Conditions: Asthma
Keywords: Asthma, allergic, eosinophilic, non-T2 high, allergy triggered asthma, reactive asthma, asthma attack, difficulty breathing
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 118
Healthy volunteers: no

Brief summary:
An unmet medical need exists for patients with moderate and severe asthma who continue to demonstrate symptoms despite being on standard of care medications, and are not eligible for other biologic therapies developed or in development for T2-high(allergic/eosinophilic) asthma. The purpose of this study was to determine if CJM112, an anti-IL-17A antibody, displayed the clinical efficacy and safety profile to support further development in patients with inadequately controlled moderate to severe asthma with low IgE and low circulating eosinophil levels.

Detailed description:
After an initial screening visit, run-in period and baseline assessments, the eligible subjects entered the treatment period and were randomized in a 3:2 ratio to one of the two treatment groups:

* 300 mg CJM112 s.c. injection received once per week for the first 4 weeks, followed by once every two weeks up to Week 12 (Day 85) + standard of care treatment.
* Matching placebo + standard of care treatment. After completion of the last dose on Day 85 of treatment period, subjects returned for the final efficacy assessment on Day 92. Following the treatment period, all subjects entered a 13-week safety follow-up period, including the End of Study (EoS) visit on Day 176.

Arms:
arm 1: Study treatment arm 2: Placebo

Interventions: intervention 1: CJM112 intervention 2: Placebo to CJM112
Intervention descriptions: intervention 1: 300 mg CJM112 (Study treatment) s.c. injection received per week for the first 4 weeks, followed by once every two weeks up to Week 12 (Day 85) + standard of care treatment. intervention 2: Placebo to match CJM112 + standard of care treatment

Protocol document:
Prot_001.pdf: 
Novartis Institutes for BioMedical Research
CJM112
Clinical Trial Protocol CCJM112X2204
A randomized, subject- and investigator-blinded, placebo-
controlled, multi-center, multiple dose study to assess the 
efficacy and safety of CJM112 in patients with inadequately 
controlled moderate to severe asthma
Document type:
Amended Protocol Version
EUDRACT number:
2017-000205-21
Version number:
v02 (Clean)
Clinical Trial Phase:
II
Release date:
15-May-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. Note: The SOM will not be part of the Clinical Study Report.
Notification of serious adverse events
Dear Investigator,
You must report a serious adverse event (SAE) (initial or follow-up) to Novartis as 
summarized below. Refer to Section 9.2 of the protocol for SAE criteria and additional 
requirements.  See also page 2 of the Site Operations Manual for further details on the method 
of reporting a SAE.

Complete SAE report

Submit SAE report to Chief Medical Office and Patient Safety (CMO & PS) within 24
hours after awareness of the SAE

Notify the Novartis Medical Lead

The fax number(s) and email address(es) are located in the Site Operations Manual.


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................6
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................11
Protocol synopsis...............................................................................................................16
1
Introduction .......................................................................................................................19
1.1
Background............................................................................................................19
1.2
Nonclinical data.....................................................................................................20
1.3
Clinical data...........................................................................................................20
1.3.1
Human safety and tolerability data .......................................................20
1.3.2
Human pharmacokinetic data................................................................22
1.3.3
Human pharmacodynamic data.............................................................23
1.4
Study purpose ........................................................................................................23
2
Study objectives and endpoints .........................................................................................24
2.1
Primary objective(s)...............................................................................................24
2.2
Secondary objective(s)...........................................................................................24
2.3
Exploratory objective(s) ........................................................................................24
3
Investigational plan ...........................................................................................................25
3.1
Study design...........................................................................................................25
3.2
Rationale of study design.......................................................................................27
3.3
Rationale for dose/regimen, route of administration and duration of treatment....27
3.4
Rationale for choice of comparator .......................................................................28
3.5
Rationale for choice of background therapy..........................................................28
3.6
Purpose and timing of interim analyses/design adaptations..................................28
3.7
Risks and benefits..................................................................................................29
3.7.1
Blood sample volumes..........................................................................30
4
Population..........................................................................................................................30
4.1
Inclusion criteria ....................................................................................................30
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4.2
Exclusion criteria...................................................................................................31
5
Restrictions for Study Subjects .........................................................................................33
5.1
Contraception requirements...................................................................................33
5.2
Prohibited treatment...............................................................................................33
5.3
Dietary restrictions and smoking...........................................................................34
5.4
Other restrictions ...................................................................................................34
6
Treatment...........................................................................................................................34
6.1
Study treatment......................................................................................................34
6.1.1
Investigational treatment and control drugs..........................................34
6.1.2
Additional study treatment....................................................................35
6.2
Treatment arms......................................................................................................35
6.3
Treatment assignment and randomization.............................................................35
6.4
Treatment blinding.................................................................................................35
6.5
Treating the subject................................................................................................37
6.6
Permitted dose adjustments and interruptions of study treatment.........................37
6.7
Emergency breaking of assigned treatment code ..................................................37
6.8
Treatment exposure and compliance .....................................................................37
6.9
Recommended treatment of adverse events ..........................................................38
6.10
Rescue medication.................................................................................................38
6.11
Concomitant treatment...........................................................................................38
7
Study completion and discontinuation ..............................................................................38
7.1
Study completion and post-study treatment ..........................................................38
7.2
Discontinuation of study treatment........................................................................39
7.3
Withdrawal of informed consent ...........................................................................40
7.4
Lost to follow-up ...................................................................................................41
7.5
Study Stopping rules..............................................................................................41
7.6
Early study termination by the sponsor .................................................................41
8
Procedures and assessments ..............................................................................................42
8.1
Assessment schedule .............................................................................................42
8.2
Informed consent procedures.................................................................................45
8.3
Subject screening...................................................................................................45
8.4
Subject demographics/other baseline characteristics.............................................46
8.4.1
Demography..........................................................................................46
8.4.2
Medical history/current medical conditions..........................................46
8.5
Efficacy / Pharmacodynamics ...............................................................................46
8.5.1
Clinical Outcome Assessments (COAs) ...............................................47


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8.5.2
Spirometry.............................................................................................47
8.6
Safety.....................................................................................................................47
8.6.1
Clinical Chemistry ................................................................................48
8.6.2
Electrocardiogram (ECG) .....................................................................48
8.6.3
Hematology...........................................................................................48
8.6.4
Immunogenicity ....................................................................................48
8.6.5
Physical Examination............................................................................49
8.6.6
Vital Signs.............................................................................................49
8.7
Pharmacokinetics...................................................................................................49
8.7.1
PK blood collection...............................................................................50
8.8
Other assessments..................................................................................................50
8.9
Use of residual biological samples ........................................................................51
9
Safety monitoring..............................................................................................................51
9.1
Adverse events.......................................................................................................51
9.2
Serious adverse event reporting.............................................................................53
9.2.1
Definition of SAE .................................................................................53
9.2.2
SAE reporting........................................................................................54
9.3
Liver safety monitoring .........................................................................................54
9.4
Renal safety monitoring.........................................................................................55
9.5
Reporting Medication errors including misuse/abuse ...........................................56
9.6
Pregnancy reporting...............................................................................................56
9.7
Early phase safety monitoring ...............................................................................57
10 Data review and database management.............................................................................57
10.1
Site monitoring ......................................................................................................57
10.2
Data collection.......................................................................................................58
10.3
Database management and quality control............................................................58
10.4
Data Monitoring Committee..................................................................................59
10.5
Adjudication Committee........................................................................................59
11 Data analysis......................................................................................................................59
11.1
Analysis sets ..........................................................................................................59
11.2
Subject demographics and other baseline characteristics......................................59
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11.3
Treatments .............................................................................................................60
11.4
Analysis of the primary variable(s) .......................................................................60
11.4.1
Variable(s).............................................................................................60
11.4.2
Statistical model, hypothesis, and method of analysis..........................60
11.4.3
Handling of missing values/censoring/discontinuations.......................60
11.5
Analysis of secondary variable(s)..........................................................................61
11.5.1
Efficacy / Pharmacodynamics...............................................................61
11.5.2
Safety.....................................................................................................61
11.5.3
Pharmacokinetics ..................................................................................61
11.5.4
Other assessments .................................................................................62
11.6
Analysis of exploratory variables ..........................................................................62
11.7
Sample size calculation..........................................................................................63
11.8
Interim analyses.....................................................................................................63
12 Ethical considerations........................................................................................................64
12.1
Regulatory and ethical compliance........................................................................64
12.2
Responsibilities of the investigator and IRB/IEC..................................................64
12.3
Publication of study protocol and results...............................................................64
13 Protocol adherence ............................................................................................................65
13.1
Protocol Amendments ...........................................................................................65
14 References .........................................................................................................................66
15 Appendix 1: Liver Event Definitions and Follow-up Requirements.................................67
16 Appendix 2: Specific Renal Alert Criteria and Actions ....................................................69
List of tables
Table 5-1
Prohibited medication ...........................................................................34
Table 6-1
Overview of study medication ..............................................................34
Table 6-2
Blinding levels ......................................................................................36
Table 8-1
Assessment schedule.............................................................................42
Table 9-1
Summary of reporting requirements for medication errors...................56
Table 15-1
Liver Event Definitions.........................................................................67
Table 15-2
Actions required for Liver Events.........................................................67
Table 15-3
Exclusion of underlying liver disease ...................................................68
Table 16-1
Specific Renal Alert Criteria and Actions.............................................69
Table 16-2
Follow-up of renal events......................................................................70
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List of figures
Figure 3-1
Study Design .........................................................................................26


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List of abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BUN
blood urea nitrogen
CFR
U.S. Code of Federal Regulation
CO2
carbon dioxide
COAR
Clinical Operations, Analytics & Regions
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CV
coefficient of variation
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
HIV
human immunodeficiency virus
HS
Hidradenitis Suppurativa
i.v.
intravenous
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
LDH
lactate dehydrogenase
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
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s.c.
subcutaneous
SAE
serious adverse event
sCR
serum creatinine
SD
standard deviation
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
T2
T helper cell type 2
ULN
upper limit of normal


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug(s) (an active drug or an inactive drug, such as a placebo) which 
is used as a comparator to the investigational drug being tested in the trial
Dosage
Dose of the study treatment given to the subject in a time unit 
(e.g. 100 mg once a day, 75 mg twice a day)
Enrollment
Point/time of subject entry into the study at which informed consent must 
be obtained (i.e. prior to starting any of the procedures described in the 
protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is associated 
with a purpose (e.g. screening, randomization, treatment, follow-up) 
which applies across all arms of a study.
Healthy volunteer
A person with no known significant health problems who volunteers to 
be a study participant 
Investigational 
drug
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and Directive 
2001/20/EC and is synonymous with “investigational new drug” or “test 
substance”
Investigational 
treatment
All investigational drug(s) whose properties are being tested in the study 
as well as their associated treatment controls. This includes any placebos, 
any active controls, as well as approved drugs used outside of their 
indication/approved dosage or tested in a fixed combination. 
Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed by 
the protocol when used within approved indication/dosage.
Medication 
number
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system.
Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease.
Patient
An individual with the condition of interest
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.


