Clinical trial NCT04074590
Conditions: Colitis, Ulcerative
Keywords: ulcerative colitis, efficacy, safety
Sponsor: Novartis Pharmaceuticals
Start date: 2020-02-03; Completion date: 2022-11-07
Enrollment: 23 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study was to assess preliminary efficacy, safety, and tolerability of LYS006 in adult patients with mild to moderate ulcerative colitis and to determine if LYS006 has an adequate clinical profile for further development in this indication.

Detailed description:
This was a randomized, placebo-controlled, subject and investigator blinded, multicenter, non-confirmatory, parallel group, proof of concept study in patients with mild to moderate ulcerative colitis. This study consisted of a screening period of up to 4 weeks, and a 8 week treatment period followed by a 30 day post treatment period safety follow up. The maximum study duration for each participant including the 4 week screening period was 16 weeks.

At the beginning of the treatment period, subjects were randomized to one of the two following treatment groups in 2:1 ratio

* LYS006
* matching placebo

Arms: arm 1: Experimental drug arm 2: Placebo comparator
Interventions: intervention 1: LYS006 intervention 2: Placebo
Intervention descriptions: intervention 1: capsule for oral use intervention 2: capsule for oral use

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
LYS006
Clinical Trial Protocol CLYS006X2202 / NCT04074590
A randomized, multi-center, subject and investigator 
blinded, placebo controlled, parallel group study to assess 
the efficacy, safety and tolerability of LYS006 in patients 
with mild to moderate ulcerative colitis
Document type:
Amended Protocol Version
EUDRACT number:
2019-003113-34
Version number:
v02 (Clean)
Clinical Trial Phase:
II
Release date:
23-Mar-2021
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-Aug-2018


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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 ........................................................................................................................6
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................10
Protocol summary..............................................................................................................19
1
Introduction .......................................................................................................................22
1.1
Background............................................................................................................22
1.2
Purpose ..................................................................................................................23
2
Objectives and endpoints...................................................................................................23
3
Study design ......................................................................................................................25
4
Rationale............................................................................................................................27
4.1
Rationale for study design .....................................................................................27
4.2
Rationale for dose/regimen and duration of treatment ..........................................28
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................30
4.4
Purpose and timing of interim analyses/design adaptations..................................30
4.5
Risks and benefits..................................................................................................30
4.5.1
Blood sample volume............................................................................32
5
Population..........................................................................................................................32
5.1
Inclusion criteria ....................................................................................................32
5.2
Exclusion criteria...................................................................................................33
6
Treatment...........................................................................................................................36
6.1
Study treatment......................................................................................................36
6.1.1
Investigational and control drugs..........................................................37
6.1.2
Additional study treatments ..................................................................37
6.1.3
Treatment arms/group ...........................................................................37
6.2
Other treatment(s)..................................................................................................38
6.2.1
Concomitant therapy.............................................................................38
6.2.2
Prohibited medication ...........................................................................38
6.2.3
Rescue medication ................................................................................39
6.2.4
Restriction for study subjects................................................................39
6.3
Subject numbering, treatment assignment, randomization....................................40
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6.3.1
Subject numbering ................................................................................40
6.3.2
Treatment assignment, randomization ..................................................40
6.4
Treatment blinding.................................................................................................40
6.5
Dose escalation and dose modification..................................................................42
6.6
Additional treatment guidance...............................................................................42
6.6.1
Recommended treatment of adverse events..........................................42
6.6.2
Treatment compliance...........................................................................42
6.6.3
Emergency breaking of assigned treatment code..................................42
6.7
Preparation and dispensation.................................................................................43
7
Informed consent procedures ............................................................................................43
8
Visit schedule and assessments .........................................................................................45
8.1
Screening ...............................................................................................................49
8.1.1
Information to be collected on screening failures.................................49
8.2
Subject demographics/other baseline characteristics.............................................50
8.3
Efficacy..................................................................................................................50
8.3.1
Mayo Score ...........................................................................................50
8.3.4
Appropriateness of efficacy assessments..............................................55
8.4
Safety.....................................................................................................................55
8.4.1
Laboratory evaluations..........................................................................56
8.4.2
Electrocardiogram (ECG) .....................................................................58
8.4.3
Pregnancy and assessments of fertility .................................................58
8.5
Additional assessments..........................................................................................58
9
Study discontinuation and completion ..............................................................................63
9.1
Discontinuation......................................................................................................63
9.1.1
Discontinuation of study treatment .......................................................63
9.1.2
Withdrawal of informed consent...........................................................63
9.1.3
Lost to follow-up...................................................................................64
9.1.4
Study stopping rules..............................................................................64
9.1.5
Early study termination by the sponsor.................................................65
9.2
Study completion and post-study treatment ..........................................................65
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10 Safety monitoring and reporting........................................................................................65
10.1
Definition of adverse events and reporting requirements......................................65
10.1.1
Adverse events ......................................................................................65
10.1.2
Serious adverse events ..........................................................................67
10.1.3
SAE reporting........................................................................................68
10.1.4
Pregnancy reporting ..............................................................................69
10.1.5
Reporting of study treatment errors including misuse/abuse................69
10.2
Additional Safety Monitoring................................................................................70
10.2.1
Liver safety monitoring.........................................................................70
11 Data Collection and Database management......................................................................72
11.1
Data collection.......................................................................................................72
11.2
Database management and quality control............................................................72
11.3
Site monitoring ......................................................................................................73
12 Data analysis and statistical methods ................................................................................74
12.1
Analysis sets ..........................................................................................................74
12.2
Subject demographics and other baseline characteristics......................................74
12.3
Treatments .............................................................................................................74
12.4
Analysis of the primary endpoint(s) ......................................................................75
12.4.1
Definition of primary endpoint: Clinical remission..............................75
12.4.2
Statistical model, hypothesis, and method of analysis..........................75
12.4.3
Handling of missing values/censoring/discontinuations.......................76
12.5
Analysis of secondary endpoints ...........................................................................77
12.5.1
Safety endpoints....................................................................................77
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12.7
Interim analyses.....................................................................................................81
12.8
Sample size calculation..........................................................................................82
12.8.1
Primary endpoint(s)...............................................................................82
12.8.2
Secondary endpoint(s)...........................................................................82
13 Ethical considerations and administrative procedures ......................................................82
13.1
Regulatory and ethical compliance........................................................................82
13.2
Responsibilities of the investigator and IRB/IEC..................................................83
13.3
Publication of study protocol and results...............................................................83
13.4
Quality Control and Quality Assurance.................................................................83
14 Protocol adherence ............................................................................................................83
14.1
Protocol amendments.............................................................................................84
15 References .........................................................................................................................85
16 Appendices ........................................................................................................................87
16.1
Appendix 1: Clinically notable laboratory values .................................................87
List of tables
Table 2-1
Objectives and related endpoints ..........................................................23
Table 6-1
Investigational and control drug............................................................37
Table 6-2
Prohibited medication ...........................................................................38
Table 6-3
Blinding levels ......................................................................................41
Table 8-2
Mayo score system for ulcerative colitis...............................................50
Table 8-4
Assessments & Specifications...............................................................55
Table 8-5
Laboratory Assessments........................................................................57
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................70
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List of figures
Figure 3-1
Study design..........................................................................................25
Figure 12-2
Operating charateristics for current design: 30 on LYS006 vs. 15 
on placebo with historical placebo........................................................82
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List of abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BMI
Body Mass Index
BUN
blood urea nitrogen
CK
creatinine kinase
CMO&PS
Chief Medical Office & Patient Safety
COVID-19
Coronavirus disease 2019
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSR
Clinical study report
CTC
Common Toxicity Criteria
CV
coefficient of variation
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
EoS
End of Study
EoT
End of Treatment
eSAE
Electronic Serious Adverse Event
eSource
Electronic Source
FDA
Food and Drug Administration
FiH
First in human
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
h
hour
HbsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
IB
Investigator's Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
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LDH
lactate dehydrogenase
LTA4H
Leukotriene A4 hydrolase
LTB4
Leukotriene A4
LTC4
Leukotriene C4
LXA4
Lipoxin A4
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
PD
pharmacodynamic(s)
PhGA
Physician's global assessment 
PT
prothrombin time
QMS
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula
RBC
red blood cell(s)
SAE
serious adverse event
SAP
Statistical Analysis Plan
sCR
serum creatinine
SD
standard deviation
SMQ
Standardized MedDRA Query
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
Total bilirubin
TNF
Tumor necrosis factor
UC
Ulcerative colitis
ULN
upper limit of normal
WBC
white blood cell(s)
WHO
World Health Organization
WoC
Withdrawal of Consent
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Glossary of terms
Additional 
treatment
Medicinal products that may be used during the clinical trial as described in 
the protocol, but not as an investigational medicinal product (e.g. any 
background therapy)
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
A study drug (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (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.
End of the clinical 
trial
The end of the clinical trial is defined as the last visit of the last subject or at a 
later point in time as defined by the protocol
Enrollment
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
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/treatment
The drug whose properties are being tested in the study
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
Screen Failure
A subject who is screened but is not treated or randomized
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource


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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 date 


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Protocol No. CLYS006X2202
Protocol summary
Protocol number
LYS006X2202
Full Title
A randomized, multi-center, subject and investigator blinded, placebo 
controlled, parallel group study to assess the efficacy, safety and tolerability of 
LYS006 in patients with mild to moderate ulcerative colitis.
Brief title
Study of efficacy, safety and tolerability of LYS006 in patients with mild to 
moderate ulcerative colitis
Sponsor and 
Clinical Phase
Novartis
Phase II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of the study is to assess preliminary efficacy, safety and 
tolerability of LYS006 in patients with mild to moderate ulcerative colitis and to 
determine if LYS006 has an adequate clinical profile for further clinical 
development in this indication.
Primary 
Objective(s) 
To assess the induction of clinical remission by LYS006 in patients with mild to 
moderate ulcerative colitis using the full Mayo score.
Secondary 
Objectives
To assess safety and tolerability of LYS006 in patients with mild to moderate 
ulcerative colitis
Study design
This is a randomized, placebo-controlled, subject and investigator blinded, 
multicenter, non-confirmatory, parallel group, proof of concept study in 
patients with mild to moderate ulcerative colitis. This study consists of a 
screening period of up to 4 weeks (minimum one week), an 8-week treatment
period followed by a 30-day post treatment period safety follow up. The 
maximum study duration for each such including the maximum 4-week 
screening period is 16 weeks. 
At the beginning of the treatment period, subjects will be randomized to one 
of the two following treatment groups in 2:1 ratio:

20 mg LYS006 (BID)

matching placebo (BID)
Population
This study will include patients with mild to moderate ulcerative colitis who 
failed an appropriate, previous treatment with 5-ASA. These patients should 
have active disease defined as having a full Mayo Score between 5 and 10
(inclusive), with baseline endoscopic sub score of 2 or 3; rectal bleeding and 
stool frequency score of 1 to 3 and physician’s global assessment 1 or 2.
Approximately 45 subjects are planned to be enrolled.
Key Inclusion 
criteria

Male and female subjects 18-75 years of age with an established
diagnosis of ulcerative colitis at least 3 months prior to screening are
eligible for the study.

Patients must have active disease with a full Mayo Score between 5 and
10 (inclusive) with an endoscopy score of 2 or 3; rectal bleeding and stool
frequency scores 1 to 3 and a physician’s global assessment with a
maximum of 1 or 2.

Patients must have responded inadequately to conventional therapy with
oral 5-ASA prior to screening.


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Key Exclusion 
criteria

Has severe UC at screening, as defined by ≥6 bloody stools per day and
at least one of the following:

Pulse >90 bpm

Oral temperature of >37.8°C

Hemoglobin of <10.5 g/dL

CRP > 30 mg/L

Erythrocyte sedimentation rate (ESR) >30 mm/h

Has previous diagnosis with Crohn's disease, indeterminate colitis,
microscopic colitis or acute diverticulitis based on medical history.

