Clinical trial NCT03944707
Conditions: Asthma
Keywords: asthma LOU064
Sponsor: Novartis Pharmaceuticals
Start date: 2019-07-18; Completion date: 2020-04-27
Enrollment: 76 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a proof-of-concept study to evaluate the efficacy of LOU064 in patients with inadequately controlled asthma. All subjects were randomized with 3:2 ratio to receive LOU064 100 mg once daily or LOU064 matching placebo for 12 weeks with standard background therapy of budesonide 80 µg/formoterol 4.5 µg two inhalations twice a day (b.i.d).

Detailed description:
This was a non-confirmatory, multi-center, randomized, placebo-controlled, subject- and investigator-blinded, parallel-group study to evaluate the efficacy and safety of LOU064 in patients with inadequately controlled asthma who were on a standardized background therapy of inhaled corticosteroid plus long acting beta-2 agonist (ICS/LABA).

The study included:

* a Screening period of up to 2 weeks to assess eligibility.
* a Run-in period of minimum 3 weeks and maximum 5 weeks where patients discontinued their current asthma therapy and were placed on budesonide 80 μg/formoterol 4.5 μg delivered by dry powder inhaler, two inhalations twice a day (b.i.d).
* a Treatment period of 12 weeks. All subjects were randomized 3:2 to receive LOU064 100 mg once daily or placebo for 12 weeks with standard background therapy of budesonide 80 μg/formoterol 4.5 μg, two inhalations b.i.d.
* a Follow-up period of 3 weeks following the last dose of study drug. Results from the interim analysis did not provide sufficient evidence of efficacy of LOU064 in inadequately controlled asthma and the sponsor decided to terminate early the study in April 2020. The median duration of exposure (12.0 weeks for LOU064 and 11.7 weeks for placebo) was close to the treatment target, as most of the subjects had completed treatment when the study was terminated.

Arms: arm 1: LOU064 100 mg once daily orally arm 2: Placebo once daily orally
Interventions: intervention 1: LOU064 100 mg intervention 2: Placebo
Intervention descriptions: intervention 1: LOU064 100 mg once daily orally administered as two 50 mg capsules intervention 2: Placebo once daily administered orally as capsules

Protocol documents:
Prot_001.pdf: 
Novartis Research and Development
LOU064
Clinical Trial Protocol CLOU064D12201 / NCT03944707
A randomized, subject- and investigator-blinded, placebo-
controlled study to assess the efficacy and safety of 
LOU064 in patients with inadequately controlled asthma
Document type:
Amended Protocol Version
EUDRACT number:
2018-003609-24
Version number:
v02 (Clean)
Clinical Trial Phase:
II
Release date:
18-Mar-2020
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template version 2.0 dated 01-Dec-2017


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study procedures. Note: The SOM will not be a part of the Clinical Study Report.


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................7
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................10
Protocol summary..............................................................................................................15
1
Introduction .......................................................................................................................20
1.1
Background............................................................................................................20
1.2
Purpose ..................................................................................................................20
2
Objectives and endpoints...................................................................................................21
3
Study design ......................................................................................................................22
4
Rationale............................................................................................................................24
4.1
Rationale for study design .....................................................................................24
4.1.1
Rationale for choice of background therapy.........................................26
4.2
Rationale for dose/regimen and duration of treatment ..........................................26
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................27
4.4
Purpose and timing of interim analyses/design adaptations..................................27
4.5
Risks and benefits..................................................................................................27
4.5.1
Blood sample volume............................................................................30
4.5.2
Risk of asthma worsening.....................................................................30
5
Population..........................................................................................................................31
5.1
Inclusion criteria ....................................................................................................31
5.2
Exclusion criteria...................................................................................................32
6
Treatment...........................................................................................................................35
6.1
Study treatment......................................................................................................35
6.1.1
Investigational and control drugs..........................................................35
6.1.2
Additional study treatments ..................................................................35
6.1.3
Treatment arms/group ...........................................................................35
6.2
Other treatment(s)..................................................................................................36
6.2.1
Concomitant therapy.............................................................................36
6.2.2
Prohibited medication ...........................................................................37
6.2.3
Rescue medication ................................................................................38
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6.2.4
Restriction for study subjects................................................................39
6.3
Subject numbering, treatment assignment, randomization....................................39
6.3.1
Subject numbering ................................................................................39
6.3.2
Treatment assignment, randomization ..................................................39
6.4
Treatment blinding.................................................................................................40
6.5
Dose escalation and dose modification..................................................................41
6.6
Additional treatment guidance...............................................................................41
6.6.1
Treatment compliance...........................................................................41
6.6.2
Recommended treatment of adverse events..........................................41
6.6.3
Emergency breaking of assigned treatment code..................................42
6.7
Preparation and dispensation.................................................................................42
7
Informed consent procedures ............................................................................................43
8
Visit schedule and assessments .........................................................................................44
8.1
Screening ...............................................................................................................50
8.1.1
Information to be collected on screening failures.................................50
8.2
Subject demographics/other baseline characteristics.............................................50
8.2.1
Spirometry Reversibility Test ...............................................................50
8.2.2
Hepatitis screen .....................................................................................50
8.2.3
HIV and tuberculosis screen .................................................................51
8.2.4
Allergy skin test ....................................................................................51
8.3
Efficacy/Pharmacodynamics .................................................................................51
8.3.1
Spirometry.............................................................................................51
8.3.2
Clinical Outcome Assessments (COAs) ...............................................51
8.3.3
eDiary for daily asthma symptoms, peak flow and rescue 
medication use.......................................................................................52
8.3.4
Appropriateness of efficacy assessments..............................................53
8.4
Safety.....................................................................................................................53
8.4.1
Laboratory evaluations..........................................................................54
8.4.2
Electrocardiogram (ECG) .....................................................................55
8.4.3
Pregnancy and assessments of fertility .................................................56
8.4.4
Other safety evaluations........................................................................56
8.4.5
Appropriateness of safety measurements..............................................56
8.5
Additional assessments..........................................................................................56
8.5.1
Pharmacokinetics ..................................................................................56
8.5.2
Biomarkers............................................................................................57
8.5.3
Other Assessments ................................................................................58
9
Study discontinuation and completion ..............................................................................59


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9.1
Discontinuation......................................................................................................59
9.1.1
Discontinuation of study treatment .......................................................59
9.1.2
Withdrawal of informed consent...........................................................60
9.1.3
Lost to follow-up...................................................................................61
9.1.4
Study stopping rules..............................................................................61
9.1.5
Early study termination by the sponsor.................................................61
9.2
Study completion and post-study treatment ..........................................................62
10 Safety monitoring and reporting........................................................................................62
10.1
Definition of adverse events and reporting requirements......................................62
10.1.1
Adverse events ......................................................................................62
10.1.2
Serious adverse events ..........................................................................64
10.1.3
SAE reporting........................................................................................65
10.1.4
Pregnancy reporting ..............................................................................66
10.1.5
Reporting of study treatment errors including misuse/abuse................66
10.2
Additional Safety Monitoring................................................................................67
10.2.1
Liver safety monitoring.........................................................................67
10.2.2
Renal safety monitoring........................................................................68
11 Data Collection and Database management......................................................................68
11.1
Data collection.......................................................................................................68
11.2
Database management and quality control............................................................68
11.3
Site monitoring ......................................................................................................69
12 Data analysis and statistical methods ................................................................................70
12.1
Analysis sets ..........................................................................................................70
12.2
Subject demographics and other baseline characteristics......................................70
12.3
Treatments .............................................................................................................70
12.4
Analysis of the primary endpoint(s) ......................................................................70
12.4.1
Definition of primary endpoint(s).........................................................71
12.4.2
Statistical model, hypothesis, and method of analysis..........................71
12.4.3
Handling of missing values/censoring/discontinuations.......................72
12.4.4
Sensitivity and Supportive analyses......................................................72
12.5
Analysis of secondary endpoints ...........................................................................73
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................73
12.5.2
Safety endpoints....................................................................................74
12.5.3
Pharmacokinetics ..................................................................................74
12.5.5
Patient reported outcomes.....................................................................75
12.6
Analysis of exploratory endpoints.........................................................................75
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12.7
Interim analyses.....................................................................................................76
12.8
Sample size calculation..........................................................................................76
12.8.1
Primary endpoint(s)...............................................................................76
12.8.2
Secondary endpoint(s)...........................................................................77
13 Ethical considerations and administrative procedures ......................................................77
13.1
Regulatory and ethical compliance........................................................................77
13.2
Responsibilities of the investigator and IRB/IEC..................................................77
13.3
Publication of study protocol and results...............................................................78
13.4
Quality Control and Quality Assurance.................................................................78
14 Protocol adherence ............................................................................................................78
14.1
Protocol Amendments ...........................................................................................79
15 References .........................................................................................................................80
16 Appendices ........................................................................................................................81
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................81
16.2
Appendix 2: Liver event and laboratory trigger definitions and follow-up 
requirements ..........................................................................................................82
16.3
Appendix 3: Specific renal alert criteria and actions and event follow-up............87
16.4
Appendix 4: Prohibited medications .....................................................................89


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List of tables
Table 2-1
Objectives and related endpoints ..........................................................21
Table 4-1
Rationale for study design.....................................................................25
Table 6-1
Investigational and control drugs..........................................................35
Table 6-2
Medication allowed under certain conditions if taken as follows.........36
Table 6-3
Prohibited medications not related to asthma treatment .......................37
Table 6-4
Prohibited asthma medications .............................................................38
Table 8-1
Assessment Schedule ............................................................................44
Table 8-2
Physical assessments.............................................................................54
Table 8-3
Laboratory assessments.........................................................................55
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................66
Table 16-1
Liver event and laboratory trigger definitions ......................................82
Table 16-2
Follow-up requirements for liver events and laboratory triggers..........83
Table 16-3
Specific renal alert criteria and actions.................................................87
Table 16-4
Renal event follow-up...........................................................................88
Table 16-5
Moderate and strong inhibitors of CYP3A4 .........................................89
Table 16-6
Moderate and strong inducers of CYP3A4 ...........................................89
List of figures
Figure 3-1
Study design flow chart.........................................................................23
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List of abbreviations
ACQ-5
Asthma Control Questionnaire -5
AE
adverse event
ALP
alkaline phosphatase
AUC
Area under the concentration –time profile
b.i.d.
twice a day
BMI
Body Mass Index
BTK
Bruton’s Tyrosine Kinase
BUN
blood urea nitrogen
CFR
U.S. Code of Federal Regulations
CK
creatinine kinase
Cmax
Maximum concentration observed in concentration/time profile
CMO&PS
Chief Medical Office & Patient Safety
CO2
carbon dioxide
COA
Clinical Outcome Assessments
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CTT
Clinical trial team
CV
coefficient of variation
DPI
Dry Powder Inhaler
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
eSource
Electronic Source
FEF
Forced Expiratory Flow
FEV1
Forced Expiratory Volume in 1 second
FSH
Follicle Stimulating Hormone
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GGT
Gamma-glutamyl transferase
h
hour
HbsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
hCG
Human Chorionic gonadotropin
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICS
Inhaled Corticosteroids
IEC
Independent Ethics Committee


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INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
LABA
Long-acting β2 agonist
LAMA
Long-acting muscarinic antagonist
LDH
lactate dehydrogenase
LFT
Liver function test
LLOQ
lower limit of quantification
LTRA
Leukotriene receptor antagonist
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
MRT
Mean residence time
FeNO
Fractionated exhaled Nitric Oxide
q.d.
once daily
PD
pharmacodynamic(s)
PEF
peak expiratory flow rate
PK
pharmacokinetic(s)
PT
prothrombin time
QTcF
QT interval corrected by Fridericia’s formula
RBC
red blood cell(s)
SABA
short-acting beta2-agonist
SAE
serious adverse event
sCR
serum creatinine
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SoC
standard of care
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
T1/2
Half-life 
TBL
total bilirubin
TEC
tec protein tyrosine kinase (TEC is a gene family of protein tyrosine kinases)
Tmax
Time of maximum concentration observed in concentration/time profile
ULN
upper limit of normal
WBC
white blood cell(s)
WHO
World Health Organization


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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)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study data 
using data collection systems, such as Web-based applications, interactive 
voice response systems and clinical laboratory interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which are 
used to capture data transcribed from paper source forms used at the point of 
care.
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.
eSource
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource combines source documents and 
case report forms (eCRFs) into one application, allowing for the real time 
collection of clinical trial information to sponsors and other oversight 
authorities, as appropriate.
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,” "Investigational Medicinal 
Product," or “test substance”
Medication pack 
number
A unique identifier on the label of each drug package in studies that dispense 
study treatment 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
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.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment
Run in Failure
A subject who is screened but not randomized/treated after the run-in period 
(where run-in period requires adjustment to subject’s medications or other 
intervention)
Screen Failure
A subject who is screened but is not treated or randomized
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
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Study treatment
Any drug or combination of drugs administered to the study participants as 
part of the required study procedures; includes investigational drug(s), 
control(s) or background therapy
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed consent. 
This number is the definitive, unique identifier for the subject and should be 
used to identify the subject throughout the study for all data collected, sample 
labels, etc.
Treatment number
A unique identifier assigned in non-randomized studies to each dosed subject, 
corresponding to a specific treatment arm 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer and does not allow any further 
collection of personal data 


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Protocol summary
Protocol number
LOU064D12201
Full Title
A randomized, subject- and investigator-blinded, placebo-controlled study to 
assess the efficacy and safety of LOU064 in patients with inadequately 
controlled asthma
Brief title
Study of efficacy and safety of LOU064 in inadequately controlled asthma 
patients
Sponsor and 
Clinical Phase
Novartis/phase II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
Asthma is characterized by chronic airway inflammation with symptoms of 
wheeze, shortness of breath, chest tightness and cough that vary over time 
and intensity. In addition, patients show variable airflow limitation. 
About 300 million people worldwide suffer from asthma and there are 
approximately 250,000 deaths caused by asthma every year.
Up to 50 % of patients are still not well controlled despite existing therapies, 
and there is high unmet need in patients with severe asthma despite guideline-
directed use of inhaled therapies. BTK inhibition is a promising therapeutic 
concept for the treatment of asthma.
LOU064 is a low molecular weight compound for oral administration that 
covalently binds and inhibits BTK with high selectivity. Pre-clinical data have 
shown a reduction of lung eosinophils in mouse models of asthma. 
Clinically, LOU064 has been shown to effectively inhibit basophil activation in 
healthy volunteers as measured by the inhibition of CD63 upregulation. 
Based on these positive pre-clinical and clinical data, LOU064 may offer a 
novel therapeutic option for treating asthma.
This Proof of Concept (Phase 2a) study is investigating the efficacy and safety 
of LOU064 in patients with inadequately controlled asthma.
All subjects will be randomized to receive LOU064 100mg q.d. or LOU064 
matching placebo (3:2) treatment for 12 weeks with standard background 
therapy of budesonide 80µg/formoterol 4.5µg, two inhalations b.i.d..
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. 
A placebo control group is essential to provide an accurate estimation of the 
true treatment effect as placebo effects are known in asthma patients. 
In addition, to minimize any placebo effects from baseline, placebo will be 
administered during the run-in period prior to baseline.
A treatment period of 12 weeks duration is needed to assess the anti-
inflammatory mode of action. Shorter treatment periods may not fully cover the 
potential effect of a drug and may not show if the effect is stable. A 12-week 
treatment duration will also provide a solid safety database for planning of 
long-term studies.