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Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and assessments; at this time 
all study drug administration is discontinued and no further assessments 
are planned.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding 
to a specific treatment arm assignment
Screen Failure
A subject who is screened but is not treated or randomized
Stage
A major subdivision of the study timeline; begins and ends with major 
study milestones such as enrollment, randomization, completion of 
treatment, etc.
Study completion
Point/time at which the subject came in for a final evaluation visit or 
when study drug was discontinued whichever is later.
Study 
drug/treatment
Any drug (or combination of drugs) administered to the subject as part of 
the required study procedures; includes investigational drug, active drug 
run-ins or background therapy.
Study treatment
Any drug administered to the study participants as part of the required 
study procedures; includes investigational drug (s), control(s) or non-
investigational medicinal product(s)
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject 
and should be used to identify the subject throughout the study for all 
data collected, sample labels, etc.
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study
Withdrawal of 
study consent 
Withdrawal of consent from the study occurs only  when a subject does 
not want to participate in the study any longer, and does not allowany 
further collection of personal data 


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Protocol synopsis
Protocol number
CCJM112X2204
Title
A 
randomized, 
subject-
and 
investigator-blinded, 
placebo-controlled, 
multi-center, multiple dose study to assess the efficacy and safety of CJM112 in 
patients with inadequately controlled moderate to severe asthma
Brief title
Study of safety and efficacy of CJM112 in moderate to severe asthmatics
Sponsor and 
Clinical Trial 
Phase
Novartis
Phase II
Intervention type
Biologic
Study type
Interventional 
Purpose and 
rationale
An unmet medical need exists for patients with moderate and severe asthma 
who continue to demonstrate symptoms despite being on standard of care 
medications, and are not eligible for other biologic therapies developed or in 
development for T2-high (allergic/eosinophilic) asthma (such as omalizumab 
and mepolizumab) because they have low circulating IgE and eosinophil levels 
at baseline. The purpose of this study is to determine if CJM112, an anti-IL-17A 
antibody, when added to existing therapy, displays the clinical efficacy and 
safety profile to support further development in patients with inadequately 
controlled moderate to severe asthma with low IgE and low circulating 
eosinophil levels.
Primary 
Objective(s)
To determine whether treatment with CJM112 in patients with inadequately 
controlled moderate to severe asthma leads to an improvement in airflow 
obstruction as reflected by change from baseline in FEV1 in mL.
Secondary 
Objectives
To determine whether treatment with CJM112 in patients with inadequately 
controlled moderate to severe asthma:
1.
leads to an improvement in FEV1% of predicted.
2.
leads to an improvement in asthma control as reflected by change from
baseline in ACQ score
3.
is safe and well tolerated by evaluating study treatment discontinuations
and adverse events
Study design
12 week, non-confirmatory, randomized, subject- and investigator-blinded, 
placebo-controlled, multi-center, parallel-arm study in which patients will be 
randomized 3:2 to CJM112:placebo.
Population
The study population will consist of approximately 110 male and female patients 
between 18 and 75 years old with uncontrolled symptoms of moderate or 
severe asthma (defined by ACQ score of ≥1.5) who are compliant on standard 
of care medications.


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Key Inclusion 
criteria
1.
Patients with a physician-diagnosed history of moderate to severe asthma
for a period of at least one year prior to screening.
2.
Patients on a stable therapy regimen of asthma for at least 3 months prior
to screening with at least medium dose inhaled glucocorticoid and at least
one additional asthma controller medication (such as inhaled long-acting
bronchodilator, leukotriene antagonist, theophylline, stable low dose
glucocorticoid, etc).
3.
Acceptable and reproducible spirometry with FEV1 ≥ 40 and ≤ 90% of
predicted at screening and baseline visits (re-testing is allowed once).
4.
ACQ score ≥ 1.5 at screening and baseline visits (re-testing is allowed
once).
5.
Total serum IgE < 150 IU/mL at screening and baseline visits
6.
Peripheral blood eosinophils <300/μL at screening and baseline visits
Key Exclusion 
criteria
1.
Previous use of biologics or other concomitant medications within the time
periods specified in the SOM/protocol.
2.
History of ongoing, chronic, or recurrent moderate or severe infectious
disease.
3.
Patients who have smoked or inhaled recreational foreign substances such
as nicotine, tobacco products, marijuana, e-cigarettes, etc within the 6
month period prior to Visit 1 or who have any smoking history of greater
than 10 pack years (Assuming 1 pack = 20 cigarettes or equivalent).
4.
Patients who have had an asthma attack/exacerbation requiring systemic
corticosteroids for at least 3 continuous days within 4 weeks prior to
screening.
5.
Patients who have had a respiratory tract infection or asthma worsening
within 4 weeks prior to Visit 1 or during the screening period.
6.
Women of child-bearing potential unless they are using highly effective
methods of contraception during dosing and for 13 weeks after stopping of
investigational drug.
Study treatment

Subcutaneous injections of CJM112 300 mg (2 injections of 150 mg)

Matching placebo
Efficacy/PD 
assessments

Spirometry measurements

ACQ score
Key safety 
assessments

Physical examination

Vital signs

ECGs

Safety laboratory tests (hematology, blood chemistry, and urinalysis)

Adverse event monitoring
Other 
assessments
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Data analysis
Key words
Phase II, safety, efficacy, CJM112, asthma, T2 low
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1
Introduction
1.1
Background
The most relevant data for the present study are summarized in the sections below. 
For detailed information, please refer to the Investigator's Brochure.
Asthma is a heterogeneous inflammatory disease of the airways that clinically manifests with 
symptoms and signs of airflow obstruction of varied severity. Although the majority of 
asthma patients can be effectively treated with currently available medications such as inhaled 
glucocorticoids and bronchodilators, a substantial subset exists who remain difficult-to-treat 
and manifest with severe disease. These patients account for a relatively large proportion of 
resource expenditure Chung et al 2014.
While asthma has been considered to be driven by T helper cell type 2(T2) cells such as IgE 
activated mast cells, eosinophils and their products, data suggest that a T2-high gene signature
is present in the airways of only 50% of asthmatics Woodruff et al 2009. Non-T2-high or 
non-eosinophilic airway inflammation occurs in approximately 50% of patients with asthma, 
of which a significant proportion include moderate and severe asthmatics Thomson 2016. 
Non-eosinophilic inflammation is associated with an impaired therapeutic response to inhaled 
corticosteroids
McGrath et al 2012, 
and 
hence 
asthmatics 
with 
non-allergic 
and 
non-eosinophilic phenotype are not eligible for available biologic therapies with anti-IgE and 
anti-IL5 antibodies. Thus, a large unmet medical need exists in moderate and severe non-
allergic non-eosinophilic asthmatics who suffer from symptoms of poorly controlled asthma 
such as cough and shortness of breath, despite being compliant on standard of care therapy. 
We hypothesize that therapy with anti-IL17 antibodies has the potential to address this unmet 
medical need in patients with asthma.
Increased levels of IL-17A that correlate with the severity of asthma have been reported in the 
circulation and airways of individuals with asthma compared to healthy controls. 
High IL-17A mRNA levels have been found in patients with moderate-to-severe asthma, even 
if those patients were treated with corticosteroids Bullens et al 2006. Pre-clinical studies in 
mouse models of allergic pulmonary inflammation have implicated a requirement for IL-17A 
and its receptor (IL-17RA) in neutrophilic airway inflammation and steroid - resistant airway 
hyper-responsiveness. Thus, the properties of IL-17A in vitro, its presence in increased 
amounts in asthma, and the pre-clinical models of the disease support a role for IL-17A in 
neutrophilic and/or T2-low forms of the disease that are poorly responsive to steroids
Cosmi et al 2011. Proof of principle that anti-IL17 therapy can lead to clinically relevant 
beneficial outcomes in a sub-group of asthmatics has been demonstrated Busse et al 2013. 
Hence, we propose to investigate the efficacy and safety of CJM112, an anti-IL17A antibody, 
in patients with inadequately controlled, non-T2 driven, moderate to severe asthma in this 
study protocol.