Previous treatment with biologics (such as anti-TNFα agents) within 3
months or 5 half-lives (whichever is longer) prior to screening endoscopy

Previous treatment with non-biologics (such as JAK inhibitors) within 4
weeks prior to screening endoscopy

Any systemic immunosuppressant or immunomodulator, such as
cyclosporine, methotrexate, azathioprine within 6 weeks and
cyclophosphamide within 3 months, prior to screening endoscopy

A dose of > 10 mg/d prednisone or equivalent in the last 4 weeks prior to
screening endoscopy. Oral budesonide is allowed if the dose is ≤ 9
mg/day with a stable dose administered for at least 4 weeks prior to the
screening endoscopy.
Study treatment

LYS006 20 mg BID: 8 weeks

Matching placebo BID: 8 weeks
Key Efficacy 
assessments

Mayo Score based on:

Stool frequency

Rectal bleeding

Endoscopic findings

Physician's Global Assessment
Other 
assessments
Key safety 
assessments

AE, SAE monitoring

Physical examinations

Monitoring of laboratory safety

ECGs

Vital signs
Data analysis
The primary endpoint of this study is the clinical remission rate at End of 
treatment (EoT)
 and Week 8 for subsequent 
protocol amendments), i.e. the proportion of patients reaching the status of 
clinical remission. This primary endpoint of clinical remission is based on full 
Mayo score, defined as a Mayo score ≤2 with no individual subscore >1. 
Patients who discontinue for reasons other than COVID-19, or receive any 
rescue medication before EoT will be considered as treatment failure. This 
binary endpoint will be analyzed with a Bayesian approach, to compare the 
remission rates between LYS006 and placebo group. An informative prior will 
be used for the remission rate for placebo (refer to Sample Size section for 
details) and a neutral prior (Kerman 2011), Beta (1/3, 1/3), for LYS006. The 
posterior probabilities as defined in the dual efficacy criteria detailed in the 
CCI
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analysis of the primary endpoint section will be provided, along with the 
posterior remission rates by group and the treatment difference with 90% 
credible intervals.
Key words
Ulcerative colitis, efficacy, safety


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1
Introduction
1.1
Background
Ulcerative colitis (UC) is a common chronic immune-mediated disorder that results in 
inflammation and ulcers in the gastrointestinal tract, and leads to symptoms such as diarrhea, 
abdominal pain and rectal bleeding. Although 5-ASA compounds as first line agents have been 
proven safe and are used extensively in UC, there is a significant proportion of patients with 
inadequate responses due to insufficient therapeutic response or toxicity.
During relapse, UC is characterized by acute neutrophilic inflammation accompanied by 
considerably enhanced mucosal levels of inflammatory lipidic mediators including Leukotriene 
B4 (LTB4). LTB4 is a potent neutrophil chemoattractant and chemoactivator. Functional 
studies have established that LTB4 accounts for the majority of the chemoattractant stimulus to 
continuing 
neutrophil 
infiltration 
found 
during 
relapse 
(Sharon and Stenson 1984; 
Cole et al 1992). 5-Lipoxygenase (5-LO, upstream to LTA4H) inhibitor Zileuton indicates 
clinical benefit of inhibiting LTB4 release in ulcerative colitis (Peppercorn et al 1994). LTA4H 
inhibition is expected to lead to better efficacy than 5-LO inhibition due to more complete 
pathway inhibition and simultaneous elevation of LXA4 (maintenance of resolution lipids), a 
mediator that has been found to be elevated during the remission period in UC patients 
(Vong et al 2012).
Therefore, LYS006, a potent LTA4H inhibitor that abrogates the production of LTB4 and 
triggers elevation of pro-resolution mediators such as LXA4, may be beneficial to subjects with 
ulcerative colitis.
 Additionally, LTA4H inhibition improves 
colitis in rats /cotton top tamarins (Whittle et al 2008; Penning 2001). These preclinical findings 
suggest that using LYS006 to target neutrophilic inflammation through the leukotriene pathway 
may be a therapeutic option for UC, in particular for subjects with active UC who have failed 
first line therapy with 5-ASA and for whom no safe treatment or combination of medical 
treatments has proven fully efficacious and/or safe and the unmet medical need is still high.
The most relevant data on LYS006 are summarized in the sections below. For detailed 
information, please refer to the Investigator's Brochure (IB).
Relevant data summary
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In parallel to the proposed Phase 2 study in UC, LYS006 is being evaluated in inflammatory acne, 
hidradenitis suppurativa and nonalcoholic steatohepatitis (all phase 2 studies). 
1.2
Purpose
The study is designed to assess clinical efficacy and safety of LYS006 in adult patients with 
mild to moderate ulcerative colitis.
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 assess the induction of clinical
remission by LYS006 in patients with
mild to moderate ulcerative colitis
compared to placebo

Clinical remission rate at week 8 using the full
Mayo score (see Section 12.4.1 for more details)
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess safety and tolerability of
LYS006 in patients with mild to
moderate ulcerative colitis compared to
placebo

Number and severity of adverse events / number
of subjects with adverse events

Safety and tolerability based on general safety
measurements (safety laboratory parameters,
vital signs and ECG parameters)
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3
Study design
This is a randomized, placebo-controlled, subject and investigator blinded, multicenter, parallel 
group study in patients with mild to moderate ulcerative colitis. Each individual subject will 
first undergo a screening period of up to 4 weeks (minimum screening duration of 7 days to 
enable collection of stool frequency and rectal bleeding subscores), a treatment period of 8 
weeks and a follow-up period of 30 days post last administration of study treatment, before the 
End of Study visit. The total duration for each subject in the study will be up to 16 weeks. See 
Figure 3-1.
Figure 3-1
Study design
Approximately 45 subjects will be randomized in a 2:1 ratio to one of the following treatment 
groups:

Group 1: LYS006 capsules (20 mg BID)

Group 2: matching placebo (BID)
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For the entire duration of the treatment period (8 weeks), subjects will receive twice-daily doses 
of LYS006 or placebo, so that the blind is maintained throughout the entire study. For further 
details, please refer to Section 6.
Safety assessments will include physical examination, ECGs, vital signs, standard clinical 
laboratory evaluations (hematology, biochemistry and urinalysis) as well as adverse event and 
serious adverse event monitoring. 
Screening
After signing informed consent, screening evaluations will take place from Day -28 to Day -1
(minimum screening duration of 7 days to enable collection of stool frequency and rectal 
bleeding subscores). During that period all safety and other assessments must be performed to 
evaluate eligibility. The endoscopy* is to be performed between Day -7 and Day -4 before the 
planned baseline visit. (Table 8-1). 
*A colonoscopy is required if the patient has no documented colonoscopy within the preceding
12 months. All other subjects can have a sigmoidoscopy performed at screening.
Subjects will be provided with the paper diaries to record data on stool frequency and rectal 
bleeding parameters on a daily basis until the end of the study. In addition, study medication 
intake data will also be recorded by the subject for compliance reasons. 
Subjects that fail screening, may be re-screened on one further occasion after discussion and 
agreement with the sponsor on a case by case basis.
Baseline
Eligible subjects will return for the Baseline visit on Day 1. Eligibility must be confirmed prior 
to randomization and required baseline assessments must be completed prior to dosing on Day 1.
Treatment
Subjects will be randomized to the respective treatment arm using a centralized Interactive 
Response Technology (IRT) system at the completion of Baseline visit, after eligibility is 
confirmed. Subjects will receive their morning dose of LYS006 or placebo at the site on Days 1, 
29 and 57, 
, once all pre-dose assessments have been 
completed. Subjects will then be provided study drug and may return home to continue their 
daily dosing regimen (self-administration).
At all study visits, subjects will undergo safety and efficacy assessments, 
as indicated in the Assessment Schedule and described in
Section 8. 
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At all visits 
 subjects will return their used drug supply kits for 
compliance and accountability assessment 
Subjects' diary data on stool frequency and rectal bleeding parameters will be checked by site 
personnel on visit days for efficacy assessment. 
 
Subjects will be contacted by the Investigator/site staff during the study to ensure 
compliance/monitor safety by telephone or other means, if it is deemed appropriate or necessary 
by the Investigator.
Follow up and End of Study visit (EoS)
After the last day of dosing (EoT), and all safety and efficacy assessments are completed, all 
subjects will enter a 30-day Post-Treatment Follow Up period without study drug 
administration. Subjects will then be asked to return to the site at Day 87 for the End of Study 
visit. At this visit, subjects will undergo final assessments as indicated in the Assessment 
schedule (Table 8-1). Upon completion of this visit, subjects will be discharged from the study.
4
Rationale
4.1
Rationale for study design
The study is blinded for study subjects and investigators/site staff until final database lock 
(except where indicated in Section 6.4) to reduce potential bias in the assessment of subjective 
readouts.
The chosen design follows the design recommended in the EMA Guideline (2018). As per 
guidelines, design of phase 2 trials should be parallel-group, subject and investigator blinded 
and placebo controlled.
Using placebo as treatment control is recommended by ICH E10 (Guyatt et al 1989): Choice of 
control group in clinical trials), to obtain information on a specific versus non-specific effects 
of active treatment. Elaborated further in Section 4.3. 
Randomization is utilized for the allocation of subjects to either of the two treatment groups to 
avoid selection bias in the assignment of treatment. Random assignment of treatment will also 
help to achieve a balanced distribution of disease severity between the two treatment groups. 
A randomization ratio of 2:1 is used because of the inclusion of historical control data from 
similar historical UC trials (Section 12.4.2), which allows less exposure to placebo in this study 
without compromising the study power.
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UC is a chronic inflammatory bowel disease with onset most frequently in young adulthood. 
Most patients with UC have a mild-to-moderate course characterized by periods of activity or 
remission. More than 90% of patients with UC are treated with 5-aminosalicylates (5-ASA) 
shortly after disease diagnosis, and most who achieve clinical remission with these medications 
continue them for maintenance of remission (Fumery et al 2018).
However, there is still unmet medical need and some patients will not respond adequately to 
5-ASA, and may need to escalate therapy to systemic corticosteroids, or immunomodulators,
or biologic therapies for induction and maintenance of remission. This population of patients
not controlled with standard dose of conventional therapies and potentially requiring an
escalation of therapy will be selected for investigating the efficacy of LYS006. Indeed, and as
outlined in the scientific rationale for LYS006 in UC, the anti-inflammatory effect of LYS006
may induce disease control in these patients, providing an alternate option for these patients,
prior escalating to immunosuppressive or biologic therapies.
Therefore, the selected population will include mild to moderate patients with full Mayo score 
from 5 to 10. In case LYS006 shows efficacy in such population, further investigation of 
LYS006 in more severe forms of UC may be considered in future studies.
In ulcerative colitis, incidence peaked in the age interval 20-30 years with a second peak in the 
ages 60-79 (Mak et al 2020), so including subjects between the ages of 18 to 75 is rational 
considering the natural tendency of disease.
4.2
Rationale for dose/regimen and duration of treatment
For this study, a dose of 20 mg BID is proposed to explore safety and efficacy in mild to 
moderate ulcerative colitis population. This dose is expected to be safe and provide full target 
inhibition 
 and therefore expected to generate a maximal clinical response.
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The 8-week treatment duration is based on the clinical consensus and current guidance 
documents. The EMA Guideline (2018) on the development of new medicinal products for the 
treatment of Ulcerative Colitis, recommends 6-12 weeks and the FDA draft guidance for 
industry on ulcerative colitis (FDA UC Draft Guidance 2016), refers to induction trials 
demonstrating efficacy after a short treatment duration such as 1 to 3 months. Assessing 
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efficacy at week 8 in this Proof-of-Concept study will inform further clinical development of 
LYS006 in ulcerative colitis. 
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
In this proof-of-concept study, the efficacy, safety and tolerability of LYS006 will be assessed 
using a subject and investigator-blinded study design as compared to placebo. The choice of 
placebo as treatment control is essential to obtain information on the specific versus non-
specific effects of active treatment (ICH E10). Placebo as treatment control also provides the 
best way of evaluating the efficacy and of assessing the true safety and tolerability profiles of 
LYS006 in the phase II trial with the first exposure of subjects with ulcerative colitis. The short 
exposure of subjects with mild to moderate UC as specified in this protocol to placebo for 
8 weeks, in addition to oral 5-ASA agents, is scientifically and ethically well accepted, as there 
is no evidence that short term restriction regarding other immunosuppressive therapy leads to 
longer term differences in outcomes. Furthermore, rescue medication will be available for 
subjects at the investigator's discretion (see Section 6.2.3).
4.4
Purpose and timing of interim analyses/design adaptations
4.5
Risks and benefits
As the therapeutic effect of LYS006 in mild to moderate UC patients on top of first–line 
standard of care is currently unproven, patients may not benefit from the study treatment. 
The risk to subjects in this trial will be minimized by adhering to the eligibility criteria, close 
clinical monitoring, and adequate post-treatment safety follow-up to capture any potential late 
occurring AEs.
while for this present study, 
daily dosing of up to 20 mg BID is planned.
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Treatment for AEs should follow general guidelines for standard-of-care, and is at the discretion 
of the investigator or treating physician. There are no specific treatment recommendations for 
AEs that may possibly occur in in this trial.
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Due to early stage of development, there may be unknown risks of LYS006 which may be 
serious.
4.5.1
Blood sample volume
Approximately 
 from each subject is planned to be collected over a period of 
16 weeks from Screening until EoS as part of the study. Additional samples may be required 
for safety monitoring.
Timings of blood sample collection are outlined in the Assessment schedule (Table 8-1).
A summary blood log is provided in the Site Operations Manual (SOM). Instructions for all 
sample collection, processing, storage and shipment information is available in the central 
Laboratory Manual.
See Section 8.5.3 regarding the potential use of residual samples.
5
Population
The study population will be comprised of patients with mild to moderate active UC, who are 
intolerant or have responded inadequately to conventional therapy with oral 5-ASA prior to 
screening. About 45 subjects will be enrolled in the study and randomized to LYS006 and 
placebo groups with an approximate ratio of 2:1. No replacement of patients is planned.
Subject selection is to be established by checking through all inclusion/exclusion criteria during 
screening and study baseline. A relevant record (e.g. checklist) must be stored with the source 
documentation at the study site.
Deviation from any entry criterion excludes a subject from enrollment into 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.
2. Male and female subjects aged 18-75 years at screening
3. Patients diagnosed with UC established at least 3 months prior to screening.
4. Patients with mild to moderate UC which is defined by a total Mayo Score between 5 and
10 (inclusive), comprised of the following subscores;