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Primary 
Objective(s) 
The primary objective for this study is to determine the efficacy of LOU064 
compared to placebo with respect to change from baseline in pre-dose FEV1 
at Week 12
Secondary 
Objectives
Objective 1: To determine the efficacy of LOU064 compared to placebo on 
changes in morning and evening peak expiratory flow rate (PEF) over the 
12-week treatment period
Objective 2: To evaluate the safety and tolerability of LOU064 in subjects with 
inadequately controlled asthma by evaluating the safety endpoints (including 
vital signs, ECG intervals, safety laboratory parameters, adverse events, and 
serious adverse events) through the End of Study/Early Termination Visit
Objective 3: To determine the efficacy of LOU064 compared to placebo on 
daytime and nighttime asthma symptom scores over the 12-week treatment 
period
Objective 4: To determine the efficacy of LOU064 compared to placebo on 
change from baseline in Asthma Control Questionnaire-5 (ACQ-5) score over 
the 12-week treatment period
Objective 5: To determine the efficacy of LOU064 compared to placebo on 
total daily short-acting β-agonist (SABA) used over the 12-week treatment 
period
Objective 6: To characterize the pharmacokinetic profile of LOU064 in subjects 
by measurement of concentrations of LOU064 in blood at steady state and 
calculation of respective PK parameters including but not limited to Cmax, 
Tmax, AUC
Study design
This is a non-confirmatory, multi-center, randomized, placebo-controlled, 
subject- and investigator-blinded, parallel-group study to evaluate the efficacy 
of LOU064 in patients with inadequately controlled asthma. All subjects will be 
randomized with 3:2 ratio to receive LOU064 100mg q.d. or LOU064 matching 
placebo treatment for 12 weeks with standard background therapy of 
budesonide 80µg/formoterol 4.5µg two inhalations b.i.d.. This study will enroll 
approximately 75 subjects for the primary analysis (subjects having week 12 
FEV1 assessment). The total duration for each subject in the study is 
approximately 20 weeks.
Population
The study population will include male and female subjects with age range 18 
to 70 with inadequately controlled asthma. Approximately 75 subjects will be 
randomized for the primary analysis. However, in case of a higher dropout rate 
than assumed (10% over 12 weeks), 
 up to 154 subjects may 
be randomized. Subjects who prematurely discontinue after randomization will 
not be replaced.
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Key Inclusion 
criteria

Male and female adult patients aged ≥ 18 to ≤ 70 years at screening.

Patients must weigh at least 40 kg to participate in the study, and must
have a body mass index (BMI) <35 kg/m2. BMI = Body weight (kg) /
[Height (m)]2  at screening

Patients with a physician-diagnosed history of asthma (according to
GINA 2018) for a period of at least 6 months prior to screening.

Patients who have been treated with:

Medium or high dose ICS, or

ICS plus long-acting beta agonist (LABA), or

ICS plus leukotriene receptor antagonist (LTRA), or

ICS plus long-acting beta agonist (LABA) and long lasting
muscarinic antagonist (LAMA)
for at least 1 month prior to screening and on the same doses of the above 
mentioned medications over at least 2 weeks prior to start of the run-in period.

Post-bronchodilator reversibility of FEV1 ≥ 12% and ≥ 200 mL at
screening. If reversibility is not demonstrated at screening, then two
additional attempts are permitted, (one at the run-in visit and the last one
during the run in period between run in visit and baseline visit).

Spirometry with pre-bronchodilator FEV1 ≥ 40% of predicted (at
screening and baseline) and ≤ 85% of predicted at the baseline visit.

ACQ-5 score ≥ 1.5 at baseline visit

≥ 80% compliance with peak expiratory flow measurement and recording
of symptoms in the eDiary during the run-in period.
Key Exclusion 
criteria

Patients who have had an asthma exacerbation requiring systemic
corticosteroids, hospitalization, or emergency room visit within 6 weeks
prior to screening or during the screening period.

Patients who have smoked or inhaled any substance other than asthma
medications within the 6 month period prior to screening, or who have a
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.).

History of life-threatening asthma event such as significant hypercarbia
(pCO2 > 45 mmHg), endotracheal intubation, non-invasive positive
pressure ventilation (NIPPV), respiratory arrest, or seizure as a result of
asthma.

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.

History or current diagnosis of ECG abnormalities indicating significant
risk of safety for subjects participating in the study such as:

Concomitant clinically significant cardiac arrhythmias, e.g. sustained
ventricular tachycardia, and clinically significant second or third
degree AV block without a pacemaker

History of familial long QT syndrome or known family history of
Torsades de Pointes

Resting heart rate (physical exam or 12 lead ECG) < 50 bpm at
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
Resting QTcF ≥ 450 msec (male) or ≥ 460 msec (female) at
screening or inability to determine the QTcF interval

Use of agents known to prolong the QT interval unless they can be
permanently discontinued for the duration of study

At screening and/or run-in period, 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.

Major surgery within 8 weeks prior to screening or surgery planned prior
to end of study.

History of live attenuated vaccine within 6 weeks prior to randomization
or requirement to receive vaccinations at any time during the study.

Hematology parameters at screening:

Hemoglobin: < 10 g/dl

Platelets: < 100 000/mm3

White blood cells: < 3 000/mm3

Neutrophils: < 1 500/mm3

Significant bleeding risk or coagulation disorders.

History of gastrointestinal bleeding, e.g. in association with use of
Nonsteroidal Anti-Inflammatory Drug (NSAID).

Requirement for anti-platelet or anticoagulant medication (e.g., warfarin,
or clopidogrel or Novel Oral Anti-Coagulant - NOAC) other than
acetylsalicylic acid (up to 100 mg/d).

History or presence of thrombotic or thromboembolic event, or increased
risk for thrombotic or thromborembolic event.
Study treatment
Investigational and control drugs

LOU064 capsules (dose strength: 50mg)

Placebo capsules
Standard background therapy

budesonide 80µg/formoterol 4.5µg delivered by DPI (Turbohaler or
equivalent if Turbohaler is not available in the country)
Efficacy 
assessments

Spirometry: FEV1

Daytime and nighttime asthma symptom score (captured in eDairy)

ACQ-5 score

number of puffs of SABA taken per day (captured in eDairy)

Peak expiratory flow rate
Pharmacokinetic 
assessments 
PK profile of LOU064 in human blood, characterized by Cmax, Tmax, AUClast 
and AUC0-24h. Additional parameters such as mean residence time, terminal 
half-life or CL/F as needed


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Key safety 
assessments

Physical examinations

Vital signs

ECG

Monitoring of laboratory markers in blood and urine

Adverse events, serious adverse events monitoring
Other 
assessments 
Data analysis
The primary objective of this study is to determine the efficacy of LOU064 
compared to placebo with respect to change from baseline in pre-dose FEV1 
at Week 12.
Repeated measurements of pre-dose FEV1 at week 2, week 4, week 8 and 
week 12 are considered in the primary analysis.
The baseline pre-dose FEV1
is defined as the average of the 
FEV1 measurements performed 45 min and 15 min prior to dosing on Day 1. 
If one of the assessment is missing, then the non-missing pre-dose FEV1 will 
be considered as baseline.
The primary endpoint will be analyzed using a Bayesian repeated measures 
model with change from baseline in pre-dose FEV1 as response, adjusting for 
effects of treatment*visit interaction, baseline pre-dose FEV1, and any 
additional 
covariate 
as 
deemed 
appropriate. 
Conditional 
on 
the 
aforementioned covariates, the responses are assumed to follow a 
multivariate normal distribution with a common unknown and unstructured 
covariance matrix explaining the association between repeated measures for 
a subject (similar to a covariance pattern model). For adjusted mean change 
from baseline in pre-dose FEV1 at week 12 under placebo, a weakly 
informative prior will be specified, while non-informative priors will be specified 
for all other unknown quantities, as appropriate.
The quantity of primary interest is the ‘true’ LOU064 effect on primary endpoint 
over placebo at week 12 and inferences will be performed in terms of the 
posterior probabilities derived from the above model.
Key words
Asthma
BTK inhibitor
LOU064
FEV1
ACQ-5 score
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1
Introduction
1.1
Background
Asthma is characterized by chronic airway inflammation with symptoms of wheeze, shortness 
of breath, chest tightness and cough that vary over time and intensity. In addition, patients show 
variable airflow limitation. About 300 million people worldwide suffer from asthma and there 
are approximately 250,000 deaths caused by asthma every year (D'Amato et al 2016).
Up to 50 % of patients are still not well controlled despite existing therapies, and there is high 
unmet need in patients with severe asthma despite guideline-directed use of inhaled therapies 
(GINA 2018). Bruton’s tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase. It is expressed 
in selected cells of the adaptive and innate immune system including B cells, macrophages, 
mast cells/basophils and thrombocytes. BTK is indispensable for signaling through the 
Fc epsilon receptor (FcεR1 for IgE) and the activating Fc gamma receptors (FcγR for IgG), as 
well as the B cell antigen receptor (BCR) and BTK inhibitors (BTKi) like ibrutinib are approved 
for the treatment of B cell malignancies (Hendriks et al 2014). Recently, it has been 
demonstrated that inhibition of BTK leads to inhibition of mast cell and basophil 
activation/degranulation in vitro and to reduced wheal sizes in skin prick tests with patients 
suffering from IgE-mediated allergies (Regan et al 2017). Thus, BTK inhibition is a promising 
therapeutic concept for the treatment of asthma.
LOU064 is a low molecular weight compound for oral administration that covalently binds and 
inhibits BTK with high selectivity. 
The pre-clinical and clinical safety profile of LOU064 is favorable. For detailed information 
please refer to the Investigator`s Brochure (IB).
1.2
Purpose
This Proof of Concept (Phase 2a) study is investigating the efficacy and safety of LOU064 in 
patients with inadequately controlled asthma who are on a standardized background therapy of 
inhaled corticosteroid plus long acting beta-2 agonist (ICS/LABA).
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2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To determine the efficacy of LOU064 
compared to placebo with respect to 
change from baseline in pre-dose FEV1 
at Week 12

Change from baseline in pre-dose FEV1 at 
Week 12 
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To characterize the pharmacokinetic 
profile of LOU064 in blood of asthma 
patients

Concentrations of LOU064 in blood at steady 
state and calculation of respective 
PK parameters including but not limited to 
Cmax, Tmax, AUC0-24h

To determine the efficacy of LOU064 
compared to placebo on changes in 
morning and evening peak expiratory 
flow rate (PEF) over the 12-week 
treatment period

Change from baseline in PEF (AM and PM), as 
assessed by mean morning and mean evening 
PEF over 12 weeks of treatment (captured in 
eDiary)

To evaluate the safety and tolerability of 
LOU064 in patients with inadequately 
controlled asthma

All safety endpoints (including vital signs, ECG
intervals, safety laboratory parameters, adverse 
events, and serious adverse events) through 
the End of Study/Early Termination Visit

To determine the efficacy of LOU064 
compared to placebo on daytime and 
nighttime asthma symptom scores over 
the 12-week treatment period

Change from baseline in daytime and nighttime 
asthma symptom score over 12 weeks of 
treatment (captured in eDiary)

To determine the efficacy of LOU064 
compared to placebo on change from 
baseline in Asthma Control 
Questionnaire-5 (ACQ-5) score over the 
12-week treatment period

Change from baseline in ACQ-5 score over 
12 weeks of treatment (ACQ-assessment for 
the week preceding each planned visit up to 
End of Study)

To determine the efficacy of LOU064 
compared to placebo on total daily short-
acting β-agonist (SABA) used over the 
12-week treatment period

Number of puffs of SABA taken per day over 12 
weeks of treatment (captured in eDiary)


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3
Study design
This is a non-confirmatory, multi-center, randomized, placebo-controlled, subject- and 
investigator-blinded, parallel-group study to evaluate the efficacy of LOU064 in patients with 
inadequately controlled asthma. All subjects will receive a standardized background therapy of 
budesonide 80µg/formoterol 4.5 µg two inhalations b.i.d.. This study will enroll approximately 
75 subjects (subjects having week 12 FEV1 assessment). However, in case of a higher dropout 
rate than assumed (10% over 12 weeks), 
up to 154 subjects may be randomized. 
Note: the trade name for budesonide/formoterol may vary between countries.
The study consists of:

a Screening Period of up to 2 weeks

a Run-in Period of minimum 3 weeks and maximum of 5 weeks

a Baseline visit

a 12-week Treatment Period

a Follow-up Period of approximately 3 weeks

an End of Study (EOS) visit approximately 3 weeks after the last study drug
administration
The total duration for each subject in the study is approximately 20 weeks.
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Screening: After signing informed consent, subjects will complete safety assessments, 
pulmonary function tests, and the ACQ-5 to assess eligibility. All subjects must demonstrate 
FEV1 reversibility for study eligibility. If reversibility is not demonstrated at the screening visit, 
then two additional attempts are permitted (one at the run-in visit and the last one during the 
run in period between run in visit and baseline visit if needed).
Subjects will be provided with an electronic peak expiratory flow (ePEF)/eDiary device in 
which they will record their PEF, daytime and nighttime asthma symptoms, and the use of 
rescue medication. Subjects will be instructed on eDiary completion and how to use the device 
for the assessment of peak flow. Subjects will perform PEF measurements twice daily 
(morning and evening) beginning the evening of the screening visit through the EOS visit.
A short acting β2-agonists (SABA; salbutamol, known also as albuterol) will be provided to all 
subjects as rescue medication. The investigator will check that the vaccination status of the 
subject is complete and there are no vaccinations planned during the study period. A complete 
vaccination status for an asthma patient to be considered for this study includes vaccination 
against influenza, diphtheria, pertussis and pneumococci.
Run-in: Subjects will return to the study site for the run-in visit on or by Day -35 for safety 
assessments and pulmonary function tests to assess eligibility.
During this visit, subjects will discontinue their current asthma therapy and be placed on 
budesonide 80µg /formoterol 4.5µg delivered by DPI (turbohaler or equivalent device if 
turbohaler not available) two inhalations b.i.d.. By the time of randomization, all subjects must 
have received a minimum of 3 weeks budesonide 80 µg/formoterol 4.5µg two inhalations b.i.d.
as background therapy. The budesonide dose level must remain constant throughout the study. 
If required, to adjust for the subject’s needs (e.g., holiday, family or work), the run-in period 
has a minimum duration of three weeks (21 days) and may be extended by up to two weeks for 
a maximum of 5 weeks (35 days).
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4
Rationale
4.1
Rationale for study design
This is a non-confirmatory, multi-center, randomized, placebo-controlled, subject- and 
investigator-blinded, parallel-group study with an minimum 3-week run-in period and a 
12 week treatment period. All subjects will receive a standardized background therapy of 
budesonide 80µg/formoterol 4.5µg two inhalations b.i.d.. Key efficacy endpoints will be 
evaluated at Week 12.
If the time difference between the Screening and Run-in visits is less than two weeks, 
hematology, clinical chemistry, urinalysis and coagulation panel do not need to be tested again 
at the Run-in visit.
All subjects will receive LOU064 matching placebo once daily in the morning for the duration 
of the run-in period. Subjects will be blinded to the identity of the treatment.
Baseline: The run-in period will end with the Baseline visit. The Baseline visit assessments can 
occur between Day -3 and Day 1 to allow for flexibility and to ensure all data required are 
available for randomization. All baseline assessments must be completed and eligibility 
confirmed prior to randomization on Day 1.
Treatment: On Day 1 of the treatment period, after completion of all pre-dose assessments, 
eligible subjects will be randomized in a 3:2 ratio to receive either LOU064 100 mg q.d. or 
placebo q.d.. Subjects will take their first dose in the clinic on Day 1. For the remainder of the 
12 week treatment period, subjects will take their daily dose in the morning at approximately 
the same time.                               Commercially Confidential Information
Each visit must be scheduled in the morning at approximately the same time, so that 
pre-dose FEV1 assessments can be performed between 6 AM and 10 AM +/- 1 hour. 
On visit days, subjects will take their dose in the clinic after completion of efficacy and safety 
assessments. Subjects will also take their standardized background therapy morning dose after 
the efficacy and safety measurements. Subjects will complete dosing on Day 85.
End of Study: A study completion visit will occur approximately 3 weeks following the last 
dose of study drug. 
Post Study safety contact: A safety follow-up will be made at approximately 30 days following 
the last dose of study drug. Please refer to the Assessment Schedule for a list of procedures to 
be performed at each visit.