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1.2
Nonclinical data
1.3
Clinical data
Relevant clinical data are summarized in the sections below. For detailed information, please 
refer to the Investigators Brochure.
1.3.1
Human safety and tolerability data
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1.3.2
Human pharmacokinetic data
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1.3.3
Human pharmacodynamic data
1.4
Study purpose
The purpose of this study is to determine whether CJM112, when added to existing therapy, 
displays the clinical efficacy and safety profile to support further development in patients with 
inadequately controlled moderate to severe asthma.
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2
Study objectives and endpoints
2.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary objective(s)

To determine whether treatment with CJM112
in patients with inadequately controlled
moderate to severe asthma leads to an
improvement in airflow obstruction

Change from baseline FEV1 in mL
2.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary 
objective(s)

To determine whether treatment with CJM112
in patients with inadequately controlled
moderate to severe asthma leads to an
improvement in FEV1% of predicted

Change from baseline FEV1 % of
predicted

To determine whether treatment with CJM112
in patients with inadequately controlled
moderate to severe asthma leads to an
improvement in asthma control

Change from baseline in ACQ
score, % of patients with ≥ 0.5
decrease in ACQ score

To assess the safety and tolerability of
CJM112 in patients with inadequately
controlled moderate to severe asthma

Study treatment discontinuations and
adverse events
2.3
Exploratory objective(s)
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3
Investigational plan
3.1
Study design
This is a non-confirmatory, randomized, subject- and investigator-blinded, placebo-controlled, 
multi-center, parallel-arm study evaluating the efficacy of CJM112 on top of standard of care 
in patients with inadequately controlled moderate to severe asthma.  This study will enroll 
approximately 110 patients. After an initial screening visit and run-in period of approximately 
4 weeks, subjects eligible per inclusion and exclusion criteria at the baseline visit will be 
randomized (3:2) to receive 
CJM112 or matching placebo 
subcutaneously over 3 months during visits at the clinical study site. All baseline safety 
evaluation results must be available prior to the first dose. After the end of the treatment 
period, subjects will be followed for an additional 13 weeks. Site visits to administer dose and 
assess safety and efficacy will be scheduled as depicted in the figure below. 
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Figure 3-1
Study Design
Screening and Run-In: Patients will provide informed consent and participate in an initial 
screening visit consisting of vital signs, physical exam, blood chemistry, ECG, pulmonary 
function tests, and ACQ. Subjects who meet all eligibility criteria at the screening visit will be 
dispensed a daily symptom diary and be asked to perform peak flow measurements over the 
approximately 4 week run-in period until the baseline visit. 
Baseline: Subjects who qualify based on screening and run-in assessments will return for a 
baseline evaluation between Day -5 to Day -2. Subjects who meet all the applicable 
inclusion/exclusion criteria at screening and baseline will be randomized and will enter the 
treatment period. All screening and baseline assessments results must be available prior to 
randomization.
Treatment Period:
At treatment period visits, safety, 
 assessments will be performed. 
Safety assessments will include physical examinations, open ended health inquiry, ECGs, 
vital signs, standard clinical laboratory evaluations (hematology, blood chemistry, urinalysis), 
AEs and SAE monitoring.
Safety Follow-up: After completing the last dose 
, subjects will enter an additional 
 follow-up period consisting of a visit on Day 92, Day 134 and an End of Study 
(EOS) visit on Day 176.
Subjects who discontinue treatment early (unless they have withdrawn consent) should 
complete the D92, D134 and End of Study visit D176. All subjects who discontinue the study 
early (including subjects who withdraw consent) will be required to complete the EOS visit.
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3.2
Rationale of study design
This study is an exploratory, multi-center, randomized, subject- and investigator-blinded, 
placebo-controlled, parallel-group, phase IIa study with a 12-week treatment epoch. 
Rationale for population: An unmet medical need exists for patients with moderate or severe 
asthma who continue to demonstrate symptoms despite being on standard of care medications 
and are not eligible for other biologic therapies developed or in development for T2-high 
(allergic/eosinophilic) asthma (such as omalizumab and mepolizumab) because they have low 
circulating IgE and eosinophil levels at baseline.
Rationale for study design: In order to optimize the rigor and integrity of the study and 
minimize bias, a randomized, subject- and investigator-blinded parallel group study design is 
used. This design is well-established in respiratory clinical trials and enables the study 
treatment to be given for an appropriate and practical length of time to assess the efficacy and 
safety of the treatment.
Rationale for placebo control: The placebo arm controls for potential bias in efficacy and 
safety assessments. The study design includes a placebo control and not an active control 
because the study treatment will be added on top of standard of care therapy for each patient. 
Rationale for run-in period: The run-in period will ensure subject's eligibility for the study 
at the baseline visit after their standard of care treatment has been adhered to during the run-in 
period and will minimize the potential for changes in key endpoints as a result of regression to 
the mean at the end of the study period.
Rationale for follow up period 
:
Hence, a 
follow up period is proposed after the last dose on study Day 85 to ensure 
patient safety, compliance with contraception requirements, and to assess for loss of efficacy 
of the investigational treatment
. 
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
The study participants will receive CJM112 300 mg or placebo s.c. injections 9 times during 
the 12 week treatment period: 5 weekly doses of 300 mg s.c. each (induction/loading) and 
4 subsequent doses every 2 weeks (maintenance). This regimen is considered practical and 
feasible for this severe asthma population. A weekly loading dose regimen of 5 doses of 
300 mg has been safe and well-tolerated with early evidence of efficacy in the ongoing 
clinical study in patients with hidradenitis suppurativa (CCJM112X2202) 
. The 12 week treatment duration 
is considered adequate to demonstrate improvements in the key endpoints in patients with 
severe asthma based on published literature Wenzel et al 2016, 
.
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3.4
Rationale for choice of comparator
Patients with asthma in this study will continue the standard of care medications as prescribed 
by their primary physicians. Hence the study design includes a placebo control and not an 
active control because the study treatment will be added on top of standard of care. 
The placebo arm is expected to control for potential bias in efficacy and safety assessments in
the study.
3.5
Rationale for choice of background therapy
Patients eligible to participate in this trial will be required to demonstrate symptoms of un-
controlled asthma (as defined by an Asthma Control Questionnaire (ACQ) score of at least 
1.5), despite compliance with standard of care therapy for moderate or severe asthma 
according to local practice. Thus the background therapy will include at least medium dose 
inhaled glucocorticoid (refer to SOM for glucocorticoid doses) and at least one additional 
asthma controller medication as required by inclusion criterion 6.
3.6
Purpose and timing of interim analyses/design adaptations
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3.7
Risks and benefits
There is no significant benefit expected for subjects participating in this study. A transient 
benefit may be observed if CJM112 provides efficacy. A positive outcome from this study 
may lead to further development of CJM112 for eligible patients with asthma.
The risk to subjects in this trial will be minimized by adherence to the eligibility criteria, close 
clinical monitoring, avoidance of prohibited concomitant medications, regular safety reviews, 
adequate safety follow up and study stopping rules.
Treatment for adverse event should follow general guidelines for standard-of-care and is at 
the discretion of the investigator or treating physician. There are no specific treatment 
recommendations for adverse events that may occur in this trial.
Women of child bearing potential should be informed that taking the investigational drug may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the subject will not reliably comply, they 
should not be entered in the study.
Because CJM112 is a monoclonal antibody, men participating in the study do not need to use 
condoms during sexual intercourse. 
CJM112 has been well tolerated in clinical trials in other indications to date. Primarily 
non-serious upper respiratory tract infections have been observed (in particular pharyngitis 
and nasopharyngitis) more frequently with CJM112 than placebo, and a potential for 
dose-dependent increase in rates of infection may exist. Most of the events were, however, 
mild or moderate in severity. Small, incremental risks in Candida infections are reported for 
IL-17 blocking agents but have not been observed so far for CJM112. 
Hypersensitivity reactions have not been observed so far for CJM112, but their future 
occurrence cannot be excluded. Study subjects should be monitored post-injection for 
hypersensitivity and anaphylaxis events for an appropriate amount of time, no less than 30 
minutes post-dose. Injection site reactions, elevations in liver enzymes, drops in neutrophil 
counts and ECG abnormalities have been observed sporadically and very rarely in 
secukinumab trials. These constitute events that may be observed and should be monitored 
routinely, as with any investigational biologic treatment. 
Due to the early stage of development, there may be unknown risks of CJM112 which may be 
serious and/or unforeseen.
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Additional risks to study subjects are related to the procedures of this clinical trial, such as 
withholding bronchodilators prior to lung function tests and blood sampling. During the 
collection of blood samples, patients may experience pain and/or bruising at the injection site. 
In addition, although rare, localized clot formation, infections and nerve injuries may occur. 
Lightheadedness or fainting may also occur during or after the blood draw.
Certain adverse events, such as shortness of breath, wheezing, cough, chest tightness and 
asthma flares or exacerbations may occur in study participants. These risks are inherent to the 
disease process and are unlikely to be caused or worsened by CJM112 or study participation, 
except when bronchodilators are withheld prior to lung function tests. If a subject is unable to 
withhold bronchodilators prior to lung function tests, he/she should be treated appropriately 
and his/her participation in this study should be re-considered.
3.7.1
Blood sample volumes
Approximately 400 mL of blood is planned to be collected over a period of 16 weeks, from 
each subject as part of the study. Additional samples collected for monitoring of any safety 
findings would be in addition to this pre-specified volume. This is not considered to be a risk 
for this population.
Timings of blood sample collection are outlined in the Assessment schedule, Section 8.1.
A summary blood log is provided in the Site Operations Manual, together with instructions 
for all sample collection, processing, storage, and shipment information.
See Section 8.9 regarding the potential use of residual samples. 
4
Population
The study population will consist of approximately 110 male and female patients with 
uncontrolled symptoms of moderate or severe asthma (defined by ACQ score of ≥ 1.5) on 
standard of care medications. Drop-outs after randomization will not be replaced. 
The investigator must ensure that all subjects being considered for the study meet the 
following eligibility criteria. No additional criteria should be applied by the investigator, in 
order that the study population will be representative of all eligible subjects.
Subject selection is to be established by checking through all applicable eligibility criteria at 
screening and baseline. A relevant record (e.g. checklist) of the eligibility criteria must be 
stored with the source documentation at the study site.
Deviation from any entry criterion excludes a subject from eligibility for the study.
4.1
Inclusion criteria
Population eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed
2. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.
3. Male and female adult patients aged ≥ 18 to ≤ 75 years.
4. Patients must weigh between 50 and 120 kg


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5. Patients with a physician-diagnosed history of moderate to severe asthma  for a period of
at least one year prior to screening
6. Patients on a stable therapy regimen for asthma for at least 3 months prior to screening
with at least medium dose inhaled glucocorticoid and at least one additional asthma
control medication (such as inhaled long-acting bronchodilator, leukotriene antagonist,
theophylline, stable low dose glucocorticoid, etc)
7. Acceptable and reproducible spirometry with FEV1 ≥ 40 and ≤ 90 % of predicted at
screening and baseline visits (Re-testing is allowed once)
8. ACQ score  ≥ 1.5 at screening and baseline visits (Re-testing is allowed once)
9. Total serum IgE < 150 IU/mL at screening and baseline visits (Re-testing is allowed once)
10. Peripheral blood eosinophils < 300/μL at screening and baseline visits (Re-testing is
allowed once)
4.2
Exclusion criteria
Population fulfilling any of the following criteria are not eligible for inclusion in this study:
1. Use of investigational drugs at the time of screening, or within 4 weeks or 5 half-lives of
screening, or as required by local regulations, whichever is longer.
2. Treatment with IL-17 or IL-17R blocking agents over the previous 12 months, including,
but not limited to secukinumab, ixekizumab, bimekizumab and brodalumab.
3. Previous use of biologics or other concomitant medications within time periods specified
in the SOM/protocol.
4. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 13 weeks after stopping of investigational drug. Highly effective
contraception methods include:

Total abstinence from heterosexual intercourse (when this is in line with the preferred
and usual lifestyle of the subject). Periodic abstinence (e.g. calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods
of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking
investigational drug.  In case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment.

