A Randomized, Two-arm, Placebo-controlled, Participant, Investigator and Sponsor-blinded, Proof-of-concept Study Investigating the Efficacy, Safety and Tolerability of QUC398 in Patients With Symptomatic Knee Osteoarthritis
Phase: PHASE2
Conditions: Osteoarthritis, Knee
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
Clinical Trial Protocol 
A randomized, two-arm, placebo-controlled, participant, 
investigator and sponsor-blinded, proof-of-concept study 
investigating the efficacy, safety and tolerability of QUC398 
in patients with symptomatic knee osteoarthritis 
Clinical Trial Protocol Number: CQUC398A12201 / NCT05462990
Version Number: v03 (Clean) 
Compound: QUC398 
Brief Title: A proof-of-concept study to examine QUC398 in participants with knee 
osteoarthritis 
Study Phase: IIa 
Sponsor Name: Novartis Pharma AG (or its affiliates outside the EEA), 
Lichtstrasse 35, 4056 Basel, Switzerland 
Regulatory Agency Identifier Numbers:  
EudraCT: 2021-002795, EU CT: 2023-509274-28, IND: 158529 
Content final Date: 28-Nov-2023 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 4.0 dated 15-Feb-2021 

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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 11 
Amendment 03 (November 2023) ..................................................................................... 15 
Amendment 02 (September 2022) ..................................................................................... 19 
Amendment 01 (June 2022) .............................................................................................. 21 
Protocol summary .............................................................................................................. 24 
1 
Introduction ....................................................................................................................... 28 
1.1 
Background ............................................................................................................ 28 
1.2 
Purpose .................................................................................................................. 30 
2 
Objectives, endpoints and estimands ................................................................................. 30 
2.1 
Primary estimands ................................................................................................. 33 
2.2 
Secondary estimands ............................................................................................. 34 
2.2.1 
First secondary estimand ....................................................................... 34 
2.2.2 
Second secondary estimand .................................................................. 35 
3 
Study design ...................................................................................................................... 36 
3.1 
Off-site procedures ................................................................................................ 38 
3.1.1 
Responsibility of Investigators .............................................................. 39 
3.1.2 
Responsibility of off-site healthcare professionals (OHPs) .................. 39 
3.1.3 
Telemedicine ......................................................................................... 39 
3.1.4 
Data flow ............................................................................................... 40 
4 
Rationale ............................................................................................................................ 40 
4.1 
Rationale for study design ..................................................................................... 40 
4.1.1 
Rationale for choice of background therapy ......................................... 41 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 41 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 42 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 43 
4.5 
Risks and benefits .................................................................................................. 43 
4.5.1 
Benefits ................................................................................................. 43 
4.5.2 
Risks associated with QUC398 ............................................................. 43 
4.5.3 
Hypothetical risks for QUC398 ............................................................ 44 
4.5.4 
Risks associated with basic pain medication ........................................ 45 
4.5.5 
SARS-CoV-2 risks ................................................................................ 45 

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4.5.6 
Risks associated with imaging procedures ............................................ 46 
4.5.7 
Blood sample volume ............................................................................ 46 
4.5.8 
Risks associated with off-site visits ...................................................... 46 
4.6 
Rationale for planned off-site procedures .............................................................. 47 
4.7 
Public Health Emergency mitigation procedures .................................................. 47 
5 
Study Population ............................................................................................................... 47 
5.1 
Inclusion criteria .................................................................................................... 48 
5.2 
Exclusion criteria ................................................................................................... 49 
6 
Study treatment and concomitant therapy ......................................................................... 52 
6.1 
Description of study treatment and treatment arms ............................................... 52 
6.1.1 
Investigational and control drugs .......................................................... 52 
6.1.2 
Additional study treatments .................................................................. 53 
6.1.3 
Treatment arms/group ........................................................................... 54 
6.2 
Other treatment(s) .................................................................................................. 55 
6.2.1 
Concomitant therapy ............................................................................. 55 
6.2.2 
Prohibited medication ........................................................................... 55 
6.2.3 
Rescue medication ................................................................................ 57 
6.2.4 
Restriction for study participants .......................................................... 58 
6.3 
Preparation and dispensation ................................................................................. 58 
6.3.1 
Handling of study treatment and other treatment .................................. 59 
6.3.2 
Instruction for prescribing and taking study treatment ......................... 60 
6.4 
Participant numbering, treatment assignment, randomization .............................. 60 
6.4.1 
Participant numbering ........................................................................... 60 
6.4.2 
Treatment assignment, randomization .................................................. 60 
6.5 
Treatment blinding ................................................................................................ 61 
6.6 
Dose escalation and dose modification.................................................................. 62 
6.7 
Additional treatment guidance ............................................................................... 62 
6.7.1 
Treatment compliance ........................................................................... 62 
6.7.2 
Recommended treatment of adverse events .......................................... 63 
6.7.3 
Emergency breaking of assigned treatment code .................................. 63 
7 
Informed consent procedures ............................................................................................ 64 
8 
Visit schedule and assessments ......................................................................................... 65 
8.1 
Screening ............................................................................................................... 72 
8.1.1 
Eligibility screening .............................................................................. 72 
8.1.2 
Information to be collected on screening failures ................................. 74 
8.2 
Participant demographics/other baseline characteristics ....................................... 74 

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8.3 
Efficacy .................................................................................................................. 74 
8.3.1 
Patient Reported Outcomes (PROs) ...................................................... 75 
8.3.2 
Knee Magnetic resonance imaging (MRI) ............................................ 76 
8.3.3 
Appropriateness of efficacy assessments .............................................. 78 
8.4 
Safety/Tolerability ................................................................................................. 78 
8.4.1 
Laboratory evaluations .......................................................................... 80 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 81 
8.4.3 
Echo-Doppler of thoracic and abdominal aorta .................................... 82 
8.4.4 
Pregnancy and assessments of fertility ................................................. 82 
8.4.5 
Appropriateness of safety measurements .............................................. 83 
8.5 
Additional assessments .......................................................................................... 83 
8.5.1 
 ............................................... 83 
8.5.2 
 .................................................................................. 85 
8.5.3 
 ............................................................................................ 85 
8.5.4 
Imaging ................................................................................................. 87 
8.5.5 
 .................................................................................... 87 
9 
Discontinuation and completion ........................................................................................ 87 
9.1 
Discontinuation from study treatment and from study .......................................... 87 
9.1.1 
Discontinuation from study treatment ................................................... 87 
9.1.2 
Discontinuation from study ................................................................... 88 
9.1.3 
Lost to follow-up ................................................................................... 89 
9.2 
Withdrawal of informed consent/Opposition to use data/biological samples ....... 89 
9.3 
Study stopping rules .............................................................................................. 90 
9.4 
Study completion and post-study treatment .......................................................... 90 
9.5 
Early study termination by the sponsor ................................................................. 90 
10 Safety monitoring, reporting and committees ................................................................... 91 
10.1 
Definition of adverse events and reporting requirements ...................................... 91 
10.1.1 
Adverse events ...................................................................................... 91 
10.1.2 
Serious adverse events .......................................................................... 93 
10.1.3 
SAE reporting........................................................................................ 94 
10.1.4 
Pregnancy reporting .............................................................................. 95 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 96 
10.2 
Additional Safety Monitoring ................................................................................ 96 
10.2.1 
Liver safety monitoring ......................................................................... 96 
10.2.2 
Renal safety monitoring ........................................................................ 97 
10.3 
Committees ............................................................................................................ 98 
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11 Data Collection and Database management ...................................................................... 98 
11.1 
Data collection ....................................................................................................... 98 
11.2 
Database management and quality control ............................................................ 98 
11.3 
Site monitoring ...................................................................................................... 99 
12 Data analysis and statistical methods ................................................................................ 99 
12.1 
Analysis sets .......................................................................................................... 99 
12.2 
Participant demographics and other baseline characteristics ............................... 100 
12.3 
Treatments ........................................................................................................... 100 
12.4 
Analysis supporting primary objectives .............................................................. 100 
12.4.1 
Definition of primary endpoint(s) ....................................................... 100 
12.4.2 
Statistical model, hypothesis, and method of analysis ........................ 100 
12.4.3 
Handling of intercurrent events of primary estimand ......................... 101 
12.4.4 
Handling of missing values not related to intercurrent event ............. 101 
12.4.5 
Sensitivity analyses ............................................................................. 101 
12.4.6 
Supplementary analysis ....................................................................... 101 
12.5 
Analysis supporting secondary objectives ........................................................... 101 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................. 101 
12.5.2 
Safety endpoints .................................................................................. 102 
12.5.3 
Patient reported outcomes ................................................................... 103 
12.6 
Analysis of exploratory endpoints ....................................................................... 103 
12.6.1 
.......................................................................................... 103 
12.6.2 
 ................................................................. 103 
12.6.3 
 .................................................................................. 103 
12.6.4 
 .................................................................................................... 104 
12.6.5 
................................................................................ 104 
12.7 
Interim analyses ................................................................................................... 104 
12.8 
Sample size calculation........................................................................................ 105 
12.8.1 
Primary endpoint(s) ............................................................................. 105 
13 Ethical considerations and administrative procedures .................................................... 105 
13.1 
Regulatory and ethical compliance ...................................................................... 105 
13.2 
Responsibilities of the investigator and IRB/IEC ................................................ 105 
13.2.1 
Data protection .................................................................................... 106 
13.2.2 
Data quality assurance ......................................................................... 106 
13.3 
Publication of study protocol and results............................................................. 106 
13.4 
Quality Control and Quality Assurance ............................................................... 107 
13.5 
Participant Engagement ....................................................................................... 107 
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14 Protocol adherence .......................................................................................................... 107 
14.1 
Protocol amendments........................................................................................... 107 
15 References ....................................................................................................................... 109 
16 Appendices ...................................................................................................................... 112 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs ....................... 112 
16.2 
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements ........................................................................................................ 113 
16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up .... 116 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 30 
Table 4-1 
Safety margins for human exposure after multiple dose 
administration on Day 29 (Day 36 for 300 mg weekly) in study 
MS200572-0003 vs NOAEL in preclinical species .............................. 42 
Table 6-1 
Investigational and control drug ............................................................ 53 
Table 6-2 
Additional study treatment .................................................................... 54 
Table 6-3 
Prohibited medication ........................................................................... 56 
Table 6-4 
Dose and treatment schedule ................................................................. 60 
Table 6-5 
Blinding and unblinding plan ................................................................ 62 
Table 8-1 
Assessment Schedule ............................................................................ 67 
Table 8-2 
Assessments and specifications............................................................. 78 
Table 8-3 
Laboratory evaluations .......................................................................... 80 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 96 
Table 16-1 
Liver event and laboratory trigger definitions .................................... 113 
Table 16-2 
Follow up requirements for liver laboratory triggers - ALT, AST, 
TBL ..................................................................................................... 113 
Table 16-3 
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia ............................................................................. 115 
List of figures 
Figure 3-1 
Study design .......................................................................................... 36 
Figure 8-1 
Timing of study procedures .................................................................. 81 
 

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List of abbreviations 
ACLT 
Anterior Cruciate Ligament Transection 
ACR 
American College of Rheumatology 
ADA 
Anti-Drug Antibodies 
ADAMTS-5 
A Disintegrin and Metalloproteinase with Thrombospondin Motifs-5 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AxMP 
Auxiliary Medicinal Product 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
 
 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
C2M 
Matrix Metalloproteinase Cleaved Neoepitope of Type II Collagen 
C3M 
Matrix Metalloproteinase Cleaved Neoepitope of Type III Collagen 
CK 
Creatine Kinase 
CLr 
Renal Clearance 
CMO&PS  
Chief Medical Office and Patient Safety 
COA 
Clinical Outcome Assessment 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CRPM 
matrix metalloproteinase cleaved C-reactive protein from synovia 
CSR 
Clinical study report 
CTC 
Common Terminology Criteria 
CTIS 
Clinical Trials Information System 
CTT 
Clinical Trial Team 
CTX-II 
C-terminal Cross-Linked Telopeptide of Type II Collagen 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
DDC 
Direct Data Capture 
DMM 
Destabilization of medical meniscus 
DMOAD 
Disease-Modifying Osteoarthritis Drug 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked Immunosorbent Assay 
eGFR 
Estimated Glomerular Filtration Rate 
EOS 
End of Study 
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EOT 
End of Treatment 
EOW 
Every Other Week 
EU-CTR 
European Union - Clinical Trials Regulation 
eSAE 
Electronic Serious Adverse Event 
eSource 
Electronic Source 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FIH 
First-in-Human 
FMA 
Femoral Medial Anterior Cartilage Subregion of the Knee 
FMC 
Femoral Medial Central Cartilage Subregion of the Knee 
FMP 
Femoral Medial Posterior Cartilage Subregion of the Knee 
FSH 
Follicle Stimulating Hormone 
GAG 
Glycosaminoglycans 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
Gamma-glutamyl Transferase 
 
 
GLDH 
Glutamate Dehydrogenase 
h 
Hour 
HBsAg 
Hepatitis B Virus Surface Antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HCVAb 
Hepatitis C Virus Antibodies 
HIV 
Human Immunodeficiency Virus 
HSCT 
Hematopoietic Stem Cell Transplant 
i.a.
Intra-articular 
i.v.
Intravenous 
IB 
Investigator's Brochure 
ICE 
Intercurrent Event 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
 
 
IMP 
Investigational Medicinal Product 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISR 
Injection Site Reaction 
IUD 
Intra-Uterine Device 
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IUS 
Intra-Uterine System 
KL 
Kellgren-Lawrence 
KOOS 
Knee Injury and Osteoarthritis Outcome Score 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Test 
LLOQ 
Lower Limit of Quantification 
LPLV 
Last Patient Last Visit 
MAD 
Multiple-Ascending Dose 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 
mJSN 
Medial Joint Space Narrowing 
mL 
Milliliter(s) 
MMP 
Matrix metalloproteinase 
MMRM 
mixed effect model for repeated measures 
 
 
MRI 
Magnetic Resonance Imaging 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NOAEL 
No Observed Adverse Effect Level 
NRS 
Numerical Rating Scale 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
OA 
Osteoarthritis 
OHP 
Off-site Healthcare Professional 
p.o. 
Oral(ly) 
PAS 
Pharmacokinetic Analysis Set 
PC 
Personal Computer 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamic(s) 
PGA 
Patient's Global Assessment 
PK 
Pharmacokinetic(s) 
PoC 
Proof of Concept 
PRO 
Patient Reported Outcomes 
Pro-C2 
Neoepitope generated at synthesis of collagen type II 
PT 
Prothrombin Time 
q4w 
Every 4 Weeks 
QMS  
Quality Management System 
QoL 
Quality of Life 
QTcF 
QT Interval Corrected by Fridericia’s Formula 
RD 
Recommended Dose 
RoW  
Rest of World 
RU 
Resource Utilization 
s.c. 
Subcutaneous 
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SAD 
Single-Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
TLR-2 
Toll Like Receptor 2 
ULN 
Upper Limit of Normal 
UTI 
Urinary Tract Infection 
 
 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 
WOMAC 
Western Ontario and McMaster Universities Arthritis Index 
WPI 
Widespread Pain Index 
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Glossary of terms 
Additional treatment 
Medicinal products that may be used during the clinical trial as 
described in the protocol, but not as an investigational medicinal 
product (e.g., any background therapy) 
Assessment 
A procedure used to generate data required by the study 
Auxiliary Medicinal 
Product (AxMP) 
Medicinal product used for the needs of a clinical trial as described in 
the protocol, but not as an investigational medicinal product (e.g., 
rescue medication, challenge agents, background treatment or 
medicinal products used to assess endpoints in the clinical trial). 
Concomitant therapy is not considered as AxMP. 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study participant  
Clinical Outcome 
Assessment (COA) 
A measure that describes or reflects how a participant feels, functions, 
or survives 
Clinical Trial Team 
A group of people responsible for the planning, execution and reporting 
of all clinical trial activities. Examples of team members include 
the Study Lead, Medical Monitor, Trial Statistician etc. 
Coded Data 
Personal Data which has been de-identified by the investigative center 
team by replacing personal identifiers with a code. 
Cohort 
A group of individuals who share a common exposure, experience or 
characteristic, or a group of individuals followed-up or traced over time 
Control drug 
A study drug (active or placebo) used as a comparator to reduce 
assessment bias, preserve blinding of investigational drug, assess 
internal study validity, and/or evaluate comparative effects of 
the investigational drug 
Discontinuation from 
study 
Point/time when the participant permanently stops receiving the study 
treatment and further protocol required assessments or follow-up, for 
any reason. No specific request is made to stop the use of 
their samples or data. 
Discontinuation from 
study treatment 
Point/time when the participant permanently stops receiving the study 
treatment for any reason (prior to the planned completion of study drug 
administration, if any). Participant agrees to the other protocol required 
assessments including follow-up. No specific request is made to stop 
the use of their samples or data. 
Dosage 
Dose of the study treatment given to the participant 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 source 
data/documents used at the point of care 
Electronic Source Direct 
Data Capture (eSource 
DDC) 
Any technology that allows the capture of clinical study source data 
electronically by investigator site staff at the point of care, into 
an electronic form that has been validated to capture clinical data. 
End of the clinical trial 
The end of the clinical trial is defined as the last visit of the last 
participant 
Enrollment 
Point/time of participant entry into the study at which informed consent 
must be obtained. The action of enrolling one or more participants 

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eSource (DDE) 
eSource Direct Data Entry (DDE) refers to the capture of clinical study 
data electronically, at the point of care. eSource Platform/Applications 
combines source documents and case report forms (eCRFs) into one 
application, allowing for the real time collection of clinical trial 
information to sponsors and other oversight authorities, as appropriate 
Estimand  
As defined in the ICH E9(R1) addendum, estimand is a precise 
description of the treatment effect reflecting the clinical question posed 
by the trial objective. It summarizes at a population-level what 
the outcomes would be in the same participants under different 
treatment conditions being compared. Attributes of an estimand include 
the population, variable (or endpoint) and treatment of interest, as well 
as the specification of how the remaining intercurrent events are 
addressed and a population-level summary for the variable. 
Hybrid Trial Design 
A trial model incorporating both onsite (traditional site based) and offsite 
(decentralized) elements within the same study design. 
Intercurrent events 
Events occurring after treatment initiation that affect either the 
interpretation or the existence of the measurements associated with 
the clinical question of interest. 
Investigational drug/ 
treatment 
The drug whose properties are being tested in the study 
Investigational Product/ 
Investigational Medicinal 
Product 
A pharmaceutical form of an active ingredient or placebo being tested 
or used as a reference (such as an active comparator) in a clinical trial, 
including a product with a marketing authorization when used or 
assembled (formulated or packaged) in a way different from the 
approved form, or when used for an unapproved indication, or when 
used to gain further information about an approved use. 
Investigational Medical 
Device 
Medical Device being assessed for safety or performance in a clinical 
investigation. This includes devices already on the market and being 
evaluated for new intended uses, new populations, new materials, or 
design changes 
Medication number 
A unique identifier on the label of medication kits 
Mis-randomized 
participants 
Mis-randomized participants are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study or the participant allocated to 
an invalid stratification factor 
Off-site 
Describes trial activities that are performed at remote location by an 
off-site healthcare professional, such as procedures performed at 
the participant's home. 
Off-site healthcare 
Professional (OHP) 
A qualified healthcare professional, such as include those used in 
the study e.g., Nurse, Phlebotomist, Physician, who performs certain 
protocol procedures for the participant in an off-site location such as 
a participant's home. 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study 
(i.e., concomitant or rescue therapy) 
Part  
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single 
dose part and a multiple dose part, or a part in participants with 
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Participant 
A trial participant (can be a healthy volunteer or a patient). "Participant" 
terminology is used in the protocol whereas term "Subject" is used in 
data collection 
Participant number 
A unique number assigned to each participant upon signing the 
informed consent. This number is the definitive, unique identifier for 
the participant and should be used to identify the participant throughout 
the study for all data collected, sample labels, etc. 
Patient-Reported 
Outcome (PRO) 
A measurement based on a report that comes directly from the patient 
about the status of a participant's health condition without amendment 
or interpretation of the patient's report by a clinician or anyone else 
Period 
The subdivisions of the trial design (e.g., Screening, Treatment, 
Follow-up) which are described in the Protocol. Periods define the study 
phases and will be used in clinical trial database setup and eventually in 
analysis 
Personal data 
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data 
includes participant identifier information, study information and 
biological samples. 
Randomization 
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine 
the assignments in order to reduce bias. 
Randomization number 
A unique identifier assigned to each randomized participant 
Re-screening 
If a participant fails the initial screening and is considered as a Screen 
Failure, he/she can be invited once for a new Screening visit after 
medical judgment and as specified by the protocol 
Run-in Failure 
A participant who is screened but not randomized/treated after 
the run-in period (where run-in period requires adjustment to 
participant’s intervention or other treatment) 
Screen Failure 
A participant who did not meet one or more criteria that were required 
for participation in the study 
Source Data/Document 
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, 
a spreadsheet or even hard-coded data, such as paper or eSource 
Start of the clinical trial 
The start of the clinical trial is defined as the signature of the informed 
consent by the first participant 
Study treatment 
Any drug or combination of drugs or intervention administered to 
the study participants as part of the required study procedures; includes 
investigational drug(s), control(s) or background therapy 
Telemedicine 
Electronic information and telecommunications technologies (both 
video-based and audio-only) to facilitate the delivery of health care and 
health related education where participant and Investigator and site 
personnel are not in the same location. 
Treatment arm/group  
A treatment arm/group defines the dose and regimen or 
the combination, and may consist of 1 or more cohorts. 

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Treatment of interest 
The treatment of interest and, as appropriate, the alternative treatment 
to which comparison will be made. These might be individual 
interventions, combinations of interventions administered concurrently, 
e.g., as add-on to standard of care, or might consist of an overall 
regimen involving a complex sequence of interventions. This is the 
treatment of interest used in describing the related clinical question of 
interest, which might or might not be the same as the study treatment. 
Variable (or endpoint) 
The variable (or endpoint) to be obtained for each participant that is 
required to address the clinical question. The specification of 
the variable might include whether the participant experiences 
an intercurrent event. 
Withdrawal of study 
consent (WoC) / 
Opposition to use of data 
/biological samples 
Withdrawal of consent from the study occurs when the participant 
explicitly requests to stop use of their data and biological samples 
(opposition to use data and biological samples) AND no longer wishes 
to receive study treatment, AND does not agree to further protocol 
required assessments. This request should be in writing (depending on 
local regulations) and recorded in the source documentation. 
Opposition to use data/biological samples occurs in the countries where 
collection and processing of personal data is justified by a different legal 
reason than consent. 