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Table 4-1
Rationale for study design
Study Design Aspect
Rationale
Overall 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. The treatment duration of 12 weeks makes 
other study designs (e.g., cross-over) inefficient. Only patients who 
have symptoms (as defined by ACQ-5) and have room for 
improvement in FEV1 (<85% of personal predicted value) at baseline 
will be enrolled.
Placebo control
A placebo control group is essential to provide an accurate estimation 
of the true treatment effect as placebo effects are known in asthma 
patients. The study design includes a placebo control and not an 
active control because the study treatment will be added on top of 
standardized background therapy for each patient. In addition, to 
minimize any placebo effects from baseline, placebo will be 
administered during the run-in period prior to baseline.
Randomization 
(strata, allocation ratio)
A randomization ratio of 3:2 is used. As per sample size 
considerations (Section 12.8) by using prior information on placebo 
effects in other studies, the expected number of randomized placebo 
patients will be 15 fewer than LOU064.  
Blinding
This is a subject- and investigator-blinded study. During the run-in 
period, patient will receive standardized background therapy along 
with LOU064 matching placebo, patients are blinded to the identity of 
the placebo treatment. During the treatment period, patients, 
investigators and other study personnel such as study nurses or 
monitors are blinded (except those who by the nature of their role 
must be unblinded, e.g., bioanalyst measuring drug concentrations) 
to avoid any bias instituted by knowledge of the treatment allocation 
to patients.
Duration of study periods
Screening period up to 2 weeks: to provide sufficient time for 
completion of all screening measures prior to entering the run-in 
period.
Run-in period of minimum 3 weeks: to standardize subjects so that 
all have the same treatment and are in steady state condition for the 
baseline assessments. This period can be expanded up to 5 weeks 
to accommodate logistics or the schedule of the patient if needed.
Treatment period of 12 weeks: to assess the anti-inflammatory mode 
of action. It is known from asthma patients that inflammation down-
regulates over time. Shorter treatment periods may not fully cover the 
potential effect of a drug and may not show if the effect is stable.
Follow-up period of 3 weeks: to assess the duration of effect post 
treatment. Sustained duration of action may be possible after BTK-
inhibition gets less than targeted inhibition.
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4.1.1
Rationale for choice of background therapy
All subjects will receive a standardized background therapy of budesonide 80µg/formoterol 
4.5µg two inhalations b.i.d.. Budesonide 80µg/formoterol 4.5µg was selected because it ensures 
that subjects receive an ICS/LABA as recommended in the applicable guidelines for treating 
patients with asthma. The ICS-component is administered at a lower dose level to make the 
study sensitive for the anti-inflammatory effects resulting from BTK-inhibition.
The standardization of the background therapy minimizes the variation that would be observed 
if patients enrolled in the study on variable doses or variable asthma control therapy. 
All subjects will receive a minimum of 3 weeks background therapy of budesonide 
80µg/formoterol 4.5µg two inhalations, twice daily prior to randomization so that all have the 
same treatment and are in steady state condition for the baseline assessments.
In addition, subjects can manage their symptoms with short acting β2-agonists as rescue 
medication when required (Section 6.2.3).
Despite receiving a standardized background therapy of ICS/LABA, subjects may still 
experience a worsening of their asthma symptoms. Refer to Section 4.5.2 and Section 9.1.1 for 
details on the monitoring and management of worsening asthma symptoms.
4.2
Rationale for dose/regimen and duration of treatment
In this study, LOU064 will be administered as 100 mg q.d. The treatment duration of 12 weeks 
is covered by pre-clinical data and is considered sufficient to allow assessment of anti-
inflammatory effects resulting in lung function improvement and symptom control in patients 
with asthma.
In CLOU064X2101 study, 132 healthy volunteers have been dosed with LOU064 in single 
ascending dose cohorts (SAD; up to 600 mg LOU064) and in multiple ascending dose cohorts 
(MAD; up to 600 mg LOU064 q.d. and up to 200 mg LOU064 b.i.d. for 12 days). LOU064 was 
well-tolerated and there was no serious or severe adverse event related to LOU064 intake in 
any of the cohorts completed. Observed adverse events (AEs) did not appear to be dose 
dependent, the majority were single events, and were generally mild in nature. Thus, preclinical 
and clinical safety information support the doses selected for this proof-of-concept study.
The dose-level and dosing regimen of LOU064 100 mg q.d. in this study were based on the 
following analyses from study CLOU064X2101:

Daily doses of 15 mg and above established a peak target occupancy approaching 100% in
blood in nearly all subjects, which remained above 80% at 24 h. Full BTK inhibition in
tissue will likely require higher doses. Tissue occupancy of 85% at the end of the 24h
dosing interval should be achieved with daily doses of 100 mg.

Inhibition of basophil activation (monitored by CD63 and CD203c up-regulation) was on
the plateau of the dose-response curve at the 100 mg dose level.
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
Effects on wheal size in skin prick tests (SPT) were on the plateau of the dose response
curve (approximately 50% mean reduction of wheal size in SPT corresponding to the
maximum effect size observed in CLOU064X2101) at the dose suggested in this study.
Since LOU064 is covalently bound to its target, it provides sustained coverage based on the 
target engagement over 24h despite its relatively short elimination half-life. Thus a once daily 
dosing regimen is considered appropriate. Recurrence of BTK related disease activity requires 
resynthesis of BTK in sufficient amounts to reactivate the pathway. Sufficient resynthesis of 
BTK is not expected to occur within one day.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Placebo was chosen as the comparator for this study in order to demonstrate that LOU064 adds 
a significant improvement in efficacy to background ICS/LABA therapy in moderate to severe 
asthmatic patients. The primary endpoint in the study, FEV1, is an effort dependent 
measurement. The secondary endpoints (ACQ-5, patient diary) are patient reported outcomes. 
Thus the placebo control arm is essential to account for effects not mediated by BTK inhibition 
(placebo effects). The placebo arm is also expected to control for potential bias in safety 
assessments in this study.
4.4
Purpose and timing of interim analyses/design adaptations
4.5
Risks and benefits
A transient benefit may be observed if LOU064 provides efficacy. A positive outcome from 
this study may lead to further development of LOU064 for eligible patients with asthma.
The risk to subjects in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring, avoidance of prohibited concomitant 
medications, regular safety reviews, adequate safety follow up, and study stopping rules. 
Appropriate eligibility criteria and stopping rules are included in this protocol.
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Based on a thorough review of safety information currently available in the literature together 
with an assessment of safety data obtained from both clinical and preclinical experience with 
LOU064, the following safety topics are considered as potential risks for LOU064 and require 
close monitoring in this study. Of important note, many safety risks identified for ibrutinib and 
acalabrutinib, two BTK inhibitors approved for the treatment of B cell malignancies, are less 
likely related to the pharmacology of inhibition of the BTK, but rather to the underlying 
indications being treated, for example, tumor lysis syndrome, second primary malignancies etc. 
Therefore, when comparing the safety risks between the marketed BTK inhibitors (eg: ibrutinib 
and acalabrutinib) and LOU064, the relevance and importance of the study patient populations 
must be taken into consideration.

Infections: BTK is an important signaling node downstream of cell surface receptors and
expressed in several immune cells of the adaptive and innate system, including B cells,
macrophages and mast cells/basophils. Therefore, LOU064 has the potential to increase the
risk of infections. Patients with X-linked agammaglobulinemia (XLA) – a genetic defect
associated with a lack of BTK – suffer from recurrent bacterial and enteroviral infections
which may be associated with neutropenia (Kumar et al 2006). However, in XLA BTK
deficiency leads to impaired B cell and plasma cell development and in turn to a close to
complete absence of immunoglobulins. In adult patients, BTK inhibition primarily
interferes with B cell activation but not plasma cell function and is therefore not associated
with a marked decrease of immunoglobulins (Hendriks et al 2014; Sun et al 2015;
Nutt et al 2015). Administration of ibrutinib (Imbruvica®) and acalabrutinib (Calquence®)
is associated with a risk of infection in patients suffering from B cell malignancies
(see Imbruvica® PI 2018 and Calquence® PI 2017). All patients participating in LOU064
clinical studies will be monitored closely for signs and symptoms of infections while in the
study. Patients with a known history of chronic recurrent or active ongoing history of
infections will be excluded from the study (refer to Section 5.2
for details).
Vaccination records of patients will be checked via patient report to ensure there are no
outstanding vaccinations recommended for this patient population.

Impaired platelet function: BTK is a signaling kinase in one of several platelet activation
pathways. In the prescribing information for both ibrutinib and acalabrutinib,
bleeding/bruising events are very common affecting approximately 50% of patients with
hematologic malignancies. Warnings on hemorrhagic events including deaths have also
been described (see Imbruvica® PI 2018 and Calquence® PI 2017). Compared to other
drugs in the same class, LOU064 demonstrated a higher selectivity for BTK vs. other
TEC kinases. Thus bleeding may be less a safety concern when compared to ibrutinib and
acalabrutinib. Patients receiving LOU064 must be closely monitored for any signs and
symptoms of bleeding while in the study. Subjects with a known history of bleeding
disorder, subjects taking medication that is known to increase the bleeding risk (other
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than acetylsalicylic acid), and subjects with an increased thromboembolic/thrombosis risk 
must be excluded from the study (refer to Section 5.2 for details).

Myelomodulation: The role of BTK inhibition in myelomodulation is not fully
understood. Treatment emergent grade 3 or 4 cytopenias (neutropenia, thrombocytopenia
and anaemia) were reported in patients with hematologic malignancies treated with
ibrutinib and acalabrutinb (see Imbruvica® PI 2018 and Calquence® PI 2017).
Therefore, patients will be closely monitored for signs and symptoms of cytopenia while
in the study, and those with a history of hematological disorders or with markedly altered
hematologic parameters at Screening must be excluded from the study (refer to
Section 5.2 for details).

Risk of cardiovascular origin: LOU064 is an in vitro inhibitor of the hERG channel
protein, without affecting other ion channels.
For ibrutinib, atrial fibrillation was described for 3% to 6% of subjects 
across multiple trials which might be associated with Na-channel inhibition (see 
Imbruvica® PI 2018). For acalabrutinib, both atrial fibrillation and atrial flutter of any
grade were reported in 3% of patients (see Calquence® PI 2017). Therefore, ECGs will be 
collected post-dose at each visit in this study. In addition, patients with a known history or 
current diagnosis of ECG abnormalities indicating significant risk of safety will be 
excluded from the study (refer to Section 5.2 for details).

Drug-drug interactions: LOU064 is a high clearance drug and metabolic clearance by
CYP3A4/5 is expected to be the predominant clearance pathway.
Precautions and guidelines regarding the use of those medications is provided in 
Section 6.2.2 and Section 16.4 of the protocol.
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
Reproductive toxicity: The risk of teratogenicity is currently unknown but reproductive
toxicology studies of LOU064 are ongoing.
 As a precaution, highly effective 
methods of contraception must be practiced. Women of child bearing potential and 
sexually active males must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and agree that in 
order to participate in the study they must adhere to the contraception requirements 
outlined in the exclusion criteria. If there is any question that the subject will not reliably 
comply, they should not enter or continue in the study.
In summary, asthma patients participating in this clinical trial may temporarily benefit from 
treatment with LOU064. This study will help to improve the scientific understanding of 
LOU064 in the management of asthma and offer the potential of developing an innovative drug 
that could potentially improve the quality of life for asthma patients. Potential risks of treatment 
with LOU064 are mitigated by compliance with inclusion/exclusion criteria, study procedures, 
close clinical monitoring and study drug discontinuation rules. As with investigational drugs in 
general, not all safety risks are known. Patients and investigators participating in this study will 
be informed should important new safety information become available.
4.5.1
Blood sample volume
A volume smaller than a typical blood donation is planned to be collected over a period of 
approximately 20 weeks from each subject as part of the study. Additional samples may be 
required for safety monitoring.
Timings of blood sample collection are outlined in the Assessment schedule.
A summary blood log is provided in the Site Operations Manual (SOM). Instructions for all 
sample collection, processing, storage and shipment information is also available in the SOM 
and/or central laboratory manual.
See the section on the potential use of residual samples.
4.5.2
Risk of asthma worsening
Despite receiving a standardized background therapy of inhaled corticosteroid and long acting 
beta-2 agonist, subjects may still experience a worsening of their asthma symptoms. 
Subjects will receive an ePEF/eDiary in which symptoms, morning and evening PEF, and the 
use of rescue medication are documented. Subjects will be instructed to alert the investigator if 
they experience a worsening of symptoms for review of their asthma control. Subjects with a 
history of a life-threatening asthma event are excluded from the study (see Section 5.2). 
Subjects who require a treatment with systemic (e.g., oral) steroid for treating an asthma 
exacerbation will be withdrawn from the study.
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5
Population
The study population will include male and female subjects with inadequately controlled 
asthma. All subjects will receive budesonide 80µg/formoterol 4.5µg two inhalations b.i.d. for a 
minimum of 3 weeks prior to randomization. Approximately 75 subjects will be randomized 
for the primary analysis. However, in case of a higher dropout rate than assumed (10% over 
12 weeks) 
up to 154 subjects may be randomized. Subjects who prematurely discontinue 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 criteria excluded a subject from eligibility for the study.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed including
any adjustment to asthma medication.
2. Male and female adult patients aged ≥ 18 to ≤ 70 years at screening
3. Patients must weigh at least 40 kg to participate in the study, and must have a body mass
index (BMI) <35 kg/m2. BMI = Body weight (kg) / [Height (m)]2  at screening
4. Patients with a physician-diagnosed history of asthma (according to GINA (2018)) for a
period of at least 6 months prior to screening.
5. Patients who have been treated with:

Medium or high dose ICS, or

ICS plus long-acting beta agonist (LABA), or

ICS plus leukotriene receptor antagonist (LTRA), or

ICS plus long-acting beta agonist (LABA) and long lasting muscarinic antagonist
(LAMA)
for at least 1 month prior to screening and on the same doses of the above mentioned 
medications over at least 2 weeks prior to start of the run-in period.
6. Post-bronchodilator reversibility of FEV1 ≥ 12% and ≥ 200 mL at screening.
If reversibility is not demonstrated at screening, then two additional attempts are permitted
(one at the run-in visit and the last one during the run in period between run in visit and
baseline visit if needed) .
7. Acceptable and reproducible spirometry with pre-bronchodilator FEV1 ≥ 40% of
predicted (at screening and baseline) and ≤ 85% of predicted at the baseline visit.
8. ACQ-5 score ≥ 1.5 at baseline visit
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9. ≥ 80% compliance with peak expiratory flow measurement and recording of symptoms in
the eDiary during the run-in period.
10. Able to communicate well with the investigator, to understand and comply with the
requirements of the study.
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Patients who have had an asthma exacerbation requiring systemic corticosteroids,
hospitalization, or emergency room visit within 6 weeks prior to screening or during the
screening and/or run in period.
2. Use of other investigational drugs at the time of screening, or within 5 half-lives of
screening, or within 30 days, whichever is longer; or longer if required by local
regulations.
3. History of hypersensitivity to any of the study treatments or excipients or to drugs of
similar chemical classes.
4. History of malignancy of any organ system (other than localized basal cell carcinoma of
the skin or in-situ cervical cancer), treated or untreated, within 5 years of screening,
regardless of whether there is evidence of local recurrence or metastases.
5. Donation or loss of 400 mL or more of blood within 8 weeks prior to baseline, or longer if
required by local regulation.
6. 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 at any time-point prior to enrollment.
7. 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 5 days 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 8 weeks before taking
investigational drug. In case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment.

