Clinical trial NCT03497897
Conditions: Inflammatory Acne
Keywords: Acne, efficacy, safety
Sponsor: Novartis Pharmaceuticals
Start date: 2018-09-10; Completion date: 2022-03-09
Enrollment: 66 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to assess preliminary efficacy and safety of LYS006 in patients with moderate to severe inflammatory acne and to determine if LYS006 has an adequate clinical profile for further clinical development.

Detailed description:
This was a randomized, placebo-controlled, subject- and investigator-blinded, multicenter, nonconfirmatory, parallel group, and proof-of-concept study in adult patients with moderate to severe inflammatory acne. After an initial screening period (up to 4 weeks), subjects were treated with LYS006 or matching placebo for 12 consecutive weeks to assess preliminary clinical efficacy, safety, and tolerability in the targeted subject population. At the beginning of the treatment period, subjects were randomized to one of three treatment groups, i.e., LYS006 20 mg twice daily (BID), LYS006 2 mg BID or matching placebo in a 3:1:3 ratio.

After treatment period completion, all subjects entered a post-treatment safety follow-up period of 4 weeks without study drug administration. The maximum duration of study participation was 20 weeks. Study completion was defined as when the last subject completed his/her study completion visit, and any repeat assessments associated with this visit were documented and followed-up appropriately by the investigator, or in the event of an early study termination decision, the date of that decision.

Arms: arm 1: LYS006, 20 mg, orally, twice daily (BID), for 12 weeks arm 2: LYS006, 2 mg, orally, BID, for 12 weeks arm 3: Matching placebo, orally, BID, for 12 weeks
Interventions: intervention 1: LYS006 20 mg intervention 2: LYS006 2 mg intervention 3: Placebo
Intervention descriptions: intervention 1: LYS006 20 mg, capsules, oral administration, BID, for 12 weeks intervention 2: LYS006 2 mg, capsules, oral administration, BID, for 12 weeks intervention 3: Matching placebo, capsules, oral administration, BID, for 12 weeks

Protocol documents:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
LYS006
Clinical Trial Protocol CLYS006X2201
A randomized, subject and investigator blinded, placebo-
controlled, multi-center study in parallel groups to assess 
the efficacy and safety of LYS006 in patients with moderate 
to severe inflammatory acne
Document type:
Amended Protocol Version
EUDRACT number:
2017-003191-30
Version number:
v06 (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
ClinicalTrials.gov Identifier: NCT03497897


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


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................7
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Pharmacokinetic definitions and symbols.........................................................................12
Glossary of terms...............................................................................................................13
Protocol summary..............................................................................................................32
1
Introduction .......................................................................................................................35
1.1
Background............................................................................................................35
1.2.1
Teratogenicity and reproductive toxicity data.......................................37
1.2.2
Pharmaceutical properties.....................................................................37
1.2.3
Pharmacology........................................................................................37
1.2.4
Toxicology ............................................................................................38
1.2.5
Non-clinical pharmacokinetics and metabolism ...................................39
1.3
Clinical data...........................................................................................................40
1.4
Study purpose ........................................................................................................40
2
Objectives and endpoints...................................................................................................41
2.1
Primary objective(s)...............................................................................................41
2.2
Secondary objective(s)...........................................................................................41
2.3
Exploratory objective(s) ........................................................................................41
3
Investigational plan ...........................................................................................................44
3.1
Study design...........................................................................................................44
3.2
Rationale for study design .....................................................................................45
3.3
Rationale for dose/regimen, route of administration and duration of treatment....46
3.4
Rationale for choice of comparator .......................................................................48
3.5
Rationale for choice of background therapy..........................................................48
3.6
Purpose and timing of interim analyses/design adaptations..................................49
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3.7
Risks and benefits..................................................................................................49
3.7.1
Blood sample volumes..........................................................................51
4
Population..........................................................................................................................51
4.1
Inclusion criteria ....................................................................................................51
4.2
Exclusion criteria...................................................................................................52
5
Restrictions for Study Subjects .........................................................................................56
5.1
Contraception requirements...................................................................................56
5.2
Prohibited treatment...............................................................................................57
5.3
Dietary restrictions and smoking...........................................................................58
5.4
Other restrictions ...................................................................................................58
6
Treatment...........................................................................................................................59
6.1
Study treatment......................................................................................................59
6.1.1
Investigational treatment and control drug(s) .......................................59
6.1.2
Additional study treatment....................................................................59
6.2
Treatment arms......................................................................................................60
6.3
Treatment assignment and randomization.............................................................60
6.4
Treatment blinding.................................................................................................61
6.5
Treating the subject................................................................................................62
6.6
Permitted dose adjustments and interruptions of study treatment.........................62
6.7
Emergency breaking of assigned treatment code ..................................................62
6.8
Treatment exposure and compliance .....................................................................63
6.9
Recommended treatment of adverse events ..........................................................63
6.10
Rescue medication.................................................................................................64
6.11
Concomitant treatment...........................................................................................64
7
Study completion and discontinuation ..............................................................................64
7.1
Study completion and post-study treatment ..........................................................64
7.2
Discontinuation of study treatment........................................................................65
7.2.1
Replacement policy...............................................................................65
7.3
Withdrawal of informed consent ...........................................................................65
7.4
Lost to follow-up ...................................................................................................66
7.5
Study stopping rules ..............................................................................................66
7.6
Early study termination by the sponsor .................................................................66
8
Procedures and assessments ..............................................................................................68
8.1
Assessment schedule .............................................................................................68
8.2
Informed consent procedures.................................................................................72
8.3
Subject screening...................................................................................................73


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8.4
Subject demographics/other baseline characteristics.............................................73
8.5
Efficacy / Pharmacodynamics ...............................................................................74
8.5.1
Clinical Outcome Assessments (COAs) ...............................................74
8.5.3
Exploratory biomarkers.........................................................................78
8.6
Safety.....................................................................................................................80
8.6.1
Physical examination ............................................................................81
8.6.2
Vital signs..............................................................................................81
8.6.3
Height and weight .................................................................................81
8.6.4
Laboratory evaluations..........................................................................81
8.6.5
Electrocardiogram (ECG) .....................................................................83
8.8
Other assessments..................................................................................................84
8.9
Use of residual biological samples ........................................................................85
9
Safety monitoring..............................................................................................................85
9.1
Adverse events.......................................................................................................85
9.2
Serious adverse event reporting.............................................................................87
9.2.1
Definition of SAE .................................................................................87
9.2.2
SAE reporting........................................................................................88
9.3
Liver safety monitoring .........................................................................................89
9.6
Reporting of study treatment errors including misuse/abuse ................................90
9.7
Pregnancy reporting...............................................................................................91
9.8
Early phase safety monitoring ...............................................................................92
10 Data review and database management.............................................................................92
10.1
Site monitoring ......................................................................................................92
10.2
Data collection.......................................................................................................93
10.3
Database management and quality control............................................................94
10.4
Data Monitoring Committee..................................................................................95
10.5
Adjudication Committee........................................................................................95
11 Data analysis......................................................................................................................95
11.1
Analysis sets ..........................................................................................................96
11.2
Subject demographics and other baseline characteristics......................................96
11.3
Treatments .............................................................................................................96
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11.4
Analysis of the primary variable(s) .......................................................................97
11.4.1
Primary Variable(s)...............................................................................97
11.4.2
Statistical model, hypothesis, and method of analysis..........................97
11.4.3
Handling of missing values/censoring/discontinuations.......................98
11.4.4
Sensitivity analyses ...............................................................................98
11.5
Analysis of secondary variable(s)..........................................................................98
11.5.1
Safety.....................................................................................................98
11.5.2
Other assessments ...............................................................................100
11.6
Analysis of exploratory variables ........................................................................100
11.6.1
Clinical Outcome Assessments...........................................................100
11.6.5
Exploratory biomarkers.......................................................................102
11.7
Sample size calculation........................................................................................102
11.8
Power for analysis of key secondary variables....................................................103
11.9
Interim analyses...................................................................................................103
12 Ethical considerations......................................................................................................104
12.1
Regulatory and ethical compliance......................................................................104
12.2
Responsibilities of the investigator and IRB/IEC................................................104
12.3
Publication of study protocol and results.............................................................104
12.4
Quality Control and Quality Assurance...............................................................104
13 Protocol adherence ..........................................................................................................105
13.1
Protocol Amendments .........................................................................................105
14 References .......................................................................................................................106
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List of tables
Table 5-1
Prohibited medication ...........................................................................57
Table 6-1
Overview of study medication ..............................................................59
Table 6-2
Blinding levels ......................................................................................62
Table 8-1
Assessment Schedule ............................................................................68
Table 8-6
Blood clinical laboratory parameters ....................................................82
Table 9-1
Guidance for capturing treatment errors ...............................................91
Table 11-1
Operating characteristics of decision rules .........................................103
List of figures
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List of abbreviations
5-LO
5-lipoxygenase
ACR
Albumin-creatinine ratio
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BCRP
Breast cancer resistance protein
BID
Bis in die (twice daily)
BMI
Body Mass Index
BUN
blood urea nitrogen
CAH
Congenital adrenal hyperplasia
CFR
U.S. Code of Federal Regulations
CHF
Congestive heart failure
CK
creatinine kinase
CMO&PS
Chief Medical Office & Patient Safety
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CRP
C-reactive protein
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
DMC
Data Monitoring Committee
DNA
Desoxyribonucleic acid
e-GFR
estimated glomerular filtration rate
ECG
Electrocardiogram
EDC
Electronic Data Capture
EEA
European Economic Area
EGFR
Epidermal growth factor receptor
ELISA
Enzyme-linked immunosorbent assay
EoT
End of Treatment
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ERCP
Endoscopic retrograde cholangiopancreatogram
FDA
Food and Drug Administration
FIH
First in human
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GPDR
General Data Protection Regulation
h
Hour
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
HS
HV
hidradenitis suppurativa
Healthy volunteer
i.v.
Intravenous
IA
Interim Analysis
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
IL
Interleukin
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intra-uterine device
IUS
Intra-uterine system
LDH
lactate dehydrogenase
LFT
Liver function test
LLN
lower limit of normal
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LOCF
Last Observation Carried Forward
MAD
Multiple Ascending Dose
MAR
Missing at Random
MDRD
Modification of diet in renal disease 
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
MMRM
Mixed effect Model for Repeated Measures
MPO
Myeloperoxidase
MRI
NASH
Magnetic resonance imaging
non-alcoholic steatohepatitis
NOAEL
No observable adverse effect level
OAT
organic anion transporter
p.o.
Oral
PAPA
Pyogenic arthritis, Pyoderma gangrenosum and acne (syndrome)
PASH
pseudoangiomatous stromal hyperplasia
PCR
Protein-creatinine ratio
PD
pharmacodynamic(s)
PDT
Photodynamic therapy
pH
Potential of hydrogen
PoC
Proof-of-concept
PRIDE
Papulopustules and/or paronychia, Regulatory abnormalities of hair growth, 
Itching, and Dryness due to Epidermal growth factor receptor inhibitors 
(syndrome)
PSTPIP1
proline-serine-threonine phosphatase interacting protein 1 
PT
prothrombin time
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QD
Quaque die (once daily)
QM
Quality management
RBC
red blood cell(s)
RCM
Reflectance Confocal Microscopy
RDC
Remote Data Capture
SAD
Single Ascending Dose
SAE
serious adverse event
SAP
Statistical Analysis Plan
SAPHO
Synovitis acne pustulosis hyperostosis osteitis (syndrome)
sCR
serum creatinine
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
TEAE
Treatment-emergent adverse event
TNF
UC
Tumor necrosis factor
ulcerative colitis
ULN
upper limit of normal
ULQ
upper limit of quantification
UV
Ultra-violet
WBC
white blood cell(s)
WHO
World Health Organization
WoC
Withdrawal of Consent
WOCBP
Women of child-bearing potential
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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug(s) (an active drug or an inactive drug, such as a placebo) 
which is used as a comparator to the investigational drug being tested 
in the trial
Dosage
Dose of the study treatment given to the subject in a time unit 
(e.g. 100 mg once a day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which 
are used to capture data transcribed from paper source forms used at the 
point of care.
Enrollment
Point/time of subject entry into the study at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described 
in the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is 
associated with a purpose (e.g. screening, randomization, treatment, 
follow-up) which applies across all arms of a study.
Healthy volunteer
A person with no known significant health problems who volunteers to 
be a study participant 
Investigational 
drug
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and Directive 
2001/20/EC and is synonymous with “investigational new drug,” 
"Investigational Medicinal Product," or “test substance”
Medication pack 
number
A unique identifier on the label of each drug package in studies that 
dispense study treatment using an IRT system
Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: 
a single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease.
Patient
An individual with the condition of interest
Personal data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding 
to a specific treatment arm assignment


