose) will be used as the estimand specifies a hypothetical 
on-treatment effect. Missing on-treatment data will not be explicitly imputed as the MMRM 
implicitly imputes missing data assuming the missing at random (MAR) mechanism.
The imputation procedures related to the pre-dose FEV1 supportive analyses (Section 2.5.4) are 
"jump-to-reference" (J2R) and MAR (Carpenter et al 2013). The imputations will be based on 
all available data (i.e. from all scheduled timepoints) using all covariates as specified in the 
MMRM. For J2R, only placebo (reference) data will be used. For MAR, data from the same 
treatment arm will be used for building the imputation model. Imputation of intermittent 
missing observations before treatment discontinuation will be carried out following a MAR 
mechanism for all treatment arms. Additional details are provided in Section 5.5.
2.5.4
Supportive analyses
A supplementary analysis will be performed that quantifies the treatment effect in all 
randomized patients during stable periods (i.e. outside of periods of acute disease worsening 
requiring additional asthma medications) with an adherence to treatment like we would see in 
clinical practice in a world without COVID-19, with the following post-randomization events 
accounted for by assessing:
a. Intake of non-study drug with effect on FEV1: the effect outside of periods of worsening 
disease that necessitate such non-study drug.
b. Discontinuation of study treatment due to any reason not covered in bullet c below: actual 
off-treatment value. If no data was retrieved after study treatment discontinuation, missing data 
will be multiply imputed based on placebo arm data: J2R assumption for the CSJ117 arms and 
MAR assumption for placebo arm.


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c. Discontinuation of study treatment due to early termination of the study by sponsor or any 
COVID-19 related reason: hypothetical value of the average between Week 8 and Week 12 pre-
dose FEV1 had the patients not stopped the study treatment.
Results will be presented similarly to those of primary analyses. Details are provided in Section 
5.5.
The subgroup analyses (subgroups defined in Section 2.2.1) will be explored for the primary 
estimand and the same MMRM as described for the primary analysis with the additional term 
of subgroup factor (if not already included in the model), the two-way interaction term of 
subgroup and treatment, and the three-way interaction term of subgroup, treatment, and visit. 
In case of analyses on subgroups with extremely imbalanced sample sizes, the subgroup levels 
can be combined, if appropriate, while fitting the analysis model. The point estimate and 95% 
CI for treatment differences between CSJ117 doses and placebo for each subgroup will be 
provided.
2.6
Analysis of the key secondary objective
There is no key secondary objective defined in the protocol.
2.7
Analysis of secondary efficacy objective(s)
No multiplicity adjustment will be carried out for secondary analyses described below. In 
addition, the treatment effect of CSJ117 compared to placebo that would have been observed 
had all patients remained on their assigned treatment will be estimated. Only on-treatment data
will be used. 
All analysis of secondary efficacy endpoints will be performed on the FAS.
Missing data for any reason will not be explicitly imputed and will be handled by the respective 
mixed effects model which implicitly imputes missing data assuming MAR.
Details on statistical models are provided in Section 5.5.
2.7.1
Secondary endpoints
2.7.1.1
FeNO
The average change from baseline in Fractional exhaled Nitric Oxide (FeNO) at Week 8 and 
Week 12 will be analyzed using the same MCP-Mod approach described for the primary 
analysis of the primary endpoint. The change from baseline in FeNO will be analyzed using a 
similar MMRM (including all scheduled post-baseline visits with FeNO data) on the FAS as 
used for the primary analysis but will include baseline FeNO instead of baseline FEV1. The 
estimated treatment difference (CSJ117 – placebo) at each visit will be reported as well as the 
average between Week 8 and Week 12 along with the associated 95% confidence interval.
2.7.1.2
ACQ-5
The ACQ-5 measures asthma symptom control and consists of 5 items (questions) on symptom 
assessment. Patient recall is one week.