Endoscopic subscore: 2 or 3 (determined from central reading of screening
endoscopy)

Stool frequency subscore: 1-3
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
Rectal bleeding subscore: 1-3

Physician's global assessment subscore: 1-2.
Please see the SOM for guidance on completion of Mayo scores
5. Disease must extend beyond 15 cm from the anal verge (assessed by screening
endoscopy).
6. Patients must have responded inadequately or have intolerance to conventional therapy
with oral 5-ASA prior to screening, and be willing to continue 5-ASA at a stable dose
during the study treatment period. Inadequate response is defined by the following:

Active disease despite induction therapy with 5-ASA agents where adequate therapy is
a stable oral 5-ASA dose.

Adequate therapy is an oral 5-ASA (mesalamine ≤4.8 g/day, sulfasalazine ≤6 g/day,
balsalazide ≤7.5 g/day or olsalazine ≤3 g/day) with a stable dose administered for at
least 4 weeks prior to the screening endoscopy.

In addition to oral 5-ASA, oral corticosteroids including oral budesonide are
permitted provided the following criteria are met and the patient is willing to continue
to continue the medication at a stable dose during the study treatment period
o
Oral corticosteroids are allowed if the dose is ≤ 10 mg/day with a stable dose
administered for at least 4 weeks prior to the screening endoscopy.
o
Oral budesonide is allowed if the dose is ≤ 9 mg/day with a stable dose
administered for at least 4 weeks prior to the screening endoscopy.
7. 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. Use of investigational drugs within 4 weeks or 5 half-lives of screening, whichever is
longer; or longer if required by local regulations.
2. Confirmed laboratory findings at screening showing:

Total white blood cell count (WBC) outside the range of 3,000 – 12,000 /μL.
o
Subjects with mild leukocytosis (WBC not higher than 15,000 /μL) may be
eligible, if the elevated WBC, according to the Investigator, is attributable to
disease activity and/or to corticosteroid therapy and other causes such as
hematological or infectious diseases can be excluded;

Platelets <100,000/μL;

Hemoglobin <9 g/dL and/or other signs of severe anemia
3. Are taking any of the prohibited medications listed in Table 6-2 and do not fulfill the
washout period.
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5. Has severe UC during the screening period, as defined by ≥6 bloody stools per day AND
at least one of the following:

Pulse >90 bpm

Oral temperature of >37.8°C

Hemoglobin of <10.5 g/dL (applicable in assessment of severe UC in the event of ≥6
bloody stools per day)

CRP >30 mg/L

Erythrocyte sedimentation rate (ESR) >30 mm/h
6. Has previous diagnosis with Crohn's disease, indeterminate colitis, microscopic colitis or
acute diverticulitis based on medical history.
7. Any severe, progressive or uncontrolled medical or psychiatric condition, or other factors
at randomization that in the judgment of the investigator prevents the patient from
participating in the study.
8. History of hypersensitivity or allergy to the investigational compound and inhibitors of
LTA4H or LTB4 being used in this study.
9. Active systemic infections (other than common cold) during the 2 weeks prior to
randomization. Evidence of Clostridium difficile infection within 8 weeks or other
intestinal pathogen infection within 4 weeks prior to the first dose of study drug.
10. History of toxic megacolon, abdominal abscess, symptomatic colonic stricture, or stoma;
history or is at risk of colectomy.
11. History or presence of impaired renal function indicated by clinically significantly
abnormal creatinine or BUN and/or urea values, or abnormal urinary constituents
(e.g. albuminuria) at screening;
15. History or symptoms of malignancy of any organ system, treated or untreated, within the 5
years prior to screening, regardless of whether there is evidence of local recurrence or
metastases. Patients with a history of basal cell carcinomas and/or up to 3 squamous cell
carcinomas of the skin are allowed if successful treatment has been performed, with no
signs of recurrence. Actinic keratoses present at screening should be managed according
to standard of care before randomization.
16. Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV) at screening. A positive
HBV surface antigen (HBsAg) test, or if standard local practice, a positive HBV core
antigen test, excludes a subject. Patients with a positive HCV antibody test should have
HCV RNA levels measured. Patients with positive (detectable) HCV RNA should be
excluded.
17. History of auto-immune or immunodeficiency diseases, or a positive human
immunodeficiency virus (HIV) test result (ELISA and Western blot) test result at
screening.
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18. 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 screening.
19. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using basic methods of contraception during dosing of
study treatment. Basic contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the
subject). Periodic abstinence (i.e., calendar, ovulation, symptothermal, postovulation
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking
study treatment. In case of oophorectomy alone, only when the reproductive status of
the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). The vasectomized male
partner should be the sole partner for that subject

Barrier methods of contraception: Condom or Occlusive cap. Not applicable to Czech
Republic.

Use of oral, injected or implanted hormonal methods of contraception (see also table
of prohibited treatment for guidance) or placement of an intrauterine device (IUD) or
intrauterine system (IUS) or other forms of hormonal contraception that have
comparable efficacy (failure rate <1%), for example hormone vaginal ring or
transdermal hormone contraception.
In case of use of oral contraception women should have been treated with the same pill 
and dose for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had

12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile
(e.g. age appropriate, history of vasomotor symptoms) or

have had surgical bilateral oophorectomy (with or without hysterectomy) or

tubal ligation at least six weeks ago.
In the case of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment is she considered not of child
bearing potential.
20. History of drug abuse or harmful alcohol use within the 12 months prior to dosing, or
evidence of such abuse. Harmful alcohol use is defined as a history of, or current alcohol
misuse/abuse, defined as “Five or more drinks on the same occasion on each of 5 or more
days in the past 30 days."
21. Donation of 400 ml or more of blood within 8 weeks prior to baseline, or longer if
required by local regulation.
22. Inability or unwillingness to undergo repeated venipunctures (e.g., due to poor tolerability
or lack of access to veins).
23. Any surgical or medical condition which might significantly alter the absorption,
distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in
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screening, in consideration of the patient’s medical history and/or clinical or laboratory 
evidence of any of the following:

Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy or bowel
resection;

Pancreatic injury or pancreatitis;

Liver disease or liver injury as indicated by abnormal liver function tests as defined
by the following 3 criteria at screening.

ALT must be within the normal range;

Serum bilirubin must not exceed 1.5 x ULN;

GGT, AST and alkaline phosphatase must not exceed 2 x ULN.
24. A history of clinically significant ECG abnormalities, or any of the following ECG
abnormalities at screening (central read) or baseline (local read):

PR > 200 msec

QRS complex > 120 msec

QTcF > 450 msec (males)

QTcF > 460 msec (females)
25. Patients with clinically relevant primary sclerosing cholangitis
26. Patients who previously received more than one class of biologic therapy for UC (i.e. anti-
TNF blockers).
27. History or current evidence of colonic dysplasia or adenomatous colonic polyps.
6
Treatment
6.1
Study treatment
LYS006 and its matching placebo will be taken orally by the subject (4 capsules each) twice 
daily, in the morning and in the evening. 
On visit days, the 
 administration shall occur at the clinical site. 
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Study drug administration on other days will occur on an outpatient basis. 
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
The Investigational drug, LYS006 5 mg IR (immediate release) capsules and matching placebo 
will be prepared and supplied by Novartis to Investigator's site as double blind patient kits. 
Each subject will take 4 capsules to make up to a dose of 20 mg twice a day. Drug will be 
administered orally in accordance with the specified study procedures in Section 6.1
Table 6-1
Investigational and control drug
Investigational 
Drug
Pharmaceutical 
Dosage Form
Unit Dose
Route of 
Administration
Supply 
Type
Sponsor 
LYS006
Hard Gelatin 
Capsule
5 mg
Oral
Double Blind 
patient kits
Novartis
Placebo
Hard Gelatin 
Capsule
0 mg
Oral
Double Blind 
patient kits
Novartis
6.1.2
Additional study treatments
No additional Novartis drug supplies beyond investigational drug and control drug on top of 
standard of care are included in this trial.
6.1.3
Treatment arms/group
Subjects will be assigned to one of the following 2 treatment groups in a randomization ratio of 
2:1, for a total of 8 weeks:

Group 1: LYS006 20 mg BID

Group 2: matching placebo BID
Subjects will take 4 capsules of 5 mg at each dose to make up to 20 mg. There will be a morning 
and evening dose (4 capsules each) for all subjects.
All subjects will receive their respective supply of LYS006 or placebo capsules every 4 weeks 
during their scheduled visits to the site.
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6.2
Other treatment(s)
6.2.1
Concomitant therapy
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject is enrolled into the study.
All prescription medications, over-the-counter drugs, procedures, and significant non-drug 
therapies (including physical therapy and blood transfusions) administered or taken within the 
timeframe defined in the entry criteria prior to the start of the study and during the study, must 
be recorded on the Concomitant medications/Significant non-drug therapies CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact 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
Subjects are required to continue to take standard of care treatment (5-ASAs and if relevant oral 
corticosteroids (max 10 mg per day prednisone or equivalent) or oral budesonide (≤9 mg/day))
at a stable dose for four weeks prior to the screening endoscopy until the End of Treatment 
period.
Subjects on concomitant chronic treatment for hypertension, diabetes and/or other for chronic 
illness that may not confound the interpretation of study results or put the subject in risk are 
allowed to continue on their regular treatment regimen but it should be documented in the 
source document. The investigator must discuss the concomitant medications with the Sponsor 
on a case by case basis where there is a potential for these medications to alter the efficacy 
measurements, interfere with the study medication, or interpretation of results.
Hormonal contraception is allowed during the study, and is mandatory if it is the only method 
of contraception (please refer to inclusion/exclusion criteria).
Administration of paracetamol (acetaminophen) is acceptable, but must be documented.
6.2.2
Prohibited medication
Table 6-2
Prohibited medication
Medication
Required wash-out
Action taken (if taken during 
study treatment period)
Any UC biologic advanced 
therapies, in particular, anti-TNF 
alpha blockers, anti-integrin 
blockers, anti-IL-12/IL-23 blockers 
Wash-out: 3 months or 5 
half-lives (whichever is 
longer) prior to screening 
endoscopy  
Discontinue study treatment
Any non-biologic advanced 
therapies, in particular JAK 
inhibitors
Wash-out: 4 weeks prior to 
screening endoscopy
Discontinue study treatment