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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
Study treatment
Any drug or combination of drugs administered to the study participants 
as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject 
and should be used to identify the subject throughout the study for all 
data collected, sample labels, etc.
Treatment number
A unique identifier assigned in non-randomized studies to each dosed 
subject, corresponding to a specific treatment arm 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested 
in the study
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study occurs only when a subject does 
not want to participate in the study any longer, and does not allow any 
further collection of personal data


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Protocol summary
Protocol 
number
CLYS006X2201
Full Title
A randomized, subject and investigator blinded, placebo-controlled, multi-center, 
parallel group study to assess the efficacy and safety of LYS006 in patients with 
moderate to severe inflammatory acne
Brief title
Study of pharmacodynamics, pharmacokinetics, safety and tolerability of 
LYS006 in patients with moderate to severe inflammatory acne
Sponsor and 
Clinical Trial 
Phase
Novartis
Phase II
Intervention 
type
Drug
Study type
Interventional
Purpose and 
rationale
The main aim of the study is to assess preliminary efficacy, safety, tolerability of 
LYS006 in patients with moderate to severe inflammatory acne and to determine 
if LYS006 has an adequate clinical profile for further clinical development.
Primary 
Objective(s)
To assess the efficacy of LYS006 versus placebo on facial inflammatory lesion 
counts in patients with moderate to severe inflammatory acne.
Secondary 
Objectives
To assess the safety and tolerability of LYS006 in patients with moderate to 
severe inflammatory acne.
Study design
This is a randomized, placebo-controlled, subject and investigator blinded, 
multicenter, non-confirmatory, parallel group, proof of concept study in patients 
with moderate to severe inflammatory acne. After an initial screening period (up 
to 4 weeks), the patients will be treated with LYS006 or matching placebo for 
12 consecutive weeks to assess preliminary clinical efficacy, safety, and 
tolerability in the targeted patient population. At the beginning of the treatment 
period, patients will be randomized to one of 3 following treatment groups:

 LYS006 (high dose)

 LYS006 (low dose)

matching placebo
Within the three treatment groups, patients will be stratified by type of center
(selected or non-selected for additional exploratory assessments). Exposure to 
placebo will be limited to a maximum of 12 weeks.
Population
The patients included in the study will be patients with moderate to severe 
inflammatory acne who are candidate for systemic therapies and for whom an 
appropriate previous treatment with topical anti-acne medication failed or was 
not well tolerated, or is not indicated. Such patients should have 20 to 100 facial 
inflammatory lesions and no more than 2 facial inflammatory nodules or cysts to 
exclude severe cases of nodulocystic acne.
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Key Inclusion 
criteria
Male and female subjects aged 18 to 45 years of age included, presenting with 
papulo-pustular acne vulgaris (inflammatory acne) at baseline with:

no more than 2 facial inflammatory nodules or cysts

and a minimum number of 10 non-inflammatory facial lesions (open and
closed comedones)

who are candidates for systemic treatment and for whom in the opinion of
the investigator, an appropriate previous treatment with topical anti-acne
medication failed, or was not well tolerated, or is not indicated (generally
due to large body surface area affected, e.g., on the back)

Grade 3 (moderate) or Grade 4 (severe) IGA score assessed by the
investigator at screening and baseline.
Key Exclusion 
criteria

Previous treatment with investigational drugs at the time of screening, or
within 4 weeks or 5 half-lives of baseline, whichever is longer; or more as
required by local regulations.

Previous treatment with any topical anti-acne therapy: prescription treatment
within 2 weeks prior to baseline OR Over-The-Counter (OTC) treatment
within 1 week prior to baseline.

Previous treatment with any oral/systemic anti-acne therapy, corticosteroids,
or immune-modulators (such as, but not limited to, cyclosporine,
methotrexate, azathioprine) within 4 weeks prior to baseline OR previous
treatment with biologics (such as anti-TNFα agents, anti-IL-1, or anti--IL-17)
within 3 months or 5 half-lives (whichever is longer) prior to baseline OR
previous treatment with anti-IL-12/23 blocking agents within the last
6 months prior to baseline OR previous surgical, physical light or laser
therapy within 4 weeks prior to baseline OR previous facial treatment with
medium depth chemical peels within 3 months prior to baseline.

Patients receiving concomitant medication(s) that is/are known to inhibit
OAT3  (see Table 5-1) and that cannot be discontinued or replaced by safe
alternative medication within 5 half-lives or 1 week (whichever is longer) prior
to baseline and for the duration of the study.

Any other forms of acne,

Active systemic infections (other than common cold) within 2 weeks prior to 
baseline.
Study treatment
LYS006 
 (high dose): 12 weeks

LYS006 
 (low dose): 12 weeks

Matching placebo
: 12 weeks
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Key safety 
assessments

AE monitoring using CTCAE grading

Physical examinations

Monitoring of laboratory markers in blood and urine

ECG

Vital signs
Data analysis
The natural log transformed inflammatory facial lesion count will be analyzed 
using a Bayesian mixed effect model for repeated measures (MMRM), with log 
transformed baseline inflammatory facial lesion count as a continuous covariate;
treatment group, visit, treatment group by visit interaction, log transformed 
baseline inflammatory facial lesion count by visit interaction and type of center 
(selected/non-selected for additional exploratory assessments) as fixed effects 
and an unstructured covariance structure will be used
Key words
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1
Introduction
1.1
Background
Moderate to severe inflammatory acne is a debilitating disease, with visible inflammatory 
lesions on the face and subsequent risk of permanent scars. Available treatments are either 
associated with serious side effects (such as isotretinoin) or are modestly effective even after 
long term treatment (such as systemic antibiotics, oral zinc, and hormonal therapies). Acne is 
recognized as a chronic inflammatory skin disease, in which innate immunity play critical roles 
(Das and Reynolds 2014). Systemic antibiotics are associated with the rise of microbiological 
resistance and their long term use is more and more under critique, as most used tetracyclines 
are bacteriostatic rather than bactericidal and antibiotic resistance is a growing concern 
(Adler et al 2017). Thus, the development of a non-antibiotic, anti-inflammatory and well-
tolerated oral agent would respond to this medical need.
Zouboulis showed that in an open label Phase IIa clinical trial including 10 patients that 
treatment with the 5-LO inhibitor zileuton showed highly clinically relevant improvement of 
acne severity scores and reduction in inflammatory lesions (Zouboulis et al 2003, 
Zouboulis 2009). A multicenter placebo controlled study with 101 patients treated 4 times daily 
with 600 mg zileuton for 12 weeks showed significant reduction in inflammatory lesions in the 
subset of patients with more severe acne (Critical Therapeutics 2005). This pointed to the 
potential implication of the leukotriene A4 hydrolase (LTA4H) pathway in acne and led to the 
proposal of testing a specific LTA4H inhibitor, LYS006, in moderate to severe inflammatory 
acne.
The most relevant data for the present study are summarized in the sections below. For detailed 
information, please refer to the Investigator's Brochure (IB).
Relevant data summary
 Inflammatory acne is characterized by high 
numbers of neutrophils in the inflamed skin and upregulation of LTB4 and its biosynthetic 
enzymes. In acne, an approximately 70-fold less potent LTB4 inhibitor (the 5-LO inhibitor 
zileuton) demonstrated some clinical efficacy (Zouboulis 2009, Collawn et al 1992). 
LTB4 inhibitors, however, have not been developed for these indications yet, and no LTA4H 
inhibitor is currently marketed in this indication. LYS006 would therefore constitute a new 
therapeutic approach for this chronic inflammatory skin disease.
 
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1.2.1
Teratogenicity and reproductive toxicity data
1.2.2
Pharmaceutical properties
1.2.3
Pharmacology
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1.2.4
Toxicology
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1.2.5
Non-clinical pharmacokinetics and metabolism
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1.3
Clinical data
The most relevant data for the present study are summarized below. For detailed information, 
please refer to the IB.
In parallel to the Phase 2 study in Acne, LYS006 is being evaluated in ulcerative colitis, 
hidradenitis suppurativa and, nonalcoholic steatohepatitis (all phase 2 studies).
1.4
Study purpose
The study is designed to assess clinical efficacy and safety of LYS006 in adult patients with 
moderate to severe inflammatory acne as well as exploring dose relationship. This information 
will support the decision to initiate a dose ranging study in inflammatory acne and guide dose 
selection for that planned study.
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2
Objectives and endpoints
2.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary objective(s)

To assess the efficacy of LYS006
versus 
placebo 
on 
facial
inflammatory 
lesion 
counts 
in
patients with moderate to severe
inflammatory acne

Baseline-adjusted total inflammatory facial
lesion count at Week 12
2.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

To assess the safety and tolerability
of LYS006 in patients with moderate
to severe inflammatory acne

Number and severity of AEs
2.3
Exploratory objective(s)
Exploratory objective(s)
Endpoints related to exploratory objective(s)
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Exploratory objective(s)
Endpoints related to exploratory objective(s)
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Exploratory objective(s)
Endpoints related to exploratory objective(s)
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3
Investigational plan
3.1
Study design
This is a randomized, placebo-controlled, subject and investigator blinded, multicenter, 
non-confirmatory, parallel-group, proof-of-concept study in adult patients with moderate to 
severe facial inflammatory acne. After an initial screening period (up to 4 weeks), the study will 
be conducted over a treatment period of 12 weeks to evaluate the clinical efficacy of LYS006 
versus placebo. Fifty-six patients will be randomized in a 3:1:3 ratio to one of the following 
treatment groups:

Group 1: LYS006 capsules, high dose 
, n=24

Group 2: LYS006 capsules, low dose
, n=8

Group 3: matching placebo
, n=24
Exposure to placebo will be limited to a maximum of 12 weeks.
After treatment period completion, all patients will enter a post-treatment safety follow-up 
period of 4 weeks without study drug administration.
The maximum duration of study participation will be 20 weeks.
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3.2
Rationale for study design
Study population
The patients included in the study are adults with moderate to severe inflammatory acne. 
Disease severity is defined with a minimal count of 20 facial inflammatory lesions 
(papules, pustules, nodules) at baseline, a minimum of 10 non-inflammatory facial lesions at 
baseline and screening, and an IGA score of 3 (moderate) or 4 (severe) assessed by the 
investigator at screening and baseline. Patients should have no more than 2 facial nodules, in 
order to exclude cases of nodulocystic acne 
 In line with the observed activity of zileuton in previous studies 
(Zouboulis et al 2003, Critical therapeutics 2005), 
Included patients should be candidates for a systemic treatment and should respect specified 
washout periods for systemic and topical anti-acne treatments (see Section 4.2 and Section 5.2). 
Patients are eligible for this study, if topical treatment alone or in combination with another topical 
treatment was not sufficient and/or was contraindicated. As an example, often involvement of the 
back alone may be considered an indication to systemic treatment, as topical treatment is difficult to 
apply by the subject himself. However, for this study, facial involvement is mandatory for inclusion. 
Washout periods have been defined based on other recent Phase 3 clinical studies in moderate to 
severe inflammatory acne such as Fleischer et al 2006, ClinicalTrials.gov NCT02320149 2014, 
and ClinicalTrials.gov NCT02322866 2014.
Treatment arms and study methodology
The following treatment groups will be compared in the primary efficacy analysis: LYS006 
high dose 
 versus placebo on baseline-adjusted facial inflammatory lesion count at 
Week 12. Other time-points may be explored. Moderate to severe acne is associated with an 
increased risk of scarring on the face. A placebo-controlled study of more than 12 weeks is 
therefore not considered. In this clinical setting, it is known that a placebo effect could occur 
with up to 30-40% spontaneous reduction in inflammatory lesion count at Week 12. In this 
context, a blinded study is deemed optimal to generate reliable data, which are not influenced 
by investigators' or patients' perception. Due to possible carry-over effects and the need for a 
wash-out period, a cross-over design is not considered appropriate for this proof-of-concept 
study.
Clinical endpoints
It is assumed that the anti-inflammatory effect with the LTA4H inhibitor LYS006 is the clinically 
most pronounced effect. Consequently, baseline-corrected facial inflammatory lesion count is chosen 
as the primary endpoint (US department of Health and Human Services 2005). Inflammatory 
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lesions (IL) are defined as papules, pustules and nodules. As counts on the face are best 
validated, the IL count will focus on the face similarly to other clinical studies in the same 
clinical setting. 
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
In the present study, doses
 are proposed to explore safety and efficacy in 
the moderate to severe acne population.
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Treatment duration is referenced by the FDA draft guidance for industry on acne vulgaris 
(US department of Health and Human Services 2005) to be at least 12 weeks despite the 
recognized fact that maximum effects may not yet be achieved. Currently ongoing or completed 
studies with systemic treatments have used a similar duration (for example, antibiotics such as 
minocycline in Fleischer et al 2006, or sarecycline in ongoing pivotal studies (ClinicalTrials.gov 
NCT02320149 2014, ClinicalTrials.gov NCT02322866 2014). It is generally accepted to 
include placebo controls in these studies in similar patient populations.
3.4
Rationale for choice of comparator
In this proof-of-concept study, the preliminary efficacy
of LYS006 will be 
assessed using a subject-blinded and investigator-blinded study design as compared to placebo. 
Moderate to severe inflammatory acne is associated with a pronounced potential placebo effect. 
In addition, lesion counts 
 are subjective assessments with a potential 
risk of substantial variability. Therefore, the proposed study design should mitigate the potential 
biases associated with the clinical setting and the endpoints related to the study objectives.
3.5
Rationale for choice of background therapy
Acne is a disease where the visible inflammatory lesions, papules and pustules, appear and 
disappear in irregular intervals and numbers. The minimal treatment duration is considered to 
be 12 weeks.
No background therapy is needed in this trial, in order to evaluate the effect of an oral therapy 
alone. In order to avoid as much as possible potential confounders, all medications to treat acne 
or acne inflammation are to be washed out before randomization (see relevant exclusion criteria 
(Section 4.2) and prohibited treatment (Section 5.2)). Adherence for anti-acne therapies is 
considered generally as poor (Thiboutot et al 2009).
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3.6
Purpose and timing of interim analyses/design adaptations
The following interim analysis (IA) may be conducted during this trial:
3.7
Risks and benefits
The risk to subjects in this trial will be minimized by adherence to the eligibility criteria, close 
clinical monitoring, and adequate post-treatment safety follow-up to capture any potential late 
occurring AEs.
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In addition, women of child-bearing potential must be informed that taking the study treatment 
may involve unknown risks to the fetus if a pregnancy was to occur during the study, and agree 
that, in order to participate in the study, they must adhere to the contraception requirements 
outlined in the Section 4.2 (Exclusion Criteria). If there is any question that the subjects will 
not reliably comply, they should not be entered or continue in the study.
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.
3.7.1
Blood sample volumes
A maximum of approximately 207 mL of blood from each subject is planned to be collected 
over a period of 20 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 (Section 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 also available in the SOM 
and central Laboratory Manual.
All blood samples will be taken by direct venipuncture in a forearm vein. Each sample should 
have a unique sample number. The actual sample collection date and time will be recorded on 
the eCRF. Sampling problems will be noted on the comments field of the eCRF.
See Section 8.9 regarding the potential use of residual samples.
4
Population
4.1
Inclusion criteria
The patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female subjects aged 18 to 45 years of age inclusive, and otherwise in good health
as determined by medical history, physical examination, and vital signs
3. Body weight between 50 and 120 kg, both inclusive, at screening.
4. Patients with papulo-pustular acne vulgaris (inflammatory acne):

presenting at baseline with :

20 to 100 facial inflammatory lesions (papules, pustules and nodules),

presenting at baseline and screening with

no more than 2 facial inflammatory nodules or cysts,

and a minimum number of 10 non-inflammatory facial lesions (open and closed
comedones)
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
who are candidates for systemic treatment and for whom in the opinion of the
investigator, an appropriate previous treatment with topical anti-acne medication :

failed,

or was not well tolerated,

or is not indicated (e.g., due to large body surface area affected, e.g., on the back)
5. Patients with Grade 3 (moderate) or Grade 4 (severe) IGA score assessed by the investigator
at screening and baseline.
6. Able to communicate well with the investigator, to understand and comply with the
requirements of the study.
4.2
Exclusion criteria
The patients fulfilling any of the following criteria are not eligible for inclusion in this study:
1. Previous treatment with investigational drugs at the time of screening, or within 4 weeks or
5 half-lives of baseline, whichever is longer; or more as required by local regulations.
2. Previous treatment with any topical anti-acne therapy:

prescription treatment within 2 weeks prior to baseline

Over-The-Counter (OTC) treatment within 1 week prior to baseline
The use of medicated anti-acne creams, medicated cleansers or medicated soaps will remain
prohibited for the duration of the study.
3. Previous treatment with any oral/systemic anti-acne therapy:

oral antibiotics, dapsone, oral zinc within 4 weeks prior to baseline

retinoids, e.g., isotretinoin, within 3 months prior to baseline

hormonal therapy (in particular anti-androgen for example spironolactone, finasteride,
and cyproterone acetate alone or in combination with estrogen derivatives) within
1 month prior to baseline.
If women of child-bearing potential are using oral contraception, this contraception can be 
used under certain conditions (see prohibited treatments for further guidance on oral 
contraception in women of child-bearing potential [WOCBP]).
4. Previous treatment with systemic corticosteroids or immunomodulators (such as, but not
limited to, cyclosporine, methotrexate, azathioprine) within 4 weeks prior to baseline.
This includes as well lesional injections of the above medications in acne prone areas (such
as corticosteroids).
5. Previous treatment with biologics (such as anti-TNFα agents, anti-IL-1, or anti-IL-17)
within 3 months or 5 half-lives (whichever is longer) prior to baseline.
6. Previous treatment with anti-IL-12/23 blocking agents (such as briakinumab and
ustekinumab or p19 antibodies) within 6 months prior to baseline.
7. Previous surgical, physical (such as ThermaClear™), light (including blue or UV light,
photodynamic therapy [PDT]) or laser therapy within 4 weeks prior to baseline.
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8. Previous facial treatment with medium depth chemical peels (excluding home regimens)
within 3 months prior to baseline.
9. Patients receiving concomitant medication(s) that is/are known to inhibit OAT3  (see Table
5-1) and that cannot be discontinued or replaced by safe alternative medication within 5 half-lives
or 1 week (whichever is longer) to baseline and for the duration of the study.
10. Any other forms of acne, such as:
11. 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.
15. Subjects with estimated Glomerular Filtration Rate (eGFR) <60 mL/min/1.73m (estimated
by MDRD) at screening.
16. History of kidney stones and/or repeated presence of crystals in urine before drug
administration.
17. History or symptoms of malignancy of any organ system, treated or untreated, within the
past 5 years, 
18. Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV).
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19. History of auto-immune or immunodeficiency diseases, or a positive human
immunodeficiency virus (HIV) test result (for example, Chemiluminescence and
Polymerase Chain Reaction) at screening.
20. 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.
21. 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
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23. History of drug abuse or unhealthy alcohol use#
24. Donation or loss of 400 ml or more of blood within 8 weeks prior to baseline, or longer if
required by local regulation.
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The study population will be comprised of male and female subjects, aged 18-45 years, with 
moderate to severe inflammatory acne. A total of approximately 56 patients will be randomized. 
The sample size may be re-assessed at time of IA and the number of randomized patients may 
be increased.
The investigators must ensure that all patients being considered for the study meet the eligibility 
criteria. No additional criterion should be applied by the investigators, in order to ensure that 
the study population is representative of all eligible patients. No additional exclusions may be 
applied by the investigator, in order to ensure that the study population will be representative 
of all eligible patients.
5
Restrictions for Study Subjects
For the duration of the study, the subjects should be informed and reminded of the restrictions 
outlined in this section.
5.1
Contraception requirements
 women of child-bearing 
potential must be informed that taking the study treatment may involve unknown risks to the 
fetus if pregnancy were to occur during the study, and agree that in order to participate in the 
study they must adhere to the contraception requirement outlined in the Section 4.2 (Exclusion 
Criteria). If there is any question that the subject will not reliably comply, they should not be
entered or continue in the study.
If there is any question that the subject will not reliably comply, the subject should not be 
entered or continue in the study. Please refer to Section 4.2 (Exclusion criteria) for details of 
contraception requirements for the study.
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5.2
Prohibited treatment
Table 5-1
Prohibited medication
Medication
Action to be taken
Requested wash-out (prior 
to randomization/first 
treatment)
IL-12 or IL-23 blocking agents such 
as briakinumab and ustekinumab, 
including p19 blocking antibodies
Discontinue study 
treatment
Wash-out: 6 months
Any biologics, other than above, in 
particular, IL-1 and IL-17 blockers
Discontinue study 
treatment
Wash-out: 3 months or at 
least 5 times the half-life, 
whichever is longer
Any systemic immunosuppressant or 
immunomodulator, such as 
cyclosporine, methotrexate, 
cyclophosphamide, azathioprin, 
corticosteroids (includes local 
injections), etc.
Discontinue study 
treatment
Wash-out: 1 month
Any systemic treatment with 
antibiotics, in particular tetracyclines 
and/or macrolides, but as well other 
oral anti-acne treatment such as 
dapsone and zinc.
Discontinue study 
treatment if antibiotic 
treatment (not for acne) is 
significantly longer than 2 
weeks. All other cases to 
be discussed with Sponsor 
on case-by-case basis.
Wash-out: 1 month
Use of any systemic hormonal 
treatment (including anti-androgens, 
for example spironolactone, 
finasteride, and cyproterone acetate 
alone or in combination with estrogen 
derivatives) within 1 month before 
baseline.
To be discussed with 
Sponsor on case by case 
basis
Wash-out: 1 month
Oral contraceptives can be continued 
if stable for the last 3 months before 
baseline if stable in dose and dosing 
regimen and type (brand) and if the 
patient plans to continue throughout 
the study treatment period.
To be discussed with 
Sponsor on case by case 
basis (in particular of dose 
and brand changes)
Wash out in case of change 
in dose, regimen or type: 3 
months
Systemic retinoids, in particular 
isotretinoin
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Medication
Action to be taken
Requested wash-out (prior 
to randomization/first 
treatment)
Surgical or physical
light and laser 
therapy (including blue light, use of 
handheld devices, tanning devices or 
photodynamic therapy) on area of 
evaluation. After baseline, use of any 
tanning device, or excessive 
exposure to sun [with intention to 
tan], any handheld light device to 
treat skin or procedures for hair 
removal in the evaluation areas are 
not permitted.
Discuss with Sponsor on 
case by case basis
Wash-out: 1 month
Any topical for acne on area for 
evaluation (face, back, chest, 
shoulder, neck), including retinoids 
(such as adapalene, tazarotene, 
isotretinoin or tretinoin), antibacterial 
and antibiotics (such as benzoyl 
peroxide, clindamycine or 
erythromycine) and any other topical 
keratolytic or peeling agents (such as 
salicylic acid, or lactic acid) or any 
other anti-acne drug (such as 
dapsone, azelaic acid). These 
topicals include over the counter 
products for acne, such as medicated 
emollients, cleansers or soaps.
To be discussed with 
Sponsor on case-by-case 
basis.
Decisions regarding drop-outs and replacements will be discussed with the sponsor on a case-by-case 
basis.
5.3
Dietary restrictions and smoking
5.4
Other restrictions
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6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the Site Operations Manual.
6.1.1
Investigational treatment and control drug(s)
The investigational drug, LYS006 1 mg and 5 mg, and matching placebo will be prepared and 
supplied by Novartis to investigator`s site as double blinded patient kits. Drug will be 
administered orally in accordance with the specified study procedures (see Section 6.5).
Table 6-1
Overview of study medication
Study drug name
Formulation
Unit dose
Packaging
Provided by
LYS006
Hard Gelatin Capsule
1 mg
Double blind patient kits
Novartis
LYS006
Hard Gelatin Capsule
5 mg
Double blind patient kits
Novartis
Placebo
Hard Gelatin Capsule
0 mg
Double blind patient kits
Novartis
6.1.2
Additional study treatment
No additional treatment beyond investigational drug and control drug are included in this trial.
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6.2
Treatment arms
Subjects will be assigned to one of the following 3 treatment groups in a ratio of 3:1:3:

Group 1: LYS006 
 (high dose) for a total of 12 weeks

Group 2: LYS006 
 (low dose) for a total of 12 weeks

Group 3: placebo
 for a total of 12 weeks
6.3
Treatment assignment and randomization
Randomized treatment will be assigned to individual patients by way of a randomization 
number on Day 1. Randomization of patients will be carried out by Interactive Response 
Technology (IRT) system.
The randomization number is only used to identify which treatment the patients have been 
randomized to receive. The Subject number assigned to a patient at screening remains the 
unique identifier for the patient throughout the study. For information on subject numbering, 
please see ‘Subject numbering’ section in the SOM.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A subject 
randomization list will be produced by the Interactive Response Technology (IRT) provider
using a validated system that automates the random assignment of subject numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers. A separate medication list will be 
produced by or under the responsibility of Novartis Drug Supply Management using a validated 
system that automates the random assignment of medication numbers to packs containing the 
investigational drug(s).
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
Follow the details outlined in the SOM regarding the process and timing of treatment 
assignment and randomization of patients.
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6.4
Treatment blinding
This is a subject and investigator-blinded study. Subjects and investigators will remain blinded 
to study treatment throughout the study, except where indicated below.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling and schedule of administration, appearance, and odor.
Site staff
All site staff (including study investigator and study nurse) will be blinded to study treatment 
throughout the study.
Unblinding a single subject at site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (see Section 6.7).
Sponsor staff
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 data 
analysis.
All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind other study team members confidential and secure except as described above.
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Following final database lock all roles may be considered unblinded.
Table 6-2
Blinding levels
Role
Time or Event
Randomization list 
generated
Treatment 
allocation & 
dosing
Safety event (single 
subject unblinded)
Interim 
Analysis 
Subjects/Patients
B
B
UI
Site staff
B
B
UI
Drug Supply and 
Randomization Office
UI
UI
UI
Unblinded sponsor staff (see 
text for details)
UI
UI
UI
Statistician/statistical 
programmer/data analysts
B
B
UI
All other sponsor staff 
including external experts not 
identified above
B
B
UI
B Remains blinded
UI Allowed to be unblinded on individual patient level
6.5
Treating the subject
LYS006 and its matching placebo will be administered to the subject via oral route
6.6
Permitted dose adjustments and interruptions of study treatment
Study treatment dose adjustments and/or interruptions are not permitted. Occasional 
interruptions in study treatment must be recorded as protocol deviations.
These changes must be recorded on the Dosage Administration Record page of the eCRF.
6.7
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely or in case of pregnancy confirmed by a positive serum pregnancy test. 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 
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to break a treatment code for a subject, he/she must provide the requested subject identifying 
information and confirm the necessity to break the treatment code for the subject. 
The investigator will then receive details of the investigational drug treatment for the specified 
subject and a fax or email confirming this information. The system will automatically inform 
the study monitor for the site and the Study Team that the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time (select as applicable) in case of emergency. The investigator 
will need to provide: 

protocol number

study drug name (if available)

subject number.
In addition, the investigator must provide oral and written information to inform the subject 
how to contact his/her backup in cases of emergency when he/she is unavailable to ensure that 
un-blinding can be performed at any time.
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given subject.
6.8
Treatment exposure and compliance
Pre-dose LYS006 blood and plasma concentrations (measures of treatment exposure) will be 
determined in all subjects treated with LYS006, as detailed in Section 8.7. 
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 at 
visits 104, 105 and 106 and information provided by the subject at visits 102 and 103. This 
information should be captured in the source document at the respective visit and in the eCRF. 
All study treatment dispensed and returned must be recorded in the Drug Accountability Log.
6.9
Recommended treatment of adverse events
There are no known expected AE 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. 
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6.10
Rescue medication
No specific rescue treatments are planned for this study. Use of rescue medication must be 
recorded on the Concomitant medications/Significant non-drug therapies eCRF.
If during the treatment period, the acne condition would worsen significantly and rescue 
treatment is medically indicated, the patient should be discontinued from the study treatment. 
If the acne condition worsens after the treatment period is finished, any medically indicated 
rescue medications can be prescribed during the follow up period. 
6.11
Concomitant treatment
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study.
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions and any physical anti-acne therapy including 
light, laser) administered or taken within the timeframe defined in the entry criteria prior to the 
start of the study and during the study, must be recorded on the Concomitant 
medications/Significant non-drug therapies CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact Novartis before randomizing a subject 
or, if the subject is already enrolled, to determine if the subject should continue participation in 
the study.
7
Study completion and discontinuation
7.1
Study completion and post-study treatment
Each subject will be required to complete the study in its entirety and thereafter no further study 
treatment will be made available to them.
Study completion is defined as when the last subject completes his/her Study Completion visit, 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the investigator, or in the event of an early study termination decision, the date 
of that decision.
All treated subjects should have a safety follow-up visit conducted 30 days after last 
administration of study treatment. All SAEs reported during this time period must be reported 
as described in Section 9.2 and the Site Operations Manual. Documentation of attempts to 
contact the subject should be recorded in the source documentation.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.


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7.2
Discontinuation of study treatment
Individual Treatment Discontinuation Rules
Patients may voluntarily discontinue the study for any reason at any time. The investigator must 
discontinue 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 other protocol deviation that results in a significant risk to the patient’s safety
Subjects who discontinue study treatment should NOT be considered withdrawn from the study 
UNLESS they withdraw their consent. Where possible, they should return for the assessments 
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 
as specified in Section 7.4.
7.2.1
Replacement policy
Replacement patients may be enrolled to replace patients who discontinue from study treatment 
before completion of Week 12 assessments. Decisions regarding drop-outs and replacements 
will be discussed with the sponsor on a case-by-case basis.
7.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time.
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
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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. 
Novartis will continue to keep and use collected study information (including any data resulting from 
the analysis of a subject’s samples until their time of withdrawal) according to applicable law.
For the United States and Japan: All biological samples not yet analyzed at the time of 
withdrawal may still be used for further testing/analysis in accordance with the terms of this 
protocol and of the informed consent form. 
For all the 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.
7.4
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject cannot be formally considered lost to follow-up until 
his/her scheduled end of study visit would have occurred.
7.5
Study stopping rules
The study may be put on hold pending full safety data review if one or more of the following 
criteria are met:

Two or more 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 if other 
safety measures need to be taken. The findings and recommendations of the internal experts will be 
documented and will be made available to the respective Ethics Committees/Review Boards.
7.6
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons 
(including slow enrollment), or for regulatory or medical reasons. Should this be necessary, 
subjects must be seen as soon as possible and treated as a prematurely discontinued subject. 
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The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the subject’s interests. The investigator 
will be responsible for informing IRBs/IECs of the early termination of the trial.


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8
Procedures and assessments
8.1
Assessment schedule
Subjects should be seen for all visits/assessments as outlined in the Assessment schedule (Table 8-1) or as close to the designated day/time as 
possible.
Missed or rescheduled visits should not lead to automatic discontinuation. Subjects who prematurely discontinue the study treatment for any 
reason should be scheduled for a visit as soon as possible. Where possible, they should return for the assessments as defined in the assessment 
table. If not possible, all of the assessments listed for the final visit should be performed. At this final visit, all dispensed investigational 
product should be reconciled, and the adverse event and concomitant medications recorded on the CRF.
If the COVID-19 pandemic limits or prevents on-site study visits, alternative methods of providing continuing care may be implemented. 
Phone calls, virtual contacts (e.g. teleconsultation) or visits by site staff/home nursing service to the participant´s home depending on local 
regulations and capabilities, can replace on-site study visits, for the duration of the pandemic until it is safe for the participant to visit the site 
again.
Table 8-1
Assessment Schedule
Epoch
Screening
Treatment
Post-Treatment Follow-Up
Visit Name
Screening
Baseline
Treatment
EOS
Visit Numbers1
1
2
101
102
103
104
105
106
2992
Days
-30 to -2
1
1
15
-8 +5
29
±5
57
±5
85
±5
115
-5 +15
Time (post-dose)
-
-
-
-
-
-
-
-
Informed consent
X
X
Inclusion / Exclusion criteria
X
X
Pregnancy test3
X
X
X
X
X
X
X
Physical Examination
S
S
S
S
Medical history/current medical conditions
X
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Epoch
Screening
Treatment
Post-Treatment Follow-Up
Visit Name
Screening
Baseline
Treatment
EOS
Visit Numbers1
1
2
101
102
103
104
105
106
2992
Days
-30 to -2
1
1
15
-8 +5
29
±5
57
±5
85
±5
115
-5 +15
Time (post-dose)
-
-
-
-
-
-
-
-
Demography
X
Body Height
X
Body Weight
X
X
Body Temperature
X
X
X
X
X
X
X
Pulse rate
X
X
X
X
X
X
X
Blood Pressure
X
X
X
X
X
X
X
Electrocardiogram (ECG)
X
X
X
X
X
X
X
Hepatitis and HIV Screen
X
Clinical Chemistry
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X16
X
X
X
X
X
X
X
X
X
X
Drug dispensation
X
X
X
Compliance check (pill count17 and patient’s information)
X
X17
X17
X17
Drug administration record
X
X
X
X
X
Concomitant medications
As required
Adverse Events
As required
Serious Adverse Events4
As required
Facial inflammatory lesion count (papules, pustules, inflammatory 
nodules, including nodulocysts)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Epoch
Screening
Treatment
Post-Treatment Follow-Up
Visit Name
Screening
Baseline
Treatment
EOS
Visit Numbers1
1
2
101
102
103
104
105
106
2992
Days
-30 to -2
1
1
15
-8 +5
29
±5
57
±5
85
±5
115
-5 +15
Time (post-dose)
-
-
-
-
-
-
-
-
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
X
X
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
Study completion information
X
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1 Visit structure given for internal programming purpose only.
2 Patients who discontinue the study early, should have the same assessments performed as for the end of treatment Visit 106 and EOS performed. 
3 Blood test at screening and EoS or last visit; additional urine tests must be done throughout the study.
4 SAEs collected up to 30 days following the End of Treatment Visit.
7 Pre-dose sample on dosing days, all patients. Sample will also be collected at EOS visit as indicated in the assessment schedule.
17 Pill count only at visits 104, 105 and 106.
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8.2
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents.
Novartis will provide to investigators a proposed informed consent form that complies with the 
ICH E14 (R2) GCP guideline (2016) and regulatory requirements and is considered appropriate 
for this study. The informed consent form will also include a section related to optional future 
research which will require a separate signature if the subject agrees to future research. 
The procedures set out in the main consent form concerning the storage, maintenance of privacy, 
and release of the data or specimens for the main study will also be adhered to for any future 
research. Any changes to the proposed consent form suggested by the investigator must be 
agreed to by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an Investigator Notification or 
an Aggregate Safety Finding. New information might require an update to the informed consent 
and then must be discussed with the subject.
Ensure subjects are informed of the contraception requirements outlined in the Section 4.2
(Exclusion criteria) and in Section 5.1 (Contraception requirements).
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
Refer to the Site Operations Manual for a complete list of Informed Consent Forms included in 
this study.
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8.3
Subject screening
It is permissible to re-screen a subject if s/he fails the initial screening; 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 patient after a 
patient has screen failed.
All required screening activities must be performed when the patient is re-screened for 
participation in the study. An individual patient may only be re-screened once for the study.
If a subject fails screening but is re-screened, the subject must be rescreened using the same 
subject number.
Once the number of patients screened and enrolled is likely to ensure target enrollment, the 
Sponsor may close the study to further screening. In this case, the patients who screen failed 
will not be permitted to re-screen.
All eligibility criteria must be re-checked, based on the most recent data available, and met prior 
to enrollment of the patient into the study.
If the rescreening is successful, the following information should be collected in the CRF:

Date the study informed consent was first signed.

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.
For screening failures (initial or after re-screening), information on what data should be 
collected is outlined in the Site Operations Manual.
8.4
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, details of prior anti-acne, and any other 
assessments that are 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 eCRF. Details are outlined in the Site Operations Manual.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.


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8.5
Efficacy / Pharmacodynamics
Pharmacodynamic and efficacy assessments are specified below, with the methods for 
assessment and recording specified in the Study Operations Manual. As clinical efficacy 
measures are rater dependent, each evaluator should be appropriately trained and qualified for 
these assessments. In particular, every effort should be made that the same evaluator 
assesses and counts the lesions throughout the study.
Assessments will be performed and pharmacodynamic samples will be collected at the time-
points defined in the Assessment schedule (Table 8-1). Follow instructions outlined in the SOM 
regarding sample collection, numbering, processing and shipment.
In order to better define the Pharmacodynamic profile, the timing of the sample collection may 
be altered based on emergent data. The number of samples/blood draws and total blood volume 
collected will not exceed those stated in the protocol.
Pharmacodynamic samples will be obtained and evaluated in all subjects at all dose levels.
8.5.1
Clinical Outcome Assessments (COAs)
Clinical Outcome measures will assess the acne severity
 and also the numbers of lesions and their type
 Due to the inter- and intra- rater variability inherent to every subjective 
grading system, it is important that every effort should be made to keep the same evaluator per 
patient between baseline to Week 12. This evaluator needs to provide documentation that s/he 
was properly trained and whether s/he was previously involved in acne clinical studies.
The counting is to be done by lesion type
. The face will be separated into 
five areas: the forehead, the right cheek, the left cheek, the chin and the nose. For each 
assessment, the evaluator will be recorded in the source documentation and change of evaluator 
should be noted in CRF.
8.5.1.1
Lesion counts
Acne is characterized by inflammatory and non-inflammatory lesions situated in the face and 
non-facial areas, such as upper trunk (chest, back and shoulders). The most frequent 
inflammatory lesions include papules and pustules, both generally less than 0.5 cm in diameter, 
while nodules are larger, deeper dermal lesions and more typical for nodulo-cystic acne. 
All inflamed lesions are generally surrounded by a halo of erythema allowing for their 
characterization as inflammatory. Some lesions, in particular nodules, may be tender.
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8.5.1.1.1 Inflammatory lesion counts
For a therapeutic effect in inflammatory acne, a reduction in inflammatory facial lesions is 
considered the main endpoint. The inflammatory lesions include papules, pustules, and nodules 
(nodules and cysts are discussed below). Papules are red inflammatory lesions in general not 
larger than 0.5cm, while pustules have a yellow center, from the pus collection in the center of 
the inflammatory lesion. At pre-specified visits, the evaluator will count papules and pustules 
separately and by area on the face only. For this purpose, inflammatory lesions will be counted 
in five areas (right and left cheek, chin, forehead, and nose). 
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8.5.3
Exploratory biomarkers
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8.6
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment schedule (Table 8-1) detailing when each 
assessment is to be performed.
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8.6.1
Physical examination
A complete physical examination will be performed as per Assessment schedule (Table 8-1) 
and 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.
Significant findings that were present prior to informed consent signature must be included in 
the Medical History page eCRF. Significant new findings that begin or worsen after informed 
consent signature must be recorded on the Adverse Event page eCRF.
8.6.2
Vital signs
Vital signs (body temperature, pulse rate, blood pressure) must be performed before dosing and 
as indicated in the Assessment schedule (Table 8-1) as per institutional standards.
Unscheduled assessment can be performed if clinically indicated.
8.6.3
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, 
but without shoes) will be measured as indicated in the Assessment schedule (Table 8-1).
Height information will be collected at screening only.
8.6.4
Laboratory evaluations
Clinically relevant deviations of laboratory test results occurring during or at completion of the 
study must be reported and discussed with Novartis personnel. The results should be evaluated 
for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted.
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 patient’s eligibility for the study. During the course of the study, 
unscheduled assessment can be performed if clinically indicated.
Local laboratory assessments may be performed if medically indicated or when the treating 
physician cannot wait for central laboratory results for decision making. In this particular 
situation, the blood sample obtained at the same time point should be submitted to the central 
laboratory for analysis in parallel with local analysis.
The results of the local laboratory will be recorded in the eCRF as unscheduled visit if the 
following criteria are met:

a treatment decision was made based on the local results, or

there are no concomitant central results available


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Details on the collection, shipment of samples and 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 8-6
Blood clinical laboratory parameters
Test category
Test name
Hematology
Hematocrit, hemoglobin, platelets, red blood cells, white blood cells (WBC), 
WBC morphology with differential (basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Clinical chemistry
Albumin, alkaline phosphatase, total bilirubin, calcium, cholesterol, chloride, 
creatinine, creatine kinase, C-Reactive Protein and hs-CRP, g-GT, glucose, 
lactate deshydrogenase, inorganic phosphorus, lipase, amylase, 
magnesium, potassium, total protein, AST (SGPT), ALT (SGOT), sodium, 
triglycerides, blood urea nitrogen (BUN) and uric acid.
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.
Viral serology
Hepatitis B, Hepatitis C, HIV at screening
Urine specimens
During on-treatment visits at the clinic, a midstream urine sample (approx. 30 ml) will be 
obtained, in order to avoid contamination with epithelial cells and sediments, and allow proper 
assessments.
A semi-quantitative “dipstick/bedside” evaluation for the following parameters will be 
performed by the central lab: specific gravity, pH, glucose, protein, bilirubin, ketones, nitrite, 
leukocytes and blood.
All urine samples should be kept at room temperature until local and/or central analysis.
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Pregnancy tests
At screening and EOS (or last visit), a serum pregnancy test will be performed centrally.
Throughout the study, local urine pregnancy test are sufficient. Additional urine pregnancy tests 
may be required, if a reason occurs such as patient reports delay in menstruation. A positive 
urine pregnancy test requires immediate interruption of study drug until serum β-hCG is 
performed and found to be negative. See Section 9.6 for guidance on pregnancy reporting and 
follow-up.
8.6.5
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.
PR interval, QRS duration, heart rate, RR, QT, QTcF (Fridericia QT) will be collected.
The preferred sequence of data collection during study visits is ECG collection first (10 min 
rest, ECG recording over next 5 min suggested), followed by vital signs, and blood sampling. 
Clinically significant abnormalities must be reported in the AE CRF.
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8.8
Other assessments
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8.9
Use of residual biological samples
9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject 
after providing written informed consent for participation in the study until the end of study 
visit. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the study treatment are also considered 
an adverse event irrespective if a clinical event has occurred. See Section 9.6 for an overview 
of the reporting requirements.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination finding, laboratory test 
finding, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms,

they are considered clinically significant,

they require therapy.
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for liver and kidney related events are 
included in Appendix 1 and Appendix 2, respectively.
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Adverse events should be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information:
1. The Common Toxicity Criteria (CTC) for AE grade (version 4.0 or higher). A copy of the
CTCAE grading will be provided separately.
If CTCAE grading does not exist for an adverse event, use:
1=mild,
2=moderate,
3=severe
4=life threatening* (see Section 9.2 for definition of a serious adverse event (SAE))
*Note: There may be cases where a CTCAE with a grade of 4 (life-threatening) may not
necessarily be an SAE (e.g. certain laboratory abnormalities in the absence of meeting
other seriousness criteria).
CTCAE grade 5 (death) is not used, but is collected as a seriousness criteria and also
collected in other CRFs (e.g. Study Completion, Death/Survival).
2. its relationship to the study treatment

Yes or

No
3. its duration (start and end dates) or if the event is ongoing an outcome of not
recovered/not resolved must be reported.
4. whether it constitutes a SAE (see Section 9.2 for definition of SAE) and which seriousness
criteria have been met
5. Action taken regarding investigational treatment.
All adverse events must be treated appropriately. Treatment may include one or more of
the following:

no action taken (e.g. further observation only)

investigational treatment dosage increased/reduced

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given

hospitalization/prolonged hospitalization (see Section 9.2 for definition of SAE)
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving,
recovered/resolved with sequelae; fatal; or unknown).
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. Once an adverse event is detected, it must be followed until 
its resolution or until it is judged to be permanent, and assessment should be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
investigational drug, the interventions required to treat it, and the outcome.


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The investigator must also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 
source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis.
*Refer to the Site Operations Manual for data capture methodology regarding AE collection for
subjects that fail screening.
9.2
Serious adverse event reporting
9.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless
hospitalization is for

routine treatment or monitoring of the studied indication, not associated with any
deterioration in condition

elective or pre-planned treatment for a pre-existing condition (that is unrelated to the
indication under study and has not worsened since the start of study drug

treatment on an emergency outpatient basis for an event not fulfilling any of the
definitions of a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the subject’s
general condition

is medically significant, e.g. defined as an event that jeopardizes the subject or may
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to ICH E14D Guideline 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. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (please refer to ICH E14D Guideline 2003).


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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 9.2.2
9.2.2
SAE reporting
Screen Failures
Note the following requirement for 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.
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 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 2011/C 172/01 or as per national regulatory requirements in 
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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.
9.3
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
Please refer to Table 15-1-Appendix 1 for complete definitions of liver events.
Follow-up of liver events
Every liver event defined in Table 15-1-Appendix 1should be followed up by the investigator 
or designated personnel at the trial site, as summarized below. Additional details on actions 
required in case of liver events are outlined in Table 15-2-Appendix 1.

Repeating liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and GGT) to confirm
elevation within 48-72 hours.
These liver chemistry repeats should always be performed using the central laboratory, with the 
results provided via the standard electronic transfer. If results will not be available from the 
central laboratory within 24 hours, then the repeats can also be performed at a local laboratory 
to monitor the safety of the subject. If a liver event is subsequently reported, any local liver 
chemistry tests previously conducted that are associated with this event should have results 
reported on the unscheduled local laboratory CRF.

If the initial elevation is confirmed, close observation of the subject will be initiated,
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to Section 7.2 (Discontinuation of study
treatment), if appropriate

Hospitalization of the subject if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include

Repeating liver chemistry tests two or three times weekly. Testing should include ALT,
AST, ALP, PT/INR, and GGT. If total bilirubin is elevated > 2 x ULN, fractionation into
direct and indirect bilirubin is required. To rule out muscular origin of transaminase
elevations, CPK should be measured along with liver chemistry tests. Frequency of retesting
can decrease to once a week or less if abnormalities stabilize or the study drug has been
discontinued and the subject is asymptomatic. Retesting should be continued up to
resolution.

Obtaining a more detailed history of symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications and
herbal and dietary supplement preparations), alcohol use, recreational drug use, and special
diets.

Exclusion of underlying liver disease, as specified in Table 15-3-Appendix 1.

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
Obtaining a history of exposure to environmental chemical agents.

Considering gastroenterology or hepatology consultations.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. Refer to the Site Operations Manual for additional details.
9.6
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.
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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& 
PS). As such, instances of misuse or abuse are also to be reported using the SAE form/CRF. 
Table 9-1 summarizes the reporting requirements.
Table 9-1
Guidance for capturing treatment errors
Treatment error type
Document in Dose 
Administration (DAR) 
CRF 
Document in AE 
CRF
Complete SAE 
form/CRF 
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see
Section 9.1 and Section 9.2, respectively.
9.7
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis 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.


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9.8
Early phase safety monitoring
The investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly between 
medically qualified personnel representing the Sponsor and investigator. Such evaluations may 
occur verbally, but the outcome and key discussion points will be summarized in writing (e-mail) 
and made available to both Sponsor and all investigator(s). Criteria pertaining to stopping the 
study/treatment or adapting the study design are presented above.
When two or more clinical site(s) are participating in the clinical study, the Sponsor will advise 
the investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any new, 
clinically relevant safety information reported from another site during the conduct of the study 
in a timely manner.
10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e., 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 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 
ensure that study drug is being stored, dispensed, and accounted for according to specifications. 
Key study personnel must be available to assist the monitor during these visits.
Continuous remote monitoring of each site’s data may be performed by Novartis or the CRO 
working on behalf of Novartis. Additionally, a central analytics organization may analyze data 
and 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. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about the 
identity of the subjects will be disclosed.


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10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 requirements. 
Designated investigator site staff will not be given access to the EDC system until they have 
been trained. Automatic validation programs check for data discrepancies and, by generating 
appropriate error messages, allow the data to be confirmed or corrected before transfer of the 
data to the CRO working on behalf of Novartis. The investigator must certify that the data 
entered into the Electronic Case Report Forms are complete and accurate. After database lock, 
the investigator will receive copies of the subject data for archiving at the investigational site.
Certain data may be captured via other source documentation (such as safety laboratory data 
report, imaging) and then transcribed, uploaded or transferred to the CRO working on behalf of 
Novartis or to Novartis. This, and any additional data treated in this manner, will be source data 
verified by the study monitor per the monitoring plan and the location of source data 
(i.e., Source, paper or a local electronic system) will be documented prior to study start in the 
Data Handling Plan. When using an electronic source record as the original point of data capture, 
there is no additional data entry step for the site for data collected directly into the application; 
rather, the electronic source record directly populates the study database.
Automatic validation programs check for data discrepancies and, by generating appropriate 
error messages, allow the data to be confirmed or corrected before transfer of the data to the 
vendor working on behalf of Novartis.
Remote monitoring of the original electronic source records will take place, however on-site 
monitoring inspections will continue to take place in order to review data entry of source 
documentation directly captured on paper and transcribed into the system, to ensure protocol 
adherence, to assess site operational capabilities, and to perform other monitoring activities that 
cannot be performed remotely.
The investigator must certify that the data entered into the eCRF are complete and accurate. 
After database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.
Data not requiring a separate written record will be defined in the Site Operations Manual and 
Assessment schedule (Table 8-1) and can be recorded directly on the CRFs. All other data 
captured for this study will have an external originating source (either written or electronic) 
with the CRF not being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.