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All 5 questions of the ACQ-5 are equally weighted. Items are scored along a 7-point response 
scale, where 0 = totally controlled and 6 = severely uncontrolled.
The total score is calculated as the mean of all five questions.
The average of mean change from baseline in ACQ-5 at Week 8 and Week 12 will be analyzed 
using the same MMRM (including all scheduled visits with ACQ data) on the FAS as used for 
the primary analysis but will include baseline ACQ-5 instead of baseline FEV1. The estimated 
treatment difference (CSJ117 – placebo) at each visit will be reported as well as the average 
between Week 8 and Week 12 along with the associated 95% confidence interval.
The proportion of patients who achieve an improvement of at least 0.5 in ACQ-5 (i.e. decrease 
of ACQ-5 score of at least 0.5 from baseline) at post-baseline visits will be analyzed using a 
repeated measurements logistic regression. The model will inlcude the same terms as for the 
MMRM analysis of the primary variable with baseline ACQ-5 instead of baseline FEV1. The 
estimated adjusted odds ratios at each visit will be displayed along with the associated 95% 
confidence intervals.
2.7.1.3
Daytime and nighttime asthma symptoms
The baseline of asthma daytime symptom diary (ADSD) and asthma nighttime symptom diary 
(ANSD) will be defined as the average of the respective scores during the run-in period.
The mean daily scores of ADSD and ANSD will be summarized by weekly intervals.
2.7.1.4
AQLQ+12
AQLQ (Asthma Quality of Life Questionnaire) is a 32-item disease specific questionnaire 
designed to measure functional impairments that are most important to patients with asthma, 
with 7-point scale (1-totally limited/problems all the time, 7-not at all limited/no problems). It 
consists of 4 domains: symptoms, emotions, exposure to environmental stimuli and activity 
limitation. Mean score will be calculated for the four domains, as well as the overall quality-of-
life score defined as the mean score of all 32 items.
The average change from baseline in AQLQ+12 (overall and by domain) at Week 8 and Week 
12 will be analyzed using the same MMRM model as specified for the primary efficacy variable 
with baseline AQLQ as covariate. The estimated adjusted treatment difference at each visit as 
well as the average between Week 8 and Week 12 will be reported along with the associated 
95% confidence interval.
The proportion of patients who achieve an improvement of at least 0.5 in the change from 
baseline in AQLQ (i.e. increase of AQLQ score of at least 0.5 from baseline) at post-baseline 
visits will be analyzed using the same repeated measurements logistic regression model for the 
ACQ-5 analysis except that baseline AQLQ will be used instead of the baseline ACQ-5. The 
estimated adjusted odds ratios at each visit will be displayed along with the associated 95% 
confidence intervals.


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2.7.1.5
Total daily use of SABA
Total daily use of short-acting β-agonist (SABA) (the number of puffs taken in the previous 24 
hours) by the patient will be analyzed using ePEF/eDiary data. The baseline of SABA use will 
be defined as the average of total daily SABA use during the run-in period.
The mean daily use of SABA will be summarized by weekly intervals.
2.7.1.6
Peak Expiratory Flow Rate (PEF)
E-diary data recorded during the run-in period will be used to calculate the baseline value.
Mean morning/evening PEF will be summarized by treatment and by weekly intervals. .
2.8
Safety analyses
Safety summaries include only data from the on-treatment period with the exception of baseline
data which will also be summarized where appropriate (e.g. change from baseline summaries).
In addition, a separate summary for death including on treatment and post treatment deaths will 
be provided.
All safety analysis will be performed on the Safety Set.
2.8.1
Adverse events (AEs)
An adverse event (AE) is any untoward medical occurrence (e.g. 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. All treatment emergent adverse events (AEs) including asthma exacerbations will be 
summarized.   
Summaries will be provided by MedDRA primary system organ class, preferred term, and 
treatment group showing the number and percentage of patients with events for the on-
treatment and off-treatment periods, respectively, as defined below: 
on-treatment period (Safety Set): AE started or worsened in [Day 1, last treatment day];
off-treatment period (Only include patients in the Safety Set who had at least one day in the 
off-treatment period): AE started or worsened in [last treatment day + 1 day, last treatment 
day + 30 days].
The rationale to summarise AE by on- and off- treatment periods is that for patients who 
complete the 12-week treatment and enter the extension study immediately, they will not have 
any AEs reported in the off-treatment period. For other patients, they would potentially have 
data from both the on- and off-treatment period (either in the follow up epoch or discontinue 
the treatment but remained on study). Therefore, to avoid the mixture of these patients, we split 
AEs into on- and off-treatment summaries.
Note that in the off-treatment AE summary, only patients who had at least one day in the off-
treatment period will be included. Since there could be imbalance in such patient population 
across different treatment arms, there is no causal interpretation for the comparison. To aid the 