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Medication
Required wash-out
Action taken (if taken during 
study treatment period)
Any systemic immunosuppressant 
or immunomodulator, such as 
cyclosporine, methotrexate, 
cyclophosphamide, azathioprine
Wash-out: 6 weeks prior to 
screening endoscopy 
(except 3 months for 
cyclophosphamide)
Discontinue study treatment
Systemic corticosteroids with 
dose > 10 mg/day (equivalent 
prednisone)
Stable dose (up to 10 mg/d 
eq prednisone) for at least 
4 weeks before screening 
endoscopy 
Discontinue study treatment
Budesonide with dose > 9 mg/day
Stable dose (up to 9
mg/day for at least 4 weeks 
before screening 
endoscopy)
Discontinue study treatment
Topical anti inflammatory 
treatments (e.g. Topical 5-
aminosalicylic acid (5-ASA) or 
topical steroids) for the treatment of 
ulcerative colitis
Washout: 2 weeks prior to 
screening endoscopy (not 
more than 2 single doses)
Discontinue study treatment
Systemic antibiotics such as 
metronidazole or ciprofloxacin
Washout: 4 weeks prior to 
screening endoscopy 
Discontinue study treatment
Antidiarrheal, antimotility 
medications
NA
Discontinue study treatment
6.2.3
Rescue medication
In cases where the investigator believes rescue medication is necessary, it may be administered 
but the subject must be discontinued from the study treatment. For example, if a subject's 
disease is worsening, a corticosteroid dose may be increased or an immunomodulatory agent 
may be introduced, and the subject should be discontinued from the study treatment.
If the ulcerative condition worsens after the treatment period is finished, any medically 
indicated rescue medications can be prescribed during the follow up period.
Use of rescue medication must be recorded on the Concomitant medications/Significant non-
drug therapies after start of study drug in the (e)CRF.
6.2.4
Restriction for study subjects
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6.2.4.2
Other restrictions
Not applicable
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
Randomized treatment will be assigned to individual subjects on Day 1. Randomization of 
subjects will be carried out by Interactive Response Technology (IRT) system.
The randomization number is only used to identify which treatment the subjects have been 
randomized to receive.
Subjects who discontinued from study treatment before or after week 8 assessments will not be 
replaced.
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 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.
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, investigator-blinded study. Subjects and investigators will remain blinded to 
study treatment throughout the study, except where indicated below.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, and odor.
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Site staff
All site staff (including study investigator and study nurse) will be blinded to study treatment 
throughout the study.
Unblinding a single subject at site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (see Section 6.6.3)
Sponsor staff
The following unblinded sponsor roles are required for this study:
Statisticians, statistical programmers and other personnel involved in study data analysis 
(e.g. drug supply manager) are allowed to access treatment assignment information for the 
purpose of any unblinded data analysis during or at the end of the study.
All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind other study team members confidential and secure unless otherwise allowed 
(Table 6-3).
Following final database lock all roles may be considered unblinded. See the 
blinding/unblinding table for an overview of the blinding/unblinding plan.
Table 6-3
Blinding levels
Role
Time or Event
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single subject 
unblinded)
Subjects/Patients
B
B
UI
Site staff
B
B
UI
Drug Supply and 
Randomization Office
UI
UI
UI
Unblinded sponsor staff 
(see text above for details)
B
UI
UI
Statistician/statistical 
programmer/data analysts
B
B
UI
All other sponsor staff not 
identified above
B
B
UI
B Remains blinded
UI Allowed to be unblinded on individual patient level
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6.5
Dose escalation and dose modification
Study 
treatment 
dose 
adjustments 
and/or 
interruptions 
are 
not 
permitted. 
Occasional interruptions in study treatment must be recorded on the Dosage Administration 
Record page of the CRF.
6.6
Additional treatment guidance
Not applicable 
6.6.1
Recommended treatment of adverse events
There are no known expected AEs associated with LYS006 that would warrant specific 
treatment. Necessary medication as well as surgical or physical treatment used to treat AEs 
must be recorded on the Concomitant medications/Significant non-drug therapies CRF.
6.6.2
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 using pill counts and 
information provided by the subject/use of the Patient Diary. This information should be 
captured in the source document at the respective visit and in eCRF. All study treatment 
dispensed and returned must be recorded in the Drug Accountability Log.
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

study drug name (if available)

subject number
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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.
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given subject.
6.7
Preparation and dispensation
A unique medication number is printed on the study medication label.
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s). The study medication has a 2-part label 
(base plus tear-off label), immediately before dispensing the medication kit to the subject, site 
personnel will detach the outer part of the label from the packaging and affix it to the source 
document.
Each study site will be supplied with study drug in packaging as described under the 
investigational and control drugs Section 6.1.1.
LYS006 will be administered to the subject via oral route of administration, at home/outpatient 
basis. See the Site Operations Manual.
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.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the subject.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
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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
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8.1
Screening
In the case where a safety 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.
It is permissible to re-screen a subject if he/she fails the initial screening e.g. due to washout 
period of concomitant medication; however, each case must be discussed and agreed with the 
sponsor on a case-by-case basis.
A new ICF will need to be signed if the investigator chooses to re-screen the subject after he/she 
has screen failed. All eligibility criteria must be re-checked, based on the most recent data 
available, and met prior to enrollment of the subject into the study.
All required screening activities must be performed when the subject is re-screened for 
participation in the study. An individual subject may only be re-screened once for the study.
Once the number of subjects screened and enrolled is likely to ensure target enrollment, the 
Sponsor may close the study to further screening. In this case, the subjects who screen failed 
will not be permitted to re-screen.
If the re-screening is successful, the following information should be collected in the CRF:

Date of the informed consent signature.

All assessments done during the first screening period.

All assessments repeated during the re-screening period (e.g. ECG, lab).

Updated information as per latest status during the re-screening period, e.g., medical
history, diagnosis.

Adverse events based on the date of re-consent.
8.1.1
Information to be collected on screening failures
Subjects who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure. See the SOM for the list of information to be collected for screening
failures and further information on re-screening. No other data will be entered into the clinical 
database for subjects who are screen failures, unless the subject experienced a serious adverse 
event during the screening phase (Section 10.1.2, Section 10.1.3 for reporting details). If the 
subject fails to be randomized, the IRT must be notified within 2 days of the screen fail that the 
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8.2
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects. Data to 
be collected will include general patient demographics, relevant medical history and current 
medical conditions prior to study entry, diagnosis and other variables believed to influence UC 
severity or response to treatment, and any other assessments done for the purpose of 
determining eligibility for inclusion in the study. All medications and significant non-drug 
therapies (including herbal medicines, physical therapy and blood transfusions) taken within 4 
weeks prior to first dose of study drug must be recorded on the CRF. Details are outlined in the 
Site Operational Manual. 
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
8.3
Efficacy
Efficacy assessments are specified below, with the methods for assessment and recording 
specified in the Study Operations Manual. Efficacy assessments will be performed 
 
 at the timepoints defined in the Assessment schedule (Table 8-1). 
Follow instructions outlined in the SOM regarding sample collection, numbering, processing 
and shipment.
8.3.1
Mayo Score
The Mayo score is an instrument designed to measure activity of UC. Mayo score comprises of four 
subscores: stool frequency, rectal bleeding, endoscopic findings and Physician's Global Assessment. 
Each subscore is graded from 0 to 3 with higher scores indicating more severe disease.
Table 8-2
Mayo score system for ulcerative colitis
Stool frequency
0
Normal number of bowel movements for this patient
1
1 to 2 bowel movements more than normal
2
3 to 4 bowel movements more than normal
3
5 or more bowel movements more than normal
Rectal bleeding
0
No blood seen
1
Streaks of blood with stool less than half the time
2
Obvious blood with stool most of the time
3
Blood alone passes
Endoscopic findings
0
Normal or inactive disease
1
Mild disease (erythema, decreased vascular pattern)
2
Moderate disease (marked erythema, absent vascular pattern, any friability, erosions)
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3
Severe disease (spontaneous bleeding, ulceration)
Physician’s global assessment
0
Normal
1
Mild disease
2
Moderate disease
3
Severe disease
The full Mayo score is the sum of four sub scores, ranging from 0 to 12.
Clinical remission is defined in Section 12.4.1.
8.3.1.1
Subject diary: Stool frequency and Rectal bleeding
Stool frequency and rectal bleeding are the main clinical symptoms of ulcerative colitis. 
Calculation of the Mayo score requires an assessment of stool frequency and rectal bleeding. 
Data on these clinical symptoms will be recorded by subjects on a daily basis using a paper 
diary until the end of the treatment period. Subjects will be provided with instructions on how 
to complete the paper diary at the screening visit. These should be reviewed at each visit until 
EoT by site staff, with retraining provided to subjects if the diaries are not completed correctly.
See the Site Operations Manual for guidance on training the subjects in the use of the diary and 
using the diary data to complete the Mayo score.
8.3.1.2
Endoscopy
Assessment of clinical efficacy through longitudinal (repeated) endoscopic examination 
provides an objective readout and decreases the risk of having false positive results (based on 
clinical symptoms only). Endoscopy is the best means for assessment of extent and severity of 
colon mucosal inflammation.
Type of endoscopy
A screening colonoscopy is required if the patient has no documented colonoscopy within the 
preceding 12 months. If a documented report of colonoscopy performed within the 12 months 
preceding screening is available in the source notes, the patient can have a sigmoidoscopy 
performed at screening.
Sigmoidoscopies will be performed at all other visits.
The colonoscopy will require a bowel preparation with drinking a liquid that will trigger bowel-
clearing diarrhea and will be performed with adequate sedation as per local clinical practice. 
The sigmoidoscopy will require enemas before the procedure to clean out the lower part of the 
colon. 
The endoscopic report (historical colonoscopy or screening endoscopy) must be available in the 
source documents. 
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Scheduling of endoscopies
Subjects should be seen for all visits/assessments as outlined, or as close to the designated day 
as possible. Missed or rescheduled visits should not lead to automatic discontinuation.