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Amendment 03 (November 2023) 
Amendment rationale 
This amendment is generated to implement learnings from ongoing and previous trials in 
osteoarthritis (OA), which are expected to facilitate the trial processes and reduce the burden to 
patients and sites. 
Additional changes were implemented
 
 (i.e., clarification of exclusion 
criterion 12 for estimated glomerular filtration rate, clarification for rescue medication use 
taking packaging insert and investigator instructions into account). 
The sponsor is making necessary changes to be prepared for the upcoming and required 
transition of this study to the EU Clinical Trials Regulation (CTR) 536/2014. 
Mandatory elements to become compliant with the EU CTR are added, including sponsor 
information on the cover page, and definition and safety reporting of auxiliary medicinal 
products (AxMPs). The specific EU CTR requirements (e.g., safety reporting requirements for 
AxMPs) will apply once this trial has been transitioned to the EU CTR. 
 
Therefore, joint space width 
measurement for assessing eligibility is changed to semiquantitative joint space narrowing 
(JSN). The target JSN 1-2 covers the previous joint space width range, is accepted in the field 
as a marker for moderate OA and ensures the presence of cartilage despite detectable 
degeneration. The change is also relevant for alignment with other Novartis OA programs. 
Additional changes are included to remove inconsistencies, provide clarifications, and improve 
wording. 
These modifications are considered substantial. 
Changes to the protocol 
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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in 
this protocol amendment. 

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Amendment 02 (September 2022) 
Amendment rationale 
The main purpose of this global protocol amendment is to add additional safety monitoring 
measures (i.e., transthoracic ultrasonographic evaluations of the aorta and a corresponding 
exclusion criterion). This is in relation to the 
 
. Additional 
changes are included to remove inconsistencies, provide clarifications, and improve wording. 
These modifications are considered substantial. This amendment is issued before the study start. 
Changes to the protocol 
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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in 
this protocol amendment. 

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Amendment 01 (June 2022) 
Amendment rationale 
The main purpose of this global protocol amendment is to address feedback from Health 
Authorities (HA) and Ethics Committees (EC) received during the review of the protocol 
including the clarification of the eligibility criteria for patients with an increased cardiovascular 
risk as well as those with renal impairment and/or liver disease, and the addition of safety 
assessments (e.g., injection site exam, patient monitoring post-injection). Additional changes 
are included to remove inconsistencies, provide clarifications, and improve wording. 
These modifications are considered substantial. This amendment is issued before the study start. 
Changes to the protocol 
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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in 
this protocol amendment. 
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Protocol summary 
Protocol number 
CQUC398A12201 
Full Title 
A randomized, two-arm, placebo-controlled, participant, investigator and 
sponsor-blinded, proof-of-concept study investigating the efficacy, safety and 
tolerability of QUC398 in patients with symptomatic knee osteoarthritis. 
Brief title 
A proof-of-concept study to examine QUC398 in participants with knee OA. 
Sponsor and 
Clinical Phase 
Novartis. Phase IIa. 
Investigation type 
Drug. 
Study type 
Interventional. 
Purpose 
This is a phase IIa study to establish the effect of QUC398 on pain and 
cartilage preservation in participants with symptomatic knee OA. 
Primary 
Objective(s)  
To assess the efficacy of q4w s.c. injections of QUC398 300 mg vs placebo 
in relieving OA pain in the target knee at week 12. 
Secondary 
Objectives 
To assess the efficacy of q4w s.c. injections of QUC398 300 mg vs placebo 
in preservation of cartilage in the medial compartment of the target knee at 
Week 52. 
To assess the efficacy of q4w s.c. injections of QUC398 300 mg vs placebo 
in relieving OA pain in the target knee over time. 
To assess the efficacy of q4w s.c. injections of QUC398 300 mg vs placebo 
in relieving additional clinical symptoms and improving function in the target 
knee over time. 
To assess the safety and tolerability of q4w s.c. injections of QUC398 
300 mg vs placebo. 
Study design 
This is a non-confirmatory study using a randomized, placebo-controlled, 
parallel-group, participant, investigator and sponsor-blinded design. 
Rationale 
There is a strong unmet need for a disease-modifying osteoarthritis drug 
(DMOAD) that can slow or halt OA disease progression. ADAMTS-5 is 
the main enzyme responsible for the degradation of aggrecan in the 
cartilage. Inhibition of ADAMTS-5 has the potential to reduce cartilage 
degradation in OA and to induce symptomatic relief by preventing the 
generation of aggrecan fragments which act as pain signal triggers. 
 
 
The benefits on pain and structure of the inhibition of ADAMTS-5 have been 
assessed in pre-clinical studies, and safety has been demonstrated in 
phase 1 clinical trials, but its role as a therapeutic target for patients with OA 
is still to be defined. 
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Study population 
The study population consists of male and female adult patients between 40 
and 80 years of age with symptomatic, mild to severe radiographic knee OA 
(Kellgren-Lawrence [KL] grade 2-4). Approximately 98 participants are 
planned to be randomized in the study. 
Key Inclusion 
criteria 
• 
Weight ≥ 50 kg and a body mass index (BMI) between 18 -35 kg/m2, at 
Screening 1 
• 
Kellgren-Lawrence grade 2 to 4 in the tibio-femoral compartment in 
the target knee confirmed by radiography in standing weight-bearing 
fixed flexion position and posterior-anterior view, at Screening 1 
• 
Radiographic medial joint space narrowing (mJSN) 1-2 within the medial 
tibio-femoral compartment of the target knee, confirmed by Xray at 
Screening 1 
• 
Symptomatic OA with moderate to severe pain (corresponding to Pain 
NRS ≥ 5 to ≤ 9) in the target knee for the majority of days in the last 
3 months prior to Screening 1, as per participant’s judgement 
• 
Symptomatic OA with moderate to severe pain (corresponding to Pain 
NRS ≥ 5 to ≤ 9) in the target knee at Screening 1 and 2. 
• 
Moderate to severe OA pain (corresponding to Pain NRS ≥5 to ≤9) in 
the target knee during the last 7 days prior to Screening 3, confirmed by: 
• 
Completed pain diary for at least 6 of the last 7 days prior to 
Screening 3, AND 
• 
Diary reported Pain NRS ≥5 to ≤9 for at least 6 of the last 7 days 
prior to Screening 3 
• 
KOOS pain subscale ≤ 60 in the target knee at Screening 1, Screening 2, 
and Screening 3 
Key Exclusion 
criteria 
• 
Painful ipsilateral hip OA defined as a Pain NRS ≥3 on the majority of 
days in the last 3 months prior to Screening 1, as reported by the patient. 
• 
Symptomatic, patello-femoral pain in the target knee as per investigator’s 
examination at Screening 1. 
• 
Severe malalignment > 7.5º in the target knee (either varus or valgus), 
measured using standardized knee X-ray at Screening 1. 
• 
Patient unable or unwilling to undergo MRI or presenting absolute 
contraindications to MRI. 
• 
Previous exposure to any ADAMTS-5 drug, including QUC398. 
• 
History or current diagnosis of relevant cardiovascular diseases and 
ECG abnormalities. 
Study treatment 
QUC398 150 mg/mL, solution for s.c. injection (1 mL). 2 injections will be 
applied per dose to complete the 300mg. 
Placebo 0 mg/mL, solution for s.c. injection (1 mL). 2 injections will be applied 
per dose to ensure blinding. 

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Efficacy 
assessments 
Change from baseline in Knee Injury and Osteoarthritis Outcome Score 
(KOOS) Pain sub-scale at Week 12. 
Change from baseline in cartilage volume of the knee index region at 
Week 52, as determined from the automated segmentation of 3D-MRI scans. 
Change from baseline in KOOS Pain subscale at Weeks 1 (Day 5), 4, 8, 12, 
16, 20, 24, 28, 32, 36, 40, 44, 48, and 52. 
Change from baseline in pain assessed by a Pain Numerical Rating Scale 
(NRS) at Weeks 1 (Day 5), 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 
48, and 52. 
Change from baseline in Total KOOS at Weeks 1 (Day 5), 4, 8, 12, 16, 20, 
24, 28, 32, 36, 40, 44, 48, and 52. 
Change from baseline in KOOS subscales: Other symptoms, Function in 
daily living, Function in sport and recreation, and Knee related quality of life 
at Weeks 1 (Day 5), 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52. 
Change from baseline in Patient’s Global Assessment (PGA) as assessed by 
NRS at Weeks 1 (Day 5), 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52. 
Key safety 
assessment 
Systemic and local Treatment-Emergent Adverse Events (TEAEs) and 
Serious TEAEs. 
Electrocardiogram parameters (ECGs). 
Vital signs (Pulse, blood pressure [BP], temperature). 
Laboratory tests (Hematology, blood chemistry, coagulation, 
 and 
urinalysis). 
Other selected 
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Data analysis 
The primary efficacy variable, change from baseline in KOOS pain subscale, 
will be analyzed using a mixed effect model for repeated measures (MMRM). 
The model will be fit to all evaluable data collected from the randomized 
participants through the Week 12. The model will include baseline, treatment, 
time-point, treatment by time-points as fixed effects and participant as 
random effect. An unstructured covariance will be assumed;
 
 
 A two-sided 90% confidence 
interval for the treatment effect (i.e., QUC398 minus placebo) at Week 12 will 
be reported. 
Key words 
Knee osteoarthritis, articular cartilage, ADAMTS-5, pain, magnetic resonance 
imaging, ARGS, PRO, biosensors. 
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1 
Introduction 
1.1 
Background 
Osteoarthritis (OA), the most common joint disorder in adults, is a serious, chronic, progressive 
joint disease with no known cure, and has been associated with an increased risk of premature 
mortality (Hunter, Bierma-Zeinstra 2019; OARSI 2016; Kluzek et al 2016). OA manifests 
clinically with joint pain, swelling and stiffness in the affected joint that can lead to activity 
limitations, and it is also associated with sleep interruption, fatigue, depression, anxiety, loss of 
independence and reduced quality of life (OARSI 2016). The lifetime risk of developing 
symptomatic knee and hip OA is 45% and 25%, respectively. OA accounts for over 90% of 
knee and hip arthroplasties (Culliford et al 2012). 
All presently available pharmacologic therapies for OA provide symptomatic relief by 
transiently reducing pain, but do not delay structural progression of OA (Bannuru et al 2019; 
Kolasinski et al 2020). In addition, long-term use of these therapies is associated with  
serious adverse effects, including fall-related bone fractures and substance dependence  
and / or abuse in patients receiving opioids, and cardiovascular risk and upper  
gastrointestinal bleeding in patients receiving nonsteroidal anti-inflammatory drugs (NSAIDs)  
(Fernandes et al 2013; McAlindon et al 2014; Nissen et al 2016; Chan et al 2017;  
Solomon et al 2017; Kolasinski et al 2020). 
Total joint replacement surgery is considered when adequate attempts of symptomatic 
pharmacologic therapies fail (Bannuru et al 2019; Kolasinski et al 2020). However, not all 
patients are satisfied with the result or benefit from joint replacement surgery 
(Hawker et al 2013), and in younger patients especially, limitations of physical activity imposed 
by artificial joints are undesirable. 
Therefore, there is a strong unmet need for a disease-modifying osteoarthritis drug (DMOAD) 
that can slow or halt OA disease progression by inhibiting structural deterioration, and  
improve symptoms. Although many putative agents have been investigated, no pharmaceutical 
agent has been approved for clinical use as a DMOAD (Tonge et al 2014; Karsdal et al 2016; 
Oo et al 2018; Alcaraz et al 2019). 
$GLVLQWHJULQDQGPHWDOORSURWHLQDVHZLWKWKURPERVSRQGLQPRWLIVဩ$'$076-5) is the main 
enzyme responsible for aggrecan degradation in cartilage (Stanton et al 2005), which is a 
hallmark of OA. Further cleavage of fragmented aggrecan by matrix metalloproteinases (MMPs) 
releases a 32-amino acid fragment which is a Toll-Like Receptor 2 (TLR-2) ligand. 
This fragment of aggrecan activates TLR-2 receptors, exacerbating pain in the OA joint 
(Lees et al 2015). Therefore, inhibition of aggrecan fragment generation by ADAMTS-5 has 
the potential to reduce cartilage degeneration and pain (Miller et al 2016). 
 
 
 
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QUC398 has been extensively evaluated in in vitro and in vivo studies. The pharmacological 
activity of QUC398 has been evaluated in in vivo studies with the cynomolgus monkey, mouse, 
and rat species. Results from these studies have shown that QUC398 is a potent inhibitor of 
ADAMTS-5 and is effective at preventing the generation of aggrecan fragments 
(glycosaminoglycans [GAG], ARGS, an amino-terminal neoepitope of aggrecan) in bovine and 
human explants. 
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1.2 
Purpose 
This is a phase IIa proof-of-concept (POC) study to establish the effect of QUC398 on pain and 
cartilage preservation, in patients with symptomatic knee OA. While the benefits on pain and 
structure of the inhibition of ADAMTS-5 have been demonstrated in pre-clinical studies 
(Glasson et al 2005; Miller et al 2016), its role as a therapeutic target for patients with OA is 
still to be defined. 
The effect of QUC398 on pain in the target knee of patients with symptomatic knee OA will be 
evaluated after 12 weeks of treatment, and the effect on preservation of cartilage volume in 
the target knee after 52 weeks of treatment. 
2 
Objectives, endpoints and estimands 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To assess the efficacy of q4w s.c. 
injections of QUC398 300 mg vs 
placebo in relieving OA pain in the 
target knee 
• 
Change from baseline in Knee Injury and 
Osteoarthritis Outcome Score (KOOS) Pain 
sub-scale at Week 12 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To assess the efficacy of q4w s.c. 
injections of QUC398 300 mg vs 
placebo in preservation of cartilage in 
the medial compartment of the target 
knee 
• 
Change from baseline in cartilage volume of the 
knee index region at Week 52, as determined 
from the automated segmentation of 3D-MRI 
scans 
• 
To assess the efficacy of q4w s.c. 
injections of QUC398 300 mg vs 
placebo in relieving OA pain in the 
target knee over time 
• 
Change from baseline in KOOS Pain subscale at 
Weeks 1 (Day 5), 4, 8, 12, 16, 20, 24, 28, 32, 36, 
40, 44, 48, and 52 
• 
Change from baseline in pain assessed by a Pain 
Numerical Rating Scale (NRS) at Weeks 1 
(Day 5), 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 
48, and 52 
• 
To assess the efficacy of q4w s.c. 
injections of QUC398 300 mg vs 
placebo in relieving clinical symptoms 
and improving function in the target 
knee over time 
• 
Change from baseline in Total KOOS at Weeks 1 
(Day 5), 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 
48, and 52 
• 
Change from baseline in KOOS subscales: Other 
symptoms, Function in daily living, Function in 
sport and recreation, and Knee related quality of 
life at Weeks 1 (Day 5), 4, 8, 12, 16, 20, 
24, 28, 32, 36, 40, 44, 48, and 52 
• 
Change from baseline in Patient’s Global 
Assessment (PGA) as assessed by NRS 
at Weeks 1 (Day 5), 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44, 48, and 52 

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Objective(s) 
Endpoint(s) 
x 
To assess the safety and tolerability of 
q4w s.c. injections of QUC398 300 mg 
vs placebo  
x 
Systemic and local Treatment-Emergent Adverse 
Events (TEAEs) and Serious TEAEs 
Electrocardiogram parameters (ECGs) 
Vital signs (Pulse, blood pressure [BP], 
temperature) 
x 
Laboratory tests (Hematology, blood chemistry, 
coagulation and urinalysis) 
x 
Echo-Doppler of thoracic and abdominal aorta 
Exploratory objective(s) 
Endpoint(s) for exploratory objective(s) 
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Objective(s) 
Endpoint(s) 
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Objective(s) 
Endpoint(s) 
2.1 
Primary estimands 
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during trial conduct which could impact the interpretation of the trial results 
(e.g., premature discontinuation of treatment). 
The primary clinical question of interest is: What is the effect of QUC398 treatment versus 
placebo on change from baseline at week 12 in pain intensity in participants with symptomatic 
knee OA? 
The justification for the primary estimand is that it will capture the effect of the study drug, 
the effect of additional basic pain medication, and the use of rescue medications as per protocol. 
The primary estimand is described by the following attributes: 
1. Population: participants suffering from symptomatic knee OA. Further details about 
the population are provided in Section 5. 
2. Endpoint: efficacy is to be measured using the change from baseline to Week 12 of 
the double-blind study period in the KOOS pain subscale score. 
3. Treatment of interest: the randomized treatments (the investigational 
treatment QUC398 or the control treatment) plus, if needed, intake of the allowed basic 
pain medication and the use of rescue medication outside of the 48 hours window prior to 
a visit. Further details about the investigational treatment and control treatment are 
provided in Section 6. 
4. Identification of possible Intercurrent Events (ICEs): 
x At least one dose administration missed before Week 12 
x Use of rescue medication within the 48 hours prior to an assessment, or for more than 
three days in the seven days leading up to an assessment (assessment day not 
included), 
x Unforeseen use of prohibited medication 
5. Summary measure: the difference between treatment groups in the mean changes from 
baseline to Week 12 of the double-blind study period in KOOS pain subscale score. 
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Handling of possible ICEs: 
All ICEs will be handled by a hypothetical strategy to estimate what the treatment effect would 
have been at Week 12 if all participants adhered to the initially randomized treatment through 
that time point. In the case of ICEs such as missing at least one dose administration or use of 
prohibited medication that would require permanent discontinuation, the assessments collected 
post-ICE occurrence will not be evaluated for the purposes of this estimand (see Section 12.4.3 
for the imputation method). For ICEs such as use of rescue medication within the 48 hours prior 
to an assessment, or for more than three days in the seven days leading to an assessment, or use 
of prohibited medication not leading to study treatment discontinuation, only the assessment 
following immediately this ICE will not be evaluated for the purposes of this estimand (see 
Section 12.4.3 for the imputation method). Although data post-ICEs are not required for 
the primary estimand, these assessments will be collected for estimation of secondary and/or 
supportive estimands. 
2.2 
Secondary estimands 
There are three secondary objectives in relation to efficacy (Table 2-1). Based on the type of 
endpoint and time of evaluation they can be split into two overall clinical questions of interest: 
• the effect of QUC398 versus placebo in preserving of cartilage in the medial compartment 
of the target knee, measured by the change in volume of the knee index region at week 52 
(MRI) 
• the effect of QUC398 vs placebo over time (Weeks 1 (Day 5), 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44, 48, and 52) in relieving OA pain, clinical symptoms and function in the target 
knee (PRO) 
Given the difference in impact of rescue medication on the PRO endpoints and the structure 
endpoints, two secondary estimands are considered. 
2.2.1 
First secondary estimand 
The justification for the first of the secondary estimands of cartilage preservation is that it will 
capture the effect of the study drug, as it applies to the objective related with difference between 
QUC398 and placebo in change in volume of the knee index region at Week 52. 
The first of the secondary estimands is described by the following attributes: 
1. Population: participants suffering from symptomatic knee OA. 
2. Endpoint: efficacy is to be measured using the change from baseline to Week 52 in 
cartilage volume of the knee index region. 
3. Treatment of interest: the randomized treatment (the investigational treatment QUC398 or 
the control treatment) 
4. Identification of possible ICEs: 
• At least two missed dose administrations 
• Unforeseen use of prohibited medication that would require permanent treatment 
discontinuation (i.e., corticosteroids, biologics) 

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5. Summary measure: the difference between treatment groups in the mean changes from 
baseline to Week 52 in cartilage volume. 
2.2.2 
Second secondary estimand 
The justification for the second of the secondary estimands of relieving OA pain, clinical 
symptoms and function in the target knee is that it will capture the effect of the study drug, 
and the effect of additional basic pain medication, and the use of rescue medications as per 
protocol. 
The second of the secondary estimand is described by the following attributes: 
1. Population: participants suffering from symptomatic knee OA. 
2. Endpoint: efficacy is to be measured using the change from baseline to Weeks 1 (Day 5) 
4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 for the corresponding assessment tool 
and method. 
3. Treatment of interest: the randomized treatment (the investigational treatment QUC398 or 
the control treatment) plus, if needed, intake of the allowed basic pain medication usage 
and the use of rescue medication outside of the 48 hours window prior to a visit. 
4. Identification of possible ICEs: 
• First time a dose administration is missed 
• At least two missed dose administrations 
• Use of rescue medication within 48 hours of a visit or for more than three days in 
the seven days prior to the visit/assessment 
• Use of prohibited medication (for which rescheduling is not allowed as per Table 6-3) 
(except live or live-attenuated vaccines) 
• Prohibited pain medication as per Table 6-3 (i.e., diacetylrhein, centrally acting 
analgesics, acetylsalicylic acid >325 mg/day, paracetamol/acetomionophen  
>3000mg/day, opioids, or systemic NSAIDs that would have required visit 
rescheduling, if used within 48 hours prior to a visit/assessment 
5. Summary measure: the difference between treatment groups in the mean changes from 
baseline to Weeks 1 (Day 5) 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 in the 
scores collected according to the corresponding tool and method. 
All ICEs for both secondary estimands will be handled by a hypothetical strategy to estimate 
what the treatment effect would have been at time point considered if all patients adhered to the 
initially randomized treatment through that time point. 
The data necessary for this estimand is the observed data while adhering to the initial 
randomized treatment. Therefore, the data collected after an ICEs such as the second missed 
dose administration or use of prohibited medication that would have required permanent 
discontinuation from study treatment will not be evaluated for the purposes of this estimand. 
For ICEs such as the first missed dose administration and the use of rescue medication within 
48 hours prior to an assessment, or for more than three days within seven days prior to 
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with the assessment immediately following that ICE will not be evaluated for the purposes of 
this estimand. 
3 
Study design 
Figure 3-1 
Study design 
 
This is a non-confirmatory study using a randomized, two-treatment arm, parallel-group, 
participant, investigator and sponsor-blinded, placebo-controlled design, with the purpose of 
investigating the efficacy, safety and tolerability of s.c. injections of QUC398 300 mg vs 
placebo every 4 weeks (q4w), in approximately 98 patients with symptomatic knee OA. 
The study consists of a screening period of up to approximately 6 weeks, used to assess 
eligibility and to taper participants off-prohibited medications. Between Day -4 to -1 visit, 
eligible participants will be randomized to one of the treatment arms. On Day 1 randomized 
participants will enter the treatment period, during which they will receive q4w s.c. injections 
of QUC398 300 mg or placebo. The last study treatment administration will occur at Week 48 
and the end of treatment (EOT) visit will occur 4 weeks later, at Week 52. An end of study 
(EOS) visit will occur 8 weeks after the EOT visit, at Week 60. The total study duration from 
screening to EOS is expected to be a maximum of 66 weeks. 
The primary analysis will be performed when all participants have reached Week 12, in order 
to assess the primary endpoint (KOOS pain at Week 12). 
Baseline: In this study, baseline is defined for all the variables except for MRI as the values 
obtained at Day 1 before the first dose of the study drug. Regarding MRI, baseline is defined as 
the scan performed between Day 1 and Day 10. 