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interpretation, the total sum of off-treatment days will also be reported in each arm in the off-
treatment AE summary tables.
Summaries will be presented in the following ways:

by treatment and preferred term (PT).

by treatment, primary system organ class (SOC) and PT.

by treatment, SOC, PT and maximum severity.
Separate summaries by SOC and PT will be provided for :

serious adverse events (SAEs)
Further SAEs will be summarized by PT separately for on-treatmnet and off-treatment periods.
Unless otherwise specified, SOCs will be sorted alphabetically and, within each SOC, the PTs 
will be sorted in descending order of frequency in the highest CSJ117 dose. A subject with 
multiple adverse events within a SOC or PT is only counted once towards the total of the SOC 
or PT.
Listings will be provided for all AEs, SAEs and fatal AEs.
2.8.1.1
Adverse events of special interest / grouping of AEs
The number and percentage of patients who reported treatment-emergent adverse events of 
special interest (AESI) will be summarized by risk name, PT and treatment group separately 
on-treatment and off-treatment periods. 
Risk names will be sorted alphabetically and, within each risk name, the PTs will be sorted in 
descending order of frequency in the highest CSJ117 dose. If a patient reported more than one 
adverse event with the same PT, the AE will be counted only once. If a patient reported more 
than one AE within the same risk, the patient will be counted only once at that risk.
The Compound Case Retrieval Strategy (CRS) will be used to determine the MedDRA search 
criteria to be used to identify AESI. The most recent list of adverse events of special interest at 
the time of database lock will be used.
A listing for all AESI will be provided.
2.8.1.2
AE reporting for CT.gov and EudraCT
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
2% and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE


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
more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
2.8.2
Deaths
Fatal AEs will be summarized and listed as specified in Section 2.8.1.
2.8.3
Laboratory data
Summaries of laboratory data will include on-treatment measurements, which are defined as 
measurements taken post-baseline but no later than 30 days after last dose of double-blind 
treatment for patients not entering the safety extension study (as described in Section 1.1) 
directly after the treatment period or not participating in the safety extension study. For patients 
entering the safety extension study directly after the treatment period, the on-treatment period 
lasts from the date of first administration of double-blind treatment to the date of the last actual 
administration of double-blind treatment.
For selected laboratory tests, the number and percentage of patients with newly occurring or 
worsening laboratory abnormalities meeting the clinically notable criteria at any time on-
treatment, considering all on-treatment data from scheduled, unscheduled and premature 
discontinuation visits, will be summarized by laboratory parameter. Notable criteria are defined 
in Section 5.3.
Furthermore, the number and percentage of patients with newly occurring or worsening 
abnormalities in liver function tests (LFT) will be summarized by treatment and at any time on-
treatment considering all on-treatment data from scheduled, unscheduled and premature 
discontinuation visit. LFT criteria are defined in Section 5.3.
The baseline value is the last value prior to first dose of double-blind treatment.
Laboratory data of patients with notable values will be listed.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
Summaries of ECG data will include on-treatment measurements, which are defined as 
measurements taken post-baseline but no later than 30 days after last dose of double-blind 
treatment for patients not entering the safety extension study (as described in Section 1.1) 
directly after the treatment period or not participating in the safety extension study. For patients 
entering the safety extension study directly after the treatment period, the on-treatment period 
lasts from the date of first administration of double-blind treatment to the date of the last actual 
administration of double-blind treatment. Triplicate ECGs and single ECGs will be performed
at different visits specified in the assessment schedule table in the protocol. For the analysis of 


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continuous ECG parameter involving triplicate ECGs, the mean value of the 3 ECG 
measurements will be used; for ECG interpretation, all findings of the 3 ECGs will be 
considered.
The number and percentage of patients with newly occurring or worsening notable Fridericia’s 
QTc values will be summarized at any time on-treatment, considering all on-treatment data 
from scheduled, unscheduled and premature discontinuation visits. For derivation of notable 
values for the triplicate ECGs, the mean of the three ECGs will be used. Notable criteria are 
defined in Section 5.4.
The number and percentage of patients with ECG abnormalities will be summarized by 
evaluation type, abnormality finding, visit and time point.The baseline value is the last value 
prior to first dose of double-blind treatment.
ECG data of patients with notable Fridericia’s QTc values will be listed.
2.8.4.2
Vital signs
Summaries of vital signs data will include on-treatment measurements, which are defined as 
measurements taken post-baseline but no later than 30 days after last dose of double-blind 
treatment for patients not entering the safety extension study (as described in Section 1.1) 
directly after the treatment period or not participating in the safety extension study. For patients 
entering the safety extension study directly after the treatment period, the on-treatment period 
lasts from the date of first administration of double-blind treatment to the date of the last actual 
administration of double-blind treatment.  
The number and percentage of patients with newly occurring or worsening notable vital sign
values will be summarized at any time on-treatment, considering all on-treatment data from 
scheduled, unscheduled and premature discontinuation visits. Notable criteria are defined in 
Section 5.4.
The baseline value is the last value prior to first dose of double-blind treatment.
Vital sign data of patients with notable values will be listed.
2.8.5
Immunogenicity
All immunogenicity analysis will be conducted for each safety set and reported separately other 
than in the CSR. 
2.8.5.1
Immunogenicity (IG) analysis sets
The Immunogenicity prevalence set includes all subjects in the Safety set with a non-missing 
baseline ADA sample or at least one non-missing post-baseline ADA sample. The 
Immunogenicity incidence set includes all subjects in the Immunogenicity prevalence set with 
a non-missing baseline ADA sample and at least one non-missing post-baseline ADA sample. 
Any ADA sample collected beyond 150 days of the last dose of CSJ117 will not be used for 
summaries or derivations and will only be included in the listing
The following definitions apply only to non-missing samples:


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
ADA-negative sample: Sample where assay result is ‘NEGATIVE’ and CSJ117 
concentration at the time of ADA sample collection is ≤ the drug tolerance level (10 
microgram/mL) 

ADA-positive sample: Sample where assay result is ‘POSITIVE’

ADA-inconclusive sample: Sample where assay is ADA negative and CSJ117 PK 
concentration at the time of ADA sample collection is > the drug tolerance level (10 
microgram/mL) or missing
The following definitions apply only to post-baseline ADA-positive samples with a 
corresponding non-missing baseline sample. To be classified as treatment-boosted or treatment-
unaffected, both the post-baseline and baseline titer must be non-missing.

treatment-induced ADA-positive sample: ADA-positive sample post-baseline with 
ADA-negative sample at baseline

treatment-boosted ADA-positive sample: ADA-positive sample post-baseline with titer 
that is at least 3 fold change greater than the ADA-positive baseline titer

treatment-unaffected ADA-positive sample: ADA-positive sample post-baseline with 
titer that is less than 3 fold change greater than the ADA-positive baseline titer
The following summaries of ADA sample status (n and %) will be provided using the 
Immunogenicity prevalence set: ADA-positive samples (i.e. ADA prevalence) both overall, by 
treatment and by time point (including baseline). For summaries by time point, the denominator 
is the number of subjects at that time point with a non-missing sample.
2.8.5.2
Subject ADA status
Any ADA sample collected beyond 150 days of the last dose of CSJ117 will not be used for 
summaries or derivations and will only be included in the listing.
Subject ADA status is defined as follows:

Treatment-induced ADA-positive subject: subject with ADA-negative sample at 
baseline and at least one treatment-induced ADA-positive sample

Treatment-boosted ADA-positive subject: subject with ADA-positive sample at baseline 
and at least one treatment-boosted ADA-positive sample

Treatment-unaffected ADA-positive subject: subject with ADA-positive sample at 
baseline, no treatment-boosted ADA-positive samples, and at least one treatment-
unaffected ADA-positive sample

Treatment-reduced ADA-positive subject: subject with ADA-positive sample at baseline 
and at least one non-missing post baseline sample, all of which are ADA-negative 
samples

ADA-negative subject: subject with ADA-negative sample at baseline and at least one 
non-missing post baseline sample, all of which are ADA-negative samples

Inconclusive subject: subject who does not qualify for any of the above definitions or a 
subject for which the baseline sample is missing and CSJ117 PK concentration at the


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time of ADA sample collection is > the drug tolerance level (10 microgram/mL) or 
missing
Following data with number and percentage of subjects will be reported/tabulated by treatment 
group and during overall study duration. The following summaries of ADA subject status (n 
and %) will be provided using the Immunogenicity incidence set (for % the denominator is the 
number of subjects in the Immunogenicity incidence set unless otherwise specified). :

ADA negative

ADA positive (prevalence set)
o
Total ADA positive with no boost

ADA inconclusive (exposure above drug tolerance according to validated method)

Missing ADA data at pre-dose

Missing ADA data at post-dose (Number of patients with atleast 1 missing sample)
Following data with number and percentage of subjects will be reported/tabulated by treatment 
group for the whole study period:
Pre-dose ADA positive
o
boosted: boosted is defined as ADA positive at pre-dose, and post dose titer 
values increase from pre-dose by more than 3-fold at any time point
(Treatment-boosted ADA-positive subjects; for % the denominator is the 
number of subjects with ADA-positive sample at baseline)
Pre-dose ADA negative
o
induced: ADA-positive sample post-baseline with ADA-negative sample at 
baseline (Treatment-induced ADA-positive subjects; for % the denominator is 
the number of subjects with ADA-negative sample at baseline)

Transient

Persistent
Overall ADA incidence (combined results of treatment-boosted and induced)
For induced ADA positive , summaries will also be provided based on the persistent or transient 
ADA status. The definition of persistent and transient is as follows.
Persistent ADA: a) Treatment-induced ADA detected at two or more sampling time points 
during the treatment (including follow-up period if any), where the first and last ADA-positive 
samples (irrespective of any negative samples in between) are separated by a period of 16 weeks 
or longer or b) Treatment-induced ADA incidence only in the last sampling time point of the 
treatment or follow up observation period or at a sampling time point within less than 16 weeks 
before an ADA-negative last sample.
Transient ADA: a) Treatment-induced ADA detected only at one sampling time point during 
the treatment or follow-up observation period (excluding the last sampling time point) and that 