Screening endoscopy: is to be performed between Day -7 and Day -4 before the baseline
visit, to allow time to obtain endoscopic subscore report from the central read.
Note: The endoscopic subscore from central read will be used to determine eligibility.
Endoscopic subscore
The mucosal appearance during the sigmoidoscopic portion of endoscopic examination will be 
assessed for the Mayo endoscopic subscore based on the scoring system provided in the 
Section 8.3.1. The endoscopic appearance will be read by the central reader through video 
recorded during the procedure. Centrally-read endoscopic sub-scores will be transferred to the 
Sponsor electronically. A report will be provided to the site for the screening score to be used 
for eligibility purposes.
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8.3.1.3
Physician's Global Assessment
The physician's global assessment (PhGA) acknowledges the three other criteria of the Mayo 
score which includes, the patient's recollection of abdominal discomfort and general sense of 
wellbeing, and other observations, such as physical findings and the patient's performance status. 
The grading will be 0, 1, 2, or 3, following the guidance in Table 8-2. PhGA must be performed 
by a qualified physician and it is recommended that the same physician performs this assessment 
for a particular subject throughout the study. Calculation of the full Mayo score requires a Physician's 
global assessment. This will be done at every visit of the subject to the site. 
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8.3.4
Appropriateness of efficacy assessments
Ulcerative colitis is a chronic, relapsing disease characterized by diffuse mucosal inflammation 
of the colon involving the rectum and may extend proximally to part of the colon or the entire 
colon involving clinical manifestations of active disease involving blood and diarrhea.
As per FDA UC Draft Guidance (2016), the primary efficacy assessment tool used in clinical 
trials for the treatment of UC should consist of a combination of signs and symptoms assessment 
scales, best measures by a patient-reported outcome instrument, in combination with an 
endoscopic scale.
The Mayo scoring system is one of the most commonly used disease activity indices in placebo-
controlled trials and registration trials in UC. In its complete form, it is composed of four parts: 
bleeding, stool frequency, physician assessment, and endoscopy findings. 
In addition, assessment of the clinical local severity through longitudinal (repeated) endoscopic 
examination provides an objective readout, decreases the risk of having false positive results 
(based on clinical symptoms only) and as a consequence is expected to limit the number of 
subjects to be exposed to the new investigational drug in this indication. .
8.4
Safety
Safety assessments are specified below; methods of assessment and recording are specified in 
the SOM, with the assessment schedules (Table 8-1) detailing when each assessment is to be 
performed.
For details on AE collection and reporting, refer to Section 10.1
Table 8-4
Assessments & Specifications
Assessment
Description
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. Further examination may be required based on medical 
history and/or symptoms.
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 on the Adverse event section of the CRF
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Assessment
Description
Vital signs
Vital signs include body*
temperature, Blood Pressure and pulse 
measurements. After the subject has been sitting for five minutes, with back 
supported and both feet placed on the floor, systolic and diastolic blood 
pressure will be measured three times using an automated validated device, 
with an appropriately sized cuff. The repeat sitting measurements will be 
made at 1 - 2 minute intervals and the mean of the three measurements will 
be used. In case the cuff sizes available are not large enough for the 
subject's arm circumference, a sphygmomanometer with an appropriately 
sized cuff may be used.
*Oral body temperature must be measured at screening if the patient has
≥6 bloody stools per day and potentially meets exclusion criterion 5.
Otherwise the site can use their standard method for collection of body
temperature.
Vital signs must be performed before dosing and as indicated in the 
Assessment schedule (Table 8-1)
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) 
in indoor clothing, but without shoes) will be measured.
Height information will be collected at screening only.
The methods for each assessment and data recording details are specified in the SOM.
8.4.1
Laboratory evaluations
Central laboratories will be used for the analysis of scheduled hematology and clinical 
chemistry blood specimens collected as part of screening and safety monitoring (as detailed in 
the Assessment schedule (Table 8-1). Only laboratory results from the central laboratory can be 
used to determine subject's eligibility for the study. During the course of the study, unscheduled 
assessment can be performed if clinically indicated.
In the case where a laboratory assessment that is listed in the inclusion/exclusion criteria is 
outside a protocol-specified range at screening, the assessment may be repeated once prior to 
randomization. If the repeat value remains outside of protocol specified ranges, the subject is 
excluded from the study.
In the case where a laboratory range is not specified by the protocol, but is outside the 
reference range of the laboratory at screening, a decision regarding whether the result is of 
clinical significance or not shall be made by the investigator and shall be based, in part, upon 
the nature and degree of the observed abnormality. The assessment may be repeated once prior 
to randomization.
In all cases, the investigator must document in the source documents, the clinical considerations 
(i.e., result was/was not clinically significant and/or medically relevant) in allowing or 
disallowing the subject to continue in the study.
Clinically relevant deviations of laboratory test results occurring during or at completion of the 
study must be reported and discussed with Novartis personnel. The results should be evaluated 
for criteria defining an adverse event and reported as such if the criteria are met. Repeated 
evaluations are mandatory until normalization of the result(s) or until the change is no longer 
clinically relevant.
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Details of the collection and shipment of samples and the reporting of results by the central 
laboratory are provided to the investigators in a separate Laboratory Manual.
Blood Specimens
The following parameters will be analyzed from blood samples:
Table 8-5
Laboratory Assessments
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells 
(WBC), WBC morphology with differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils)
Chemistry
Albumin, Alkaline phosphatase, ALT , AST , Gamma-glutamyl-transferase 
(GGT), Total Bilirubin, Lactate dehydrogenase (LDH), Bicarbonate, 
Calcium, Magnesium, Phosphorus, Chloride, Sodium, Potassium, 
Creatinine, Creatine kinase, Total Cholesterol, LDL, HDL, Total Protein, 
Triglycerides, Blood Urea Nitrogen (BUN) or Urea, Uric Acid, 
 
 Glucose, Estimated Glomerular Filtration Rate (eGFR) estimated by 
MDRD.
For postmenopausal women, FSH is measured at screening to assist in 
confirming menopausal status.
If the total bilirubin concentration is increased above 1.5 times the upper 
limit of normal, direct and indirect reacting bilirubin should be differentiated.
HIV and hepatitis 
markers
Hepatitis B, Hepatitis C, HIV at screening
Pregnancy Test
Serum / Urine pregnancy test
Urine specimens
Please see central lab manual for more information on sample collection and handling.
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8.4.2
Electrocardiogram (ECG)
A central reading of standard 12-Lead ECGs will be implemented. Full details of all procedures 
relating to the ECG collection and reporting are contained in the core laboratory technical 
manual or in the Site Operations Manual. At Baseline, local reading is allowed in order to assess 
the eligibility of the subject before randomization.
PR interval, QRS duration, heart rate, RR interval, QT interval, QTcF (Fridericia QT) will be 
collected.
The SOM has the preferred sequence of data collection during study visits, notably ECG 
collection (10 min rest, ECG recording over next 5 min suggested), precedes vital signs and 
blood sampling. 
Clinically significant abnormalities must be reported as adverse events in the AE CRF.
8.4.3
Pregnancy and assessments of fertility
At screening and EoS (or last visit), a serum pregnancy test will be performed centrally.
Throughout the study, local urine pregnancy tests are sufficient. Additional urine pregnancy 
tests may be required, if a reason occurs such as subject reports delay in menstruation.
A positive urine pregnancy test requires immediate interruption of study drug until serum 
ß-hCG is performed and found to be negative. See Section 10.1.4 for guidance on pregnancy 
reporting and follow-up.
8.5
Additional assessments
No additional tests will be performed on subjects entered into this study.
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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 is defined as when study treatment is stopped 
earlier than the protocol planned duration. Discontinuation of study treatment can be decided 
by either the subject or the investigator. Subjects may voluntarily discontinue the study for any 
reason and at any time. Investigator must discontinue the study treatment for a given subject, if, 
on balance, he/she believes that continuation would be detrimental to the patient's well-being.
Study treatment must be discontinued under the following circumstances:

Subject withdraws consent

Pregnancy

Any protocol deviation that results in a significant risk to the subject’s safety

Major disease worsening requiring rescue medication Section 6.2.3) as judged by the
investigator
Subjects who discontinue study treatment should NOT be considered withdrawn from the study 
UNLESS they withdraw their consent. Where possible, they should return for their End of 
Treatment visit as soon as possible after the last day of study medication, as defined in the 
Assessment schedule (Table 8-1). If they fail to return for these assessments for unknown 
reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact them for 
additional follow up as specified in Section 9.1.3.
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.
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Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table (Table 8-1).
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 all 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 and his/her scheduled end of the study visit have occured.
9.1.4
Study stopping rules
The study may be put on hold pending full safety data review if one or more of the following 
criteria are met:

Two or more investigational drug (LYS006) related SAEs are reported

Other clinically significant events that in the opinion of the investigator or sponsor
preclude to continue dosing
In these cases, ad hoc internal experts will carefully evaluate the safety data of the entire study. 
the experts will recommend whether the study can be continued, should be stopped or is other 
safety measures need to be taken. 
In the event of the study stopping rules being met and the study being put on hold pending a 
full safety review, Novartis will promptly notify all concerned investigators/institutions, Ethics 
Committees/Review 
Boards
and 
the 
Regulatory 
Authorities. 
The 
findings 
and 
recommendations of the internal experts will be documented and will be made available to the 
respective Ethics Committees/Review Boards and the Regulatory Authorities.
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9.1.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/risk assessment of participating in the study, practical reasons 
(including slow enrollment), or for regulatory or medical reasons. 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 
discontinued subject. The investigator may be informed of additional procedures to be followed 
in order to ensure that adequate consideration is given to the protection of the subject’s interests. 
The investigator will be responsible for informing IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
Each subject will be required to complete the study in its entirety and thereafter no further study 
treatment will be made available to them. Study completion/ End of the clinical trial is defined 
as when the last subject completes his/her End of Study visit and any repeat assessments 
associated with this visit have been documented and followed-up appropriately by the 
Investigator or, in the event of an early study termination decision, the date of that decision.
All treated subjects should have a safety follow-up visit conducted 30 days after the last 
administration of study treatment. All SAEs reported during this time period must be reported 
as described in Section 10.1.3 and the SOM. The investigator must provide follow-up medical 
care for all subjects who are prematurely withdrawn from the study, or must refer them for 
appropriate ongoing care.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
In addition, all reports of intentional misuse and abuse of the study treatment are also considered 
an adverse event irrespective if a clinical event has occurred. See Section 10.1 for an overview 
of the reporting requirements.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
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the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events should be recorded on 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 Common Toxicity Criteria (CTC) AE grade: Adverse events will be assessed and
graded according to the Common Terminology Criteria for Adverse Events (CTCAE)
version 5.0 of higher
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
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 (or 5 half-lives or end of 
study visit, whichever is longer) 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.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
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
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. Investigators have the responsibility for managing the safety of 
individual subject and identifying adverse events. 
 
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 or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the
indication under study and has not worsened since 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.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to ICH E2D Guideline FDA 2003).
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 
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emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guideline FDA 2003).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to Novartis Chief Medical Office and Patient Safety (CMO & PS) as per 
Section 10.1.3
10.1.3
SAE reporting
10.1.3.1 Screen failures
SAEs occurring after the subject has provided informed consent until the time the subject is 
deemed a Screen Failure must be reported to Novartis.
10.1.3.2 Randomized / Treated Subjects
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last administration of study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence as described below.
Any SAEs experienced after this period should only be reported to Novartis if the Investigator 
suspects a causal relationship to study treatment.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Follow-up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable) and whether the 
subject continued or withdrew from the study participation. Each re-occurrence, complication, 
or progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator's Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment a 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 
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Follow the detailed instructions outlined in the Site Operations Manual regarding the 
submission process for reporting SAEs to Novartis. Note: SAEs must be reported to Novartis 
within 24 hours of the investigator learning of its occurrence/receiving follow-up information.
10.1.4
Pregnancy reporting
If a female trial subject becomes pregnant, the study treatment should be stopped, and the trial 
subject must be asked to read and sign pregnancy consent form to allow the Study Doctor follow 
up on her pregnancy. To ensure subject safety, each pregnancy occurring after signing the 
informed consent must be reported to Novartis within 24 hours of learning of its occurrence. 
The pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications.
Pregnancy should be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Chief Medical Office and Patient Safety (CMO&PS) 
Department. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
The study drug must be discontinued, though the subject may stay in the study, if she wishes to 
do so. All assessments that are considered as a risk during pregnancy must not be performed. 
The subject may continue all other protocol assessments.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
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, patient/subject 
or consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
All study treatment errors and uses outside of what is foreseen in the protocol will be collected 
in the dose administration record (DAR) CRF. Study treatment errors are only to be reported to 
Chief Medical Office and Patient Safety (CMO & PS) department if the treatment error is 
associated with an SAE.
All instances of misuse or abuse must be documented in the adverse event (AE) CRF 
irrespective of the misuse/abuse being associated with an AE/SAE. In addition, all instances of 
misuse or abuse must be reported to Novartis Chief Medical Office and Patient Safety (CMO & 
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Table 10-1 summarizes the reporting requirements.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dose 
Administration (DAR) 
CRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see 
Section 10.1 respectively.
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE):

Liver laboratory triggers, which will require repeated assessments of the abnormal
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and contributing
factors are recorded on the appropriate CRFs
 Additional details on actions required in case 
of liver events are outlined in Repeat liver chemistry tests (i.e. 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 unplanned local laboratory CRF.