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10.3
Database management and quality control
Novartis staff and the CRO working on behalf of Novartis review the data entered into the CRFs 
by investigational staff for completeness and accuracy and instruct the site personnel to make 
any required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query Form 
will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it back 
to Novartis staff or to the CRO working on behalf of Novartis who will make the correction to 
the database. The signed copy of the Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the Medical 
dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
ECG readings will be processed centrally and the results will be sent electronically to Novartis 
(or a designated CRO).
Randomization codes and data about all study drug(s) dispensed to the subject and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis.
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.
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10.4
Data Monitoring Committee
In this proof-of-concept study, there is no a priori information as per the FDA Guidance of 
“situations in which safety concerns may be unusually high” or the patient population being 
studied is “potentially fragile population such as children, pregnant women or the very elderly, 
or other vulnerable populations, such as those who are terminally ill or of diminished mental 
capacity.” Thus, an independent data monitoring committee will not be constituted.
The Novartis clinical team will review the safety data on a regular basis. A preliminary review 
of the safety data and assessment of efficacy, based on the calculated Bayesian probability of 
success will be performed at the first interim analysis by the Novartis clinical trial team and the 
overall recommendations on study continuation shared with the investigators. A re-assessment 
of the sample size based on the observed coefficient of variation in the primary endpoint 
between patients may also be performed.
At the time of the first interim analysis, the inflammatory facial lesion counts performed by the 
investigator will be used to compare the 
 high dose group with the placebo group. A 
Bayesian analysis will be performed to estimate the probability of success of the trial given the 
current data.
It is envisioned that the team may make three types of recommendations at the first interim 
analysis, namely:

No safety or efficacy issues, ethical to continue the study as planned,

Substantial coefficient of variation between patients in the primary endpoint requiring re-
assessment of the sample size,

Serious safety concerns precluding further treatment in the study, regardless of efficacy.
10.5
Adjudication Committee
Not required.
11
Data analysis
The analyses will be conducted on all subject data at the time when interim analysis occurs and 
also when the trial ends. Study data will be analyzed by Novartis and/or a designated contract 
research organization (CRO). Any data analysis carried out independently by the investigator 
should be submitted to Novartis before publication or presentation.
The following study data will be summarized: demographic and baseline characteristics, 
efficacy assessments, safety assessments, pharmacokinetic and biomarker assessments.
Categorical data will be presented as contingency tables (frequencies and percentages). 
For continuous data, summary statistics including mean, standard deviation, median, minimum, 
and maximum will be presented if not otherwise specified. In addition, individual listings of all 
raw data captured in the clinical database will be presented by treatment group and patient. All 
data from participating clinical sites will be combined, so that an adequate number of patients 
will be available for analysis.
CCI


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11.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The following analysis sets will be used and will be derived prior to database lock. As required, 
additional analysis sets will be defined in the Statistical Analysis Plan (SAP).
Safety Analysis Set
The safety analysis set will include all subjects that received at least one dose of study drug.
Pharmacodynamic (PD) Analysis Set
The PD analysis set will include all subjects with available PD data, who received any study 
drug and with no protocol deviations with relevant impact on PD data. Protocol deviations 
leading to exclusion from the PD analysis set will be added in the SAP.
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and subject. 
Summary statistics will be provided by treatment group. Subject demographics will include age, 
sex, race, ethnicity, country, height, weight and BMI. Baseline disease characteristics include 
but are not limited to: facial inflammatory lesion counts (papules, pustules, nodules),
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject.
11.3
Treatments
Data for study drug administration and concomitant therapies will be listed by treatment group 
and subject.
Duration of exposure to study drug in days, as well as actual total doses, actual dose intensities
(total amount of drug administered per unit of time), and relative dose intensities (ratio of actual 
dose intensity to planned dose intensity) will be summarized using descriptive statistics by 
treatment group for the safety analysis set. 
Compliance to the study treatment will be assessed by the number of dose interruptions and 
percent of days with received planned dose by treatment group for the safety analysis set.
Concomitant therapies prior to and after the start of study treatment will be listed and 
summarized by treatment group for the safety analysis set.
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11.4
Analysis of the primary variable(s)
The primary aim of this study is to assess the efficacy of LYS006 versus placebo on 
inflammatory facial lesion counts in patients with moderate to severe inflammatory acne. 
Therefore, a statistical analysis will be performed on the log transformed inflammatory facial 
lesion count after 12 weeks. The primary analyses will be based on on-treatment data.
Data recorded after a patient discontinues study treatment will not be included in the primary 
analyses.
11.4.1
Primary Variable(s)
The primary variable is the natural log transformed total inflammatory facial lesion counts (sum 
of papules, pustules, and nodules) at Week 12.
11.4.2
Statistical model, hypothesis, and method of analysis
Data up to Week 12 will be included in a Bayesian mixed effect model for repeated measures
(MMRM) for the comparison of LYS006 high dose group versus placebo group at 12 weeks, 
which is of primary interest. Data from the LYS006 low dose group will also be included in 
this primary model at the time of IA and later analyses, but will mainly be summarized as 
described in Section 11.6. 
The natural log transformed inflammatory facial lesion count is expected to be approximately 
normally distributed. It will be analyzed using a Bayesian mixed effect model for repeated 
measures (MMRM) using Proc MCMC in SAS software (Chen 2011). Baseline adjustment will 
be implemented by including the log transformed baseline inflammatory facial lesion count in 
the model as a continuous covariate. The model will also include treatment group, visit, 
treatment group by visit interaction, log transformed baseline inflammatory facial lesion count 
by visit interaction and type of center 
as fixed effects. Non-informative priors will be utilized for the fixed effects and 
for the covariance. An unstructured covariance will be assumed; other covariance structures 
will be investigated if there is a convergence issue. As supportive analyses, other factors such 
as gender, race, center and assessor may also be considered in the primary analysis model either 
as a fixed effect or as a sub-group analyses variable to investigate for potential heterogeneity. 
The log transformed baseline inflammatory facial lesion count will be centered and 
standardized prior to being included in the model.
Bayesian posterior probabilities will be used to assess the following PoC criteria as a guidance 
for decision making (Fisch et al 2015), though other criteria may be taken into account:
Efficacy criteria (only for primary objective) at IA and at the final analysis:

If there is at least 90% probability that the treatment effect of LYS006 at 12 weeks is
better than placebo, i.e., Prob (y_LYS006 - y_placebo < 0) > 90%, and

If there at least 50% probability that the treatment effect at 12 weeks is at least 25% in
favor of LYS006, i.e., Prob (y_LYS006 - y_placebo < - 0.288) > 50%.
where y is the log transformed facial inflammatory lesion count.
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The posterior estimates of the treatment effect and the treatment difference (along with its 90% 
credible interval) at each post baseline visit (with Week 12 being of primary interest) will be 
provided. The results will be reported in terms of adjusted absolute and percent changes from 
baseline by back-transforming the estimates from the log-scale. The absolute change from 
baseline and the percentage change from baseline in total inflammatory facial lesion count will 
also be summarized by group and visit. Data will also be presented in graphics such as spaghetti 
plots.
11.4.3
Handling of missing values/censoring/discontinuations
All patients with available data after baseline and until Week 12 will be included in the interim 
and in the primary analyses. If study drug is permanently discontinued before Week 12, data 
collected after permanent discontinuation will not be considered for the purpose of the primary 
analyses. The primary variable analysis model is known to give unbiased results under the 
assumption that missing data are at random (MAR), i.e. given observed data the missingness 
does not depend on unobserved data. In the event that many patients discontinue treatment, 
alternative estimands considering the effect of LYS006 versus placebo may also be investigated. 
Further details will be provided in the Statistical Analysis Plan (SAP).
11.4.4
Sensitivity analyses
11.5
Analysis of secondary variable(s)
11.5.1
Safety
For all safety analyses, the safety analysis set will be used if not otherwise specified. All listings 
and tables will be presented by treatment group.
Vital signs
All vital signs data will be listed by treatment group, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics
will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment group, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time.
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Clinical laboratory evaluations
For laboratory tests covered by the CTCAE version 4.0 or higher, the laboratory data will be 
graded accordingly. The calculation of CTCAE grades will be based on the observed laboratory 
values only, clinical assessments will not be taken into account. For laboratory tests covered by 
CTCAE, a Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
Grade 5 will not be used.
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests:

frequency table for newly occurring on-treatment grades 3 or 4

shift tables using CTCAE grades to compare baseline to the worst on-treatment value

for laboratory tests where CTCAE grades are not defined, shift tables using the
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value.