Male sterilization (at least 6 months prior to screening). For female subjects in the
study the vasectomized male partner should be the sole partner for that subject.

Use of oral, injected or implanted hormonal methods of contraception or placement of
an intrauterine device (IUD) or intrauterine system (IUS) 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 be stable on the same pill for a 
minimum of 3 months before taking investigational drug.
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Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child bearing potential.
5. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive hCG
laboratory test.
6. History of ongoing, chronic or recurrent moderate or severe infectious disease.
7. Patients with chronic lung diseases other than asthma, including (but not limited to)
chronic obstructive pulmonary disease, clinically significant bronchiectasis, sarcoidosis,
interstitial lung disease, cystic fibrosis, Churg-Strauss syndrome, allergic broncho-
pulmonary aspergillosis, or clinically significant chronic lung diseases related to a history
of tuberculosis or asbestosis.
8. History of severe systemic Candida infections or evidence of Candidiasis in the 2 weeks
prior to baseline visit.
9. Active systemic infections during the 2 weeks prior to baseline.
10. History of immunodeficiency diseases, including a positive HIV (ELISA and Western
blot) test result at screening.
11. A positive Hepatitis B surface antigen or Hepatitis C test result at screening
12. Any live vaccines (this includes nasal-spray flu vaccine) starting from 6 weeks before
baseline
13. Any severe, progressive or uncontrolled, acute or chronic, medical or psychiatric
condition, or other factors such as abnormal vital signs, ECG or physical findings, or
clinically relevant abnormal laboratory values, that in the judgment of the investigator
may increase the risk associated with study participation/treatment or may interfere with
interpretation of study results, and thus would make the patient inappropriate for entry into
or continuing the study.
14. History of hypersensitivity or allergy to the investigational compound/compound class
being used in this study.
15. Donation or loss of 400 ml or more of blood within 8 weeks prior to baseline, or longer if
required by local regulation.
16. History of drug or alcohol abuse within the 12 months prior to dosing.
17. At screening, history or symptoms of malignancy of any organ system (except for a
history of basal cell carcinoma and/or up to 3 squamous cell carcinomas of the skin, if
successful treatment has been performed, with no signs of recurrence; actinic keratosis, if
present at screening, should be treated according
to standard therapy before
randomization), treated or untreated, within the past 5 years, regardless of whether there is
evidence of local recurrence or metastases.
18. Patients with known active Crohn’s disease.


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19. Patients who have smoked or inhaled recreational foreign substances such as nicotine,
tobacco products, marijuana, e-cigarettes, etc within the 6 month period prior to Visit 1, or 
who have any smoking history of greater than 10 pack years (e.g. 10 pack years = 1 
pack/day x 10 years or ½ pack/day x 20 years, etc.) (Assume 1 pack = 20 cigarettes or 
equivalent).
20. History of life-threatening asthma event in the previous year, such as significant 
hypercarbia (pCO2 > 45 mmHg), endotracheal intubation, non-invasive positive pressure 
ventilation (NIPPV), respiratory arrest, or seizure as a result of asthma.
21. Patients who have had an asthma attack/exacerbation requiring systemic corticosteroids 
for at least 3 continuous days within 4 weeks prior to screening (re-screening is permitted). 
22. Patients who have had a respiratory tract infection or asthma worsening within 4 weeks 
prior to Visit 1 (Screening) or during the screening period. Patients may be re-screened 
4 weeks after recovery from their respiratory tract infection or asthma worsening.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
5
Restrictions for Study Subjects
During recruitment, screening/informed consent review, and baseline visit, the subjects must
be informed and reminded of the restrictions outlined in this section.
5.1
Contraception requirements
Please refer to exclusion criteria (Section 4.2) for details of contraception requirements for the 
study.
Women of child bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study, and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the subject will not reliably comply, they 
should not be entered or continue in the study.
Male subjects are not required to wear a condom for the duration of the study. However, he 
should 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. 
5.2
Prohibited treatment
Each concomitant drug must be individually assessed against all exclusion criteria and the 
table below to see if it is allowed. If in doubt, the investigator should contact the medical 
monitor before randomizing a patient or allowing a new medication to be started. 
The following drugs are excluded to ensure patient safety and prevent confounding of efficacy 
in this clinical trial.


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Table 5-1
Prohibited medication
Medication
Prohibited period
Action to be taken
IL-17 or IL17R blocking agents, including, 
but not limited to secukinumab, ixekizumab, 
bimekizumab and brodalumab.
12 months prior to screening 
through end of study
Exclude until patient 
re-qualifies for study
Anti-IgE biologic therapy such as 
omalizumab
3 months prior to screening 
through end of study
Exclude until patient 
re-qualifies for study
Anti-IL 4, 5 or 13 biologic therapy such as 
mepolizumab or dupilumab
3 months prior to screening 
through end of study
Exclude until patient 
re-qualifies for study
Other investigational drugs 
4 weeks or 5 half-lives, 
whichever is longer
Exclude until patient 
re-qualifies for study
Live vaccine
6 weeks prior to baseline visit 
through end of study
Exclude until patient 
re-qualifies for study
5.3
Dietary restrictions and smoking
Study participants must refrain from smoking or inhaling nicotine or tobacco products or 
other recreational inhaled foreign substances such as marijuana, e-cigarettes, etc for the 
duration of the study. 
Participants should refrain from alcohol and caffeine intake 24 hours and 8 hours prior to each 
study visit respectively.
5.4
Other restrictions
Study participants are expected to refrain from strenuous physical exercise (e.g. weight 
training, aerobics, football) until after Study Completion evaluation. Restrictions on 
bronchodilators are described in Section 6.10 and Section 6.11 of the protocol.
6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions 
to be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the Site Operations Manual. Refer to Section 5.3 for 'Dietary restrictions and 
smoking' during study treatment. 
6.1.1
Investigational treatment and control drugs
Table 6-1
Overview of study medication
Study drug 
name
Formulation
Unit dose
Packaging 
Provided 
by
CJM112
150mg/1mL
Liquid in vial
150 mg/mL
Double Blind patient specific kits
Novartis
Placebo to 
CJM112
Liquid in vial
0 mg/mL
Double Blind patient specific kits
Novartis


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6.1.2
Additional study treatment
No additional treatment beyond investigational drug and placebo are included in this trial. 
The study participant or the investigational site are responsible for sourcing all other 
treatments such as standard of care inhalers, rescue inhalers, etc.
6.2
Treatment arms
6.3
Treatment assignment and randomization
At the Day 1 visit, all eligible patients will be randomized and treatment will be assigned via 
Interactive Response Technology (IRT). Randomization will be stratified by region (US, EU, 
and Rest of World). Standard of care practice for management of asthma may vary by region 
due to availability of inhalers; thus, we will stratify randomization by region. The IRT can be 
contacted via the interactive web response system (IWRS). The investigator or his/her 
delegate will contact the IRT after confirming that the subject fulfills all the 
inclusion/exclusion criteria.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. 
A subject randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of subject numbers to randomization numbers. 
These randomization numbers are linked to the different treatment arms, which in turn are 
linked to medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the investigational drug(s).
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
Follow the details outlined in the Site Operations Manual regarding the process and timing of 
treatment assignment and randomization of subjects.
6.4
Treatment blinding
This is a subject and investigator-blinded study. Subjects and investigators will remain 
blinded to study treatment throughout the study, except where indicated below.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, and odor.
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Site staff
All site staff (including study investigator and study nurse) will be blinded to study treatment 
throughout the study.
Unblinding a single subject at site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (see Section 6.7).
Sponsor staff
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team under blinded conditions unless otherwise allowed.
The study statistician will be able to access the randomization list for interim analyses and is 
allowed to share unblinded information with the rest of the clinical team as appropriate for 
internal decision purposes, as outlined in Table 6-2. For example, unblinded summaries and 
unblinded individual data can be shared with the team for interim analyses.
Study programmers and other personnel involved in study data analysis (e.g. biomarker 
expert) are allowed to access treatment assignment information for the purpose of conducting
interim analyses.
The clinical trial team is allowed to share unblinded results with other sponsor staff 
(e.g. decision boards) as required for internal decision making on the study or the project at 
the time of interim analyses while the study is ongoing.
All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind other study team members confidential and secure except as described above.
Following final database lock all roles may be considered unblinded.
Table 6-2
Blinding levels
Role
Time or Event
Randomization list 
generated
Treatment 
allocation & 
dosing
Safety event 
(single subject 
unblinded)
Interim 
Analysis 
Subjects/Patients
B
B
UI
B
Site staff
B
B
UI
B
Unblinded site staff (see text for 
details) 
B
UI
UI
UI
Drug Supply and Randomization 
Office
UI
UI
UI
UI
Unblinded sponsor staff (see text 
for details)
B
UI
UI
UI
Statistician/statistical 
programmer/data analysts
B
B
UI
UI
Biomarker expert and data 
manager
B
B
UI
UI
All other sponsor staff not 
identified above
B
B
UI
UI
B Remains blinded
UI Allowed to be unblinded on individual patient level