If the initial elevation is confirmed, close observation of the subject will be initiated,
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to the Section 9.1: Discontinuation of
study treatment section), if appropriate

Hospitalization of the subject if appropriate

Causality assessment of the liver event
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
Thorough follow-up of the liver event should include

Repeating liver chemistry tests two or three times weekly. Testing should include
ALT, AST, PT/INR and GGT. If total bilirubin is elevated >2 x ULN, fractionation
into direct and indirect bilirubin is required. To rule out muscular origin of
transaminase elevations, CPK should be measured along with liver chemistry tests.
Frequency of retesting can decrease to once a week or less if abnormalities stabilize
or the study drug has been discontinued and the subject is asymptomatic. Resting
should be continued up to resolution.

Obtaining a more detailed history of symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications and
herbal and dietary supplement preparations), alcohol use, recreational drug use, and
special diets.

Exclusion of underlying liver disease, as specified in Table 16-3; Section 16.2

Imaging such as abdominal US, CT or MRI, as appropriate

Obtaining a history of exposure to environmental chemical agents.

Considering gastroenterology or hepatology consultations.
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF. Refer to the SOM for additional details.
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11
Data Collection and Database management
11.1
Data collection
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
Designated investigator staff will enter the data required by the protocol into the Electronic Case 
Report Forms (eCRF) using fully validated secure web-enabled software that conforms to 21 
CFR Part 11 requirements. Designated investigator site staff will not be given access to the 
EDC system until they have been trained. Automatic validation programs check for data 
discrepancies and, by generating appropriate error messages, allow the data to be confirmed or 
corrected in the eCRFs 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 captured for this study will have an external originating source (either written or 
electronic) with the CRF not being considered as source.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis staff (or designated CRO working on behalf of Novartis) review the data entered into 
the CRFs by investigational staff for completeness and accuracy and instruct the site personnel 
to make any required corrections or additions. Queries are sent to the investigational site using 
an electronic data query. Designated investigator site staff are required to respond to the query 
and confirm or correct the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
ECG readings will be processed centrally and the results will be sent electronically to Novartis 
(or a designated CRO).
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Patient reported outcomes will be collected via paper diaries. Relevant data will be entered into 
the CRF.
Randomization codes and data about all study drug(s) dispensed to the subject and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). 
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.
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. 
Any changes to the database after that time can only be made after written agreement by 
Novartis management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis or 
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 or delegated CRO 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 CRFs must be traceable to these source documents in the 
subject’s file. Data not requiring a separate written record will be defined before study start and 
will be recorded directly on the CRFs. The investigator must also keep the original informed 
consent form signed by the subject (a signed copy is given to the subject).
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The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the CRFs are performed according 
to the study-specific monitoring plan. No information in source documents about the identity 
of the subjects will be disclosed.
12
Data analysis and statistical methods
Data analysis will be conducted on all subject data at the time the trial ends, or at the time of 
any interim analysis. Any data analysis carried out independently by the investigator should be 
submitted to Novartis before publication or presentation.
Full details will be described in Statistical Analysis Plan (SAP) document.
12.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The safety analysis set will include all subjects that received any study drug.
The PD analysis set will include all subjects who received any study drug and had no protocol 
deviations with relevant impact on PD data.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data including Mayo scores/subscores, previous anti-
TNFα treatment experience, baseline corticosteroid use/dose and disease duration will be 
summarized overall and also by treatment group for the safety analysis set. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
12.3
Treatments
The safety set will be used for treatment compliance analysis. 
Data for study drug administration and changes in dosage will be listed by treatment group and 
subject.
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Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed by treatment group and subject.
12.4
Analysis of the primary endpoint(s)
The primary aim of the study is to assess the induction of clinical remission by LYS006 
compared to placebo in patients with mild to moderate ulcerative colitis. The PD analysis set 
will be used for the primary analysis.
12.4.1
Definition of primary endpoint: Clinical remission
The primary endpoint of this study is the clinical remission rate at the End of treatment (EoT) 
visit (
 Week 8 for subsequent protocol amendments), i.e. the 
proportion of the patients who reach the status of clinical remission at the EoT visit. 
Clinical remission is defined as a full Mayo score of 2 points or lower, with no individual 
subscore exceeding one point.
Subjects with early discontinuation for reasons other than COVID-19 before the EoT visit, or 
use of rescue/prohibited medication during the treatment period, or missing endoscopy score at 
EoT will be considered failed to reach remission. 
Discontinuation prior to the defined treatment period, or subjects who were not able to complete 
endoscopy at EoT visit due to local COVID-19 related restrictions will be considered as missing 
data.
12.4.2
Statistical model, hypothesis, and method of analysis
The binary endpoint of clinical remission rate will be modelled with binomial distribution and 
analyzed via Bayesian approach. The clinical remission rate for the LYS006 group will be given 
a neutral prior (Kerman 2011), Beta (1/3, 1/3). The clinical remission rate for the placebo group 
will be given an informative prior derived via the meta-analytic predictive (MAP) approach 
(Neuenschwander et al 2010 and Schmidli et al 2014). The derivation of this informative prior 
can be found in the study sample size documentation. This prior is based on the control groups 
from a number of historical UC trials (Rutgeerts et al 2005, Reinisch et al 2011, 
Sandborn et al 2012 and Ito et al 2010) and the selection of historical UC studies was based on 
patient population and the endpoint. The MAP prior for the placebo remission rate will be a 
mixture of four beta-distributions, Beta (18.9, 167.4), Beta (3.2, 24.2), Beta (1.0, 3.3) and 
Beta (1,1), with the mixture weights being 0.43, 0.34, 0.03 and 0.2 respectively. The last non-
informative component is added to robustify the outcome in case of any difference between 
within-study placebo group and those from the historical studies.
With the specified priors and the observed remission rates from this study, the posterior 
distributions for clinical remission rates in LYS006 and placebo will be computed. The posterior 
probabilities as defined in the dual efficacy criteria below will be provided, along with the 
posterior remission rates by group and the treatment difference with 90% credible intervals.
The dual efficacy criteria are defined as ("diff" refers to the difference of true remission rates 
in LYS006 and placebo):
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(1) EoT clinical remission rate better than placebo with high confidence (90%), i.e. Prob
(diff > 0) > 90%, AND
(2) Average magnitude of effect on EoT clinical remission rate > 15% over placebo, i.e. Prob
(diff > 15%) > 50%.
12.4.3
Handling of missing values/censoring/discontinuations
In the primary analysis, subjects who discontinue from the study for reasons other than COVID-
19 prior to EoT visit, or have received rescue or prohibited medication for the treatment of 
ulcerative colitis during the treatment period will be considered failed to reach clinical 
remission. Discontinuation prior to the defined treatment period, or subjects who were not able 
to complete endoscopy at EoT visit due to local COVID-19 related restrictions will be 
considered as missing data. Any missing subscore at 
 Week 8 
(subsequent protocol amendments ) will lead to a non-evaluable clinical remission status and 
the subject will also be considered failed to reach clinical remission. Reasons for missing Mayo 
scores or subscores need to be collected to understand the impact of such analysis 
approach. Imputation methods such as tipping point analysis may be explored. 
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12.5
Analysis of secondary endpoints
Assessing safety and tolerability of LYS006 in this population is the secondary objective of the 
study.
12.5.1
Safety endpoints
For all safety analyses, the safety set will be used. All tables, figures and listings tables will be 
presented by treatment group.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided, if there were death during the study. In particular, summary 
tables for adverse events (AEs) will summarize only on-treatment events, with a start date 
during the on-treatment period (treatment-emergent AEs).
Adverse events
All information obtained on adverse events will be displayed by treatment group and subject.
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.
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Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, and other significant adverse events leading to discontinuation.
The number and percentage of subjects with adverse events of infections, 
 will be summarized by treatment.
A subject with multiple adverse events within a primary system organ class/preferred term is 
only counted once towards the total of this primary system organ class/preferred term.
Summaries will also be provided for the number of adverse events by treatment.
Vital signs
Abnormalities (and relevant orthostatic changes) will be flagged and reported. The subjects 
with abnormal values will be visualized along with all subjects in overlaid individual plots by 
treatment group. 
ECG
Abnormalities will be flagged and reported. For continuous ECG parameters, the subjects with 
abnormal values will be visualized along with all subjects in overlaid individual plots by 
treatment group. Clinically notable events such as those in Exclusion Criteria 24 will be 
summarized separately by treatment group.
Clinical laboratory evaluations
Shift tables using the low/normal/high classification based on laboratory normal ranges will be 
used to compare baseline to the worst on-treatment value. For continuous laboratory parameters, 
the subjects with abnormal values will be visualized along with all subjects in overlaid 
individual plots by treatment group.
In particular, abnormalities in selected liver, 
 function parameters/events 
(Section 10.2) will be summarized separately by treatment group. Graphical presentation will 
be used as needed.
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12.7
Interim analyses
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12.8
Sample size calculation
Approximately a total of 45 subjects are planned to be enrolled, with a randomization ratio of 
2:1. Use of historical control data, as described in Section 12.4.2 helps to reduce the within-
study control. 
12.8.1
Primary endpoint(s)
Figure 12-2 below illustrates the operating characteristics for the design of 45 subjects with 2:1 
randomization ratio. The outcome of approximately 50% data is also shown in the same figure. 
The informative prior for the placebo group is included in the analysis. Assuming the true 
treatment difference in remission rate is 25% between LYS006 and placebo 
, the probability of meeting the dual efficacy criteria, stated 
in Section 12.4.2, is 86% with the full 45 subjects and 73%, for half the size. If there is no 
difference between LYS006 and placebo in clinical remission rate, the chance of meeting dual 
criteria is below 5% as shown in the left hand panel of the figure and the chance of meeting 
neither criterion is 92%, as shown in the right hand panel. 
Figure 12-2
Operating charateristics for current design: 30 on LYS006 vs. 15 on 
placebo with historical placebo
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 International Conference on Harmonisation (ICH) Harmonized Tripartite Guidelines 
for Good Clinical Practice, with applicable local regulations (including European Directive 
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2001/20/EC, US Code of Federal Regulations Title 21), and with the ethical principles laid 
down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures 
(e.g. advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis by the time of 
Last Patient Last Visit to be a reviewer and signatory for the clinical study report.
13.3
Publication of study protocol and results
The key design elements of this 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 
either be submitted for publication and/or 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.).
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 or overseen by 
Novartis Pharma Auditing and Compliance Quality Assurance (or CRO working on behalf of 
Novartis), a group 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 


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incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 10 (Safety Monitoring) must be followed and the Study Lead 
informed.