listing of all laboratory data with values flagged to show the corresponding CTCAE
grades and the classifications relative to the laboratory normal ranges.
Adverse events (AEs)
All information obtained on AEs will be displayed by treatment group and subject.
Summary tables for AEs 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. Listings of all AEs will be provided.
The incidence of TEAEs (new or worsening after first dose) will be summarized by system 
organ class or preferred term, severity and by treatment group.
Deaths reportable as SAEs and non-fatal SAEs will be listed by patient and tabulated by type 
of AE and treatment group.
SAEs, non-serious AEs and AEs of special interest
 will 
be tabulated.
A subject with multiple AEs within a body system is only counted once towards the total of this 
body system.
Study drug compliance assessment
Study drug compliance will be assessed by summarizing the duration of exposure, the actual 
total doses, frequency of dose interruption, and actual and relative dose intensities. Reason for 
dose interruption will be listed by patient and summarized.
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Other safety evaluations
Pregnancy test results will be listed by treatment group, subject and visit/time.
11.5.2
Other assessments
Not applicable.
11.6
Analysis of exploratory variables 
Details of statistical methodologies for exploratory variables will be described in the SAP. 
Graphical presentation of the data will be performed where applicable.
11.6.1
Clinical Outcome Assessments
Facial inflammatory lesion count over time
Total inflammatory facial lesion count data over time will be visualized via individual profile 
plots for all subjects, where group allocation and responder status at Week 12 will be indicated. 
Individual facial inflammatory lesion counts (papules, pustules and nodules) over time will be 
summarized by lesion type, treatment group and visit/time and also be visualized by spaghetti 
plots and group summary plots. Estimates of the treatment effect over time will be taken from
a MMRM model as described for the primary variable.
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11.6.5
Exploratory biomarkers
11.7
Sample size calculation
In total approximately 56 subjects are to be randomized with a 3:1:3 ratio to LYS006 high dose, 
low dose and placebo group. This should provide complete 12-week data of approximately 20 
patients in the LYS006 high dose and placebo groups, with the assumption of around 20% 
dropout rate.
The table below shows the cumulative operating characteristics of the trial for the primary 
endpoint (LYS006 high dose versus placebo) at the interim analysis (IA), when approximately 
15 patients in the LYS006 high dose group and 15 patients in the placebo group have completed 
12 weeks (at about 75% enrolment); and at the final analysis when all patients have completed 
12 weeks. The operating characteristics are presented with the probabilities to declare 
preliminary efficacy at IA and final analysis under different true difference in lesion counts 
between treatment groups (active-placebo/placebo).
With the log-normal assumption and a median of 20 lesions in the placebo group at Week 12, 
the 25% effect (active minus placebo being -0.288 on the log scale) corresponds to 
approximately 5 lesions difference in the median, which is considered the targeted difference 
from placebo (Section 11.4.2). If the true effect is 35% over placebo (active minus placebo
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being -0.431 on the log scale), the probability of meeting the efficacy criteria is 87%, with 20 
subjects from either LYS006 high dose group or placebo group. Effect of 35% corresponds to 
approximately 7 lesions difference in median, assuming a median of 20 lesions in the placebo 
group at week 12. If the true effect over placebo is 0, there is approximately 5% chance of 
declaring efficacy.
Table 11-1
Operating characteristics of decision rules
15:15 (IA)
20:20 (final analysis)
Sample size*
Chance of meeting both 
efficacy criteria
Chance of meeting both 
efficacy criteria 
True effect = 0
5%
5%
True effect = 35%
80%
87%
11.8
Power for analysis of key secondary variables
Not Applicable.
11.9
Interim analyses
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12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations 
Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles 
laid down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g. 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis by the time of 
Last Patient Last Visit to be a reviewer and signatory for the clinical study report. 
12.3
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results.
12.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
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, 
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13
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.
13.1
Protocol Amendments
Any change to the protocol can only be made in a written protocol amendment that must be
approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation.
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 9 (Safety Monitoring) must be followed and the Study Lead 
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14
References
References are available upon request.
Adler BL, Kornmehl H, Armstrong AW (2017) Antibiotic Resistance in Acne Treatment. 
JAMA Dermatol; 153(8):810-11.
Ahlgrimm-Siess V, Laimer M, Rabinovitz HS, et al (2018) Confocal Microscopy in Skin 
Cancer. Current dermatology reports; 7(2):105-18.
Anon (1995) Report of the Rodent Bladder Carcinogenesis Working Group. Food Chem 
Toxicol; 33(9): 699-802.
Chen F (2011) The RANDOM statement and more: moving on with PROC MCMC. SAS 
Institute Inc, Cary, NC. SAS Global Forum Proceedings; Paper No: 334-2011.
Chernyshov P, Zouboulis C, Tomas-Aragones L, et al (2018) Quality of life measurement in 
acne. Position Paper of the European Academy of Dermatology and Venereology Task Forces 
on Quality of Life and Patient Oriented Outcomes and Acne, Rosacea and Hidradenitis 
Suppurativa. J Eur Acad Dermatol Venereol; 32(2): 194-208.
ClinicalTrials.gov, NCT02320149 (2014) Study to Evaluate Safety & Efficacy of Sarecycline 
in 
Treatment 
of 
Acne 
(Internet). 
Available 
from: 
<https://clinicaltrials.gov/ct2/show/NCT02320149> (Accessed 05 February 2018).
ClinicalTrials.gov, NCT02322866 (2014) Randomized, Double-blind, Placebo-controlled 
Study to Evaluate Safety & Efficacy of Sarecycline in Treatment of Acne (Internet). Available 
from: <https://clinicaltrials.gov/ct2/show/NCT02322866> (Accessed 05 February 2018).
Collawn C, Rubin P, Perez N, et al (1992) Phase II study of the safety and efficacy of a 5-
lipoxygenase inhibitor in patients with ulcerative colitis. Am J Gastroenterol; 87(3): 342-6.
Critical Therapeutics (2005) Press release: Critical Therapeutics Announces Results from Phase 
II 
Study 
of 
Zileuton 
in 
Acne 
Patients
(Internet). 
Available 
from: 
<https://www.businesswire.com/news/home/20050714005349/en/Critical-Therapeutics-
Announces-Results-Phase-II-Study> (Accessed 05 February 2018).
Das S, Reynolds RV (2014) Recent advances in acne pathogenesis: implications for therapy. 
Am J Clin Dermatol; 15(6): 479-88.
Drake RL, Wogl AW, Mitchell AWM, et al (2009) Pelvis and Perineum. Gray’s Atlas der 
Anatomie: Elsevier; ch.5: 218-19.
Finlay AY, Khan GK (1994) Dermatology Life Quality Index (DLQI)--a simple practical 
measure for routine clinical use. Clin Exp Dermatol; 19(3): 210-6.
Fisch R, Jones I, Jones J, et al (2015) Bayesian design of proof-of-concept trials. Therapeutic 
Innovation and Regulatory Science; 49(1): 155-62.
Fleischer AB, Dinehart S, Stough D, et al (2006) Safety and efficacy of a new extended-release 
formulation of minocycline. Cutis; 78(4 Suppl): 21-31.
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Halvorsen JA, Stern RS, Dalgard F, et al (2011) Suicidal ideation, mental health problems, and 
social impairment are increased in adolescents with acne: a population-based study. J Invest
Dermatol; 131(2): 363-70.
ICH E2D: International Conference on Harmonisation (2003) Post-approval safety data 
management (Internet). Available from: 
<http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/post-approval-safety-
data-management-definitions-and-standards-for-expedited-reporting.html> (Accessed on 05 
February 2018).
ICH E6 (R2): International Conference on Harmonisation (2016). Good Clinical Practice 
(Internet). Available from: < http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/integrated-addendum-good-clinical-practice.html> (Accessed on 05 February 
2018).
Kurd SK, Troxel AB, Crits-Christoph P, et al (2010) The risk of depression, anxiety, and suicidality 
in patients with psoriasis: a population-based cohort study. Arch Dermatol; 146(8): 891-5.
Lee JW, Yoo KH, Park KY, et al (2011) Effectiveness of conventional, low-dose and 
intermittent oral isotretinoin in the treatment of acne: a randomized, controlled study. Br J 
Dermatol; 164(6):1369-75.
Loeffler K, Gäbel G (2015) Kidney and urinary tract. Anatomie und Physiologie der Haustiere: 
UTB; 14th ed.: 281-94.
Martin AR, Lookingbill DP, Botek A, et al (2001) Health-related quality of life among patients 
with facial acne -- assessment of a new acne-specific questionnaire. Clin Exp Dermatol. 26(5):
380-5.
National Cancer Institute Common Toxicity Criteria version (NCI-CTCAE) accessed at 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html on 03-Dec-2018
Picardi A, Lega I, Tarolla E (2013) Suicide risk in skin disorders. Clin Dermatol; 31(1): 47-56.
Purvis D, Robinson E, Merry S, et al (2006) Acne, anxiety, depression and suicide in teenagers: 
a cross-sectional survey of New Zealand secondary school students. J Paediatr Child Health; 
42(12): 793-6.
Schoen T, Blum J, Paccaud F, et al (2013) Factors associated with 24-hour urinary volume: the 
Swiss salt survey. BMC Nephrol; 14: 246.
Tan J, Thiboutot D, Gollnick H, et al (2017) Development of an atrophic acne scar risk 
assessment tool. J Eur Acad Dermatol Venereol; 31(9): 1547-54.
Tan JK, Tang J, Fung K, et al (2007) Development and validation of a comprehensive acne 
severity scale. J Cutan Med Surg; 11(6): 211-6.
Thiboutot D, Gollnick H, Bettoli V, et al (2009) New insights into the management of acne: an 
update from the Global Alliance to Improve Outcomes in Acne group. J Am Acad Dermatol; 
60(5 Suppl): S1-50.
Thiboutot DM, Dréno B, Abanmi A, et al (2018) Practical management of acne for clinicians: 
An international consensus from the Global Alliance to Improve Outcomes in Acne. J Am Acad 
Dermatol; 78(2S1): S1-S23.


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US department of Health and Human Services, Food and Drug Administration, Rockville, MD 
(2005) CDER: Guidance for Industry; Acne Vulgaris: Developing Drugs Treatment. Draft 
guidance.
Zouboulis CC (2009) Zileuton, a new efficient and safe systemic anti-acne drug. 
Dermatoendocrinol; 1(3): 188-92.
Zouboulis CC, Nestoris S, Adler YD, et al (2003) A new concept for acne therapy: a pilot study 
with zileuton, an oral 5-lipoxygenase inhibitor. Arch Dermatol; 139(5): 668-70.


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SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
LYS006
CLYS006X2201
A randomized, subject and investigator blinded, placebo-
controlled, multi-center study in parallel groups to assess 
the efficacy and safety of LYS006 in patients with moderate 
to severe inflammatory acne
Statistical Analysis Plan (SAP)
Author(s):
Document type:
SAP Documentation – NIBR 
Document status:
Final Amendment 3
Release date:
04-May-2022
Number of pages:
32
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
ClinicalTrials.gov Identifier: NCT03497897
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Table of contents
Table of contents .................................................................................................................7
List of tables & figures........................................................................................................8
1
Introduction .........................................................................................................................9
1.1
Scope of document ..................................................................................................9
1.2
Study reference documentation ...............................................................................9
1.3
Study objectives.......................................................................................................9
1.3.1
Primary objective(s)................................................................................9
1.3.2
Secondary objective(s)............................................................................9
1.3.3
Exploratory objective(s)..........................................................................9
1.4
Study design and treatment....................................................................................11
2
First interpretable results (FIR) .........................................................................................12
3
Interim analyses.................................................................................................................16
4
Statistical methods: Analysis sets......................................................................................17
6
Statistical methods for Efficacy/Pharmacodynamic (PD) parameters ..............................19
6.1
Primary objectives .................................................................................................19
6.1.1
Variables ...............................................................................................19
6.1.2
Descriptive analyses..............................................................................19
6.1.3
Statistical model, assumptions and hypotheses.....................................20
6.1.4
Sensitivity analyses ...............................................................................21
6.1.5
Supportive analyses...............................................................................21
6.2
Exploratory objectives...........................................................................................22
6.2.1
Variables ...............................................................................................23
6.2.2
Descriptive analyses..............................................................................24
6.2.3
Statistical model, assumptions and hypotheses.....................................25
6.2.4
Graphical presentation of results...........................................................26
7
Statistical methods for safety and tolerability data............................................................26
7.1
Variables................................................................................................................26
7.2
Descriptive analyses ..............................................................................................26
7.3
Graphical presentation of results ...........................................................................29
9
Statistical methods for biomarker data..............................................................................30
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9.2
Descriptive analyses ..............................................................................................31
9.3
Graphical presentation of results ...........................................................................32
10 Reference list.....................................................................................................................32
List of tables & figures
Table 4-1
Protocol deviation codes and analysis sets............................................17
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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 “CLYS006X2201”.
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(s)
Primary objective(s)
Endpoints related to primary objective(s)

To assess the efficacy of LYS006
versus 
placebo 
on 
facial
inflammatory 
lesion 
counts 
in
patients with moderate to severe
inflammatory acne

Baseline-adjusted total inflammatory facial
lesion count at Week 12
1.3.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

To assess the safety and tolerability
of LYS006 in patients with moderate
to severe inflammatory acne

Number and severity of AEs
1.3.3
Exploratory objective(s)
Exploratory objective(s)
Endpoints related to exploratory objective(s)
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Exploratory objective(s)
Endpoints related to exploratory objective(s)
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Exploratory objective(s)
Endpoints related to exploratory objective(s)
1.4
Study design and treatment
This is a randomized, placebo-controlled, subject and investigator blinded, multicenter, 
non-confirmatory, parallel-group, proof-of-concept study in adult patients with moderate to 
severe facial inflammatory acne. After an initial screening period (up to 4 weeks), the study will 
be conducted over a treatment period of 12 weeks to evaluate the clinical efficacy of LYS006 
versus placebo. Fifty-six (56) patients will be randomized in a 3:1:3 ratio to one of the following 
treatment groups:

Group 1: LYS006 capsules, high dose
 
 N=24

Group 2: LYS006 capsules, low dose
 N=8

Group 3: LYS006 placebo
, N=24
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Exposure to placebo will be limited to a maximum of 12 weeks.
After treatment period completion, all patients will enter a post-treatment safety follow-up 
period of 4 weeks without study drug administration.
The maximum duration of study participation will be 20 weeks.
2
First interpretable results (FIR)
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3
Interim analyses 
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4
Statistical methods: Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received. This 
implies that for subjects for whom the actual treatment received does not match the randomized 
treatment, the treatment actually received will be used for the analysis.
The Safety analysis set will include all subjects that received at least one dose of study drug.
The PD analysis set will include all subjects with available PD data, who received any study 
drug and with no protocol deviations with relevant impact on PD data.
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
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
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to
DBL.
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6
Statistical methods for Efficacy/Pharmacodynamic (PD) 
parameters
All subjects within the PD analysis set will be included in the PD data analysis.
6.1
Primary objectives
The primary aim of this study is to assess the efficacy of LYS006 versus placebo on 
inflammatory facial lesion counts in patients with moderate to severe inflammatory acne.
The primary analyses will be based on on-treatment data. Data recorded after a patient 
discontinues study treatment will not be included in the primary analyses. This corresponds to 
the aim of this proof of concept of assessing the effect of LYS006 when taken as planned versus 
placebo used alone. 
6.1.1
Variables 
The primary variable is the natural log transformed total inflammatory facial lesion counts (sum 
of papules, pustules, and nodules) at Week 12.
Baseline is defined as the Baseline (Visit 2) assessment.
6.1.2
Descriptive analyses
Total inflammatory facial lesion count will be listed by treatment group, subject and visit/time,
and descriptive statistics will be provided, for raw, absolute change from baseline and 
percentage change from baseline, by treatment group and visit/time. Summary statistics will 
include mean (arithmetic and geometric), SD, CV (arithmetic and geometric), median, 
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minimum, maximum; geometric mean and its CV will only be provided for the raw values. A 
geometric mean will not be reported if the dataset includes zero values.
Graphical methods will be employed to show mean and individual (Spaghetti) plots over time.
Note: Any plots that are reported separately by treatment (i.e., plots with one graph per page 
for each treatment), will use the same y-axis scale for each treatment. 
6.1.3
Statistical model, assumptions and hypotheses
Data up to Week 12 will be included in a Bayesian mixed effect model for repeated measures 
(MMRM) for the comparison of LYS006 high dose group versus placebo group at 12 weeks, 
which is of primary interest. Data from the LYS006 low dose group will also be included in 
this primary model at the time of IA and later analyses, but will mainly be summarized as 
described in the descriptive analyses section above. 
The natural log transformed inflammatory facial lesion count is expected to be approximately 
normally distributed. It will be analyzed using a Bayesian mixed effect model for repeated 
measures (MMRM) using Proc MCMC in SAS software (Chen 2011). Baseline adjustment will 
be implemented by including the log transformed baseline inflammatory facial lesion count in 
the model as a continuous covariate. The model will also include treatment group, visit, 
treatment group by visit interaction, log transformed baseline inflammatory facial lesion count 
as fixed effects. Non-informative priors will be utilized for the fixed effects and 
for the covariance coming from a normal distribution and an inverse Wishart distribution, 
respectively. An unstructured covariance will be assumed; other covariance structures will be 
investigated if there is a convergence issue. The log transformed baseline inflammatory facial 
lesion count will be centered and standardized prior to being included in the model.
Bayesian posterior probabilities will be used to assess the following proof-of-concept (PoC) 
criteria as a guidance for decision making (Fisch et al 2015), though other criteria may be taken 
into account:
Efficacy criteria (only for primary objective) at IA and at the final analysis:

If there is at least 90% probability that the treatment effect of LYS006 at 12 weeks is
better than placebo, i.e., Prob (y_LYS006 - y_placebo < 0) > 90%, and

If there is at least 50% probability that the treatment effect at 12 weeks is at least 25% in
favor of LYS006, i.e., Prob (y_LYS006 - y_placebo < - 0.288) > 50%.
Where y is the log transformed facial inflammatory lesion count.
The posterior estimates of the treatment effect and the treatment difference (along with its 90% 
credible interval) at each post baseline visit (with Week 12 being of primary interest) will be 
provided. The results of the treatment effects will be presented as geometric means by back-
transforming the estimates from the log-scale. The results of the treatment comparison to 
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placebo will be reported in terms of ratio of the geometric means by back-transforming the 
estimates from the log-scale.
6.1.3.1
Model checking procedures
All patients with available data after baseline and until Week 12 will be included in the interim 
and in the primary analyses. If study drug is permanently discontinued before Week 12, data 
collected after permanent discontinuation will not be considered for the purpose of the primary 
analyses. The primary variable analysis model is known to give unbiased results under the 
assumption that missing data are at random (MAR), i.e. given observed data the missingness 
does not depend on unobserved data. In the event that many patients discontinue treatment, 
alternative estimands considering the effect of LYS006 versus placebo may also be investigated.
6.1.3.2
Graphical presentation of results
Model-based geometric mean treatment estimates (+/- SE) as well as model-based geometric 
mean treatment ratio estimates (+/- SE) will be plotted over time and by treatment. The baseline 
value will also be presented in the model-based geometric mean treatment estimates (+/- SE) 
graphs for better visualization purposes. The baseline value that will be displayed is the 
averaged baseline value across treatments.
6.1.4
Sensitivity analyses
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6.1.5 
Supportive analyses
In order to have better understanding of the treatment effect, the absolute change from baseline 
and the percentage change from baseline in total inflammatory facial lesion count will also be 
explored using a Bayesian mixed effect model for repeated measures (MMRM) using Proc 
MCMC in SAS software (Chen 2011). Baseline inflammatory facial lesion count will be 
included in the model as a continuous covariate. The model will also include treatment group, 
visit, treatment group by visit interaction, baseline inflammatory facial lesion count  
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as 
fixed effects. Non-informative priors will be utilized for the fixed effects and for the covariance 
coming from a normal distribution and an inverse Wishart distribution, respectively. An 
unstructured covariance will be assumed; other covariance structures will be investigated if 
there is a convergence issue. The baseline inflammatory facial lesion count will be centered and 
standardized prior to being included in the model.


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The posterior estimates of the treatment effect and the treatment difference (along with its 90% 
credible interval) at each post baseline visit (with Week 12 being of primary interest) will be 
provided. The results of the treatment effects will be presented as arithmetic means and the 
results of the treatment comparison to placebo will be reported in terms of difference of the 
arithmetic means.
The Bayesian posterior probability for statistical significance, i.e., the probability that the 
treatment effect of LYS006 is better than placebo, Prob (LYS006 - placebo < 0), will be 
obtained.
As an additional supportive analysis, the same Bayesian MMRM as for the primary analysis 
will be fitted and appropriate contrasts will be estimated in order to compare LYS006 high dose 
group versus placebo group on the average treatment effect combining week 8 and week 12 
data.
6.1.5.1
Model checking procedures
All patients with available data after baseline and until Week 12 will be included in the interim 
and in the above supportive analyses. If study drug is permanently discontinued before Week 12, 
data collected after permanent discontinuation will not be considered for the purpose of the 
above supportive analyses.
6.1.5.2
Graphical presentation of results
Model-based arithmetic mean treatment estimates (+/- SE) as well as model-based arithmetic
mean treatment difference estimates (+/- SE) will be plotted over time and by treatment.
Baseline will also be presented as 0 in these model-based plots for better visualization of the 
absolute and percent changes from baseline over time.
Posterior density plots for the treatment effect will also be obtained.
As additional supportive analyses, other factors such as gender, race, center, assessor and 
approach of the assessment (digital or clinic) may also be considered in the primary analysis 
model and the above supportive analysis models either as a fixed effect or as a sub-group 
analyses variable to investigate for potential heterogeneity. If heterogeneity is observed, then 
this method may be applied to other investigated PD endpoints.
Further, supportive analyses may be performed adding other covariates in the models such as 
baseline IGA and other baseline characteristics.
6.2
Exploratory objectives
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6.2.1
Variables 
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6.2.2
Descriptive analyses
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6.2.3
Statistical model, assumptions and hypotheses
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6.2.4
Graphical presentation of results
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 AEs/SAEs, vital signs (body 
temperature, height, weight, blood pressure and pulse rate), ECG intervals (PR interval, QRS 
duration, heart rate, RR, QT and QTcF), laboratory measurements (hematology, clinical 
chemistry, urinalysis), as well as subject demographics, baseline characteristics, and treatment 
information.
7.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and subject. 
Summary statistics will be provided by treatment group. Subject demographics will include age, 
sex, race, ethnicity, country, height, weight and BMI. Baseline disease characteristics include 
but are not limited to: facial inflammatory lesion counts (papules, pustules, nodules),
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject.
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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, since the intent is to show how 
much 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 concomitant therapies will be listed by treatment group
and subject.
Duration of exposure to study drug in days, as well as actual total doses, actual dose intensities 
(total amount of drug administered per unit of time), and relative dose intensities (ratio of actual 
dose intensity to planned dose intensity) will be summarized using descriptive statistics by 
treatment group for the safety analysis set. 
Compliance to the study treatment will be assessed by the frequency of dose interruptions and 
percent of days with received planned dose by treatment group for the safety analysis set.
Compliance to the study treatment in the percent of capsules taken will be summarized by visit 
and overall, and also listed.
Reason for dose interruption will be listed by subject and summarized.
Concomitant therapies prior to and after the start of study treatment will be listed and 
summarized by treatment group for the safety analysis set.
Vital signs
All vital signs data will be listed by treatment group, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment group and visit/time.


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ECG evaluations
All ECG data will be listed by treatment group, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment group and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, subject, and visit/time and if normal ranges
are available abnormalities will be flagged. A separate listing will be provided presenting all 
parameters in a subject with any abnormal values. Summary statistics will be provided by 
treatment group and visit/time.
The laboratory data will be graded by the low/normal/high classifications based on laboratory 
normal ranges.
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests:

Shift tables using the low/normal/high/(low and high) classification to compare
baseline to the worst on-treatment value.

Listing of all laboratory data with values flagged to show the classifications relative to
the laboratory normal ranges.
Adverse events
All information obtained on adverse events 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. Listings of all AEs will be provided.
The incidence of TEAEs (new or worsening after first dose) will be summarized by system 
organ class (SOC) and/or preferred term (PT), maximum severity and by treatment.
Deaths reportable as SAEs and non-fatal SAEs will be listed by subject and tabulated by type 
of AE and treatment.
SAEs, non-serious AEs, AEs leading to study drug discontinuation, drug-related AEs
A subject with multiple AEs within a body system is only counted once towards the total of this 
body system and treatment.
Adverse event reporting for Clinical Trial Safety Disclosure (CTSD)
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables, 1) on 
treatment-emergent adverse events which are not serious adverse events with an incidence 
greater than X% and 2) on treatment-emergent serious adverse events and SAE suspected to be 
related to study treatment, will be provided by SOC and PT on the safety analysis set population. 
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.
CCI
 
 
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The summary will be done 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:

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.
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 of results
Boxplots to visualize trends in longitudinal safety data (vital signs, ECG evaluations and lab 
parameters) will be created. Mean and overlaying individual figures will be presented for 
selected parameters from vital signs, ECG evaluations and lab parameters.
Note: Any plots that are reported separately by treatment (i.e., plots with one graph per page 
for each parameter and treatment), will use the same y-axis scale for each treatment of a given 
parameter.
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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
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9
Statistical methods for biomarker data
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9.2
Descriptive analyses
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9.3
Graphical presentation of results
10
Reference list
1. Chen F (2011) The RANDOM statement and more: moving on with PROC MCMC. SAS
Global Forum Proceedings, p. 334-2011.
2. Fisch R, Jones I, Jones J, et al (2015) Bayesian Design of Proof-of-Concept Trials.
Therapeutic Innovation & Regulatory Science; 49. p. 155-162.
3. Fleischer AB, Dinehart S, Stough D, Plott RT. Safety and efficacy of a new extended-release
formulation of minocycline. Solodyn Phase, 2. Study Group, and Solodyn Phase, 3. Study
Group. Cutis 2006;78(4 Suppl):21-31.
4. Gold LS, Cruz A, Eichenfield L, et al (2010) Effective and safe combination therapy for
severe acne vulgaris: a randomized, vehicle-controlled, double-blind study of adapalene
0.1%-benzoyl peroxide 2.5% fixed-dose combination gel with doxycycline hyclate 100 mg.
Cutis p. 94-104.
5. Gsponer, T., Gerber, F., Bornkamp, B., Ohlssen, D., Vandemeulebroecke, M. and Schmidli,
H. (2014), A practical guide to Bayesian group sequential designs. Pharmaceut. Statist., 13:
71-80. doi: 10.1002/pst.1593
6. Lee JW, Yoo KH, Park KY, et al (2011) Effectiveness of conventional, low-dose and
intermittent oral isotretinoin in the treatment of acne: a randomized, controlled comparative
study. Br. J. Dermatol., 164: 1369-75.
7. Leyden J, Bergfeld W, Drake L, et al (2004) A systemic type I 5 alpha-reductase inhibitor
is ineffective in the treatment of acne vulgaris. J. Am. Acad. Dermatol., 50(3): 443-7.
8. U.S. Department of Health and Human Services, Food and Drug Administration, Center for
Drug Evaluation and Research (CDER), Acne Vulgaris: Establishing Effectiveness of
Drugs Intended for Treatment Guidance for Industry
9. European Medicines Agency (2021). Guidance on the Management of Clinical Trials during
the COVID-19 (Coronavirus) Pandemic
10. Food and Drug Administration (2021). Guidance on Conduct of Clinical Trials of Medical
Products during the COVID-19 Public Health Emergency: Guidance for Industry,
Investigators, and Institutional Review Boards
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