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6.5
Treating the subject
CJM112 150mg/1mL or placebo will be administered to the subject via the subcutaneous 
(s.c.) route of administration at the study site. See the Site Operations Manual for further 
details.
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
6.6
Permitted dose adjustments and interruptions of study treatment
Study treatment dose adjustments and/or interruptions are not permitted unless they are 
absolutely necessary for subject's safety. Any dose adjustments and/or interruptions will be 
recorded as protocol deviations. All changes must be recorded on the Dosage Administration 
Record CRF.
6.7
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 study 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 system at any time in case of emergency. The investigator will need to 
provide: 

protocol number

study drug name (if available)

subject number.
In addition, the investigator must provide oral and written information to inform the subject 
how to contact his/her backup in cases of emergency when he/she is unavailable to ensure that 
un-blinding can be performed at any time.
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given subject.
6.8
Treatment exposure and compliance
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6.9
Recommended treatment of adverse events
AEs should be treated per the judgement of the responsible physician. Medication used to treat AEs 
must be recorded on the Concomitant medications/Significant non-drug therapies CRF.
6.10
Rescue medication
Use of short-acting rescue inhalers/bronchodilators for asthma, such as albuterol/salbutamol, 
is permitted. They must be sourced by the investigational site or the subjects themselves. Both 
short and long acting bronchodilators must be withheld prior to the study visits as described in 
the SOM. No other specific rescue treatments are planned for this study. Use of rescue 
medication must be recorded on the Concomitant medications/Significant non-drug therapies 
CRF.
6.11
Concomitant treatment
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study.
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the 
timeframe defined in the entry criteria prior to the start of the study and during the study, must 
be recorded on the Concomitant medications/Significant non-drug therapies CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency 
and route of administration, the start and discontinuation date and the reason for therapy.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact Novartis before randomizing a subject 
or, if the subject is already enrolled, to determine if the subject should continue participation 
in the study.
7
Study completion and discontinuation
7.1
Study completion and post-study treatment
Each subject will be required to complete the study in its entirety, and thereafter no further 
study treatment will be made available to them.
Study completion is defined as when the last subject completes their End of Study visit and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the 
date of that decision.
All subjects should complete the follow up visits 201, 202 and an End of Study visit 299. 
Additionally, in case the treatment is prematurely interrupted due to AE or any other reason 
and not resumed, site should conduct visit 201 approximately 7 days after the last treatment 
visit, visit 202 approximately 6 weeks after visit 201, and visit 299 approximately 6 weeks
after visit 202. Thus, the patient will complete all 3 follow up visits, which will enable patient 
safety assessment for 13 weeks after the last dose. Additional unscheduled safety visits may 
be conducted per the judgement of the PI if required to ensure patient safety.


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All SAEs reported during the entire study duration must be reported as described in 
Section 9.2 and the Site Operations Manual.  If a subject is lost to follow-up, documentation 
of attempts to contact the subject should be recorded in the source documentation. 
Subjects are expected to continue their standard of care treatment during and after the study.
7.2
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped 
earlier than the protocol planned duration. Discontinuation of study treatment can be decided 
by either the subject or the investigator.
Study treatment must be discontinued under the following circumstances:

Subject decision - subjects may choose to discontinue study treatment for any reason at 
any time.

The investigator believes that continuation would negatively impact the safety of the 
subject or the risk/benefit ratio of trial participation.

Any protocol deviation that results in a significant risk to the subject’s safety.

Pregnancy (see Section 8.6 (Safety) and Section 9.6 (Pregnancy reporting)) 

Adverse events, abnormal laboratory values or abnormal test result that indicate a safety 
risk to the subject. 

Patients who experience an asthma exacerbation during the treatment epoch that requires 
treatment with systemic corticosteroids.

Patients with > 50% decrease in FEV1 confirmed by a repeat measurement during the 
study period.

Emergence of the following severe adverse events : 

Severe, grade 3 or higher allergic or hypersensitivity reaction

Severe, acute, grade 3 or higher infection as judged by the investigator

Severe neutropenia grade 3 or higher

If a liver or renal event occurs, follow guidelines outlined in Appendix 1 and Appendix 2
regarding discontinuation of study treatment.  

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.
Treatment for patients experiencing an asthma exacerbation with systemic steroids is 
considered standard of care. The dose and duration for such treatment will be left at the 
discretion of the clinical site study investigator, so that appropriate treatment can be tailored 
to the severity of the patient’s clinical condition. Treatment discontinuations due to asthma 
exacerbations will be considered “treatment failures”.
Use of prohibited treatment as per Table 5-1 might result in treatment discontinuation 
(decision will be taken on case by case basis after consultation with Sponsor).


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The appropriate personnel from the site and Novartis will assess whether investigational drug 
treatment should be discontinued for any subject whose treatment code has been broken 
inadvertently for any reason.
If discontinuation of study treatment occurs, investigator must determine the primary reason 
for the subject’s premature discontinuation of study treatment and record this information on 
the Dosage Administration CRF.
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 7.3, Withdraw of Informed Consent). Where possible, they should 
return for visits 201, 202 and 299. If they fail to return for these visits for unknown reasons, 
every efforts (e.g. telephone, e-mail, letter) should be made to contact the subject/pre-
designated contact as specified in Section 7.4 (Lost to follow-up). 
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.  
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
7.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, 
letter) to understand the primary reason for the subject’s decision to withdraw his/her consent 
and record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their time of withdrawal) according to 
applicable law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may
still be used for further testing/analysis in accordance with the terms of this protocol and of 
the informed consent form.


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For EU and Rest of the World: All biological samples not yet analyzed at the time of 
withdrawal will no longer be used, unless permitted by applicable law. They will be stored 
according to applicable legal requirements.
7.4
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A subject cannot be formally considered lost to follow-
up until his/her scheduled end of study visit would have occurred.
7.5
Study Stopping rules
The study may be put on hold pending full safety data review if one or more of the following 
criteria are met:

Two or more similar investigational drug (CJM112)-related SAEs are reported

Other clinically significant events that in the opinion of the investigator or sponsor 
preclude to continue dosing (especially events that are suspected to be drug related, such 
as severe infections, anaphylaxis)
In these cases, ad hoc internal experts along with representative site investigators will 
carefully evaluate the safety data of the entire study. The experts and investigators will 
recommend whether the study can be continued, should be stopped or if other safety measures 
need to be taken. The findings and recommendations of the internal experts and investigators 
will be documented and will be made available to all investigators, their respective 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) and health authorities, 
as appropriate.
7.6
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. Should this be necessary, subjects must be 
seen as soon as possible and treated as a prematurely withdrawn subject. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration is 
given to the protection of the subjects' interests. The investigator will be responsible for 
informing IRBs/IECs of the early termination of the trial.


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8
Procedures and assessments
8.1
Assessment schedule
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8.2
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
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. The date of signing of informed consent 
(and withdrawal, if later withdrawn) should be documented in the CRF.
Novartis will provide to investigators a proposed informed consent form that complies with 
the ICHE6 GCP guideline and regulatory requirements and is considered appropriate for this 
study. The informed consent form will also include a section related to optional future 
research which will require a separate signature if the subject agrees to future research.  
Any changes to the proposed consent form suggested by the investigator must be agreed to by 
Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. 
Any new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification or an Aggregate Safety Finding. New information might require an update to the 
informed consent and then must be discussed with the subject.
Ensure subjects are informed of the contraception requirements outlined in the Section 4.2
(Exclusion criteria) and in Section 5.1 (Contraception requirements).
Pregnancy outcomes must be collected for any females who become pregnant during the 
study and from the female partners of any males who took study treatment in this study. 
Consent to report information regarding these pregnancy outcomes should be obtained from 
the mother.
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
8.3
Subject screening
Re-screening once per subject is allowed if deemed feasible or necessary by the study site 
investigator. Information on what data should be collected for screening failures is outlined in 
the Site Operations Manual.
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8.4
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects.  
Relevant medical history/current medical conditions data will also be collected until signature 
of informed consent.  This will include detailed information on their asthma and allergy 
history, such as age of onset of asthma, duration since first diagnosis of asthma, 
environmental and drug allergies (including allergy to aspirin), asthma exacerbations, failed 
therapy, family history of asthma and allergies, smoking history, and so on. Details are 
outlined in the Site Operations Manual.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
8.4.1
Demography
Subject demographic and baseline characteristic data will be collected on all subjects.  
Relevant medical history/current medical conditions data will also be collected until signature 
of informed consent.  Details are outlined in the Site Operations Manual.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
8.4.2
Medical history/current medical conditions
Relevant medical history and current medical conditions will be recorded on the CRF until 
signature of the informed consent.
Where possible, diagnoses and not symptoms will be recorded.
Any event or change in the subject’s condition or health status occurring prior to informed 
consent will be reported in the Relevant medical history / Current medical conditions section 
of the CRF.
8.5
Efficacy / Pharmacodynamics
Lung function test reports will be subject to central reading and adjudication. Kindly refer to 
the SOM for further details.
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8.5.1
Clinical Outcome Assessments (COAs)
Clinically relevant questionnaires that will be administered during the course of the study 
include two validated questionnaires (the Asthma Control Questionnaire or ACQ, 
). These will be administered at various 
timepoints during the study as depicted in the Assessment schedule. Additionally, daily 
symptoms, 
 and rescue inhaler use will be captured on an electronic 
device which will be dispensed to each subject by the study site. Further details will be 
described in the SOM.
8.5.2
Spirometry
Spirometry testing will be performed according to the American Thoracic Society guidelines 
at screening to assess patients’ eligibility for the study and at repeated intervals as detailed in 
the Assessment schedule. Details regarding equipment, study site personnel training and 
certification, spirometric values captured in the database and quality control will be included 
in the SOM.
8.6
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment schedule (Section 8.1) detailing when each 
assessment is to be performed.
Study inclusion and exclusion criteria will be reviewed at screening and baseline. Review of 
medical history and concomitant medications and any changes therein must be reviewed at 
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each study visit. Alcohol test, drug screen, cotinine test, hepatitis and HIV screen will be 
conducted at screening and baseline. Review of EKG, vital signs and physical exam will be 
conducted during the study as per the Assessment schedule. Clinical chemistry, hematology 
and urinalysis samples will be collected and results reviewed by eligible study site personnel
at regular intervals. Hypersensitivity reactions have not been observed so far for CJM112, but 
their future occurrence cannot be excluded. Study subjects should be monitored post-injection 
for hypersensitivity and anaphylaxis events for an appropriate amount of time, no less than 30 
minutes post-dose. Women of child-bearing potential will be subject to pregnancy test as per 
the Assessment schedule. Patient diary will be reviewed at each visit. Adverse events will be 
reviewed and documented at each visit. 
8.6.1
Clinical Chemistry
Sodium, potassium, creatinine, BUN/urea, uric acid, chloride, albumin, calcium, alkaline 
phosphatase, total bilirubin, bicarbonate/HCO3, LDH, GGT, AST, ALT, amylase, lipase, 
hs-CRP, CK, glucose, total cholesterol, triglycerides. If the total bilirubin concentration is 
increased above 1.5 times the upper limit of normal, direct and indirect reacting bilirubin 
should be differentiated.
8.6.2
Electrocardiogram (ECG)
Full details of all procedures relating to the ECG collection and reporting are contained in the 
core laboratory technical manual or in the Site Operations Manual.
In the event that a clinically significant ECG abnormality is identified at the site (e.g. severe 
arrhythmia, conduction abnormality of QTcF > 500 ms, significant T wave changes) the ECG 
is repeated to confirm the diagnosis.
Clinically significant abnormalities must be reported in the AE CRF.
If the subject is hemodynamically compromised, the investigator or a medically qualified
person must initiate appropriate safety procedures without delay (for example cardioversion).
The following parameters will be entered into the eCRF: PR interval, QRS duration, heart rate, 
RR, QT, QTc, QTcF.
The Fridericia QT correction formula (QTcF) should be used for clinical decisions.
8.6.3
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differentials, ESR, 
and platelet count will be measured.
8.6.4
Immunogenicity
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8.6.5
Physical Examination
See Site Operations Manual for details.
8.6.6
Vital Signs

Body temperature

Blood pressure (BP)

Pulse

Respiratory Rate

Oxygen saturation by pulse oximetry
8.7
Pharmacokinetics
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8.7.1
PK blood collection
8.8
Other assessments
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8.9
Use of residual biological samples
Residual blood and urine samples may be used for another protocol specified endpoint.
9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the study treatment are also 
considered an adverse event irrespective if a clinical event has occurred. See Section 9.5 for 
an overview of the reporting requirements.
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 the subject during or between visits or through physical examination finding, laboratory 
test finding, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms,

they are considered clinically significant,

they require therapy.
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
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subject and identifying adverse events. Alert ranges for liver and kidney related events are 
included in Appendix 1 and Appendix 2, respectively. 
Adverse events must be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information:
1. the severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. its relationship to the study treatment

Yes or

No
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 SAE (see Section 9.2 for definition of SAE) and which seriousness
criteria have been met
5. Action taken regarding investigational treatment.
All adverse events must be treated appropriately. Treatment may include one or more of
the following:

no action taken (e.g. further observation only)

investigational treatment dosage increased/reduced

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given

hospitalization/prolonged hospitalization (see Section 9.2 for definition of SAE)
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving,
recovered/resolved with sequelae; fatal; or unknown).
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB).  Once an adverse event is detected, it must be 
followed until its resolution or until it is judged to be permanent, and assessment should be 
made at each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the investigational drug, the interventions required to treat it, and the outcome.
The investigator must also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.


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9.2
Serious adverse event reporting
9.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the
indication under study and has not worsened since the start of study drug

treatment on an emergency outpatient basis for an event not fulfilling any of the
definitions of a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the subject’s
general condition

is medically significant, e.g. defined as an event that jeopardizes the subject or may
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
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 (see Annex IV, ICH-E2D Guideline).
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. 
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 (see Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to Novartis Drug Safety & Epidemiology (DS&E) as per Section 9.2.2.


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9.2.2
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the end of the study [must be reported to 
Novartis within 24 hours of learning of its occurrence as described below. Any SAEs 
experienced after this period should only be reported to Novartis if the investigator suspects a 
causal relationship to study treatment.
Note: SAEs reported by subjects deemed to be screen failures must be reported to Novartis as 
outlined here with appropriate information also captured in the CRFs as specified in the 
Site Operations Manual.
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 
within 24 hours of the investigator receiving the follow-up information. 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.
Follow- up information provided must describe whether the event has resolved or continues, 
if and how it was treated, whether the blind was broken or not (if applicable) and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 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.
Follow the detailed instructions outlined in the Site Operations Manual regarding the 
submission process for reporting SAEs to Novartis.   Note:  SAEs must be reported to 
Novartis within 24 hours of the investigator learning of its occurrence/receiving follow-up 
information.
9.3
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
Please refer to Table 15-1 in Appendix 1 for complete definitions of liver events.


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Follow-up of liver events
Every liver event defined in Table 15-1 of Appendix 1 should be followed up by the 
investigator or designated personnel at the trial site, as summarized below. Additional details 
on actions required in case of liver events are outlined in Table 15-2 of Appendix 1. 

Repeating liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and γGT) to confirm
elevation within 48-72 hours.
These liver chemistry repeats should always be performed using the central laboratory,
with the results provided via the standard electronic transfer.  If results will not be
available from the central laboratory within 24 hours, 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 reported on the unscheduled local laboratory 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 Section 7.2 (Discontinuation of study
treatment), if appropriate

Hospitalization of the subject if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include:

Repeating liver chemistry tests two or three times weekly. Testing should include
ALT, AST, ALP, PT/INR, and gGT. If total bilirubin is elevated > 2 x ULN,
fractionation into direct and indirect bilirubin is required. To rule out muscular origin
of transaminase elevations, CPK should be measured along with liver chemistry tests.
Frequency of retesting can decrease to once a week or less if abnormalities stabilize
or the study drug has been discontinued and the subject is asymptomatic. Retesting
should be continued up to resolution.

Obtaining a more detailed history of symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications
and herbal and dietary supplement preparations), alcohol use, recreational drug use,
and special diets.

Exclusion of underlying liver disease, as specified in Table 15-3.

Imaging such as abdominal US, CT or MRI, as appropriate

Obtaining a history of exposure to environmental chemical agents.

Considering gastroenterology or hepatology consultations.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF.
9.4
Renal safety monitoring
Every renal laboratory trigger or renal event must be followed up by the investigator or 
designated personnel at the trial site. Recommended follow-up assessments are listed in 
Section 16 (Appendix 2).


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9.5
Reporting Medication errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject 
or consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
All study treatment errors and uses outside of what is foreseen in the protocol will be 
collected in the dose administration record (DAR) CRF.  Study treatment errors are only to be 
reported to Novartis Drug Safety and Epidemiology department if the treatment error is 
associated with an SAE.
All instances of misuse or abuse must be documented in the adverse event (AE) CRF 
irrespective of the misuse/abuse being associated with an AE/SAE. In addition, all instances 
of misuse or abuse must be reported to Novartis Drug Safety and Epidemiology. As such, 
instances of misuse or abuse are also to be reported using the SAE form/CRF. Table 9-1
summarizes the reporting requirements.
Table 9-1
Summary of reporting requirements for medication errors
Treatment error type
Document in Dose 
Administration (DAR) CRF
Document in AE 
CRF
Complete SAE 
form/CRF
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see 
Section 9.1 and Section 9.2, respectively.
9.6
Pregnancy reporting
To ensure 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 must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.


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The study drug must be discontinued, though the subject may stay in the study, if she wishes 
to do so. All assessments that are considered as a risk during pregnancy must not be 
performed. The subject may continue all other protocol assessments.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
9.7
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly 
between medically qualified personnel representing the
Sponsor and Investigator. 
Such evaluations may occur verbally, but the outcome and key discussion points will be 
summarized in writing (e-mail) and made available to both Sponsor and all Investigator(s). 
Criteria pertaining to stopping the study/treatment or adapting the study design are presented above.
When two or more clinical site(s) are participating in the clinical study, the Sponsor will 
advise the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any 
new, clinically relevant safety information reported from another site during the conduct of 
the study in a timely manner.
10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. 
During the study Novartis employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. The monitor will visit the site to check 
the completeness of subject records, the accuracy of entries on the CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and ensure that study drug 
is being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the monitor during these visits.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject's file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the eligibility criteria, documentation of 
SAEs, and the recording of data that will be used for all primary and safety variables. 
Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about 
the identity of the subjects will be disclosed.


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10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to ClinBAY. The Investigator must certify that the data entered into the 
Electronic Case Report Forms are complete and accurate. After database lock, the investigator 
will receive copies of the subject data for archiving at the investigational site.
Data not requiring a separate written record will be defined in the Site Operations Manual and 
Assessment schedule and can be recorded directly on the CRFs. All other data captured for 
this study will have an external originating source (either written or electronic) with the CRF 
not being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
10.3
Database management and quality control
Novartis staff or CRO working on behalf of Novartis review the data entered into the CRFs by 
investigational staff for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to Novartis staff or CRO working on behalf of Novartis who will make the correction to 
the database. The signed copy of the Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Diary data will be entered into an electronic diary by the subject. The system will be supplied 
by a vendor(s), who will also manage the database. The database will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data about all study drug(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 database will be sent 
electronically to Novartis (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.


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The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked 
and the treatment codes will be unblinded and made available for data analysis. Any changes 
to the database after that time can only be made by joint written agreement between the 
COAR Analytics NIBR Franchise Head and the relevant NIBR TA Head.
10.4
Data Monitoring Committee
Not required.
10.5
Adjudication Committee
Not required.
11
Data analysis
The analyses will be conducted on all subject data at the time the trial ends. 
11.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The safety analysis set will include all subjects that received any study drug.
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and 
subject. Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject.
All data for background and demographic variables will be listed by treatment and subject. 
Summary statistics will be provided for all subjects, as well as for each treatment sequence.
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Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment sequence and subject.
11.3
Treatments
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment group and subject.
11.4
Analysis of the primary variable(s)
11.4.1
Variable(s)
11.4.2
Statistical model, hypothesis, and method of analysis
11.4.3
Handling of missing values/censoring/discontinuations
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The repeated measures regression model can accommodate subjects with missing follow-up 
FEV1 and will produce valid estimates of mean and covariance parameters if the data are 
missing at random.
11.5
Analysis of secondary variable(s)
11.5.1
Efficacy / Pharmacodynamics
11.5.2
Safety
Vital signs
All vital signs data will be listed by treatment group, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment group, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, subject, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
treatment and visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment group and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system.
Other safety evaluations
Pregnancy test results will be listed by treatment group, subject and visit/time.
11.5.3
Pharmacokinetics
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11.5.4
Other assessments
11.6
Analysis of exploratory variables
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11.7
Sample size calculation
11.8
Interim analyses
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12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US Code of Federal 
Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the 
ethical principles laid down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g. advertisements) and any other written information to be provided to subjects. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis around the 
time of Last Patient Last Visit to be a reviewer and signatory for the clinical study report. 
12.3
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
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13
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented.
13.1
Protocol Amendments
Any change to the protocol can only be made in a written protocol amendment that must be 
approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation.
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 9 (Safety Monitoring) must be followed and the Study Lead 
informed.


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14
References
Bullens DM, Truyen E, Coteur L, et al (2006) IL-17 mRNA in sputum of asthmatic patients: 
linking T cell driven inflammation and granulocytic influx? Respir. Res. p. 135.
Busse WW, Holgate S, Kerwin E, et al (2013) Randomized, double-blind, placebo-controlled 
study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to 
severe asthma. Am. J. Respir. Crit. Care Med. p. 1294-302.
Chung KF, Wenzel SE, Brozek JL, et al (2014) International ERS/ATS guidelines on 
definition, evaluation and treatment of severe asthma. Eur. Respir. J. p. 343-73.
Cosmi L, Liotta F, Maggi E, et al (2011) Th17 cells: new players in asthma pathogenesis. 
Allergy p. 989-98.
McGrath KW, Icitovic N, Boushey HA, et al (2012) A large subgroup of mild-to-moderate 
asthma is persistently noneosinophilic. Am. J. Respir. Crit. Care Med. p. 612-9.
Thomson NC (2016) Novel approaches to the management of noneosinophilic asthma. 
Ther Adv Respir Dis p. 211-34.
Wenzel S, Castro M, Corren J, et al (2016) Dupilumab efficacy and safety in adults with 
uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids 
plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b 
dose-ranging trial. Lancet p. 31-44.
Woodruff PG, Modrek B, Choy DF, et al (2009) T-helper type 2-driven inflammation defines 
major subphenotypes of asthma. Am. J. Respir. Crit. Care Med. p. 388-95.
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15
Appendix 1: Liver Event Definitions and Follow-up 
Requirements
Table 15-1
Liver Event Definitions
Definition
Thresholds
Potential Hy’s law cases

ALT or AST > 3 × ULN and TBL > 2 × ULN without initial increase
in ALP to > 2 × ULN
ALT or AST elevation with 
coagulopathy

ALT or AST > 3 × ULN and INR > 1.5 (in the absence of
anticoagulation)
ALT or AST elevation 
accompanied by symptoms

ALT or AST > 3 × ULN accompanied by (general) malaise,
fatigue, abdominal pain, nausea, or vomiting, or rash, or
eosinophilia
Isolated ALT or AST elevation

ALT or AST > 8 × ULN

5 x ULN < ALT/AST ≤ 8 x ULN

3 x ULN < ALT/AST ≤ 5 x ULN
Isolated ALP elevation

ALP > 2 × ULN (in the absence of known bone pathology)
Others

Any clinical event of jaundice (or equivalent term)

Any adverse event potentially indicative of liver toxicity
Table 15-2
Actions required for Liver Events
Criteria
Actions required
Potential Hy’s Law case

Discontinue the study treatment immediately

Hospitalize, if clinically appropriate

Establish causality

Complete CRFs per liver event guidance
ALT or AST elevation with coagulopathy
ALT or AST elevation accompanied by 
symptoms
Isolated ALT or AST elevation > 8 × ULN
Jaundice
Isolated ALT or AST elevation > 5 to ≤ 8 
× ULN

If confirmed, consider interruption or discontinuation
of study drug

If elevation persists for more than 2 weeks,
discontinue the study drug

Establish causality

Complete CRFs per liver event guidance
Isolated ALT or AST elevation > 3 to ≤ 5 
× ULN (patient is asymptomatic)

Monitor liver chemistry tests two or three times weekly
Isolated ALP elevation

Repeat liver chemistry tests within 48-72 hours

If elevation is confirmed, measure fractionated ALP; if
>50% is of liver origin, establish hepatic causality

Complete CRFs per liver event guidance
Any AE potentially indicative of liver 
toxicity

Consider study treatment interruption or
discontinuation

Hospitalize if clinically appropriate

Complete CRFs per liver event guidance


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


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16
Appendix 2: Specific Renal Alert Criteria and Actions
Table 16-1
Specific Renal Alert Criteria and Actions
Criteria
Action required
Serum creatinine (sCr) increase
25 – 49% compared to baseline

Consider causes and possible interventions

Follow up within 2-5 days
Serum creatinine increase > 50%

Consider causes and possible interventions

Repeat assessment within 24-48h if possible

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected

Consider hospitalization and specialized 
treatment
Protein-creatinine or albumin-creatinine ratio 
increase ≥ 2-fold
or
new onset dipstick proteinuria ≥ 1+
or
Albumin-creatinine ratio (ACR) ≥ 30 mg/g or ≥ 
3 mg/mmol;
or
Protein-creatinine ratio (PCR )≥ 150 mg/g or 
>15 mg/mmol

Consider causes and possible interventions

Assess serum albumin & serum protein

Repeat assessment to confirm

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected
New onset glucosuria on urine dipstick (unless 
related to concomitant treatment, diabetes)
Assess & document:

Blood glucose (fasting)

Serum creatinine

Urine albumin-creatinine ratio
New hematuria on dipstick
Assess & document:

Urine sediment microscopy

Assess sCr and urine albumin-creatinine ratio

Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation

Consider bleeding disorder
Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases when a nephrologist considers a renal biopsy, it is strongly 
recommended to make specimen slides available for evaluation by Novartis to potentially 
identify project-wide patterns of nephrotoxicity.)


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Whenever a renal event is identified, a detailed subject history and examination are indicated 
to identify, document and potentially eliminate risk factors that may have initiated or 
contributed to the event:

Blood pressure assessment (after 5 min rest, with an appropriate cuff size)

Signs and symptoms such as fever, headache, shortness of breath, back or abdominal pain,
dysuria, hematuria, dependent or periorbital edema

Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output

Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic
failure, contrast media or other known nephrotoxin administration, or other potential
causes of renal dysfunction, e.g., dehydration, hemorrhage, tumor lysis
Table 16-2
Follow-up of renal events
Action
Follow up
Assess*, document and record in the Case Report 
Form (CRF) or via electronic data load. Review and 
record possible contributing factors to the renal 
event (co-medications, other co-morbid conditions) 
and additional diagnostic procedures (MRI etc) in 
the CRF.

Urine dipstick and sediment microscopy

Blood pressure and body weight

Serum creatinine, electrolytes (sodium,
potassium, phosphate, calcium),
bicarbonate and uric acid

Urine output
Monitor subject regularly (frequency at 
investigator’s discretion) until:

Event resolution: (sCr within 10% of
baseline or protein-creatinine ratio within
50% of baseline)

or

Event stabilization: sCr level with ±10%
variability over last 6 months or protein-
creatinine ratio stabilization at a new level
with ±50% variability over last 6 months.
* Urine osmolality: in the absence of diuretics or chronic kidney disease this can be a very
sensitive metric for integrated kidney function that requires excellent tubular function. A high
urinary osmolality in the setting of an increase in sCr will point toward a “pre-renal” cause
rather than tubular toxicity.

SAP_000.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
CJM112
CCJM112X2204
A randomized, subject- and investigator-blinded, placebo
controlled, multi-center, multiple dose study to assess the
efficacy and safety of CJM112 in patients with inadequately
controlled moderate to severe asthma
Statistical Analysis Plan (SAP)
Author(s):
Document type:
SAP Documentation – NIBR 
Document status:
Amendment 04
Release date:
14-Aug-2019
Number of pages:
30
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Personal Protected Data


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Table of contents
Table of contents .................................................................................................................9
List of tables and figures ...................................................................................................10
1
Introduction .......................................................................................................................11
1.1
Scope of document ................................................................................................11
1.2
Study reference documentation .............................................................................11
1.3
Study objectives.....................................................................................................11
1.3.1
Primary objective ..................................................................................11
1.3.2
Secondary objective(s)..........................................................................11
1.3.3
Exploratory objective(s)........................................................................12
1.4
Study design and treatment....................................................................................13
2
First interpretable results (FIR) .........................................................................................13
3
Interim analyses.................................................................................................................14
4
Statistical methods: Analysis sets......................................................................................15
5
Statistical methods for Pharmacokinetic (PK) parameters................................................16
5.1
Variables................................................................................................................16
5.2
Descriptive analyses ..............................................................................................16
6
Statistical methods for Efficacy /Pharmacodynamic (PD) parameters .............................17
6.1
Primary objective...................................................................................................17
6.1.1
Variables ...............................................................................................17
6.1.2
Descriptive analyses..............................................................................17
6.1.3
Statistical model, assumptions and hypotheses.....................................17
6.2
Handling of missing values/censoring/discontinuations .......................................18
6.3
Secondary objectives .............................................................................................20
6.3.1
Variables ...............................................................................................20
6.3.2
Descriptive analyses..............................................................................20
6.3.3
Statistical model, hypothesis, and method of analysis..........................21
6.4
Exploratory objectives...........................................................................................21
6.4.1
Variables ...............................................................................................21
6.4.2
Descriptive analyses..............................................................................24
6.4.3
Statistical model, assumptions and hypotheses.....................................24
7
Statistical methods for safety and tolerability data............................................................25
7.1
Variables................................................................................................................25
7.2
Descriptive analyses ..............................................................................................26
7.3
Graphical presentation...........................................................................................28
8
Statistical methods for biomarker data..............................................................................28
9
Reference list.....................................................................................................................29


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10 Appendix 1: Historical clinical trials use in meta-analyses of informative prior of 
FEV1..................................................................................................................................30
List of tables and figures
Figure 1-1 
Study design..........................................................................................13
Table 4-1
Protocol deviation codes and analysis sets............................................15
Table 10-1
Mean change from baseline of FEV1 (L) at Week 12 in the placebo 
group of the selected six studies...............................................................................................30


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1
Introduction 
1.1
Scope of document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CJM112X2204”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
Tables, Figures, Listings (TFL) details the presentation of the data, including shells of summary 
tables, figures and listings, and Programming Datasets Specification (PDS) contains 
programming specifications e.g. for derived variables and derived datasets, to support the 
creation of CSR and IA outputs.
1.2
Study reference documentation
Final study protocol (version v01) is available at the time of finalization of the original 
Statistical Analysis Plan and the version v02 of the study protocol is available at the finalization 
of SAP Amendment 3.
1.3
Study objectives
1.3.1
Primary objective
Primary objective
Endpoints 
related 
to 
primary 
objectives

To 
determine 
whether 
treatment 
with
CJM112
in patients with inadequately
controlled moderate to severe asthma leads to
an improvement in airflow obstruction.