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References
References are available upon request
Clinical Trial Facilitation Group (2014). Recommendations related to contraception and 
pregnancy testing in clinical trials.  
Cole AT, Smith C, McLaughlan J, et al (1992). In vitro neutrophil shape change induced by 
colonic homogenates in homogenates in colitis –inhibition by leukotriene B4 receptor 
antagonist SC41930. Gut p. 33-65.
European Medicines Agency. (2018) Guideline on the development of new medicinal 
products for the treatment of ulcerative colitis.
Food and Drug Administration (2003) E2D Post-approval safety data management: 
definitions and standards for expedited reporting (Guidance Document).
Food and Drug Administration (2016) Ulcerative Colitis: Clinical Trial Endpoints Guidance 
for Industry (Draft Guidance).
Fumery M, Singh S, Dulai PS, et al (2018) Natural History of Adult Ulcerative Colitis in 
Population-based Cohorts: A Systematic Review. Clin. Gastroenterol. Hepatol. p. 343-356.e3.
Guyatt G1, Mitchell A, Irvine EJ, et al (1989) International Council for Harmonization of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) (2000). ICH E10: Choice 
of control group and related issues in clinical trials.
Harbord M, Eliakim R, Bettenworth D, et al (2017), for the European Crohn’s and Colitis 
Organisation [ECCO], Third European Evidence-based Consensus on Diagnosis and 
Management of Ulcerative Colitis. Part 2: Current Management, Journal of Crohn's and 
Colitis, Volume 11, Issue 7, p. 769–784 
Ito H, Iida M, Matsumoto T, et al (2010) Direct comparison of two different mesalamine 
formulations for the maintenance of remission in patients with ulcerative colitis: a double-
blind, randomized study. Inflamm. Bowel Dis. p. 1567-74.
Kerman J (2011) Neutral noninformative and informative conjugate beta and gamma prior 
distributions. Electronic Journal of Statistics. p. 1450-70.
Lewis JD, Chuai S, Nessel L, et al (2008) Use of the noninvasive components of the Mayo 
score to assess clinical response in ulcerative colitis. Inflamm. Bowel Dis. p. 1660-6.
Mak WY, Zhao M, Ng SC, Burisch J (2020) The epidemiology of inflammatory bowel 
disease: East meets west. J Gastroenterol Hepatol. 35(3):380-389.
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Neuenschwander B, Capkun-Niggli G, Branson M, et al (2010) Summarizing historical 
information on controls in clinical trials. Clin Trials p. 5-18.
Penning TD (2001) Inhibitors of leukotriene A4 (LTA4) hydrolase as potential anti-
inflammatory agents. Curr. Pharm. Des. p. 163-79.
Peppercorn M, Das K, Elson C, et al (1994) Zileuton, a 5-lipoxygenase inhibitor, in the 
treatment of active ulcerative colitis: a double-blind, placebo controlled trial p. A751.
Reinisch W, Sandborn WJ, Hommes DW, et al (2011) Adalimumab for induction of clinical 
remission in moderately to severely active ulcerative colitis: results of a randomised 
controlled trial. Gut p. 780-7.
Rubin DT, Ananthakrishnan AN, Siegel CA (2019) ACG Clinical Guideline Ulcerative 
Colitis in Adults. American Journal of Gastroenterology: March 2019 - Volume 114 - Issue 3 
- p 384-413.
Rutgeerts P, Sandborn WJ, Feagan BG, et al (2005) Infliximab for induction and maintenance 
therapy for ulcerative colitis. N. Engl. J. Med. p. 2462-76.
Sandborn WJ, van Assche G, Reinisch W, et al (2012) Adalimumab induces and maintains 
clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology p. 
257-65.e1-3.
Sands BE, Peyrin-Biroulet L, Loftus EV Jr,(2019) VARSITY Study Group. N Engl J Med. P. 
26;381(13):1215-1226
Schmidli H, Gsteiger S, Roychoudhury S, et al (2014) Robust meta-analytic-predictive priors 
in clinical trials with historical control information. Biometrics p. 1023-32.
Schoen T, Blum J, Paccaud F, et al (2013) Factors associated with 24-hour urinary volume: 
the Swiss salt survey. BMC Nephrol p. 246.
Sharon P, Stenson WF (1984) Enhanced synthesis of leukotriene B4 by colonic mucosa in 
inflammatory bowel disease. Gastroenterology p. 453-60.
Vong L, Ferraz JG, Dufton N, et al (2012) Up-regulation of Annexin-A1 and lipoxin A(4) in 
individuals with ulcerative colitis may promote mucosal homeostasis. PLoS ONE p. e39244.
Wang M-H, Mousa O, Friton J, et al (2020) Inflammatory Bowel Diseases, p. 774–779.
Whittle BJ, Varga C, Berko A, et al (2008) Attenuation of inflammation and cytokine 
production in rat colitis by a novel selective inhibitor of leukotriene A4 hydrolase. Br. J. 
Pharmacol. p. 983-91.


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Appendices
16.1
Appendix 1: Clinically notable laboratory values
Please refer to the Central Laboratory Manual for a list of clinically significant laboratory values.


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SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
LYS006
LYS006X2202 / NCT04074590
A randomized, multi-center, subject and investigator 
blinded, placebo controlled, parallel group study to assess 
the efficacy, safety and tolerability of LYS006 in patients 
with mild to moderate ulcerative colitis 
Statistical Analysis Plan (SAP)
Author(s):
Document type:
SAP Documentation – NIBR 
Document status:
Amendment 4 / Final
Release date:
06-Mar-2023
Number of pages:
36
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 .................................................................................................................8
List of tables ........................................................................................................................9
List of Figures......................................................................................................................9
1
Introduction .......................................................................................................................10
1.1
Scope of document ................................................................................................10
1.2
Study reference documentation .............................................................................10
1.3
Study objectives.....................................................................................................10
1.3.1
Primary Objective .................................................................................10
1.3.2
Secondary Objective .............................................................................10
1.4
Study design and treatment....................................................................................12
2
First interpretable results (FIR) .........................................................................................13
3
Interim analyses.................................................................................................................17
4
Statistical methods: Analysis sets......................................................................................17
6
Statistical methods for Pharmacodynamic (PD) parameters.............................................19
6.1
Primary objective...................................................................................................19
6.1.1
Variables ...............................................................................................19
6.1.2
Descriptive analyses..............................................................................20
6.1.3
Statistical model, assumptions and hypotheses.....................................20
6.2
Secondary objectives .............................................................................................22
7
Statistical methods for safety and tolerability data............................................................26
7.1
Variables................................................................................................................26
7.2
Descriptive analyses ..............................................................................................27
7.3
Graphical presentation...........................................................................................32
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9
Reference list.....................................................................................................................35
10 Appendix ...........................................................................................................................36
10.1
Imputation rules for AE and ConMed dates..........................................................36
List of tables
Table 4.1
Protocol deviation codes and analysis sets............................................17
Table 10-1
Imputation of start dates (AE, CM).......................................................36
Table 10-2
Imputation of end dates (AE, CM)........................................................36
List of Figures
Figure 1-1
Study design..........................................................................................13
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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 “CLYS006X2202”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol for the final analysis, as well as the outputs planned for the interim 
analyses.
1.2
Study reference documentation
1.3
Study objectives
1.3.1
Primary Objective
Primary objective
Endpoint related to primary objective

To assess the induction of clinical
remission by LYS006 in patients with
mild to moderate ulcerative colitis
(UC) compared to placebo

Clinical remission rate at Week 8 using the
full Mayo score
1.3.2
Secondary Objective
Secondary objective
Endpoints related to secondary objective

To assess safety and tolerability of
LYS006 in patients with mild to
moderate ulcerative colitis compared to
placebo

Number and severity of adverse events/
number of subjects with adverse events

Safety and tolerability based on general safety
measurements (safety laboratory
measurements, vital signs and ECG
parameters)
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1.4
Study design and treatment
This is a randomized, placebo-control, subject and investigator blinded, multicenter, parallel 
group study in patients with mild to moderate ulcerative colitis (UC).
Approximately 45 patients will be randomized in a 2:1 ratio to one of the following groups: 

Group 1: LYS006 capsules (20 mg BID)

Group 2: matching placebo (BID)
Figure 1-1 depicts the design of the study, starting from a screening epoch of up to 4 weeks
(minimum screening duration of 7 days to enable collection of stool frequency and rectal 
bleeding subscores), a treatment period of 8 weeks and a follow-up period of 30 days post last 
administration of study treatment, before the End of Study (EoS) visit. The total duration for 
each subject in the study will be up to 16 weeks.
For the entire duration of the treatment period (8 weeks), subjects will receive twice-daily doses 
of LYS006 or placebo. Each subject will take 4 capsules to make up to a dose of 20 mg twice 
a day.
Baseline visit will be Day 1. Baseline and drug administration can be done the same day if all 
eligibility criteria are met. 
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Figure 1-1
Study design
2
First interpretable results (FIR)
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3
Interim analyses
4
Statistical methods: Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The safety analysis set will include all subjects that received any study drug.
The PD analysis set will include all subjects who received any study drug and had no protocol 
deviations with relevant impact on PD data.
The data collected from the subjects 
will be pooled for all the analyses listed in 
this document.
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 (safety) analysis in case of these 
protocol deviations:
Exclude subject completely 
from all (safety) analysis sets
INCL01
Deviation from inclusion criterion 1 (Written 
informed consent must be obtained before any 
assessment is performed)
Yes
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Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PD analysis in case of these 
protocol deviations:
Exclude subject from PD 
analysis set
INCL01
Deviation from inclusion criterion 1 (Written 
informed consent must be obtained before any 
assessment is performed)
Yes
TRT04
Wrong dose of study drug
Yes
OTH12PA2
Change in Standard of Care treatment
Yes
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to
DB lock.
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6
Statistical methods for Pharmacodynamic (PD) parameters
All subjects within the PD analysis set will be included in the PD data analysis.
6.1
Primary objective
The primary aim of this study is to assess the induction of clinical remission by LYS006 
compared to placebo in patients with mild to moderate UC using the total Mayo score.
6.1.1
Variables
The primary PD variable of this study is the clinical remission rate at the EoT visit 
, i.e. the proportion of 
patients who reach the status of clinical remission at the EoT visit. 
Clinical remission is based on total Mayo score, defined as a total Mayo score of 2 points or 
lower, with no individual subscore exceeding one point. The total Mayo score is the sum of four
subscores, ranging from 0 to 12: stool frequency (recorded on a daily basis by a diary card), 
rectal bleeding (recorded on a daily basis by a diary card), endoscopic findings and Physician's 
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Global Assessment (PhGA). Each subscore grading ranges from 0 to 3, from free of disease to 
severe disease. 
The stool frequency subscore should be calculated from the most recent three consecutive days 
within the week prior to the day of endoscopy bowel preparation. If three consecutive days are 
not available, the most recent non-consecutive 3 days within the week prior to the day of 
endoscopy bowel preparation should be used. The stool frequency subscore is the average of 
the 3 daily stool frequency subscores. The rectal bleeding subscore will be calculated in the 
same manner as stool frequency subscore.
6.1.2
Descriptive analyses
The raw total Mayo scores and subscores will be listed by treatment group, subject and 
visit/time. Descriptive statistics of both the raw and change from baseline at 2-week and 8-week 
visit will be provided by treatment group when relevant.
6.1.2.1
Graphical presentation of results
Scatter plots to visualize trends over time in total Mayo score, 
 and individual endoscopic, stool frequency, rectal bleeding and PhGA subscores
will be created by treatment group.
6.1.3
Statistical model, assumptions and hypotheses
The binary endpoint of clinical remission rate (Yes/No) will be modelled with binomial 
distribution and analyzed via Bayesian approach with baseline total Mayo score and treatment 
group as explanatory variables, to compare the remission rates between the LYS006 and 
placebo groups.
Prior distributions:

LYS006 group: Clinical remission rate_LYS006 ~ Beta (1/3, 1/3)