Male sterilization (at least 6 months prior to screening). For female subjects on the
study the vasectomized male partner should be the sole partner for that subject.

Use of oral (estrogen and progesterone), 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
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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.
If local regulations deviate from the contraception methods listed above and require more 
extensive measures to prevent pregnancy, local regulations apply and will be described in 
the ICF.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks prior to screening. 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. Refer to Section 8.4.3
(Pregnancy and Assessments of Fertility).
8. Sexually active males unwilling to use a condom during intercourse while taking
investigational drug and for 7 days after stopping investigational drug. A condom is
required for all sexually active male participants to prevent them from fathering a child
AND to prevent delivery of the investigational drug via seminal fluid to their partner.
In addition, male participants should not donate sperm for the time period specified above.
If local regulations deviate from the contraception methods listed above to prevent
pregnancy, local regulations apply and will be described in the Informed Consent Form.
9. Patients who have smoked or inhaled any substance other than asthma medications within
the 6 month period prior to screening, or who have a 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.).
10. History of life-threatening asthma event such as significant hypercarbia
(pCO2 > 45 mmHg), endotracheal intubation, non-invasive positive pressure ventilation
(NIPPV), respiratory arrest, or seizure as a result of asthma.
11. 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, immune deficiency, splenectomy or impaired immune
function.
12. Taking medications prohibited by the protocol (see Section 6.2.2 (Prohibited medication)
and Table 6-3 and Table 6-4).
13. History or current diagnosis of ECG abnormalities indicating significant risk of safety for
subjects participating in the study such as:

Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular
tachycardia, and clinically significant second or third degree AV block without a
pacemaker

History of familial long QT syndrome or known family history of Torsades de Pointes

Resting heart rate (physical exam or 12 lead ECG) < 50 bpm at screening


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
Resting QTcF ≥ 450 msec (male) or ≥ 460 msec (female) at screening or inability to
determine the QTcF interval

Use of agents known to prolong the QT interval unless they can be permanently
discontinued for the duration of study
14. Any severe, progressive or uncontrolled, acute or chronic, medical or psychiatric
condition, immune deficiency, spleen dysfunction 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.
15. Major surgery within 8 weeks prior to screening or surgery planned prior to end of study.
16. History of live attenuated vaccine within 6 weeks prior to randomization or requirement to
receive vaccinations at any time during the study. Recommended vaccination schemes for
asthma patients must be complete, including influenza, pertussis, diphtheria, pneumococci
vaccination.
17. Hematology parameters at screening:

Hemoglobin: < 10 g/dl

Platelets: < 100 000/mm3

White blood cells: < 3 000/mm3

Neutrophils: < 1 500/mm3
18. Significant bleeding risk or coagulation disorders.
19. History of gastrointestinal bleeding, eg in association with use of Nonsteroidal Anti-
Inflammatory Drug (NSAID).
20. Requirement for anti-platelet or anticoagulant medication (eg, warfarin, or clopidogrel or
Novel Oral Anti-Coagulant - NOAC) other than acetylsalicylic acid (up to 100 mg/d).
21. History or presence of thrombotic or thromboembolic event, or increased risk for
thrombotic or thromboembolic event.
22. History or current treatment for hepatic disease including but not limited to acute or
chronic hepatitis, cirrhosis or hepatic failure or Aspartate Aminotransferase
(AST)/Alanine Aminotransferase (ALT) levels or International Normalized Ratio (INR) of
more than 1.5x upper limit of normal (ULN) at screening.
23. History of renal disease or creatinine level above 1.5x ULN at screening.
24. Known or suspected history of ongoing, chronic or recurrent infectious disease including
but not limited to opportunistic infections (eg tuberculosis, atypical mycobacterioses,
listeriosis or aspergillosis), HIV, Hepatitis B/C.
25. Any disease or illness, other than asthma, that may require the use of systemic
corticosteroids during the study period.


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6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the SOM.
6.1.1
Investigational and control drugs
Novartis Global Clinical Supply (GCS) will provide the following IMP supplies in 
appropriately blinded labeled bottles.
Table 6-1
Investigational and control drugs
Investigational/ 
Control Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply type
Sponsor (global 
or local)
LOU064 50 mg
Capsule
Oral use
Double-blind 
supply; bottles
Novartis Global
LOU064 placebo
Capsule
Oral use
Double-blind 
supply; bottles
Novartis Global
6.1.2
Additional study treatments
All subjects will receive a standardized background therapy of budesonide 80µg/formoterol 
4.5µg two inhalations
b.i.d. beginning at the Run-in visit through the EOS visit. 
Budesonide 80µg/formoterol 4.5µg delivered by DPI (turbohaler or equivalent device if 
turbohaler is not available in the site/country) will either be supplied to the study sites locally 
by Novartis or provided by the study site to the subject and reimbursed by Novartis. Note that 
dose designations may vary between countries. In some countries the metered dose (budesonide 
100µg/formoterol 6µg) released into the inhaler chamber is found on the product labels. 
This dose is the same as budesonide 80µg/formoterol 4.5µg delivered (from the inhaler 
mouthpiece).
6.1.3
Treatment arms/group
At the Run-in visit, all subjects will be assigned to receive placebo q.d.. Subjects will take two 
placebo capsules in the morning at home for the duration of the run-in period.
On Day 1, subjects will be randomized to one of the following 2 treatment arms in a ratio of 3:2

LOU064

Placebo
All subjects will take 
 LOU064 or matching placebo in the morning at home 
(except for Days 15, 29, 57 and 85, which are to be taken on site during the clinic visit). 
All subjects will receive their respective LOU064 or placebo capsules for 12 weeks (from Day 1 
through Day 85).
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6.2
Other treatment(s)
6.2.1
Concomitant therapy
Medication for treatment of asthma taken within the 3 months prior to screening will be 
recorded in the Prior and Concomitant Asthma Medications CRF. The dose of asthma treatment 
should be stable for at least 2 weeks prior to start of the run-in period.
The investigator will instruct the subject to notify the study site about any new medications 
(including medications that are not related to the treatment of asthma) he/she takes after the 
subject was enrolled into the study, ideally before initiating a new treatment.
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
in the concomitant medications / significant non-drug therapies or procedures pages.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a subject or allowing a new medication to be started. If the subject is already 
enrolled, contact Novartis to determine if the subject should continue participation in the study.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
Table 6-2
Medication allowed under certain conditions if taken as follows
Class of Medication
Condition under which medication is permitted
intra nasal corticosteroids
stable dose for start of run-in period until end of study
H1-antagonists
stable dose for start of run-in period until end of study
topical corticosteroids
permitted
inactivated influenza, pneumococcal or 
any other inactivated vaccine
not administered within 14 days prior to the 1st dose in 
treatment period and anytime thereafter during the trial


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6.2.2
Prohibited medication
Use of the treatments displayed in Table 6-3 and Table 6-4 need to be avoided according to the 
specifications provided. Subjects should be instructed to abstain from these medication unless 
absolutely necessary. Each concomitant drug must be individually assessed against all 
exclusion criteria and the tables below to see if it is allowed. If in doubt, the investigator must 
contact the Novartis medical monitor or designee before randomizing a patient or allowing a 
new medication to be started.
Restrictions for medications other than study drug apply according to below tables:
Table 6-3
Prohibited medications not related to asthma treatment
Medication
Prohibition period
Other investigational drugs
30 days or 5 half-lives, whichever is longer prior 
to Screening until end of study
Immunosuppressive medication with or without 
known effect on asthma including but not limited 
to hydroxychloroquine, methotrexate, 
cyclosporine A, cyclophosphamide, tacrolimus 
and mycophenolate mofetil
30 days or 5 half-lives (whichever is longer) prior 
to start of run-in period until end of study
Intravenous (i.v.) immunoglobulins or 
plasmapheresis
30 days prior to start of run-in period until end of 
study
Regular (daily or every other day) doxepin (oral)
14 days prior to start of run-in period until end of 
study
Live attenuated vaccine
6 weeks prior to randomization until end of study
Moderate and strong inhibitors of CYP3A4 
(see Table 16-5 in Appendix 4)
From start of run-in period until end of study
Moderate and strong inducers of CYP3A4 
(see Table 16-6 in Appendix 4)
From start of run-in period until end of study
Any drug known to prolong QTc interval 
(see https://crediblemeds.org for guidance)
5 half-lives or until pharmacodynamic effect has 
disappeared prior to start of run-in period 
(whichever is longer) until end of study
Anti-platelet or anticoagulant medication (for 
example, warfarin, or clopidogrel or Novel Oral 
Anti-Coagulant - NOAC) other than 
acetylsalicylic acid (up to 100 mg/d)
From start of run-in period until end of study
parental or oral corticosteroids
30 days prior to start of run-in period until end of 
study
systemic anticholinergics
7 days prior to run-in until end of study
Non-selective systemic β-blocking agents
7 days prior to run-in until end of study


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Table 6-4
Prohibited asthma medications
Medication
Prohibition period
Other investigational drugs
30 days or 5 half-lives, whichever is longer prior 
to Screening until end of study
Short-acting anticholinergics
8 hours prior to spirometry assessment at run-in 
visit until end of study
Long-acting anticholinergics
7 days prior to start of run-in period until end of 
study
Fixed combinations of short-acting β2 agonists 
and short-acting anticholinergics
8 hours prior to spirometry assessments at 
run-in visit until end of study
Mast cell stabilizers (e.g., cromoglycate, 
nedocromil, ketotifen) and leukotriene 
antagonists (e.g., montelukast)
7 days prior to start of run-in period until end of 
study
Monoclonal antibodies, investigational or 
approved, for the treatment of asthma (e.g., 
omalizumab)
5 months prior to start of run-in period until end 
of study
long-acting β2 agonists (for twice daily treatment) 
or fixed dose combination of ICS/LABA b.i.d 
other than study medication (standard 
background therapy)
24 hours prior to start of run-in period until end 
of study
ultra-long-acting β2 agonists (for once daily 
treatment) or fixed dose combination of 
ICS/LABA o.d other than study medication
(standard background therapy)
48 hours prior to start of run-in period until end 
of study
Xanthines
7 days prior to start of run-in period until end of 
study
6.2.3
Rescue medication
At the Screening visit all subjects will be provided with a SABA (salbutamol [100 µg] 
corresponding to albuterol [90 µg]) which they will be instructed to use throughout the study as 
rescue medication on as needed basis. Subjects will be advised that between visits they can take 
their rescue medication for symptoms of asthma. Rescue medication will either be supplied to 
the study sites locally by Novartis or provided by the study site to the subject and reimbursed 
by Novartis.
Nebulized salbutamol/albuterol is not allowed as rescue medication and will not be supplied.
No other rescue treatment is allowed at any time throughout the study.
To standardize measurements, subjects will be instructed not to use their rescue medication
(withhold the rescue medication for at least 6 hours prior to spirometry assessment) upon rising 
in the morning on days requiring spirometric assessments indicated in Table 8-1, unless 
absolutely necessary. If rescue medication is taken within 6 hours prior to spirometry at any of 
the scheduled visits (starting from the Run-in visit), the visit should be rescheduled to the next 
possible day. Additionally, if it’s not possible to reschedule the visit, rescue medication is taken 
within 6 hours prior to spirometry, this information will be recorded by the study site staff using 
the equipment provided by the central spirometry vendor.


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Daily use of rescue medication (the number of puffs taken in the previous 12 hours) will be 
recorded (once in the morning and once in the evening) by the subject using the eDiary.
Unless clinically indicated, the type of rescue medication a subject used, the device used to 
deliver the medication and the way it is administered must not be adjusted.
6.2.4
Restriction for study subjects
For the duration of the study, the subjects should be informed and reminded of the restrictions 
outlined in this section.
6.2.4.1
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.
Subjects should refrain from alcohol and caffeine intake 12 hours and 8 hours respectively prior 
to each study visit.
All subjects will be asked to fast (i.e., no food and liquid except water) for at least 8 hours prior 
to dose administration on Day 15 (Week 2) and Day 85 (Week 12) and will continue to fast for 
1 hour thereafter. This is due to the fact that blood samples for pharmacokinetic measurements 
are taken on this day. There is no restriction of fasting at other visits.
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
The subject number assigned to a subject at screening remains the unique identifier for the 
subject throughout the study. For information on subject
numbering, please see 
‘Subject numbering’ section in the Site Operations Manual.
6.3.2
Treatment assignment, randomization
On Day 1, all eligible subjects will be randomized via Interactive Response Technology (IRT) 
to one of the treatment arms. The investigator or his/her delegate will contact the IRT after 
confirming that the subject fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the subject, which will be used to link the subject to a treatment arm 
and will specify a unique medication number for the first package of study treatment to be 
dispensed to the subject.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Global Clinical Supply using a validated system that automates the random assignment of 
medication numbers to packs containing the study treatment.


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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 (i.e., LOU064 or placebo) throughout the study; except for during run-in 
period, when all subjects will receive LOU064 matching placebo along with background 
therapy, only subjects are blinded to the identity of this treatment.
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.
Site staff
All site staff (including study investigator and study nurse) will be blinded to study treatment 
throughout the study with the exception of the run-in period. Only the subject will be blinded 
to study treatment (i.e., placebo) during the run-in period. Unblinding a single subject at site for 
safety reasons (necessary for subject management) will occur via an emergency system in place 
at the site.
Sponsor staff
The following unblinded sponsor roles are required for this study:

Unblinded sample analyst(s) (PK, 
)

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.
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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.
6.5
Dose escalation and dose modification
LOU064 and background therapy 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 eCRF.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
The investigator must promote compliance by instructing the subject to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the subject’s safety and 
the validity of the study. The subject must also be instructed to contact the investigator if he/she 
is unable for any reason to take the study treatment as prescribed. Compliance will be assessed 
by the investigator and/or study personnel at each visit using capsule counts and information 
provided by the subject. This information should be captured in the source document at each 
visit. All study treatment dispensed and returned must be recorded in the Drug Accountability 
Log. Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
subjects treated with LOU064, as detailed in Section 8.5.1.
6.6.2
Recommended treatment of adverse events
At present there is insufficient information to provide specific recommendations regarding 
treatment of adverse events. Treatment of adverse events should be symptomatic. In case of 
questions regarding treatment of AEs caused by investigational product the investigator may 
contact the sponsor. Study drug discontinuation criteria as provided in Section 9.1.1 must be 
followed.
In case of exacerbations of asthma, adequate treatment of exacerbation as per the national or 
international (GINA 2018) recommendations should be instituted. These include administration 
of short acting beta-2 agonist, systemic steroids, short acting anticholinergics, administration of 
controlled oxygen and supervision until the patient is considered stable. Note that exacerbations 
that requiring treatment with systemic (e.g., oral or i.v. administration) steroids will require 
discontinuation of the patient from the study (Section 9.1.1).
In case of infections, institute the adequate antibiotic treatment. Check the immunoglobulin 
levels of the subject. In case of concurrent hypo-immunoglobulinemia and serious infection 
consider administration of immunoglobulins.
In case of bleeding events (e.g., bleeding or hematoma without trauma), bleeding into organs, 
stop treatment. In case of serious event consider administration of platelet concentrate.
Medication used to treat AEs must be recorded on the Concomitant Medications/Significant 
non-drug therapies CRF.