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sampling point is 16 weeks or more before an ADA negative last sample or b) Treatment-
induced ADA detected at two or more sampling time points during the treatment (including 
follow-up period if any), where the ﬁrst and last ADA-positive samples (irrespective of any 
negative samples in between) are separated by a period less than 16 weeks, and the subject’s 
last sampling time is ADA Negative.
ADA titer kinetics will be summarized by treatment group with data reported as boxplot (titer 
range, Q1, Median (Q2), Q3, and outliers) of ADA titer at each time point for each treatment 
group up to Week 24.  The plot will include total subjects, number of subjects with positive 
ADA, and % of subjects with positive ADA at each time point.  Please see example below from 
Shankar et al.
Listings of all ADA titer values will be presented for all subjects by treatment group, subject, 
and visit/time and by study period. Samples collected at unscheduled visits will not part of the 
analysis. ADA titer values will be summarized as a table by treatment arm for ADA titer at each 
time point for each arm up to Week 24.
Systemic exposure of CSJ117 will be measured concomitantly with ADA levels for 
interpretation purposes.  Systemic exposure data will be summarized and listed. No correlative 
analysis will be conducted.
Additional analyses might be performed to assess immunogenicity and may depend on 
emergent data from the study.
2.9
Pharmacokinetic endpoints
Pharmacokinetic analysis will be conducted and reported separately other than in the CSR.
CSJ117 plasma concentration data will be listed by treatment, subject, and visit/sampling time 
point. Descriptive summary statistics will be provided by treatment and visit/sampling time 
point, including the frequency (n, %) of concentrations below the lower limit of quantification 
(LLOQ) and reported as zero. Summary statistics will include mean (arithmetic and geometric), 
standard deviation, coefficient of variation (arithmetic and geometric), median, minimum, and 


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maximum. Concentrations below LLOQ will be treated as zero in summary statistics and for 
PK parameter calculations.  If at a single time point a substantial number of concentrations are 
below LLOQ, they may be substituted with a pre-defined value, such as ½ LLOQ for calculation 
of PK parameters.
Summary serum concentrations would be plotted by visit. Dose proportionality of serum 
concentrations will be assessed. .
2.11
Patient-reported outcomes
Patient-reported outcomes in this study include ACQ-5, and AQLQ+12, which are discussed 
respectively in Section 2.7.1.2, Section 2.7.1.3, and Section 2.7.1.4.
2.13
Interim analysis
2.13.1
Safety
IAs are planned for the monitoring of safety data and do not inflate the type I error for the 
primary efficacy hypothesis testing. Thus no adjustment for multiplicity is required. These 
analyses will be performed by an external Independent Statistician and an Independent 
Programmer for an independent external safety DMC. Persons directly involved in the conduct 
of the clinical trial will not be involved in performing the IA or reviewing the results. The DMC 
will be provided with reports which are semi-blinded. If necessary, the study treatment can be 
unblinded by the chair of the DMC. The DMC will review safety data and make 
recommendations regarding the conduct of the trial and/or alteration of the current protocol, 
including termination of a treatment arm.
The DMC meetings will occur approximately twice a year.
More details will be outlined in the DMC charter and a separate DMC SAP.
2.13.2
Efficacy
One or more interim analyses may be conducted to support decision-making in relation to the 
current clinical study, or the future of the sponsor’s clinical development plan or in case of any 
safety concerns from this study or ongoing clinical studies.


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3
Sample size calculation
For the primary endpoint pre-dose FEV1, we assume a variance of 0.1461 L at week 8, 0.1456 
L at week 12, and a covariance of 0.1163 between the week 8 and 12 assessments (based on a 
recent asthma dose ranging study (Bateman et al 2017) and literature data (Corren et al 2017). 
On this basis, the average of the week 8 and 12 assessments has a standard deviation of 0.3622 
L.
We assume 2:1:1:1:2:2 randomization to placebo, CSJ117 0.5 mg o.d., CSJ117 1 mg o.d., 
CSJ117 2 mg o.d., CSJ117 4 mg o.d. and CSJ117 8 mg o.d..
With these assumptions 531 patients result in above 80% power (on average across dose 
response shapes) to have a significant contrast test at the one-sided 2.5% significance level for 
a maximum treatment effect over placebo of 0.120 L in the absence of missing data. If we 
assume that 15% of patients will have missing data and if we conservatively assume that these 
patients will not contribute any information to the primary analysis, 625 patients are needed for 
the dose response part of the trial. These calculations were performed using ADDPLAN DF 
4.0.9.
The precision of the DR curve estimation were obtained from simulations. Specifically, the 
average half-length of 95% confidence interval of the estimated DR curve is 57.61 mL, and that 
of the estimated placebo-adjusted DR curve is 76.93 mL.
4
Change to protocol specified analyses
Due to depriorization of the program, this study will be terminated early and will have 
abbreviated CSR instead. The following protocol specified analyses will be removed: 

The mean daily scores of ADSD and ANSD will be analyzed using a similar MMRM 
as specified for the primary analysis but including the appropriate weeks and baseline 
as a covariate. The estimated treatment difference (CSJ117 – placebo) at each week 
as well as the average between Week 8 and Week 12 will be reported along with the 
associated 95% confidence interval.

The mean of change from baseline in the total daily use of SABA over the 12 weeks 
of treatment will be analyzed using an ANCOVA model with factors for treatment 
group, randomization strata (eosinophil count ≥ 300 or < 300 cells/µl, region), as well 
as baseline total daily SABA use, and baseline pre-dose FEV1 as continuous linear 
covariates. The estimated treatment difference (CSJ117 – placebo) will be reported 
along with the associated 95% confidence interval.

The mean daily use of SABA will be analyzed using a similar MMRM as specified 
for the primary analysis but including the appropriate visits and baseline as a 
covariate. The estimated treatment difference (CSJ117 – placebo) at each week will 
be reported along with the associated 95% confidence interval.

Between-treatment differences of the change from baseline in mean morning/evening 
PEF will be performed using the same ANCOVA models as specified for rescue 
medication data except that baseline rescue medication use will be replaced with 




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5.3
Laboratory parameters derivations
The following table shows the direction of interest when analyzing worst case values in form 
of maximum and/or minimum post-baseline values. If the direction of interest is given as "High" 
the maximum value will be calculated and used as worst value, if the direction is given as "Low" 
the minimum value will be taken, and if it is given as "Low and high", both the minimum value 
and the maximum value will be calculated and presented in summary tables.


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Table 5-1
Directions of interest for worst case value for laboratory parameters
Laboratory Parameter
Direction of interest for worst case value
A. Hematology
Hemoglobin
Low
Hematocrit
Low
Erythrocytes
Low
WBC
Low and high
Basophils
High
Eosinophils
High
Lymphocytes
Low and high
Monocytes
High
Neutrophils
Low and high
Platelets
Low and high
B. Chemistry
Albumin
Low
Alkaline Phosphatase
High
ALT/SGPT
High
AST/SGOT
High
Bilirubin Total
High
Blood Urea Nitrogen (BUN)
High
Creatinine
High
Gamma GT
High
Potassium
Low and high
Magnesium
Low and high
Calcium
Low and high
LDH
High
Phosphorus
Low and high
Sodium
Low and high
CRP
High
Fibrinogen
High
HbA1c
Low and high
The following table shows the criteria for clinically notable laboratory values. Not all 
parameters have notable criteria defined:


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Table 5-2
Clinical notable criteria for selected laboratory tests
Laboratory parameter (unit)
Lower bound of 
clinically notable range
Upper bound of 
clinically notable range
Hematology
Hematocrit (v/v)
     Male
     Female
0.37
0.32
Hemoglobin (g/L)
    Male
    Female
115
95
Platelets (x10E9/L)
75 
700
WBC (x109/L)
2.8
16.0
Chemistry
Albumin (g/L)
25
-
Alkaline Phosphatase (U/L)
-
3xULN
ALT/SGPT (U/L)
-
3xULN
AST/SGOT (U/L)
-
3xULN
Bilirubin Total (mcmol/L)
-
34.2
BUN (mmol/L)
-
9.99
Creatinine (mcmol/L)
-
176.8
Gamma GT (U/L)
-
3 x ULN
Potassium (mmol/L)
3
6
Magnesium (mmol/L)
0.51
1.07
Sodium (mmol/L)
125
160
v = volume, ULN = upper limit of normal 


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Table 5-3
Notable liver function test values
Criterion
ALT > 3 x the upper limit of normal range (ULN)
ALT > 5 x ULN
ALT > 8 x ULN
ALT > 10 x ULN
ALT > 20 x ULN
ALT or AST > 3 x ULN
ALT or AST > 5 x ULN
ALT or AST > 8 x ULN
ALT or AST > 10 x ULN
ALT or AST > 20 x ULN
Total bilirubin > 1 x ULN
Total bilirubin > 1.5 x ULN
Total bilirubin > 2 x ULN
Total bilirubin > 3 x ULN
ALP > 1.5 x ULN
ALP > 2 x ULN
ALP > 3 x ULN
ALP > 5 x ULN
ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
ALT or AST > 5 x ULN and total bilirubin > 2 x ULN
ALT or AST > 8 x ULN and total bilirubin > 2 x ULN
ALT or AST > 10 x ULN and total bilirubin > 2 x ULN
ALT or AST > 20 x ULN and total bilirubin > 2 x ULN
ALP > 3 x ULN and total bilirubin > 2 x ULN
ALP > 5 x ULN and total bilirubin > 2 x ULN
ALT or AST > 3 x ULN and Total Bilirubin > 2 x ULN and ALP < 2 x ULN (Hy's law)
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ALP = alkaline phosphatase
When a criterion contains multiple laboratory parameters, the criterion will only be considered 
to have been met when all conditions occur within a 3-day window. A case where all criteria
are met at a post-baseline time point will be considered as newly occurring if the criteria are not 
met at baseline and will be considered as worsening if the criteria are met at baseline and at 
least one component is worsening from baseline irrespective of whether the other(s) are better.
5.4
Vital signs and ECG – definition of clinically notable values
The following two tables show the clinical notable criteria for vital signs and QTcF respectively.


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Table 5-4
Clinical notable criteria for vital signs
Vital sign parameter (unit)
Lower bound of clinically 
notable range
Upper bound of clinically 
notable range
Notable value considering newly occurring or worsening cases
Systolic blood pressure (mmHg)
< 75
> 200
Diastolic blood pressure (mmHg)
< 40
> 115
Pulse rate (bpm)
< 40
> 130
Notable change from baseline
Systolic blood pressure (mmHg)
≤ 90 and decrease from 
baseline by ≥ 20 
≥ 180 and increase from 
baseline by ≥ 20
Diastolic blood pressure (mmHg)
≤ 50 and decrease from 
baseline by ≥ 15
≥ 105 and increase from 
baseline by ≥ 15
Pulse rate (bpm)
≤ 50 and decrease from 
baseline by ≥ 15
≥ 120 and increase from 
baseline by ≥ 15
Weight (kg)
Decrease > 7% from 
baseline
Increase > 7% from 
baseline
Table 5-5
Clinical notable criteria for QTcF (Fridericia’s formula)
ECG parameter (unit)
Clinically notable range
Notable value considering newly occurring or worsening cases (Males)
QTc (msec)
> 450 
QTc (msec)
> 480
QTc (msec)
> 500 
Notable value considering newly occurring or worsening cases (Females)
QTc (msec)
> 460 
QTc (msec)
> 480
QTc (msec)
> 500 
Notable change from baseline
QTc (msec)
30 – 60
QTc (msec)
> 60
Combined criterion
QTc (msec)
> 500 & increase > 60
5.5
Statistical models
Primary analysis
The following MMRM will be used for pre-dose FEV1:
Dependent variable = intercept + treatment + region + baseline FEV1 + eosinophils count at 
screening (≥ 300 or < 300 cells/µl) + FEV1 prior to inhalation + FEV1 within 30 min post 
inhalation of salbutamol/albuterol + visit + treatment*visit + baseline value*visit + error.








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SAP
CCSJ117A12201C
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