Change from baseline FEV1 in L.
1.3.2
Secondary objective(s)
Secondary objective(s)
Endpoints 
related 
to 
secondary 
objectives

To 
determine 
whether 
treatment 
with
CJM112
in patients with inadequately
controlled moderate to severe asthma leads to
an improvement in FEV1% of predicted.

Change from baseline FEV % of
predicted.

To 
determine 
whether 
treatment 
with
CJM112
in patients with inadequately
controlled moderate to severe asthma leads to
an improvement in asthma control.

Change from baseline in ACQ
score, % of patients with ≥ 0.5
decrease in ACQ score.

To assess the safety and tolerability of
CJM112 in
patients with inadequately
controlled moderate to severe asthma.

Study treatment discontinuations
and adverse events.


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1.3.3
Exploratory objective(s)
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1.4
Study design and treatment
This is a non-confirmatory, randomized, subject- and investigator-blinded, placebo-controlled, 
multi-center, parallel-arm study evaluating the efficacy of CJM112 on top of standard of care 
in patients with inadequately controlled moderate to severe asthma.
This study will enroll approximately 110 male and female patients between 18 and 75 years old 
with uncontrolled symptoms of moderate or severe asthma (defined by ACQ score of ≥1.5) who 
are compliant on standard of care medications. 
After an initial screening visit and run-in period of 4 weeks, subjects eligible per inclusion and 
exclusion criteria at the baseline visit will be randomized (3:2) to receive 
CJM112 or matching placebo subcutaneously over 3 months during 
visits at the clinical study site. All baseline safety evaluation results must be available prior to 
the first dose. After the end of the treatment period, subjects will be followed for an additional 
 Site visits to administer dose and assess safety and efficacy will be scheduled as 
depicted in the figure below. 
At least two interim analyses (IA) will be conducted, as further described below.
Figure 1-1
Study design
2
First interpretable results (FIR)
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3
Interim analyses 
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4
Statistical methods: Analysis sets
For subjects for which the actual treatment received does not match the randomized treatment 
the treatment actually received will be used for the analysis.
The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and experienced 
no protocol deviations with relevant impact on PK data.
The PD analysis set will include all subjects with any available PD data and experienced no 
protocol deviations with relevant impact on PD or efficacy data. If a subject has an asthma 
exacerbation adverse event during the study, all subsequent efficacy assessments will be 
excluded from the PD analysis set. 
The analysis sets and protocol deviation codes are related as follows:
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PD analysis in case of these PDs:
Exclude subject from PD 
analysis set
INCL05
Deviation from inclusion criterion 5
Yes
INCL07
Deviation from inclusion criterion 7
Yes
EXCL01
Deviation from exclusion criterion 1
Yes
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Category
Deviation code
Text description of deviation
Data exclusion
EXCL02
Deviation from exclusion criterion 2
Yes
EXCL03
Deviation from exclusion criterion 3
Yes
EXCL07
Deviation from exclusion criterion 7
Yes
EXCL20
Deviation from exclusion criterion 20
Yes
EXCL21
Deviation from exclusion criterion 21
Yes
EXCL22
Deviation from exclusion criterion 22
Yes
COMD01
Use of prohibited medication during the study
Yes ( from this visit 
onwards)
WITHO1
Patient who met withdrawal criteria but were 
not withdrawn 
Yes (from the visit
subjects met 
withdrawal criteria 
onwards)
If updates to this table are needed, an amendment to the SAP will be implemented prior to DBL.
5
Statistical methods for Pharmacokinetic (PK) parameters
All subjects within the PK analysis set will be included in the PK data analysis.
5.1
Variables 
5.2
Descriptive analyses
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6
Statistical methods for Efficacy /Pharmacodynamic (PD) 
parameters
6.1
Primary objective
To determine whether treatment with CJM112 in patients with inadequately controlled
moderate to severe asthma leads to an improvement in airflow obstruction.
6.1.1
Variables 
6.1.2
Descriptive analyses
6.1.2.1
Graphical presentation of results
6.1.3
Statistical model, assumptions and hypotheses
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6.2
Handling of missing values/censoring/discontinuations
The repeated measures analysis includes all available information in terms of measurements at
all times. If missing measurements are assumed missing at random, an analysis of the available 
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data provides consistent estimates of model parameters, i.e. given observed data the missing-
ness does not depend on unobserved data. Alternative assumptions may be explored to 
investigate the robustness of the results under plausible non-missing at random situations.
Reasons for dropouts will be explored.
A Kaplan Meier plot of time to dropout (any reason) will be produced to assess dropouts.
The inclusion of the data of subjects who miss at least one dose will be determined on a case-
by-case basis, and will be decided during the Protocol Deviation assignment in a blinded fashion.
For spirometry assessments, a pre- and post-bronchodilator assessment should be conducted 
during baseline and at visits 105, 107, 201, and 299. Both short and long acting bronchodilators 
must be withheld prior to the study visits as described in the SOM, patients must be instructed 
to withhold bronchodilators (both short and long acting) prior to performing spirometry at 
applicable visits, as follows:

Short-acting β2-agonists (SABAs) ≥ 6 h

SAMA ≥ 8 h

Long-acting bronchodilators (LABAs and LAMAs) given twice daily ≥ 24 h

Long-acting bronchodilators (LABAs and LAMAs) given once daily ≥ 48 h
When bronchodilators are given combined with ICS, the ICS component will have to be 
withheld as well. When such situation arises, and rescheduling of the visit is not possible, the
spirometry test results and other parameters that involves Spirometry results, e.g. ACQ7, will 
be omitted from analysis for that visit.
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6.3
Secondary objectives
To determine whether treatment with CJM112 in patients with inadequately controlled 
moderate to severe asthma leads to an improvement in 

FEV1% of predicted.

asthma control
6.3.1
Variables 
6.3.2
Descriptive analyses
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6.3.3
Statistical model, hypothesis, and method of analysis
6.4
Exploratory objectives
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6.4.2
Descriptive analyses
6.4.3
Statistical model, assumptions and hypotheses
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7
Statistical methods for safety and tolerability data
All subjects within the safety analysis set will be included in the safety data analysis.
7.1
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature, oxygen saturation by 
pulse oximetry), ECG intervals, laboratory measurements, as well as subject demographics, 
baseline characteristics, and treatment information.
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7.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and patient.
Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and patient.
Treatment
Data for study drug administration, rescue medication and concomitant therapies will be listed 
by treatment group and patient.
Vital signs
All vital signs data will be listed by treatment group, patient, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment group and visit/time.
ECG evaluations
All ECG data will be listed by treatment group, patient and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment group and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, patient, and visit/time and if normal ranges 
are available abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a subject with any abnormal values. Summary statistics will be provided by 
treatment group and visit/time.
Boxplots of laboratory data will also be provided.
Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system and treatment.
The number and percentage of subjects with adverse events by maximum severity of adverse 
events will be tabulated by body system and preferred term with a breakdown by treatment.
The number and percentage of subjects with adverse events classified as related to study drug 
will be tabulated by body system and preferred term with a breakdown by treatment.
Asthma exacerbation AE
Adverse events related to asthma will also be analyzed separately using safety analysis set as 
detailed below.


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The number and percentage of subjects with any one AE preferred term corresponding to 
exacerbation of asthma will be summarized for each treatment group. 
In addition the ‘Time to first exacerbation’ in days, will be presented graphically by treatment 
group using a Kaplan-Meier plot. A summary table the number and percentage who had 
exacerbations treated with antibiotics without steroids by treatment group will be presented 
together with the Kaplan-Meier plot. Descriptive statistics will also be summarized in a tabular 
format. Time to first exacerbation is defined as:
Start date of the AE – Date of first treatment dose + 1
A Cox proportional hazard model with previous exacerbations and baseline IgE will be 
performed to compare the time to first exacerbation between CJM112 and placebo. 
Patients that have completed the study but did not experience any event during the study will 
be right censored at their EOS.
Patients that discontinued from the study but did not experience any event during the study 
will be right censored at the day of discontinuation.
Patients that are still ongoing in the study but did not experience any event by the time of data 
cut date then these subjects will be right censored at this date.
ClinicalTrials.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

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 and percent of deaths will be provided by treatment group. 
Other safety evaluations
Immunogenicity
All immunogenicity results will be listed by subject and visit/time.
Pregnancy 
Pregnancy test results will be listed by treatment group, subject and visit/time.


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7.3
Graphical presentation 
8
Statistical methods for biomarker data
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9
Reference list
Fisch R, Jones I, Jones J, et al (2015) Bayesian Design of Proof-of-Concept Trials. Therapeutic 
Innovation & Regulatory Science; 49: 155-162.
Busse W, Holgate S, Kerwin E, et al (2013) Randomized, Double-Blind, Placebo-controlled
Study of Brodalumab, a Human Anti–IL-17 Receptor Monoclonal Antibody, in Moderate to 
Severe Asthma.
Wenzel S, Castro M, Corren J, et al (2016) Dupilumab efficacy and safety in adults with 
uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus 
a long-acting β2 agonist: a randomized double-blind placebo-controlled pivotal phase 2b dose-
ranging trial.
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10
Appendix 1: Historical clinical trials use in meta-analyses of 
informative prior of FEV1.
Table 10-1
Mean change from baseline of FEV1 (L) at Week 12 in the placebo 
group of the selected six studies
Selected study
Selected population
n
FEV1 change from baseline (L)
SE
AIN457D2204
IgE < 100 IU/ml
7
0.007
0.098
QBX258X2201
IgE <400 IU/ml
9
0.015
0.116
QAW029A2206
overall
136
0.038
0.039
QAW039A2214
non-atopic
93
0.03
0.029
Dupilumab
(Wenzel et al, 2016)
eos count < 300
71
0.1
0.040
Brodalumab
(Busse et al, 2013)
overall
76
0.056
0.036