A Two-part, Randomized, Placebo-controlled, Patient and Investigator Blinded, Study Investigating the Safety, Tolerability and Preliminary Efficacy of Intra-articular LNA043 Injections in Regenerating the Articular Cartilage of the Knee in Patients With Articular Cartilage Lesions (Part A) and in Patients With Knee Osteoarthritis (Part B).
Phase: PHASE2
Conditions: Osteoarthritis
Sponsor: Novartis Pharmaceuticals

Novartis Institutes for BioMedical Research
LNA043
Clinical Trial Protocol CLNA043X2202 / NCT03275064
A two-part randomized, placebo-controlled, patient and 
investigator blinded, Proof of Concept study investigating 
the safety, tolerability and preliminary efficacy of 
multiple intra-articular LNA043 injections in regenerating 
the articular cartilage of the knee in patients with 
articular cartilage lesions (Part A) and in patients with 
knee osteoarthritis (Part B)
Document type:
Amended Protocol Version
EUDRACT number:
2016-004052-30
Version number:
v07 (Clean)
Clinical Trial Phase:
II
Release date:
22-Dec-2020
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis

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

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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................7
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Pharmacokinetic definitions and symbols.........................................................................11
Glossary of terms...............................................................................................................13
Protocol synopsis...............................................................................................................27
1
Introduction .......................................................................................................................30
1.1
Background............................................................................................................30
1.2
Nonclinical data.....................................................................................................31
1.2.1
Non-clinical pharmacology...................................................................31
1.2.2
Non-clinical pharmacokinetics..............................................................32
1.2.3
Pre-clinical safety..................................................................................32
1.2.4
Teratogenicity and reproductive toxicity data.......................................33
1.3
Clinical data...........................................................................................................33
1.3.1
Human safety and tolerability data .......................................................33
1.3.2
Human pharmacokinetic data................................................................35
1.3.3
Human pharmacodynamic data.............................................................35
1.4
Study purpose ........................................................................................................36
2
Study objectives and endpoints .........................................................................................36
2.1
Primary objective(s)...............................................................................................36
2.2
Secondary objective(s)...........................................................................................37
2.3
Exploratory objective(s) ........................................................................................37
3
Investigational plan ...........................................................................................................38
3.1
Study design...........................................................................................................38
3.1.1
Part A ....................................................................................................38
3.1.2
Part B.....................................................................................................40
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3.2
Rationale of study design.......................................................................................41
3.2.1
Part A ....................................................................................................42
3.2.2
Part B.....................................................................................................42
3.3
Rationale for dose/regimen, route of administration and duration of treatment....43
3.3.1
Part A ....................................................................................................43
3.3.2
Part B.....................................................................................................44
3.4
Rationale for choice of comparator .......................................................................44
3.5
Purpose and timing of interim analyses/design adaptations..................................45
3.6
Risks and benefits..................................................................................................45
3.6.1
Blood sample volumes..........................................................................47
4
Population..........................................................................................................................47
4.1
Inclusion criteria ....................................................................................................49
4.2
Exclusion criteria...................................................................................................50
5
Restrictions for Study Subjects .........................................................................................52
5.1
Contraception requirements...................................................................................52
5.2
Prohibited treatment...............................................................................................53
5.3
Dietary restrictions and smoking...........................................................................54
5.3.1
Part A ....................................................................................................54
5.3.2
Part B.....................................................................................................54
5.4
Other restrictions ...................................................................................................54
6
Treatment...........................................................................................................................55
6.1
Study treatment......................................................................................................55
6.1.1
Investigational treatment and control drugs..........................................55
6.1.2
Additional study treatment....................................................................55
6.2
Treatment arms......................................................................................................55
6.2.1
Part A ....................................................................................................55
6.2.2
Part B.....................................................................................................55
6.3
Treatment assignment and randomization.............................................................56
6.4
Treatment blinding.................................................................................................56
6.5
Treating the subject................................................................................................58
6.6
Permitted dose adjustments and interruptions of study treatment.........................58
6.7
Emergency breaking of assigned treatment code ..................................................58
6.8
Treatment exposure and compliance .....................................................................59
6.9
Recommended treatment of adverse events ..........................................................59
6.10
Rescue medication.................................................................................................59
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6.10.1
Part A ....................................................................................................59
6.10.2
Part B.....................................................................................................60
6.11
Concomitant treatment...........................................................................................60
7
Study completion and discontinuation ..............................................................................60
7.1
Study completion and post-study treatment ..........................................................60
7.2
Discontinuation of study treatment........................................................................61
7.3
Lost to follow-up ...................................................................................................62
7.4
Withdrawal of informed consent ...........................................................................62
7.5
Study Stopping rules..............................................................................................62
7.5.1
Part A ....................................................................................................62
7.5.2
Part B.....................................................................................................63
7.6
Early study termination by the sponsor .................................................................63
8
Procedures and assessments ..............................................................................................64
8.1
Assessment schedule .............................................................................................64
8.2
Informed consent procedures.................................................................................72
8.3
Subject screening...................................................................................................72
8.4
Subject demographics/other baseline characteristics.............................................73
8.5
Efficacy / Pharmacodynamics ...............................................................................74
8.5.1
Knee MRI..............................................................................................74
8.6
Safety.....................................................................................................................75
8.6.1
Physical examination ............................................................................76
8.6.2
Vital signs..............................................................................................76
8.6.3
Height and weight .................................................................................76
8.6.4
Laboratory evaluations..........................................................................76
8.6.5
Electrocardiogram (ECG) .....................................................................77
8.6.6
Pregnancy and assessment of fertility...................................................77
8.6.7
Immunogenicity ....................................................................................78
8.7
Pharmacokinetics...................................................................................................78
8.8
Other assessments..................................................................................................79
8.9
Use of residual biological samples ........................................................................80
9
Safety monitoring..............................................................................................................80
9.1
Adverse events.......................................................................................................80
9.2
Serious adverse event reporting.............................................................................82
9.2.1
Definition of SAE .................................................................................82
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9.2.2
SAE reporting........................................................................................83
9.3
Liver safety monitoring .........................................................................................84
9.4
Renal safety monitoring.........................................................................................85
9.4.1
Part A ....................................................................................................85
9.4.2
Part B.....................................................................................................85
9.5
Reporting Medication errors including misuse/abuse ...........................................86
9.6
Pregnancy reporting...............................................................................................86
9.7
Early phase safety monitoring ...............................................................................87
10 Data review and database management.............................................................................87
10.1
Site monitoring ......................................................................................................87
10.2
Data collection.......................................................................................................88
10.3
Database management and quality control............................................................88
10.4
Data Monitoring Committee..................................................................................89
10.5
Adjudication Committee........................................................................................89
11 Data analysis......................................................................................................................89
11.1
Analysis sets ..........................................................................................................89
11.2
Subject demographics and other baseline characteristics......................................90
11.3
Treatments .............................................................................................................90
11.4
Analysis of the primary variable(s) .......................................................................90
11.4.1
Variable(s).............................................................................................90
11.4.2
Statistical model, hypothesis, and method of analysis..........................90
11.5
Handling of missing values/censoring/discontinuations .......................................91
11.6
Summary statistics of safety..................................................................................91
11.6.1
Sensitivity analyses ...............................................................................92
11.7
Analysis of secondary variable(s)..........................................................................92
11.7.1
Efficacy / Pharmacodynamics...............................................................92
11.7.2
Pharmacokinetics ..................................................................................92
11.7.3
Pharmacokinetic / pharmacodynamic interactions................................93
11.7.4
Immunogenicity ....................................................................................93
11.7.5
Other assessments .................................................................................93
11.8
Analysis of exploratory variables ..........................................................................93
11.9
Sample size calculation..........................................................................................94
11.9.1
Part A ....................................................................................................94
11.9.2
Part B.....................................................................................................95
11.10 Power for analysis of key secondary variables......................................................95
11.11 Interim analyses.....................................................................................................95
11.11.1
Part A ....................................................................................................95

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11.11.2
Part B.....................................................................................................95
12 Ethical considerations........................................................................................................96
12.1
Regulatory and ethical compliance........................................................................96
12.2
Responsibilities of the investigator and IRB/IEC..................................................96
12.3
Publication of study protocol and results...............................................................96
13 Protocol adherence ............................................................................................................96
13.1
Protocol Amendments ...........................................................................................97
14 References .........................................................................................................................98
15 Appendix 1: Liver Event Definitions and Follow-up Requirements...............................100
16 Appendix 2: Specific Renal Alert Criteria and Actions ..................................................102
List of tables
Table 1-1
Overall incidence of AE in LNA043X2202 Part A ..............................34
Table 1-2
Incidence of AE in LNA043X2202 Part A by preferred term 
(greater or equal to 2 events).................................................................34
Table 5-1
Prohibited treatment Part A...................................................................53
Table 5-2
Prohibited treatment Part B...................................................................54
Table 6-1
Overview of study medication ..............................................................55
Table 6-2
Blinding Levels (Part A and B).............................................................57
Table 8-1
Assessment Schedule Part A.................................................................64
Table 8-2
Assessment schedule Part B..................................................................68
Table 9-1
Summary of reporting requirements for medication errors...................86
Table 15-1
Liver Event Definitions.......................................................................100
Table 15-2
Actions required for Liver Events.......................................................100
Table 15-3
Exclusion of underlying liver disease .................................................101
Table 16-1
Specific Renal Alert Criteria and Actions for Part A..........................102
Table 16-2
Follow-up of renal events for Part A...................................................103
Table 16-3
Specific Renal Alert Criteria and Actions for Part B..........................104
Table 16-4
Renal Event Follow Up for Part B ......................................................105
List of figures
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List of abbreviations
ACI
Autologous Chondrocyte Implantation
ACR
American College of Rheumatology
ADA
Anti-Drug Antibody
ADL
Activities of Daily Living
AE
adverse event
AESIs
ALP
adverse event of special interest
alkaline phosphatase
ALT
alanine aminotransferase
ANGPLT3
angiopoietin-like 3 protein
AST
aspartate aminotransferase
BMI
Body Mass Index
BP
Blood Pressure
BUN
blood urea nitrogen
CFR
U.S. Code of Federal Regulation
CK
creatinine kinase
CMO&PS
Chief Medical Office & Patient Safety
COAR
Clinical Operations, Analytics & Regions
CR-MSCs
Cartilage Resident Mesenchymal Stem Cells 
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CTC
Common Toxicity Criteria
CV
coefficient of variation
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
EoS
End of study
FIH
First in human
GAG
Glycosaminoglycans
GCP
Good Clinical Practice
GLP
Good laboratory practice

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GGT
Gamma-glutamyl transferase
h
hour
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HIV
human immunodeficiency virus
i.a.
intra-articular
i.v.
intravenous
IA
Interim Analysis
IB
Investigator's Brochure
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICRS
International Cartilage Repair Society
IEC
Independent Ethics Committee
IG
Immunogenicity
IHC
Immunohistochemistry
IN
Investigator Notification
IRB
Institutional Review Board
IUD
Intrauterine device
IUS
Intrauterine System
JSW
Joint Space Width
K&L
Kellgren and Lawrence
kg
kilogram(s)
LDH
lactate dehydrogenase
LLOQ
lower limit of quantification
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
MMRM
Mixed Model Repeated Measures
MRI
Magnetic Resonance Imaging
MSC
mesenchymal stem cells
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NIRT
Novartis Interactive Response Technology
NSAIDs
Nonsteroidal anti-inflammatory drugs
OA
Osteoarthritis
PA
posteroanterior
PCR
Protein-creatinine ratio
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PoC
Proof of Concept
PoM
Proof of Mechanism
QoL
Quality of Life
RBC
red blood cell(s)
SAD
single ascending dose
SAE
serious adverse event
SAP
Statistical Analysis Plan
sCR
serum creatinine
SD
standard deviation
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
TKR
Total Knee Replacement
ULN
upper limit of normal
WBC
white blood cell(s)
WHO
World Health Organization
WOCBP
Women of child bearing potential
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Pharmacokinetic definitions and symbols
Ae0-t
Amount of drug (or defined metabolite) excreted into the urine from time zero 
to time 't' where t is a defined time point after administration [mass units or % 
of dose]
AUC0-t
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to time 't' where t is a defined time point after administration [mass 
x time / volume]
AUCinf
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to infinity [mass x time / volume]
AUClast
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to the time of the last quantifiable concentration [mass x time / 
volume]
AUCtau
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to the end of the dosing interval tau [mass x time / volume]
AUCtau,ss
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to the end of the dosing interval tau at steady state [mass x time / 
volume]
Cav,ss
The average steady state plasma (or serum or blood) concentration during 
multiple dosing
CL
The systemic (or total body) clearance from plasma (or serum or blood) 
following intravenous administration [volume / time]
CL/F
The apparent systemic (or total body) clearance from plasma (or serum or 
blood) following extravascular administration [volume / time]
CLr
The renal clearance from plasma (or serum or blood) [volume / time]
Cmax
The observed maximum plasma (or serum or blood) concentration following 
drug administration [mass / volume]
Cmax,ss
The observed maximum plasma (or serum or blood) concentration following 
drug administration at steady state [mass / volume]
Cmin,ss
The lowest plasma (or serum or blood) concentration observed during a 
dosing interval at steady state [mass / volume]
F
Bioavailability of a compound. Fabs is the absolute bioavailability, i.e. the 
fraction (or percentage) of the administered extravascular dose systemically 
available. Frel is the relative bioavailability, i.e. the bioavailability relative to 
a reference
MRT
Mean residence time determined as AUMCinf/AUCinf following intravenous 
administration [time]
Racc
The accumulation ratio
T1/2
The terminal elimination half-life [time]

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T1/2,acc
The effective half-life based on drug accumulation at steady state [time]
Tmax
The time to reach the maximum concentration after drug administration 
[time]
Vss
The volume of distribution at steady state following intravenous 
administration [volume]
Vz
The volume of distribution during the terminal elimination phase following 
intravenous administration [volume]
Vz/F
The apparent volume of distribution during the terminal elimination phase 
following extravascular administration [volume]

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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug(s) (an active drug or an inactive drug, such as a placebo) which 
is used as a comparator to the investigational drug being tested in the 
trial
Dosage
Dose of the study treatment given to the subject in a time unit 
(e.g. 100 mg once a day, 75 mg twice a day)
Enrollment
Point/time of subject entry into the study at which informed consent must 
be obtained (i.e. prior to starting any of the procedures described in the 
protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is associated 
with a purpose (e.g. screening, randomization, treatment, follow-up) 
which applies across all arms of a study.
Investigational 
drug
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and Directive 
2001/20/EC and is synonymous with “investigational new drug” or “test 
substance”
Investigational 
treatment
All investigational drug(s) whose properties are being tested in the study 
as well as their associated treatment controls. This includes any placebos, 
any active controls, as well as approved drugs used outside of their 
indication/approved dosage or tested in a fixed combination. 
Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed by 
the protocol when used within approved indication/dosage.
Patient
An individual with the condition of interest
Period
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc.
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and assessments; at this time 
all study drug administration is discontinued and no further assessments 
are planned.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding 
to a specific treatment arm assignment
Screen Failure
A subject who is screened but is not treated or randomized
Stage
A major subdivision of the study timeline; begins and ends with major 
study milestones such as enrollment, randomization, completion of 
treatment, etc.

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Study completion
Point/time at which the subject came in for a final evaluation visit or 
when study drug was discontinued whichever is later.
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug for any 
reason; may or may not also be the point/time of premature subject 
withdrawal.
Study 
drug/treatment
Any drug (or combination of drugs) administered to the subject as part 
of the required study procedures; includes investigational drug, active 
drug run-ins or background therapy.
Study treatment
Any drug administered to the study participants as part of the required 
study procedures; includes investigational drug (s), control(s) or 
non-investigational medicinal product(s)
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject 
and should be used to identify the subject throughout the study for all 
data collected, sample labels, etc.
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested 
in the study
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study is defined as when a subject does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study related 
contact, and does not allow analysis of already obtained biologic 
material

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Protocol synopsis
Protocol number
CLNA043X2202
Title
A two-part, randomized, placebo-controlled, patient and investigator blinded, 
Proof of Concept study investigating the safety, tolerability and preliminary 
efficacy of multiple intra-articular LNA043 injections in regenerating the 
articular cartilage of the knee in patients with articular cartilage lesions (Part 
A) and in patients with knee osteoarthritis (Part B).
Brief title
Study of safety, tolerability and preliminary efficacy of multiple intra-articular 
LNA043 injections in patients with articular cartilage lesions (Part A) and in 
patients with knee osteoarthritis (OA) (Part B).
Sponsor and 
Clinical Trial 
Phase
Novartis
Phase 2
Intervention type
Biologic
Study type
Interventional 
Purpose and 
rationale
The purpose of this study is to assess the efficacy, safety and tolerability of 
multiple intra-articular (i.a.) injections of LNA043, in regenerating the articular 
surface in patients with cartilage lesions of the knee. This study aims to 
establish Proof of Concept (PoC), namely regeneration of the articular 
cartilage, in order to provide information on the potential clinical utility of 
LNA043, with the ultimate goal of replacing current surgical procedures for 
cartilage repair with an injectable, less invasive regenerative therapy. 
Both lesions of the femoral condyles and patella will be considered, in order 
to address a broad population and maximize the clinical relevance of this study 
(Part A). In Part B patients with medial femoral disease will be enrolled to 
evaluate the efficacy of LNA043.
Primary 
Objective(s)
To assess the efficacy of multiple i.a. injections of LNA043 in regenerating the 
articular cartilage tissue
To assess safety and local tolerability of multiple i.a. injections of LNA043
Secondary 
Objectives
To assess the extent of the repair cartilage tissue following multiple i.a. 
injections of LNA043
To evaluate systemic and local PK of LNA043 following multiple i.a. injections 
of LNA043
To assess the potential immunogenicity of LNA043
Study design
This is a non-confirmatory, two-part, randomized, placebo-controlled, patient 
and investigator blinded study
Population
The study population will be comprised of approximately 60 male and female 
patients with symptomatic partial thickness (ICRS grade II-IIIA) cartilage 
lesions of one knee in Part A, and approximately 75 male and female patients 
with knee OA (Kellgren&Lawrence score of 2-3) in Part B.
In total, approximately 135 patients are expected to be randomized into the 
study.

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Key Inclusion 
criteria

Part A: Patient is ≥18 and ≤55 years old at time of screening. 
Part B: Patient is ≥18 and ≤75 years old at time of screening.  

Part A: Patient has a body mass index (BMI) <30 kg/m2 at screening, for 
patients with a BMI >30 but ≤33 kg/m2, eligibility will be decided by 
consultation with the sponsor.
Part B: Patient has a body mass index (BMI) ≤35 kg/m2 at screening.

Part A ONLY: Patient has a symptomatic, single, articular cartilage 
defect of one knee, grade II or IIIA according to the ICRS classification, 
localized to either the femoral condyles/femoral trochlea or to the patella, 
based on MRI or arthroscopy performed within 9 months before 
screening visit and confirmed by screening 3T MRI.

PART A ONLY: Patient has an onset of pain and impairment of function 
between two (2) months and two (2) years before screening.

 

Part B ONLY: Diagnosis of femorotibial OA in the target knee

Part B ONLY: K&L grade 2 or 3 OA of the knee with minimum Joint 
Space Width (JSW) 2.00-4.00 mm at screening

Part B ONLY: History of pain due to OA in the target knee for at least 6 
months at screening
Key Exclusion 
criteria

Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective 
methods of contraception during dosing and for 15 days after stopping of 
investigational drug. 

Part A: Regular smokers (> 5 cigarettes/day). Urine cotinine levels will 
be measured during screening for all patients. Regular smokers will be 
defined as any patient who reports tobacco use of > 5 cigarettes/day 
and/or who has a urine cotinine ≥ 500 ng/mL. 
Part B: Regular smokers (> 10 cigarettes/day).

PART A ONLY: Patient has radiologically apparent degenerative joint 
disease in the target knee as determined by Kellgren and Lawrence grade ≥2 
based on X-ray evaluation performed within 9 months from screening.

Patient has had surgical treatment of the target knee using mosaicplasty, 
microfracture, meniscectomy >50% 
(Note: prior diagnostic arthroscopy with debridement and lavage, <50% 
meniscectomy, lateral release, patellar realignment, medial patellofemoral 
ligament reconstruction are acceptable if performed at least 2 months prior to 
screening; anterior cruciate ligament reconstruction is acceptable if performed 
12 months prior to screening, or less if restoration of joint function is evident, 
and agreed by the sponsor). 

Patient has an unstable target knee joint (including but not limited to 
posttraumatic or congenital laxity) or insufficiently reconstructed ligaments 
based on medical history and physical examination by the investigator. 

PART A ONLY: Patient has patellofemoral dysplasia Dejour Grade B-D 
based on X-ray or MRI evaluation 

Patient has malalignment (valgus- or varus-deformity) in the target knee 
≥5° (Part A) or > 7.5° (Part B) based on X-ray evaluation at screening. 
In suspected cases, the mechanical axis must be established 
radiographically through complete leg imaging during standing and in 
postero-anterior (PA) projection. 
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
Part B ONLY: Clinical signs of inflammation in the target knee

Part B ONLY: History of knee replacement in either knee

Part B ONLY: Presence of severe hip OA conditioning lower limb
function

Part B ONLY: Nephrotic syndrome and/or significant proteinuria

Part B ONLY: History of coagulopathy or medical condition requiring
anticoagulation which would preclude knee injection  (antiplatelet or
anticoagulant treatment [for patients using warfarin, INR to be <3 prior to
injection], is allowed)
Study treatment
Part A:

Single i.a. injection of 20 mg [LNA043],

Single i.a. injection of placebo to 20 mg [LNA043],
Part B:

Single i.a. injection of 40 mg [LNA043],

Single i.a. injection of 20 mg [LNA043],

Single i.a. injection of placebo,
Efficacy/PD 
assessments
Part A:

Articular cartilage bi-layer collagen organization evaluated with
T2 relaxation times measured in superficial and deep layers by
T2 mapping MRI
Part B:

Change in volume of cartilage defect filling evaluated with MRI
Key safety 
assessments

Adverse event monitoring

3 hours observation period post every i.a. LNA043 administration

Physical examination

Monitoring of laboratory markers in blood and urine
Other 
assessments

Data analysis
The primary efficacy variable in Part A, articular cartilage bi-layer collagen 
organization, assessed based on MRI at Week 16 and 28, and the primary 
efficacy variable in Part B, change from baseline in volume of cartilage defect 
filling evaluated with MRI at Weeks 28 and 52, will be analyzed using a mixed 
model with repeated measures (MMRM), including baseline and both time 
points to compare treatment groups at Week 16 and Week 28
Key words
Articular cartilage, partial thickness cartilage lesion, knee, cartilage regeneration
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1
Introduction
1.1
Background
When articular cartilage damage occurs, healing is limited. Currently, there is no approved 
pharmacological treatment to regenerate durable hyaline cartilaginous tissue, capable of 
withstanding joint stress and supporting an active life style. Current surgical procedures 
(e.g., microfracture) typically lead to fibrous, fibrocartilaginous and/or calcified repair tissue 
with limited biochemical and biomechanical properties. Clinical evidence has also shown that 
untreated focal defects of the articular cartilage may progress, leading to osteoarthritis (OA) and 
requiring joint replacement later in life, with potentially unsatisfactory outcomes for the patients and 
high costs for the community. Therefore, there is a high unmet medical need for more effective 
and efficient ways of repairing the articular cartilage, in order to intervene earlier, less 
invasively and stop the disease progression to OA.
Articular cartilage has limited healing potential. During cartilage damage, the number of 
cartilage resident mesenchymal stem cells (CR-MSCs) increases. CR-MSCs are capable of 
multi-lineage differentiation, including chondrogenesis, when exposed to an appropriate 
signaling environment in vitro. The LNA043 program arose from an effort to identify molecules 
able to target CR-MSCs to undergo differentiation into chondrocytes and facilitate hyaline 
articular cartilage repair by inducing the production of SOX9, type II collagen and aggrecan, 
but not inducing fibrosis or osteogenesis. LNA043 is a modified, recombinant version of the 
human angiopoietin-like 3 (ANGPTL3) protein, comprising its C-terminal domain. LNA043 
acts directly on CR-MSCs and articular chondrocytes through binding to α5β1 and αVβ3 
integrins (RGD class) on the cell surface to transmit its anabolic repair effects on cartilage cells. 
These events promote the formation of articular cartilage extracellular matrix proteins in mature 
chondrocytes and in CR-MSCs while supporting re-growth of CR-MSCs.
Considering the previous 
 clinical experience, and the lack of a 
disease-modifying treatment for these patients, a favorable benefit/risk ratio is anticipated for 
the patients included in the present study.
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The most relevant data for the present study are summarized in the sections below. For detailed 
information, please refer to the Investigator's Brochure. 
1.2
Nonclinical data
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1.3
Clinical data
1.3.1
Human safety and tolerability data
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In Part A of the ongoing PoC LNA043X2202 study, no deaths, drug-related SAEs or 
discontinuations due to adverse events were reported following weekly repeat doses of 20mg 
with cut-off date 31-Jan-2020. A higher incidence of study drug-related AEs was reported for 
LNA043 (Table 1-1). The 3 severe AEs for LNA043 were headache and 2 back pain, while the 
one for placebo was hypertension. 
Table 1-1
Overall incidence of AE in LNA043X2202 Part A
AEs, Subjects with AEs
LNA043 20 mg
N=43
nE, nS (%)
Placebo
N=15
nE, nS (%)
Total
N=58
nE, nS (%)
AEs, Any
51, 23 (53.5)
10, 7 (46.7)
61, 30 (51.7)
AEs of mild toxicity
27, 16 (37.2)
5, 4 (26.7)
32, 20 (34.5)
AEs of moderate toxicity
21, 13 (30.2)
4, 4 (26.7)
25, 17 (29.3)
AEs of severe toxicity
3, 3 (7.0)
1, 1 (6.7)
4, 4 (6.9)
Study drug-related AEs
17, 10 (23.3)
1, 1 (6.7)
18, 11 (19.0)
Serious AEs
1, 1 (2.3)
0
1, 1 (1.7)
AEs leading to discontinuation of study treatment
0
0
0
A higher incidence of joint swelling (9.3% vs 0%) and arthralgia (11.6% vs 6.7%) is reported 
for LNA043 (Table 1-2). Most of these occurred after the i.a. injection, resolved spontaneously 
or with paracetamol/NSAIDs and are consistent with a mild/moderate local reaction of the knee 
to the drug. This is also consistent with the AE-incidence of i.a. hyaluronans and of similar i.a. 
biologics (e.g., sprifermin) (Hochberg et al 2019). No AEs compatible with hypersensitivity 
reactions have been reported. No anti-LNA043 antibodies were detected in any of the tested 
samples.
Table 1-2
Incidence of AE in LNA043X2202 Part A by preferred term (greater or 
equal to 2 events)
LNA043 20mg
N= 43
n (%)
Placebo 
N= 15
n (%)
Total
N= 58
n (%)
Subjects with at least one AE(s) 
23  (53.5)
7  (46.7)
30  (51.7)
Arthralgia
5  (11.6)
1   (6.7)
6  (10.3)
Headache
5  (11.6)
1   (6.7)
6  (10.3)
Joint Swelling
4   (9.3)
0
4   (6.9)
Back Pain
2   (4.7)
1   (6.7)
3   (5.2)
Upper Respiratory Tract Infection
2   (4.7)
1   (6.7)
3   (5.2)
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1.3.2
Human pharmacokinetic data
1.3.3
Human pharmacodynamic data
The CLNA043X2201 study is completed and has been performed in patients undergoing 
Autologous Chondrocyte Implantation (ACI) to treat a cartilage lesion. LNA043 was 
administered i.a. right after the end of the first surgery and the donor site was monitored with 
Magnetic Resonance Imaging (MRI) at 4- and 12-week to detect cartilage regeneration at this 
site. Both the extent of tissue growth and the quality of tissue composition were evaluated with 
7 Tesla MRI. 7 Tesla MRI scanners are needed to perform a compositional evaluation of the 
proteoglycan component of the cartilage extracellular matrix. Analysis of data showed that, at 
both time points, tissue compatible with early hyaline cartilage was detected at the donor site. 
Most of the cartilage regeneration occurred within the first 4 weeks, with a minimal further 
improvement from 4 to 12 weeks, suggesting a longer pharmacodynamic (PD) effect of 
LNA043.
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1.4
Study purpose
The purpose of this two-part study is to assess the efficacy, safety and tolerability of multiple 
intra-articular (i.a.) injections of LNA043, in regenerating the articular surface in patients with 
cartilage lesions of the knee (Part A) and knee osteoarthritis (Part B). 
 In Part A, this study aims to establish Proof of 
Concept (PoC), namely regeneration of the articular cartilage, in order to provide information 
on the potential clinical utility of LNA043, with the ultimate goal of replacing current surgical 
procedures for cartilage repair with an injectable, less invasive regenerative therapy. 
Both lesions of the femoral condyles and patella will be considered, in order to address a broad 
population and maximize the clinical relevance of this study. In Part B, this study aims at further 
evaluating the cartilage anabolic activity of LNA043 in a more severe knee OA population, and 
at testing the potential benefit of a higher dose of LNA043 administered i.a. monthly instead of 
weekly. This study will support the further development of LNA043 in a broader clinical setting 
and with different dose regimens.
2
Study objectives and endpoints
2.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary objective(s)

To assess the efficacy of multiple
i.a. injections of LNA043 in
regenerating the articular cartilage
tissue

Articular cartilage bi-layer collagen
organization evaluated with T2 relaxation
times measured in superficial and deep layers
by T2 mapping Magnetic Resonance
Imaging (MRI) at Week 16 and 28 (Part A)

Change in cartilage volume/thickness in the
index region at Week 28 and 52 (Part B)

To assess safety and local
tolerability of multiple i.a. injections
of LNA043

Systemic and local Adverse Events

Electrocardiograms (ECGs)

Vital signs

Hematology, blood chemistry, urinalysis
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2.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

To assess the extent of the repair
cartilage tissue following multiple
i.a. injections of LNA043

Change in volume of cartilage defect filling
evaluated with MRI at Week 16 and 28 (Part A)

Articular cartilage bi-layer collagen
organization evaluated with T2 relaxation
times measured in superficial and deep layers
by T2 mapping Magnetic Resonance
Imaging (MRI) at Week 28 and 52 (Part B)

To evaluate systemic and local PK
of LNA043 following multiple i.a.
injections of LNA043

Serum and synovial fluid PK profile of
LNA043 and ANGPTL3

To assess the potential
immunogenicity of LNA043

Presence and characterization of anti-
LNA043 antibodies in serum at Day 1,
Day 15, Day 50, Day 106 and Day 190
(Part A) and Day 1,  Day 29,  Day 57,
Day 85, Day 113, Day 197 and Day 365
(Part B)
2.3
Exploratory objective(s)
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3
Investigational plan
3.1
Study design
3.1.1
Part A
This is a non-confirmatory, randomized, placebo-controlled, patient and investigator blinded 
study in patients with a partial thickness cartilage lesion of the knee.
Following their informed consent, patients will be assessed for eligibility at the screening visit. 
Whenever possible, the MRI should be performed in advance, or immediately after eligibility 
assessment on the same day of screening within the screening period (Day -35/-5). 
Safety laboratory assessments should be performed as close as possible to dosing Day 1. 
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Investigators may perform an unscheduled visit between Screening and first treatment on Day 1 
if deemed to confirm eligibility of the subject, or verify safety.
On Day 1, eligible patients will receive either an i.a. injection of LNA043 (20 mg 
) 
or matching placebo (
) according to a 3:1 randomization ratio.
At each treatment visit, safety and pharmacokinetics will be assessed as detailed in the 
Assessment schedule (Table 8-1). The investigator will schedule telephone calls with the patient 
approximately 48 hours after each study drug administration, and two weeks after the last 
injection, for follow-up assessment of safety. In case of safety concerns, the patient will return 
to the hospital for assessment and follow-up. 
 The EOS visit assessments should be performed also in case of 
premature patient discontinuation for any reason (except in case of consent withdrawal).
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3.1.2
Part B
This is a non-confirmatory, randomized, placebo-controlled, patient and investigator blinded 
study in patients with K&L 2-3 knee OA.
Following their informed consent, patients will be assessed for eligibility at the screening visit. 
Investigators may perform an unscheduled visit between Screening and first treatment on Day 
1 if deemed to confirm eligibility of the subject, or verify safety.
Screening X-ray will be evaluated by the central reader for eligibility. Baseline MRI will be 
performed after eligibility has been verified. On Day 1, eligible patients will receive a 
 i.a. 
injection of either LNA043 20 mg, LNA043 40 mg, or matching placebo according to a 1:1:1 
randomization ratio. 
During the treatment period, safety and 
pharmacokinetics will be assessed as detailed in the Assessment schedule (Table 8-2).
Patients will be monitored on site 3 hours after the i.a. injections. The investigator will schedule 
telephone calls with the patient approximately 48 hours after each study drug administration for 
follow-up assessment of safety. In case of safety concerns, the patient will return to the clinical 
site for assessment and follow-up. 
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3.2
Rationale of study design
The design of this study addresses the primary objective of cartilage healing in patients with 
articular cartilage defects of the knee and knee OA and takes into account (i) the clinical need; 
(ii) clinical and preclinical data on LNA043; (iii) current practice with intra-articular injectable
drugs; and (iv) the burden on patients with articular cartilage lesions and knee OA.
The combination of MRI with cartilage-specific pulse sequences (Juras et al 2016a) 
will ensure appropriate evaluation 
of LNA043 effect, from both a morphological and a functional standpoint. 
The study has been designed as patient and investigator blinded in order to ensure that b h 
investigators and patients remain in a state of equipoise, so that a putative difference betw
n 
the treated and control groups can be interpreted as an effect of study treatment. To evalu e 
potential unconscious bias at the patient level, patients will be asked at EoS, which treatment 
they believe they have received. Since the assessment of the envisioned endpoints is 
independent of the investigator, a comparable evaluation at the investigator level is not planned. 
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3.2.1
Part A

Randomization will be 3:1 (treatment:placebo), in order to reduce the number of people
exposed to placebo, who will not have the chance for therapeutic benefit.

Regarding the patient population, both lesions to the patella and to the femoral
condyles/trochlea will be addressed. This will allow us to examine LNA043's effect in these
two patient groups, characterized by different clinical, morphological and biomechanical
features, and by a differential response to surgical procedures (Filardo et al 2014), in order
to better inform further development of LNA043. Accordingly, randomization will be
stratified by type of lesion (femoral condyle/trochlea or patella).

A follow-up period at Week 52 (48 weeks after the last study dose) is considered adequate
to evaluate cartilage healing and to better understand the kinetics of cartilage growth,
durability of the regenerated tissue
and long-term efficacy in this population.
(Le Graverand-Gastineau 2010, Raynauld et al 2004)

Inclusion criteria (e.g., BMI<33, age range 18-55 years), and a limited range of lesion depth
(partial thickness lesions), corresponding to grade II-IIIA according to the International Cartilage
repair Society (ICRS) classification) (Brittberg and Winalski 2003), have been selected in
order to ensure homogeneity in a small patient sample.
3.2.2
Part B

Based on the positive results of the CLNA043X2201 study and of this ongoing
CLNA043X2202 study (Part A), a broader patient population of knee OA with high medical
need patient population is now being evaluated in part B.

The patient population of knee OA K&L 2-3 with JSW 2.00-4.00mm has been selected
based on the post-hoc analysis of the FORWARD trial (Gühring et al 2019), 

The MRI data collected at different time points will allow for the evaluation of the short-
and long-term effect of one monthly cycle of i.a. treatment with LNA043 and a comparison
between the 2 doses tested (20 mg and 40 mg). Meanwhile, since the image analysis will
cover well-defined regions the articular cartilage throughout the knee as has been done in
part A, results from part B, especially those obtained from the 20 mg group, may also be
compared with the results from part A to evaluate the potential added benefit of the monthly
dosing regimen in the index region (as defined in part B) vs the damaged region (as defined
in part A).

The monthly dosing regimen (x 4) has been selected based on the results of the FIH clinical
study, which suggests a long PD effect of LNA043.
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3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
3.3.1
Part A
The dose of LNA043 given in this study will be 20 mg, by i.a. injection 
In conclusion, clinical experience to date with LNA043 indicates that this compound is safe and 
well-tolerated. A dose of 20 mg has been selected for repeat dosing, once weekly for four weeks, 
based on safety and feasibility, and in order to maximize the likelihood of delivering a sustained, 
pharmacodynamic effect on cartilage repair in the knee. Moreover, the proposed dose regimen 
is also consistent with current non-operative practices for the symptomatic treatment of 
cartilage lesions, including e.g., i.a. hyaluronan injections which are administered up to five 
times once-weekly. 
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3.3.2 
Part B 
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Protocol No. CLNA043X2202 
Pait B of this study aims to assess a potential incremental treatment benefit of 20 mg/knee vs 
40 mg/knee dose 
CCI 
. Based on the available clinical data, the 
40 mg/dose in 
, might 
have favorable risk-benefit profile compared to the single and repeated weekly dosing 
regimens tested up to date. 
The proposed dosing regimen takes into account that: 
•
LNA043 displayed a favorable safety profile with no significant dmg related safety
signals, up to the maximum evaluated dose of 40 mg/knee in the FIH SAD study.
• 
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•
Up to date understanding of dose-response chai·acteristics of LNA043 in the targeted
population is limited. However, dose dependency of PD responses in the FIH SAD study
indicate that the 40 mg/knee dose may be associated with an incremental treatment
benefit without major safety and tolerability concerns.
•
Impo1tantly, the PD results from FIH SAD, showed upregulation of chondrogenic genes
for up to 21 days, indicating lasting effects and monthly dosing regimen seem to be more
appropriate to fully elicit potential treatment benefit of LNA043.
In summaiy, the less frequent, once-monthly administration of LNA043 up to 40 mg/knee 
is not expected to be associated with an increased safety/tolerability risk but potentially lead 
to an incremental treatment benefit for treated patients. Impo1tantly, Pait B of the study 
provides essential info1mation for fuither optimization of the dosing regimen. 
3.4 
Rationale for choice of comparator 
No ca1tilage-anabolic compound able to promote caitilage healing has been approved so far. 
Therefore, the compai·ator will be placebo. 
Placebo contains the saine fo1mulation and excipients as the investigational drng, without the 
active agent. Additionally, the study will be perfonned with identical standai·d of care 
procedures in both the control and investigational drng anns. 
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3.5
Purpose and timing of interim analyses/design adaptations
3.6
Risks and benefits
It is not known whether there will be a benefit for the patients participating in this study. 
However, data from the completed and ongoing studies demonstrate a cartilage anabolic activity 
of LNA043, with the potential to regenerate the articular cartilage of the knee. No disease 
modifying therapy exists as standard of care for patients with articular cartilage damage, 
including from osteoarthritis. Therefore, no such therapies will be withheld by joining this study. 
The risk to patients in this trial will be minimized by adherence to the eligibility criteria, close 
clinical monitoring, and stopping rules. 
Invasive, study-specific procedures include synovial fluid aspiration and i.a. injection of 
LNA043: as with any intra-articular injection, a risk of iatrogenic infection exists. 
Recent reports found infection rates following i.a. injection of steroids between 1 in 3000 and 
1 in 50,000 (Lavelle et al 2007). However, few orthopedists and rheumatologists have 
encountered a case of poststeroid septic arthritis (Charalambous et al 2003). In addition, when 
proper technique is applied in a healthy population, and when a non-steroidal drug is used, this 
rate is supposed to be considerably lower. 
Sterile technique will be used in all phases of drug reconstitution and administration to further 
reduce the risk of infection. Potential adverse effects may include local reactions at the site of 
injection, such as local pain, swelling or inflammation. Potential adverse events will be 
monitored clinically. Synovial fluid aspiration will be performed at the same time as the i.a. 
injection of LNA043, with no additional harm or discomfort for the patient. Systemic 
concentrations following i.a. administration to the patients studied in the FIH study remained 
<300 ng/mL and within the physiologic range for circulating concentrations of ANGPTL3. In 
addition, based on the current data available, LNA043 is not expected to persistently bind to or 
block its receptors. 
Being a modified protein, hypersensitivity and/or immunogenicity to LNA043 may occur. 
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In the completed and ongoing clinical studies, no case of local or systemic hypersensitivity 
reactions have been observed, and no patient developed ADA after a single or multiple intra-
articular injection of LNA043. The impact of neutralizing antibodies that may cross-react with 
endogenous ANGPTL3 is not known, but the likely impact is considered relatively low. 
Humans with loss-of-function variants in both copies of the ANGPTL3 gene have low plasma 
LDL-C, low HDL-C, and low triglycerides, but no obvious adverse consequences, suggesting 
that absence of ANGPTL3 does not result in any serious effects. Development of anti-LNA043 
antibodies will be monitored, as well as any potential reactions related to such antibodies, such 
as antibody-mediated arthropathy or impact on lipid metabolism or renal function, will be 
monitored closely with the corresponding safety plan in place.
Based on a comprehensive analysis of all safety data from both completed and ongoing 
preclinical and clinical studies, there is no evidence to suggest that treatment with LNA043 
increases the risk of hypersensitivity in humans. 
 
In order to mitigate this risk in humans, patients with a history of 
hypersensitivity reactions to any of the study treatments or excipients or to drugs of similar 
chemical classes will be excluded from participation in this study. Study drug administration 
will be administered at locations with emergency care facilities, and patients are required to 
undergo observation for three hours post-injection prior to leaving the site, to ensure their safety.
Patients who experience any Grade hypersensitivity reaction must not be re-dosed.
Women of child bearing potential will be informed that taking the investigational drug may 
involve unknown risks to the fetus if a pregnancy was to occur during the study, and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the subject will not reliably comply, they 
should not be entered in the study.
Risks of imaging procedures
For screening purposes, a standing long leg view of the lower limbs and a Merchant view of the 
patello-femoral joint are required. These are often performed during the routine evaluation of 
patients with knee pain, but not always. Consequently, in some patients they will be obtained 
only for research purposes. The total amount of radiation exposure per subject from these 
X-rays will be about 100 µSv. This amount of radiation is equivalent to approximately
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13.8 days 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.
The only imaging technique used in this study for follow-up purposes is MRI. MRI is a 
non-invasive radiology technique that has no x-ray radiation exposure. No MRI contrast agent 
will be administered in this study. 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 a MRI image quality. For more information, see exclusion criterion 11.
There may be unknown risks of LNA043 which may be serious.
Covid-19 risk assessment
Novartis is committed to supporting the safety and well-being of our study participants,
investigators, and site staff. All local regulations and site requirements should be applied in the 
countries that are affected by the COVID-19 pandemic. The Novartis clinical trial team will 
review the situation in each participating country and work with Investigators to continue to 
ensure the safety of participants during the conduct of the trial. 
A benefit/risk assessment has been made and has been determined to not significantly change 
for the participants that are planned to be enrolled in the proposed clinical trial. As the 
COVID-19 situation evolves, Investigators must use their best judgement to minimize risk to 
participants during the conduct of the study.
3.6.1
Blood sample volumes
A maximum of 227 mL of blood is planned to be collected in each part over a period of up to 
61 weeks, from each subject as part of the study. Samples for monitoring of any safety findings 
would be in addition to this. This is not considered to be a risk for this population.
Timings of blood sample collection are outlined in the Assessment Schedule, Table 8-1 and 
Table 8-2.
A summary blood log is provided in the Site Operations Manual, together with instructions for 
all sample collection, processing, storage and shipment information.
See Section 8.9 regarding the potential use of residual samples. 
4
Population
Part A
In Part A, the study population will be comprised of male and female patients with partial 
thickness cartilage lesions of one knee. A total of approximately 60 patients will be enrolled in 
the study and randomized. Randomization will be stratified by type of lesion (femoral condyle 
or patella). At least 48 patients are expected to complete the study (20% drop out rate). 
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The investigator must ensure that all patients included in the study meet the eligibility criteria. 
No additional criteria should be applied by the investigator, in order that the study population 
will be representative of all eligible patients. Patient selection is to be established by checking 
through all eligibility criteria at screening and before dosing. A relevant record (e.g. checklist) 
of the eligibility criteria must be stored with the source documentation at the study site.
Deviation from any entry criterion excludes a patient from enrollment into the study.
Part B
In Part B, the study population will be comprised of male and female patients with knee OA 
(K&L 2-3). A total of approximately 75 patients will be enrolled in the study and randomized. 
At least 69 patients are expected to complete the study (10% drop out rate). Additional patients 
may be enrolled if the dropout rate will exceed 10%. The investigator must ensure that all 
patients included in the study meet the eligibility criteria. No additional criteria should be 
applied by the investigator, in order that the study population will be representative of all 
eligible patients. Patient selection is to be established by checking through all eligibility criteria 
at screening and before dosing. A relevant record (e.g. checklist) of the eligibility criteria must 
be stored with the source documentation at the study site.
In total, 135 patients are expected to be randomized into the study.
Deviation from any entry criterion excludes a patient from enrollment into the study.
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4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any study-related assessment is
performed.
2. Able to communicate well with the investigator, to understand and comply with the
requirements of the study.
3. Part A: Patient is ≥18 and ≤55 years old at time of screening.
Part B: Patient is ≥18 and ≤75 years old at time of screening.
4. Part A: Patient has a body mass index (BMI) <30 kg/m2 at screening. For patients with a
BMI >30 but ≤33 kg/m2, eligibility has to be confirmed by consultation with the sponsor.
Part B: Patient has a body mass index (BMI) ≤35 kg/m2 at screening.
5. Part A ONLY: Patient has a symptomatic, single, partial thickness articular cartilage defect
of one knee, grade II or IIIA according to the ICRS classification, localized to either the
femoral condyles/femoral trochlea or to the patella, based on MRI or arthroscopy performed
within 9 months before screening visit and confirmed by screening 3T MRI.
6. Part A ONLY: Patient has an onset of pain and impairment of function between two (2)
months and two (2) years before screening.
7.
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8. Part B ONLY: Diagnosis of femorotibial OA in the target knee by standard American 
College of Rheumatology (ACR) criteria at study start (clinical AND radiographic criteria)
9. Part B ONLY: Patient has a K&L grade 2 or 3 OA of the knee as detailed below according 
to Schiphof et al (2008)) with JSW 2.00-4.00 mm 
10. Part B ONLY: Patient must have symptomatic disease predominantly in one (the index) 
knee, with minimal or no symptoms in the contralateral knee. Symptomatic disease is 
defined as having pain in the knee more than 50% of the days during the last 3 months from 
screening, according to PI’s evaluation.
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4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study:
1. Use of other investigational drugs within 5 half-lives of enrollment, or until the expected
pharmacodynamic effect has returned to baseline, whichever is longer.
2. History of hypersensitivity to any of the study treatments or excipients or to drugs of similar
chemical classes.
3. History or current diagnosis of ECG abnormalities indicating significant risk of safety for
patients participating in the study such as:

Concomitant clinically significant cardiac arrhythmias, e.g. sustained
ventricular tachycardia, and clinically significant second or third degree AV
block without a pacemaker

Personal history or family history of long QT syndrome or Torsades de
Pointes
4. History of immunodeficiency diseases, including a positive HIV (ELISA and Western blot)
test result.
5. Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV). A positive HBV surface
antigen (HBsAg) test, or if standard local practice, a positive HBV core antigen test,
excludes a patient. Patients with a positive HCV antibody test should have HCV RNA levels
measured. Patients with positive (detectable) HCV RNA should be excluded.
6. History of malignancy of any organ system (other than localized basal or squamous cell
carcinoma of the skin or in-situ cervical cancer), treated or untreated, within the past 5 years,
regardless of whether there is evidence of local recurrence or metastases.
7. Pregnant or nursing (lactating) women.
8. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception during
dosing and for 15 days after stopping of investigational drug. Highly effective contraception
methods include:

Total abstinence from heterosexual intercourse (when this is in line with the
preferred and usual lifestyle of the patient). Periodic abstinence (e.g. calendar,
ovulation, symptothermal, post-ovulation methods) and withdrawal are not
acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or
without hysterectomy), total hysterectomy or tubal ligation at least six weeks
before taking investigational drug.  In case of oophorectomy alone, only when
the reproductive status of the woman has been confirmed by follow up
hormone level assessment.

Male sterilization (at least 6 months prior to screening). For female patients on the
study the vasectomized male partner should be the sole partner for that patient.

Use of oral, injected or implanted hormonal methods of contraception or
placement of an intrauterine device (IUD) or intrauterine system (IUS) or
other forms of hormonal contraception that have comparable efficacy (failure
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In case of use of oral contraception, women should be stable on the same pill for a minimum 
of 3 months before taking investigational drug.
Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. 
In the case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment is she considered not of child 
bearing potential.
9. Part A: Regular smokers (> 5 cigarettes or equivalent use of tobacco products per day in
the previous 3 months). Urine cotinine levels will be measured during screening for all
patients. Regular smokers will be defined as any patient who reports tobacco use of
> 5 cigarettes or equivalent/day and/or who has a urine cotinine ≥ 500 ng/mL.
Part B: Regular smokers (> 10 cigarettes or equivalent use of tobacco products per day in
the previous 3 months).
10. Part A: Use of prohibited medications:
Part B: Use of prohibited medications:
11. Patient has a known autoimmune disease susceptible to immunosuppressive treatment,
inflammatory arthropathy (including but not limited to rheumatoid arthritis, psoriatic
arthritis, ankylosing spondylitis, CPPD, gout), active acute or chronic infection of the joint,
Lyme disease involving the knee, systemic cartilage disorder, or a known systemic
connective tissue disease.
12. Patient unable to undergo MRI or presents absolute contraindications to MRI (e.g., metallic
implants, metallic foreign bodies, pacemaker, defibrillator).
13.
14. Part A ONLY: Patient has radiologically apparent degenerative joint disease in the target
knee as determined by Kellgren and Lawrence grade ≥2 based on X-ray evaluation
performed within 9 months from screening.
15. Patient has had surgical treatment of the target knee using mosaicplasty, microfracture,
meniscectomy >50% (Note: prior diagnostic arthroscopy with debridement and lavage,
<50% meniscectomy, lateral release, patellar realignment, medial patellofemoral ligament
reconstruction are acceptable if performed at least 2 months prior to screening; anterior
cruciate ligament reconstruction is acceptable if performed 12 months prior to screening, or
less if restoration of joint function is evident, and agreed by the sponsor).
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16. Patient has an unstable target knee joint (including but not limited to posttraumatic or
congenital laxity) or insufficiently reconstructed ligaments based on medical history and
physical examination by the investigator.
17. Part A ONLY: Patient has patellofemoral dysplasia Dejour Grade B-D based on X-ray or
MRI evaluation.
18. Part A: Patient has malalignment (valgus- or varus-deformity) in the target knee ≥ 5° based
on X-ray evaluation. In suspected cases, the mechanical axis must be established
radiographically through complete leg imaging during standing and in PA projection.
Part B: Patient has malalignment (valgus- or varus-deformity) in the target knee > 7.5°
based on X-ray evaluation. In suspected cases, the mechanical axis must be established
radiographically through complete leg imaging during standing and in PA projection.
19. Vulnerable subjects, e.g. subjects kept in detention, soldiers, employees of the sponsor or a
clinical research organization, involved in this study
20. History of drug abuse or unhealthy alcohol use within the 12 months prior to dosing, or
evidence of such abuse as indicated by the laboratory assays conducted during screening.
Unhealthy alcohol use is defined as a history of, or current alcohol misuse/abuse, defined
as five or more drinks on the same occasion on each of 5 or more days in the past 30 days.
21. Part B (ONLY): Patients with Nephrotic syndrome and/or significant proteinuria (≥ 3+ on
dipstick or protein-creatinine ratio ≥ 1 g/g Cr) at screening
22. Part B (ONLY): History of coagulopathy or medical condition requiring anticoagulation
which would preclude knee injection (antiplatelet or anticoagulant treatment [for patients
using warfarin, INR to be <3 prior to injection], is allowed).
23. Part B (ONLY): Clinical signs of inflammation (i.e., redness) in the target knee.
24. Part B (ONLY): History of knee replacement (unilateral or total) in either knee.
25. Part B (ONLY): Presence of severe hip OA conditioning lower limb function according to
PI’s evaluation.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
5
Restrictions for Study Subjects
During recruitment, screening/informed consent review, the subjects must be informed and 
reminded of the restrictions outlined in this section.
5.1
Contraception requirements
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if a pregnancy was to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirement during dosing and 
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If there is any question that the subject will not reliably comply, the subject should not be 
entered or continue in the study.  Male subjects should be informed that if a female partner 
becomes pregnant while he is enrolled in the study, contact with the female partner will be 
attempted to request her consent to collect pregnancy outcome information. Please refer to 
exclusion criteria (Section 4.2) for details of contraception requirements for the study.
5.2
Prohibited treatment
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 (see Section 6.10), subject has to be 
discontinued from study drug, but will continue the study until V399.
Table 5-1
Prohibited treatment Part A
Medication
Prohibited period
Action to be taken
Local i.a. treatment into the knee, including 
but not restricted to viscosupplementation 
and corticosteroids (impact on tissue 
repair/confounding of efficacy)
discontinue study treatment
Corticosteroid use by any route except 
topical (impact on tissue repair)
discontinue study treatment
Nonsteroidal anti-inflammatory drugs 
(NSAIDs), including aspirin (greater than 
100 mg/day) by any route except topical 
(impact on cartilage tissue repair).
See Section 6.10 (Rescue medication) for 
exceptions  
Must be recorded on the 
Concomitant medications/ 
Significant non-drug therapies 
section of the CRF.
Paracetamol greater than 3000 mg per day 
(confounding of liver function) 
See Section 6.10 (Rescue medication) for 
exceptions
Must be recorded on the 
Concomitant medications/ 
Significant non-drug therapies 
section of the CRF.
Oral glucosamine, chondroitin sulfate, or any 
nutraceutical with potential activity on 
cartilage repair (confounding of efficacy)
Must be recorded on the 
Concomitant medications/ 
Significant non-drug therapies 
section of the CRF.
Paracetamol and/or NSAIDs are not allowed 
during seven days before visit 201, 202,  299 
and V399
 
PRO to be performed  
≥7 days post last 
paracetamol/ NSAID intake, 
but ≤2 weeks after planned 
visit date.
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Table 5-2
Prohibited treatment Part B
Medication
Prohibited period
Action to be taken
Local i.a. treatment into the knee, including 
but not restricted to viscosupplementation 
and corticosteroids (impact on tissue 
repair/confounding of efficacy)
discontinue study treatment
Long-term treatment (>14 days) with oral 
corticosteroids >5 mg/day. 
Must be recorded on the 
Concomitant medications/ 
Significant non-drug therapies 
section of the CRF.
Paracetamol greater than 3000 mg per day 
(confounding of liver function) 
See Section 6.10 (Rescue medication) for 
exceptions
Must be recorded on the 
Concomitant medications/ 
Significant non-drug therapies 
section of the CRF.
Oral glucosamine, chondroitin sulfate, or any 
nutraceutical with potential activity on 
cartilage repair (confounding of efficacy)
Must be recorded on the 
Concomitant medications/ 
Significant non-drug therapies 
section of the CRF.
Note: The use of oral corticosteroids (≤5 mg/day oral prednisone or equivalent) for an indication 
other than OA pain will be allowed during the trial. In addition, short-term use of any tapering 
course of oral corticosteroids for ≤ 14 days will be allowed. Topical corticosteroids are allowed.
5.3
Dietary restrictions and smoking
5.3.1
Part A
No use of > 5 cigarettes per day or equivalent use of tobacco products is allowed during the 
study until V399. 
5.3.2
Part B
No use of > 10 cigarettes per day or equivalent use of tobacco products is allowed during the 
study until EOS.
5.4
Other restrictions
During 48 hours post injection, subjects should consider only modest exertion of the concerned 
knee joint and/or leg. 
No high-impact physical exercise (e.g. football, basketball, running, contact sports) is allowed 
from Day 1 until EoS. 
Non-drug treatments (e.g. physiotherapy) must be reported in the Concomitant 
medications/Significant non-drug therapies CRF. Further recommendations are given in the 
SOM.
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6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the SOM.
6.1.1
Investigational treatment and control drugs
Table 6-1
Overview of study medication
Study drug name
Formulation
Unit dose
Packaging 
Provided by
LNA043
Lyophilisate in Vial 
(LYO)
10mg
Open label bulk 
supply
Novartis 
Placebo to 
LNA043
Lyophilisate in Vial 
(LYO)
0mg
Open label bulk 
supply
Novartis
6.1.2
Additional study treatment
No additional treatment beyond investigational drug and control drug are included in this trial.
6.2
Treatment arms
6.2.1
Part A
Subjects will be assigned to one of the following two treatment arms in a ratio of “3:1”
Study treatments are defined as:

A:  single i.a. injection of 20 mg LNA043,

B:  single i.a. injection of placebo to 20 mg LNA043,
6.2.2
Part B
Subjects will be assigned to one of the following three treatment arms in a ratio of “1:1:1”
Study treatments are defined as:

A:  single i.a. injection of 20 mg LNA043,

B:  single i.a. injection of 40 mg LNA043,

C: single i.a. injection of placebo
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6.3
Treatment assignment and randomization
After eligibility confirmation, at the first dosing visit (Day 1) (or one day before), subjects will 
be randomized via Novartis Interactive Response Technology (NIRT) to one of the two (Part A) 
or three (Part B) treatment arms. The investigator or his/her delegate will log in the NIRT 
system after confirming that the patient fulfills all the inclusion/exclusion criteria. The NIRT 
will assign a treatment arm to the patient. The treatment arm information will not be 
communicated to the caller (investigator or his/her delegate).
Follow the details outlined in the SOM regarding the process and timing of treatment 
assignment and randomization of subjects.
The investigator will enter the screening number in the eCRF.
Randomization will be stratified by type of lesion (femoral condyle or patella) only in Part A. 
Randomization will not be stratified in Part B.
6.4
Treatment blinding
This is a subject and investigator-blinded study. Subjects and investigators will remain blinded 
to study treatment throughout the study, except where indicated below.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, and odor.
Site staff
With the exception of any unblinded site staff identified below, all site staff (including study 
investigator and study nurse) will be blinded to study treatment throughout the study.
Unblinding a single subject at site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (see Section 6.7).
Drug product will be supplied in bulk, so an unblinded pharmacist or delegate who is 
independent of the study team will be required in order to maintain the blind. After blinded 
investigator or his/her delegate performs the randomization in NIRT system, the unblinded 
pharmacist will log into the NIRT system and see the treatment arm assigned to the randomized 
subject. Appropriate measures must be taken by the unblinded pharmacist to ensure that the 
treatment assignments are concealed from the rest of the blinded site staff.
Sponsor staff
The following unblinded sponsor roles are required for this study. 
Unblinded field monitor(s)
Unblinded clinical staff managing drug re-supply to site
Unblinded sample analyst(s) (PK blood)
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The unblinded field monitors are required to review drug accountability and allocation at site. 
The unblinded monitors will be unblinded through unblinded user access to the NIRT system 
and review of source documentation compiled by the unblinded pharmacist or delegate, which 
details treatment allocation to individual subjects. The names of the unblinded monitor(s) are 
detailed in the Monitoring Plan.
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team under blinded conditions unless otherwise allowed.
Study programmers and other personnel involved in study data analysis (e.g.
) 
are allowed to access treatment assignment information for the purpose of conducting interim 
analyses.
The clinical trial team is allowed to share unblinded results with other sponsor staff 
(e.g. decision boards) as required for internal decision making on the study or the project at the 
time of interim analyses while the study is ongoing.
All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind other study team members confidential and secure except as described above.
Following final database lock all roles may be considered unblinded.
Table 6-2
Blinding Levels (Part A and B)
Role
Time or Event
NIRT set-up 
& go-live
Randomization & 
treatment arm 
assignment & dosing
Safety event 
(single subject 
unblinded)
Interim 
analysis
Subjects/Patients
B
B
UI
B
Site staff
B
B
UI
B
Unblinded site staff
(see text for details)
B
UI
UI
UI
Drug Supply and 
Randomization Office
UI
UI
UI
UI
Unblinded sponsor staff 
(see text for details)
B
UI
UI
UI
Statistician/statistical 
programmer/data analysts
B
UI
UI
UI
Independent committees 
used for assessing interim
results
NA
NA
NA
NA
All other sponsor staff not 
identified above
B
B
UI
B*
B Remains blinded
B* blinded at individual level
NA Not applicable
UI Allowed to be unblinded on individual patient level
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6.5
Treating the subject
LNA043/placebo (
 Part A and 
 Part B) will be administered at the study site to 
the patient via the following route of administration: intra-articular injection. See the pharmacy 
manual for further details.
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
For Part B only:
Injections to the target knee should not be considered when overlying skin infections, wounds 
or inflammatory diseases such as psoriasis are present.
After injection, the patient must be advised to:

Consult a doctor or emergency room immediately in case of severe systemic delayed 
reactions.

Observe any local or systemic reactions that may occur subsequently, seek appropriate 
medical care as needed and inform the attending doctor at the next visit.
Any allergic reactions (both local and systemic) should be recorded before the patient leaves 
the clinic.
6.6
Permitted dose adjustments and interruptions of study treatment
Study treatment dose adjustments are not permitted.
6.7
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the NIRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide the 
requested subject identifying information and confirm the necessity to break the treatment code 
for the subject. The investigator will then receive details of the investigational drug treatment 
for the specified subject and a fax or email confirming this information. The system will 
automatically inform the study monitor for the site and the Study Team that the code has been 
broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the NIRT at any time in case of emergency.   The investigator will need to 
provide: 

protocol number

study drug name (if available)

subject number.
In addition, the investigator must provide oral and written information to inform the subject 
how to contact his/her backup in cases of emergency when he/she is unavailable to ensure that 
un-blinding can be performed at any time.
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An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given subject 
and, if applicable, whether the subject can continue into the next trial phase (e.g., an unblinded 
extension).
6.8
Treatment exposure and compliance
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all subjects 
treated with LNA043, as detailed in Section 8.7.
Compliance to the treatment regimen is ensured by administration of LNA043 i.a. injections by 
the investigator (or her/his delegates). Information on the study treatment administration or any 
deviation from the dose regimen must be recorded in the Case Report Form (CRF). All study 
treatment dispensed and returned must be recorded in the Drug Accountability Log.
6.9
Recommended treatment of adverse events
Treatment of AEs should be in line with the Investigational site procedures.
From the completed and ongoing clinical trials, no case of local or systemic hypersensitivity 
reactions have been observed with LNA043 to date. Due to the potential risk of serious allergic 
reactions, immediate access to full resuscitation equipment and drugs must be available, 
including adrenaline for injection and staff trained in the use thereof (i.e. at locations with 
emergency care facilities). If symptoms of a systemic reaction, such as urticaria, angioedema 
or severe asthma occur, symptomatic treatment should be initiated immediately according to 
local treatment protocols. Study participants in Part A will be monitored at the clinical site for 
at least 1 (one) hour post intra-articular injection or longer at the discretion of the Investigator 
to ensure adequate safety monitoring. Study participants in Part B are required to undergo 
observation for three hours post-injection prior to leaving the site. Patients who experience any 
Grade hypersensitivity reaction in Part B must not be re-dosed. 
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF.
6.10
Rescue medication
6.10.1
Part A
Paracetamol/acetaminophen up to 3000 mg/day is allowed as rescue medication to treat local 
pain to the target knee. In case paracetamol/acetaminophen is not effective, NSAIDs will be 
allowed for up to 3 consecutive days as rescue medication.
Both paracetamol and NSAIDs are not allowed during seven days before any follow-up visit 
 
 
Use of rescue medication must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF.
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6.10.2
Part B
Paracetamol/acetaminophen up to 3000 mg/day and NSAIDs are allowed as rescue medication 
to treat local pain to the target knee. 
Use of rescue medication must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF.
6.11
Concomitant treatment
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study.
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the timeframe 
defined in the entry criteria prior to the start of the study and during the study, must be recorded 
on the Concomitant medications/Significant non-drug therapies CRF.
In the event of an available COVID-19 vaccine in the future, vaccination of study subjects will 
be permitted during the study duration. The investigator must document their discussion with 
the subject regarding COVID-19 vaccination in the source documentation, and follow the 
instructions described above related to the eCRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited
medication. If in doubt, the investigator should contact Novartis before randomizing a subject 
or, if the subject is already enrolled, to determine if the subject should continue participation in 
the study.
7
Study completion and discontinuation
7.1
Study completion and post-study treatment
Each subject will be required to complete the study in its entirety and thereafter no further study 
treatment will be made available to them.
Study completion and end of the trial is defined as when the last subject has completed the long-
term follow-up (Week 52) 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.
The information collected is kept as source documentation.  All SAEs reported during this time 
period must be reported as described in Section 9.2 and the SOM. Documentation of attempts 
to contact the subject should be recorded in the source documentation.
After study participation, the patients will continue to be treated according to the local standard 
clinical practice. The investigator must provide follow-up medical care for all subjects who 
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7.2
Discontinuation of study treatment
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7.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject cannot be formally considered lost to follow-up until 
his/her scheduled end of study (EOS) visit would have occurred.
7.4
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time.
Withdrawal of consent from the study is defined as when a subject:

Does not want to participate in the study anymore and

Does not allow further collection of personal data.
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
Assessment Schedule (Table 8-1).
Novartis will continue to keep and use collected study information (including any data resulting from 
the analysis of a subject’s samples until the time of withdrawal) according to applicable law.
All biological samples not yet analyzed at the time of withdrawal will no longer be used, unless 
permitted by applicable law. They will be stored according to applicable legal requirements.
7.5
Study Stopping rules
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7.6
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. Should this be necessary, subjects must 
be seen as soon as possible and treated as a prematurely withdrawn subject. The investigator 
may be informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the subject’s interests.
In case of an early termination the Sponsor will notify the end of the trial to the national 
competent authorities and the  Institutional Review Boards (IRBs)/Independent Ethics 
Committees (IECs) concerned immediately and at the latest within 15 days after the trial is 
halted, will clearly explain the reasons, and will describe follow-up measures, if any, taken for 
safety reasons.
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8
Procedures and assessments
8.1
Assessment schedule
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Table 8-2
Assessment schedule Part B
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8.2
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
If incapable of doing so, in cases where the subject’s representative gives consent (if allowed
according to local requirements), the subject must be informed about the study to the extent 
possible given his/her understanding. If the subject is capable of doing so, he/she must indicate 
assent by personally signing and dating the written informed consent document or a separate 
assent form.
Novartis will provide to investigators a proposed informed consent form that complies with the 
ICHE6 GCP guideline and regulatory requirements and is considered appropriate for this study. 
The informed consent form will also include a section related to optional future research which 
will require a separate signature if the subject agrees to future research. Any changes to the 
proposed consent form suggested by the investigator must be agreed to by Novartis before 
submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an Investigator Notification (IN) 
or an Aggregate Safety Finding. New information might require an update to the informed 
consent and then must be discussed with the subject.
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
8.3
Subject screening
In general, it is permissible to re-screen a subject if s/he fails the initial screening; however, 
each case must be discussed and agreed with the Sponsor on a case-by-case basis. 
Initial screening assessments (i.e. Physical examination, laboratory assessments, ECGs, vital 
signs, pregnancy test, gait assessment) are valid and can be used in case of re-screening up to 
90 days after the initial assessment date if the patients do not report a change in health status. 
Initial screening X-Rays and MRIs are valid and can be used in case of re-screening up to 180 
days after the initial assessment date if the patients do not report a change in symptoms 
(qualitative or quantitative).
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Information on what data should be collected for screening failures is outlined in the 
Site Operations Manual.
8.4
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects. 
Participant race and 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. Relevant medical history/current medical conditions data will also be 
collected until signature of informed consent.  Date of onset of symptoms (Part A), ICRS 
grading of the lesion (Part A), 
 cartilage lesion localization (i.e lateral femoral condyle, medial 
femoral condyle, trochlea, patella – Part A) will be collected in the CRF as baseline 
characteristics. Details are outlined in the SOM. 
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
Hepatitis screen, HIV screen
All subjects will be screened for Hepatitis B surface antigen (HBsAg). Screening for Hepatitis 
C will be based on HCV antibodies. 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 subject counseling will be made available by the Investigator in the event of 
a positive finding. Notification of state and federal authorities, as required by law, will be the 
responsibility of the Investigator. Results will be available as source data and will not be 
recorded within the eCRF.
Alcohol test, Drug screen, cotinine test
Subjects will be tested at screening for substances of abuse (e.g., alcohol, amphetamines, 
barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates) in Part A and Part B and 
cotinine concentration in Part A only. Results will be available as source data and will not be 
recorded within the eCRF.
X-ray
In Part A, X-rays will be performed at screening in case no former examination results are 
available to confirm eligibility by excluding apparent degenerative joint disease, patellofemoral 
dysplasia Dejour Grade B-D (optional), and/or valgus- or vagus-deformity of ≥ 5° in the target knee. 
In Part B, X-rays will be performed at screening for all subjects to confirm eligibility, at the 
hospital or nearby facility. 
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8.5
Efficacy / Pharmacodynamics
Articular cartilage bi-layer collagen organization (primary endpoint in part A) and articular 
cartilage volume and thickness (primary endpoint in part B) are evaluated with knee MRI 
described in Section 8.5.1.  
8.5.1
Knee MRI
Hyaline cartilage is characterized by two main distinct layers between the articular surface and 
bone interface, marked by orientation of collagen fibrils. Besides the collagen matrix being 
highly structured, glycosaminoglycans (GAG) are also abundant in hyaline cartilage. In early 
stages of cartilage degeneration and fibrocartilage, subtle changes typically involve these major 
constituents of the cartilage solid matrix.
MRI will be obtained from the injured knee to visualize the cartilage tissue either in the femoral, 
tibial or patellar region depending on the defect location. The imaging protocol was developed 
to primarily quantify changes in the bi-layer collagen organization, but also cartilage loss and, 
when visible, sub-chondral bone edema. Details inherent to the image acquisition and analysis 
can be found in the imaging charter.
8.5.1.1
Image collection
Magnetic Resonance (MR) images acquisition will be performed by a trained MRI professional
at the hospital or nearby facility. The MRI radiologist will be blinded to the treatment received 
by the patient. All patients will be imaged using a clinical high-field MRI scanner. For each 
MRI session, images will be acquired as described in the imaging protocol to assess bi-layer 
collagen organization, the extent of cartilage injury (i.e. cartilage volume and thickness in index 
region) and knee features such as bone marrow edema.
MR images will be acquired at the imaging site(s) and sent for independent central review by 
imaging specialists. The reviewers will be blinded to the treatment received by the patient. 
8.5.1.2
Image processing
The image analysis will be performed centrally, as defined in the imaging charter, in order to 
assess changes in cartilage quality in the defective region of articular cartilage 
(primary endpoint in Part A and secondary endpoint in Part B) as well as in weight-bearing and 
non-weight-bearing regions of articular cartilage. Other endpoints will include the extent of the 
repair tissue at the site of injury such as the % of defect filling (secondary endpoint in Part A) 
or cartilage volume in the index region (primary endpoint in Part B) and knee features such as
bone marrow edema.
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.
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8.6
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the SOM, with the Assessment Schedule (Table 8-1 and Table 8-2) detailing when each 
assessment is to be performed.
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8.6.1
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/or pelvic exams may be performed. See the SOM for 
details.
8.6.2
Vital signs

Body temperature

Blood pressure (BP)

Pulse rate
Details on how vital signs should be measured can be found in the SOM.
8.6.3
Height and weight

Height

Body weight

Body mass index (BMI) will be calculated (Body weight (kg) / [Height (m)]2)
8.6.4
Laboratory evaluations
Clinically relevant deviations of laboratory test results occurring during or at completion of the 
study must be reported and discussed with Novartis personnel. The results should be evaluated 
for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted.
8.6.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential 
(monocytes, eosinophils, basophils, neutrophils, lymphocytes), platelet count, aPTT, and 
PT/INR will be measured.
8.6.4.2
Clinical chemistry
Sodium, potassium, creatinine, urea, uric acid, chloride, albumin, calcium, alkaline phosphatase, 
total bilirubin, LDH, GGT, AST, ALT,  CK, glucose, total cholesterol, LDL, HDL, triglycerides.
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal, direct 
and indirect reacting bilirubin should be differentiated.
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8.6.4.3
Urinalysis
Urine test by dipstick (e.g. Combur9): leucocytes, nitrite, pH, protein, glucose, ketones, 
urobilinogen, bilirubin, blood/ hemoglobin.
If the dipstick result is positive for protein, nitrite, leucocytes and/or blood the sample will be 
sent for microscopic analysis of WBC, RBC and casts.
8.6.5
Electrocardiogram (ECG)
Single 12 lead ECGs are collected. The original ECGs, appropriately signed and dated, should 
be collected and archived at the study site.
ECGs will be performed as outlined in the Assessment Schedule (Table 8-1 and Table 8-2).
Each ECG tracing should be labelled with study number, subject number, date and time, be 
appropriately signed and dated to confirm review and filed in the study site source documents. 
For any ECGs with subject safety concerns, two additional ECGs should be performed to 
confirm the safety finding. QTcF (Fridericia) interval longer than 450 msec for males and 460 
msec for females and other clinically significant ECG findings prior to dosing with 
investigational treatment must be discussed with the Sponsor.
Clinically significant abnormalities should be recorded on the relevant section of the Medical 
history/Current medical conditions/AE eCRF page as appropriate.
The eCRF will contain:

Date and time of ECG

Heart rate

RR and PR interval

QRS duration

QT duration

QTcF.
The Fridericia QT correction formula (QTcF) should be used for clinical decisions.
8.6.6
Pregnancy and assessment of fertility
All pre-menopausal women who are not surgically sterilized will have pregnancy testing.  
See the Assessment Schedule, Table 8-1 and Table 8-2, for timing of the protocol required 
pregnancy testing; additional pregnancy testing may be performed to meet local requirements*.  
A positive urine pregnancy test requires immediate interruption of study treatment until serum 
β-hCG is performed and found to be negative.
*If additional pregnancy testing is needed per local requirements, those additional results will 
be kept as source documentation only. 

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8.6.7
Immunogenicity
IG samples will be collected at the time points defined in the Assessment schedule (Section 8.1
and Section 8.2). 
Further details on sample collection, numbering, processing and shipment can be found in the 
SOM.
8.6.7.1
Immunogenicity analytical method
A validated ligand binding assay will be used for the detection of anti-LNA043 antibodies, and 
cross-reactivity to ANGPTL3 and ANGPTL4. Positive samples will be further analyzed for 
presence of neutralizing antibodies using a validated ligand binding assay.
IG samples remaining after immunogenicity analysis may be used for exploratory assessment 
or other bioanalytical purposes (e.g. cross check between different sites). Given the exploratory 
nature of the work, the analytical method used for those assessments will not be validated.
8.7
Pharmacokinetics
Validated bioanalytical assays will be used to determine LNA043 and ANGPTL3 in synovial 
fluid and serum.
PK samples will be collected at the timepoints defined in the Assessment schedule, Table 8-1
and Table 8-2. Follow instructions outlined in the SOM regarding sample collection, numbering, 
processing and shipment. See Section 8.9 regarding the potential use of residual samples.
In order to better define the PK profile, the timing of the PK sample collection may be altered 
based on emergent data. The number of samples/blood draws and total blood volume collected 
will not exceed those stated in the protocol. 
PK samples will be obtained from all subjects.
For standard pharmacokinetic abbreviations and definitions see the list provided at the 
beginning of this protocol.
Due to a limited PK sampling, only summary statistics of measured PK concentrations will be 
reported, and no further PK parameters will be determined in this study.
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8.8
Other assessments
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8.9
Use of residual biological samples
Residual blood, serum and synovial fluid samples may be used for another protocol specified 
endpoint.
9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until V399 (for Part A) and V499 (for Part B). Therefore, an AE may or may not be 
temporally or causally associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the study treatment are also considered 
an adverse event irrespective if a clinical event has occurred. See Section 9.5 for an overview 
of the reporting requirements.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination finding, laboratory test 
finding, or other assessments.
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Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms,

they are considered clinically significant,

they require therapy.
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values that  are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for liver and kidney related events are 
included in Appendix 1 and Appendix 2, respectively.
Adverse events must be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information:
1. the Common Toxicity Criteria (CTC) AE grade (version 4.03). 
If CTC-AE grading does not exist for an adverse event, use:

1 = mild,

2 = moderate,

3 = severe

4 = life threatening* (see Section 9.2 for definition of a serious adverse event (SAE))
*Note: There may be cases where a CTCAE with a grade of 4 (life-threatening) may 
not necessarily be an SAE (e.g. certain laboratory abnormalities in the absence of 
meeting other seriousness criteria).

CTC-AE grade 5 (death) is not used, but is collected as a seriousness criteria and also 
collected in other CRFs (e.g. Study Completion, Death/Survival).
2. its relationship to the study treatment  

Yes or

No
3. its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported.
4. whether it constitutes a SAE (see Section 9.2 for definition of SAE) and which seriousness 
criteria have been met  
5. Action taken regarding investigational treatment.
All adverse events must be treated appropriately. Treatment may include one or more of 
the following: 

no action taken (e.g. further observation only)

investigational treatment dosage increased/reduced

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given

hospitalization/prolonged hospitalization (see Section 9.2 for definition of SAE)
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown). 

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Information about common side effects already known about the investigational drug can be 
found in the IB.  Once an adverse event is detected, it must be followed until its resolution or 
until it is judged to be permanent, and assessment should be made at each visit (or more 
frequently, if necessary) of any changes in severity, the suspected relationship to the 
investigational drug, the interventions required to treat it, and the outcome.
The investigator must also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 
source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis.
9.2
Serious adverse event reporting
9.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study) and has not worsened since the start of study drug

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (see Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 

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dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (see Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to Novartis Drug Safety & Epidemiology (DS&E) as per Section 9.2.2.
9.2.2
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the End of Study (Week 28) or Long term 
follow-up (Week 52) visit in part A or EOS (Week 52) visit in part B, as appropriate depending 
on the subject, must be reported to Novartis within 24 hours of learning of its occurrence as 
described below. Any SAEs experienced after this period should only be reported to Novartis 
if the investigator suspects a causal relationship to study treatment.
Note: SAEs reported by subjects deemed to be screen failures must be reported to Novartis as 
outlined here with appropriate information also captured in the CRFs as specified in the 
Site Operations Manual.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Follow- up information provided must describe whether the event has resolved or continues, 
if and how it was treated, whether the blind was broken or not (if applicable) and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an IN to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries.
Follow the detailed instructions outlined in the SOM regarding the submission process for 
reporting SAEs to Novartis.   Note:  SAEs must be reported to Novartis within 24 hours of the 
investigator learning of its occurrence/receiving follow-up information.

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9.3
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
Please refer to Table 15-1-Appendix 1 for complete definitions of liver events.
Follow-up of liver events
Every liver event defined in Table 15-1-Appendix 1 should be followed up by the investigator 
or designated personnel at the trial site, as summarized below. Additional details on actions 
required in case of liver events are outlined in Table 15-2-Appendix 1. 

Repeating liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and γGT) to confirm 
elevation within 48-72 hours.  
These liver chemistry repeats should always be performed using the central laboratory, 
with the results provided via the standard electronic transfer.  If results will not be 
available from the central laboratory within 24 hours, then the repeats can also be 
performed at a local laboratory to monitor the safety of the subject. If a liver event is 
subsequently reported, any local liver chemistry tests previously conducted that are 
associated with this event should have results reported on the unscheduled local laboratory CRF.  

If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to Section 7.2 (Discontinuation of study 
treatment), if appropriate

Hospitalization of the subject if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include: 

Repeating liver chemistry tests two or three times weekly. Testing should include 
ALT, AST, ALP, PT/INR, and gGT. If total bilirubin is elevated > 2 x ULN, 
fractionation into direct and indirect bilirubin is required. To rule out muscular origin 
of transaminase elevations, CPK should be measured along with liver chemistry tests. 
Frequency of retesting can decrease to once a week or less if abnormalities stabilize 
or the study drug has been discontinued and the subject is asymptomatic. 
Retesting should be continued up to resolution. 

Obtaining a more detailed history of symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets.

Exclusion of underlying liver disease, as specified in Table 15-3.

Imaging such as abdominal US, CT or MRI, as appropriate

Obtaining a history of exposure to environmental chemical agents.

Considering gastroenterology or hepatology consultations.

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All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF.
9.4
Renal safety monitoring
9.4.1
Part A
Renal events are defined as one of the following:

confirmed (after ≥ 24h) increase in serum creatinine of ≥ 25% compared to baseline 
during normal hydration status

new onset (≥1+) proteinuria, hematuria or glucosuria; or as a

doubling in the urinary albumin-creatinine ratio or urinary protein-creatinine ratio (PCR) 
(if applicable).
The following two categories of abnormalities/adverse events have to be considered during the 
course of the study:

Serum creatinine triggers that will require follow up and repeat assessments of the 
abnormal laboratory parameter

Urine dipstick triggers that will require follow up and repeat assessments of the abnormal 
laboratory parameter
Every renal laboratory trigger or renal event must be followed up by the investigator or 
designated personnel at the trial site. Recommended follow-up assessments are listed in 
Section 16-Appendix 2.
9.4.2
Part B
Renal events are defined as one of the following:

confirmed (after ≥ 24h) increase in serum creatinine of ≥ 25% compared to baseline 
during normal hydration status

urinary protein-creatinine ratio >1 g/g Cr

New onset dipstick proteinuria ≥ 3+

New onset dipstick haematuria ≥ 3+ (excluding menstruation, infection, extreme exercise, 
or trauma).
The following two categories of abnormalities/adverse events have to be considered during the 
course of the study:

Serum creatinine triggers that will require follow up and repeat assessments of the 
abnormal laboratory parameter

Urine dipstick triggers that will require follow up and repeat assessments of the abnormal 
laboratory parameter
Every renal laboratory trigger or renal event must be followed up by the investigator or 
designated personnel at the trial site. Recommended follow-up assessments are listed in 
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9.5
Reporting Medication errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject 
or consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
All study treatment errors and uses outside of what is foreseen in the protocol will be collected 
in the dose administration record (DAR) CRF.  Study treatment errors are only to be reported 
to Novartis CMO&PS department if the treatment error is associated with an SAE.
All instances of misuse or abuse must be documented in the adverse event (AE) CRF 
irrespective of the misuse/abuse being associated with an AE/SAE. In addition, all instances of 
misuse or abuse must be reported to Novartis CMO&PS. As such, instances of misuse or abuse 
are also to be reported using the SAE form/CRF. 
Table 9-1 summarizes the reporting requirements.
Table 9-1
Summary of reporting requirements for medication errors
Treatment error type
Document in Dose 
Administration (DAR) CRF
Document in AE 
CRF
Complete SAE 
form/CRF
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated 
with an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a 
SAE
For more information on AE and SAE definition and reporting requirements, please see 
Section 9.1 and Section 9.2, respectively.
9.6
Pregnancy reporting
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 
Doctor ask about her pregnancy. To ensure subject safety, each pregnancy occurring after 
signing the informed consent must be reported to Novartis within 24 hours of learning of its 
occurrence. The pregnancy should be followed up for up to 12 months following the birth to 
determine outcome, including spontaneous or voluntary termination, details of the birth, and 
the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis CMO&PS Department. Pregnancy follow-up should be 
recorded on the same form and should include an assessment of the possible relationship to the 
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Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
9.7
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly between 
medically qualified personnel representing the Sponsor and Investigator. Such evaluations may 
occur verbally, but the outcome and key discussion points will be summarized in writing (e-mail) 
and made available to both Sponsor and all Investigator(s). Criteria pertaining to stopping the 
study/treatment or adapting the study design are presented above.
When two or more clinical site(s) are participating in the clinical study, the Sponsor will advise 
the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any new, 
clinically relevant safety information reported from another site during the conduct of the study 
in a timely manner.
10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. 
During the study, Novartis employs several methods of ensuring protocol and GCP compliance 
and the quality/integrity of the sites’ data. The monitor will visit the site to check the 
completeness of subject records, the accuracy of entries on the CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and ensure that study drug 
is being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the monitor during these visits.
Continuous remote monitoring of each site’s data may be performed by Novartis. Additionally, a 
central analytics organization may analyze data and identify risks & trends for site operational 
parameters, and provide reports to Novartis Clinical Teams to assist with trial oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject's file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the eligibility criteria, documentation of SAEs, and 
the recording of data that will be used for all primary and safety variables. Additional checks 
of the consistency of the source data with the CRFs are performed according to the study-

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specific monitoring plan. No information in source documents about the identity of the subjects 
will be disclosed.
10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 requirements. 
Designated investigator site staff will not be given access to the EDC system until they have 
been trained. Automatic validation programs check for data discrepancies and, by generating 
appropriate error messages, allow the data to be confirmed or corrected before transfer of the 
data to the Contract Research Organization (CRO) working on behalf of Novartis. The 
Investigator must certify that the data entered into the Electronic Case Report Forms are 
complete and accurate. After database lock, the investigator will receive copies of the subject 
data for archiving at the investigational site.
Data not requiring a separate written record will be defined in the SOM and 
Assessment schedule and can be recorded directly on the CRFs. All other data captured for this 
study will have an external originating source (either written or electronic) with the CRF not 
being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
10.3
Database management and quality control
CRO working on behalf of Novartis review the data entered into the CRFs by investigational 
staff for completeness and accuracy and instruct the site personnel to make any required 
corrections or additions. Queries are sent to the investigational site using an electronic data 
query. Designated investigator site staff is required to respond to the query and confirm or 
correct the data. If the electronic query system is not used, a paper Data Query Form will be 
faxed to the site. Site personnel will complete and sign the faxed copy and fax it back to CRO 
working on behalf of Novartis who will make the correction to the database. The signed copy 
of the Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the World Health 
Organization (WHO) Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Medical history/current medical conditions and adverse events 
will be coded using the Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization data about all study drug(s) dispensed to the subject will be tracked using the 
Novartis Interactive Response Technology (NIRT) database. The database will be sent 
electronically to Novartis (or a designated CRO).
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Each occurrence of a code break via NIRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.
The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked 
and the treatment codes will be unblinded and made available for data analysis. Any changes 
to the database after that time can only be made by joint written agreement between the COAR 
Analytics NIBR Franchise Head and the relevant NIBR TA Head.
10.4
Data Monitoring Committee
Not required.
10.5
Adjudication Committee
Not required.
11
Data analysis
The analysis will be conducted on all subject 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.
11.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received LNA043 and with no protocol 
deviations that impact on PK data.
The primary pharmacodynamic (PD) analysis set will include all subjects with available PD 
data. The secondary PD analysis set will include all subjects with available PD data and no 
protocol deviations with relevant impact on PD data. Details of which protocol deviations have 
impact on PD data will be provided in the Statistical Analysis Plan (SAP).
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11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and subject. 
Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject.
11.3
Treatments
Data for study drug administration and concomitant therapies will be listed by treatment group 
and subject.
11.4
Analysis of the primary variable(s)
11.4.1
Variable(s)
The primary efficacy variable is the articular cartilage bi-layer collagen organization evaluated 
with MRI at Week 16 and 28 (part A) and change from baseline in cartilage volume/thickness 
in the index region, assessed based on MRI at Weeks 28 and 52 (part B).
The primary safety variables are:

Systemic and local Adverse Events

ECGs

Vital signs

Hematology, blood chemistry, urinalysis
11.4.2
Statistical model, hypothesis, and method of analysis
The primary efficacy variables will be analyzed using the secondary PD analysis set and the 
primary safety variables using the safety analysis set.
11.4.2.1 Part A
The primary efficacy variable, articular cartilage bi-layer collagen organization, assessed based 
on MRI at Weeks
16 and 28, will be analyzed using a mixed model repeated measures 
(MMRM) analysis of variance model, including baseline and all time points to compare 
treatment groups at Weeks
16 and Week 28.  The model will include treatment, timepoint, 
treatment*timepoint, and type of lesion as fixed effects, subject as a random effect, and baseline 
measure as a fixed covariate. If deemed appropriate, the endpoint measure data will be 
transformed to facilitate analysis. 90% two-sided confidence intervals for the treatment effect 
will be formed at Weeks
16 and Week 28. Considering that the time course of response to 
LNA043 is not known, statistically significant differences between active drug and placebo at 
either Week 16 or Week 28 will be considered as a positive result.
11.4.2.2 Part B
The primary efficacy variable, change from baseline in cartilage volume/thickness in the index 
region, assessed based on MRI at Weeks 28 and 52. will be analyzed using a mixed model 
repeated measures (MMRM), including baseline and all time points to compare treatment 
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groups at Week 28 and Week 52.  The model will include baseline measure, treatment,
timepoint, treatment*timepoint as fixed effects, participant as a random effect. 90% two-sided 
confidence intervals for the treatment effect will be formed at Weeks 28 and 52. If deemed 
appropriate, the endpoint measure data will be transformed to facilitate analysis. Considering 
that the time course of response to LNA043 is not known, statistically significant differences 
between active drug (either LNA043 dose) and placebo at either Week 28 or Week 52 will be 
considered as a positive result.
The safety variables will be summarized descriptively by treatment group for part A and part B.
Exploratory variables will be summarized descriptively by treatment group and associations 
with primary and secondary variables will be explored.
11.5
Handling of missing values/censoring/discontinuations
Subjects with missing PK concentrations in some but not all periods will be included in a mixed 
model analysis assuming missing at random.
Missing data for MRI outcomes will not be imputed.
11.6
Summary statistics of safety
Vital signs
All vital signs data will be listed by treatment group, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment group, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, subject, and visit/time and if normal ranges 
are available abnormalities will be flagged. Summary statistics will be provided by treatment 
and visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment group and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system.
The number (and proportion) of subjects with AEs of special Interest (AESI) will be 
summarized by treatment. 
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11.6.1
Sensitivity analyses
Not applicable.
11.7
Analysis of secondary variable(s)
Part A
The secondary efficacy variable, change in volume of cartilage defect filling, assessed based on 
MRI at Week 16 and 28, will be analyzed using a mixed model repeated measures (MMRM) 
analysis of variance model, including baseline and both timepoints to compare treatment groups 
at Week 16 and Week 28.  The model will include treatment, timepoint, treatment*timepoint, 
and type of lesion as fixed effects, subject as a random effect, and baseline measure as a fixed 
covariate. 90% two-sided confidence intervals for the treatment effect will be formed at both 
Week 16 and Week 28. If deemed appropriate, the endpoint measure data will be transformed 
to facilitate analysis. Considering that the time course of response to LNA043 is not known, 
statistically significant differences between active drug and placebo at either Week 16 or Week 
28 will be considered as a positive result.
Part B
The secondary efficacy variable, change from baseline in articular cartilage bi-layer collagen 
organization, assessed based on MRI at Weeks 28 and 52 will be analyzed using a mixed model 
repeated measures (MMRM).  The model will include baseline measure, treatment, timepoint, 
treatment*timepoint as fixed effects, participant as a random effect. The model will be used to 
form 90% two-sided confidence intervals for the treatment effect at Weeks 28 and 52. If deemed 
appropriate, the endpoint measure data will be transformed to facilitate analysis. 
Considering that the time course of response to LNA043 is not known, statistically significant 
differences between active drug (either LNA043 dose) and placebo at either Week 28 or 
Week 52 will be considered as a positive result.
11.7.1
Efficacy / Pharmacodynamics
Not Applicable.
11.7.2
Pharmacokinetics
LNA043 serum and synovial fluid concentration data will be listed by subject, and 
visit/sampling time point. Descriptive summary statistics will be provided by treatment and 
visit/sampling time point, 
Summary statistics will include mean (arithmetic and geometric), Standard Deviation (SD), CV 
(arithmetic and geometric), median, minimum and maximum. An exception to this is Tmax 
where median, minimum and maximum will be presented. 
. A geometric mean 
will not be reported if the dataset includes zero values. Pharmacokinetic parameters will be 
calculated as described in Section 8.7 and will be listed by treatment and subject.
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11.7.3
Pharmacokinetic / pharmacodynamic interactions
Not Applicable.
11.7.4
Immunogenicity
All immunogenicity results will be listed by treatment group, subject and visit/time.
11.7.5
Other assessments
Not Applicable
11.8
Analysis of exploratory variables
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11.9
Sample size calculation
11.9.1
Part A
A sample size of 36 LNA043 treated patients and 12 Placebo patients (48 patients, 3:1 
LNA043:Placebo) will allow for approximately 90% power, with a 1-sided alpha of 0.05, to 
detect a 20% relative difference between LNA043 and Placebo overall, and 
. 
Stated differently, a two-sided 90% confidence interval for the treatment effect will exclude 
zero with probability 90%.
A 20% relative improvement in T2 mapping between treatments is considered to be potentially 
clinically meaningful and statistically different than the 10% random variability. So, in the 
calculations above, an effect size of 0.2/0.18=1.11 is used.
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11.9.2
Part B
11.10
Power for analysis of key secondary variables
Not applicable
11.11
Interim analyses
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12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations 
Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles 
laid down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the IRB/IEC for the trial protocol, written informed consent form, consent form updates, subject 
recruitment procedures (e.g. advertisements) and any other written information to be provided 
to subjects. Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and all 
of the instructions and procedures found in this protocol and to give access to all relevant data 
and records to Novartis monitors, auditors, Novartis Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an 
inspection of the clinical site is requested by a regulatory authority, the investigator must inform 
Novartis immediately that this request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis around the time 
of Last Patient Last Visit to be a reviewer and signatory for the clinical study report. 
12.3
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results.
13
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.

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13.1
Protocol Amendments
Any change to the protocol can only be made in a written protocol amendment that must be 
approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation.
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 9 (Safety Monitoring) must be followed and the Study Lead 
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14
References
References are available upon request
Brittberg M, Winalski CS (2003) Evaluation of cartilage injuries and repair. J Bone Joint Surg 
Am p. 58-69.
Charalambous CP, Tryfonidis M, Sadiq S, et al (2003) Septic arthritis following intra-articular 
steroid injection of the knee--a survey of current practice regarding antiseptic technique used 
during intra-articular steroid injection of the knee. Clin. Rheumatol. p. 386-90.
Enck P, Klosterhalf S, Weimer K, et al (2011) The placebo response in clinical trials: more
questions than answers, Phil. Trans. R. Soc. B; 366, 1889–1895
Filardo G, Kon E, Andriolo L, et al (2014) Treatment of "patellofemoral" cartilage lesions 
with matrix-assisted autologous chondrocyte transplantation: a comparison of patellar and 
trochlear lesions. Am J Sports Med p. 626-34.
Gühring H, Kraines J, Moreau F, et al (2019) OP0010 Cartilage thickness modification with 
Sprifermin in knee osteoarthritis patients translates into symptomatic improvement over 
placebo in patients at risk of further structural and symptomatic progression: Post-Hoc 
analysis of the Phase II FORWARD trial.  Annals of the Rheumatic Diseases; 78:70-71.
Hochberg MC, Guermazi A, Guehring H et al (2019) Effect of Intra-Articular Sprifermin vs 
Placebo on Femorotibial Joint Cartilage Thickness in Patients With Osteoarthritis. Jama, 322(14), 
p.1360.
Juras V, Bohndorf K, Heule R, et al (2016a) A comparison of multi-echo spin-echo and triple-echo 
steady-state T2 mapping for in vivo evaluation of articular cartilage. Eur Radiol p. 1905-12.
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Laferton JAC, Vijapura S, Baer L, et al (2018) Mechanisms of Perceived Treatment Assignment 
and Subsequent Expectancy Effects in a Double Blind Placebo Controlled RCT of Major 
Depression. Front. Psychiatry, 9, 424
Lavelle W, Lavelle ED, Lavelle L (2007) Intra-articular injections. Med. Clin. North Am. p. 241-50.
Le Graverand-Gastineau MP (2010) Disease modifying osteoarthritis drugs: facing 
development challenges and choosing molecular targets. Curr Drug Targets. May;11(5):528-
35.
Raynauld JP, Martel-Pelletier J, Berthiaume MJ, et al (2004) Quantitative magnetic resonance 
imaging evaluation of knee osteoarthritis progression over two years and correlation with 
clinical symptoms and radiologic changes. Arthritis Rheum. Feb;50(2):476-87.
Schiphof D, Boers M, Bierma-Zeinstra SMA (2008) Differences in descriptions of Kellgren 
and Lawrence grades of knee osteoarthritis. Ann Rheum Dis;67:1034–1036
Van Rossom S, Wesseling, M, Smith CR (2019) The influence of knee joint geometry and 
alignment on the tibiofemoral load distribution: A computational study. The Knee 26, 813-
823
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15
Appendix 1: Liver Event Definitions and Follow-up 
Requirements
Table 15-1
Liver Event Definitions
Definition
Thresholds
Potential Hy’s law cases

ALT or AST > 3 × ULN and TBL > 2 × ULN without initial 
increase in ALP to > 2 × ULN
ALT or AST elevation with 
coagulopathy

ALT or AST > 3 × ULN and INR > 1.5 (in the absence of 
anticoagulation)
ALT or AST elevation 
accompanied by symptoms

ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash, or 
eosinophilia
Isolated ALT or AST 
elevation

ALT or AST > 8 × ULN

5 x ULN < ALT/AST ≤8 x ULN

3 x ULN < ALT/AST ≤5 x ULN
Isolated ALP elevation

ALP > 2 × ULN (in the absence of known bone pathology)
Others

Any clinical event of jaundice (or equivalent term)

Any adverse event potentially indicative of liver toxicity
Table 15-2
Actions required for Liver Events
Criteria
Actions required
Potential Hy’s Law case

Discontinue the study treatment immediately

Hospitalize, if clinically appropriate

Establish causality

Complete CRFs per liver event guidance
ALT or AST elevation with 
coagulopathy
ALT or AST elevation accompanied by 
symptoms
Isolated ALT or AST elevation > 8 × 
ULN
Jaundice
Isolated ALT or AST elevation > 5 to ≤ 8 
× ULN

If confirmed, consider interruption or discontinuation 
of study drug

If elevation persists for more than 2 weeks, 
discontinue the study drug

Establish causality

Complete CRFs per liver event guidance
Isolated ALT or AST elevation > 3 to ≤ 5 
× ULN (patient is asymptomatic)

Monitor liver chemistry tests two or three times 
weekly
Isolated ALP elevation

Repeat liver chemistry tests within 48-72 hours

If elevation is confirmed, measure fractionated ALP; if 
>50% is of liver origin, establish hepatic causality

Complete CRFs per liver event guidance
Any AE potentially indicative of liver 
toxicity

Consider study treatment interruption or 
discontinuation

Hospitalize if clinically appropriate

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Table 15-3
Exclusion of underlying liver disease
Disease
Assessment
Hepatitis A, B, C, E

IgM anti-HAV; HBSAg, IgM anti-HBc, HBV DNA; anti-HCV, 
HCV RNA, IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV infection

IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-
EBV
Autoimmune hepatitis

ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis

Ethanol history, gGT, MCV, CD-transferrin
Nonalcoholic steatohepatitis

Ultrasound or MRI
Hypoxic/ischemic hepatopathy

Medical history: acute or chronic CHF, hypotension, hypoxia, 
hepatic venous occlusion. Ultrasound or MRI.
Biliary tract disease

Ultrasound or MRI, ERCP as appropriate.
Wilson disease

Caeruloplasmin
Hemochromatosis

Ferritin, transferrin
Alpha-1-antitrypsin deficiency

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16
Appendix 2: Specific Renal Alert Criteria and Actions
Table 16-1
Specific Renal Alert Criteria and Actions for Part A
Criteria
Action required
Serum creatinine (sCr) increase
25 – 49% compared to baseline

Consider causes and possible interventions

Follow up within 2-5 days
Serum creatinine increase > 50%

Consider causes and possible interventions

Repeat assessment within 24-48h if possible

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected

Consider hospitalization and specialized 
treatment
Protein-creatinine or albumin-creatinine ratio 
increase ≥ 2-fold
or
new onset dipstick proteinuria ≥ 1+
or
Albumin-creatinine ratio ≥ 30 mg/g or ≥ 3 
mg/mmol;
or
Protein-creatinine ratio (PCR )≥ 150 mg/g or 
>15 mg/mmol

Consider causes and possible interventions

Assess serum albumin & serum protein

Repeat assessment to confirm

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected
New onset glucosuria on urine dipstick 
(unless related to concomitant treatment, 
diabetes)
Assess & document:

Blood glucose (fasting)

Serum creatinine

Urine albumin-creatinine ratio
New hematuria on dipstick
Assess & document:

Urine sediment microscopy

Assess sCr and urine albumin-creatinine ratio

Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation

Consider bleeding disorder
Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases when a nephrologist considers a renal biopsy, it is strongly 
recommended to make specimen slides available for evaluation by Novartis to potentially 
identify project-wide patterns of nephrotoxicity.)

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Confidential
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Protocol No. CLNA043X2202
Whenever a renal event is identified, a detailed subject history and examination are indicated 
to identify, document and potentially eliminate risk factors that may have initiated or 
contributed to the event:

Blood pressure assessment (after 5 min rest, with an appropriate cuff size)

Signs and symptoms such as fever, headache, shortness of breath, back or abdominal pain, 
dysuria, hematuria, dependent or periorbital edema

Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output

Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other potential 
causes of renal dysfunction, e.g., dehydration, hemorrhage, tumor lysis
Table 16-2
Follow-up of renal events for Part A
Action
Follow up
Assess*, document and record in the Case Report 
Form (CRF) or via electronic data load. Review and 
record possible contributing factors to the renal 
event (co-medications, other co-morbid conditions) 
and additional diagnostic procedures (MRI etc) in 
the CRF.

Urine dipstick and sediment microscopy

Blood pressure and body weight

Serum creatinine, electrolytes (sodium, 
potassium, phosphate, calcium), 
bicarbonate and uric acid

Urine output
Monitor subject regularly (frequency at 
investigator’s discretion) until:

Event resolution: (sCr within 10% of 
baseline or protein-creatinine ratio within 
50% of baseline)
or

Event stabilization: sCr level with ±10% 
variability over last 6 months or protein-
creatinine ratio stabilization at a new level 
with ±50% variability over last 6 months.
* Urine osmolality: in the absence of diuretics or chronic kidney disease this can be a very 
sensitive metric for integrated kidney function that requires excellent tubular function. A high 
urinary osmolality in the setting of an increase in sCr will point toward a “pre-renal” cause 
rather than tubular toxicity.

Novartis
Confidential
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Amended Protocol Version v07 (Clean)
Protocol No. CLNA043X2202
Table 16-3
Specific Renal Alert Criteria and Actions for Part B
Renal Event
Actions
Confirmed serum creatinine increase 25 –
49%
Consider causes and possible interventions 
Follow up within 2-5 days
Serum creatinine increase  50 % +
Consider causes and possible interventions 
Repeat assessment within 24-48h if possible
Consider drug interruption or discontinuation unless 
other causes are diagnosed and corrected
Consider patient hospitalization and specialized 
treatment
New onset dipstick proteinuria ≥ 3+
OR
Protein-creatinine ratio (PCR) ≥ 1g/g Cr 
(or mg/mmol equivalent as converted by 
the measuring laboratory)
Consider causes and possible interventions 
Assess serum albumin & serum total protein 
Repeat assessment to confirm
Consider drug interruption or discontinuation unless 
other causes are diagnosed and corrected
New onset hematuria ≥ 3+ on urine 
dipstick (excluding menstruation, infection, 
extreme exercise, or trauma)
Assess & document
Repeat assessment to confirm
Distinguish hemoglobinuria from hematuria
Urine sediment microscopy
Assess sCr 
Exclude infection, trauma, bleeding from the distal 
urinary tract/bladder, menstruation
Consider bleeding disorder
+ Corresponds to KDIGO criteria for Acute Kidney Injury
Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases, when a nephrologist considers a renal biopsy, it is recommended 
to make slide specimen available for evaluation by the RSG to potentially identify project-wide 
patterns of nephrotoxicity.)
Whenever a renal event is identified, a detailed patient history and examination are indicated to 
identify and potentially eliminate risk factors that may have initiated or contributed to the event: 

Blood pressure assessment (after 5-minute rest, with an appropriate cuff size)

Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain, 
dysuria or hematuria, dependent or periorbital edema

Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output

Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other diseases or 
causes, e.g., dehydration due to delirium, tumor lysis

Novartis
Confidential
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Amended Protocol Version v07 (Clean)
Protocol No. CLNA043X2202
Table 16-4
Renal Event Follow Up for Part B
FOLLOW-UP OF RENAL EVENTS
Assess, document and record in CRF

Urine dipstick and sediment microscopy evidence of DIN: crystals, red blood cells 
(dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial 
cells

Blood pressure and body weight 

Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and 
uric acid

Urine output
Review and record possible contributing factors to the renal event (co-medications, other co-morbid 
conditions) and additional diagnostic procedures (MRI etc.) in the CRF
Monitor patient regularly (frequency at investigator’s discretion) until -

Event resolution: (sCr within 10% of baseline or PCR < 1 g/g Cr, or albumin-creatinine ratio <300 
mg/g Cr) or

Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months.

Analysis of urine markers in samples collected over the course of the DIN event