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6.6.3
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide the 
requested subject identifying information and confirm the necessity to break the treatment code 
for the subject. The investigator will then receive details of the investigational drug treatment 
for the specified subject and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the study team that the code has been 
broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide:

protocol number

subject number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.
After emergency unblinding, the subject will not receive further study treatment.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under the 
investigational and control drugs section.
LOU064 or placebo will be administered to the subject via the following route of 
administration: oral. Administration will occur at home with the exception of the following 
visits: Day 1, Day 15 (Week 2), Day 29 (Week 4), Day 57 (Week 8) and Day 85 (Week 12), 
when drug administration will occur at the study site.
Whenever there is a scheduled site visit during the run in, treatment and follow-up period, 
subjects should come to site in the morning, the study medication and the morning dose of 
standard background therapy ICS/LABA will only be taken after the spirometry assessment at 
the visit day.
On the day of site visits with spirometry assessments, investigators should try to plan site visits 
at approximately the same time (no more than two hours different than the Baseline visit)
See the Site Operations Manual for further details.


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7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g., all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the subject source documents. The date of signing of informed consent 
(and withdrawal, if later withdrawn) must be documented in the CRF.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the subject.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
Male subjects must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information.
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval.
Refer to the Site Operations Manual for a complete list of ICFs included in this study.
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8
Visit schedule and assessments
The assessment schedule lists all of the assessments and when they are performed. All data obtained from these assessments must be supported 
in the subject’s source documentation.
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as close to the designated day/time as possible. 
Missed or rescheduled visits should not lead to automatic discontinuation. Subjects who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed for the final visit (i.e., end of study) will be 
performed. At this final visit, all dispensed investigational product should be reconciled, and the adverse event and concomitant medications 
recorded on the CRF.
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8.1
Screening
It is permissible to re-screen a subject once if he/she fails the initial screening; however, each 
case must be discussed and agreed with the Sponsor on a case-by-case basis.
In the case where a safety laboratory assessment at screening is outside of the range specified 
in the exclusion criteria, the assessment may be repeated once prior to randomization. If the repeat 
value remains outside of the specified ranges, the subject must be excluded from the study.
If a subject re-screens for the study, then the subject must sign a new ICF and be issued a new 
subject number prior to any screening assessment being conducted. The investigator/qualified 
site staff will record if the subject was re-screened on the re-screening CRF along with the 
screening number the subject was issued prior to the current screening number.
The date of the new informed consent signature must be entered on the informed consent eCRF 
corresponding to the new screening subject number. For re-screening, all screening assessments 
must be performed per protocol.
Information on what data must be collected for screening failures and further information on 
re-screening is outlined in the Site Operations Manual.
8.1.1
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure. Information on what data must collected for screening failures and 
further information on re-screening is outlined in the SOM.
8.2
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects. 
Relevant medical history/current medical conditions data will also be collected until signature 
of informed consent. Details are outlined in the SOM.
Smoking history will also be collected. Details are outlined in the SOM.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgement, the test abnormality occurred prior to informed consent signature.
8.2.1
Spirometry Reversibility Test
Spirometry reversibility testing will be performed at screening to assess eligibility for the study. 
If reversibility is not demonstrated at the screening visit, then two additional attempts are 
permitted (one at the run-in visit and the last one during the run in period between run in visit 
and baseline visit if needed).
Reversibility testing will be performed according to the American Thoracic Society 
guidelines. Details regarding equipment, study site personnel training and certification, and 
quality control are provided in the SOM and/or vendor manual.
8.2.2
Hepatitis screen
All subjects will be screened for Hepatitis B and C. Further details are provided in the SOM.


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8.2.3
HIV and tuberculosis screen
If indicated by patient history (e.g., patient belongs to a HIV risk group but was not yet tested; 
known previous exposure to tuberculosis patients and/or living in an environment with known 
high tuberculosis rate), a HIV (by serological testing) or tuberculosis screen (serological testing, 
check for clinical symptoms, chest X-ray if applicable) should be considered.
8.2.4
Allergy skin test
The allergy skin testing is conducted to identify subjects who are sensitive to any of the 
allergen(s) being tested and to identify the specific substance (s) that the subject is sensitive to. 
If study centers cannot perform the allergen skin prick test, a screening for specific IgE will be 
performed (see Section 8.5.3.2). The tests are used to identify allergens that are causing 
symptoms and to determine if the patient's asthma is atopic or non-atopic.
An allergy skin test will be completed as per the Assessment Schedule: such test will include 
applying an extract of an allergen to the skin, scratching or pricking the skin to allow exposure, 
and then evaluating the skin's reaction.
If an allergen provokes an allergic reaction, a raised itchy bump (wheal) will develop. The size 
of the wheal (the raised area and not the redness) will be measured in millimeters with a ruler 
and recorded. The wheal size for each antigen will be recorded on the Skin Prick Test CRF.
8.3
Efficacy
Efficacy outcomes and 
samples will be collected at the timepoints defined 
in the Assessment schedule, Section 8. Follow instructions outlined in the Site Operations 
Manual / vendor manual regarding lung function testing, symptom questionnaires, sample 
collection, numbering, processing, and shipment.
8.3.1
Spirometry
Spirometry testing will be performed with the MasterScope system (manufactured by 
eResearchTechnology GmbH) according to the American Thoracic Society guidelines. Criteria 
for acceptability and reproducibility need to be met. Details regarding equipment, study site 
personnel training and certification, spirometric values captured in the database, and quality 
control are provided in the SOM and/or vendor manual. Spirometry testing will be subject to 
central reading.
8.3.2
Clinical Outcome Assessments (COAs)
The validated questionnaire (Asthma Control Questionnaire or ACQ 1999) will be administered 
at various timepoints during the study as depicted in the Assessment Schedule. Further details 
will be described in the SOM. 
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8.3.3
eDiary for daily asthma symptoms, peak flow and rescue medication 
use
The study will use the asthma diary reported by Santanello et al 1997. This asthma diary was 
validated in studies of patients aged 18 to 65 years (Santanello et al 1997). The diary was 
subsequently included as a measure in placebo-controlled studies of montelukast in patients 
aged 15 years and older (Reiss et al 1998, Malmstrom et al 1999) and shown to be responsive 
to both montelukast and inhaled beclomethasone therapy in this age range.
All subjects will be provided with a patient electronic diary (eDiary or eDiary/ePEF: Asthma 
Monitor AM3 Option G+, manufactured by eResearchTechnology GmbH) to record daily 
asthma symptoms, PEF and SABA (salbutamol/albuterol) use. Subjects will be instructed to 
routinely complete the patient diary twice daily - at the same time each morning and each 
evening, approximately 12 hours apart. The eDiary/ePEF recordings are to be reviewed at each 
clinic visit as detailed in the Assessment schedule. Sites and subjects will receive training and 
guidance on the use of the eDiary/ePEF device. Further details are provided in the SOM and/or 
vendor manual.
The data captured in the patient eDiary will be used in conjunction with the patient's asthma 
characteristics to monitor the patient's asthma. Subjects will be instructed to call the study site 
if they experience symptoms of worsening asthma. Additionally, the eDiary will be 
programmed to generate some alerts of signs of possible worsening asthma based on data 
collected. These alerts will be sent to the subject and/or to investigator.
8.3.3.1
Daily symptom scores
The asthma diary contains daytime and nocturnal asthma symptom questions
(Santanello et al 1997). The format of the electronically administered diary may vary.
8.3.3.2
Number of inhalations of rescue medication
The total number of inhalations of SABA (number of puffs taken in the previous 12 hours) will 
be recorded in the morning and evening by the subject in the eDiary/ePEF.
8.3.3.3
Peak expiratory flow (PEF)
PEF will be measured at consistent times for a subject in the morning and evening each day as 
outlined in the Assessment schedule. The measurements will be performed using an 
eDiary/ePEF provided to the subjects.
Subjects must be encouraged to perform morning and evening PEF measurements BEFORE 
the use of any rescue medication (i.e., SABA), and subjects will be asked to record if they have 
taken their SABA 6 hours prior to the peak flow assessment.
At each time point, the subject will be instructed to perform 3 consecutive maneuvers within 
approximately 10 minutes. These PEF values are captured in the eDiary/ePEF.


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8.3.3.4
Worsening of asthma (and related eDiary alerts)
The data captured in the patient eDiary will be used in conjunction with the patient’s asthma 
characteristics to monitor the patient’s asthma. Asthma worsening criteria will be programmed 
into the eDiary/ePEF. Subjects will be instructed to call the study site if they experience 
symptoms of worsening asthma. Additionally, the eDiary will be programmed to generate some 
alerts of signs of possible worsening asthma based on data collected. These alerts will be sent 
to the subject and/or to the investigator.
These alerts include:

An increase in SABA use on at least 2 of any 3 consecutive days exceeding the equivalent
of 8 puffs/day (diary alert)

Night time awakenings requiring SABA use on at least 2 out of any 3 consecutive nights
(diary alert)

<60% of PEF compared to baseline (diary alert)
The subject's personal best PEF in the clinic at the Run-in visit will be set as the subject's 
baseline for the run-in period, and the personal best PEF in the clinic on Day 1 prior to dosing 
will be set as the subject's baseline for the treatment period.
If subjects develop any of the above criteria, the subject should notify the investigator and be 
evaluated by the investigator and treated as clinically appropriate.
If any of these criteria are met while a patient is in the screening, placebo run-in, or treatment 
periods of the study, they may be withdrawn if, in the opinion of the investigator, it is 
appropriate to do so.
Worsening of asthma symptoms may require unscheduled evaluation between visits. Study site 
personnel must be available to monitor and document the subject's progress until the asthma 
worsening as resolved.
8.3.4
Appropriateness of efficacy assessments
The measures described above (spirometry, PEF-measurements, diaries, records of rescue 
medication and patient reported outcomes ACQ) are well-established and widely used outcome 
measures in asthma trials.
8.4
Safety
Safety assessments are specified below with the Assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to AE section.


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Table 8-2
Physical assessments
Assessment
Specification
Physical examination
A complete physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, 
heart, abdomen, back, lymph nodes, extremities, vascular, and 
neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed.
The complete physical examination will be done at screening and End of 
Study visit. At the other visits it will be examination of general appearance, 
the lungs, skin, mucosa of eyes, throat, mouth cavity.  
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are 
present prior to signing informed consent must be recorded on the 
appropriate CRF that captures medical history. Significant findings made 
after signing informed consent which meet the definition of an Adverse 
Event must be recorded as an adverse event.
Vital signs
Vital signs include:

Body temperature

Blood pressure (BP)

Pulse
Height and weight

Height (Screening only)

Body weight

Body mass index (BMI) will be calculated as (Body weight (kg) /
[Height M)]2) (Screening only)
The methods, assessment, specification, and recording for each assessment will be detailed in 
the SOM.
8.4.1
Laboratory evaluations
A central laboratory will be used for analysis of all specimens detailed in this section unless 
noted otherwise. Details on the collections, shipment of samples and reporting of results by the 
central laboratory are provided in the laboratory manual.
Clinically notable laboratory findings are defined in Section 16.1.
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/Current medical conditions/AE CRF /e(CRF) page as appropriate.


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Table 8-3
Laboratory assessments
Test category
Test name
Hematology
Hematocrit, Hemoglobin ,
Mean Corpuscular Hemoglobin (MCH), 
Mean Corpuscular 
Hemoglobin 
Concentration 
(MCHC), 
Mean Corpuscular Volume (MCV), Platelets, Red blood cells (RBC), 
White blood cells (WBC) and Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils, Bands)
Chemistry
Albumin, Alkaline phosphatase, ALT, AST, GGT, LDH, Calcium, 
Magnesium, Phosphorus, Chloride, Sodium, Potassium, Creatinine 
Kinase (CK), Creatinine, total Bilirubin (in case of clinically significant 
elevation: direct Bilirubin and indirect Bilirubin will be assessed), Amylase, 
Lipase, Blood Glucose; CRP; Blood Urea Nitrogen (BUN) or Urea, Uric 
Acid; in case of liver value deviations refer to Section 16.2 (liver events)
Only at baseline (Day 1) and Week 12: total Cholesterol, Low density 
Lipoprotein (LDL), High density Lipoprotein (HDL), Total Protein, 
Triglycerides
Urinalysis
Done on site: Macroscopic Panel (e.g., Dipstick) (Color, Bilirubin, Blood, 
Glucose, Ketones, Leukocytes esterase, Nitrite, pH, Protein, Specific 
Gravity, Urobilinogen); in case of abnormal findings pls. confirm and 
consider appropriate follow-up (e. g. urine protein analyses, urine 
microscopy, urine microbiolgy) for recommendations refer to Section 16.3
for definitions of alert criteria and recommendations for follow-up .
Coagulation
Prothrombin time (PT)/International normalized ratio (INR), Activated 
partial thromboplastin time (APTT)
Hepatitis markers
At Screening only: Hepatitis B surface antigen (HBsAg), Hepatitis B 
surface antibody (HBsAb); Hepatitis B core antibody (anti-HBc) Hepatitis 
B-Deoxyribonucleic acid (HBV- DNA) if appropriate; Hepatitis C virus
antibody (HCVAb); Hepatitis C-Ribonucleic acid (HCV-RNA) if appropriate
Additional tests
IgE, IgG, IgA, IgM; Follicle-stimulating hormone (FSH) (for female subjects 
with unclear fertility status; at screening); B-hCG for pregnancy (serum 
and urine)
8.4.2
Electrocardiogram (ECG)
Full details of all procedures relating to the ECG collection and reporting are contained in the 
Site Operations Manual.
PR interval, QRS duration, heart rate, RR interval, QT interval, QTc will be measured. 
The Fridericia QT correction formula (QTcF) must be used for clinical decisions.
Unless auto-calculated by the ECG machine, the investigator must calculate QTcF at the 
Screening visit to assess eligibility. See the SOM for additional details.
Clinically significant abnormalities must be reported as adverse events.


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8.4.3
Pregnancy and assessments of fertility
A condom is required for all sexually active male participants to prevent them from fathering a 
child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, 
male participants should not donate sperm after being randomized and exposed to LOU064.
All pre-menopausal women who are not surgically sterile will have a serum pregnancy test at 
Screening, Day 29 (Week 4), Day 57 (Week 8), Day 85 (Week 12) and End of Study. A urine 
pregnancy test will be performed at the placebo Run-in visit and randomization (Day 1; BEFORE 
administration of the study medication, Day 15 (Week 2)). A positive urine test needs to be confirmed 
with serum test. If positive, the subject must be discontinued from study treatment.
Additional pregnancy testing might be performed if requested by local requirements.
Assessments of fertility
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child 
bearing potential must also be available as source documentation in the following cases:
1. surgical bilateral oophorectomy without a hysterectomy
2. reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile.
In the absence of the above medical documentation, FSH testing is required of any female 
subject, regardless of reported reproductive/menopausal status at screening/baseline.
8.4.4
Other safety evaluations
Not applicable
8.4.5
Appropriateness of safety measurements
The safety assessments selected will provide sufficient safety information for LOU064 in the 
target population.
8.5
Additional assessments
8.5.1
Pharmacokinetics
Pharmacokinetic (PK) samples will be collected at the visits defined in the Assessment schedule. 
Follow instructions outlined in the SOM regarding sample collection, numbering, processing 
and shipment. Residual PK samples may be used to explore additional PK aspects such as 
metabolite formation or plasma protein binding of LOU064.
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8.5.2
Biomarkers
8.5.2.2
Use of residual biological samples
Residual blood and urine samples may be used for another protocol specified endpoint.
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8.5.3
Other Assessments
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9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the subject or the investigator.
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being.
Study treatment must be discontinued under the following circumstances:

Subject/guardian decision

Pregnancy

Current use of prohibited treatment as per recommendations in the prohibited treatment
section (Section 6.2.2)

Subject received a live virus vaccination since the last visit

Any situation in which study participation might result in a safety risk to the subject

Following emergency unblinding

Emergence of the following adverse events:

AEs including hypersensitivity reactions for which continued exposure to the study
drug would be detrimental

Abnormal liver laboratory results requiring discontinuation (see Section 16.2)

Abnormal renal laboratory results requiring discontinuation (see Section 16.3)

Spontaneous bleeding event

Platelets < 75 000/mm3

Required interventions (surgery) with bleeding risk

Any laboratory abnormalities (for anemia or neutropenia criteria see Section 16.1) or
safety findings that in the judgment of the investigator, taking into consideration the
patient's overall status, prevents the patient from continuing participation in the study

An asthma exacerbation requiring treatment with systemic corticosteroids
(e.g., oral/parenteral)

Need for prohibited asthma medication (as per Section 6.2.2) to achieve acceptable
symptom control of asthma, e.g., patient requires higher amount of ICS; patient needs
higher amount of rescue medication at a total daily dose level higher than labeled to
achieve acceptable symptom control

Development of chronic or recurrent infections including but not limited to
opportunistic infections
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
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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 9.1.2 withdraw of informed consent). Where possible, they should 
return for the assessments indicated in the assessment schedule. If they fail to return for these 
assessments for unknown reasons, every effort (e.g., telephone, e-mail, letter) should be made 
to contact the subject/pre-designated contact as specified in Section 9.1.3. This contact should 
preferably be done according to the study visit schedule.
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. 
This telephone contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

new / concomitant treatments

adverse events/Serious Adverse Events
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
If discontinuation occurs because treatment code has been broken, please refer to Emergency
breaking of treatment code section.
9.1.2
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 
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Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until the time of withdrawal) according to applicable 
law.
For US: All biological samples not yet analyzed at the time of withdrawal may still be used for 
further testing/analysis in accordance with the terms of this protocol and of the informed consent 
form.
For EU and other countries: 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.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g., dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed.
9.1.4
Study stopping rules
The study may be put on hold pending a full safety data review, if any of the following criteria 
are met:

Two or more (in different subjects) similar study-treatment (LOU064) related SAEs are
reported

Two or more other clinically significant, severe events (in different subjects) that preclude
to continue dosing (events that are considered study drug related: development of
recrurrent/opportunistic infection, thromboembolism, spontaneous bleeding events, drug
related renal or liver events, neutropenia, anemia, thrombocytopenia <75.000/microliter )

The Sponsor considers that the number and/or severity of AEs, abnormal safety
monitoring tests or abnormal laboratory findings justify putting the study on hold.
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.
9.1.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination may include:

Unexpected, significant, or unacceptable safety risk to subjects enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety and
efficacy data

Discontinuation of study drug development.


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In taking the decision to terminate, Novartis will always consider the subject welfare and safety. 
Should early termination be necessary, subjects must be seen as soon as possible and treated as 
a prematurely withdrawn subject. The investigator may be informed of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection of the 
subject’s interests. The investigator or sponsor depending on the local regulation will be 
responsible for informing IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their Study Completion visit (i.e., 
Last Subject Last 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 (e.g., each subject will be required to complete 
the study in its entirety and thereafter no further study treatment will be made available to them).
All randomized and/or treated subjects should have a safety follow-up call conducted 30 days 
after last administration of study treatment. The information collected is kept as source 
documentation. All SAEs reported during this time period must be reported as described in 
Section 10.1.3 and SOM. Documentation of attempts to contact the subject should be recorded 
in the source documentation.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.


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Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information (as far as possible) 
(if the event is serious refer to Section 10.1.2):
1. The severity grade:

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression
of underlying illness (i.e. progression of the study indication) the assessment of causality
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a
lack of efficacy or progression of underlying illness are not caused by the trial drug, they
happen in spite of its administration and/or both lack of efficacy and progression of
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a
single subject
3. its duration (start and end dates) or if the event is ongoing, an outcome of not
recovered/not resolved must be reported.
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which
seriousness criteria have been met
5. action taken regarding with study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose Reduced/increased

Drug interrupted/withdrawn
6. its outcome
a. not recovered/not resolved;
b. recovered/resolved;
c. recovering/resolving,
d. recovered/resolved with sequelae;
e. fatal; or unknown.
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g., continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.


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Information about adverse drug reactions for the investigational drug can be found in the 
Investigator Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease. See Section 16.1, Section 16.2, and Section 16.3 for alert ranges for 
laboratory and other test abnormalities.
Follow the instructions found in the Site Operations Manual for data capture methodology 
regarding AE collection for subjects that fail screening.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above


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Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred (see details in Section 10.1.5).
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety within 24 hours of learning of its occurrence. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site.
1. Screen Failures (e.g., a subject who is screened but is not treated or randomized): SAEs
occurring after the subject has provided informed consent until the time the subject is
deemed a Screen Failure must be reported to Novartis.
2. Run-In Failures (e.g., a subject who is screened but not randomized/treated after the run-in
period (where run-in period requires adjustment to subject’s medications or other
intervention)): SAEs collected between time subject signs ICF until time that subject is
determined to be a run-in failure.
3. Randomized OR Treated Subjects: SAEs collected between time subject signs ICF until
30 days after the subject has discontinued or stopped study treatment.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
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.
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 Chief Medical Office and 
Patient Safety (CMO & PS) Department associate may urgently require further information 
from the investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.


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Any SAEs experienced after the 30 day period following the last administration of study 
treatment should only be reported to Novartis Safety if the investigator suspects a causal 
relationship to study treatment.
10.1.4
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. A minimum of 12 months of the newborn must be followed up.
Pregnancy should be recorded and reported by the investigator to the Novartis CMO&PS. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment. Any SAE experienced during pregnancy 
must be reported.
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.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE and reported 
to Novartis Safety only if associated with an SAE. Misuse or abuse will be collected and 
reported in the safety database irrespective of it being associated with an AE/SAE within 
24 hours of Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dose 
Administration (DAR) 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections.


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10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE):

Liver laboratory triggers, which will require repeated assessments of the abnormal
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and are recorded
in the source documentation
Please refer to Table 16-1 in Section 16.2 for complete definitions of liver laboratory triggers 
and liver events.
Every liver event defined in Table 16-1 should be followed up by the investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case 
of liver events are outlined in Table 16-2 in Section 16.2.

Repeat liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and G-GT) to confirm
elevation. These liver chemistry repeats will be performed using the central laboratory.
If results will not be available from the central laboratory, then the repeats can also be
performed at a local laboratory to monitor the safety of the subject. If a liver event is
subsequently reported, any local liver chemistry tests previously conducted that are
associated with this event should have results reported on the appropriate eCRF.

If the initial elevation is confirmed, close observation of the subject will be initiated

Discontinuation of the investigational drug (refer to the Section 9.1.1 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. These investigations can include based on
investigator’s discretion: serology tests, imaging and pathology assessments,
hepatologist’s consultancy

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

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 eCRF.
Refer to the Site Operations Manual for additional details.


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10.2.2
Renal safety monitoring
Every renal laboratory trigger or renal event as defined in Table 16-3 in Section 16.3 should be 
followed up by the investigator or designated personnel at the trial site as summarized in 
Table 16-4 in Section 16.3.
Refer to the Site Operations Manual for additional details.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure 
web-enabled software that conforms to 21 CFR Part 11 requirements. Investigator site staff will 
not be given access to the EDC system until they have been trained. Automatic validation 
programs check for data discrepancies in the eCRFs, allow modification and/or verification of 
the entered data by the investigator staff.
The investigator/designee is responsible for assuring that the data (entered into eCRF) is 
complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
11.2
Database management and quality control
Novartis personnel (or designated Contract Research Organization (CRO)) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 
site staff are required to respond promptly to queries and to make any necessary changes to the 
data.
Concomitant treatments and prior medications entered into the database will be coded using the 
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.
Randomization codes and data about all study treatment(s) dispensed to the subject and all 
dosage changes will be tracked using IRT. The system will be supplied by a vendor, who will 
also manage the database. The data will be sent electronically to Novartis (or a designated CRO) 
at specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.


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Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis/delegated CRO representative will review the protocol and data capture requirements 
(i.e., eSource DDE or eCRFs) with the investigators and their staff. During the study, 
Novartis employs several methods of ensuring protocol and GCP compliance and the 
quality/integrity of the sites’ data. The field monitor will visit the site to check the completeness 
of subject records, the accuracy of data capture / data entry, the adherence to the protocol and 
to Good Clinical Practice, the progress of enrollment, and to ensure that study treatment is being 
stored, dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits. Continuous remote monitoring of each 
site’s data may be performed by a centralized Novartis/delegated CRO/CRA organization. 
Additionally, a central analytics organization may analyze data & identify risks & trends for 
site operational parameters, and provide reports to Novartis clinical teams to assist with trial 
oversight.
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 eCRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the eCRFs 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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12
Data analysis and statistical methods
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
The Safety Set includes all subjects who received at least one dose of study treatment.
The PK analysis set will include all subjects with at least one available valid (i.e., not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that affect PK data.
The PD analysis set will include all subjects with available PD data and no protocol deviations 
with relevant impact on PD data.
Subjects will be analyzed according to the study treatment received, unless otherwise specified.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data including key disease characteristics will be listed and 
summarized descriptively by treatment group based on PD analysis set.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by treatment group, as applicable.
12.3
Treatments
The Safety set will be used for the analyses below.
The duration of study treatment exposure in months will be summarized using descriptive 
statistics. The number of subjects with permanent study drug discontinuation and the reasons 
will be summarized by treatment group. All dose administration records will be listed at a 
subject level.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group.
12.4
Analysis of the primary endpoint(s)
The primary objective of this study is to determine the efficacy of LOU064 compared to placebo 
with respect to change from baseline in pre-dose FEV1 (L) at Week 12.


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12.4.1
Definition of primary endpoint(s)
The primary analysis variable is the change from baseline in pre-dose FEV1 after 12 weeks of 
treatment with LOU064 at 100mg q.d. or placebo.
The baseline pre-dose FEV1 is defined as the average of the FEV1 measurements performed 
45 min and 15 min prior to dosing on Day 1. If one of the assessment is missing, then the non-
missing pre-dose FEV1 will be considered as baseline.
Repeated measurements of pre-dose FEV1 at week 2, week 4, week 8 and week 12 are 
considered in the primary analysis.
12.4.2
Statistical model, hypothesis, and method of analysis
The primary endpoint will be analyzed using a Bayesian repeated measures model with change 
from baseline in pre-dose FEV1 as response, adjusting for effects of treatment*visit interaction, 
baseline pre-dose FEV1, and any additional covariate as deemed appropriate. Conditional on 
the aforementioned covariates, the responses are assumed to follow a multivariate normal 
distribution with a common unknown and unstructured covariance matrix explaining the 
association between repeated measures for a subject (similar to a covariance pattern model). 
Prior distributions for the unknown quantities included in the model are specified as below.
A weakly informative prior will be used for adjusted mean change from baseline at week 12 
under placebo (placebo response). The prior reflects the predicted placebo response as estimated 
from a Bayesian meta-analysis on similar historical trials, accounting for a substantial between-
trial variability. A Bayesian meta analysis estimates that the placebo response to be normally 
distributed with a mean of 46ml and SD of 84ml at week 12. To ensure that this weakly 
informative Bayesian prior will be in alignment with the trial data, a robust mixture prior will 
be used in the analysis. The mixture prior allows for more uncertainty in the placebo response. 
The mixture has a second distribution that has 10% weight and assumes placebo is normally 
distributed with a mean of 46ml and larger SD of 260ml).
Integrating this prior with the observed FEV1 data implies an additional amount of information 
equivalent to 5 subjects on placebo.
For adjusted mean responses at all other time points under placebo treatment and for LOU064 
treatment at all time points, non-informative prior will be used in the Bayesian repeated analysis 
model. An inverse wishart distribution will be used as a non-informative prior for the covariance 
matrix accounting for the association between responses at each time point.
The quantity of primary interest is the ‘true’ LOU064 effect on primary endpoint over placebo 
and inferences will be performed in terms of the posterior probabilities derived from the above 
model. 


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12.4.3
Handling of missing values/censoring/discontinuations
The primary analysis methodology uses all available information on the primary endpoint 
without making any explicit imputation for missing FEV1 measurements. However, the 
modeling implicitly borrows information from the patient history and from similar patient 
profiles and provides consistent estimates of model parameters under ‘Missing at random 
(MAR)’ assumption. Alternative missing data handling may be used if there is substantial 
rationale for considering the missing values to be missing not at random (MNAR).
12.4.4
Sensitivity and Supportive analyses
Descriptive summaries will also be provided for change from baseline in pre-dose FEV1 by 
time and treatment group. Primary endpoint analysis may be repeated on the subgroups 
prospectively defined on demographic/ baseline characteristics. Details will be specified in the 
statistical analysis plan.
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12.5
Analysis of secondary endpoints
All secondary efficacy/
 endpoints will be analyzed based on PD analysis set, 
while the safety endpoints will be analyzed based on safety set, unless otherwise specified.
12.5.1
Efficacy 
 endpoint(s)
All the secondary efficacy/ pharmacodynamic endpoints will be analyzed based on PD analysis 
set, unless specified otherwise. The secondary efficacy/
 variables include -
1. Change from baseline in ACQ-5 score over 12 weeks of treatment (ACQ assessment for
the week preceding each planned visit up to end of study)
2. Number of puffs of SABA taken per day over 12 weeks of treatment (captured in eDiary)
3. Change from baseline in PEF (AM and PM), as assessed by mean morning and mean
evening PEF over 12 weeks of treatment (daily capture of PEF in eDiary)
4. Change from baseline in daytime and nighttime asthma symptom score over 12 weeks of
treatment (captured in eDiary)
12.5.1.1 Analysis methods for secondary efficacy/ 
All secondary endpoints except (2) (Number of puffs of SABA taken per day over 12 weeks of 
treatment) will be analyzed using a similar methodology as followed for primary endpoint, with 
the exception that –

baseline value of the secondary outcome will be used as a covariate instead of baseline
FEV1

Non-informative priors will be used for mean responses for each timepoint under
LOU064/ placebo treatment.
For secondary endpoint (2), mean number of puffs of SABA taken in past 12 hours (morning/ 
evening) and overall will be calculated for each subject separately for run-in period (used as 
baseline value) and double blind treatment period of 12 weeks. Change from baseline in mean 
daily use of puffs of SABA over 12 weeks will be analyzed using a Bayesian regression model. 
The model will assess effects of treatment (LOU064/ placebo), baseline use of puffs of SABA 
per day, baseline pre-dose FEV1, baseline daytime asthma symptom score and any additional 
covariate as deemed appropriate.
In a similar manner as followed for primary endpoint (Section 12.4.2), for each of the secondary 
endpoints, the posterior probabilities of ‘true’ effect of LOU064 over placebo will be derived 
from the fitted model. The posterior probabilities will be compared to the pre-specified criteria 
mentioned in Section 12.4.2 at interim/ final stage as a guide for PoC evaluation of treatment 
effect on the endpoint.
For each endpoint except rescued medication usage, the adjusted posterior mean estimates over 
12 weeks with 2-sided 80% credible limits will be plotted for each of the treatment for 
descriptive purposes. Frequency of use of rescue medications will be summarized by treatment 
group descriptively and will also be listed at a subject level.
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12.5.2
Safety endpoints
All safety endpoints will be analyzed based on safety set and will be summarized by actually 
received treatment group.
Adverse events
Adverse event summaries will only include treatment emergent AEs, defined as any AE that 
develops after initiation of the study treatments or any event already present that worsens 
following exposure to the study treatment.
The number (and percentage) of subjects with treatment emergent adverse events (events started 
after the first dose of study medication or events present prior to start of double-blind treatment 
but increased in severity based on preferred term) will be summarized in the following ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum severity.

by treatment, Standardized MedDRA Query (SMQ) and preferred term
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation.
A subject with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
All AEs, deaths and serious adverse events will be listed by patient and treatment group.
Vital signs
All vital signs data will be listed by treatment group, subject, and visit/time and if ranges are 
available, abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit/time.
12-lead ECG
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. Shift tables using the low/normal/high/ (low and high) classification will be used 
to compare baseline to the worst on-treatment value.
12.5.3
Pharmacokinetics
PK analysis set will be used for the analysis of all pharmacokinetic parameters.
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LOU064 blood concentration data and the derived PK parameters will also be listed by 
treatment, subject, and visit/sampling time point.
Graphical methods will be employed to show mean and individual time-concentration profiles.
12.5.5
Patient reported outcomes
Refer to Section 12.5.1
12.6
Analysis of exploratory endpoints
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12.7
Interim analyses
12.8
Sample size calculation
Approximately 75 subjects will be randomized to LOU064 100 mg q.d. or placebo in a 3:2 ratio 
in order to achieve at least 65 completers. The planned sample size is driven by the following 
considerations on primary endpoint. (The sample size used the freely available software 
(Fisch et al (2015).)
12.8.1
Primary endpoint(s)
The planned sample size is selected to ensure an optimal operating characteristic for evaluation 
of PoC regarding the treatment effect on the primary endpoint according to the criteria 
mentioned in Section 12.4.2. 
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12.8.2
Secondary endpoint(s)
Not applicable
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures 
(e.g., advertisements) and any other written information to be provided to subjects. Prior to 
study start, the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and to give access to all relevant data and records to 
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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.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g., Clinicaltrials.gov, EudraCT 
etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and health authorities, where required, it cannot be 
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14.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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15
References
References are available upon request
Asthma Control Questionnaire or ACQ Juniper EF, O’Byrne PM, Guyatt GH, et al (1999). 
Development and validation of a questionnaire to measure asthma control.  Eur Respir J; 902-7.
Available from: < http://www.qoltech.co.uk/acq.html> (Accessed May 1999)
D'Amato G, Vitale C, Molino A, et al (2016) Asthma-related deaths. Multidiscip Respir Med; 
11:37.
Calquence® PI(2017) AstraZeneca Calquence(acalabrutinib)100mg capsule for oral 
administration. Full Prescribing Information; 1-17.
Fisch R, Jones I, Jones J, et al (2015) Bayesian Design of Proof-of-Concept Trials. 
Therapeutic Innovation & Regulatory Science; 155-162
Global Initiative for Asthma (GINA) (2018). Global Strategy for Asthma Management and 
Prevention
Available from: https://ginasthma.org/wp-content/uploads/2018/04/wms-GINA-2018-report-
V1.3-002.pdf (accessed January 22nd, 2019)
Hendriks RW, Yuvaraj S, Kil LP (2014) Targeting Bruton's tyrosine kinase in B cell 
malignancies. Nat Rev Cancer; 219-32.
Imbruvica® PI (2018) Janssen Imbruvica (ibrutinib) 70mg, 140mg capsule/140mg, 280mg, 
420mg and 560mg tablet for oral administration. Full Prescribing Information; 1-45
Kumar A, Teuber SS, Gershwin ME (2006) Current perspectives on primary 
immunodeficiency diseases. Clin Dev Immunol; 223-59.
Malmstrom K1, Rodriguez-Gomez G, Guerra J, et al (1999) Oral montelukast, inhaled 
beclomethasone, and placebo for chronic asthma. A randomized, controlled trial. 
Montelukast/Beclomethasone Study Group; 487.
Nutt SL, Hodgkin PD, Tarlinton DM, et al (2015) The generation of antibody-secreting 
plasma cells. Nat Rev Immunol; 160-71.
Regan JA, Cao Y, Dispenza MC, et al (2017) Ibrutinib, a Bruton's tyrosine kinase inhibitor 
used for treatment of lymphoproliferative disorders, eliminates both aeroallergen skin test and 
basophil activation test reactivity. J. Allergy Clin Immunol; 875-879.e1.
Reiss TF, Chervinsky P, Dockhom RJ, et al (1998) Montelukast, a once-daily leukotriene 
receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-
blind trial. Montelukast Clinical Research Study Group; 1213-20.
Santanello NC, Barber BL, Reiss TF, et al (1997) Measurement characteristics of two asthma 
symptom diary scales for use in clinical trials. Eur Respir J; 646-51.
Sun C, Tian X, Lee YS, et al (2015) Partial reconstitution of humoral immunity and fewer infections 
in patients with chronic lymphocytic leukemia treated with ibrutinib. Blood; 2213-9.


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16
Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
The following specific criteria have been identified for this study. Should these criteria be met, 
a re-test must be done within 5 days after the first assessment. Discontinuation of the study 
treatment should be considered (specifically in case of worsening of value from baseline is 
observed) if the abnormal hematology parameter is confirmed:

Hemoglobin: < 10 g/dl 

Platelets: < 75,000/mm3

White blood cells: < 3000/mm3

Neutrophils: < 1500/mm3
For all other laboratory assessments, the central laboratory will flag laboratory values falling 
outside of the normal ranges on the central laboratory report (which the investigator should 
review and sign-off) and the investigator will report any values considered clinically significant 
in the eCRF.
Notable values for vital signs and change from baseline will be summarized.
Notable values are defined as follows: heart rate of < 50 and > 100 bpm; systolic blood pressure 
of < 90 and ≥ 140 mmHg; diastolic blood pressure of < 60 and ≥ 90 mmHg.
For ECGs a notable QTc value is defined as a QTc (Fridericia’s) interval of greater than 
450 msec for males or greater than 460 msec for females – all such ECGs will require 
assessment for clinical relevance by the investigator.


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16.2
Appendix 2: Liver event and laboratory trigger definitions and 
follow-up requirements
Table 16-1
Liver event and laboratory trigger definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS
3 x ULN < ALT / AST ≤ 5 x ULN
1.5 x ULN < TBL ≤ 2 x ULN
LIVER EVENTS
ALT or AST > 5 × ULN
ALP > 2 × ULN (in the absence of known bone pathology)
TBL > 2 × ULN (in the absence of known Gilbert syndrome)
ALT or AST > 3 × ULN and INR > 1.5
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN 
and TBL > 2 × ULN [mainly conjugated fraction] without 
notable increase in ALP to > 2 × ULN)
Any clinical event of jaundice (or equivalent term)
ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia
Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms TBL: total bilirubin; ULN: upper limit of normal


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Table 16-2
Follow-up requirements for liver events and laboratory triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law casea

Discontinue the study 
treatment immediately

Hospitalize, if clinically 
appropriate

Establish causality

Record the AE and 
contributing factors (e.g. 
concomitant medication, 
medical history, laboratory 
values) in the appropriate 
eCRF.
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
ALT or AST
> 8 × ULN

Discontinue the study 
treatment immediately

Hospitalize if clinically 
appropriate

Establish causality

Record the AE and 
contributing factors (e.g. 
concomitant medication, 
medical history, laboratory 
values) in the appropriate 
eCRF.
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN and INR > 1.5

Discontinue the study 
treatment immediately

Hospitalize, if clinically 
appropriate

Establish causality

Record the AE and 
contributing factors (e.g. 
concomitant medication, 
medical history, laboratory 
values) in the appropriate 
eCRF.
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)


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


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


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Based on investigator's discretion, investigation(s) for contributing factors for the liver event 
can include: serology tests, imaging and pathology assessments, hepatologist's consultancy; 
obtaining more detailed history of symptoms and prior concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease. 


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16.3
Appendix 3: Specific renal alert criteria and actions and event 
follow-up
Table 16-3
Specific renal alert criteria and actions
Renal Event
Actions
Confirmed serum creatinine increase 25 – 49%

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 patient hospitalization and 
specialized treatment
New onset dipstick proteinuria ≥ 3+
When urine proteins are measured as a follow-
up of positive urine dipstick measurements:
Protein-creatinine ratio (PCR) ≥ 1 g/g Cr (or 
mg/mmol equivalent as converted by the 
measuring laboratory)

Consider causes and possible interventions

Assess serum albumin & serum total protein

Repeat assessment to confirm

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected
New onset hematuria ≥ 3+ on urine dipstick
Assess & document

Repeat assessment to confirm

Distinguish hemoglobinuria from hematuria

Urine sediment microscopy

Assess sCR

Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation

Consider bleeding disorder
+ Corresponds to KDIGO criteria for Acute Kidney Injury 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 recommended to make slide specimen available for evaluation by the 
RSG to potentially identify project-wide patterns of nephrotoxicity.)
Whenever a renal event is identified, a detailed patient history and examination are indicated to 
identify and potentially eliminate risk factors that may have initiated or contributed to the event:

Blood pressure assessment (after 5-minute rest, with an appropriate cuff size)

Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain, dysuria or 
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 diseases or causes, e.g., 
dehydration due to delirium, tumor lysis


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Table 16-4
Renal event follow-up
FOLLOW-UP OF RENAL EVENTS
Assess, document and record in eCRF

Urine dipstick and sediment microscopy evidence of DIN: crystals, red blood cells 
(dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial 
cells

Blood pressure and body weight

Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and 
uric acid

Urine output
Review and record possible contributing factors to the renal event (co-medications, other co-morbid 
conditions) and additional diagnostic procedures (MRI etc.) in the eCRF.
Monitor patient regularly (frequency at investigator's discretion) until:

Event resolution: (sCr within 10% of baseline or PCR < 1 g/g Cr, or ACR <300 mg/g Cr) 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.

Analysis of urine markers in samples collected over the course of the DIN event


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16.4
Appendix 4: Prohibited medications
The lists provided in the table below are non-exhaustive. In case of any doubt, the corresponding 
SmPC should be checked.
Table 16-5
Moderate and strong inhibitors of CYP3A4
Strong inhibitors of CYP3A4
boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir, darunavir/ritonavir, elvitegravir/ritonavir, 
grapefruit juice, idelalisib, indinavir, indinavir/ritonavir, 
itraconazole, ketoconazole, LCL161, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, 
saquinavir, saquinavir/ritonavir, telaprevir, telithromycin, 
tipranavir/ritonavir, troleandomycin, Viekira pack, voriconazole
Moderate inhibitors of CYP3A4
ACT-178882, amprenavir, aprepitant, atazanavir, casopitant, 
cimetidine, ciprofloxacin, crizotinib, cyclosporine, darunavir, 
diltiazem, dronedarone, erythromycin, faldaprevir, ferula 
asafetida resin (herbal product), FK1706, fluconazole, imatinib, 
isavuconazole, netupitant, nilotinib, schisandra, sphenanthera, 
tofisopam, verapamil
Table 16-6
Moderate and strong inducers of CYP3A4
Strong inducers of CYP3A4
avasimibe, carbamazepine, enzalutamide, rifampin, mitotane, 
phenobarbital, phenytoin, rifabutin, St. John’s wort (herbal 
product)
Moderate inducers of CYP3A4
bosentan, efavirenz, etravirine, lersivirine, lopinavir, modafinil, 
nafcillin, ritonavir/tipranavir, semagacestat, talviraline, 
thioridazine

SAP_000.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
LOU064
CLOU064D12201 / NCT03944707
A randomized, patient- and investigator-blinded, placebo 
controlled study to assess the efficacy and safety of 
LOU064 in patients with inadequately controlled asthma
Statistical Analysis Plan (SAP)
Author(s):
Document type:
SAP Documentation – NIBR
Document status:
Amendment 1
Release date:
24-Aug-2020
Number of pages:
19
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 .................................................................................................................3
List of tables ........................................................................................................................3
1
Introduction .........................................................................................................................4
1.1
Scope of document ..................................................................................................4
1.2
Study reference documentation ...............................................................................4
1.3
Study objectives.......................................................................................................4
1.4
Study design and treatment......................................................................................5
2
First interpretable results (FIR) ...........................................................................................7
3
Interim analyses...................................................................................................................7
4
Statistical methods: Analysis sets........................................................................................7
5
Statistical methods for Pharmacokinetic (PK) parameters..................................................8
5.1
Variables..................................................................................................................9
5.2
Descriptive analyses ................................................................................................9
5.3
Statistical model, assumptions and hypotheses .......................................................9
6
Statistical methods for Pharmacodynamic (PD) parameters...............................................9
6.1
Primary objective.....................................................................................................9
6.1.1
Variables .................................................................................................9
6.1.2
Descriptive analyses................................................................................9
6.1.3
Statistical model, assumptions and hypotheses.......................................9
6.2
Secondary objectives .............................................................................................12
6.2.1
Variables ...............................................................................................12
6.2.2
Descriptive analyses..............................................................................13
6.2.3
Statistical model, assumptions and hypotheses.....................................13
6.3
Exploratory objectives...........................................................................................14
7
Statistical methods for safety and tolerability data............................................................15
7.1
Variables................................................................................................................15
7.2
Descriptive analyses ..............................................................................................15
7.3
Graphical presentation...........................................................................................17
8
Statistical methods for biomarker data..............................................................................18
List of tables
Table 4-1
Protocol deviation codes and analysis sets..............................................8
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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 “CLOU064D12201”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
This SAP has been developed in accordance with clinical trial protocol amended version v01 
(dated: 09 May 2019).
1.3
Study objectives
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To determine the efficacy of LOU064
compared to placebo with respect to
change from baseline in pre-dose FEV1
at Week 12

Change from baseline in pre-dose FEV1 at Week
12
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To characterize the pharmacokinetic
profile of LOU064 in blood of asthma
patients

Concentrations of LOU064 in blood at steady state
and calculation of respective PK parameters
including but not limited to Cmax, Tmax, MRT,
AUClast

To determine the efficacy of LOU064
compared to placebo on changes in
morning and evening peak expiratory
flow rate (PEF) over the 12-week
treatment period

Change from baseline in PEF (AM and PM), as
assessed by mean morning and mean evening
PEF over 12 weeks of treatment (captured in
eDiary)

To evaluate the safety and tolerability of
LOU064 in patients with inadequately
controlled asthma

All safety endpoints (including vital signs, ECG
intervals, safety laboratory parameters, adverse
events, and serious adverse events) through the
End of Study/Early Termination Visit

To determine the efficacy of LOU064
compared to placebo on daytime and
nighttime asthma symptom scores over
the 12-week treatment period

Change from baseline in daytime and nighttime
asthma symptom score over 12 weeks of
treatment (captured in eDiary)

To determine the efficacy of LOU064
compared to placebo on change from
baseline in Asthma Control
Questionnaire-5 (ACQ-5) score over the
12-week treatment period

Change from baseline in ACQ-5 score over 12
weeks of treatment (ACQ-assessment for the week
preceding each planned visit up to End of Study)


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
To determine the efficacy of LOU064
compared to placebo on total daily
short-acting β-agonist (SABA) used 
over the 12-week treatment period

Number of puffs of SABA taken per day over 12
weeks of treatment (captured in eDiary)
1.4
Study design and treatment
This is a non-confirmatory, multi-center, randomized, placebo-controlled, subject- and 
investigator-blinded, parallel-group study to evaluate the efficacy of LOU064 in patients with 
inadequately controlled asthma. This study will enroll approximately 75 subjects. However, in 
case of a higher dropout rate than assumed (10% over 12 weeks), and/or a higher variability 
of the primary endpoint in the planned first interim analyses than expected, up to 154 subjects 
may be randomized. 
The study consists of:

Screening Period of up to 2 weeks

Run-in Period of minimum 3 weeks and maximum of 5 weeks

Baseline visit

12-week Treatment Period

Follow-up Period of approximately 3 weeks

End of Study (EOS) visit approximately 3 weeks after the last study drug
administration
The total duration for each subject in the study is approximately 20 weeks.
Figure 1-1
Study design
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Screening:
Subjects will be provided with an electronic peak expiratory flow (ePEF)/eDiary device in 
which they will record their PEF, daytime and nighttime asthma symptoms, and the use of 
rescue medication. Subjects will be instructed on eDiary completion and how to use the 
device for the assessment of peak flow. Subjects will perform PEF measurements twice daily 
(morning and evening) beginning the evening of the screening visit through the EOS visit. 
The investigator will check that the vaccination status of the subject is complete and there are 
no vaccinations planned during the study period. 
Run in: 
The run-in period has a minimum duration of three weeks (21 days) and may be extended by 
up to two weeks for a maximum of 5 weeks (35 days). If the time difference between the 
Screening and Run-in visits is less than two weeks, hematology, clinical chemistry, urinalysis 
and coagulation panel do not need to be tested again at the Run-in visit. All subjects will 
receive LOU064 matching placebo once daily in the morning for the duration of the run-in 
period. Subjects will be blinded to the identity of the treatment.
Baseline:
The run-in period will end with the Baseline visit, between Day -3 and Day 1, when 
randomization will take place. All baseline assessments must be completed and eligibility 
confirmed prior to randomization on Day 1. The Baseline visit can be performed on the same 
day as the Day 1 visit. 
Treatment:
On Day 1 of the treatment period, after completion of all pre-dose assessments, eligible 
subjects will be randomized in a 3:2 ratio to receive either LOU064 
 or placebo 
Subjects will complete dosing on Day 85. 
End of Study: 
A study completion visit will occur approximately 3 weeks following the last dose of study 
drug. 
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2
First interpretable results (FIR)
3
Interim analyses
4
Statistical methods: Analysis sets
The screening set (‘all subjects’) includes all patients who signed informed consent.
The randomized set includes all patients who were randomized.
The safety set includes all patients who received at least one dose of study treatment.
The PK analysis set will include all patients with at least one available valid (i.e., not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that affect PK data. 
The PD analysis set will include all subjects with available PD data and no protocol 
deviations with relevant impact on PD data. A subject with available PD data is a subject with 
at least one on-treatment spirometry assessment or with PD diary data (asthma scores, PEF)
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for at least 14 days. Patients will be analyzed according to the study treatment received, unless 
otherwise specified. 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 all analyses (including safety) in 
case of these PDs: 
Exclude subject completely 
from all analysis sets
(including safety)
I1
ICF not obtained
S1
Subject did not take the study drug ever
Subjects are excluded from PD analysis in case of these PDs:
Exclude subject from PD 
analysis set
TRT03
Treatment non-compliance (*)
Subjects are excluded from PK analysis in case of these PDs:
Exclude subject from PK 
analysis sets
(*) In case of this violation, the patient is still a member of the PD analysis set but efficacy data 
collected after the deviations are excluded from the PD analysis set. Namely for patient 1006010 
efficacy data related to the last 4 weeks of the treatment period are excluded from the analysis 
set.
5
Statistical methods for Pharmacokinetic (PK) parameters
PK analysis set will be used for the analysis of all pharmacokinetic parameters.
Timing of the blood sample collection for pharmacokinetic evaluation is outlined in the 
assessment schedule of protocol amended version v01 Table 8-1.
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5.1
Variables
The PK parameters which will be determined from the blood concentration time data include 
(but are not limited to): Cmax, Tmax, MRT, AUClast, AUC0-24h, T1/2. Pharmacokinetic 
parameters will be determined using WinNonlin Phoenix (version 8.0 or higher). PK 
parameters will be log-transformed.
5.2
Descriptive analyses
Pharmacokinetic parameters will be summarized using descriptive statistics including mean 
(arithmetic and geometric), SD, and CV (arithmetic and geometric), median, minimum and 
maximum, frequency (n, %) 
. An 
exception to this is Tmax where median, minimum and maximum will be presented. The 
descriptive summaries for PK parameters will be provided by treatment and visit/ sampling 
times.
5.3
Statistical model, assumptions and hypotheses
Not applicable.
6
Statistical methods for Pharmacodynamic (PD) parameters
6.1
Primary objective
The primary objective of this study is to determine the efficacy of LOU064 compared to placebo 
with respect to change from baseline in pre-dose FEV1 (L) at Week 12.
6.1.1
Variables
The primary analysis variable is the change from baseline in pre-dose FEV1 after 12 weeks of 
treatment with LOU064 at 100 mg q.d. or placebo.
The baseline pre-dose FEV1 is defined as the average of the FEV1 measurements performed 
45 min and 15 min prior to dosing on Day 1. Only valid assessments will be considered. 
Invalid assessments are the ones not meeting the required wash-out from beta-agonists as 
indicated by the variable PHBMDN or with an unacceptable quality flag (variable 
REIRESFL).  If one of the assessments is missing, then the non-missing pre-dose FEV1 will 
be considered as baseline. If both the assessments are missing the value collected at the 
baseline visit will be considered.
The pre-dose FEV1 measurements at week 2, week 4, week 8 and week 12 are handled in the 
same way.
6.1.2
Descriptive analyses
Summary statistics will be provided by treatment and visit both on absolute and changes from 
baseline values.
6.1.3
Statistical model, assumptions and hypotheses
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The primary endpoint will be analyzed using a Bayesian repeated measures model with 
change from baseline in pre-dose FEV1 as response, adjusting for effects of treatment*visit 
interaction and baseline pre-dose FEV1. 
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6.1.3.1
Model checking procedures
Diagnostic output from the PROC MCMC model will be reviewed and the model will be 
checked by assessing posterior distributions.
6.1.3.2
Graphical presentation of results
Posterior mean (SD) plots with 2-sided 80% credible intervals based on the fitted model and 
individual profiles will be produced by treatment and time.
6.2
Secondary objectives
6.2.1
Variables
Secondary efficacy variables supporting the secondary objectives are:

Change from baseline in PEF (morning and evening) (eDiary, daily)

Change from baseline in daytime and nighttime asthma symptom score (eDiary,
daily)

Change from baseline in ACQ-5 score (eDiary, per visit)

Number of puffs of SABA taken per day (eDiary, daily)
PEF values taken from 02:00 to 13:59 are considered morning assessments, while values 
taken from 14:00 to 23:59 are considered evening assessments. 
For each day daytime and nighttime symptom scores will be obtained as the mean score over 
the 4 items related to daytime and the 2 items associated to nocturnal period.
The number of puffs of SABA taken for day will be derived as the sum of morning and 
evening puff registered in that day (even if the morning assessment may record puffs taken 
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before the midnight of the previous day). If only the morning or the evening assessment is 
available the other assessment will be considered as = 0 puffs. If no assessment if available 
for one day the number of puffs taken for that day is set to missing.
For data recorded daily, the following periods are defined:

Screening period= from the day of the screening visit to the day before the run-in
visit. Data collected in this period won’t be summarized.

Run-in period = from the day after the run-in visit to the day before the first
dosing (study day -1). This period will be considered for the definition of the
baseline values.

Treatment period = from day 2 to the day of the last administration. This period
will be further divided in:

Week1- Week 4 = from day 2 to day 29

Week 5- 8 = from day 30 to day 57

Week 9-12 = from day 58 to day 85.

Week 13 and beyond= from day 86 to the last day of treatment (if applicable).
Data collected in this period (if any) won’t be summarized.

Post treatment period = from the day after the last day of treatment till the end of
study. Data collected in this period won’t be summarized.
6.2.2
Descriptive analyses
Data will be summarized by treatment and time point (ACQ5) or interval (eDiary data).
6.2.3
Statistical model, assumptions and hypotheses
ACQ-5
This secondary endpoint will be analyzed using a similar methodology as followed for 
primary endpoint, with the exception that :

ACQ- 5 baseline value (score collected at the baseline visit) will be used as a covariate
instead of baseline FEV1

Non-informative priors will be used for mean responses for each time point under
LOU064/ placebo treatment.
Asthma symptom scores and PEF
The morning and evening PEF scores collected by e-peak flow/diary device will be analysed 
separately. For all daily collected measurements (morning and evening PEF, morning asthma 
symptoms score and evening asthma symptoms score) a similar methodology will be used as 
for the primary endpoint. However, the model will be fitted to the mean of 4-week intervals 
for each of these endpoints. The average score for each time interval is defined as the sum of 
daily scores divided by the number of days where eDiary records have been made on the 
respective score. The non-missing data within that interval will be used to calculate the mean 
value, as long as there are at least 16 days with non-missing eDiary data for the run-in period


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and 14 days with non-missing data for post-baseline scores in a 4-week period. Otherwise, the 
value will be set as missing for that interval. These average scores will then be used in the 
model, which elsewise only differs from the primary models by the following two points:

Baseline value of the secondary outcome will be used as covariate instead of baseline
FEV1

Non-informative priors will be used for mean responses for each time point under
LOU064/placebo treatment.
SABA
For this secondary endpoint, the mean number of puffs of SABA taken in past 12 hours 
(morning/ evening) and overall will be calculated for each subject separately for run-in period 
(used as baseline value) for the 12 week-treatment period. Change from baseline in mean 
daily use of puffs of SABA over 12 weeks will be analyzed using a Bayesian regression 
model. The non-missing data within that interval will be used to calculate the mean value, as 
long as there are at least 16 days with non-missing eDiary data for the run-in period and 28 
days with non-missing data for post-baseline period. The model will assess effects of 
treatment (LOU064/ placebo), baseline use of puffs of SABA per day, baseline pre-dose 
FEV1 and baseline daytime asthma symptom score.
Display of model results (holds for all endpoints)
In a similar manner as followed for primary endpoint (Section 6.1), for each of the secondary 
endpoints, the posterior probabilities of ‘true’ effect of LOU064 over placebo will be derived 
from the fitted model. The posterior probabilities will be compared to the prespecified criteria 
mentioned in Section 6.1 at interim/ final stage as a guide for PoC evaluation of treatment 
effect on the endpoint.
6.2.3.1
Model checking procedures
Diagnostic output from the PROC MCMC model will be reviewed and the model will be 
checked by assessing posterior distributions.
6.2.3.2
Graphical presentation of results
For PEF, Asthma symptom score and ACQ-5 the adjusted posterior mean estimates over 12 
weeks with 2-sided 80% credible limits will be plotted for each of the treatment over time.
Individual profiles will be produced by treatment.
6.3
Exploratory objectives
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7
Statistical methods for safety and tolerability data
7.1
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as subject demographics, baseline characteristics, and 
treatment information.
7.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and 
subject. Age will be summarized as a continuous variable as well as a categorical data (18-
64,>= 65). Summary statistics will be provided by treatment group.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
The following baseline characteristics will be also summarized by treatment:

Smoking status (never / former / current)

Number of asthma exacerbations in the last 12 months  (considering the  following
categories: 0, 1, 2,  >2)

FEV1 pre-dose (L and % predicted )

Reversibility (ml and in % vs pre bronchodilator). In case of multiple attempts the last
one before day 1 will be considered). A reversibility test will be considered valid even
if performed without the wash-out from beta agonists (variable PHBMDN), provided
that no quality issue is raised (variable REIRESFL)

ACQ5 score

Assessment of atopic status (skin prick test and RAST)

IgE at screening or at end of study visit (if both available the screening assessment
will be considered)

Eosinophils at day 1

CRP

Impact of COVID-19 pandemic. This will be assessed reporting frequencies and
percentages of subjects randomized and completing the study before the pandemic,
randomized before but completing the study during the pandemic and randomized
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during the pandemic. The start of the pandemic is defined = 01MAR2020. A visit 
occurred on 01mar2020 is classified as during the pandemic.
Specifically for the assessment of atopic status the following data will be provided:

Number of subjects performing skin prick test for at least one allergen


Number of subjects performing RAST test (for at least one allergen)

Percentages will be derived  vs the total number of pts tested for each test.
Finally, frequencies and percentages (on the total number of patients in the safety sets) of pts 
falling in the following 3 categories will be provided:

Atopic (positive to skin prick test or RAST test)

Non atopic (patients with data available for skin prick test or RAST without any
positive result)

Not Evaluable (without any Skin Prick test or RAST data)
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.
A summary of protocol deviations by treatment group will be provided too, as well as a 
distribution of the patients by country and site.
Treatment
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment group and subject.
The duration of study treatment exposure is calculated as:
Treatment exposure (in weeks) = 52*(Last date of study drug administration – First date 
of study drug administration + 1)/365.25
Treatment exposure will be descriptively summarized by treatment using n, mean, standard 
deviation, median, minimum, and maximum.
Vital signs
Analysis of vital sign measurements using summary statistics for the change from baseline for
each post-baseline visit will be performed. These descriptive summaries will be presented by 
vital sign, treatment group and visit/time. Change from baseline will only be summarized for 
subjects with both baseline and post-baseline values.
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ECG evaluations
Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
Laboratory data listing will be provided presenting all parameters in a subject with any 
abnormal values. Summary statistics will be provided by treatment and visit/time. Shift tables 
using the low/normal/high/ (low and high) classification will be used to compare baseline to 
the worst on-treatment value.
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 system organ 
class (SOC) 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.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on <on-
treatment/treatment emergent> adverse events which are not serious adverse events with an 
incidence greater than 5% and on <on-treatment/treatment emergent> serious adverse events 
and SAEs suspected to be related to study treatment will be provided by system organ class 
and preferred term on the safety set population.
If for the same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date
of the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by SOC and PT.
Other safety evaluations
Not applicable.
Immunogenicity
Not applicable.
7.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created.


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8
Statistical methods for biomarker data
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