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Screening period 
The screening period consists of 3 visits as listed in the assessment schedule (Table 8-1). 
Screening 1: Following the signing of the informed consent, participants will undergo 
assessments to confirm their eligibility. The required assessments may be conducted over 
several days if it is in the best interest of the participants, or for logistical reasons. X-ray will 
be performed in the target knee and sent for central assessment by an independent reviewer, to 
assess participant’s eligibility. The order of assessments that should be followed to minimize 
participant burden is described in Section 8.1. Participants treated with prohibited concomitant 
medications will initiate a washout period at Screening 1 (see Table 6-3). Screening 1 may be 
scheduled up to 40 calendar days prior to Day 1 but should ideally occur as close as possible 
prior to Day 1. 
Screening 2: It should be scheduled between 20 and 9 calendar days prior to Day 1. 
Participants will go to the clinical site for pain assessment and review of the results of the 
Screening 1 assessments. If the participants are still eligible, they will be instructed to complete 
a pain diary every day from this visit until the Week 12 visit, and to wear the 
 sensor 
during daytime from this visit until the Week 4 visit. Participants will be requested to undergo 
Echo-Doppler of thoracic and abdominal aorta at Screening 2 or between Screening 2 and 
Screening 3. 
Screening 3 (phone call): Eligibility will be re-assessed based on the results of the pain diary 
and KOOS pain of 7 days prior to the phone call, and on the results of the Echo-Doppler of 
thoracic and abdominal aorta. The investigator may schedule the call between Day -4 and 
Day -1, allowing the participant to complete at least 7 days of the pain diary and the KOOS pain 
questionnaire. If eligibility is confirmed, the participant will be randomized to one of 
the treatment arms. 
Treatment period 
The treatment period will consist of 15 visits: 
x Treatment initiation visit on Day 1: first study treatment administration. 
x Participants will have on-site assessments on Day 1, Day 5, Week 4, Week 8, and 
Week 12, as outlined in the assessment schedule. 
x After Week 12, participants may have the possibility to perform some visits in an off-site 
setting if allowed by local legislation and if feasible based on local capabilities: 
x On-site visits: Week 28 (including a knee MRI) and Week 40; 
x On-site or off-site visits (as applicable): Weeks 16, 20, 24, 32, 36, 44, 48. Off-site 
visits will include s.c. administration of QUC398 300 mg or placebo, as well as pain 
assessment with PROs and blood / urine sampling according to the Assessment 
Schedule. 
x An on-site EOT visit will occur at Week 52, i.e., 4 weeks after the last study treatment 
administration, and will include a knee MRI. 
During the treatment period, participants will undergo efficacy, safety, PK and PD assessments 
as outlined in the assessment schedule (Table 8-1). 
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Follow-up period 
Participants will be followed up for 8 weeks after the EOT visit: 
• An optional visit will occur at Week 56, during which blood samples will be taken for PK 
and PD assessment. Participants may have the possibility to perform this visit in a remote 
setting, if allowed by local legislation and feasible based on local capabilities. 
• An on-site EOS visit will then occur at Week 60, i.e., 8 weeks after the EOT visit. 
Assessments will be performed as listed in the assessment schedule (Table 8-1) 
SARS-CoV-2 
To mitigate potential SARS-CoV-2 infections among participants, guidance and requirements 
provided by the local regulatory authorities or local site-specific SOPs will be followed 
(e.g., participants may be screened for SARS-CoV-2 by polymerase chain reaction (PCR) or 
comparable approved methodology prior to admission at the study/hospital site for any 
overnight stays following local site-specific SOPs). 
If a COVID-19 vaccine is available, vaccination of trial participants with non-live vaccines will 
be permitted during the study duration, as described in Section 6.2.1. 
3.1 
Off-site procedures 
At the investigator’s direction and based on benefit-risk considerations of the participant’s 
clinical condition, qualifying participants may be offered the option to have certain clinical trial 
procedures performed at an off-site location, as defined in Section 8. A hybrid model is planned 
for this study incorporating both on-site and off-site visits. The off-site procedures will be 
utilized in certain countries and sites as determined by protocol needs and based on national 
and local/site regulations. Participants have the option of participating in one or more off-site 
visits, based on their preference and the investigator’s discretion. 
One or more of the following elements may be implemented to support off-site visits where 
allowed by national and local regulations: 
• Telemedicine 
• Off-site healthcare professionals (OHP) 
• Direct-to-patient shipment of study supplies 
• Direct-to-patient shipment of study treatment (refer to Section 6) 
• Electronic Source (eSource) Direct Data Capture (DDC) 
Procedures for off-site visits utilizing the above listed elements are further detailed in 
the Operational Manual for study CQUC398A12201. 

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3.1.1 
Responsibility of Investigators 
Procedures that are performed off-site remain under the oversight of the investigator, who 
retains accountability for the conduct of all safety and efficacy assessments delegated to an 
OHP, and will ensure the rights, safety and wellbeing of participants. This includes the 
following (but not limited to): 
• The identification, management and reporting of AEs and SAEs are performed in 
accordance with the protocol and applicable regulations 
• OHPs have appropriate qualifications, training, and experience to successfully conduct 
off-site procedures 
• Source data collected off-site are reviewed and evaluated in a timely manner 
• The investigator or delegate is available to be contacted by the OHP if any issues or 
concerns are noted during an off-site visit 
• Where relevant, the investigator or delegate will be present via telemedicine for a portion 
of the off-site visit to support the physical examination 
3.1.2 
Responsibility of off-site healthcare professionals (OHPs) 
OHPs must have the required qualifications, training, and experience to conduct off-site 
assessments. OHPs are responsible to conduct delegated assessments and collect relevant data 
at off-site visits in accordance with the clinical trial protocol, International Conference for 
Harmonization (ICH) Good Clinical Practice (GCP) guidelines, and national and local 
regulations and guidelines. 
The OHPs will be provided by a third-party vendor sourced by Novartis. Where a site wishes 
to use OHPs that are not provided by Novartis this must be agreed with Novartis before use. 
Any issues or safety concerns identified by the OHP will be promptly communicated to the 
investigator or delegate according to a pre-defined communication plan. 
3.1.3 
Telemedicine 
The sponsor has qualified and contracted a third-party vendor to provide telemedicine platform 
technology for this study. The selected platform is a validated system complying with relevant 
ICH E6 GCP guidelines. Trial participants can interact with site personnel using online 
communication tools built into the platform, enabling the following capabilities: 
• Secure videoconferencing which allows the patient, OHP and site personnel to be 
connected 
• Reminders to be automatically sent to participants (e.g., visit or dosing reminders) 
• eSource Direct Data Capture (DDC) (see Section 3.1.4) 

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3.1.4 
Data flow 
The OHPs will enter data at off-site visits into electronic source documentation forms contained 
in an eSource DDC platform, which has been validated for use in clinical research. Where paper 
source documentation exists, images of documentation will be uploaded electronically into the 
same platform as certified copies, and the original documentation will then be sent to the trial 
site. 
Data contained in the platform are available to site and sponsor staff based on role-based access 
and permissions and will be stored in a robust and secure cloud-based back-end environment. 
Only sponsor staff who are responsible for field monitoring activities will have access to the 
source data, which may include some personally identifiable information, consistent with the 
access that is provided to a field monitor in a traditional onsite clinical trial model. 
Relevant data in the eSource DDC platform may be manually transcribed by site staff into the 
study EDC system. Alternatively, the platform allows for configuration that enables data to be 
automatically exported into the study EDC system. 
Certified copies of data in the eSource DDC platform will be provided to investigator and/or 
site personnel, and promptly and regularly uploaded into the participant’s medical records, 
according to local guidelines. 
Investigators will have continuous, near real time access to this study and all participant records 
within this study in the eSource DDC platform, with the ability to add, edit, review and sign 
forms within participant records. 
The platform maintains a secure, GCP-compliant audit trail and uses measures such as 
encryption and access controls to ensure that data privacy and security is maintained. 
Additional details will be provided in the Operational Manual for study CQUC398A12201. 
4 
Rationale 
4.1 
Rationale for study design 
The design of this study addresses the primary objective of assessing the ability of QUC398 to 
alleviate pain in patients with symptomatic knee OA, and the secondary objective of evaluating 
the capability of QUC398 to preserve cartilage. 
This study takes into account (i) the clinical need; (ii) clinical and preclinical data on QUC398; 
(iii) current practice with s.c. injectable drugs; and (iv) the burden on patients with symptomatic 
knee OA. 
The combination of well-established Patient Reported Outcomes (PROs) such as KOOS 
(Roos et al 2003) and of MRI measuring the cartilage volume in the index region will ensure 
appropriate evaluation of the QUC398 effect from a symptomatic, functional and 
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For the investigation of the QUC398 treatment effect on OA pain, the study has been designed 
as participant, investigator and sponsor-blinded in order to ensure that mentioned parties remain 
in a state of equipoise, so that a putative difference between the treated and control groups can 
be interpreted as an effect of study treatment. 
Based on preclinical data with QUC398 and literature on pain and structural progression of OA 
in patients with symptomatic knee OA, a 12-week treatment period with QUC398 is considered 
adequate to evaluate a change in pain in the target knee, and a 52-week treatment period to 
evaluate the preservation of the cartilage. 
Inclusion criteria (e.g., radiographic knee OA Kellgren-Lawrence [KL] grade 2-4, medial joint 
space narrowing (mJSN) 1-2 (Altman, Gold 2007), age 40-\HDUVEDVHOLQH.226OHYHO
EDVHOLQHSDLQOHYHO156WR 9) have been selected to enrich for patients with symptomatic 
and progressive knee OA in order to (i) focus on pain improvement in a high risk population; 
(ii) evaluate the halt in cartilage breakdown. 
In order to maximize the chances of selecting patients with primary OA, patients aged 
< 40 years are excluded, as their knee OA is often caused by trauma, and patients are expected 
to have OA in another large joint. Patients should have had pain on the majority of days of the 
last 3 months to ensure that the pain is chronic and not due to a flare. The inclusion of patients 
ZLWK:LGHVSUHDG3DLQ,QGH[:3,LVWRPLQLPL]HELDVSRWHQWLDOO\DIIHFWLQJWKH reporting 
of pain and function by the presence of generalized pain (Yazici et al 2020). 
4.1.1 
Rationale for choice of background therapy 
It is necessary to standardize and document participants’ pain medication as it can potentially 
confound study results; this is particularly important since the primary endpoint of the study is 
based on a pain assessment. Therefore, only the use of paracetamol/acetaminophen, up to 
3000 mg/day, alone or in combination with low-dose codeine (e.g., co-codamol) is allowed as 
basic (non-rescue) medication for pain control until the EOT visit (Week 52). 
4.2 
Rationale for dose/regimen and duration of treatment 
The s.c. dose of QUC398 300 mg, injected every 4 weeks (q4w), in the present study represents 
the maximum dose level tested in the SAD/MAD studies in healthy subjects and knee OA 
patients and aims at achieving maximum inhibition of cartilage breakdown, represented by 
ARGS levels, and to increase the likelihood to achieve a meaningful pain reduction at Week 12. 
This dose was safe and well-tolerated in the preceding studies. For detailed information on 
the safety outcomes of the SAD/MAD studies, please refer to Section 4.5.2. 
In the phase 1a SAD study (
) a single s.c. dose of QUC398 at 300 mg resulted 
in a continued downregulation of serum ARGS levels around or below the LLOQ of the 
analytical assay for approximately 49 days, which is considered a relevant biomarker for clinical 
efficacy. A monthly dose of QUC398 at 300 mg is therefore expected to achieve a continuous 
and significant reduction of ARGS. 
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The dosing frequency in the MAD study was weekly and EOW, while the proposed regimen in 
the present study is q4w. The exposure after weekly s.c. administrations of QUC398 300 mg is 
about -fold higher compared to a single dose administration, i.e., the exposures expected with 
this q4w dosing regimen are covered by the exposures produced in the MAD study in knee OA 
patients. 
The safety margins at the no observed adverse effect level (NOAEL) in mice and monkeys 
versus the serum exposure of QUC398 following weekly s.c. injections of 300 mg (MAD study) 
were at least 
-fold (AUC based) and 
-fold (Cmax based). This representation under 
predicts the safety margins and should be updated once the predicted exposure following q4w 
administrations of 300 mg QUC398 are available. The NOAEL doses were set to the highest 
technical feasible doses in the preclinical safety studies and might provide the most conservative 
estimation of the safety margins. 
Table 4-1 
Safety margins for human exposure after multiple dose administration 
on Day 29 (Day 36 for 300 mg weekly) in study MS200572-0003 vs 
NOAEL in preclinical species 
 
Based on Mouse 200 mg/kg 
AUClast 68840 μg/mL*h a Cmax 1310 
μg/mL 
Based on Cynomolgus Monkey 
150 mg/kg 
AUClast 510162 μg/mL*h b Cmax 
4038 μg/mL 
QUC398 Dose 
(Human) 
AUC based 
safety margin c 
Cmax based 
safety margin 
AUC based 
safety margin c 
Cmax based 
safety margin 
75 mg q2W 
150 mg q2W 
300 mg q2W 
300 mg q1W 
AUC = area under the curve; AUClast = area under the serum concentration versus time curve from 
time zero until tlast (after first or last dose); Cmax = maximum observed concentration. 
a AUClast as area under the curve corresponding to time=0h to 672h after a single dose. Animals in 
the repeated dose group will have been exposed to higher values but no extrapolation of the AUC 
after the last dose was performed. 
b AUClast as the area under the curve from the last dosing event (504h) to the last sampling point 
(672h). AUCs over this dosing interval were not extrapolated to the 4-week study duration as steady 
state was possibly not yet reached after the 4th dose. 
c AUCtau at last dosing interval in study MS200572-0003 was used for the human as most 
conservative assessment. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
No structure modifying (anti-catabolic or anabolic) compound has been approved to date to 
treat OA. Placebo will be used as the comparator to provide objective control for the evaluation 
of treatment effects on efficacy (i.e., pain, function and structure), safety, tolerability and PD, 
with a background of mandated pain medication to meet standard of care for OA pain. 
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4.4 
Purpose and timing of interim analyses/design adaptations 
The analysis of the primary endpoint will be performed after all participants have completed 
Week 12 or discontinued prior to Week 12. 
Simultaneously, an interim analysis on the structural endpoints will be performed including all 
available data on cartilage volume and thickness (MRI data at Week 28 and Week 52). 
Additional interim analyses may be conducted to support decision making concerning the 
current clinical study, the sponsor’s clinical development projects in general, or in case of any 
safety concerns. 
Additional information is presented in the interim analysis section. 
4.5 
Risks and benefits 
The risk to patients in this trial will be minimized by adherence to the eligibility criteria, close 
clinical monitoring, and stopping rules. 
Risks associated with QUC398, imaging procedures and blood draws are described in separate 
sections below. For risks associated with paracetamol/acetaminophen, with or without low dose 
opioids, the investigator should refer to the product’s insert for further information. 
4.5.1 
Benefits 
It is not known whether there will be a benefit for the patients with symptomatic knee OA 
participating in this study. Preclinical data indicate a possible chondroprotective and 
symptom-alleviating effect, while clinical data show a good safety profile. 
So far, no approved therapy exists addressing the unmet medical need of cartilage protection in 
patients with degenerative cartilage disorders. Therefore, no such therapies will be withheld by 
joining this study. 
4.5.2 
Risks associated with QUC398 
QUC398 is a not fully human nanobody and may induce immunogenicity in humans. In the 
non-clinical and clinical studies thus far, ADAs have been detected, but were not associated 
with any impact on safety, PK or PD of QUC398. 
QUC398 showed a favorable safety profile with no systemic hypersensitivity reactions to the 
highest tested doses in repeated dose preclinical toxicity studies for up to 39 weeks, and in the 
two phase 1 studies in humans, in the SAD study using doses up to 300 mg and in the MAD 
study, up to and including the dose of 300 mg s.c. weekly for 6 weeks. 
Potential adverse events may include local injection site reactions (ISR), such as local pain, 
swelling or inflammation, and will be monitored clinically. In the FIH, SAD study 
, ISRs were experienced by 11.1% of the healthy participants and there were 
no severe ISRs. In the MAD study (MS200572-0003), ISRs were experienced by a mean of 
33.3% of all patients treated with QUC398, including 33.3% and 50.0% of participants in the 
QUC398 300 mg every other week and 300 mg weekly cohorts, respectively. There were no 
severe ISRs. 
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In the SAD study, there were no deaths, SAEs, or TEAEs leading to discontinuation during the 
study. Overall, 40 (74.1%) participants reported at least 1 TEAE; 12 (66.7%) participants on 
placebo and 28 (77.8%) participants on QUC398. The most prevalent TEAEs were 
nasopharyngitis, headache, contact dermatitis, ISR and myalgia. The majority of TEAEs were 
mild in severity. One participant, receiving 150 mg QUC398, reported a severe TEAE of back 
pain (worsening of existing back pain), which was assessed as unrelated to QUC398. 
In the MAD study, there were no deaths and 31 (96.9%) participants reported at least 1 TEAE; 
8 (100%) participants on placebo and 23 (95.8%) participants on QUC398. The most common 
TEAEs reported for all treatments were headache, arthralgia, ISR and muscle tightness. 
Two participants presented with a serious TEAE (grade 3): (i) an asthmatic crisis (grade 3) 
considered to be provoked by a flu and not considered to be related to QUC398 by the 
investigator, and (ii) a participant with increase in knee OA pain (grade 3) who was receiving 
placebo. Two participants were discontinued from study treatment due to musculoskeletal 
TEAEs. The events were not considered treatment-related. Ten participants reported TEAEs 
that were assessed as related to the study treatment; (i) 8 participants treated with QUC398 
presented with ISRs; (ii) 1 participant, receiving 300 mg QUC398 every other week, had 
injection pain; (iii) 1 participant, receiving 300 mg QUC398 weekly, reported musculoskeletal 
stiffness. 
In the SAD and the MAD studies, there were no relevant effects on ECG variables and 
waveforms or on blood pressure variables. 
Detailed information can be found in the Investigator’s Brochure. 
To mitigate the possible risk of severe hypersensitivity reactions in humans, participants with 
a history of hypersensitivity reactions to the study treatment or any of the excipients, or to drugs 
of similar classes, will be excluded from participation in this study. 
Participants should be observed for a minimum of 15 minutes after every study treatment 
administration for any potential hypersensitivity reaction. During the observation period it is 
recommended that an investigator/medical doctor is on site. Participants who experience any 
grade of systemic hypersensitivity (e.g., rash, not related to the injection site, wheezing, 
anaphylactic reaction) will not be re-dosed. Study stopping rules for hypersensitivity are found 
in Section 9.3. 
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any question that the participant will not reliably comply, they 
should not be entered or continue in the study. 
4.5.3 
Hypothetical risks for QUC398 
Hypothetical risk and recommended treatment of infection 
In non-clinical studies, there was no evidence of infections following treatment with QUC398. 
Based on the current available data from previous single-ascending dose and multiple ascending 
dose studies there has been no evidence of increased risk of infections related to QUC398 
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As with any immune-modulating compound, there is a theoretical risk of immune system 
impairment, which might increase risk of infection in treated participants. However, QUC398 
is not expected to elicit broad immune suppression. Moreover, the target ADAMTS-5 is not 
essential for health. To mitigate potential risks of immune suppression and infection in this 
study, exclusion criteria include other immune suppressive treatments administered 28 days or 
5 half-lives, whichever is longer, prior to screening. Participants will also be excluded with 
known or suspected immunodeficiency state or evidence of active or latent, serious bacterial, 
fungal or viral infections. See Section 5.2. 
 
Some publications based on animal models of 
 or analyzing tissues from 
patients that required surgery for complications 
, suggested that the 
 
 in the blood vessels’ wall, induced by inflammation and ageing, is 
associated with an increased risk of 
.
 
 
 
 This risk is categorized 
as theoretical for QUC398 because of the lack of causal evidence connecting 
 
 
No
 or any other cardiovascular events have been observed neither in 
pre-clinical studies nor in clinical trials for QUC398. 
To investigate this hypothetical risk, the level of 
, 
will be monitored during the study as a potential
. 
Additionally, participants with a history of heart failure Class III and IV, unstable angina, 
myocardial infarction, coronary artery bypass graft surgery, recent percutaneous coronary 
intervention, valvular and/or aortic defects, aortic or brain aneurysms, or uncontrolled 
hypertension will be excluded from participation in this study. 
4.5.4 
Risks associated with basic pain medication 
Even though paracetamol/acetaminophen most likely does not cause serious liver damage in 
recommended doses, it can cause elevation in the liver enzymes. In case of elevation of liver 
function test, please refer to Section 16.2. 
4.5.5 
SARS-CoV-2 risks 
In response to the COVID-19 pandemic site-specific procedures should be implemented to 
minimize COVID-19 infection risks for participants and site staff as per local guidance. 
These documents may cover, but are not limited to, local COVID-19 testing, infection 
prevention/control, hygiene and social distancing measures. Investigator must instruct 
participants to contact the investigator immediately if the participants develop any symptoms 
and/or signs of infection (e.g., fever, loss of smell, loss of taste, muscle aches, persistent or 
productive cough, abdominal pain, vomiting, nausea, shortness of breath, dysuria and/or 
diarrhea). 
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In the event of an infection, investigators should consider early treatment with specific 
antimicrobial therapy based on clinical diagnosis or suspicion there of (e.g., anti-viral treatment 
for herpes simplex or zoster or SARS-CoV-2) in consultation with infectious disease experts, 
as appropriate. 
No data are available on either the effects of live vaccination or the secondary transmission of 
infection by live vaccines in patients receiving QUC398, therefore only vaccination with 
non-live vaccines is allowed during the study. Live or live-attenuated vaccines are not allowed 
from 12 weeks prior to planned Day 1 and until 60 days after the last treatment. 
4.5.6 
Risks associated with imaging procedures 
For screening purposes, a fixed flexion knee Xray view is required. The total amount of 
radiation exposure per participant from this X-ray view will be about 5 µSv. This amount of 
radiation is equivalent to approximately 17 hours of background exposure (approx. 0.3 µSv per 
hour at sea level). For effective radiation doses under 3 mSv (300 mrem), the risk is considered 
to be “minimal”. Therefore, the radiation exposure in this study involves minimal risk and is 
necessary to ensure eligibility of patients. 
Magnetic resonance imaging (MRI) will be used in this study to monitor the effects of QUC398 
on cartilage structure and composition. MRI is a non‑invasive radiology technique that has no 
radiation exposure. Thus, in principle, MRI scans can be repeated in the same patient as often 
as necessary. The MRI scanning equipment may cause a feeling of claustrophobia in susceptible 
persons. The presence of metal in the body may also be a safety hazard or affect the MRI image 
quality. For more information, see Section 5.2 (Exclusion criteria). 
4.5.7 
Blood sample volume 
A volume smaller than a typical blood donation is planned to be collected over a period of 
66 weeks, from each participant as part of the study. The approximate volumes are mentioned 
in the informed consent form (ICF). Additional samples may be required for safety monitoring. 
Timings of blood sample collection are outlined in the assessment schedule (Table 8-1). 
The summary blood log, instructions for sample collection, processing, storage and shipment 
information are available in the Laboratory Manual. 
See Section 8.5.3.1 on the potential use of residual samples. 
4.5.8 
Risks associated with off-site visits 
Participants are not anticipated to be exposed to greater risks when participating in off-site 
assessments. OHPs will perform assessments according to the protocol and study manuals for 
onsite visits, thus data integrity is expected to be comparable to onsite assessments. 
Safety management in an off-site setting will adhere to the same quality standards as for the 
traditional onsite model and remains under the responsibility of the investigator (refer to  
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4.6 
Rationale for planned off-site procedures 
The study participants may be offered to perform pre-specified visits in an off-site location (i.e., 
the participant’s house) in order to minimize the burden on participants and to increase 
flexibility, as described in Section 3 and defined in Section 8. This has the potential to broaden 
access to the study for both participants and investigators. The hybrid approach will allow 
participants to maintain contact with investigators, both in person during clinic visits at site and 
through the telemedicine platform during off-site participation. 
The scope of off-site procedures was determined based on thorough operational feasibility 
assessments to assure comparability with onsite assessments, together with consideration of 
patient safety, investigator, and patient feedback. 
4.7 
Public Health Emergency mitigation procedures 
In the event of a Public Health Emergency, as declared by Local or Regional authorities e.g., 
pandemic, epidemic or natural disaster, additional mitigation procedures to ensure participant 
safety and trial integrity may be implemented. 
Notification of the Public health emergency as declared by local or regional authorities should 
be discussed among investigators and Novartis. All procedures adapted to the situation must be 
submitted, if required as per local regulations, through a protocol amendment for approval by 
Local or Regional Health Authorities and Ethics Committees prior to implementation of 
mitigation procedures. 
5 
Study Population 
The study population consists of male and female adult patients between 40 and 80 years of age 
with symptomatic, mild to severe radiographic knee OA (KL grade 2-4). 
Approximately 98 participants are planned to be randomized in this study. 
The investigator must ensure that a patient meets all of the inclusion and none of the exclusion 
criteria before enrolling him/her into the trial. No additional criteria should be applied by the 
investigator when considering a patient’s eligibility. 
In the case where a safety laboratory assessment at screening meets any of the exclusion criteria 
but the condition is expected to be transient and resolved prior to first dose, the assessment may 
be repeated once prior to randomization. If the repeat value remains exclusionary, then the 
participant will be excluded from the study. 
Selection of the target knee: in case of bilateral knee OA, the target knee is defined as the knee 
that meets the criteria for KL grade 2-4 and the radiologic mJSN 1-2 criteria. In the event that 
both knees meet these criteria, the target knee will be designated by the highest pain NRS. 

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5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1.   Written informed consent must be obtained before any assessment is performed. 
2.  Able to communicate well with the investigator, to understand and comply with the 
requirements of the study. 
3.  Male or female participants ≥ 40 and ≤ 80 years of age on the day of informed consent 
signature. 
4.  Weight ≥ 50 kg and a body mass index (BMI) between 18 -35 kg/m2, at Screening 1. 
5.  Diagnosis of primary tibiofemoral knee OA by standard American College of 
Rheumatology (ACR) clinical and radiographic criteria (Altman et al 1986) at 
Screening 1. 
6.  Kellgren-Lawrence grade 2 to 4 in the tibiofemoral compartment in the target knee 
confirmed by radiography in standing weight-bearing fixed flexion position and 
posterior-anterior view, at Screening 1. 
7a.  mJSN 1-2 (Altman, Gold 2007) in the medial tibiofemoral compartment of the target 
knee, confirmed with Xray by central reader at Screening 1. 
8.  Symptomatic OA with moderate to severe pain (corresponding to Pain NRS ≥ 5 to ≤ 9) in 
the target knee for the majority of days in the last 3 months prior to Screening 1, as per 
participant’s judgement. 
9.  Symptomatic OA with moderate to severe pain (corresponding to Pain NRS ≥ 5 to ≤ 9) in 
the target knee at Screening 1 and 2. 
10.  Moderate to severe OA pain (corresponding to Pain NRS ≥5 to ≤9) in the target knee 
during the last 7 days prior to Screening 3, confirmed by: 
• Completed pain diary for at least 6 of the last 7 days prior to Screening 3, AND 
• Diary reported Pain NRS ≥5 to ≤9 for at least 6 of the last 7 days prior to Screening 3 
11.  KOOS pain subscale ≤ 60 in the target knee at Screening 1, Screening 2, and Screening 3 
12.  Primary source of pain throughout the body is due to OA in the target knee, and a 
Widespread Pain Index (WPI) score ≤ 4 at Screening 1. 
13.  In the event the participant has a history of OA in the contralateral hip or knee, pain NRS 
should be ≤4 at Screening 3. 
14a. If the participant is using chronic NSAID or selective COX-2 inhibitors (excluding 
topical NSAIDs) for any pain indication including OA pain in the target knee, the 
participant must be willing to switch to the study basic medication: 
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5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1.  History of, or planned, following surgical interventions: 
• Knee replacement (partial or total) in either knee. 
• Arthroscopy or lavage of either knee, within 6 months prior to Screening 1 or planned 
during the study. 
• Mosaicplasty, microfracture, meniscectomy > 50% or osteotomy of the target knee. 
Any other previous surgical intervention of the target knee needs to be discussed with 
the clinical team. 
• Hip prosthesis recently implanted (within 1 year prior to Screening 1) or hip 
replacement on either side planned within the study period. 
2.  Painful ipsilateral hip OA (corresponding to Pain NRS ≥3) on the majority of days in the 
last 3 months prior to Screening 1, as reported by the participant. 
3.  Known autoimmune disease with inflammatory arthritides (including but not limited to 
rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus 
erythematosus), crystal-induced arthritides (gout, pseudogout associated arthritis), active 
acute or chronic infection or past infection of the knee joint, Lyme disease involving the 
knee, reactive arthritis, systemic cartilage disorders, moderate to severe fibromyalgia 
(widespread pain index, WPI >4 out of 19), or a known systemic connective tissue 
disease. 
4.  Metabolic or genetically-based abnormalities associated with arthropathy or collagen 
deficiencies (e.g., arthrogryposis multiplex congenita, hemophilia, neurogenic arthropathy, 
Ehlers-Danlos syndrome, Marfan’s syndrome, osteogenesis imperfecta, hypermobility or 
hyperelasticity syndromes). 
5.  Symptomatic, patello-femoral pain in the target knee as per investigator’s examination at 
Screening 1. 
6.  Severe malalignment > 7.5º in the target knee (either varus or valgus), measured using 
standardized knee X-ray at Screening 1. 
7.  Participant is unable or unwilling to undergo MRI or presenting absolute 
contraindications to MRI (e.g., metallic implants, metallic foreign bodies, pacemaker, 
defibrillator). 
8.  Any diagnosed psychiatric condition that includes, but is not limited to, a history of mania, 
bipolar disorder, psychotic disorder, schizophrenia, or schizoaffective disorder, depression 
or anxiety which may jeopardize patient safety, pain perception or compliance with study 
procedures, as judged by the investigator. 
9a. Use of the following prohibited medications within the period defined below: 
• Any local i.a. treatment into the target knee, including but not limited to hyaluronic 
acid, viscosupplementation and corticosteroids (12 weeks prior to planned Day 1). 
• Long-term treatment (> 2 weeks prior to planned Day 1) with oral 
corticosteroids > 5 mg/day (8 weeks prior to planned Day 1). 
• Any biological drug (26 weeks prior to planned Day 1). 

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• Glucosamine, chondroitin sulfate (oral), or any other nutraceutical with potential 
activity on cartilage repair (from Screening 1). 
• Diacetylrhein (12 weeks prior to planned Day 1). 
• Centrally acting analgesics (6 weeks or 5 half-lives, whichever is shorter, prior to 
planned Day 1). 
• Any live or live-attenuated vaccine (12 weeks prior to planned Day 1). 
• Any medications predicted to impact the ST-segment on ECG or drugs with known 
moderate-high risk of QT prolonging properties (from Screening 1). 
10.  Use of other investigational drugs at the time of enrollment, or within 5 half-lives of 
enrollment, or until the expected PD effect has returned to baseline, whichever is longer; 
or longer if required by local regulations. 
11.  Previous exposure to any ADAMTS-5 drug, including QUC398. 
12a. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of drugs, or which may jeopardize the participants’ 
safety in case of participation in the study. The investigator should make this 
determination in consideration of the participants’ medical history and/or clinical or 
laboratory evidence of any of the following: 
• History of or known liver disease or liver injury as indicated by abnormal liver 
function tests: 
• ALT, AST, GGT or alkaline phosphatase must not exceed 2 x ULN. 
• Serum bilirubin must not exceed 1.4 x ULN (if the subject has known Gilbert 
syndrome, the total bilirubin level must not exceed 2 x ULN). 
If necessary, laboratory testing may be repeated on one occasion (as soon as 
possible) prior to randomization, to rule out any laboratory error. 
• History or presence of moderate to severe renal impairment (KDIGO 2012), 
corresponding to eGFR<60 mL/min/1.73 m2, or impaired renal function as indicated 
by clinically significantly abnormal creatinine or BUN and/or urea values, or abnormal 
urinary constituents (e.g., proteinuria). 
• Evidence of urinary obstruction or difficulty in voiding at Screening 1. 
• Total WBC count < 3,000/µL, neutrophils < 1,500/µL, hemoglobin < 8.5 g/dL 
(85 g/L) or platelet count < 100,000/µL at Screening 1. 
13.  Any known active infections, including skin or knee infections or suspected infections 
that may compromise the immune system such as chronic Hepatitis B (HBV), Hepatitis C 
(HCV) infection, or Human Immunodeficiency Virus (HIV) infection. 
A positive HBV surface antigen (HbsAg) test, or if standard local practice, a positive 
HBV core antigen test, excludes a participant. Participants with positive HbsAb, but with 
negative HbsAg and negative anti-HBV core, are allowed to participate in the study since 
these results are compatible with vaccination against HBV. Participants with a positive 
HCV antibody test should have HCV RNA levels measured. Participants with positive 
(detectable) HCV RNA should be excluded. 

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14. Known heart failure classified as New York Heart Association Class III and IV. 
History of or known unstable angina, myocardial infarction, coronary artery bypass graft 
surgery, or percutaneous coronary intervention (such as angioplasty or stent placement) 
within 365 days of screening. Presence or known history of valvular and/or aortic defects, 
or of blood vessel aneurisms. Uncontrolled hypertension, defined as a systolic blood 
pressure (SBP) > 160 mmHg or diastolic blood pressure (DBP) > 100 mmHg at 
Screening 1 and 2. 
15a. History or current diagnosis of ECG abnormalities indicating significant safety risk for 
participants participating in the study, such as signs of myocardial infarction or ischemia, 
or concomitant clinically significant cardiac arrhythmias (e.g., sustained ventricular 
tachycardia and clinically significant second- or third-degree AV block without 
a pacemaker). Participants with QTcF ≥ 450 or < 300 or inability to determine the QTcF 
interval at Screening 1 and participants with evidence or history/family history of long 
QT syndrome, history or risk of Torsades de Pointes or long QT syndrome, or other 
comorbidities which can confound the ECG and assessments. 
16a. History of lymphoproliferative disease or any known malignancy or history of 
malignancy of any organ system within the past 5 years of Screening 1 (except for basal 
cell carcinoma, squamous cell carcinoma, or actinic keratoses that have been treated with 
no evidence of recurrence in the past 3 months, or carcinoma in situ of the cervix or 
non-invasive malignant colon polyps that have been removed). 
17a. History of drug abuse or unhealthy alcohol use within the 12 months prior to expected 
first dose, or evidence of such abuse as indicated by the laboratory assays conducted 
during Screening 1. See also Section 8.1.1.3 (Alcohol test, Drug screen, Urine cotinine). 
Unhealthy alcohol use is defined as a history of, or current, alcohol misuse/abuse or 
“Five or more drinks on the same occasion on each of 5 or more days in the past 
30 days.” 
18.  Heavy smoker defined as currently smoking > 20 cigarettes per day or equivalent use of 
tobacco products, at Screening 1. Past history of heavy smoking is allowed. 
19a. History of recreational cannabis use within 4 weeks prior to dosing, or evidence of such 
use as indicated by the laboratory assays conducted during Screening. This exclusion 
criterion applies even if cannabis use is legalized where the site is located. See also 
Section 8.1.1.3 (Alcohol test, Drug screen, Urine cotinine). 
20.  Pregnant or nursing (lactating) women at Screening 1 or 2. 
21.  Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
while taking study treatment and for 3 months after stopping of study drug. 
 
Highly effective contraception methods include: 
• Total abstinence from heterosexual intercourse (when this is in line with the preferred 
and usual lifestyle of the participant). Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods 
of contraception. 

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• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking 
study drug. In case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow-up hormone level assessment. 
• Male sterilization (at least 6 months prior to Screening 1). For female participants on 
the study, the vasectomized male partner should be the sole partner for that 
participant. 
• Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS) or other forms of hormonal contraception that have comparable efficacy (failure 
rate < 1%), for example hormone vaginal ring or transdermal hormone contraception. 
In case of use of oral contraception, women should be stable on the same pill for a 
minimum of 3 months before taking study drug. 
If local regulations deviate from the contraception methods listed above and require more 
extensive measures to prevent pregnancy, local regulations apply and will be described in 
the ICF. 
Women are considered post-menopausal and not of childbearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., 
age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
6 weeks ago. In the case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow-up hormone level assessment is she considered not 
of child bearing potential. See also Section 8.4.4 (Pregnancy and Assessments of 
Fertility). 
22.  History of hypersensitivity to any of the study treatments or excipients. 
23.  Signs or symptoms, in the judgment of the investigator, of a clinically significant 
systemic viral, bacterial or fungal infection within 30 days prior to Screening 1. 
24. Aortic diameter of > 40 mm as measured by Echo-Doppler of thoracic and abdominal 
aorta at Screening 2 or between Screening 2 and Screening 3. 
6 
Study treatment and concomitant therapy 
6.1 
Description of study treatment and treatment arms 
6.1.1 
Investigational and control drugs 
In this protocol, the term study drug or study treatment refers to QUC398 or Placebo, while 
the term investigational drug refers exclusively to QUC398. 
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for participant numbering, prescribing/dispensing, and administering study 
treatment are outlined in the Pharmacy Manual. 
See Section 6.2.4.1 for relevant dietary and smoking restrictions linked to dose administration 
visits. 

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Table 6-1 
Investigational and control drug 
Treatment Title 
QUC398 150 mg/mL  
Placebo 0 mg/mL 
Treatment 
Description 
Solution for injection (1 mL) 
Solution for injection (1 mL)  
Type  
Biologic 
Biologic 
Dose Formulation 
Vial  
Vial  
Unit Dose 
Strength(s) 
150 mg/mL 
0 mg/mL 
Dosage Level(s) 
300 mg (2 x 1 mL injections, 150 mg 
each) q4w 
Placebo 0 mg/mL (2 x 1 mL 
injections, 0 mg each) q4w 
Route of 
Administration 
Subcutaneous injection 
Subcutaneous injection 
Use 
Experimental 
Placebo  
IMP 
Yes 
Yes 
Sourcing 
Sponsor (global) 
Sponsor (global) 
Packaging and 
Labeling 
Study treatment will be provided in 
glass vials. Each vial will be labeled 
as required per country requirement. 
Study treatment will be provided in 
glass vials. Each vial will be labeled 
as required per country requirement. 
The minimum duration between two dosings of study treatment is three weeks, the maximum 
is six weeks. 
6.1.2 
Additional study treatments 
It is imperative to standardize and document participants pain medication as it can potentially 
confound results. Therefore, only the use of paracetamol/acetaminophen, up to 3000 mg/day, 
alone or in combination with low dose codeine, e.g., co-codamol, is allowed as basic 
(non-rescue) medication for pain control, regardless of the origin of the pain, until Week 52. 
This medication is herein referred to as “basic pain medication”. Basic pain medication will be 
used as needed by the participant within the aforementioned margins, and according to the 
package inserts and investigator instructions. For sites, handling of the basic pain medication 
(e.g., labelling, storage location/conditions, temperature control, controlled substance measures, 
resupply (if needed)) is the investigator’s responsibility, taking into consideration local 
regulations and the corresponding package inserts. Basic pain medication is considered to be 
Auxiliary Medicinal Products (AxMP) under the EU Clinical Trial Regulation 536/2014. AxMP 
safety reporting requirements will only apply once the trial has been transitioned under EU 
Clinical Trial Regulation 536/2014. 
At each study visit, participants will be provided with a quantity of the basic pain medication, 
either the paracetamol/acetaminophen or the paracetamol/acetaminophen plus codeine 
combination product, that is estimated to be sufficient until the next planned study visit, starting 
at Screening 1 and until Week 52. 
Participants who use other pain medications must be switched to the basic pain medication at 
Screening 1 (inclusion criterion). 
The participant should only use the basic pain medication provided by the investigator, even if 
he/she previously used or can purchase the same compound privately. 

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The basic pain medication can be taken at any point in the study, also within 48 hours of a study 
visit. To the extent possible, no other pain medication should be used up until Week 52 (see 
Section 6.2.3 Rescue medication). 
Participants will be provided with a pain diary in which they will document their daily pain and 
the use of (any) pain medication up to Week 12 (see Section 8.3.1.4). The investigator or 
delegate must review the pain diary at each visit until Week 12, to ensure the number of returned 
basic pain medication tablets are reasonable compared to the documented use in the pain diary, 
and to monitor the potential use of rescue medication as per Section 6.2.3 (drug accountability 
will be performed on basic pain medication). 
Table 6-2 
Additional study treatment 
Treatment Title 
Paracetamol/acetaminophen  
500 mg* 
Paracetamol/acetaminophen in 
combination with low dose 
codeine 500/30 mg* 
Treatment Description 
As needed 
As needed 
Type  
Drug 
Drug 
Dose Formulation 
Tablet 
Tablet 
Unit Dose Strength(s) 
500 mg* 
500 mg paracetamol/acetaminophen 
plus 30 mg codeine* 
Dosage Level(s) 
Up to 3000 mg per day 
Up to 3000 mg 
paracetamol/acetaminophen plus 
180 mg codeine per day 
Route of 
Administration 
Oral 
Oral 
Use 
Background intervention 
Background intervention 
Authorization status of 
the AxMP in EEA 
Yes 
Yes 
Sourcing 
Provided locally by sponsor, or 
local pharmacy  
Provided locally by sponsor, or local 
pharmacy 
Packaging and 
Labeling 
Original packaging, and labeled 
as per local regulations 
Original packaging, and labeled as 
per local regulations  
* Tablet strengths can be different, depending on the country. 
Only one or both of the alternatives may be supplied to the investigator site, depending on the country. 
No other treatment beyond investigational drug, placebo and basic pain medication are provided 
in this trial. 
The basic pain medication must be recorded on the concomitant medications Case Report Form 
(CRF). 
6.1.3 
Treatment arms/group 
Participants will be assigned to one of the following 2 treatment arms in a ratio of 1:1: 
• QUC398 300 mg, q4w s.c. injections 
• Placebo, q4w s.c. injections 

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6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
The investigator must instruct the participant to notify the study site about any new medications 
he/she takes after the participant was enrolled into the study. 
All prescription medications, over-the-counter drugs, including the provided basic pain 
medication, and significant non-drug therapies (including physical therapy and blood 
transfusions) administered or taken within the timeframe defined in the entry criteria prior to 
the start of the study and during the study, must be recorded on the Concomitant 
medications/Significant non-drug therapies CRF. 
Medication entries should be specific to generic 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 
participant or allowing a new medication to be started. If the participant is already enrolled, the 
investigator should contact Novartis to determine if the participant should continue 
participation in the study. 
If a COVID-19 vaccine is available, vaccination of trial participants with non-live vaccines will 
be permitted during the study duration. The investigator must document their discussion with 
the participant regarding COVID-19 vaccination in the source documentation, and follow the 
instructions described above related to the CRF. 
6.2.1.1 
Permitted concomitant therapy 
Topical NSAIDs and topical steroids are allowed during the study. 
A daily dose of aspirin of up to 325 mg/day is allowed during the study. 
NSAIDs are allowed without restrictions after Week 52 but should still not be taken within 
48 hours of a visit where Pain (NRS) or KOOS assessments are conducted (EOS visit). 
Non-pharmaceutical therapies, such as electrotherapy, acupuncture, physiotherapy, and 
chiropractic treatment are allowed during the study. 
All permitted concomitant therapy must be reported in the Concomitant medications/Significant 
non-drug therapies eCRF. 
6.2.2 
Prohibited medication 
Use of the treatments displayed in the table below is NOT allowed in the reported timeframe. 
If required outside of the definitions of Rescue medication (Section 6.2.3), actions have to be 
taken as described by Table 6-3 below. 

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Table 6-3 
Prohibited medication 
Medication 
Prohibition period 
Action taken 
Local i.a. treatment into the 
target knee, including but not 
restricted to hyaluronic acid, 
viscosupplementation and 
corticosteroids 
12 weeks prior to Day 1 to EOS 
Report protocol deviation and 
discontinue study treatment 
Systemic including oral 
corticosteroid > 5 mg/day for 
more than 14 consecutive 
days (topical, intranasal and 
ophthalmic are permitted) 
8 weeks prior to Day 1 to EOS 
Report protocol deviation and 
discontinue study treatment 
Any biological drug 
26 weeks prior to Day 1 to EOS 
Report protocol deviation and 
discontinue study treatment 
Glucosamine, chondroitin 
sulfate (oral), or any other 
nutraceutical with potential 
activity on cartilage repair 
From Screening 1 to EOS 
Report protocol deviation and 
discontinue prohibited 
medication as soon as 
possible 
Diacetylrhein (Diacerein) 
12 weeks prior to Day 1 to EOS 
Report protocol deviation, 
discontinue prohibited 
medication as soon as 
possible, and reschedule 
study visit if taken within the 
last 48 hours* 
Centrally acting analgesics, 
e.g., pregabalin, duloxetine, 
medical marijuana and CBD 
oil 
6 weeks or 5 half-lives, whichever 
is shorter, prior to Day 1 to EOS 
Report protocol deviation, 
discontinue prohibited 
medication as soon as 
possible, and reschedule 
study visit if taken within the 
last 48 hours* 
Any live or live-attenuated 
vaccine 
12 weeks prior to Day 1 and until 
90 days after the last study 
treatment 
Report protocol deviation and 
discontinue study treatment 
Acetylsalicylic acid > 325 
mg/day 
Screening 1 to EOS 
Report protocol deviation, 
discontinue or adjust dosing 
of prohibited medication (as 
needed) as soon as possible, 
and reschedule study visit 
if taken within the last 
48 hours* 
Paracetamol/acetaminophen  
> 3000 mg/day 
Screening 1 to EOS 
Report protocol deviation, 
discontinue or adjust dosing 
of prohibited medication (as 
needed) as soon as possible, 
and reschedule study visit 
if taken within the last 
48 hours* 

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Medication 
Prohibition period 
Action taken 
Opioids, including tramadol 
and transdermal fentanyl 
patches, except oral low dose 
codeine combination drugs 
Screening 1 to EOS 
Report protocol deviation, 
discontinue prohibited 
medication as soon as 
possible, and reschedule 
study visit if taken within the 
last 48 hours* 
NSAIDs (including 
combinations with codeine or 
caffeine, as well as selective 
COX-2 inhibitors) beyond the 
use as rescue medication 
(see Section 6.2.3).  
Topical NSAIDs are 
permitted. 
Screening 1 to Week 52 
Report protocol 
deviation, discontinue 
prohibited medication as soon 
as possible, and reschedule 
study visit if taken within the 
last 48 hours* 
Any medications predicted to 
impact the ST-segment on 
ECG. 
Drugs with known QT 
prolonging properties. 
Screening 1 to Week 52 
Report protocol deviation and 
discontinue study treatment 
* If taken within the last 48 hours before a study visit, the entire visit should be rescheduled to the first 
possible time point outside the 48-hour limit (after last intake), even if this pushes the visit to outside 
the visit window specified in Table 8-1. If the rescheduled visit is again compromised by prohibited 
medication intake within 48 hours, the investigator should contact the sponsor to agree on whether to 
reschedule the visit further. 
All prohibited medication must be reported in the Concomitant medications eCRF. 
6.2.3 
Rescue medication 
If 
adequate 
pain 
control 
is 
not 
achieved 
with 
basic 
pain 
medication 
(paracetamol/acetaminophen alone or in combination with low-dose codeine as described in 
Section 6.1.2), then NSAIDs will be permitted as rescue medication for up to 3 days per week, 
but must not be taken within 48 hours of a visit where Pain (NRS) or KOOS assessments are 
conducted, up until Week 52, inclusive. 
After Week 52, NSAIDs are allowed without restrictions but should still not be taken within 
48 hours from a visit where Pain (NRS) or KOOS assessments are conducted (EOS visit). 
In the event that NSAIDs have been taken within 48 hours of a study visit, the entire visit should 
be rescheduled to the first possible time outside of the 48-hour limit (see Table 6-3). 
Rescue medication will not be provided by the sponsor. 
Decisions regarding specific NSAIDs to be used as rescue medication should be made by the 
site's principal investigator, based on local practice and individual patient needs. The maximum 
dose should not exceed the approved dose in each country. Rescue medication should be used 
according to the corresponding package insert and investigator instructions while taking into 
account specific precautions. 
Use of rescue medication must be documented by the participant in the pain diary and recorded 
in the Concomitant medications eCRF. 

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6.2.4 
Restriction for study participants 
For the duration of the study, participants should be informed and reminded of the restrictions 
outlined in this section. 
6.2.4.1 
Dietary restrictions and smoking 
From Screening 1 to EOS, the participant should not smoke > 20 cigarettes per day or use other 
tobacco products in amounts corresponding to > 20 cigarettes per day. Use of nicotine products 
is allowed as per package insert. 
At visits where ECG measurements are performed, participants must refrain from smoking, 
consuming alcohol, methylxanthine-containing beverages, citrus-containing fruits or beverages, 
and tonic water in the 4 hours previous to the ECG collection. 
In order to avoid wide variations in urine volumes on PK collection days, participants should 
be encouraged to have a fluid intake of approximately 240 mL every 4 hours during their waking 
hours, in addition to the fluid taken with meals (only on PK collection days). 
6.2.4.2 
Other restrictions 
Participants will be required to adhere to the measures and procedures outlined by the study site, 
to prevent SARS-CoV-2 infections among trial participants and clinical site staff. 
6.3 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described in Section 6.1.1. 
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the IRT and obtaining the medication number(s). The study medication has a 2-part 
label (base plus tear-off label), immediately before dispensing the medication kit, site personnel 
will detach the outer part of the label from the packaging and affix it to the source document. 
The study treatment is blinded and the syringe for s.c. injection must be prepared by adequately 
trained and qualified personnel, after the investigator or delegate has randomized a participant 
and information about the assigned treatment arm (kit assignment) has been received from the 
IRT system. The volume of injection will be the same between participants receiving QUC398 
or placebo, i.e., 2 x 1 mL. 
Because participants are randomized to a treatment arm only after eligibility has been confirmed 
at Screening 3, the investigator is responsible for establishing effective communication with the 
pharmacist, to ensure the study drug is prepared as soon as possible after randomization, and 
made available on Day 1. It is particularly important to give reasonable notice of an upcoming 
randomization and dosing visit if the syringe is reconstituted at an external pharmacy and has 
to be transported to the site. 
The investigator site will be provided with a Pharmacy Manual, in which details on all drug 
handling are described. 

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For off-site visits by OHPs, where delivery of study medication directly to a participant’s secure 
off-site location (e.g., home) is permitted by national and local governing regulations, the 
dispatch of study medication directly to the participant may be performed under the 
accountability of the Investigator. The dispatch of the study treatment from the site to the 
participant’s home remains under the accountability of the investigator. Each shipment will 
consist of a single dose of study treatment, to be administered at the off-site visit. Regular phone 
calls or virtual contacts will occur between the site and the participant for instructional purposes, 
safety monitoring, investigation of any adverse events, and discussion of the participant’s health 
status. 
The treatment for off-site administration will be handled and shipped in line with the pharmacy 
manual and required procedures for shipping. 
6.3.1 
Handling of study treatment and other treatment 
6.3.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The investigator or designated site staff (blinded or unblinded, as applicable) must maintain an 
accurate record of the shipment and dispensing of study treatment in a drug accountability log. 
Monitoring of drug accountability will be performed by field monitors during site or remote 
monitoring visits, and at the completion of the trial. 
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, the investigator will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to the Novartis 
monitor or to the Novartis address provided in the investigator folder at each site. 
In the US, the study treatment and all required clinical study supplies will be distributed direct 
to the participant utilizing an extension of the IND for compliance purposes. 
6.3.1.2 
Handling of other treatment 
Basic pain medication and rescue medication will be handled as described in Section 6.1.2 and 
Section 6.2.3. 

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6.3.2 
Instruction for prescribing and taking study treatment 
Table 6-4 
Dose and treatment schedule 
Investigational / Control Drug 
(Name and Strength) 
Dose 
Frequency 
and/or Regimen 
QUC398 150 mg/mL 
300 mg (2 x 1 mL injections, 150 mg each) 
q4w 
Placebo 0 mg/mL 
0 mg (2 x 1 mL injections, 0 mg each) 
q4w 
All kits of study treatment assigned by the IRT will be recorded in the IRT system. 
Study treatment will be administered as 2 injections into a skin fold of the participant's abdomen, 
by the investigator or delegate. Each injection should be at least 10 cm apart from the previous 
one. The skin at the injection site must be suitably disinfected before the injection by use of an 
alcohol wipe to clean the skin. The injection site must not be covered to avoid the possibility of 
any irritation from the bandaging material and any drops of blood must be carefully dabbed 
away with a dry cloth until the wound has closed. Participants should be observed for a 
minimum of 15 minutes after every study treatment administration for any potential 
hypersensitivity reaction. 
The first dose will be administered to participants on Day 1, followed by administrations every 
4 weeks (q4w) until Week 48, inclusive. 
6.4 
Participant numbering, treatment assignment, randomization 
6.4.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. The Participant No. consists of the Center Number 
(Center No.) (as assigned by Novartis to the investigative site) with a sequential participant 
number suffixed to it, so that each participant’s participation is numbered uniquely across the 
entire database. Upon signing the ICF, the participant is assigned to the next sequential 
Participant No. available. 
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No. 
6.4.2 
Treatment assignment, randomization 
After the Screening 3 phone call (between Day -4 and Day -1), all eligible participants will be 
randomized via Interactive Response Technology (IRT) to one of the treatment arms. 
The investigator or his/her delegate will contact the IRT after confirming that the participant 
fulfills all the inclusion/exclusion criteria. The IRT will assign a randomization number to the 
participant, which will be used to link the participant to a treatment arm and will specify a 
unique medication number for the first package of study treatment to be dispensed to the 
participant. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. 
A participant randomization list will be produced by the IRT provider using a validated system 

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that automates the random assignment of participant numbers to randomization numbers. 
These randomization numbers are linked to the different treatment arms, which in turn are 
linked to medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Global Clinical Supply (GCS) using a validated system that 
automates the random assignment of medication numbers to packs containing the study 
treatment. 
The randomization scheme for participants will be reviewed and approved by a member of 
the Randomization Office. 
6.5 
Treatment blinding 
This is a participant, investigator and sponsor-blinded study. Participants, investigators and the 
sponsor will remain blinded to study treatment throughout the study, except where indicated 
below. 
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration and appearance. 
Site personnel 
All site personnel will be blinded to study treatment throughout the study. 
Unblinding a single participant at site for safety reasons (if necessary for participant 
management) will occur via an emergency system in place at the site (see Section 6.7.3). 
Sponsor staff or delegate 
The following unblinded sponsor roles are required for this study: 
• Unblinded bioanalyst(s) (QUC398 PK) 
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team under blinded conditions. Sample data may be provided to 
the independent committee/analysis team, if used, under unblinded conditions. 
All sponsor staff (study statistician, study programmer, biomarker expert, clinical trial team, 
decision boards etc.) will stay blinded to treatment assignments (except in the case of a safety 
event necessitating unblinding) until the Week 12 analysis. 
The study statistician will be able to access the randomization list for interim analyses and is 
allowed to share unblinded information with the rest of the clinical team as appropriate for 
internal decision purposes, as outlined in Table 6-5. For example, unblinded summaries and 
unblinded individual data can be shared with the team for interim analyses. 
Study programmers and other personnel involved in study data analysis (e.g., biomarker expert) 
are allowed to access treatment assignment information for the purpose of conducting interim 
analyses. 

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The clinical trial team is allowed to share unblinded results with other sponsor staff (e.g., 
decision boards) as required for internal decision making on the study or the project at the time 
of interim analyses while the study is ongoing. 
All unblinded sponsor personnel will otherwise keep randomization lists and data or 
information that could unblind other study team members confidential and secure until the 
Week 12 analysis. 
Following final database lock, all roles may be considered unblinded. See the 
blinding/unblinding table for an overview of the blinding/unblinding plan. 
Table 6-5 
Blinding and unblinding plan 
Role 
Time or Event 
Randomization 
list generated 
Treatment 
allocation & 
dosing 
Safety event 
(single subject 
unblinded) 
Interim 
Analysis & 
dose 
escalation 
Participants 
B 
B 
UI 
B 
Site staff 
B 
B 
UI 
B 
Drug Supply and 
Randomization Office 
UI 
UI 
UI 
UI 
Statistician/statistical 
programmer/data analysts 
B 
B 
UI 
UI 
Unblinded sponsor staff 
(see text for details) 
B 
UI 
UI 
UI 
All other sponsor staff not 
identified above 
B 
B 
UI 
UI 
B Remains blinded 
UI Allowed to be unblinded on individual patient level 
6.6 
Dose escalation and dose modification 
Investigational or other study treatment dose adjustments and/or interruptions are not permitted. 
6.7 
Additional treatment guidance 
6.7.1 
Treatment compliance 
Compliance to the treatment regimen is ensured by administration of QUC398 300 mg or 
placebo s.c. injections by the investigator or delegate. Information on the study treatment 
administration or any deviation from the dose regimen must be recorded in the eCRF. All vials 
for study treatment and potentially returned vials must be recorded in the Drug Accountability 
Log. The monitor(s) will review Drug Accountability Logs during site visits. 
Dispensed and returned basic pain medication must be recorded in the source documents. 
Off-site treatment administration compliance will be assessed by the OHP and information 
provided to the investigator and/or study personnel. 

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6.7.2 
Recommended treatment of adverse events 
Treatment of AEs should be in line with the investigator site procedures. 
For the management of allergic reaction and anaphylaxis, it is recommended to follow the 
guidelines by the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE). 
In case of any sign of acute reaction, the participant will be managed with treatment as 
determined by the treating physician on a case-by-case basis, according to local protocols, and 
depending on severity, using symptomatic treatment such as antihistamines, NSAIDs, 
acetaminophen, intravenous fluids, corticosteroids, or adrenaline. 
Medication or other therapies used to treat AEs must be recorded on the Concomitant 
medications/Significant non-drug therapies eCRF. 
6.7.3 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely. 
Most often, discontinuation from study treatment and knowledge of the possible treatment 
assignments are sufficient to treat a study participant who presents with an emergency condition. 
Emergency treatment code breaks are performed using the IRT. When the investigator contacts 
the system to break a treatment code for a participant, he/she must provide the requested 
participant identifying information and confirm the necessity to break the treatment code for 
the participant. The investigator will then receive details of the investigational drug treatment 
for the specified participant and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the study team that the code has been 
broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide: 
• protocol number 
• name (if available) 
• participant number 
In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
Novartis will evaluate on a case-by-case basis if a participant will be permitted to continue study 
participation after an emergency code break. 

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7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH E6 GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational treatment can 
be found in the Investigator's Brochure (IB). This information will be included in the participant 
informed consent and should be discussed with the participant 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 participant. 
The following informed consents are included in this study: 
x Main study consent, which also included: 
x A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during 
this study 
x A subsection that requires a separate signature for the ‘Optional Consent for Week 56 
Visit’ to allow for 
 
x As applicable, Pregnancy Outcomes Reporting Consent for female participants or 
the female partners of any male participants who took study treatment 
x 
 
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information. 
The study includes an 
 which requires a separate signature if the 
participant agrees to participate. It is required as part of this protocol that the Investigator 
presents this option to the participants, as permitted by local governing regulations. The process 
for obtaining consent should be exactly the same as described above for the main informed 
consent. 
Declining to participate in these 
 and/or Additional Research) will 
in no way affect the participant’s ability to join the main research study. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
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The study includes the option for the participant to have certain study procedures performed 
off-site by an off-site healthcare professional instead of at the study site if permitted by national 
and local governing regulations and if accepted by the investigator. A separate signature is 
required in a supplementary ICF if the participant agrees to participate in off-site procedures. 
The process for obtaining consent should be exactly the same as described above for the main 
informed consent. 
As per Section 4.7, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, Investigator may 
conduct the informed consent discussion remotely (e.g., telephone, videoconference) if 
allowable by a local Health Authority. 
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g., the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.). 
8 
Visit schedule and assessments 
The assessment schedule (Table 8-1) lists all of the assessments when they are performed. 
All data obtained from these assessments must be supported in the participant’s source 
documentation. 
Participants 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. 
For screening purposes, the following order of assessments is recommended: 
1. Clinical eligibility, starting with OA pain in the target knee 
2. Laboratory assessments 
3. X-ray 
4. Other (e.g., pain diary, 
) 
After eligibility has been confirmed at Screening 3, the following order of assessments is 
recommended: 
1. Assessment of rescue and/or prohibited medication use 
2. Pain assessments, in the order KOOS, Pain NRS, PGA 
3. Pain diary review and basic pain medication review/dispensation 
4. Vital signs, ECG 
5. Blood sampling 
6. 
 
 
. 
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Other orders of priority to consider are: 
Randomization must occur after eligibility has been confirmed at Screening 3. 
The preferred sequence of data collection during study visits is ECG recording, vital signs, 
blood sampling and then
 
 
MRI can be performed before or after other clinical assessments at a visit, also on a different 
day if needed for logistical reasons, but should always be done within the visit window. 
Participants who discontinue from study treatment are to return for the EOT visit as soon as 
possible, and return for safety follow-up assessments 8 weeks later (EOS visit). 
Participants who discontinue from the study or withdraw their consent/oppose the use of their 
data/biological samples should be scheduled for a final evaluation visit if they agree, as soon as 
possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled, and the adverse event and 
concomitant medications not previously reported must be recorded on the CRF. 
The “X” in the table denotes the assessments to be recorded in the clinical database or received 
electronically from a vendor. The “S” in the table denotes the assessments that are only in the 
participant’s source documentation and do not need to be recorded in the clinical database. 
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Table 8-1 
Assessment Schedule 
Period 
Screening 
Treatment 
Post-Treatment Follow-Up 
Visit Name Screening 
1 
Screening 
2 
Screening 
3 
(Randomi-
zation)1 
Day 
1 
Day 
5 
Week 
4 
Week 
8 
Week 
12 
Week 16 /  
Week 20 /  
Week 242 
Week 
28 
Week 32 / 
Week 362 
Week 
40 
Week 44 / 
Week 482 
EOT - 
Week 
52 
Week 
562,3 
EOS - 
Week 60 
Days -40 to -21 
-20 to -9 
-4 to -1 
1 
5 
±2 
29 
±3 
57 
±3 
85 
±3 
113 ±3 /  
141 ±3 /  
169 ±3 
197 
±3 
225 ±3 /  
253 ±3 
281 
±3 
309 ±3 /  
337 ±3 
365 
±3 
393 
±3 
421 
±7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / 
Exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genetic consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history/current 
medical 
conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis screen 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV screen 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Test and 
Drug Screen  
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking history 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
Vital Signs4 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 

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Period 
Screening 
Treatment 
Post-Treatment Follow-Up 
Visit Name Screening 
1 
Screening 
2 
Screening 
3 
(Randomi-
zation)1 
Day 
1 
Day 
5 
Week 
4 
Week 
8 
Week 
12 
Week 16 /  
Week 20 /  
Week 242 
Week 
28 
Week 32 / 
Week 362 
Week 
40 
Week 44 / 
Week 482 
EOT - 
Week 
52 
Week 
562,3 
EOS - 
Week 60 
Days -40 to -21 
-20 to -9 
-4 to -1 
1 
5 
±2 
29 
±3 
57 
±3 
85 
±3 
113 ±3 /  
141 ±3 /  
169 ±3 
197 
±3 
225 ±3 /  
253 ±3 
281 
±3 
309 ±3 /  
337 ±3 
365 
±3 
393 
±3 
421 
±7 
Physical 
Examination 
S 
 
 
S 
S 
 
 
S 
 
S 
 
S 
 
S 
 
S 
Electrocardiogram 
(ECG)5 
X 
 
 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Hematology 
X 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
Clinical Chemistry 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Coagulation 
Panel 
X 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
X 
X 
X 
X 
X 
X6 
X 
X 
X 
X 
X 
 
X 
Pregnancy and 
assessments of 
fertility7 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
WPI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
KOOS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Patient's Global 
Assessment 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pain NRS 
X 
X 
X8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X-ray target knee 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Period 
Screening 
Treatment 
Post-Treatment Follow-Up 
Visit Name Screening 
1 
Screening 
2 
Screening 
3 
(Randomi-
zation)1 
Day 
1 
Day 
5 
Week 
4 
Week 
8 
Week 
12 
Week 16 /  
Week 20 /  
Week 242 
Week 
28 
Week 32 / 
Week 362 
Week 
40 
Week 44 / 
Week 482 
EOT - 
Week 
52 
Week 
562,3 
EOS - 
Week 60 
Days -40 to -21 
-20 to -9 
-4 to -1 
1 
5 
±2 
29 
±3 
57 
±3 
85 
±3 
113 ±3 /  
141 ±3 /  
169 ±3 
197 
±3 
225 ±3 /  
253 ±3 
281 
±3 
309 ±3 /  
337 ±3 
365 
±3 
393 
±3 
421 
±7 
MRI target knee 
 
 
 
X10 
 
 
 
 
 
X 
 
 
 
X 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
  
 
 
 
 
 
 
Study drug 
administration 
 
 
 
X11 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
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Period 
Screening 
Treatment 
Post-Treatment Follow-Up 
Visit Name Screening 
1 
Screening 
2 
Screening 
3 
(Randomi-
zation)1 
Day 
1 
Day 
5 
Week 
4 
Week 
8 
Week 
12 
Week 16 /  
Week 20 /  
Week 242 
Week 
28 
Week 32 / 
Week 362 
Week 
40 
Week 44 / 
Week 482 
EOT - 
Week 
52 
Week 
562,3 
EOS - 
Week 60 
Days -40 to -21 
-20 to -9 
-4 to -1 
1 
5 
±2 
29 
±3 
57 
±3 
85 
±3 
113 ±3 /  
141 ±3 /  
169 ±3 
197 
±3 
225 ±3 /  
253 ±3 
281 
±3 
309 ±3 /  
337 ±3 
365 
±3 
393 
±3 
421 
±7 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Echo-Doppler of 
thoracic and 
abdominal aorta 
 
X20 
 
 
 
 
 
 
 
 
 
 
 
X21 
 
 
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Period 
Screening 
Treatment 
Post-Treatment Follow-Up 
Visit Name Screening 
1 
Screening 
2 
Screening 
3 
(Randomi-
zation)1 
Day 
1 
Day 
5 
Week 
4 
Week 
8 
Week 
12 
Week 16 /  
Week 20 /  
Week 242 
Week 
28 
Week 32 / 
Week 362 
Week 
40 
Week 44 / 
Week 482 
EOT - 
Week 
52 
Week 
562,3 
EOS - 
Week 60 
Days -40 to -21 
-20 to -9 
-4 to -1 
1 
5 
±2 
29 
±3 
57 
±3 
85 
±3 
113 ±3 /  
141 ±3 /  
169 ±3 
197 
±3 
225 ±3 /  
253 ±3 
281 
±3 
309 ±3 /  
337 ±3 
365 
±3 
393 
±3 
421 
±7 
Study completion 
information 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Phone call visit. 
2 May be performed at an off-site location, if allowed by local laws and regulations and as agreed with the Investigator. 
3 Optional visit: only for participants who consented to optional PK and PD samples 
4 Pre- and post-dose  BP, body temperature,  and pulse rate measurements will be performed. 
5 Triplicate ECGs except single 12-lead ECG at Screening 1. 
6 Only at Week 20 
7 Only for women of childbearing potential: Serum pregnancy test at Screening 1, Screening 2, and Week 60 (EOS) visits, urine pregnancy test at all other visits except 
Screening 3 (phone call) and Day 5 visits. 
8 Only for NRS pain in the contralateral hip or knee, if applicable to the participant. 
10 MRI assessment is allowed from Day 1 to Day 10. 
11 Study drug to be administrated after all scheduled pre-dose assessments in Day 1 completed. 
13
 
17 
. This optional sample can be collected anytime during Day 1 or thereafter. 
 Echo-Doppler of thoracic and abdominal aorta is to be performed at Screening 2 or between Screening 2 and Screening 3. 
21 Echo-Doppler of thoracic and abdominal aorta is to be performed at Week 52 (EOT) or between Week 52 (EOT) and Week 60 (EOS). 
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8.1 
Screening 
It is permissible to re-screen a participant 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 Screening 
number assigned, and a new written informed consent signed by the participant and investigator. 
Re-screening is permitted if the reason(s) for failing the initial screening were unrelated to the 
knee X-ray. The participant will not need to undergo another knee X-ray and the initial one may 
be used for re-screening purposes, if re-screening occurs within 6 months of the X-ray date. 
The objective of this measure is to avoid unnecessary radiation exposure, given that meaningful 
radiologic changes are not likely to occur during the period of re-screening. 
Echo-Doppler of the thoracic and abdominal aorta does not have to be repeated if re-screening 
occurs within 6 months of the Echo-Doppler date. 
Participants can repeat the KOOS once without being screen failed if the pain subscale score 
was > 60 and < 70 at Screening 1, Screening 2, or Screening 3. Participants can be re-screened 
once if KOOS pain at Screening 1, Screening 2, or Screening 3 is not within the permitted range 
despite its repetition, provided that the other pain criteria listed in inclusion criterion 8 and 9 
were within the permitted range. 
8.1.1 
Eligibility screening 
This section describes assessments which are performed at screening in order to evaluate 
a participant's eligibility. Eligibility assessments which are performed at screening to describe 
the population or also later during the study to evaluate efficacy, safety or other outcomes, are 
described in separate sections. 
The screening assessments should be completed as per the assessment schedule (Table 8-1), 
starting with informed consents. Assessments should be performed from the less 
invasive/burdensome to the more invasive/burdensome assessments for the participant. 
In the case where a safety laboratory assessment at screening meets any of the exclusion criteria 
but where the condition is expected to be transient and resolved prior to first dose, or if 
a laboratory error is suspected, the assessment may be repeated once prior to randomization. 
If the repeat value still meets the exclusion criterion, the patient does not qualify for the study. 
During screening, the investigator should detect any active infections that would disqualify the 
participant for this study (exclusion criterion). The decision to locally test the participant for 
active SARS-Cov-2 infection in order to evaluate the exclusion criterion is at the investigator's 
discretion and should be in adherence to local policies or regulations. However, it is highly 
recommended that PCR or antigen testing for COVID-19 be completed within 1 week prior to 
first dosing. If testing is performed, negative test results are required prior to enrolment into the 
study. Additional testing throughout the study may occur at the discretion of the investigating 
physician. COVID-19 testing should be completed via nasal or throat swabs. If testing is not 
performed, the investigator must document their discussion with the participant regarding 
testing, and the rationale for not testing, in the source documentation. These requirements may 
be ignored if the pandemic is declared ended by the country where the site is located, and 
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8.1.1.1 
Pain 
Widespread Pain Index (WPI) (Wolfe et al 2016) will be assessed at Screening 1 only, to 
exclude participants with substantial pain from undiagnosed diseases. 
Other pain PROs are collected for screening purposes as well as for efficacy evaluation, as 
described in Section 8.3.1. 
The same method of collection as for the PROs described in Section 8.3.1 will be used. 
8.1.1.2 
Hepatitis screen, HIV screen 
All participants will be screened for Hepatitis B surface antigen antibody (HBsAb), Hepatitis B 
surface antigen (HBsAg), and Hepatitis B core antibody (HBcAb). 
If HBsAg or HBcAb is positive the participant will be excluded. 
Screening for Hepatitis C will be based on HCV antibodies (HCVAb) and if positive, HCV 
RNA levels should be determined. 
Evaluation for HIV seropositivity will be performed, and, if positive, confirmation by a second 
technique available at the laboratory site e.g., Western blot. Appropriate counseling will be 
made available by the investigator in the event of a positive confirmatory test. Notification of 
state and federal authorities, as required by law, will be the responsibility of the investigator. 
8.1.1.3 
Alcohol test, Drug screen, Urine cotinine 
Participants will be tested for substances of abuse (e.g., alcohol, amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine and opiates) with a urine sample as they may interfere 
with the participants’ perception of pain, which is the primary endpoint of the study, and with 
safe adherence to this protocol (e.g., unknown interaction effects with study treatment, proper 
conduct of assessments). Positive tests for opioids such as codeine and/or benzodiazepines are 
not considered exclusionary if ongoing at study start and recorded on the Concomitant 
Medication page in the eCRF. If the initial drug screen was failed, one re-test for cannabinoids 
is allowed. 
Cotinine in urine will not be analyzed at screening. However, the investigator should clarify 
tobacco use habits for participants who use tobacco since heavy smokers, defined as 
smoking > 20 cigarettes/day, are excluded from the study as described in Section 6.2.4.1. 
Nicotine replacement therapies are allowed. 
8.1.1.4 
Knee X-ray 
A standardized flexion knee X-ray will be performed at Screening 1 to evaluate the KL, mJSN 
and malalignment eligibility criteria, using a non-fluoro, standardized and quality-controlled 
method, as described in the Imaging Manual. The local radiologist and/or investigator should 
review the images for incidental findings relevant to the participant's safety. A central reader 
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If a participant has been screened for a similar Novartis trial with the same conventional X-ray 
projections, these images can be used within six months of the X-ray date, provided the 
participant confirms there are no significant changes in local symptoms since the initial image 
was taken. 
8.1.2 
Information to be collected on screening failures 
A screen failure occurs when a participant who consents to participate in the clinical study is 
subsequently found to be ineligible and therefore not dosed with randomly assigned study 
treatment. In this situation, the investigator must provide minimal set of screen failure 
information. Data and samples collected from participants prior to screen failure may still be 
analyzed. 
The reason for screen failure should be recorded on the appropriate eCRF. The protocol version 
log, subject status, disposition, visit dates, demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for screen failure participants. No other data 
will need to be entered into the clinical database for participants who are screen failures, unless 
the participant experienced a serious adverse event or an adverse event related to AxMPs during 
the screening phase (see Section 10.1.3 for SAE reporting details). 
Participants who are randomized and fail to start treatment, e.g., participants randomized in 
error, will be considered an early terminator. The reason for early termination should be 
recorded on the appropriate eCRF. 
The IRT must be notified within 2 days of the screen failure/early termination. 
8.2 
Participant demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in the eCRF. 
Participant race/ethnicity are collected and analyzed to identify variations in safety or efficacy 
due to these factors, as well as to assess the diversity of the study population as required by 
Health Authorities. 
Participant demographics: age, sex, race/predominant ethnicity (if permitted) and relevant 
medical history/current medical conditions (until date of signature of informed consent) will be 
recorded in the eCRF. Where possible, the diagnosis and not symptoms should be recorded. 
All prescription medications, over-the-counter drugs and significant non-drug therapies prior to 
the start of the study must be documented. See Section 6.2.1 Concomitant Therapy for further 
details on what information must be recorded on the appropriate page of the eCRF. 
8.3 
Efficacy 
The efficacy assessments described in this section will be evaluated in all participants in all 
treatment arms. 
Pain (primary endpoint) will be assessed by KOOS, as described in Section 8.3.1. 
Cartilage volume (secondary endpoint) as well as other structure components (e.g., bone 
marrow lesions) will be evaluated by MRI as described in Section 8.3.2. 

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PD samples will be obtained and evaluated in all participants, including the placebo group. 
The samples will be collected at the time points defined in the assessment schedule (Table 8-1). 
Instructions are outlined in the Laboratory Manual regarding sample collection, numbering, 
processing, and shipment. 
8.3.1 
Patient Reported Outcomes (PROs) 
The PROs used in this study are KOOS, Pain (NRS), PGA (NRS), a Pain diary (to record pain 
intensity and pain medication; described in this Section 8.3.1), and WPI (described in  
Section 8.1.1.1). 
To assess the presence of pain in joints other than the index knee, the participant will be asked 
to mark the painful joints in the 
 and score the pain in each of these joints using 
a pain NRS. 
The participant must complete the PRO assessments at the scheduled visit before any other 
clinical assessments are conducted, either at the site or in an off-site visit, when permitted by 
local regulations and agreed by the investigator and the participant. 
The questionnaires should be completed in the language most familiar to the participant. 
The participant should be given sufficient space and time to complete the PRO measures. 
A participant’s refusal to complete all or any part of a PRO measure should be documented in 
the eCRF. 
The site personnel or delegated person should check the PRO measures collected for 
completeness and ask the participant to complete any missing responses. 
The investigator is asked to review the KOOS pain subscale and the concomitant medication 
recorded in the diary for responses which may indicate potential AEs or SAEs before any 
clinical study examinations. If AEs or SAEs are confirmed, study investigators should not 
encourage the participant to change responses reported in the completed questionnaires. 
Study investigators must follow reporting instructions outlined in Section 10. 
8.3.1.1 
Knee Injury and Osteoarthritis Outcomes Score (KOOS) 
Knee-related symptoms and function will be assessed by means of the KOOS measure 
(Roos et al 2011) collected at regular intervals. The KOOS has a recall period of seven days 
and includes 42 items grouped into 5 subscales: Pain, Other symptoms, Activities of Daily 
Living (ADL), Function in Sport and Recreation (Sport/Rec), and Knee related Quality of Life 
(QoL). Standardized answer options are given (5 Likert boxes) and each question gets a score 
from 0-4. A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) 
is calculated for each subscale (KOOS User Guide 2003). 
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8.3.1.2 
Pain Numerical Rating Scale (NRS) 
The participant’s pain in the target knee using NRS (Hawker et al 2011) is assessed to confirm 
eligibility and at regular intervals throughout the study. 
The Pain NRS utilizes an 11-point scale from 0 – 10, has a recall period of 24 hours, and the 
participants will be asked to rate the pain intensity at its worst. 
For the assessment of painful joints other than the index knee, the participants will be asked to 
score the pain at each joint marked in the 
 with the same recall period 
and anchor questions as for the target knee. 
8.3.1.3 
Patient’s Global Assessment (PGA) 
The PGA of OA disease activity will be performed using a NRS (11-point scale from 0 – 10) 
with a recall period of 24 hours, and it is completed by the participant prior to drug 
administration at visits specified in the assessment schedule. 
8.3.1.4 
Pain diary 
Daily assessments of pain intensity (NRS) in the target knee, as well as any pain medication 
intake will be recorded by the participant in the study-specific pain diary, from Screening 2 
until Week 12. Use of prescribed or OTC pain medications will still need to be documented as 
Concomitant Medications according to Section 6.2.1. 
The participant may choose when but should assess the pain intensity at approximately the same 
time on every day, also on study visit days. The Pain (NRS) assessment in the diary and the 
Pain (NRS) assessment performed at site during study visits are done at different time points 
and therefore documented separately in the eCRF. 
From Screening 2 to Week 12, participants will either be provided with a new pain diary that 
covers at least the period until the next planned visit, or will be completed via an electronic 
device where all visits are available. 
8.3.2 
Knee Magnetic resonance imaging (MRI) 
The baseline MRI will only be performed after randomization of the participant. 
MRI can be performed before or after the application of the study drug, and even on a different 
day if needed for logistical reasons, but should always be done within the visit window. 
MRI will be obtained from the target knee. Specific MRI pulse sequences will be used to 
quantify changes in volume and thickness of cartilage; 
 
 
 
 The index region is defined as the union of the 
femoral medial anterior (FMA), central (FMC) and posterior (FMP) cartilage subregions in the 
knee. 
 
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8.3.2.1 
Image collection 
The MRI acquisition will be performed by a trained MRI professional at each site. The MRI 
radiologist will be blinded to the treatment received by the participant. All MRI acquisitions 
will be done using a clinical MRI 3T scanner and a multi-channel knee coil. For each MRI 
session, images will be acquired as described in the scanning guide manual to assess cartilage 
structure and texture as well as bone marrow lesions. Both 2D and 3D non-contrast MRI pulse 
sequences will be used to these ends. 
MR images will be acquired at selected and qualified imaging site(s) and sent for independent 
central review by imaging specialists. The reviewers will be blinded to the treatment received 
by the participant. 
8.3.2.2 
Image processing 
The image analysis will be performed centrally, as defined in the Imaging Manual, in order to 
assess changes in cartilage volume, thickness, T2 and texture both in the index region and the 
rest of the joint as well as changes in 
 volume. 
The coded medical images will be used primarily for analysis as described in this protocol; 
however, the images may also be used for the development and evaluation of new analysis 
methods directly related to the area of research that this study covers. 
Segmentation of knee articular cartilage will be performed for the measurement of cartilage 
volume and thickness by using a CE marked and FDA approved (510(k) number K231351) 
automated segmentation software (Chondral Quant, Siemens, Erlangen, Germany). 
The software allows a robust automated segmentation of the femoral, tibial and patellar 
cartilage as well as the Region-of-Interest analysis. It uses 3D active shape models, the 
extraction of the expected bone–cartilage interface, and cartilage segmentation using a 
graph-based method. As a result, the complete set of parameters is provided (volumetry and 
descriptive statistics of quantitative MR parameters). These include volumes (in milliliters) and 
cartilage thickness (in millimeters) separately for 21 regions (femur: medial posterior-FMP, 
medial central-FMC, medial anterior-FMA, trochlea medial-FTM, trochlea central-FTC, 
trochlea lateral-FTC, lateral posterior-FLP, lateral central-FLC and lateral anterior-FLA; lateral 
posterior-TLP, lateral central-TLC, lateral anterior-TLA, medial posterior-TPM, medial 
anterior-TMA; lateral inferior-PLI, lateral central-PLC, lateral superior-PLS, medial 
inferior-PMI, medial central-PMC, medial superior-PMS). This definition of the subfields is 
based on a modified ICRS score as published before (Surowiec et al 2014). This subdivision of 
the knee joint is more accurate than the subdivision provided by the MOAKS classification. 
The automated software will calculate cartilage volume and cartilage thickness within each of 
these subfields. 
Structural MR images will also be analyzed for the determination of 
 volume. 
 
 
 
 
 
 
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 analysis will be performed on
 As previously shown 
 seem to correlate with the 
 
and therefore, this method may help to improve the quantification of degenerated 
cartilage tissue. The main 
 that will be considered are: 
 
 
8.3.3 
Appropriateness of efficacy assessments 
The PRO KOOS score is an expanded version of the Western Ontario and McMaster 
Universities Arthritis Index (WOMAC) score, which traditionally has been used in OA trials 
(KOOS User Guide 2003). KOOS includes WOMAC OA index LK 3.0 in its complete and 
original format, allowing WOMAC scores to be derived from the KOOS instrument. 
Compared to WOMAC, the KOOS score gives a more comprehensive picture because it also 
includes “Function in sport and recreation” and “Knee related QoL”. KOOS has a 7-day recall 
period. 
The Pain (NRS) score is traditionally used to assess pain. 
KOOS, with a 7-day recall period, and pain NRS, with a 24-hour recall period, are used in 
combination to guarantee a full understanding of pain behavior. 
The PGA (NRS) score is traditionally used to evaluate the overall OA disease status of 
the patient. 
Imaging techniques including X-rays and MRI are standard measures used for assessing joint 
structure in participants with OA (Hayashi et al 2019). 
The use of an automated segmentation software will make it possible to overcome the inherent 
limitations in the manual segmentation of MR images, i.e., a time-consuming process, possible 
measurement inaccuracies related to the subjectivity of the radiologist and incomplete knee 
coverage. In addition, a unique feature of the chosen software (i.e., MR Chondral Quant) will 
allow 
 for a comprehensive 
assessment of cartilage, covering both structural (volume and thickness) and qualitative (
 
 aspects. 
8.4 
Safety/Tolerability 
Safety assessments are specified below with the assessment schedule (Table 8-1) detailing 
when each assessment is to be performed. 
For details on AE collection and reporting, refer to Section 10.1. 
Table 8-2 
Assessments and specifications 
Assessment 
Specification 
Physical examination 
A complete physical examination will include the examination of 
general appearance, skin, neck (including thyroid), eyes, ears, nose, 
throat, lungs, heart, abdomen, back, lymph nodes, extremities, 
vascular, and neurological. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and pelvic exams will be 
performed. 
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Assessment 
Specification 
A knee joint examination will also be performed as part of the physical 
examination at all time points specified in Table 8-1, and includes 
examination for warmth, swelling/bulge sign and patellar tap sign as 
well as for patellofemoral pain. 
Targeted physical examinations to elaborate self-reported symptoms, 
complaints, injection site reactions or post-injection flares as 
applicable, can be done at any visit. An injection site exam will be 
performed at every visit. Participants should be observed for a 
minimum of 15 minutes after every study treatment administration for 
any potential hypersensitivity reaction. 
Information for all physical examinations must be included in the 
source documentation at the study site. Clinically relevant findings that 
are present prior to signing informed consent must be recorded on the 
appropriate eCRF that captures medical history. Significant findings 
made after signing informed consent which meet the definition of an 
Adverse Event must be recorded as an adverse event. 
Vital signs 
Vital signs will include the collection of (pre-and post-dose) otic, oral or 
armpit body temperature (recorded in °C), blood pressure (BP) and 
pulse measurements. 
The same method for measuring the body temperature should be used 
throughout the study. 
Systolic and diastolic blood pressure will be measured (pre- and 
post-dose) after the participant has been sitting for five minutes, with 
back supported and both feet placed on the floor, three times at 
3-minute intervals using an automated validated device, e.g., OMRON, 
with an appropriately sized arm cuff. In case the cuff sizes available 
are not large enough for the participant’s arm circumference, a 
sphygmomanometer with an appropriately sized cuff may be used. 
The mean of the three measurements will be used for evaluations and 
entered in the eCRF. 
If the blood pressure is out-of-range at Screening 1 or 2 or on Day 1, 
three additional readings can be obtained after approximately 
30 minutes, in the manner described above. The mean of the last three 
readings must be within the ranges provided in the eligibility criteria in 
order for the patient to qualify. 
Pulse rate will be measured (pre- and post-dose) by palpation of radial 
pulse during 60 seconds after each measurement of blood pressure. 
The mean of the three measurements will be registered in the eCRF. If 
radial pulse cannot be measured, femoral pulse can be used. 
In case of repeated blood pressure assessments, the mean value from 
both set of measurements (initial and repeat) should be entered in the 
eCRF. 
Height and weight 
Height in centimeters (cm) (Screening 1) and body weight (to the 
nearest 0.1 kilogram (kg) in indoor clothing, but without shoes) will be 
measured as per assessment schedule. 
At screening 1 body mass index (BMI) will be calculated to one decimal 
using the following formula: 
BMI = Body weight (kg) / [Height (m)]2 

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8.4.1 
Laboratory evaluations 
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate. 
In all cases, the investigator must document in the source documents, the clinical considerations 
(i.e., result was/was not clinically significant and/or medically relevant) in allowing or 
disallowing the participant to continue in the study. 
A central laboratory will be used for analysis of all safety specimens collected. Details on the 
collection, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the Central Laboratory Manual. 
If the COVID-19 pandemic limits or prevents the use of central laboratory services, e.g., due to 
transport restrictions of tissue samples, the sponsor may request essential laboratory screening 
and/or safety assessments to be analyzed by a local laboratory, if available. If used, relevant 
documentation should be obtained from the local laboratory to evaluate the validity of the data, 
considering potential differences in analysis assays, reference ranges, etc. between the local and 
central laboratories. It must be clear from the final data set what data originate from local 
laboratory analyses. 
Urinalysis 
A midstream urine sample (approx. 30 mL) will be obtained, in order to avoid contamination 
with epithelial cells and sediments, and allow proper assessments. 
Special clinical laboratory evaluations 
All abnormal laboratory results must be evaluated for criteria defining an adverse event and 
reported as such if the criteria are met (see Section 10.1). For laboratory related adverse events, 
follow-up evaluations are mandatory until normalization of the result(s) or until the result is no 
longer considered to be clinically significant. 
Table 8-3 
Laboratory evaluations 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Erythrocytes, Erythrocytes Mean Corpuscular 
Hemoglobin, Erythrocytes Mean Corpuscular Hemoglobin Concentration, 
Erythrocytes Mean Corpuscular Volume, Platelets, Leukocytes, 
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils) 
Chemistry 
Clinical chemistry: Albumin, Bicarbonate, BUN (Urea Nitrogen/Urea), 
Calcium, Chloride, Creatinine, Creatine kinase, Cystatine C, Potassium, 
Sodium, Total Protein, Uric Acid, 
Liver function tests: Alkaline phosphatase, ALT, AST, Gamma-glutamyl-
transferase (GGT), Lactate dehydrogenase (LDH), Total Bilirubin (if Total 
Bilirubin is above 1.5 times the upper limit of normal, direct and indirect 
reacting Bilirubin should be performed). 
Lipids and glucose: Total Cholesterol, HDL, LDL, Triglycerides, Glucose, 
HbA1c. 

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Test Category 
Test Name 
 
 
 
Urinalysis 
Microscopic Panel (Erythrocytes, Leukocytes, Casts, Crystals, Bacteria, 
Epithelial cells). 
Macroscopic Panel (Dipstick) (Color, Bilirubin, Occult Blood, Macroscopic 
Blood, Glucose, Ketones, Leukocytes esterase, Nitrite, pH, Protein, 
Specific Gravity, Urobilinogen). 
Chemistry Panel (protein, creatinine, protein-creatinine ratio). 
Coagulation 
Prothrombin time (PT), International Normalized Ratio (INR)  
Hepatitis markers 
HbsAg, HbsAb, HbcAb, HCVAb 
HBV-DNA and HCV RNA, as per Section 8.1.1.2 
Pregnancy Test 
Serum / Urine pregnancy test, see Section 8.4.3 
8.4.2 
Electrocardiogram (ECG) 
Single 12-lead ECG at Screening 1, and triplicate 12-lead ECGs from Day 1 onwards, will be 
performed as outlined in the assessment schedule (Table 8-1), and will undergo central reading. 
Full details of all procedures relating to the ECG collection and reporting are contained in 
the technical manual provided to the site by the ECG vendor. 
ECGs must be recorded after at least 10 minutes rest in the supine position to ensure a stable 
baseline. Psychological stimuli with effect on autonomic nerve tone should be kept to 
a minimum. This includes watching television, using the cell phone, or listening to music before 
and during the ECG collection. 
Participants must refrain from smoking, consuming alcohol, methylxanthine-containing 
beverages, citrus-containing fruits or beverages, and tonic water in the 4 hours prior to the 
ECG collection. 
The preferred sequence of cardiovascular data collection during study visits is (pre-dose) ECG 
collection first, followed by vital signs, blood sampling, and any remaining assessments for that 
visit (refer to flow diagram below). 
Figure 8-1 
Timing of study procedures 
 
Triplicate 12-lead ECGs are to be recorded 2 minutes apart. 
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The Fridericia QT correction formula (QTcF) must be used for clinical decisions. The mean 
QTcF value for each visit will be calculated from the triplicate ECGs for each participant. 
PR interval, QRS duration, heart rate, RR, QT, QTcF (Fridericia QT) will be collected. 
Clinically significant abnormalities must be reported as AE in the CRF. 
Clinically significant ECG findings at baseline must be discussed with the sponsor before 
administration of study treatment. 
In order to enable ECG evaluation by the central ECG laboratory for eligibility assessment, 
ECGs should be submitted to the central ECG laboratory prior to the planned randomization 
date, within the timeframe detailed in the technical manual provided by the central ECG 
laboratory. In the event that a QTcF value of > 450 ms (males) or > 460 ms (females) is observed 
or if an unscheduled ECG is performed for safety reasons, it is recommended to collect a 
time-matched PK sample and record the time and date of the last study drug intake to determine 
the drug exposure. 
In the event that a clinically significant ECG abnormality is identified at the site (e.g., severe 
DUUK\WKPLDFRQGXFWLRQDEQRUPDOLW\RI47F)PVRUPVDQGRUDQLQFUHDVH! 60 ms, 
a copy of the assessment is sent to the central ECG laboratory for expedited review and the 
ECG is repeated to confirm the diagnosis. If the participant is hemodynamically compromised, 
the investigator or a medically qualified person must initiate appropriate safety procedures 
without delay (for example cardioversion). 
All ECGs, including unscheduled safety ECGs with clinically relevant findings collected during 
the study needs to be transmitted to the central ECG laboratory for review. 
Clinically significant abnormalities must be recorded on the eCRF as either medical 
history/current medical conditions or adverse events as appropriate. 
8.4.3 
 
8.4.4 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Central serum pregnancy testing is required at Screening 1, Screening 2, and at EOS. 
Local urine pregnancy tests will be performed at all other visits except Screening 3 (phone call) 
and Day 5, and if applicable, before administration of the study treatment. A positive local urine 
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test needs to be confirmed with central serum test. If positive, the participant will be 
discontinued from study treatment. 
Local pregnancy test and associated results will be collected on the eCRF. 
Assessments of fertility 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of 
child-bearing potential must also be available as source documentation in the following cases: 
1. Surgical bilateral oophorectomy without a hysterectomy 
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 
In the absence of the above medical documentation, FSH testing is required of any female 
participant regardless of reported reproductive/menopausal status at Screening. 
8.4.5 
Appropriateness of safety measurements 
Cardiovascular effects (blood pressure increases, ECG changes and correlated histological 
cardiac lesions) were reported in cynomolgus monkeys in published studies (Larkin et al 2014, 
Larkin et al 2015) of an ADAMTS-5 targeting monoclonal antibody (GSK2394002). 
This finding was not observed for QUC398, neither in pre-clinical investigations (4-week, 
13-week and 39-week repeat-dose studies in cynomolgus monkeys), nor in clinical 
investigations (SAD and MAD phase 1 studies). 
In order to fully evaluate the cardiovascular safety of QUC398 and to rule out a possible class 
effect, ECGs will be performed predose, at Cmax and at steady state, as well as throughout 
the study. 
The rest of the safety assessments selected are standard for this indication/participant population. 
8.5 
Additional assessments 
8.5.1 
 
8.5.1.1 
 
8.5.1.2 
 
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8.5.1.2.1 
 
8.5.1.2.2 
 
8.5.1.2.3 
 
8.5.1.2.4 
 
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8.5.2 
 
 
 
 
 
 
 
 
 
8.5.3 
 
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x 
 
8.5.3.1 
Use of residual biological samples 
Residual serum, plasma and urine samples may be used for another protocol specified endpoint. 
Any residual samples remaining after the protocol-defined analysis has been performed may be 
used for additional exploratory analysis related to the purpose of this study. 
 
 
 
 
Given the exploratory nature of the work, the analytical method used for those 
assessments will not be validated. As such, the results from this exploratory analysis will not 
be included in the clinical study report. 
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8.5.4 
Imaging 
The methods for assessment and recording are specified in the Imaging Manual. 
The coded medical images will be used primarily for analysis as described in this protocol; 
however, the images may also be used for the development and evaluation of new analysis 
methods directly related to the area of research that this study covers. 
Incidental findings are beyond the scope of central imaging vendor. If an 
investigator/radiologist recognizes any incidental finding in the images during the course of 
conducting the clinical trial, the investigator should follow up as part of his/her duty of care to 
ensure the safety and wellbeing of the participant. 
8.5.5 
 
9 
Discontinuation and completion 
9.1 
Discontinuation from study treatment and from study 
9.1.1 
Discontinuation from study treatment 
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason, prior to the planned completion of study drug administration. 
Discontinuation of study treatment can be initiated by either the participant or the investigator. 
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 
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Discontinuation from study treatment is required under the following circumstances: 
• Participant decision 
• Pregnancy 
• Use of prohibited treatment as per recommendations in the Prohibited medication section 
(see Section 6.2.2) 
• Any situation in which continued study participation might result in a safety risk to 
the participant 
• Following emergency unblinding 
• Emergence of the following adverse events: 
• A life-threatening adverse event (corresponding to NCI-CTCAE grade 4 or higher) 
considered at least possibly related to QUC398 treatment 
• An AE of severe intensity (corresponding to NCI-CTCAE grade 3 or higher) 
considered at least possibly related to QUC398 treatment 
• Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the participant’s overall status, prevents the participant from continuing 
participation in the study 
• If a liver or renal event occurs, follow guidelines outlined in Section 16.2 and 
Section 16.3 regarding discontinuation of study treatment 
If discontinuation from study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s discontinuation from study treatment and 
record this information. 
Participants who discontinue from study treatment agree to return for the EOT and follow-up 
visits indicated in the assessment schedule (refer to Section 8). 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule. 
After discontinuation from study treatment, at a minimum, in abbreviated visits, the following 
data should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
9.1.2 
Discontinuation from study 
Discontinuation from the study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. 
If the participant agrees, a final evaluation (EOS visit) at the time of the participant’s study 
discontinuation should be made to ensure participant’s safety, as detailed in the assessment 
schedule (refer to Section 8). 

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9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue from study treatment or discontinue from study or withdraw 
consent/oppose to the use of their data/biological samples, the investigator must show "due 
diligence" by documenting in the source documents steps taken to contact the participant, e.g., 
dates of telephone calls, registered letters, etc. A participant should not be considered as lost to 
follow-up until due diligence has been completed. 
9.2 
Withdrawal of informed consent/Opposition to use 
data/biological samples 
Withdrawal of consent/opposition to use data/biological samples occurs when a participant: 
• Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples) 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be in writing (depending on local regulations) and recorded in the source 
documentation. 
In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/opposition to use data/biological samples and record this information. 
Where consent to the use of Personal and Coded Data is not required in a certain country's legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their Personal Data. 
Study treatment must be discontinued, and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
table (refer to Section 8). 
Further details on withdrawal of consent or the exercise of participants' data privacy rights are 
included in the corresponding informed consent form. 

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9.3 
Study stopping rules 
Overall study stopping rules 
The study will be stopped and no further dosing and/or new recruitment will occur pending full 
safety review, if any of the following criteria are met: 
• Any death or life-threatening event (corresponding to NCI-CTCAE grade 4 or higher) 
considered to at least possibly related to QUC398 treatment 
• Two (2) or more SAEs of a similar type (other than death or life-threatening event, 
corresponding to (NCI-CTCAE grade 3 or higher) considered to at least possibly related to 
QUC398 treatment 
• An acute allergic reaction of grade 3 severity or greater, or if one (1) or more participants 
develop a life-threatening (grade 4) or fatal acute allergic reaction according to 
the NCI-CTCAE, within 24 hours following QUC398 administration (i.e., active drug), 
unless clearly caused by exposure to a known allergen (e.g., peanut allergy). 
• Two (2) or more participants are discontinued due to a liver event as defined in 
Section 16.2 
• Two (2) or more participants are discontinued due to a renal event as defined in 
Section 16.3 
• Number and/or severity of AEs, abnormal safety monitoring tests, or abnormal laboratory 
findings justify putting the study on hold 
The safety review will be conducted jointly between medically qualified representatives of the 
sponsor and the investigators. The study may resume following the safety review, if the 
investigator and sponsor agree it is safe to proceed and necessary approvals have been obtained 
from authorities according to local regulations. 
9.4 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their End of Study visit and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision. 
No further study treatment will be made available to the participants after study completion. 
9.5 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination can be: 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of investigational drug development 

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In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a participant who discontinued from study treatment: instructions for contacting the 
participant, when the participant should stop taking drug, when the participant should come in 
for a final visit, will be provided at that time. 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 participant’s interests. The investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial. 
10 
Safety monitoring, reporting and committees 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
 Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
For medical devices, an adverse event (AE) is any untoward medical, unintended disease or 
injury or untoward clinical signs, including an abnormal laboratory finding, in participants, 
users or other persons, in the context of a clinical investigation, whether or not related to the 
device. 
The Investigator and any qualified designees are responsible for managing the safety of 
individual participants. They are also responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and for following up all AEs and SAEs. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments (Patient-Reported Outcomes are considered as other 
assessments to detect adverse events, see Section 8.3.1). 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The Common Toxicity Criteria (CTC)  
AEs will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version. 

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2. The causality 
The investigator is obligated to assess the relationship to any treatment used in the study 
(two different study treatments, and two AxMPs) and each occurrence of each AE. 
The investigator will use clinical judgment to determine the relationship. A reasonable 
possibility of a relationship conveys that there are facts, evidence, and/or arguments to 
suggest a causal relationship, rather than a relationship cannot be ruled out. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. 
For causality assessment, the investigator will also consult the IB and/or product 
information, for marketed products. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
3. Its duration (start and end dates or ongoing) and the outcome must be reported. 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met. 
5. Action taken regarding with study treatment. 
All adverse events must be treated appropriately. Treatment may include one or more of 
the following: 
• Dose not changed 
• Drug interrupted/permanently discontinued 
6. Its outcome (i.e., recovery status or whether it was fatal) 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using 
a diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 60 days following the last dose of 
study treatment or end of study visit, whichever is longer. The end of study visit for early 
discontinuation is defined in Section 8. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g., continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Information about adverse drug reactions can be found in the Investigator's Brochure (IB) for 
the investigational drug, or in the product information for marketed products. 
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 

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Clinically significant abnormal laboratory values or test results must be identified through 
a review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. Alert ranges for laboratory and other test abnormalities are included 
in Appendix 1. 
Reporting of AEs related to AxMP(s) 
All AEs related to any authorized auxiliary medicinal product used in this study must be 
reported to Novartis. 
In assessing causality, the investigators will use the points above. 
If a suspicion that medical occurrence could be related to study treatment (and/or interaction 
with study treatment) cannot be ruled out, the reporting rules for study treatment apply. 
AxMP safety reporting requirements will only apply once the trial has been transitioned under 
EU Clinical Trial Regulation 536/2014. 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g., defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 

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require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the 
ICH-E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
Treatment-emergent elevations in AST or ALT (>3x ULN) in combination with total 
bilirubin >2x ULN or jaundice in the absence of cholestasis (defined as ALP < 2 ULN) or other 
causes of hyperbilirubinemia can be an indicator of severe drug induced liver injury (Hy’s Law). 
For this reason, a potential Hy’s Law case requires expedited reporting, and will be handled as 
a serious unexpected adverse event (assessing it as medically significant in the absence of any 
other seriousness criteria). It must be reported as an SAE to the sponsor promptly (i.e., even 
before all other possible causes of liver injury have been excluded). Reporting should include 
all available information, especially that needed for evaluating the diagnosis, severity and 
likelihood that the study treatment caused the reaction. For patient monitoring and to better 
understand potential etiologies, the investigator must initiate a close follow-up until complete 
resolution of the problem and completion of all attempts to obtain supplementary data. 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and for at least 60 days following the last dose of study treatment 
or end of study visit, whichever is longer must be reported to Novartis safety immediately, 
without undue delay, but under no circumstances later than within 24 hours of obtaining 
knowledge of the events (Note: if more stringent, local regulations regarding reporting timelines 
prevail). The end of study visit for early discontinuation is defined in Section 8. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. Information about all SAEs is collected and recorded 
on the electronic Serious Adverse Event Report Form (with paper backup, if needed); all 
applicable sections of the form must be completed in order to provide a clinically thorough 
report. 
Screen Failures: SAEs occurring after the participant has provided informed consent until the 
time the participant is deemed a Screen Failure must be reported to Novartis. 
Randomized Participants: SAEs collected between time participant signs ICF until at least 
60 days following the end of study visit, whichever is longer. The end of study visit for early 
discontinuation is defined in Section 8. 

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All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information (Note: if more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 
Any SAEs experienced after the 60 day-period following the last study visit should only be 
reported to Novartis Safety if the investigator suspects a causal relationship to study treatment, 
unless otherwise specified by local law/regulations. 
Reporting of SAEs related to AxMP(s) 
All SAEs related to any auxiliary medicinal product (whether authorized or not) used in this 
study must be reported to Novartis within 24 hours of the site becoming aware of it. In assessing 
causality, the investigators will use the points above. If a suspicion that the medical occurrence 
could be related to study treatment (or and interaction with study treatment) cannot be ruled out, 
the reporting rules for study treatment apply. 
The SAE reporting requirements for AxMPs will apply once this trial has been transitioned 
under EU Clinical Trial Regulation 536/2014. 
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) 
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 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 national regulatory 
requirements in participating countries, including EU Clinical Trial Regulation 536/2014. 
10.1.4 
Pregnancy reporting 
Pregnancies 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the investigator to collect and report information regarding the pregnancy. 
To ensure participant 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. 

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Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment of any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE and reported 
to Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see 
the respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure participant 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 16-1 in Appendix 2 for complete definitions of liver laboratory triggers. 
Once a participant is exposed to study treatment, every liver event defined in Table 16-1 should 
be followed up by the investigator or designated personnel at the trial site, as summarized below. 
Additional details on actions required in case of liver events are outlined in Table 16-2 and 

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Table 16-3. Repeat liver chemistry tests (i.e., ALT, AST, TBL, PT/INR, ALP and G-GT) to 
confirm elevation. 
• These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the participant. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results recorded on the appropriate CRF. 
• If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the study drug (refer to the Discontinuation of study treatment section), 
if appropriate 
• Hospitalization of the participant if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include, based on investigator's discretion: 
• serology tests, imaging and pathology assessments, hepatologist’s consultancy 
• obtaining a more detailed history of symptoms and prior or concurrent diseases 
• obtaining a history of concomitant drug use, alcohol use, recreational drug use, and 
special diets 
• exclusion of underlying liver disease, as specified in Table 16-2 and Table 16-3 
• imaging such as abdominal US, CT or MRI, as appropriate 
• obtaining a history of exposure to environmental chemical agents 
• considering gastroenterology or hepatology consultations 
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF. 
10.2.2 
Renal safety monitoring 
Once a participant is exposed to study treatment, the following two categories of abnormal renal 
laboratory alert values should be assessed during the study period: 
• Serum creatinine increase or eGRF ≥ 25% compared to baseline during normal hydration 
status 
• Any one of the following: 
• Urine protein-creatinine ratio ≥1g/g or ≥100 mg/mmol, OR 
• New onset dipstick proteinuria ≥ 2+, OR 
• New onset dipstick hematuria ≥ 3+ (after excluding menstruation, UTI, extreme 
exercise, or trauma) 
Abnormal renal event findings must be confirmed within 48 hours after the first assessment 
(when results become available). 
Every renal laboratory trigger or renal event as defined in Section 16.3 should be followed up 
by the investigator or designated personnel at the trial site as summarized in Section 16.3. 

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10.3 
Committees 
Not applicable. 
11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure 
web-enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will 
not be given access to the EDC system until they have been trained. Automatic validation 
programs check for data discrepancies in the eCRFs, allow modification and/or verification of 
the entered data by the investigator staff. 
The investigator/designee is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. The Investigator must 
certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the participant and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis. 

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Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis/moved to restricted area to be accessed by independent programmer 
and statistician. Any changes to the database after that time can only be made after written 
agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e., eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of participant records, 
the accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits. Continuous remote monitoring of each site’s data 
may be performed by a centralized Novartis CRA. Additionally, a central analytics organization 
may analyze data & identify risks & trends for site operational parameters, and provide reports 
to Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each participant 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 
participant's file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the data capture and/or data entry. Novartis monitoring standards require 
full verification for the presence of informed consent, adherence to the inclusion/exclusion 
criteria, documentation of SAEs, and of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the eCRFs are performed according 
to the study-specific monitoring plan. No information in source documents about the identity 
of the participants will be disclosed. 
12 
Data analysis and statistical methods 
The primary analysis will be conducted after all participants have completed Week 12 or 
discontinued treatment prior to Week 12. The final analysis will be conducted on all 
participants' data at the time the trial ends. Any data analysis carried out independently by the 
investigator should be submitted to Novartis before publication or presentation. 
12.1 
Analysis sets 
The full analysis set (FAS) will include all participants that received any study drug. 
The safety analysis set will include all participants that received any study drug. The FAS and 
Safety set are identical in this study. 

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The PK analysis set (PAS) will include all participants with at least one available valid (i.e., not 
flagged for exclusion) PK concentration measurement, who received QUC398 and with no 
protocol deviations that impact PK data. 
Participants will be analyzed according to the initial treatment received. 
12.2 
Participant demographics and other baseline characteristics 
All data for background and demographic variables will be listed by treatment group and 
participant. Summary statistics will be provided by treatment group for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. 
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and participant. 
12.3 
Treatments 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
The duration of exposure in days to QUC398 will be summarized by means of descriptive 
statistics using the safety set. 
Concomitant medications and significant non-drug therapies prior to and after the start of 
the study treatment will be summarized according to the Anatomical Therapeutic Chemical 
(ATC) classification system, by treatment group. 
12.4 
Analysis supporting primary objectives 
The primary aim of this study is to evaluate the efficacy with q4w s.c. injections of QUC398 
300 mg. To this end, a statistical analysis will be done to compare change from baseline in 
KOOS pain subscale at Week 12 for participants receiving QUC398 vs those receiving placebo. 
12.4.1 
Definition of primary endpoint(s) 
The primary endpoint of the study is the change from baseline in KOOS pain subscale at 
Week 12. KOOS pain subscale score will be analyzed on 100 points scale, low scores meaning 
high pain. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The primary efficacy variable, change from baseline in KOOS pain subscale, will be analyzed 
using a mixed effect model for repeated measures (MMRM). The model will be fit to all 
evaluable data collected from the randomized participants through the Week 12. The model will 
include baseline, treatment, time-point, treatment by time-points as fixed effects. 
An unstructured covariance will be assumed; 
 
 
 A two sided 90% 
CCI

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confidence interval for the treatment effect (i.e., QUC398 minus placebo) at Week 12 will be 
reported. 
12.4.3 
Handling of intercurrent events of primary estimand 
As described in Section 2.1, handling of ICEs will follow a hypothetical strategy. Data collected 
post-ICE will be considered missing and implicitly imputed by the MMRM under the MAR 
assumption (i.e., assuming that participants with missing data would have efficacy outcomes 
like those of similar participants in their treatment group who continue their randomized 
treatment). In case of an unexpectedly high number of discontinuations (in particular due to a 
similar reason) from the study treatment are observed, the assumptions underlying the strategy 
considered might be revised and modified as appropriate. Potential changes would be detailed 
in the SAP. 
12.4.4 
Handling of missing values not related to intercurrent event 
Some intermittently missing data may be expected due to participants occasionally missing a 
study visit while continuing with the randomized treatment. Such data will be implicitly 
imputed by the MMRM under the MAR assumption. 
12.4.5 
Sensitivity analyses 
The robustness of conclusions from the primary analysis to the assumptions that missing data 
arise from, and MAR mechanism may be stress-tested via a delta adjustment tipping-point 
analysis, and/or performing sensitivity analysis considering a jump-to-reference imputation. 
12.4.6 
Supplementary analysis 
The average amount of concomitant and rescue medications will be presented by treatment 
group. In case a substantial difference between treatment groups is observed on average amount 
of concomitant and/or rescue medications, its inclusion as a covariate may be considered in the 
MMRM. Other approaches may be also explored. 
Also, additional analyses may be carried out when the assessments for participants who use 
rescue medication within 48 hours prior to the visit and/or for at least three days are included, 
and/or when the estimands strategy would be a treatment policy strategy. The same MMRM 
model as for the primary estimation will be adopted. 
12.5 
Analysis supporting secondary objectives 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
The secondary efficacy variable, change from baseline over time in KOOS pain subscale, 
KOOS total score, KOOS subscale for other symptoms, function in daily living, function in 
sport and recreation, knee an related quality of life score, and pain NRS will be analyzed using 
a mixed effect model for repeated measures (MMRM). The model will include baseline as fixed 
covariate, treatment, time-point, treatment by time-points as fixed effects and participant as 
random effect. A two sided 90% confidence interval for the treatment effect (i.e., QUC398 
minus placebo) will be reported. 

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For the secondary efficacy variable, change from baseline in cartilage volume of the knee index 
will be analyzed using a MMRM. The model will be fit to all available data collected from the 
randomized participants at scheduled assessments during the adherence to randomized 
treatment, that is, through week 52 or the latest time point prior to an ICE. If deemed appropriate, 
the endpoint measure data will be transformed to facilitate analysis. The model will include 
baseline as fixed covariate, treatment, time-point, treatment by time-points as fixed effects and 
participant as random effect. A two sided 90% confidence interval for the treatment effect (i.e., 
QUC398 minus placebo) will be reported. 
Some intermittently missing data may be expected due to participants occasionally missing a 
study visit while continuing with the randomized treatment. For these cases, the analysis model 
assumes that participants with missing data (included data not evaluable due to ICEs) would 
have efficacy outcomes like those of similar participants in their treatment group who continue 
their randomized treatment through the time point at which data are missing. This type of 
assumption is referred to as missing at random (MAR). 
12.5.2 
Safety endpoints 
For all safety analyses, the Safety Set will be used. All listings and tables will be presented by 
treatment group. 
Safety summaries (tables, figures) include only data from the on-treatment period with 
the exception of baseline data which will also be summarized where appropriate (e.g., change 
from baseline summaries). In addition, a separate summary for death including on treatment 
and post-treatment deaths will be provided. In particular, summary tables for adverse events 
(AEs) will summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). 
Adverse events 
All information obtained on adverse events will be displayed by treatment group and participant. 
The number (and percentage) of participants with treatment-emergent adverse events will be 
summarized by treatment, primary system organ class and preferred term, with a breakdown by 
treatment. 
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 
Vital signs 
All vital signs data will be summarized by treatment and visit/time. 
12-lead ECG 
All ECG data will be summarized by treatment and visit/time. 

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Clinical laboratory evaluations 
All laboratory data will be summarized by treatment group, and visit/time. Shift tables using 
the low/normal/high/ (low and high) classification will be used to compare baseline to the worst 
on-treatment value. 
12.5.3 
Patient reported outcomes 
Please see Section 12.5.1 for details. 
12.6 
 
12.6.2 
Other efficacy assessments 
12.6.3 
 
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12.6.4 
 
12.6.5 
 
12.7 
Interim analyses 
The analysis of the primary endpoint will be performed after all participants have completed 
Week 12, or have discontinued prior to Week 12. Simultaneously, an interim analysis on the 
structural endpoints will be performed including all available data on cartilage volume and 
thickness (MRI data at Week 28 and Week 52). 
A final analysis will be performed after all participants have completed Week 60 (or 
discontinued prior to Week 60). Formal testing of the primary endpoint with full level alpha 
will be performed at the primary analysis time point. 
Additional interim analyses may be conducted to support decision making concerning 
the current clinical study, the sponsor’s clinical development projects in general or in case of 
any safety concerns. 
Unblinded interim analysis results will be reviewed by the clinical team. 
The clinical team may communicate interim results (e.g., evaluation of PoC criteria or 
information needed for planning/modifying another study) to relevant Novartis teams for 
information, consulting and/or decision purposes. 
Interim results may be used to prepare abstracts to scientific meetings. This would typically 
require investigator input to abstract preparation. Every attempt will be made to assure that the 
investigator will not have access to individual participants' data, but rather will review aggregate, 
summary data. 
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12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
A positive treatment effect is indicated by an increase in the KOOS pain subscale score at 
Week 12. Assuming a true treatment difference in KOOS pain score of 10 points and a standard 
deviation of 19, a sample size of 90 evaluable participants provides approximately 80% power 
that the primary analysis will be statistically significant at one-sided 5% significance level. 
In order to account for possible early discontinuations an approximate 10% dropout rate is 
considered, thus the number of participants enrolled will be approximatively 98. 
 
 
 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This study was designed and will be implemented, executed and reported in accordance with 
the protocol and the following: 
x Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) international ethical guidelines 
x Applicable ICH Tripartite Guidelines for Good Clinical Practice (GCP) 
x Applicable local regulations (including European Directive 2001/20/EC or European 
Clinical Trial Regulation 536/2014, US CFR 21) 
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated at that specific site. 
Any amendments to the protocol will require IRB/IEC and Health Authority approval before 
implementation of changes made to the study design, except for changes necessary to eliminate 
an immediate hazard to study participants. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. 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 
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requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.2.1 
Data protection 
Participants will be assigned a unique identifier by Novartis. Any participant records or datasets 
that are transferred to Novartis will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by 
Novartis in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Novartis, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
Novartis has appropriate processes and policies in place to handle personal data breaches 
according to applicable privacy laws. 
13.2.2 
Data quality assurance 
Monitoring strategy, methods, responsibilities, and requirements, are provided in the 
monitoring plan, contracts. Details may include definition of study critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring). 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of Novartis. No records may be transferred to 
another location or party without written notification to Novartis. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT or Clinical Trials Information System (CTIS) public website. 
In addition, after study completion (defined as last patient last visit) and finalization of the study 
report the results of this trial will be submitted for publication and posted in a publicly accessible 
database of clinical trial results, such as the Novartis clinical trial results website and all required 
Health Authority websites (e.g., Clinicaltrials.gov, EudraCT, CTIS public website, etc.). 
Summary results of primary and secondary endpoints will be disclosed based upon the global 
Last Participant Last Visit (LPLV) date, since multinational studies are locked and reported 
based upon the global LPLV. 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided. 

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Any data analysis carried out independently by the Investigator must be submitted to Novartis 
before publication or presentation. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk-based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
13.5 
Participant Engagement 
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the time-points indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis. 
• Thank You letter 
• Plain language trial summary - after CSR publication 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case-by-case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 

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

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15 
References 
References are available upon request 
Alcaraz MJ, Guillén MI, Ferrándiz ML (2019) Emerging therapeutic agents in osteoarthritis. 
Biochem Pharmacol p. 4-16. 
Altman R, Asch E, Bloch D, et al (1986) Development of criteria for the classification and 
reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and 
Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum p. 
1039-49. 
Altman RD, Gold GE (2007) Atlas of individual radiographic features in osteoarthritis, 
revised. Osteoarthritis Cartilage; 15(Suppl A):A1-56. 
Bannuru RR, Osani MC, Vaysbrot EE, et al (2019) OARSI guidelines for the non-surgical 
management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage p. 1578-
1589. 
 
Chan FKL, Ching JYL, Tse YK, et al (2017) Gastrointestinal safety of celecoxib versus 
naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal 
bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised 
trial. Lancet p. 2375-2382. 
Culliford DJ, Maskell J, Kiran A, et al (2012) The lifetime risk of total hip and knee 
arthroplasty: results from the UK general practice research database. Osteoarthritis Cartilage 
p. 519-24. 
Fernandes L, Hagen KB, Bijlsma JW, et al (2013) EULAR recommendations for the non-
pharmacological core management of hip and knee osteoarthritis. Ann Rheum Dis p. 1125-35. 
Glasson SS, Askew R, Sheppard B, et al (2005) Deletion of active ADAMTS5 prevents 
cartilage degradation in a murine model of osteoarthritis. Nature p. 644-8. 
Hawker GA, Badley EM, Borkhoff CM, et al (2013) Which patients are most likely to benefit 
from total joint arthroplasty? Arthritis Rheum p. 1243-52. 
Hawker GA, Mian S, Kendzerska T, et al (2011) Measures of adult pain: Visual Analog Scale 
for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire 
(MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale 
(CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and 
Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken) p. S240-52. 
Hayashi D, Roemer FW, Guermazi (2019) A Magnetic resonance imaging assessment of knee 
osteoarthritis: current and developing new concepts and techniques. Clin Exp Rheumatol p. 
88-95. 
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Hunter DJ, Bierma-Zeinstra S (2019) Osteoarthritis. Lancet p. 1745-1759. 
Karsdal MA, Michaelis M, Ladel C, et al (2016) Disease-modifying treatments for 
osteoarthritis (DMOADs) of the knee and hip: lessons learned from failures and opportunities 
for the future. Osteoarthritis Cartilage p. 2013-2021. 
KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic 
Kidney Disease (Internet) Available from https://kdigo.org/wp-
content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf (Accessed 23 May 2022). 
Kluzek S, Sanchez-Santos MT, Leyland KM, et al (2016) Painful knee but not hand 
osteoarthritis is an independent predictor of mortality over 23 years follow-up of a population-
based cohort of middle-aged women. Ann Rheum Dis p. 1749-56. 
Kolasinski SL, Neogi T, Hochberg MC, et al (2020) 2019 American College of 
Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the 
Hand, Hip, and Knee. Arthritis Rheumatol p. 220-233. 
KOOS User Guide (2003) (Internet) Available from http://www.koos.nu/ (Accessed 26 
February 2021). 
Larkin J, Lohr TA, Elefante L, et al (2015) Translational development of an ADAMTS-5 
antibody for osteoarthritis disease modification. Osteoarthritis Cartilage p. 1254-66. 
Larkin J., Lohr t., Elefante L., et al (2014) The highs and lows of translational drug 
development: antibody-mediated inhibition of ADAMTS-5 for osteoarthritis disease 
modification p. S483-84. 
Lees S, Golub SB, Last K, et al (2015) Bioactivity in an Aggrecan 32-mer Fragment Is 
Mediated via Toll-like Receptor 2. Arthritis Rheumatol p. 1240-9. 
McAlindon TE, Bannuru RR, Sullivan MC, et al (2014) OARSI guidelines for the non-
surgical management of knee osteoarthritis. Osteoarthritis Cartilage p. 363-88. 
Miller RE, Tran PB, Ishihara S, et al (2016) Therapeutic effects of an anti-ADAMTS-5 
antibody on joint damage and mechanical allodynia in a murine model of osteoarthritis. 
Osteoarthritis Cartilage p. 299-306. 
Nissen SE, Yeomans ND, Solomon DH, et al (2016) Cardiovascular Safety of Celecoxib, 
Naproxen, or Ibuprofen for Arthritis. N Engl J Med p. 2519-29. 
Oo WM, Yu SP, Daniel MS, et al (2018) Disease-modifying drugs in osteoarthritis: current 
understanding and future therapeutics. Expert Opin Emerg Drugs p. 331-347. 
Osteoarthritis Research Society International (2016) Osteoarthritis: a serious disease. White 
paper submitted to the U.S. Food and Drug Administration, viewed 16 December 2019 
p. 1-103. 
Roos EM, Engelhart L, Ranstam J, et al (2011) ICRS Recommendation Document: Patient-
Reported Outcome Instruments for Use in Patients with Articular Cartilage Defects. Cartilage 
p. 122-36. 

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Roos EM, Lohmander LS. The Knee injury and Osteoarthritis Outcome Score (KOOS): from 
joint injury to osteoarthritis. Health Qual Life Outcomes. 2003; p. 1(1):1–8. 
Solomon DH, Husni ME, Libby PA, et al (2017) The Risk of Major NSAID Toxicity with 
Celecoxib, Ibuprofen, or Naproxen: A Secondary Analysis of the PRECISION Trial. Am J 
Med p. 1415-1422.e4. 
Stanton H, Rogerson FM, East CJ, et al (2005) ADAMTS5 is the major aggrecanase in mouse 
cartilage in vivo and in vitro. Nature p. 648-52. 
Surowiec RK, Lucas EP, Fitzcharles EK, et al (2014) T2 values of articular cartilage in 
clinically relevant subregions of the asymptomatic knee. Knee Surg Sports Traumatol 
Arthrosc p. 1404-14. 
Tonge DP, Pearson MJ, Jones SW (2014) The hallmarks of osteoarthritis and the potential to 
develop personalised disease-modifying pharmacological therapeutics. Osteoarthritis 
Cartilage p. 609-21. 
Upadhyaya K, Ugonabo I, Satam K, et al (2021) Echocardiographic Evaluation of the 
Thoracic Aorta: Tips and Pitfalls. Aorta (Stamford) p. 1-8. 
US Preventive Services Task Force (2019) Screening for Abdominal Aortic Aneurysm US 
Preventive Services Task Force Recommendation Statement. JAMA p. 2211-8. 
Wolfe F, Egloff N, Häuser W (2016) Widespread Pain and Low Widespread Pain Index 
Scores among Fibromyalgia-positive Cases Assessed with the 2010/2011 Fibromyalgia 
Criteria. J Rheumatol p. 1743-8. 
Yazici Y, McAlindon TE, Gibofsky A, et al (2020) Lorecivivint, a Novel Intraarticular CDC-
like Kinase 2 and Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A Inhibitor 
and Wnt Pathway Modulator for the Treatment of Knee Osteoarthritis: A Phase II 
Randomized Trial. Arthritis Rheumatol p. 1694-1706. 
Zafar MA, Li Y, Rizzo JA, et al (2018) Height alone, rather than body surface area, suffices for 
risk estimation in ascending aortic aneurysm. J Thorac Cardiovasc Surg p.1938-50 
 
 
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16 
Appendices 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs 
Please refer to the Laboratory Manual for details. 

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16.2 
Appendix 2: Liver event and laboratory trigger definitions & 
follow-up requirements 
Abnormal liver chemistry and a liver event as per table below must be followed up by repeat 
testing within 48 to 72 hours of ALT, AST, ALP, GGT, total bilirubin (direct and indirect if 
total bilirubin is increased > 2 x ULN), INR, albumin, CK and GLDH. 
Table 16-1 
Liver event and laboratory trigger definitions 
 
Definition/ threshold 
Liver laboratory triggers 
If ALT, AST and total bilirubin normal at 
baseline: 
• 
ALT or AST > 5 × ULN 
• 
ALP > 2 × ULN (in the absence of known 
bone pathology) 
• 
Total bilirubin > 3 × ULN (in the absence of 
known Gilbert syndrome) 
• 
ALT or AST > 3 × ULN and INR > 1.5 
• 
Potential Hy’s Law cases (defined as ALT or 
AST > 3 × ULN and Total bilirubin > 2 × ULN 
[mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN) 
• 
Any clinical event of jaundice (or equivalent 
term) 
• 
ALT or AST > 3 × ULN accompanied by 
(general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with 
eosinophilia 
• 
Any adverse event potentially indicative of a 
liver toxicity 
If ALT or AST abnormal at baseline: 
• 
ALT or AST > 3 x baseline or > 200 U/L 
(whichever occurs first) 
Table 16-2 
Follow up requirements for liver laboratory triggers - ALT, AST, TBL 
  
ALT 
TBL 
Liver Symptoms 
Action 
ALT increase without bilirubin increase: 
 
 
If normal at 
baseline: 
ALT > 3 x ULN  
Normal 
 
For 
participants with 
Gilbert’s 
syndrome: No 
change in 
baseline TBL 
None 
• 
No change 
to study 
treatment 
• 
Measure 
ALT, AST, 
ALP, GGT, 
TBIL, INR, 
albumin, CK, 
and GLDH 
within 48-72 
hours. 
• 
Follow-up for 
symptoms. 
If elevated at 
baseline: 
ALT > 3 x 
baseline 
or > 200 U/L 
(whichever 
occurs ﬁrst) 

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ALT 
TBL 
Liver Symptoms 
Action 
 
If normal at 
baseline: 
ALT > 5 x ULN 
for more than two 
weeks 
OR 
ALT > 8 x ULN 
Normal 
 
For 
participants with 
Gilbert’s 
syndrome: No 
change in 
baseline TBL 
None 
• 
Interrupt 
study drug 
• 
Measure 
ALT, AST, 
ALP, GGT, 
TBIL, INR, 
albumin, CK, 
and GLDH 
within 48-72 
hours. 
• 
Follow-up for 
symptoms. 
• 
Initiate close 
monitoring 
and workup 
for competing 
etiologies. 
• 
Study drug 
can be 
restarted only 
if another 
etiology is 
identiﬁed and 
liver enzymes 
return to 
baseline. 
If elevated at 
baseline: 
ALT > 3 x 
baseline 
AND 5 x ULN for 
more than two 
weeks 
OR 
ALT ≥ 5 x 
baseline 
AND ≥ 8 x ULN 
ALT increase with bilirubin increase: 
 
If normal at 
baseline: 
ALT > 3 x ULN 
TBL > 2 x ULN 
(or INR > 1.5) 
For participants 
with Gilbert’s 
syndrome: 
Doubling of direct 
bilirubin 
None 
If elevated at 
baseline: 
ALT > 2 x 
baseline 
AND > 3 x ULN 
  
If normal at 
baseline: 
ALT > 3 x ULN 
Normal or 
elevated* 
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain* 
If elevated at 
baseline: 
ALT > 2 x 
baseline 
AND > 3 x ULN 
* This situation suggests liver injury based on (i) elevation of ALT, and (ii) the presence of symptoms of 
liver injury. Even if bilirubin is normal, the presence of liver symptoms indicates potentially severe liver 
injury. 

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Table 16-3 
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia 
Based on investigator’s discretion, investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease. 
Criteria 
Actions required 
Follow-up monitoring 
Total Bilirubin (isolated) 
 
 
>1.5 – 3.0 ULN 
• 
Maintain treatment 
• 
Repeat LFTs within 48-72 
hours 
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline 
> 3 - 10 × ULN (in the absence 
of known Gilbert syndrome) 
• 
Interrupt treatment 
• 
Repeat LFT within 48-72 
hours 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g., 
conmeds, med hx, lab) in 
the appropriate CRF 
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline Test for hemolysis 
(e.g., reticulocytes, 
haptoglobin, unconjugated 
[indirect] bilirubin) 
> 10 x ULN 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize the participant 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g., 
concomitant medications, 
medical history, laboratory 
and imaging investigations) 
in the appropriate CRF 
Monitor LFTs until resolution to 
≤ Grade 1 or to baseline 
(frequency at investigator 
discretion) 
Any AE potentially indicative of 
a liver toxicity 
• 
Consider study treatment 
interruption or 
discontinuation 
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g., 
conmeds, med hx, lab)in 
the appropriate CRF 
Investigator discretion 

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16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up 
Renal Event 
Actions 
eGFR decrease 25 – 49% 
• 
Consider causes and possible interventions 
• 
Repeat laboratory values within 48 hrs of 
receipt of abnormal test results. Assess 
patient for signs and symptoms of illness, 
AKI, etc. 
eGFR decrease ≥ 50 % *  
OR if <18 years old, eGFR < 35 mL/min/1.73 m2 
• 
Consider causes and possible interventions 
• 
Repeat laboratory values within 48 hrs of 
receipt of abnormal test results. Assess 
patient for signs and symptoms of illness, 
AKI, etc. 
• 
Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected 
• 
Consider referral to nephrologist for 
diagnosis and management 
• 
Consider patient hospitalization and 
specialized treatment 
New onset dipstick proteinuria ≥3+ 
OR 
Protein-creatinine ratio ≥1g/g Cr (or mg/mmol 
equivalent as converted by the measuring 
laboratory) 
• 
Repeat assessment to confirm 
• 
Confirm presence of true proteinuria by 
quantification: protein:creatinine on first 
morning void 
• 
Assess serum albumin & serum total protein 
• 
Consider causes and possible interventions 
• 
Consider referral to nephrologist 
• 
Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected 
New onset hematuria ≥3+ on urine dipstick 
• 
Assess & document 
• 
Obtain urine microscopy to distinguish 
hemoglobinuria or myoglobinuria from 
hematuria 
• 
Assess sCr 
• 
Exclude infection, trauma, calculi, bleeding 
from the distal urinary tract/bladder, 
menstruation 
• 
Consider bleeding disorder