Placebo group: Clinical remission rate_Placebo ~ Beta (18.9, 167.4), Beta (3.2, 24.2),
Beta (1.0, 3.3) and Beta (1,1)
The clinical remission rate for the LYS006 group will be given a neutral prior (Kerman 2011), 
Beta (1/3, 1/3). The clinical remission rate for the placebo group will be given an informative 
prior derived via the meta-analytic predictive (MAP) approach (Neuenschwander et al. 2010 
and Schmidli et al. 2014). This prior is based on the control groups from a number of historical 
UC trials (Rutgeerts et al. 2005, Reinisch et al. 2011, Sandborn et al. 2012 and Ito et al. 2010) 
and the selection of historical UC studies was based on patient population and the endpoint. 
The MAP prior for the placebo remission rate will be a mixture of the following four beta-
distributions, Beta (18.9, 167.4), Beta (3.2, 24.2), Beta (1.0, 3.3) and Beta (1, 1), with the 
mixture weights being 0.43, 0.34, 0.03 and 0.2 respectively. The last non-informative 
component is added to robustify the outcome in case of any difference between within-study 
placebo group and those from the historical studies.
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With the specified priors and the observed remission rates from this study, the posterior 
distributions for clinical remission rates in LYS006 and placebo groups will be computed. The 
posterior probabilities as defined in the dual efficacy criteria below will be provided, along with 
the posterior remission rates by group and the treatment difference with 90% credible intervals.
The dual efficacy criteria are defined as ("diff" refers to the difference of true remission rates 
in LYS006 and placebo):
(1) EoT clinical remission rate better than placebo with high confidence (90%), i.e.,
Prob (diff > 0) > 90%, and
(2) Average magnitude of effect on EoT clinical remission rate > 15% over placebo, i.e.,
Prob (diff > 15%) > 50%.
6.1.3.1
Model checking procedures
Subjects who discontinued from the study for reasons other than COVID-19 before the EoT
visit, or have received rescue or prohibited medication for the treatment of UC during the 
treatment period will be considered failed to achieve clinical remission. Any 
 data for a 
subject that were recorded at or after the start of a rescue or prohibited medication should be 
removed from the 
 statistical analyses.
Any missing subscore
will lead to a non-evaluable clinical remission status and the subject will also be 
considered failed to achieve clinical remission. Reasons for missing Mayo scores or subscores
need to be collected to understand the impact of such analysis approach. Imputation methods 
such as tipping point analysis may be explored.
Discontinuation prior to EoT, or subjects for which central reading of EoT endoscopy was not 
available due to local COVID-19 related restrictions will be considered as missing data.
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The homogeneity of the total Mayo scores between subjects 
will be explored 
visually by each visit.
6.2
Secondary objectives
Not Applicable.
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7
Statistical methods for safety and tolerability data
All subjects within the safety analysis set will be included in the safety data analysis.
7.1
Variables
The safety and tolerability variables are the number and severity of Adverse events 
(AEs)/Serious adverse events (SAEs), physical examinations, 12-lead ECG intervals (PR 
interval, QRS duration, heart rate, RR interval, QT interval and QTcF), vital signs (body 
temperature, height, weight, blood pressure and pulse rate), standard clinical laboratory 
evaluations (hematology, biochemistry and urinalysis), study-specific safety laboratory 
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evaluations
as well as subject demographics, baseline characteristics, and treatment 
information.
7.2
Descriptive analyses
Subject demographics and other baseline characteristics
Demographics and baseline characteristics variables are defined in Section 2. All data for 
background and demographic variables will be listed by treatment group and subject. Summary 
statistics will be provided overall and 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.
Relevant medical histories, current medical conditions at baseline, results of laboratory screens 
and any other relevant information will be listed by treatment group and subject.
Protocol deviations
In addition to the pre-defined standard protocol deviation terms, Novartis has defined 6 new 
protocol deviations and the corresponding relationship (health status related vs. site lockdown, 
subject concerns, etc.) to the COVID-19 pandemic in line with “Guidance on Conduct of 
Clinical Trials of Medical Products during the COVID-19 Public Health Emergency” (January 
2021) from FDA and “Guidance on the Management of Clinical Trials during the COVID-19 
(Coronavirus) Pandemic” (February 2021) from EMA as listed below.

Missing visits

Changes in procedures and assessments

Planned visits not done at sites

Changes in drug supply method

Treatment not given

Subject discontinuation due to COVID-19 situation
A summary table for the pandemic related/not pandemic related protocol deviations by category 
and relationship (and in total) will be provided by treatment group for all subjects randomized. 
For those related to the pandemic, “all COVID-19 pandemic related” protocol deviations will 
be summarized together and by specific type of reason (site issue, subject’s infection, etc.). The 
percentages will be calculated out of total randomized patients, to show how the pandemic 
related deviations impacted the study as a whole.
All protocol deviations will be listed. A separate listing will be provided for COVID-19 related 
protocol deviations.
Treatment
Data for study drug administration and changes in dosage will be listed by treatment group and
subject, including but not limited to: 

Dates of first and last exposure

Any changes in dosage or missed doses (Y/N)?

If changes in dosage or missed doses = Yes:
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o
Doses prescribed and administered (in mg)
o
Total daily dose (in mg)
o
Frequency of dosing
o
Start and end dates of dose change
o
Type of dose change
o
Reason for dose change
Compliance to the study treatment data (% of missing doses and % of capsules taken with 
respect to the total number of expected doses/capsules during the treatment period) will not be 
analyzed or reported, the study drug accountability data not being captured in the CRF.
Concomitant medications prior to and after the start of the study treatment will be listed by 
treatment group and subject and summarized by treatment group for the safety analysis set.
Vital signs
A listing will be provided presenting all vital signs measurements in a subject with any 
abnormal values (based on reference ranges). This listing will be sorted by treatment group, 
subject and visit/time. If there is any abnormality of a vital sign for a subject, all measurements 
of this vital sign for the subject will be presented in this listing. Abnormalities will be flagged 
using the following reference ranges:
Vital Sign Parameter
Reference Range
Systolic Blood Pressure
90-140 mmHg
Diastolic Blood Pressure
50-90 mmHg
Pulse Rate
40-90 bpm
Body Temperature
35.0-37.5 C
Baseline will be defined as the last available pre-dose measurement. 
Summary statistics (absolute values) will be provided by treatment group and visit/time. 
Measurements obtained at Screening and EoS will be included in the tabulations for the overall 
safety population only.
Clinical laboratory evaluations
A listing with laboratory parameters and their corresponding lab test codes (if applicable) and 
units will be provided for each lab category (hematology, biochemistry, and urinalysis).
A listing will be provided presenting all laboratory parameters in a subject with any out of range 
values. This listing will be sorted by treatment group, subject and visit/time for each lab 
category. If there is any abnormality of a parameter for a subject, all measurements of this 
parameter for the subject will be presented in this listing. Out of range values will be flagged as 
recorded in the database, e.g. for numerical results as “L” (for values lower than the lower limit 
of the reference range) and “H” (for values higher than the upper limit of the reference range). 
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Summary statistics (absolute values) of hematology and biochemistry tests will be provided by 
treatment group and visit/time. Measurements obtained at Screening and EoS will be included 
in the tabulations for the overall safety population only.
In particular, the following by-treatment summaries will be generated:

Shift tables using the low/normal/high classification based on laboratory normal ranges
to compare baseline to the worst on-treatment value (separately for hematology,
biochemistry and urinary laboratory tests)
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ECG evaluations
A listing will be provided presenting all ECG data in a subject with any abnormal values (based 
on the PI’s interpretation). This listing will be sorted by treatment group, subject and visit/time. 
If there is any abnormality (marked as abnormal by the PI) of an ECG parameter for a subject, 
all measurements of this parameter for the subject will be presented in this listing. 
Abnormalities, based on the PI’s interpretation, will be flagged. Clinically notable values will 
also be flagged in the listing using the following criteria:
ECG Parameter
Clinically Notable Criteria
PR
PR > 200 msec
QRS
QRS complex > 120 msec
QTcF
Males: QTcF > 450 msec
Females: QTcF > 460 msec
Baseline will be defined as the last available pre-dose measurement. 
Summary statistics (absolute values) will be provided by treatment group and visit/time. 
Measurements obtained at Screening and EoS will be included in the tabulations for the overall 
safety population only.
A categorical summary of QT/QTcF interval data based on the number of subjects meeting or 
exceeding predefined limits in terms of absolute QT/QTcF intervals or changes from baseline, 
at any time post-baseline, will be presented by treatment group. Specifically, frequency counts 
and percentages will be provided for each category of interest. The QT/QTcF categories of 
interest will be as follows: 
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Observed Value 
(msec)
Change from Baseline 
(msec)
Males:
≤30
> 30 - 60
> 60
≤ 450
> 450 - 480
> 480 - 500
>500
Females:
≤ 460
> 460 - 480
> 480 - 500
> 500
Adverse events
All AEs occurring during this clinical trial will be coded using MedDRA. All information 
obtained on AEs will be displayed by treatment group and subject.
Summary tables for AEs will include only AEs that started or worsened after first dose, the 
treatment-emergent AEs (TEAEs). However, all safety data (including those from the pre and 
post-treatment periods) will be listed and those collected during the pre-treatment and post-
treatment period are to be flagged. 
The number and percentage of subjects with TEAEs will be tabulated by system organ class 
(SOC) and preferred term (PT) with a breakdown by treatment and also by SOC, PT and 
maximum severity with a breakdown by treatment. Summaries will also be provided for the 
number of AEs by treatment.
Separate summaries will be provided for study medication related AEs, deaths, SAEs, and other 
significant AEs leading to discontinuation.
The number and percentage of subjects with events of special interest 
will be summarized by treatment.
A subject with multiple AEs within a SOC/PT and treatment is only counted once towards the 
total of this SOC/PT and treatment.
Subject listings of all AEs will be provided. Deaths and other serious or clinically significant 
non-fatal AEs will be listed separately.
Adverse event reporting for Clinical Trial Safety Disclosure (CTSD)
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables, 1) on TEAEs
which are not SAEs with an incidence greater than X% and 2) on treatment-emergent SAEs and 
SAEs suspected to be related to study treatment will be provided by SOC and PT on the safety 
analysis set. These tables will be produced by Novartis. The value of the cutoff value X will be 
decided with the team when disclosure tables are prepared.
The summary will be done overall and by treatment i.e. active (LYS006) or Placebo, regardless 
of the dose level.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:
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
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
All other safety evaluations (e.g. pregnancy test results for women) will be listed by treatment 
group, subject and visit/time.
7.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vital signs, ECG evaluations and lab 
parameters) will be created by treatment group. Mean and overlaying individual plots will be 
presented for selected parameters from vital signs, ECG evaluations and lab parameters.
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9
Reference list
4. Guyatt G, et al (1989) A new measure of Health Status for Clinical Trials in inflammatory
bowel disease. Gastroenterology; 96:804-10.
5. Kerman J (2011) Neutral noninformative and informative conjugate beta and gamma prior
distributions. Electronic Journal of Statistics; 5:1450-70.
6. Neuenschwander B, Capkun-Niggli G, Branson M, et al (2010) Summarizing historical
information on controls in clinical trials. Clin Trials; 7:5-18.
7. Schmidli H, Gsteiger S, Roychoudhury S, et al (2014) Robust meta-analytic-predictive
priors in clinical trials with historical control information. Biometrics; 70(4):1023-32.
8. Rutgeerts P, Sandborn WJ, Feagan BG, et al (2005) Infliximab for induction and
maintenance therapy for ulcerative colitis. N. Engl. J. Med; 353(23):2462-76.
9. Reinisch W, Sandborn WJ, Hommes DW, et al (2011) Adalimumab for induction of clinical
remission in moderately to severely active ulcerative colitis: results of a randomised
controlled trial. Gut; 60(6):780-7.
10. Sandborn WJ, van Assche G, Reinisch W, et al (2012) Adalimumab induces and maintains
clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology;
142(2):257-65.e1-3.
11. Ito H, Iida M, Matsumoto T, et al (2010) Direct comparison of two different mesalamine
formulations for the maintenance of remission in patients with ulcerative colitis: a double-
blind, randomized study. Inflamm. Bowel Dis; 16(9):1567-74.
12. Regor JC, McDonald JW, Klar N, et al (1997) An evaluation of utility measurement in
Crohn’s disease. Inflamm Bowel Dis; 3:265–76.
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10
Appendix
10.1
Imputation rules for AE and ConMed dates
Table 10-1
Imputation of start dates (AE, CM)
Missing 
Element
Rule
day, month, 
and year

No imputation will be done for completely missing start dates
day, month

If available year = year of study treatment start date then
o
If stop date contains a full date and stop date is earlier than
study treatment start date then set start date = 01JanYYYY
o
Else set start date = study treatment start date.

If available year > year of study treatment start date then 01JanYYYY

If available year < year of study treatment start date then 01JulYYYY
day

If available month and year = month and year of study treatment start
date then
o
If stop date contains a full date and stop date is earlier than
study treatment start date then set start date= 01MONYYYY.
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start
date then 01MONYYYY
If available month and year < month and year of study treatment start
date then 15MONYYYY
Table 10-2
Imputation of end dates (AE, CM)
Missing 
Element
Rule
day, month, 
and year

No imputation will be done for completely missing end dates
day, month

No imputation will be done for partial end dates
day

No imputation will be done for partial end dates
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings.