Clinical trial NCT03610516
Conditions: Lupus Nephritis
Keywords: anti-CD40 CFZ533 moderately active lupus nephritis
Sponsor: Novartis Pharmaceuticals
Start date: 2018-09-12; Completion date: 2023-06-29
Enrollment: 57 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study was to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary therapeutic efficacy of multiple doses of CFZ533 anti-CD40 monoclonal antibody in patients with moderately active lupus nephritis.

Detailed description:
This was a randomized, subject and investigator blind, placebo controlled multicenter study with multiple doses of CFZ533 administered by 1-hour intravenous infusion over a 24 week treatment period, as compared to matched placebo infusion. The treatment period was followed by a 24-week safety follow-up period.The duration of the study (including the screening period) for each patient was approximately 53 weeks. The investigational drug or placebo was administered on top of standard of care therapy for lupus nephritis.

Patients were screened within 29 days of the first study drug infusion. Eligibility was confirmed at the baseline visit within one week before the first dose. Eligible patients were assigned a randomization number and receive the intravenous infusion within 3 days of baseline visit.

Arms: arm 1: Investigational drug CFZ533 will be administred as multiple doses arm 2: Investigational drug matching placebo will be administered as multiple doses
Interventions: intervention 1: CFZ533 intervention 2: Placebo
Intervention descriptions: intervention 1: Multiple doses of 10 mg/kg CFZ533 intravenous (IV) infusion. CFZ533 was administered every 4 weeks (Q4W; from Day 1 to Day 141), plus an additional dose of 10 mg/kg IV at Day 15, resulting in a Q2W loading regimen up to the third dose on Day 29. intervention 2: multiple doses of placebo intravenous infusion

Protocol documents:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
CFZ533 (iscalimab)
Clinical Trial Protocol CCFZ533X2202
A randomized, placebo-controlled, patient and 
investigator blinded study investigating the safety, 
tolerability, pharmacokinetics and preliminary 
efficacy of multiple doses of CFZ533 in patients with 
moderately active proliferative lupus nephritis
ClinicalTrials.gov identifier: NCT03610516
Document type:
Amended Protocol Version
EUDRACT number:
2017-003230-93
Version number:
v04 Clean (Incorporating amendment 04)
Clinical Trial Phase:
II
Release date:
26-Jul-2021
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


Novartis
Confidential
Page 2
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. Note: The SOM will not form part of the Clinical Study Report.
Notification of serious adverse events
Dear Investigator,
You must report a serious adverse event (SAE) (initial or follow-up) to Novartis as summarized 
below. Refer to Section 9.2 of the protocol for SAE criteria and additional requirements.  See 
also page 2 of the Site Operations Manual for further details on the method of reporting a SAE.

Complete SAE report

Submit SAE report to Novartis Chief Medical Office & 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. 


Novartis
Confidential
Page 3
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
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............................................................................................................9
Pharmacokinetic definitions and symbols.........................................................................14
Glossary of terms...............................................................................................................15
Protocol summary..............................................................................................................29
1
Introduction .......................................................................................................................33
1.1
Background............................................................................................................33
1.1.1
Scientific rationale for targeting CD40/CD154 co-stimulation in 
lupus nephritis.......................................................................................33
1.1.2
CFZ533 overview..................................................................................34
1.1.3
Relevant data summary.........................................................................35
1.2
Nonclinical data.....................................................................................................35
1.3
Clinical data...........................................................................................................38
1.3.1
Human safety and tolerability data .......................................................38
1.3.2
Human pharmacokinetic and pharmacodynamic data ..........................39
1.4
Study purpose ........................................................................................................41
2
Objectives and endpoints...................................................................................................42
2.1
Primary objective(s)...............................................................................................42
2.2
Secondary objective(s)...........................................................................................42
2.3
Exploratory objective(s) ........................................................................................43
3
Investigational plan ...........................................................................................................44
3.1
Study design...........................................................................................................44
Commercially Confidential Information (CCI)
Commercially Confidential Information


Novartis
Confidential
Page 4
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
3.2
Rationale of study design.......................................................................................46
3.3
Rationale for dose/regimen, route of administration and duration of treatment....47
3.3.1
Loading regimen ...................................................................................47
3.3.2
Maintenance regimen............................................................................49
3.3.3
Bodyweight-adjusted dosing.................................................................49
3.4
Rationale for choice of comparator .......................................................................50
3.5
Purpose and timing of interim analyses/design adaptations..................................50
3.6
Risks and benefits..................................................................................................50
3.6.1
Potential benefit ....................................................................................50
3.6.2
Potential risks associated with exposure to CFZ533 and their 
mitigation ..............................................................................................50
3.6.3
Blood sample volumes..........................................................................54
4
Population..........................................................................................................................54
4.1
Inclusion criteria ....................................................................................................54
4.2
Exclusion criteria...................................................................................................56
5
Restrictions for Study Subjects .........................................................................................58
5.1
Contraception requirements...................................................................................58
5.2
Prohibited treatment...............................................................................................58
5.3
Dietary restrictions and smoking...........................................................................59
5.4
Other restrictions ...................................................................................................59
6
Treatment...........................................................................................................................59
6.1
Study treatment......................................................................................................59
6.1.1
Investigational treatment and control drug(s) .......................................59
6.1.2
Additional study treatment....................................................................60
6.2
Treatment arms......................................................................................................60
6.3
Treatment assignment and randomization.............................................................60
6.4
Treatment blinding.................................................................................................61
6.5
Treating the subject................................................................................................62
6.6
Permitted dose adjustments and interruptions of study treatment.........................62
6.7
Emergency breaking of assigned treatment code ..................................................62
6.8
Treatment exposure and compliance .....................................................................63
6.9
Recommended treatment of adverse events ..........................................................63
6.10
Rescue medication.................................................................................................64
6.11
Concomitant treatment...........................................................................................64
7
Study completion and discontinuation ..............................................................................64
7.1
Study completion and post-study treatment ..........................................................64
7.2
Discontinuation of study treatment........................................................................65


Novartis
Confidential
Page 5
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
7.3
Withdrawal of informed consent ...........................................................................66
7.4
Lost to follow-up ...................................................................................................67
7.5
Study stopping rules ..............................................................................................67
7.6
Early study termination by the sponsor .................................................................68
8
Procedures and assessments ..............................................................................................68
8.1
Assessment schedule .............................................................................................68
8.2
Informed consent procedures.................................................................................71
8.3
Subject screening...................................................................................................72
8.4
Subject demographics/other baseline characteristics.............................................72
8.5
Efficacy / Pharmacodynamics ...............................................................................72
8.5.1
Total soluble CD40 in plasma...............................................................72
8.5.2
Urinary protein creatinine ratio (UPCR)...............................................72
8.6
Safety.....................................................................................................................73
8.6.1
Physical examination ............................................................................73
8.6.2
Vital signs..............................................................................................73
8.6.3
Height and weight .................................................................................73
8.6.4
Laboratory evaluations..........................................................................73
8.6.5
Immunogenicity ....................................................................................75
8.6.6
Electrocardiogram.................................................................................75
8.6.7
Pregnancy..............................................................................................76
8.6.8
Other safety assessments.......................................................................76
8.7
Pharmacokinetics...................................................................................................79
8.8
Other assessments..................................................................................................80
9
Safety monitoring..............................................................................................................83
9.1
Adverse events.......................................................................................................83
9.2
Adverse event of special interest ...........................................................................85
Commercially Confidential Information


Novartis
Confidential
Page 6
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
9.3
Serious adverse event reporting.............................................................................85
9.3.1
Definition of SAE .................................................................................85
9.3.2
SAE reporting........................................................................................86
9.4
Liver safety monitoring .........................................................................................87
9.5
Renal safety monitoring.........................................................................................88
9.6
Reporting of study treatment errors including misuse/abuse ................................88
9.7
Pregnancy reporting...............................................................................................89
9.8
Early phase safety monitoring ...............................................................................90
10 Data review and database management.............................................................................90
10.1
Site monitoring ......................................................................................................90
10.2
Data collection.......................................................................................................90
10.3
Database management and quality control............................................................91
10.4
Data Monitoring Committee..................................................................................92
10.5
Adjudication Committee........................................................................................92
11 Data analysis......................................................................................................................92
11.1
Analysis sets ..........................................................................................................92
11.2
Subject demographics and other baseline characteristics......................................93
11.3
Treatments .............................................................................................................93
11.4
Analysis of the primary variable(s) .......................................................................93
11.4.1
Primary Variable(s)...............................................................................93
11.4.2
Statistical model, hypothesis, and method of analysis..........................93
11.4.3
Handling of missing values/censoring/discontinuations.......................93
11.4.4
Summary statistics of safety..................................................................94
11.4.5
Sensitivity analyses ...............................................................................94
11.5
Analysis of secondary variable(s)..........................................................................95
11.5.1
Efficacy / Pharmacodynamics...............................................................95
11.5.2
Pharmacokinetics ..................................................................................95
11.5.3
Pharmacokinetic / pharmacodynamic relationships..............................96
11.5.4
Other assessments .................................................................................96
11.6
Analysis of exploratory variables ..........................................................................96
11.7
Sample size calculation..........................................................................................97
11.8
Power for analysis of key secondary variables......................................................98
11.9
Interim analyses.....................................................................................................98
12 Ethical considerations........................................................................................................99
Commercially Confidential Information


Novartis
Confidential
Page 7
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
12.1
Regulatory and ethical compliance........................................................................99
12.2
Responsibilities of the investigator and IRB/IEC..................................................99
12.3
Publication of study protocol and results...............................................................99
12.4
Quality Control and Quality Assurance.................................................................99
13 Protocol adherence ..........................................................................................................100
13.1
Protocol Amendments .........................................................................................100
14 References .......................................................................................................................101
15 Appendix 1: Liver Event Definitions and Follow-up Requirements...............................105
16 Appendix 2: Specific Renal Alert Criteria and Actions..................................................107
17 Appendix 3: 1997 Update of the 1982 ACR Revised Criteria for Classification of 
Systemic Lupus Erythematosus.......................................................................................109
18 Appendix 4: Classification of Lupus nephritis................................................................110
List of tables
Table 6-1
Overview of study medication ..............................................................59
Table 6-2
Blinding and unblinding plan................................................................62
Table 8-1
Assessment schedule.............................................................................69
Table 8-2
Hepatitis screening................................................................................77
Table 8-3
CMV screening .....................................................................................78
Table 9-1
Guidance for capturing study treatment errors......................................89
Table 15-1
Liver Event Definitions.......................................................................105
Table 15-2
Actions required for Liver Events.......................................................105
Table 15-3
Exclusion of underlying liver disease .................................................106
Table 16-1
Specific Renal Alert Criteria and Actions...........................................107
Table 16-2
Follow-up of renal events....................................................................108
Table 17-1
ACR Revised Criteria for Classification of SLE ................................109
Table 18-1
Classification of Lupus nephritis ........................................................110
List of figures
Figure 3-1
Study Design .........................................................................................46
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 8
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Figure 3-2
Predicted time-course of CFZ533 concentration ..................................47


Novartis
Confidential
Page 9
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
List of abbreviations
AE
adverse event
AESI
Adverse events of special interest 
ADA
Anti-drug antibodies 
ADCC
α-GST
Antibody dependent  cell-mediated cytotoxicity 
Alpha-glutathione S-transferase
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANA 
Antinuclear autoantibody 
aPTT
Activated partial thromboplastin time
BMI
Body Mass Index
BP
Blood pressure 
BUN
Blood Urea Nitrogen
BW 
Body weight 
CDC 
Complement dependent cytotoxicity 
CFR
U.S. Code of Federal Regulation
CM
Centimeters 
CMO&PS
Chief Medical Office & Patient Safety
CMV
COVID-19
Human cytomegalovirus
Coronavirus disease of 2019
CNS 
Central nervous system 
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CRP 
C-reactive protein
CRR
Complete renal remission 
CSF
Cerebrospinal fluid 
CTA
Clinical trial application 
CTC
Common Toxicity Criteria
CV
coefficient of variation
CysC
Cystatin C
Commercially Confidential Information


Novartis
Confidential
Page 10
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
DAR
Dose administration record 
DMC
Data Monitoring Committee
EBV
Epstein-Barr virus 
ECG
electrocardiogram
eCRF
Electronic case report forms 
EDC
Electronic Data Capture
EFD
embryo-fetal development
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
eSAE
ESR
electronic Serious Adverse Event
Erythrocyte Sedimentation Rate
FDA
Food and Drug Administration
FMV
First morning void
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
h
hour
HbA1c
Hemoglobin A1c
HBsAg
hepatitis B surface antigen
Anti-HBc
Hepatitis B core antibody
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IB
Investigators brochure 
i.v.
intravenous
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IN
Investigator Notification


Novartis
Confidential
Page 11
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISG 
Interferon gene signature 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
Kg
Kilogram
KLH 
Keyhole limpet hemocyanin 
LDH
lactate dehydrogenase
LLN
lower limit of normal
LN
Lupus nephritis 
MABEL
minimum anticipated biological effect level
MAR
Missing at random
MAS 
Macrophage activation syndrome 
MedDRA
medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
MMF 
mycophenolate mofetil
MRSD
maximum recommended starting dose
NCA
Non-compartmental analysis 
NCDS
Novartis Clinical Data Standards
NGAL 
neutrophil gelatinase-associated lipocalin
NSAIDs
Nonsteroidal anti-inflammatory drugs
PBMC
peripheral blood mononuclear cells
p.o.
oral
PCR
Polymerase chain reaction
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 12
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
pSS
primaru Sjögren’ s syndrome 
PT
prothrombin time
QM
Quality Management 
QTcF
QT correction formula 
RA
Rheumatoid arthritis 
RBC
red blood cell(s)
RF
Rheumatoid factor 
RNA 
Ribonucleic acid 
s.c.
Subcutaneous
SAE
serious adverse event
SAP
Statistical analysis plan
sCR
serum creatinine
SD
standard deviation
SELENA 
Safety of Estrogens in Lupus Erythematosus National Assessment
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SLE
Systemic Lupus Erythematosus
SoC
Standard of care 
SOM
Site Operations Manual
SOPs
Standard operating procedures 
SUSAR
Suspected Unexpected Serious Adverse Reactions
TB
Tuberculosis 
TBL
total bilirubin
TE
Thromboembolic 
TEG
Thromboelastography
TME
target mediated elimination
TTx
Tetanus toxoid 
ULN
upper limit of normal
UPCR
urinary protein creatinine ratio
Commercially Confidential Information


Novartis
Confidential
Page 13
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
WBC
white blood cell(s)
WHO
World Health Organization
WoC
Withdrawal of Consent
Commercially Confidential Information


Novartis
Confidential
Page 14
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Pharmacokinetic definitions and symbols
AUClast
AUClast is the area under the plasma concentration-time curve calculated to 
the last quantifiable concentration point (or to 0, in situations where 
concentrations below the limit of quantification (BLQ) are treated as zero)
Cmax
The observed maximum plasma (or serum or blood) concentration following 
drug administration [mass / volume]
Cmin
The observed minimum plasma concentration following drug administration
Ctrough
The observed plasma concentration that is just prior to the beginning of, or 
at the end of a dosing interval
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]
Tmax
The time to reach the maximum concentration after drug administration 
[time]


Novartis
Confidential
Page 15
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Glossary of terms
Assessment
A procedure used to generate data required by the study
Clinic spot urine
Urine sample collected at the clinic during site visit 
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
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which 
are used to capture data transcribed from paper source forms used at the 
point of care.
Enrollment
Point/time of subject entry into the study at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described 
in the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is 
associated with a purpose (e.g. screening, randomization, treatment, 
follow-up) which applies across all arms of a study.
First morning void
urine
First morning void urine sample collected at patient’s home 
Investigational 
drug
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and Directive 
2001/20/EC and is synonymous with “investigational new drug,” 
"Investigational Medicinal Product," or “test substance”
Medication pack 
number
A unique identifier on the label of each drug package in studies that 
dispense study treatment using an IRT system
Patient
An individual with the condition of interest
Personal Data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding 
to a specific treatment arm assignment
Screen Failure
A subject who is screened but is not treated or randomized


Novartis
Confidential
Page 16
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Source 
Data/Document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Study treatment
Any drug or combination of drugs administered to the study 
participants as part of the required study procedures; includes 
investigational drug(s), control(s) or background therapy
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject 
and should be used to identify the subject throughout the study for all 
data collected, sample labels, etc.
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested 
in the study
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study occurs only when a subject does 
not want to participate in the study any longer, and does not allow any 
further collection of personal data


Novartis
Confidential
Page 17
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Commercially Confidential Information


Novartis
Confidential
Page 18
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Commercially Confidential Information


Novartis
Confidential
Page 19
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Commercially Confidential Information


Novartis
Confidential
Page 20
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Commercially Confidential Information


Novartis
Confidential
Page 21
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Commercially Confidential Information


Novartis
Confidential
Page 22
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Commercially Confidential Information


Novartis
Confidential
Page 23
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Commercially Confidential Information


Novartis
Confidential
Page 24
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Commercially Confidential Information


Novartis
Confidential
Page 25
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Commercially Confidential Information


Novartis
Confidential
Page 26
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Commercially Confidential Information


Novartis
Confidential
Page 27
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Commercially Confidential Information


Novartis
Confidential
Page 28
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Commercially Confidential Information


Novartis
Confidential
Page 29
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Protocol summary
Protocol number
CCFZ533X2202
Full Title
A randomized, placebo-controlled, patient and investigator blinded study 
investigating the safety, tolerability, pharmacokinetics and preliminary 
efficacy of multiple doses of CFZ533 in patients with moderately active 
proliferative lupus nephritis
Brief title
Safety, pharmacokinetics and preliminary efficacy study of CFZ533 in 
patients with lupus nephritis
Sponsor and Clinical 
Trial Phase
Novartis
Phase II
Intervention type
Drug
Study type
Interventional 
Purpose and 
rationale
This study is to evaluate the safety, tolerability, pharmacokinetics, 
pharmacodynamics, and preliminary therapeutic efficacy of multiple doses 
of CFZ533 anti-CD40 monoclonal antibody in patients with moderately 
active lupus nephritis (LN)
Primary Objective(s)

To evaluate the safety and tolerability of 24 weeks of treatment with 
multiple intravenous (IV) doses of 10 mg/kg CFZ533 as an add-on 
therapy of CFZ533 to standard of care in moderately active lupus 
nephritis (LN) patients

To assess the effect of CFZ533 on renal proteinuria using urinary 
protein creatinine ratio (UPCR) in moderately active LN patients 
after 24 weeks of treatment as an add-on therapy to standard of 
care as compared to placebo
Secondary Objectives

To assess the effect of CFZ533 on relevant renal outcomes at 
different time points

To evaluate the pharmacokinetics (PK) and pharmacodynamics 
(PD) of CFZ533 in LN patients after multiple 10 mg/kg IV doses

To evaluate the immunogenicity of CFZ533 in LN patients after 
multiple 10 mg/kg IV doses
Study design
Randomized, double-blind, placebo-controlled, non-confirmatory study in 
approximately 60 subjects, up to a maximum of 75 subjects
Population
Female and male subjects with moderately active lupus nephritis at the age 
of ≥18 years and ≤75 years
Key Inclusion criteria

Men and women with systemic lupus erythematosus (see below), 
aged ≥ 18 years and ≤ 75 years at screening, fulfilling at least 4 out 
of 11 criteria for SLE as defined by the American College of 
Rheumatology (Tan et al 1982, revised by Hochberg 1997)

Subjects must have a body mass index (BMI) within the range of 
18 - 40 kg/m2. (BMI = Body weight (kg) / [Height (m)]2) at screening 
visit

Histological diagnosis of proliferative lupus nephritis World Health 
Organization (WHO) ISN/RPS (Weening et al 2004) Class III or IV 
within 5 years of screening

Presence of antinuclear autoantibody (ANA titer ≥1:80 at screening)


Novartis
Confidential
Page 30
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202

First morning void or spot urine UPCR ≥ 0.5 mg/mg (56.52 
mg/mmol) at screening visit and baseline visit 

At least one of the following:
a) low complement level (C3 < 0.9 g/L) or C4 < 0.1 g/L), and/or
b) elevated anti-dsDNA (≥30 IU/mL), and/or
c) urine sediment consistent with active proliferative lupus 
nephritis such as presence of cellular (granular or red blood 
cell) casts or hematuria (>5 red blood cells per high power 
field) if other causes such as menstrual bleeding are excluded

Patient must have sufficient kidney function as estimated by eGFR 
> 30 mL/min/1.73 m2at screening and baseline visits (Levey et al 2009)

Patients must have active disease as defined by proteinuria and 
additional symptoms as above despite standard of care therapy for 
lupus nephritis as considered appropriate by the treating physician
(e.g., corticosteroids and/or immunosuppressive or
immunomodulatory treatments such as mycophenolate, 
azathioprine, methotrexate or hydroxychloroquine) . For guidance, 
see published guidelines such as by Bertsias et al 2012 and 
Hahn et al 2012

Women of child-bearing potential (defined as all women 
physiologically capable of becoming pregnant) must use highly 
effective methods of contraception during dosing and until study 
completion. 
Key Exclusion criteria

Any glomerulonephritis other than WHO Class III or IV lupus 
nephritis.  Patients with proliferative nephritis (Class III or IV) who, in 
addition, have overlapping histological signs for other 
glomerulonephritis, e.g., Class V, are eligible at the investigator`s 
discretion

Hypoalbuminemia (serum albumin of less than 2.0 g/dL)

Patients who have received
a) oral or i.v. cyclophosphamide within 3 months prior to
randomization
b) i.v. corticosteroid bolus (dose > 1mg/kg) within 3 months prior 
to randomization
c) rituximab or other B cell depleting agent received prior to 
randomization within

≤ 6 months: no inclusion

> 6 but ≤12 months: B cell count must be within 
normal range

>12 months prior to randomization: no special 
requirements
d) belimumab within 6 months prior to randomization
e) any other biologic drug or an investigational drug within three 
(3) months or five times the half-life, whichever is longer from 
randomization
f) any calcineurin inhibitors (e.g., tacrolimus or cyclosporin A) 
within 
3
months
prior 
to
randomization
[For China, Hong Kong, and Korea only: calcineurin inhibitors,
except tacrolimus (≤ 3mg/day), within 3 months prior to 
randomization]


Novartis
Confidential
Page 31
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202

Patients who are at significant risk for thromboembolic events based 
on the following:
a) History of either thrombosis or 3 or more spontaneous 
abortions
b) Presence of lupus anticoagulant or prolonged activated partial 
thromboplastin time (aPTT) and no prophylactic treatment with 
aspirin or anticoagulants as per local standard of care

Positive serology for

HIV antibodies,

CMV IgM in the absence of positive CMV IgG, or quantifiable 
CMV DNA by PCR (patients with detectable but NOT 
quantifiable DNA test result may be eligible for the study),

Or hepatitis B surface antigen (HBsAg) or hepatitis B core 
antibody (anti-HBc), except if HBV DNA is negative and 
hepatitis B monitoring (HBsAg and HBV DNA tested every 4 
weeks until the end of study) is implemented; and hepatitis C 
antibodies confirmed by an appropriate licensed test at 
screening.

Have had signs or symptoms of a clinically significant systemic viral, 
bacterial or fungal infection within 30 days prior to randomization

Live vaccines within 8 weeks of first study drug infusion
Study treatment

CFZ533 150 mg or placebo Liquid in vial for injection
o
CFZ533 10 mg/kg administered by intravenous infusion
o
placebo administered by intravenous infusion
Intravenous infusion will be administered at Days 1, 15, 29,  57, 85, 
113, and 141
Pharmacokinetic 
assessments

Free CFZ533 in plasma
Efficacy/PD 
assessments

Urinary protein creatinine ratio (UPCR)

Total soluble CD40 (target engagement) in plasma
Key safety 
assessments

Adverse events/Serious adverse events

Vital signs

ECG evaluation

Standard hematology and chemistry evaluations

Immunogenicity
Other assessments
Commercially Confidential Information


Novartis
Confidential
Page 32
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Data analysis
The primary variable is the ratio from baseline in urinary protein creatinine 
ratio (UPCR) at Week 25, using first morning void. This ratio will be log 
transformed prior to the analysis. A repeated measures mixed model will 
be fitted with factors for treatment group (CFZ533 or placebo) and visit (e.g. 
Week 5, 9, 13 etc.). The model will also include a factor for the prednisone 
dose-equivalent at baseline (≤ 10 mg, >10 mg), which is a stratification 
factor for the randomization. Log-transformed baseline UPCR will be 
included in the model as a covariate along with the interactions between 
visit and all of the fixed effects. A normal errors model will be assumed with 
an unstructured covariance matrix to account for the correlation within 
subjects.
At each of the visits, the difference between the CFZ533 and placebo group 
will be estimated (along with its corresponding 95% confidence interval) 
and then back-transformed to provide an estimate of the ratio between 
treatment groups.
Descriptive statistics will be provided for the safety data (e.g. AEs, vital 
signs, ECGs, hematology and chemistry evaluations etc.). For serious 
adverse events and adverse events of special interest, statistical analyses 
comparing the event rates in the two treatment groups will be performed.
Key words
CFZ533, anti-CD40, moderately active lupus nephritis


Novartis
Confidential
Page 33
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
1
Introduction
1.1
Background
Systemic Lupus Erythematosus (SLE) is a chronic inflammatory disease characterized by 
autoantibody production and other distinct immunological abnormalities (Frieri 2013, 
Gurevitz et al 2013). It may affect the skin, joints, kidneys, lungs, heart, serous membranes, 
nervous system or other organs. Lupus Nephritis (LN) is a common manifestation of SLE 
clinically affecting approximately 60% of patients with greater representation in children and
young adults. Despite recent advances in the treatment of many autoimmune diseases including 
SLE, , LN remains a major cause of morbidity and mortality in SLE patients with 5-20% of LN 
patients progressing to end stage renal disease within 10 years of diagnosis (Faurschou et al
2010). Intensive induction therapies with intravenous (IV) and/or oral corticosteroids combined 
with IV cyclophosphamide or oral mycophenolate mofetil (MMF) achieve a satisfactory renal 
response only in about half of the patients and carry a significant burden of toxicity. 
Maintenance therapies with lower doses of oral corticosteroids, azathioprine, or MMF often fail 
to maintain remission (Waldman and Appel 2006).
1.1.1
Scientific rationale for targeting CD40/CD154 co-stimulation in lupus 
nephritis
Pharmacological inhibition of CD40-CD154 interactions using anti-CD40 or anti-CD154 antibodies 
reduced autoimmune disease pathology in numerous pre-clinical and clinical studies and prolonged
allograft survival in non-human primates (Aoyagi et al 2009; Watanabe et al 2013). 
CD40-CD154 interactions have been shown to be involved in the pathology of SLE and LN. 
Anti-CD154 treatment of lupus prone animals was found to ameliorate renal disease 
(Mohan et al 1995). Elevated sCD154 levels in SLE sera has also been documented, and 
activated T and B cells from the periphery of active SLE patients were found to express CD154 
(Desai-Mehta et al 1996). Additionally, augmented CD40 expression was observed on renal 
parenchymal cells from patients suffering proliferative lupus nephritis (Yellin et al 1997), 
potentially linking CD40 signaling to organ-specific pathology. When lupus patients with active 
proliferative lupus nephritis were treated with rituximab and oral prednisolone, remission was 
preceded by down-regulation of CD154 on CD4+ T cells (Sfikakis et al 2005). In addition, an 
anti-CD154 antibody, BG9588, improved serologic activity and decreased hematuria in patients 
with proliferative lupus nephritis in an open-label phase 2 study (Boumpas et al 2003). 
Treatment of SLE patients with BG9588 led to the disappearance of CD38high Ig-secreting 
plasma cells from the periphery (Grammer et al 2003) and reduced the frequency of anti-
dsDNA antibody-producing B cells in the peripheral blood (Huang et al 2002). However, 
treatment with BG9588 (due to its platelet activating effects) provoked life-threatening 
thromboembolic (TE) events precluding further clinical development (Kawai et al 2000). 
An alternative approach that targets the CD40 signaling pathway but is devoid of TE events 
would have a great potential for the safe and efficacious treatment of lupus nephritis.


Novartis
Confidential
Page 34
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
1.1.2
CFZ533 overview
CFZ533 (iscalimab) is a non-agonistic, fully human, non-depleting (Fc-silencing mutation 
N297A), antagonistic IgG1 anti-CD40 antibody that binds to the CD154 binding site on CD40 
and prevents the binding of CD154 to CD40. Since it is Fc-silent, CFZ533 binding is able to 
block the CD40/CD154 costimulatory pathway and inhibit cellular proliferation and other 
effector functions, but does not cause antibody-dependent cell-mediated cytotoxicity (ADCC) 
or complement dependent cytotoxicity (CDC).  
CFZ533 inhibits CD154-induced activation in vitro and T cell-dependent Ab formation and 
germinal center formation in vivo. CFZ533 was able to prolong non-human primate renal 
allograft survival alone or in combination with sub-therapeutic doses of cyclosporine. 
In addition, CFZ533 was able to completely suppress primary and secondary antibody 
responses to immunization with a T cell-dependent antigen. 
CFZ533 is expected to be devoid of the thromboembolic risk characteristic of the Fc active anti-
CD154 antibodies such as BG9588 as CFZ533 does not activate platelets. The hypothesis that 
BG9588-induced TE in an Fc-dependent manner was supported by recent data with CDP7657 
(dapirolizumab pegol), an anti-CD154 Fab fragment, that showed no evidence of platelet 
activation (Chamberlain et al 2017, Tocoian et al 2015). Comprehensive preclinical studies, 
specifically exploring whether there is a propensity of CFZ533 to cause thrombosis using the 
most sensitive species for TE events showed no sign or event of TE. 
As of November 2020, a total of approximately 837 subjects have been enrolled into the 
CFZ533 clinical program: 88 healthy subjects (CCFZ533X1101 and CCFZ533X2101), 20 
patients with rheumatoid arthritis (CCFZ533X2101), 59 patients with renal transplant
(CCFZ533X2201), 
155
patients 
with 
Sjögren’s
syndrome 
(CCFZ533X2203
and 
CCFZ533B2201), 44 patients with myasthenia gravis (CCFZ533X2204), 15 patients with 
Graves` 
disease
(CCFZ533X2205),
19 
patients 
with 
hidradenitis 
suppurativa
(CCFZ533H12201BC), 340 patients with kidney transplant (CCFZ533A2201), 39 with liver 
transplant
(CCFZ533A2202), 
26 
patients 
with 
systemic 
lupus 
erythematosus
(CVAY736X2208), 30 patients with lupus nephritis (CCFZ533X2202), 2 patients with Type 1 
Diabetes (CCFZ533X2207) of which approximately 608 subjects received CFZ533. Based on 
this CFZ533 is well-tolerated, with no increased risk for drug-related thromboembolic events 
in dosed subjects.
Based on preliminary data, multiple doses of 10 mg/kg IV CFZ533 were safe and improved the 
signs and symptoms of primary Sjögren’s syndrome (pSS) as measured by relevant clinical 
endpoints. As pSS is, in many aspects, similar to SLE (also characterized by circulating 
autoantibodies and CD40 pathway-related abnormalities), efficacy in pSS may further 
strengthen the rationale for targeting CD40 in lupus nephritis.  
Collectively, these results suggest that inhibition of the CD40/CD154 pathway by CFZ533 may 
represent a safe and efficacious novel therapeutic approach for the treatment of lupus nephritis
and where, despite progress, the unmet medical need is high.


Novartis
Confidential
Page 35
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
1.1.3
Relevant data summary
The most relevant data for the present study are summarized in the sections below. For detailed 
information, please refer to the IB .
1.2
Nonclinical data
Commercially Confidential Information


Novartis
Confidential
Page 36
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Commercially Confidential Information


Novartis
Confidential
Page 37
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Commercially Confidential Information


Novartis
Confidential
Page 38
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
1.3
Clinical data
1.3.1
Human safety and tolerability data
As of November 2020, a total of approximately 837 subjects have been enrolled into the 
CFZ533 clinical program. The program has included Phase 1 trials in healthy volunteers 
(CCFZ533X1101
and CCFZ533X2101, n=88) and in rheumatoid arthritis patients 
(CCFZ533X2101, n=20); and Phase 2 trials in patients undergoing renal transplant
(CCFZ533X2201, n=59), with primary Sjögren’s
syndrome
(CCFZ533X2203, and 
CCFZ533B2201, 155 patients), with myasthenia gravis (CCFZ533X2204, n=44), with Graves` 
disease (CCFZ533X2205, n=15), with hidradenitis suppurativa (CCFZ533H12201BC, n=19), 
with kidney transplant (CCFZ533A2201, n=340), with liver transplant (CCFZ533A2202, n=39), 
with Sjögren’s syndrome (CCFZ533B2201, n=86), with systemic lupus erythematosus 
(CVAY736X2208, n=26), and with lupus nephritis (CCFZ533X2202, n=30), with Type 1 
diabetes (CCFZ533X2207, n=2). Results from two clinical trials relevant for the proposed study 
in lupus nephritis are summarized below; more details are included in the Investigator`s 
Brochure. 
1.3.1.1
Study CCFZ533X2101: First in human trial
This was a First-in-Human, non-confirmatory, randomized, double-blind, placebo-controlled, 
single-ascending dose study. The study was conducted in 7 centers and utilized a 2 part design. 
Part 1 evaluated single ascending doses of CFZ533 (0.03, 0.1, 0.3, 1 and 3 mg/kg) and placebo 
administered as an IV infusion over approximately 1-2 hours in non-Chinese healthy subjects 
(Cohorts 1 through 5), healthy subjects of Chinese descent (3 mg/kg and placebo, Cohort 9) and 
patients with rheumatoid arthritis (10 and 30 mg/kg and placebo, Cohorts 6 and 7). 
Part 2 evaluated a single SC dose of 3 mg/kg CFZ533 and placebo in healthy subjects 
(Cohort 8). A total of 76 subjects were enrolled including 56 healthy subjects (Cohorts 1 to 5, 
and 8 and 9) and 20 patients with rheumatoid arthritis (Cohorts 6 and 7).
Overall, single doses of CFZ533 from 0.03 to 3 mg/kg IV and 3 mg/kg SC in healthy subjects, 
and from 10 to 30 mg/kg IV in patients with rheumatoid arthritis, appeared to be safe and well 
tolerated. There was no evidence of any dose-related increases in the incidence of AEs or 
notable differences between non-Chinese and Chinese healthy subjects (3 mg/kg) or between 
IV and SC (3 mg/kg) administration in non-Chinese healthy subjects. There were no deaths and 
no subjects withdrew due to AEs. There were no SAEs in healthy subjects. Two patients with 
rheumatoid arthritis experienced a total of 3 SAEs (due to hospitalization), none of which were 
considered to be treatment-related. Of note, no thromboembolic event occurred.  
There were no apparent differences between CFZ533 treatment groups and placebo for any 
hematology, biochemistry or urinalysis parameters. No notable changes were observed for 
EBV/CMC surveillance parameters, coagulation parameters, total IgG and IgM, cytokine 
parameters, or renal function parameters. There was no evidence of a dose-related effect of 
CFZ533 on any rheumatoid arthritis markers. There were also no clinically relevant changes in 
vital signs or changes in ECG parameters.


Novartis
Confidential
Page 39
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
1.3.1.2
Study CCFZ533X2203: Proof of Concept in primary Sjögren`s 
syndrome
A multi-center, randomized, double-blind, placebo controlled, parallel group study to assess the 
safety, tolerability, pharmacokinetics and preliminary efficacy of CFZ533 in patients with 
primary Sjögren’s syndrome (pSS) has been completed. 
The study comprised three sequential cohorts. Cohorts 1 (3 mg/kg SC) and 2 (10 mg/kg IV) 
applied a design with two periods where Period 1 was a 12-week, double blind,  placebo 
controlled period followed by Period 2 which was an additional open label (all-CFZ533) 12 
week extension. Cohort 3 was open label with two active (CFZ533) parallel arms. 
Twelve (12) patients were included in Cohort 1, 32 in Cohort 2, and 25 patients were included 
in Cohort 3. In Cohorts 1 and 2, CFZ533 or placebo was administered at Weeks 1, 3, 5 and 9 in 
Period 1 followed by Period 2 when CFZ533 was administered at Weeks 13, 15, 17 and 21. The 
doses of CFZ533 administered in Cohort 1 and Cohort 2 were 3 mg/kg SC and 10 mg/kg IV, 
respectively. In Cohort 3 Arm 1 (N=13), CFZ533 was administered at 600 mg SC weekly on 4 
occasions (loading doses), followed by 300 mg SC weekly on 9 occasions (maintenance 
regimen starting on Day 29). In Cohort 3 Arm 2 (N=12), the loading dose of 10 mg/kg IV 
CFZ533 on Day 1 was followed by 300 mg SC weekly on 12 occasions (maintenance regimen 
starting on Day 8).
Overall, based on final data of this study, repeated dosing with different dose levels of CFZ533 
over 21 weeks was safe and well tolerated in patients with Sjögren’s syndrome. Multiple doses 
of 10 mg/kg IV. CFZ533 improved the signs and symptoms of Sjögren’s syndrome as measured 
by ESSDAI.
1.3.2
Human pharmacokinetic and pharmacodynamic data
1.3.2.1
Study CCFZ533X2101
In healthy subjects as well as in patients with rheumatoid arthritis, after single IV or 
SC administration, CFZ533 PK profiles were consistent with target mediated disposition 
resulting in non-linear PK profiles and more rapid clearance when CD40 receptor occupancy 
dropped below approximately 90%.
Despite some inter-individual variability in the PK profiles from the Chinese subjects, the 
disposition of CFZ533 in Chinese subjects was generally similar as for non-Chinese subjects, 
and the target engagement was also similar (about 4 weeks) after 3 mg/kg IV CFZ533. At this 
dose level, similar PK/PD profiles were demonstrated through free CFZ533 profiles in plasma, 
CD40 occupancy on peripheral B cells measuring free CD40 and total CD40, and total sCD40 
concentrations in plasma.
In patients with rheumatoid arthritis at 10 mg/kg IV, as measured by free CD40 on whole blood 
B cells compared to mean pre-dose, and total sCD40 profiles in plasma, full CD40 occupancy 
was generally maintained for 8 weeks. At 30 mg/kg IV, PK and total sCD40 profiles in plasma 
are consistent with a duration of target engagement of 16 weeks.
In healthy subjects CD40 engagement by CFZ533 generally led to a decrease in total CD40 on 
peripheral B cells by about 50%, tracking CD40 occupancy on B cells as measured by free 
CD40 on B cells. This is likely due to internalization and/or shedding of the membrane bound 


Novartis
Confidential
Page 40
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
CD40 upon binding to CFZ533. In patients with rheumatoid arthritis the decrease in total CD40
on peripheral B cells was not confirmed.
The relationship between CFZ533 in plasma and CD40 occupancy on whole blood B cells (free 
CD40 on B cells) was defined, and CFZ533 concentrations of 0.3-0.4 µg/mL were associated 
with full (defined as ≥90%) CD40 occupancy on whole blood B cells.
More generally, non-specific and specific elimination pathways have been identified for 
CFZ533. The non-specific and high capacity pathway mediated by FcRn receptors is commonly 
shared by endogenous IgGs. The specific target mediated disposition of CFZ533 led to the 
formation of CFZ533-CD40 complexes that were partially internalized (with subsequent 
lysosomal degradation) and/or shed from the membrane. Target-mediated processes resulted in 
saturable and nonlinear disposition of CFZ533. The formation of CFZ533-CD40 complexes 
was dose/concentration-dependent, with saturation occurring at high concentrations of CFZ533.
Overall, the disposition of CFZ533 is dependent on the relative contribution of the specific 
(target mediated) and non-specific elimination pathways to the overall clearance of CFZ533. 
Nonlinear PK behavior was observed when CFZ533 concentrations were lower than that of the 
target, while at higher concentrations with CD40 receptors being saturated, the non-specific 
pathways predominate and the elimination of CFZ533 was linear.
As expected for a typical IgG1 antibody targeting a membrane bound receptor and 
demonstrating target mediated disposition, the extent of exposure of CFZ533 (AUClast) 
increased more than the increase in dose (hyper-proportionality). Consequently, this is expected 
to be associated with a decrease in the volume of distribution and clearance of CFZ533 at higher 
doses.
One subject at 1 mg/kg IV CFZ533 (1 week full CD40 occupancy) developed specific 
antibodies to CFZ533 detected 6 weeks after CFZ533 plasma concentrations were below the 
limit of quantification, and definitively too low to block any CD40 pathway-relevant effects in 
tissue. The presence of anti-drug antibodies (ADAs) in this subject did not compromised 
exposure, and was not associated with an immune related safety signal. This corresponds to an 
ADA incidence of 2% in this study.
A single dose of 3 mg/kg (IV and SC) of CFZ533 transiently suppressed anti-KLH responses 
to the first KLH immunization, at CFZ533 concentrations corresponding to full (≥90%) receptor 
occupancy (for about 3-4 weeks). Anti-KLH primary responses were detected in all subjects as 
CFZ533 concentration, and accompanying receptor occupancy, declined. All subjects were able 
to mount recall responses to a second KLH immunization (administered after loss of receptor 
occupancy was anticipated).
Data suggest that CD40 engagement by CFZ533 prevented recombinant human CD154 
(rCD154) mediated B cell activation in human whole blood. The rCD154-induced-CD69 
expression on B cells was generally suppressed during a period corresponding to full CD40 
occupancy on B cells. When CD40 occupancy was incomplete, the functional activity of 
rCD154 was restored.
There was no evidence of any effect of CFZ533 on immunophenotyping data.


Novartis
Confidential
Page 41
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
1.3.2.2
Study CCFZ533X1101
1.4
Study purpose
This study is designed to explore the safety, tolerability, pharmacokinetics and preliminary 
efficacy of CFZ533 compared with placebo as add-on to standard of care therapy in patients 
with moderately active proliferative lupus nephritis.
Commercially Confidential Information


Novartis
Confidential
Page 42
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
2
Objectives and endpoints
2.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary objective(s)

To evaluate the safety and tolerability of 
24 weeks of treatment with CFZ533 as 
an add-on therapy to standard of care in 
moderately active lupus nephritis (LN)
patients
AEs/SAEs
Vital signs
ECG evaluation
Standard hematology and chemistry 
evaluations

To assess the effect of CFZ533 on renal 
proteinuria in moderately active lupus 
nephritis patients after 24 weeks of 
treatment as an add-on therapy to 
standard of care as compared to placebo
Ratio from baseline in urinary protein 
creatinine ratio (UPCR) at Week 25
(using first morning void)
2.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

To assess the effect of CFZ533 on 
relevant renal outcomes at different time
points
Ratio from baseline in the following 
parameters:
o
UPCR (first morning void)
o
hematuria and cellular casts
Proportion of patients who fulfill the 
criteria for complete renal remission 
(CRR) according to ACR 
recommendation (Wofsy et al 2012)

To evaluate the pharmacokinetics (PK) 
and pharmacodynamics (PD) of CFZ533 
in LN patients, after multiple 10 mg/kg 
IV doses
PK: Free CFZ533 concentrations in 
plasma. 
Parameters (free CFZ533): Ctrough,ss or 
Cmin,ss, Cmax,ss, and AUClast (after 
last dose)
PD: Total soluble CD40 concentrations 
in plasma: pre-dose, during treatment 
and follow up. Rate, extent and duration 
of target engagement.

To evaluate the immunogenicity of 
CFZ533 in LN patients, after multiple 10 
mg/kg IV doses
Anti-CFZ533 antibodies in plasma: 
baseline, during treatment and follow-up,
incidence of ADA-positive patients


Novartis
Confidential
Page 43
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
2.3
Exploratory objective(s)
Exploratory objective(s)
Endpoints related to exploratory objective(s)
Commercially Confidential Information


Novartis
Confidential
Page 44
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Exploratory objective(s)
Endpoints related to exploratory objective(s)
3
Investigational plan
3.1
Study design
This is an exploratory, randomized (2:1 active:placebo), subject- and investigator-blind, 
placebo-controlled, multicenter study evaluating the safety, tolerability, pharmacokinetics and 
preliminary efficacy of multiple doses of 10 mg/kg CFZ533 administered intravenously (IV) in
lupus nephritis patients. 
The study will randomize approximately 60 subjects with moderately active lupus nephritis. 
The study comprises two periods. The 24-week treatment period will be followed by a 24-week 
safety follow-up period (starting on Day 169). The duration of the study (including a screening
period of up to 4 weeks) for each subject will be approximately 53 weeks. The investigational 
drug or placebo will be administered on top of standard of care therapy for lupus nephritis. 
The randomization will be stratified by baseline daily dose equivalent of prednisone (≤10 mg, 
>10 mg). Patients who do not receive corticosteroids at baseline will be included in the ≤10 mg 
stratum.
Subjects will be screened within 29 days of the first study drug infusion. Eligibility will be 
confirmed at the baseline visit within one week before the first dose. All baseline safety 
evaluation results must be available prior to dosing, and meeting eligibility criteria. 
Eligible subjects will enter the treatment period, and will be randomized at a 2:1 ratio to receive 
treatment with either CFZ533 or placebo. Subjects will receive the intravenous infusion on 
Day 1 within seven days of the baseline visit, followed by PK, PD, and safety assessments until 
one hour after completed infusion.
Commercially Confidential Information


Novartis
Confidential
Page 45
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
All infusions will take place in a monitored facility with assessment of vital signs ahead of the 
infusion. Subjects will be discharged 1 hour post-dose following satisfactory review of safety 
data (AE events, vital signs) by the Investigator.
Each patient will come to the study site for the follow-up evaluations on Day 169, Day 197, 
Day 225, Day 253, Day 281, Day 309, and Day 337, respectively. Patients should remain on 
their standard of care therapies. Dose of standard of care (SoC) therapies (see eligibility criteria 
and permitted co-medications) must remain unchanged during the study. However, in case of 
SoC related toxicities, doses of concomitant medications may be adjusted at the investigator’s 
discretion. 
Safety assessments will include physical examinations, ECGs, vital signs, standard clinical 
laboratory evaluations (also including serum amylase and lipase), hematology (including blood 
coagulation assays), blood chemistry, urinalysis, adverse event, serious adverse event and AEs 
of special interest monitoring.
Proteinuria will be assessed using urine samples collected in the patients’ home (first morning 
void sample) and at the clinic (clinic spot urine sample). 
PK/PD and immunogenicity assessments at pre-dose, and during treatment and follow up
periods include (i) free CFZ533 in plasma (Ctrough or Cmin, and Cmax in steady state 
conditions), total soluble CD40 in plasma, and (iii) anti-CFZ533 antibodies in plasma.
For a detailed outline of safety assessments, please refer to the Assessment schedule.
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 46
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Figure 3-1
Study Design
3.2
Rationale of study design
A randomized, placebo-controlled, subject and investigator blind approach is planned to 
minimize potential bias in reporting safety and clinical efficacy data in this exploratory study 
with CFZ533 in lupus nephritis patients. Patients will be randomized to CFZ533 or placebo in 
a 2:1 ratio in order to minimize exposure to placebo and to gather more data on CFZ533. 
Stratified randomization is planned in order to limit imbalances between active and placebo 
arms in baseline intake of oral corticosteroids. Placebo will be used as comparator to provide 
objective evaluation of potential AEs and other safety data, as well as of clinical efficacy. Use of 
placebo will be administered on top of standard of care therapy so patients remain on an 
established treatment regimen with the study medication added.
Treatment
CFZ533 10 mg/kg * 
Follow-up
End of 
Study
Baseline
Screening 
Randomization 2:1
Follow Up
approx. 40 subjects
Placebo* 
Follow-up
approx. 20 subjects
* CFZ533 or placebo 10 mg/kg i.v. on Day 1, 15, 29, 57, 85, 113, and 141 
Visit          1                                2  101 102 103   104     105      106     199   201    202       203 
204      205     206       299
Week 
-4 to -2 
-1     1    3     5        9        13       17       21 
25      29       33       37        41       45         49 
Day 
-28 to -8 
- 7 to 
-3    1   15   29      57       85      113     141     169    197     225 
253      281      309       337
Visits
Commercially Confidential Information


Novartis
Confidential
Page 47
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
This study will use first morning void urine protein to creatinine ratio (UPCR), an established 
renal endpoint, as the key efficacy outcome measure. Based on internal data (Novartis Study 
CERL080A2420 testing mycophenolate (Myfortic) in lupus nephritis patients), as well as 
published evidence (Zeher et al 2011), this endpoint is expected to be sufficiently sensitive to 
provide preliminary evidence for efficacy after 24 weeks of treatment. 
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
Figure 3-2 displays the predicted time-course of CFZ533 concentrations in plasma, following
the intravenous dosing regimen described in Section 3.1, and assuming similar kinetics of the 
drug and its target in LN and primary Sjögren’s Syndrome patients (ongoing study 
CCFZ533X2203).  
Figure 3-2
Predicted time-course of CFZ533 concentration
The line represents the predicted time-course of CFZ533 concentration for the typical patient; the band 
represents the 90% prediction interval, meaning that 90% of the patients’ concentration is expected in 
that area.
3.3.1
Loading regimen
Renal CD40 expression is up-regulated in World Health Organization (WHO) class III and class 
IV LN patients (proliferative LN; Yellin et al 1997), potentially linking CD40 signaling to 
organ-specific pathology. The levels of soluble CD40 (sCD40) are also significantly increased 
in patients with SLE, and an association between the levels of sCD40 and the rs1883832 C/T 
polymorphism of CD40 gene was observed (Chen et al 2015). Additionally, in SLE patients 
(Vakkalanka et al 1999) the concentration of soluble CD154 was higher than in disease controls 
or healthy subjects, and segregation of SLE patients by severe, moderate, or mild extent of 


Novartis
Confidential
Page 48
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
disease showed a relationship between disease severity and sCD154 concentration, denoting 
up-regulation/activation of the CD40-CD154 pathway in SLE.
In this study CFZ533 will be administered at 10 mg/kg IV every 4 weeks (Q4W; from Day 1 to 
Day 141), plus an additional dose of 10 mg/kg IV at Day 15.
The initial Q2W (every 2 weeks) loading regimen (for the first 3 doses) is justified because 
CFZ533 is subject to target mediated elimination, and elevated CD40 expression in the body is 
associated with high elimination (clearance) rate of CFZ533, loss of target engagement and loss 
of CD40 pathway blockade in target tissues, if CD40 is not fully saturated. The Q2W regimen 
for the first 3 doses is expected to provide full CD40 occupancy at start of treatment. In these 
conditions, the contribution of CD40 to the overall clearance of CFZ533 is minimal, and the 
disposition of CFZ533 is mainly the consequence of CFZ533 binding to FcRn receptors (a high 
capacity receptor responsible for IgG homeostasis by recycling/salvage). This was clearly 
demonstrated through PK/PD data collected in HVs and RA patients (CCFZ533X2101), kidney 
transplant patients (CCFZ533X2201), primary Sjögren’s Syndrome patients (CCFZ533X2203) 
and Grave’s disease patients (CCFZ533X2205) patients.
Generally, patients with systemic autoimmune diseases present with an increase CD40 
expression compared to healthy subjects. Elevated serum/plasma sCD40 levels have been 
reported in RA (Study CCFZ533X2101, and MacDonald et al 1997), Systemic Sclerosis 
(Komura et al 
2007), 
and 
Graves’ 
ophthalmopathy/GD 
(Study 
CCFZ533X2205, 
Mysliwiec et al 2007). In salivary glands biopsies obtained from pSS patients, CD40 was 
constitutively expressed by lymphocytes, ductal epithelial cells and endothelial cells 
(Dimitriou et al 2002), which is in line with elevated plasma levels noted in Study 
CCFZ533X2203. In Type 1 Diabetes patients, elevated sCD40 correlated well with patients’ 
inflammatory state (Chatzigeorgiou et al 2010), and in diabetic patients, cellular CD40 (on 
peripheral blood mononuclear cells) showed a significantly positive correlation with plasma 
concentrations of sCD40, interleukin-6 (IL-6), C-reactive protein (CRP) and hemoglobin A1c 
(HbA1c). Additionally, elevated levels of soluble CD40 ligand (sCD154) in serum of patients 
with systemic autoimmune diseases were noted (Goules et al 2006).
These additional data in patients with systemic autoimmune diseases further justify the need for 
a Q2W regimen for the first 3 doses to provide full target saturation at start of treatment, in 
conditions where CD40 expression is enhanced.
Due to kidney damage, proteinuria is commonly observed in patients with SLE/LN. The effect 
of renal impairment on the PK of biologics is dependent on the ability of the compound to 
undergo glomerular filtration, which is largely driven by molecular weight (MW). CFZ533 has 
a MW of ca. 146 kD, and renal clearance usually plays a minimal role in the elimination of 
biologics with MW greater than 69 kDa (Meibohm and Zhou 2012).
An association between increased baseline proteinuria and increased clearance was observed in 
the population PK of belimumab (a human mAb that inhibits B-cell activating factor, BAFF) in 
SLE (Struemper et al 2013). Also, there is evidence that in some forms of renal disease, such as 
diabetic nephropathy, there may be an increase in the renal elimination of IgGs 
(Bakoush et al 2002). This is further justifying the need for a loading regimen for CFZ533.


Novartis
Confidential
Page 49
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
3.3.2
Maintenance regimen
3.3.3
Bodyweight-adjusted dosing
While a fixed dosing regimen would be favored for its ease of use, a bodyweight (BW)-adjusted 
dosing is justified in this study.
Whether CFZ533 should be administered as a flat (fixed) dose or based on BW mainly depends 
on the effect of BW on the PK/PD of CFZ533. At this point in time the effect of BW on the 
disposition of CFZ533 is not fully characterized, especially in the low BW range.
The LN population is predominantly represented by female patients, and it is anticipated that
patients within a BW range of 40-150 kg will be enrolled in this study. While, no gender effect 
is expected for the disposition of CFZ533 (the effect of sex on the exposure of IgG-type 
antibodies is often insignificant after the difference in BW has been taken into account), 
Commercially Confidential Information


Novartis
Confidential
Page 50
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
a BW-adjusted dosing is likely to reduce the interpatient variability in exposure in the proposed 
BW range. 
Only subjects with a body mass index (BMI) within the range of 18 to 40 kg/m2 will be eligible 
to participate in the study.
3.4
Rationale for choice of comparator
Placebo to CFZ533 will be used as comparator to provide objective evidence of potential AEs 
and other safety data, as well as clinical efficacy and PD data generated from subjects exposed 
to the experimental therapy. Since there is no established, clinically effective disease modifying 
treatment for lupus nephritis patients who are clinically active despite conventional 
immunosuppressive therapies, treatment with placebo on top of standard of care therapy is justified.
3.5
Purpose and timing of interim analyses/design adaptations
3.6
Risks and benefits
3.6.1
Potential benefit
Despite progress, unmet medical need in lupus nephritis patients remains high. Current 
standard of care therapies comprise conventional immunosuppressive which are not fully 
efficacious in all patients and associated with significant toxicities. Based on the scientific 
rationale for targeting CD40 pathway in lupus and the data available for CFZ533, CD40 
inhibition by CFZ533 has a potential therapeutic benefit for lupus nephritis patients who are 
clinically active despite standard of care. 
3.6.2
Potential risks associated with exposure to CFZ533 and their 
mitigation
Currently, limited data exists regarding the use of agents that block the CD40/CD154 pathway.
Preclinical and data from the Phase 1 and 2 programs for CFZ533 as well as data from
compounds acting on the same pathway (CD40-CD154) have been taken into account to
estimate the potential risks associated with CFZ533. The current IB (Section 6, Investigator
Guidance) also provides detailed instructions regarding the risks and their mitigation.
Commercially Confidential Information


Novartis
Confidential
Page 51
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
3.6.2.1
Infections
Subjects treated with CFZ533 may be at an increased risk of infection. CD40 ligation is
linked to the functional activity of antigen presentation, as well as T-cell priming, B-cell
differentiation, antibody production and immune memory. Administration of CFZ533 is
expected to result in general immunosuppression with a decreased capacity to mount a response
to novel immunogens, including those of bacterial, viral, fungal and parasitic origin when full 
receptor occupancy has been achieved.
Although the ability to mount a primary immune response will be affected by CFZ533, the
memory B-cell repertoire and immune recall response should remain intact and protective.
In addition, subjects will have adequate preformed antibody to maintain protective humoral
response for extended periods of time (months).
No T- cell or B-cell lymphopenia or infection was noted in the Phase 1 study. In patients
receiving weekly to bi-monthly administration of the parent antibody lucatumumab, the rate
of infection was very low and similar to control, supporting this above hypothesis.
Subjects with current, active or latent infection susceptible to reactivation will be excluded
from entry into this clinical study.
The risk of infection may increase if CFZ533 is combined with steroids or strong
immunosuppressive drugs. In the current study, low dose steroid (up to 30 mg prednisone or
equivalent per day) and drugs with low to moderate risk for immunosuppression will be
allowed
in
combination
with CFZ533.
Strong
immune-suppressive
drugs such
as
cyclophosphamide or cyclosporine A will be prohibited. 
During the conduct of the current study, a fatal SAE was reported (Investigator Notification 
case ID: NVSC2019TN015399) in Nov 2019.
Subjects enrolled in the current study will be monitored regularly and carefully for signs and
symptoms which might indicate a severe infection. All subjects will be screened and regularly 
monitored for CMV infection (also see Section 8.6.8.2.). Subjects will be informed to contact
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 52
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
the study physician if they present with signs and symptoms of an infection such as fever,
nausea, myalgia, headache, arthralgia, chills, diarrhea, stiff neck, and malaise for further
assessment and treatment if necessary.
3.6.2.2
Vaccination
Vaccination of subjects during treatment with CFZ533 and prior to clearance of the antibody is 
likely to result in therapeutic failure (i.e., non-protective antibody titers) due to the 
pharmacologic activity of the antibody. For subjects participating in this study, all vaccinations 
should be up to date based on local guidelines. Reduced or absent immunization effectiveness 
may be expected for both live (attenuated) and non-live (e.g. inactivated (killed), viral-vector, 
mRNA) vaccines. For further information refer to the Investigator’s Brochure Section 4.2.7.
Administration of live (attenuated) SARS-CoV-2 vaccines is prohibited within 8 weeks of the 
first infusion of CFZ533, while receiving CFZ533 treatment and for at least 14 weeks after the 
last dose of the study medication.
While there is no absolute contraindication for the use of non-live (e.g. inactivated (killed), 
viral-vector, mRNA) SARS-CoV-2 vaccines, reduced or absent immunization effectiveness 
may be expected during treatment with CFZ533 and until 14 weeks after the last dose.
If treatment with CFZ533 is stopped, insufficient humoral immune response is likely to persist 
until 14 weeks after the last dose (until CFZ533 exposure decreases in the blood and tissues 
below the pharmacologically relevant level).
If SARS-CoV-2 vaccine is considered mandatory by local governance, administration of the 
vaccine should be provided at least 4 weeks before randomization or postponed for at least 14
weeks following the last dose of study drug, due to anticipated reduced or absent immunization 
effectiveness in treated patients. 
Although there is no mandate to vaccinate clinical trial participants against SARS-CoV-2 prior 
to entry into the trial, patients will be advised to have completed vaccination series (if multi-
dose regimen) against SARS-CoV-2 at least 4 weeks prior to randomization (or as long as 
needed before the first dose of CFZ533 based on when the protective immune response is 
expected to develop as indicated for the specific vaccine), if available, and according to local 
practice. 
Patients who have decided not to get vaccinated may enter the trial if they have been informed 
that, should they receive a SARS-CoV-2 vaccination during the trial, the vaccination would 
likely be ineffective, and maximizing vaccine effectiveness would require study drug 
discontinuation and a waiting period of at least 14 weeks before vaccination.
For patients already in the study, the decision of vaccination for SARS-CoV-2 should be done 
on a case-by-case basis and in consultation between the treating physician and patient. 
Vaccination failure is a known risk.
For patients enrolled in Novartis clinical trials who do receive a SARS-CoV-2 vaccine which 
has been permitted* for use by a local Health Authority, vaccine documentation will be 
recorded as a concomitant medication. Institutional Review Board/Ethics Committee (IRB/EC) 
approval and inclusion in Informed Consent are not required. [*Permitted includes full approval, 
conditional 
approval, 
emergency 
use 
authorization, 
provisional/temporary/interim 


Novartis
Confidential
Page 53
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
authorization by Health Authority i.e., outside of a COVID- 19 clinical trial to evaluate the 
effectiveness/safety of a SARS-CoV-2 vaccine.] 
3.6.2.3
Immunogenicity
3.6.2.4
Thrombophilia
Currently, a theoretical risk without clinical evidence exists for CFZ533 to cause 
thromboembolic events based on previous experience with monoclonal antibodies that bind to 
CD154 (CD40L). Such antibodies have been associated with a risk of thrombophilia in both 
clinical and non-clinical studies in primates. These thromboembolic events have been linked to 
the direct activation of platelets which express both CD154 and a low affinity, activating Fc 
receptor FcγRIIA. Upon binding to CD154, the Fc-domains of the anti-CD154 mAb may interact 
with the platelet FcγRIIA receptors, and induce cross-linking and aggregation. While anti-
CD154 antibodies are clearly associated with a high risk for thrombophilia, both preclinical and 
clinical data from an extensive phase 2 clinical program across healthy subjects and patients 
across different indications have not indicated an associated risk with CFZ533. Detailed 
information can be found in the current IB version.
Although the risk is theoretical, hematologic and coagulation parameters will be regularly
monitored in the current study. Furthermore, patients with conditions such as anti-
phospholipid syndrome where the risk is already high will be excluded unless they are on a 
stable anti-thrombotic prophylaxis.
3.6.2.5
Malignancy including lymphoproliferative disorders
A hypothetical risk for lymphoproliferative disorders for some patients under strong 
immunosuppression cannot be excluded for CFZ533. To date, however, no lymphoproliferative 
disorders have been detected in NHP studies, or in clinical trials in healthy volunteers or patients 
where CFZ533 was evaluated. In the ASKP1240 trials, no lymphoproliferative disorders were 
reported to date. In the renal transplant study (CCFZ533X2201) the incidence of malignancies 
were comparable among the treatment groups with 5.9% in the CFZ533 group and 5.6% in the 
control group.
Epstein-Barr virus (EBV) infection is commonly associated with 
Commercially Confidential Information


Novartis
Confidential
Page 54
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
lymphoproliferative disorders in transplant and immunosuppressed patients. Inclusion of 
patients who are EBV negative will be defined by the specific clinical trial protocol where 
applicable. The clinician should monitor hematology regularly for changes consistent with a 
lymphoproliferative disorder. Patients with history of malignancy of any organ system, treated 
or untreated, within the past 5 years are excluded from the clinical trials.
3.6.3
Blood sample volumes
A maximum of 650 mL of blood is planned to be collected over a period of 53 weeks from each 
subject as part of the study. Additional samples may be required for safety monitoring.
Timings of blood sample collection are outlined in the Assessment schedule (Section 8.1).
A summary blood log is provided in the Site Operations Manual (SOM). Instructions for all 
sample collection, processing, storage and shipment information is also available in the SOM 
and central Laboratory Manual.
4
Population
The study population will be comprised of female and male subjects (in the age range of 18 to
75 years) with moderately active lupus nephritis who are on a stable dose of immunosuppressive 
treatment and demonstrate moderate disease activity despite standard of care therapy. 
Moderate disease activity is defined as having clinical signs of renal disease activity such as 
proteinuria (≥0.5) but without an immediate need for induction therapy or for whom standard 
induction therapy with high dose corticosteroids and mycophenolate or cyclophosphamide is 
not an option. A total of approximately 60 subjects will be randomized (2:1 ratio active:placebo)
to participate in the study.
The Investigator must ensure that all subjects being considered for participation in the study 
will meet the following eligibility criteria. No additional criteria should be applied by the 
Investigator, in order that the study population will be representative of all eligible subjects.
Subject selection is to be established by checking through all inclusion and exclusion criteria at 
screening and baseline. A relevant record (e.g., checklist) of the eligibility criteria must be filed 
with the subject’s source documentation at the study site.
Deviation from any eligibility criterion excludes a subject from enrollment into the study, and 
randomization to study treatment. 
4.1
Inclusion criteria
Population eligible for inclusion in this study must fulfill all of the following criteria:
1. Understand the study procedures and provide written informed consent before any study-
related assessment is performed.
2. Men and women with systemic lupus erythematosus (see below), aged ≥18 years and 
≤75 years at screening, fulfilling at least 4 out of 11 criteria for SLE as defined by the 
American College of Rheumatology (Tan et al 1982, revised by Hochberg 1997).
Commercially Confidential Information


Novartis
Confidential
Page 55
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
3. Subjects must have a body mass index (BMI) within the range of 18 - 40 kg/m2. 
(BMI = Body weight (kg) / [Height (m)]2) to participate in the study at Screening visit.
4. Histological diagnosis of proliferative lupus nephritis World Health Organization (WHO)
ISN/RPS (Weening et al 2004) Class III or IV within 5 years of screening.
5. Presence of antinuclear autoantibody (ANA titer ≥1:80 at screening)
6. First morning void or spot urine UPCR ≥0.5 mg/mg (56.52 mg/mmol) at Screening visit
and Baseline visit
7. At least one of the following at Screening visit:
a. low complement level (C3 < 0.9 g/L or C4 < 0.1 g/L), and/or
b. elevated anti-dsDNA (≥30 IU/mL), and/or
c. urine sediment consistent with active proliferative lupus nephritis such as presence of 
cellular (granular or red blood cell) casts or hematuria (>5 red blood cells per high power 
field) if other causes such as menstrual bleeding are excluded
8. Patient must have sufficient kidney function as estimated by eGFR > 30 mL/min/1.73m2 at 
screening and baseline visits
9. Patients must have active disease as defined by proteinuria and additional symptoms as 
defined above (criterion 7) despite standard of care therapy for lupus nephritis as considered 
appropriate by the treating physician (e.g., corticosteroids and/or immunosuppressive or 
immunomodulatory treatments such as mycophenolate, azathioprine, methotrexate or 
hydroxychloroquine). For guidance, see published guidelines such as by Bertsias et al 2012
and Hahn et al 2012
10. If the patient is taking oral corticosteroid treatment at screening, the dose (max. 30 mg 
prednisone or equivalent per day) must be stable for at least 2 weeks prior to randomization
14. Women of child-bearing potential (defined as all women physiologically capable of 
becoming pregnant) must use highly effective methods of contraception before entering the 
study, during dosing and until study completion. 
Highly effective contraception methods include:

Total abstinence from heterosexual intercourse (when this is in line with the preferred 
and usual lifestyle of the subject). Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
Commercially Confidential Information


Novartis
Confidential
Page 56
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
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-partner sterilization (at least 6 months prior to screening). For female subjects in 
the study, the vasectomized male partner should be the sole partner for that subject.

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 rate < 1%), for example hormone 
vaginal ring or transdermal hormone contraception. Women should have been stable 
on their chosen method of OC for a minimum of 3 months before entering the trial.

Postmenopausal females must have had no regular menstrual bleeding for at least one 
(1) year prior to initial dosing. Menopause will be confirmed by a plasma FSH level of 
>20 IU/L at screening. 
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.
All female patients of childbearing potential must have negative pregnancy test results at 
Screening and Baseline visits.
4.2
Exclusion criteria
Eligible Population fulfilling any of the following criteria are not eligible for inclusion in this 
study:
1. Any glomerulonephritis other than WHO Class III or IV lupus nephritis. Patients with 
proliferative nephritis (Class III or IV) who, in addition, have overlapping histological signs 
for other glomerulonephritis, e.g. Class V are eligible at the investigator`s discretion.
2. Hypoalbuminemia (serum albumin of less than 2.0 g/dL).
3. Patients who have received
a) oral or IV cyclophosphamide within 3 months prior to randomization.
b) IV corticosteroid bolus (dose higher than 1 mg/kg) within 3 months prior to 
randomization.
c) rituximab or other B cell depleting agent received prior to randomization within

≤ 6 months: no inclusion

> 6 but ≤12 months: B cell count must be within normal range

>12 months prior to randomization: no special requirements 
o
.
d) belimumab within 6 months prior to randomization.
e) any other biologic drug or an investigational drug within three (3) months or five times 
the half-life, whichever is longer prior to randomization.


Novartis
Confidential
Page 57
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
f) calcineurin inhibitor (e.g., tacrolimus, cyclosporin A) within 3 months prior to
randomization.
[For China, Hong Kong, and Korea only: calcineurin inhibitors except tacrolimus 
(≤3 mg/day) within 3 months prior to randomization.]
4. Patients who are at significant risk for thromboembolic events based on the following:

History of either thrombosis or 3 or more spontaneous abortions

Presence of lupus anticoagulant or prolonged  aPTT and no prophylactic treatment with 
aspirin or anticoagulants as per local standard of care
7. Have had signs or symptoms of a clinically significant systemic viral, bacterial or fungal 
infection within 30 days prior to randomization
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 58
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
13. Live vaccines within 8 weeks of study drug infusion
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
5
Restrictions for Study Subjects
For the duration of the study, the subjects should be informed and reminded of the restrictions 
outlined in this section.
5.1
Contraception requirements
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirement outlined in the 
Section 4.1 (Inclusion Criteria). If there is any question that the subject will not reliably comply, 
they should not be entered or continue in the study.
5.2
Prohibited treatment
The following treatments are prohibited during the course of the trial and before the first dosing, 
due to their mechanisms of action that can act as a confounder for the study objectives and 
results:

Oral or i.v. cyclosphosphamide treatment within 3 months prior to first dosing with study 
drug.

I.V. corticosteroid bolus (dose higher than 1 mg/kg) within 3 months prior of first dosing
with study drug.

Rituximab or other B cell depleting agent received prior to randomization within

≤ 6 months

> 6 but ≤12 months, and B cell count not within normal range

Belimumab within 6 month of first dosing with study drug.

Any other biologic or an investigational drug within 3 months or five times the half-life
before the first dosing with study drug, whichever is longer
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 59
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202

Calcineurin inhibitors (e.g., tacrolimus, cyclosporin A) within 3 months of first dosing 
with study drug.
[For China, Hong Kong, and Korea only: Calcineurin inhibitors except tacrolimus 
(≤ 3mg/day) within 3 months of first dosing with study drug.]
In case of any of the above therapies becomes necessary during the trial, (e.g. cyclophosphamide 
rescue due to major disease worsening), the washout period for CFZ533 (approximately 16 weeks)
and potential interactions need to be considered by the Investigator.
5.3
Dietary restrictions and smoking
Subjects should maintain their usual diet and life habits during the entire study.  
5.4
Other restrictions
No strenuous physical exercise (e.g. weight training, aerobics, football) until after Study Completion 
evaluation. Patients may otherwise continue with their usual level of physical activity.
6
Treatment
6.1
Study treatment
The investigational drug, CFZ533 and matching placebo, will be prepared by Novartis and 
supplied to the Investigator site as double-blinded medication kits.
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the Site Operations Manual. 
6.1.1
Investigational treatment and control drug(s)
The dosage form of the supplied drug is a “ready to use” aqueous buffered sterile solution also 
referred to as CFZ533 Concentrate for infusion (liquid in vial). The solution contains 150 mg/ml 
CFZ533 and the excipients L-histidine, sucrose, and polysorbate 20, pH 6.0 ± 0.5. The placebo 
control selected for this study is a solution with matching composition of inactive excipients.
Table 6-1
Overview of study medication
Study 
drug 
name
Formulation
Appearance
Unit dose
Packaging
Provided 
by
CFZ533
Solution for 
infusion
Opalescent to clear, 
colorless solution
150 mg/mL*
6 ml 
Type I glass vials,
double blind
Novartis
Placebo
Solution for 
infusion
Opalescent to clear, 
colorless solution
0 mg/mL*
6 ml 
Type I glass vials,
double blind
Novartis
*The vials contain a 20% overfill to allow a complete withdrawal of the labeled amount of CFZ533 or
placebo.


Novartis
Confidential
Page 60
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Clinical supplies are to be dispensed only in accordance with the pharmacy manual. 
A pharmacist or authorized designee is required to prepare the study drug. Instructions for
storage and handling of study medication vials, and preparation of infusion solution are 
described in the Pharmacy Manual (which is provided as a separate document).
6.1.2
Additional study treatment
No additional treatment beyond investigational drug (CFZ533 and placebo) are included in this 
trial.
6.2
Treatment arms
Subjects will be assigned to one of the following two treatment arms in a ratio of 2:1:

CFZ533: multiple doses of 10 mg/kg CFZ533 IV infusion

Placebo: multiple doses of placebo IV infusion
6.3
Treatment assignment and randomization
If the subject’s eligibility is confirmed at the Baseline visit, the subject will be randomized, and 
treatment will be assigned, via the IRT system that will be set up for the randomization of 
eligible subjects, and for distribution and assignment of the study medication. Eligible subjects
will be assigned to a treatment arm (see Site Operations Manual for details). 
The Subject number assigned to a subject at screening remains the unique identifier for the 
subject throughout the study. The randomization number is only used to identify which 
treatment the subjects have been randomized to receive.  For information on subject numbering, 
please see ‘Subject numbering’ section in the SOM.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Global Clinical Supply using a validated system that automates the random assignment of 
medication numbers to packs containing the investigational drug(s).
The randomization will be stratified by baseline daily dose equivalent of prednisone (≤10mg, 
>10mg). Patients who do not receive corticosteroids at baseline will be included in the ≤10mg 
stratum.
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
Follow the details outlined in the Site Operations Manual regarding the process and timing of 
treatment assignment and randomization of subjects.


Novartis
Confidential
Page 61
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
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
All site staff (including study investigator and study nurse) will be blinded to study treatment 
throughout the study.
Unblinding a single subject at site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (see Section 6.7).
Sponsor staff or delegate
The following unblinded sponsor roles are required for this study amend as appropriate:
Unblinded sample analysts for PK, PD and IG.
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.
The study statistician will be able to access the randomization list for interim analyses and is 
allowed to share unblinded information with the rest of the clinical team as appropriate for 
internal decision purposes, as outlined in Section 6.4. For example, unblinded summaries and 
unblinded individual data can be shared with the team for interim analyses.
Study programmers and other personnel involved in study data analysis (e.g. biomarker expert) 
are allowed to access treatment assignment information for the purpose of conducting interim 
analyses.
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.


Novartis
Confidential
Page 62
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Following final database lock all roles may be considered unblinded.
Table 6-2
Blinding and unblinding plan
Role
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single subject 
unblinded)
Interim 
Analysis 
Subjects/Patients
B
B
UI
B
Site staff
B
B
UI
B
Drug Supply and Randomization 
Office
UI
UI
UI
UI
Statistician/statistical programmer/ 
data analysts (e.g. PK)
B
B
UI
UI
Independent committees used for 
assessing interim results, if 
required (e.g. DMC)
B
B
UI
UI
All other sponsor staff not 
identified above (trial team, project 
team, management & decision 
boards, support functions)
B
B
UI
UI
Key:
UI:Allowed to be unblinded on individual patient level 
B: Remains blinded
6.5
Treating the subject
CFZ533 10 mg/kg or placebo will be administered to the subject as an intravenous infusion at 
the study site. See the Site Operations Manual and Pharmacy Manual for further details.
6.6
Permitted dose adjustments and interruptions of study treatment
Study drug dose adjustments and/or interruptions are not permitted in this study; in case of an 
AE or for any reason (e.g., non-compliance, operational hurdle) resulting in a deviation from 
the required dosing scheme, consultation and agreement with Novartis will be necessary to 
decide whether the subject can continue or needs to be withdrawn from the study. Any change 
in dosing must be recorded on the Dosage Administration Record eCRF. In case of notable 
adverse events, SAEs including loss of efficacy and/or associated PK/PD data collected during 
the study, changes to a different dosing scheme level may be considered and implemented via 
a protocol amendment.
Upon review data at interim analysis, dose adjustment for study drug may occur. This will be 
implemented via a protocol amendment. 
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 IRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide the 


Novartis
Confidential
Page 63
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
requested subject identifying information and confirm the necessity to break the treatment code 
for the subject. The investigator will then receive details of the investigational drug treatment 
for the specified subject and a fax or email confirming this information. The system will 
automatically inform the study monitor for the site and the Study Team that the code has been 
broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT cards at any time  in case of emergency.   The investigator will need to 
provide: 

protocol number

study drug name

subject number.
In addition, the investigator must provide oral and written information to inform the subject 
how to contact his/her backup in cases of emergency when he/she is unavailable to ensure that 
un-blinding can be performed at any time.
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given subject. 
6.8
Treatment exposure and compliance
Pharmacokinetic data and parameters (measures of treatment exposure) will be determined in 
all subjects treated with CFZ533, as detailed in Section 8.7.
6.9
Recommended treatment of adverse events
Parenteral administration of monoclonal antibodies can be associated with acute, severe 
reactions (occurring within the first few hours post dose) secondary to hypersensitivity, 
immunogenicity, or ADCC-mediated cell depletion. 
In this study, CFZ533 will be administered as intravenous infusion. No infusion reactions have 
been noted in the Phase 1 and Phase 2 clinical program with CFZ533 so far; however, 
investigators should be aware of the possibility and be prepared to treat such events.
Subjects will be monitored at the site for at least 1 hour post dose or longer, at the discretion of 
the Investigator, to ensure adequate safety monitoring. In case of any signs of an acute reaction, 
clinical treatment will be provided as determined by the treating physician on a case-by-case 
basis and depending on the severity, using symptomatic treatment, anti-histamines, 
Nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, intravenous fluids, 
corticosteroids, or adrenaline.
For the severity evaluation of allergic reaction, anaphylaxis and cytokine release and any other 
adverse event which may potentially lead to treatment discontinuation, it is recommended to 
follow the guidelines by the National Cancer Institute Common Toxicity Criteria version 4.03 
(NCI-CTCAE 2010).
Use of rescue medication must be recorded on the Concomitant medications / Significant 
non-drug therapies eCRF after start of study drug.


Novartis
Confidential
Page 64
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
6.10
Rescue medication
Standard of care treatment for lupus nephritis includes conventional immunomodulatory 
therapy (e.g. antimalarials), non-steroidal anti-inflammatory drugs, and immuno-suppressive 
agents such as corticosteroids, cyclophosphamide, calcineurin inhibitors, mycophenolate, or 
azathioprine. B cell depleting agent rituximab is also used for certain cases. Medication for SLE 
is similar, but often including further immunosuppressives such as methotrexate, and recently,
also the anti-BAFF monoclonal antibody, belimumab. 
In case of severe, clinically significant flare of nephritis or any other SLE manifestations (based 
on investigator’s judgment), introduction or dose increase of any standard of care therapies (e.g. 
corticosteroids) will be at the discretion of the treating physician. Rescue medicine is to be 
provided by the study center or personal physician. Use of rescue medication (after start of 
CFZ533 or placebo) must be recorded in the eCRF at the Concomitant medications/Significant 
non-drug therapies section.
6.11
Concomitant treatment
Certain standard of care therapies (corticosteroids, mycophenolate, azathioprine, methotrexate, 
antimalarials) in a stable dose are permitted, while others like cyclophosphamide, rituximab, 
belimumab, calcineurin inhibitors [For China, Hong Kong, and Korea only: (except tacrolimus 
≤ 3 mg/day)] are prohibited, as defined in the eligibility criteria. Corticosteroids and 
antimalarials may be combined with maximum one further permitted standard of care 
medication (as listed above), to minimize the risk of over-immunosuppression.
 
 
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.
Medication entries should be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the Investigator should contact Novartis before randomizing a subject 
or, if the subject is already enrolled, to determine if the subject should continue participation in 
the study.
7
Study completion and discontinuation
7.1
Study completion and post-study treatment
Each subject will be required to complete the study in its entirety and thereafter no further study 
treatment will be made available to them.
Study completion is defined as when the last subject completes their Study Completion visit, 
and any repeat assessments associated with this visit have been documented and followed-up 
Commercially Confidential Information


Novartis
Confidential
Page 65
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision.
7.2
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration. Discontinuation of study treatment can be decided by either 
the subject or the investigator. For CTCAE grading, version 4.03 will be used (NCI CTCAE).
Study treatment must be discontinued under the following circumstances:

Subject/guardian decision - subjects may choose to discontinue study treatment for any 
reason at any time

The investigator believes that continuation would negatively impact the safety of the 
subject or the risk/benefit ratio of trial participation.

CTCAE Grade 3 or higher adverse event unless it can be conclusively shown that AE is 
not related to study treatment

Severe hypersensitivity reaction, infusion reaction, including any of the following: 
anaphylaxis, fever, chills, urticaria, dyspnea, headache, myalgia, hypotension. Immediate 
interruption of the infusion to administer study treatment is required in such cases.

Any protocol deviation that results in a significant risk to the subject’s safety.

Pregnancy 

Major worsening of renal function (e.g.  >40% increase from Baseline creatinine level)

Major worsening of proteinuria (e.g. confirmed 3-fold increase from Baseline)

Acute infection as a severe AE as judged by the investigator

In case of suspected or confirmed active CMV infection - see Section 8.6.8.2.

Significant increase in extra-renal SLE disease activity (e.g. new onset severe CNS lupus)

Significant changes in standard coagulation test results, including prothrombin time (PT), 
activated partial thromboplastin time (aPTT) and thromboelastography (TEG) suggesting 
an increased risk for hypercoagulability or any sign or symptom of a thromboembolic 
event

Any other AE or complication where continued dosing of the patient is considered to be 
placing them at excess risk

Patient withdraws consent (when patient must also be withdrawn from the study)

Use of prohibited treatment as outlined in Section 5.2.

If a liver or renal event occurs, follow guidelines outlined in protocol Appendix 1 and 
Appendix 2 regarding discontinuation of study treatment. 
The appropriate personnel from the site and Novartis will assess whether investigational drug 
treatment should be discontinued for any subject whose treatment code has been broken 
inadvertently for any reason.
If discontinuation of study treatment occurs, the investigator must determine the primary 
reason for the subject’s premature discontinuation of study treatment and record this
information on the Dosage Administration CRF. The investigator must also contact the IRT to 
register the subject’s discontinuation from study treatment.


Novartis
Confidential
Page 66
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Patients who discontinue study treatment are to continue their study participation, and to 
complete all study visits. 
Patients who decide they do not wish to participate in the study further should NOT be 
considered withdrawn from the study UNLESS they withdraw their consent.  If they fail to 
return for the study visits for unknown reasons, every effort (e.g. telephone, e-mail, letter) 
should be made to contact the subject. This contact should preferably be done according to the 
study visit schedule.
The following data should be collected at minimum via telephone/email contact:
new / concomitant treatments
adverse events/Serious Adverse Events
Any unresolved AEs will be followed with additional post-study visits as determined 
appropriate by the study site investigator and sponsor.
Patients who discontinue the study must be reminded not to become pregnant for 14 weeks after 
the last dose of study medication.
7.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:
• Does not want to participate in the study anymore, and
• Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
Assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law.
For US: All biological samples not yet analyzed at the time of withdrawal may still be used for 
further testing/analysis in accordance with the terms of this protocol and of the informed consent 
form.
For EU and ROW: 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.


Novartis
Confidential
Page 67
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
7.4
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject cannot be formally considered lost to follow-up until 
his/her scheduled end of study visit would have occurred.
7.5
Study stopping rules
Stopping Rules
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should 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 patient's interests. The investigator 
will be responsible for informing IRBs and/or ECs of the early termination of the trial. 
The study will be paused with no further dosing, and recruitment on hold, pending full safety 
review if patient(s) experience(s) the following events if related to treatment of CFZ533:
1. One (1) patient with CFZ533-related death
2. Three (3) or more patients with a serious adverse event that is suspected to be related to 
CFZ533 by the Investigator
3. One (1) patient presenting with suspected CFZ533-related cytokine release syndrome,
4. One (1) patient presenting with a suspected CFZ533-related thromboembolic event that is 
at least of moderate severity
5. More than one (1) patient with allergic reaction of CTCAE Grade 3 or higher severity 
6. Any treatment-related, CTCAE Grade 3 or higher adverse event Criteria considered drug 
related by the Investigator with the following exceptions:

Events not requiring treatment, and diagnostic procedures involving elective or non-
urgent hospital admission,

Disease Specific Events due to the patients underlying LN diagnosis,

AEs/SAEs unrelated to the experimental compound as determined by the Investigator 
or Novartis
7. Two (2) or more patients presenting with:

Progressive renal insufficiency or acute kidney injury defined as a Grade 2 increase in 
serum creatinine (1.5 x ULN) in the setting of euvolemia at any time during the study 
related to CFZ533

Emergent hypogammaglobulinemia defined as total serum IgG below 5.65 g/L or 
IgM below 0.40 g/L and a reduction in total serum IgG or IgM concentration by 50% 
or more from baseline, considered clinically significant by the investigator

Severe systemic infection or severe opportunistic infection that requires treatment, 
e.g., sepsis, urosepsis, mycoses, pneumonia.


Novartis
Confidential
Page 68
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
8. Clinically significant (according to the Investigator) and study drug-related, persisting 
changes from baseline in vital signs, electrocardiograms, or relevant, persistent changes in 
laboratory parameters, which are not consistent with existing co-morbidities, in more than 
one (1) subject within the first 5 treated patients or an incidence of >20% thereafter.
9. Other clinically significant changes or effects in the opinion of the Sponsor that are 
deemed unsafe to continue dosing.
In addition, all blinded safety data, including disease specific events, will be evaluated by the 
Sponsor continuously. The study may be paused pending further data analysis and the decision 
to adjust the dose or modify the medication if the following criteria occur:

The Sponsor considers that the number and/or severity of AEs justify discontinuation 
of the study.

Other clinically significant changes or effects in the opinion of Sponsor that are 
deemed unsafe to continue dosing.
Furthermore, a Data Monitoring Committee will be established to monitor safety and based on 
their recommendation the study may be put on hold or modified.
7.6
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. Should this be necessary, subjects must 
be seen as soon as possible and treated as a prematurely discontinued subject. The investigator 
may be informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the subject’s interests. The investigator will be 
responsible for informing IRBs/IECs of the early termination of the trial.
8
Procedures and assessments
8.1
Assessment schedule
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible.
Missed or rescheduled visits should not lead to automatic discontinuation. Subjects who 
prematurely discontinue the study drug for any reason should be continuing their study 
participation, i.e., to complete all study visits. 
If an epidemic or pandemic (e.g. COVID-19 pandemic) limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented. Phone calls, virtual 
contacts (e.g. teleconsult) or visits by site staff to the participant´s home depending on local 
regulations and capabilities, can replace on-site study visits, for the duration of the pandemic 
until it is safe for the participant to visit the site again.


Novartis
Confidential
Page 69
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Table 8-1
Assessment schedule
Epoch
Screening
Treatment
Follow Up
Visit Name
SCR
BL
Treatment
Follow Up
EOS
Visit Numbers
1
2
101
102
103
104
105
106
199
201 202 203 204 205 206
299
Week
-4 to -1
1
3
5
9
13
17
21
25
29
33
37
41
45
49
Day
-28 to -8
-7 to -3
1
15
± 1
29
± 2
57
± 2
85
± 2
113
± 2
141
± 2
169
± 3
197
± 3
225
± 3
253
± 3
281
± 3
309
± 3
337
+ 3
Pre/Post1
Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post
Informed consent
X
Genetic consent
X
Eligibility criteria
X
X
Medical history/current conditions
X
Demography
X
Body height
X
Body weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body temperature
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood pressure/pulse rate
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology/Clinical Chemistry/
Urinanalysis9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hepatitis, CMV, HIV screen
X2
X8
X8
X8
X8
X8
X8
X8
X8
X8
X8
X8
X8
X8
TB screen
X
FSH3
X
Pregnancy test3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ESR, CRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IgG, IgM
X
X
X
X
X
X
X
C3, C4 Complement
X
X
X
X
X
X
X
Lupus anticoagulant
X
X
X
X
Coagulation test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK collection1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PD collection (total soluble CD40)
X
X
X
X
X
Immunogenicity
X
X
X
X
X
Drug administration
X
X
X
X
X
X
X
Study completion
X
Concomitant meds/Therapies
As required
Adverse Events
As required
Comments
As required
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 70
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
1 Pre-dose collection: ahead of drug administration; post-dose collection: 1h AFTER completion of the i.v. infusion
2 HIV and Hepatitis results to be available in Source data, will not be recorded within the eCRF
3 FSH level and serum pregnancy test at Visit 1 for female subjects, all other visits pregnancy test in urine (if FSH ≤20)
8 CMV IgG, IgM and DNA (by PCR) done for all subjects. Hepatitis B monitoring done in subjects with positive serology for anti-
HBc at screening (results to be available in Source data, will not be recorded within the eCRF). .
9 A first morning void urine sample will be collected in the patients’ home and a second spot urine sample will be collected at the 
investigational site for the analysis of UPCR, albumin, and creatinine. 
Commercially Confidential Information


Novartis
Confidential
Page 71
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
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 applicable, 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.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents.
Novartis will provide to investigators a proposed informed consent form that complies with the 
ICHE6 Good Clinical Practice (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.  The procedures set out in the main consent form concerning the storage, maintenance 
of privacy, and release of the data or specimens for the main study will also be adhered to for 
any future research. Any changes to the proposed consent form suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an Investigator Notification or 
an Aggregate Safety Finding. New information might require an update to the informed consent 
and then must be discussed with the subject.
Ensure subjects are informed of the contraception requirements outlined in the Section 4.2
(Exclusion criteria) and in Section 5.1 (Contraception requirements).
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
Refer to the Site Operations Manual for a complete list of Informed Consent Forms included in 
this study.
Commercially Confidential Information


Novartis
Confidential
Page 72
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
8.3
Subject screening
It is permissible to re-screen a subject if s/he fails the initial screening; however, each case must 
be discussed and agreed with the Sponsor on a case-by-case basis.
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. 
Relevant medical history/current medical conditions data will also be collected until signature 
of informed consent.  Details are outlined in the Site Operations Manual.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
8.5
Efficacy / Pharmacodynamics
Pharmacodynamic (PD) samples will be collected at the timepoints defined in the 
Assessment schedule. Follow instructions outlined in the Site Operations Manual regarding 
sample collection, numbering, processing and shipment.
In order to better define the PD profile, the timing of the sample collection may be altered based 
on emergent data. The number of samples/blood draws and total blood volume collected will 
not exceed those stated in the protocol. The results of the sample analyses needs to remain 
blinded during the study.
Generally, PD samples will be obtained and evaluated in all subjects, including the placebo 
group. 
8.5.1
Total soluble CD40 in plasma
Blood samples collected for total soluble CD40 in plasma (target engagement) will be obtained 
from all patients to protect blinding, but analysis will be performed only for CFZ533 treated 
patients.
A SOM accompanies this protocol, providing operational details for study conduct (incl. subject 
numbering, blood log with sample numbers). Further details on sample collection, processing 
and shipment will be provided in the Central Lab Manual. The detailed methods and analysis 
will be described in the Bioanalytical Data Report.
8.5.2
Urinary protein creatinine ratio (UPCR)
Urinary protein creatinine ratio (UPCR) as routine measurement by Central Lab will be assessed 
on dedicated visit days.  The first morning void will be collected in the patients’ home and a 
second spot urine sample will be collected at the investigational site.
Commercially Confidential Information


Novartis
Confidential
Page 73
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
8.6
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment schedule detailing when each assessment is 
to be performed.
During an epidemic or pandemic (e.g. COVID-19 pandemic) that limits or prevents on-site 
study visits regular phone or virtual calls will occur for safety monitoring and discussion of the 
participant´s health status until the participant can again visit the site.
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.
Information for all physical examinations must be included in the source documentation at the 
study site and will not be recorded the eCRF. Significant findings that are present prior to
informed consent are included in the Relevant Medical History eCRF. Significant’ findings 
observed after informed consent signature which meet the definition of an Adverse Event must 
be appropriately recorded on the Adverse Event eCRF.
8.6.2
Vital signs
Vital signs include blood pressure (BP) and pulse measurements. After the subject has been 
sitting for at least 3 minutes, with back supported and both feet placed on the floor, systolic and 
diastolic BP will be measured using a validated device, with an appropriately sized cuff. In case 
the cuff sizes available are not large enough for the subject’s arm circumference, a 
sphygmomanometer with an appropriately sized cuff may be used.
If heart-rate or blood pressure is out-of-range at screening or baseline, the Investigator may obtain two 
additional readings, so that a total of up to three consecutive assessments are made, with the subject 
seated quietly for approximately five minutes preceding each repeat assessment. 
8.6.3
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, 
but without shoes) will be measured.
8.6.4
Laboratory evaluations
In the case where a laboratory assessment that is listed in the inclusion/exclusion criteria is 
outside of a protocol-specified range at screening or baseline, the assessment may be repeated 
once prior to randomization. If the repeat value remains outside of protocol-specified ranges, 
the subject is excluded from the study.
In the case where a laboratory range is not specified by the protocol, but is outside the 
reference range for the laboratory at screening or baseline, a decision regarding whether the 
result is of clinical significance or not shall be made by the Investigator and shall be based, in 


Novartis
Confidential
Page 74
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
part, upon the nature and degree of the observed abnormality. The assessment may be repeated 
once prior to randomization.
Further retests at screening or baseline could be permitted if deemed necessary by the 
investigator; however, each case must be discussed and agreed with the Sponsor on a case-by-
case basis.
In all cases, the Investigator must document in the source documents, the clinical considerations
(i.e., result was/was not clinically significant and/or medically relevant) in allowing or 
disallowing the subject to continue in the study.
Clinically relevant deviations of laboratory test results occurring during or at completion of the 
study must be reported and discussed with Novartis personnel. The results should be evaluated 
for criteria defining an adverse event and reported as such if the criteria are met. Repeated 
evaluations are mandatory until normalization of the result(s) or until the change is no longer 
clinically relevant. 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 
(e.g., neutrophils, basophils, eosinophils, monocytes, lymphocytes) and platelet count will be 
measured.
8.6.4.2
Clinical chemistry
Albumin, alkaline phosphatase, total bilirubin, bicarbonate/CO2, calcium, cholesterol, chloride, 
creatinine, CK, GGT, glucose, LDH, inorganic phosphorus, lipase, amylase, magnesium, 
potassium, total protein, AST, ALT, sodium, triglycerides, urea/BUN and uric acid.
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal, direct 
and indirect reacting bilirubin should be differentiated.
8.6.4.4
Complement
C3 and C4 will be measured to assess complement activity. 
8.6.4.5
Coagulation test
Prothrombin time (PT) and activated partial thromboplastin time (aPTT) will be measured. 
Additional parameters, e.g., INR, may be assessed at Investigator’s discretion.
8.6.4.6
C-reactive protein (CRP) and ESR
C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) will be assessed.
Commercially Confidential Information


Novartis
Confidential
Page 75
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
8.6.4.7
Auto-antibodies
Anti-nuclear antibodies (ANA), rheumatoid factor (RF), anti-ds DNA antibodies, Anti-Smith 
antibody, anticardiolipin IgG and anticardiolipin IgM will be assessed.
8.6.4.8
Serum and plasma immunoglobulins
Serum total immunoglobulin G (IgG) and M (IgM) will be assessed. Lupus anticoagulant will 
also be assessed from plasma.
8.6.5
Immunogenicity
The immunogenicity of multiple IV doses of CFZ533 will be assessed via the quasi-quantitative 
analysis of anti-CFZ533 antibodies in plasma.
Blood samples collected for immunogenicity testing will be obtained from all patients and 
analysis will be performed for CFZ533 and placebo-treated patients (assess pre-existing ADAs).
The details of sample processing, handling, storage, shipment and analytical method will be 
described in a separate laboratory manual.
8.6.6
Electrocardiogram
The Fridericia QT correction formula (QTcF) should be used for clinical decisions.
Single 12 lead ECGs are collected. The original ECGs, appropriately signed, should be collected 
and archived at the study site.
Each ECG tracing should be labeled with study number, subject initials, 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. 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

PR interval

QT uncorrected

QTcF

QRS duration.
Commercially Confidential Information


Novartis
Confidential
Page 76
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
8.6.7
Pregnancy
Pregnancy tests are required of all women of childbearing potential. Female subjects with 
documented post-menopausal status (as confirmed by FSH > 20 at screening) are not required 
to be tested for pregnancy. 
Serum pregnancy tests will be performed at screening. At all other times urine pregnancy tests 
may be used.
If a urine pregnancy test is performed and is found to be positive, this will require 
immediate performing a serum β-hCG test. If positive, the Sponsor and Investigator will decide 
if discontinuation from the trial is required or whether study assessments can continue without 
compromising the patient’s safety.
8.6.8
Other safety assessments
8.6.8.1
Quantiferon test
A QuantiFeron test will be performed and read at screening (or within 6 months prior to 
randomization) in order to evaluate the infection with tuberculosis (TB). Test may be repeated 
if test result is not unambiguous. A positive QuantiFeron test at screening will exclude the 
subjects from participation in the study.
T-SPOT or other types ELISPOT assays based on interferon-gamma release may also be used 
for tuberculosis diagnosis as per local practice.
Precautions against tuberculosis should be handled according to the best medical practice 
consistent to the local standards in each country with prior consultation with Novartis. Patients 
requiring administration of antibiotics against latent tuberculosis should complete their 
treatment and should be considered cured prior to being re-considered for entry into this study 
(consultation with Novartis must occur before allowing the patient to enter the study).
Results will be available as source data and will not be recorded within the eCRF.
8.6.8.2
Hepatitis, CMV, HIV screening
Hepatitis
All subjects will be screened for Hepatitis B surface antigen (HBsAg) and Hepatitis B core 
antibody (anti-HBc); HBV DNA testing will be performed if needed. 

If HBsAg is positive then the patient is not eligible, regardless of other test results, and 
HBV DNA test is not required. 

If HBsAg and anti-HBc are both negative, then the patient is eligible and HBV DNA test 
is not required. 

If HBsAg is negative and anti-HBc is positive then HBV DNA test has to be performed to 
confirm eligibility: the subject is only eligible if HBV DNA is negative.
-
For such subjects an expert in hepatitis must be consulted and recommendations
followed. If enrolled, hepatitis B monitoring must be implemented: HBsAg and HBV 
DNA tested every 4 weeks until the end of study.


Novartis
Confidential
Page 77
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
-
In case of sero-conversion (i.e., if either HBsAg or HBV DNA turn positive) 
preemptive anti-viral treatment (e.g., lamivudine or entecavir) must be initiated 
immediately.
For subjects who are ineligible for the study based on hepatitis B screening, appropriate 
treatment should be considered.
Table 8-2
Hepatitis screening
HBsAg
Anti-HBc
HBV DNA
Eligible
Comment
-
-
not required
Yes
-
+
-
Yes
Monitoring required
-
+
+
No
Consider treatment
+
  + or -  
not required
No
Consider treatment
Screening for Hepatitis C will be based on HCV antibodies and HCV RNA.
CMV
Guidance to investigators:
CMV infections will be recorded as Adverse Events and on the CMV-specific CRF page. CMV 
infection is identified by assessments of laboratory and/or clinical sign/symptoms. 
Cytomegalovirus disease is defined according to published criteria (Ljungman et al 2017; 
Choo et al 2019) as described below.
a. ACTIVE CYTOMEGALOVIRUS INFECTION is defined as a detectable 
cytomegalovirus viral load in the absence of signs or symptoms attributable to 
cytomegalovirus. Active cytomegalovirus infection can be the result of cytomegalovirus 
reactivation or primary cytomegalovirus infection.
b. PROVEN DISEASE: For pneumonia, central nervous system (CNS) disease, 
gastrointestinal disease, hepatitis, nephritis, cystitis, myocarditis, pancreatitis, and disease 
in other organs, definite tissue-invasive disease requires the correct clinical syndrome 
combined with the detection of cytomegalovirus in tissue samples (or in bronchoalveolar 
lavage fluid for pneumonia) by virus isolation, immunohistochemical analysis, in situ
hybridization, or conventional histologic features. Detection of cytomegalovirus by PCR 
alone is not sufficient.

Cytomegalovirus viral syndrome requires fever (oral temperature >38°C) for two or 
more days within a 4-day period, neutropenia or thrombocytopenia, and the detection 
of cytomegalovirus in the blood by culture or the detection of antigen, DNA, or RNA. 
Human herpes virus -6 (HHV-6) infection needs to be excluded.

For central nervous system (CNS) disease, detection of cytomegalovirus in 
cerebrospinal fluid (CSF) samples by culture or PCR is sufficient.

For retinitis, typical cytomegalovirus lesions must be confirmed by an ophthalmologist; 
detection of cytomegalovirus is not required.
c. PROBABLE DISEASE requires the correct clinical syndrome but the detection of 
cytomegalovirus cannot be confirmed as outlined above.


Novartis
Confidential
Page 78
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Detection During Screening and monitoring:
1. At study screening, patients with active viral infections (quantifiable CMV DNA by PCR 
or positive IgM in the absence of a positive IgG) will not be eligible for randomization
2. All patients will be monitored for potential CMV reactivation or new primary infections by 
CMV (IgG and IgM) serology and viral DNA using PCR from randomization visit and 
monthly thereafter
3. In case of suspicion CMV infection, CMV serology will be performed as soon as possible, 
i.e. not waiting for the next scheduled CMV monitoring. 
4. For patients currently ongoing in the study (i.e. patients enrolled under Protocol version 02 
dated 22May2019 and continuing with study follow up period), CMV monitoring should be 
implemented at the next scheduled visit as per protocol
Table 8-3
CMV screening
IgM
IgG
DNA 
(PCR) 
detectable
DNA (PCR) 
quantifiable
Eligible
Comment
+
-
No
Regardless of DNA results: patient not 
eligible. 
+
No
Regardless of any other results: patient 
not eligible. 
Examples of non-eligibility
+
-
-
-
No
IgM positive and IgG negative: patient 
not eligible.
-
-
+
+
No
DNA quantifiable: patient not eligible
If the patient has neither (IgM+ and IgG-) nor quantifiable DNA: patient eligible
+
+
+
-
Yes
IgM positive. but IgG positive, too. 
DNA not quantifiable.
+
+
-
Yes
IgM negative, DNA not quantifiable.
-
-
+
-
Yes
DNA detectable but not quantifiable.
  
-
-
-
Yes
All negative.
The patient is NOT eligible if either [DNA by PCR is quantifiable] or [IgM is positive and IgG is negative]. 
If there is suspicion of false positive result, the test can be repeated.
Management of asymptomatic, confirmed or probable disease

During the study, for patients who develop evidence of an asymptomatic active CMV
infection based on viral load measurement (quantifiable CMV DNA in copies/mL or IU 
equivalent), it is required that:

CMV monitoring is increased to at least weekly intervals of DNA monitoring by serial 
PCR assessments as well as clinical monitoring for early signs of CMV end organ 
disease until resolution

Consider initiation of pre-emptive anti-CMV therapy when PCR-determined viral load 
is >1,000 copies/mL, in consultation with an infectious disease expert

Consider reducing or stopping the dose of other immunosuppressive agents


Novartis
Confidential
Page 79
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202

Consider stopping the study drug

If primary CMV infection is suspected based on confirmed prior negative serology
CMV IgG, repeat CMV IgG serology after resolution of primary infection and after
completion of study treatment

During the study, for patients with confirmed or probable CMV disease activity who
develop clinical symptoms, it is required that:

Appropriate anti-CMV therapy is initiated

The study drug is stopped

Consider stopping or reducing the dose of other immunosuppressive agents.

For patients with potential infectious symptoms during the trial in the absence of laboratory
support of CMV etiology, consider age- and country-appropriate infectious exposure risks;
consider direct isolation of pathogens, virology, and/or serology and initiating appropriate
targeted anti-viral or anti-bacterial therapies as indicated in consultation with an expert.
HIV
Evaluation for HIV sero-positivity 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.
8.6.8.3
Infections
All occurrences of infections must be carefully monitored by the Investigator. Significant 
findings, which meet the definition of infection, must be recorded in the Adverse Event eCRF.
8.7
Pharmacokinetics
PK blood samples will be collected at the timepoints defined in the Assessment schedule
(Section 8.1). Follow instructions outlined in the Site Operations Manual regarding sample 
collection, numbering, processing and shipment. 
Pharmacokinetic (PK) samples will be obtained from all patients (CFZ533 and placebo-treated) 
to maintain blinding, but the analysis (free CFZ533 concentration in plasma) will only be 
conducted for CFZ533 treated patients.
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 80
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
For standard pharmacokinetic abbreviations and definitions see the list provided at the beginning 
of this protocol. PK samples will be collected at pre-dose and 1-hour after the end of the intravenous 
infusion on dosing days, and at time of the scheduled visit during the Follow-up Period.
The following pharmacokinetic parameters will be determined for free CFZ533 in plasma 
(i) Ctrough,ss or Cmin,ss, and Cmax,ss will be directly derived from the bioanalytical data and 
listings, and (ii) AUClast from the last dose at Day 141 will be determined using the actual 
recorded sampling times and non-compartmental methods with Phoenix WinNonlin 
(Version 8.0 or higher). The linear trapezoidal rule will be used for AUClast calculation.
No other parameters (e.g. clearance, volume of distribution, or half-life) will be derived using 
non-compartmental analysis (NCA). The pharmacokinetics of CFZ533 is non-linear and 
characterized by target-mediated disposition where CD40 binding by CFZ533 is leading to CFZ533 
elimination (this includes receptor-mediated endocytosis by the membrane bound CD40, and 
subsequent metabolism of the CFZ533-CD40 complexes). As such, it is expected that:

The amount of drug-target complex does influence the pharmacokinetics of CFZ533,

Tissue metabolism may have a significant impact on the disposition of CFZ533 (the 
volume of distribution will be dependent on clearance),

The volume of distribution may not be accurately inferred from plasma concentration 
alone, and the values for the volume of distribution obtained from a NCA may be 
incorrect,

Volume of distribution and clearance parameters (as inferred from NCA analysis) would 
decrease when the dose increases.
The NCA approach is not appropriate due to violations of the assumptions that the disposition of the 
drug is linear, and that the elimination is from sites that are in rapid equilibrium with blood.
For each PK and total soluble CD40 (PD; Section 8.5.1) samples, the actual recorded sampling 
time will captured, and the elapsed time since the first and since the last dose will be calculated. 
8.8
Other assessments
Commercially Confidential Information


Novartis
Confidential
Page 81
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Commercially Confidential Information


Novartis
Confidential
Page 82
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Commercially Confidential Information


Novartis
Confidential
Page 83
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject 
after providing written informed consent for participation in the study until the end of study 
visit. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the study treatment are also considered 
an adverse event irrespective if a clinical event has occurred. See Section 9.6 for an overview 
of the reporting requirements.
Commercially Confidential Information


Novartis
Confidential
Page 84
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination finding, laboratory test 
finding, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms,

they are considered clinically significant,

they require therapy.
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for liver and kidney related events are 
included in Appendix 1 and Appendix 2, respectively. 
All adverse events should be recorded on the Adverse Events CRF under the signs, symptoms 
or diagnosis associated with them, and accompanied by the following information:
1. The severity grade 
mild: 
usually transient in nature and generally not interfering with normal activities
moderate: sufficiently discomforting to interfere with normal activities
severe: 
prevents normal activities
2. its relationship to the study treatment 

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 9.3 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 9.3 for definition of SAE)


Novartis
Confidential
Page 85
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown). Information about common side 
effects already known about the investigational drug can be found in the Investigator's 
Brochure (IB) or will be communicated between IB updates in the form of Investigator 
Notifications.  Once an adverse event is detected, it must be followed until its resolution or 
until it is judged to be permanent, and assessment should be made at each visit (or more 
frequently, if necessary) of any changes in severity, the suspected relationship to the 
investigational drug, the interventions required to treat it, and the outcome.
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.
Adverse events potentially leading to treatment discontinuation should also be assessed using 
the CTCAE grading, version 4.03. CTCAE grading will not be recorded into the eCRF.
9.2
Adverse event of special interest
Adverse events of special interest (AESI) are defined, based on potential risks associated with 
exposure to CFZ533 (see Section 3.6.2), as any of the following adverse events:

Infections (see Section 3.6.2.1)

Immunogenicity (see Section 3.6.2.3)

Thrombophilia (see Section 3.6.2.4)

Malignancy including lymphoproliferative disease (see Section 3.6.2.5)
For AESI, statistical analyses comparing the event rates in two treatment groups will be 
performed.
9.3
Serious adverse event reporting
9.3.1
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:
o routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
o 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


Novartis
Confidential
Page 86
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
o 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
o social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to ICH-E2D Guideline 2004).
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (please refer to ICH-E2D Guideline 2004).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to Novartis Chief Medical Office and Patient Safety (CMO&PS) as per Section 9.3.2.
9.3.2
SAE reporting
Screen Failures
Note the following requirement for Screen Failures: SAEs occurring after the subject has 
provided informed consent until the time the subject is deemed a Screen Failure must be 
reported to Novartis. 
Randomized Subjects
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence as described below.
Any SAEs experienced after this period should only be reported to Novartis if the investigator 
suspects a causal relationship to study treatment.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.


Novartis
Confidential
Page 87
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Follow-up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable) and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment a Chief Medical Office and 
Patient Safety (CMO& PS) Department associate may urgently require further information from 
the investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) 
will be collected and reported to the competent authorities and relevant ethics committees in 
accordance with EU Guidance 2011/C 172/01 or as per national regulatory requirements in 
participating countries.
Follow the detailed instructions outlined in the Site Operations Manual regarding the 
submission process for reporting SAEs to Novartis. Note: SAEs must be reported to Novartis 
within 24 hours of the investigator learning of its occurrence/receiving follow-up information.
9.4
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
Once a participant is exposed to study treatment, 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 GGT) to confirm 
elevation within 48-72 hours.
These liver chemistry repeats should always be performed using the central laboratory, with the 
results provided via the standard electronic transfer.  If results will not be available from the 
central laboratory within 24 hours, then the repeats can also be performed at a local laboratory 
to monitor the safety of the subject. If a liver event is subsequently reported, any local liver 
chemistry tests previously conducted that are associated with this event should have results 
reported on the unscheduled local laboratory CRF.

If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to Section 7.2 (Discontinuation of study 
treatment), if appropriate

Hospitalization of the subject if appropriate


Novartis
Confidential
Page 88
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202

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.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. Refer to the Site Operations Manual for additional details. 
9.5
Renal safety monitoring
Once a participant is exposed to study treatment, 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 Appendix 2.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. Refer to the Site Operations Manual for additional details.
9.6
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject 
or consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
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 
CMO&PS department if the treatment error is associated with an SAE.


Novartis
Confidential
Page 89
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
All instances of misuse or abuse must be documented in the adverse event (AE) CRF 
irrespective of the misuse/abuse being associated with an AE/SAE. In addition, all instances of 
misuse or abuse must be reported to Novartis Chief Medical Office and Patient Safety 
(CMO&PS). As such, instances of misuse or abuse are also to be reported using the SAE 
form/CRF. Table 9-1 summarizes the reporting requirements.
Table 9-1
Guidance for capturing study treatment errors
Treatment error type
Document in Dose 
Administration (DAR) CRF 
Document in AE 
CRF
Complete SAE 
form/CRF 
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated 
with an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a 
SAE
For more information on AE and SAE definition and reporting requirements, please see 
Section 9.1 and Section 9.2, respectively.
9.7
Pregnancy reporting
Reproductive toxicity and teratogenicity data are not available for the investigational drug at 
this time, therefore no guidelines on therapeutic recommendations in case of pregnancy are 
available. This study enrolls women who are either considered to be of non-child-bearing 
potential or who use highly effective methods of contraception, thus pregnancy is not an 
expected outcome for any female study participant. However, in the case that a pregnancy in a 
female study participant should occur, please follow the below reporting guidelines.
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Chief Medical Office and Patient Safety (CMO& PS) 
Department. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
The study drug must be discontinued, though the subject may stay in the study, if she wishes to 
do so. All assessments that are considered as a risk during pregnancy must not be performed. 
The subject may continue all other protocol assessments.
If a trial participant becomes pregnant, the trial participant must be asked to read and sign the 
pregnancy consent form to allow the study doctor to ask about her pregnancy. 


Novartis
Confidential
Page 90
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
9.8
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly between 
medically qualified personnel representing the Sponsor and Investigator. Such evaluations may 
occur verbally, but the outcome and key discussion points will be summarized in writing 
(e-mail) and made available to both Sponsor and all Investigator(s). Criteria pertaining to 
stopping the study/treatment or adapting the study design are presented above.
When two or more clinical site(s) are participating in the clinical study, the Sponsor will advise 
the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any new, 
clinically relevant safety information reported from another site during the conduct of the study 
in a timely manner.
10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource or eCRFs) 
with the investigators and their staff. During the study Novartis employs several methods of 
ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. The monitor 
will visit the site to check the completeness of subject records, the accuracy of data capture / 
data entry, the adherence to the protocol and to Good Clinical Practice, the progress of 
enrollment, and ensure that study drug is being stored, dispensed, and accounted for according 
to specifications. Key study personnel must be available to assist the monitor during these visits.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject's file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about the 
identity of the subjects will be disclosed.
10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the electronic Case 
Report Forms (eCRF) 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 


Novartis
Confidential
Page 91
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
transfer of the data to the CRO working on behalf of Novartis. The Investigator must certify 
that the data entered into the eCRFs 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 Site Operations Manual and 
Assessment schedule and can be recorded directly on the eCRFs. 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
A CRO working on behalf of Novartis will 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 the
CRO working on behalf of Novartis who will make the correction to the database. The signed 
copy of the Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the Medical 
dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data about all study drug(s) dispensed to the subject and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. 
Any changes to the database after that time can only be made after written agreement by 
Novartis management. 


Novartis
Confidential
Page 92
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
10.4
Data Monitoring Committee
A Data Monitoring Committee (DMC) will be established (according to Novartis Standard 
Operating Procedures) with the primary task to perform ongoing review of safety. The DMC is 
an unblinded board comprised of specialists with specific knowledge on the disease area, drug 
development and issues related to conducting clinical trials. Specific details on the composition 
and the scope of its mandate will be presented in a DMC charter document. 
The DMC will be responsible for the following:

Ongoing review of study data; the triggering events will be defined in the DMC charter

To advise the clinical team of a need for protocol modifications/amendments in order to 
minimize potential risk for subjects

To request additional information or make recommendation including stopping of 
enrolment, if needed.

The chair of the DMC will be responsible for providing summaries/executive reports of 
each DMC meeting to the clinical team, arranging ongoing communication between 
members of the DMC, and maintaining files with all correspondence pertaining to the 
study.
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 any study drug and with no 
protocol deviations that impact on PK data.
Commercially Confidential Information


Novartis
Confidential
Page 93
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
The PD analysis set will include all subjects with available PD data and no protocol deviations 
with relevant impact on PD data.
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 (rescue medication) and concomitant therapies will be listed 
by treatment group and subject.
11.4
Analysis of the primary variable(s)
11.4.1
Primary Variable(s)
The primary variable is the ratio from baseline in first morning void urinary protein creatinine 
ratio (UPCR) at Week 25.
11.4.2
Statistical model, hypothesis, and method of analysis
The ratio from baseline in first morning void UPCR will be log transformed prior to the analysis.
A repeated measures mixed model will be fitted with factors for treatment group (CFZ533 or 
placebo) and visit (e.g. Week 5, 9, 13 etc.). The model will also include a factor for the 
prednisone dose-equivalent at baseline (≤10 mg, >10 mg), which is a stratification factor for 
the randomization. Log-transformed baseline first morning void UPCR will be included in the 
model as a covariate along with the interactions between visit and all of the fixed effects. 
A normal errors model will be assumed with an unstructured covariance matrix to account for 
the correlation within subjects. The model will be estimated using maximum likelihood 
techniques.
At each of the visits, the difference between the CFZ533 and placebo group will be estimated 
(along with its corresponding 95% confidence interval) and then back-transformed to provide 
an estimate of the ratio between treatment groups.
11.4.3
Handling of missing values/censoring/discontinuations
Data from patients taking rescue medication during the trial (or failing to tolerate steroid taper, 
for patients receiving oral corticosteroid at baseline) will be excluded from the date of rescue 
medication intake. Data from patients who discontinue study treatment will also be excluded,
from the date of study drug discontinuation. The primary analysis is unbiased under the 
assumption that the missing data are missing at random (MAR). 
If the UPCR from the first morning void sample is not available, then the UPCR from the 
corresponding spot sample taken at the investigator site will be used in the analyses.  


Novartis
Confidential
Page 94
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
11.4.4
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.
For serious adverse events and adverse events of special interest (AESI), statistical analyses 
comparing the event rates in two treatment groups will be performed.
11.4.5
Sensitivity analyses
Commercially Confidential Information


Novartis
Confidential
Page 95
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
11.5
Analysis of secondary variable(s)
11.5.1
Efficacy / Pharmacodynamics
11.5.1.1 Total soluble CD40 in plasma
Total soluble CD40 concentration in plasma will be listed by treatment, 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), SD, CV (arithmetic and 
geometric), median, minimum and maximum.
11.5.1.2 UPCR, hematuria and cellular casts
First morning void and clinic spot urine sample UPCR, hematuria and cellular casts will be 
listed by treatment, subject and visit/sampling time-point.  Descriptive statistics will be 
provided by treatment and visit/sampling time.
11.5.1.3 Complete renal remission (CRR)
A patient will be defined as being in complete renal remission if they fulfill all the following 
criteria (as per the ACR definition described in Wofsy et al 2012):

First morning void UPCR ≤ 0.2 mg/mg

eGFR within 25% of baseline value

Normal urine sediment
The proportion of patients fulfilling the definition of complete renal remission will be listed and 
summarized by treatment and visit.
If the UPCR from the first morning void sample is not available, then the UPCR from the 
corresponding spot sample taken at the investigator site will be used in the derivation of 
complete renal remission.
11.5.2
Pharmacokinetics
Pharmacokinetic parameters will be directly derived from the PK concentration data or using 
non-compartmental analysis, as described in Section 8.7. These parameters will be listed by 
treatment and subject. Descriptive summary statistics will include mean (arithmetic and 
geometric), SD, and CV (arithmetic and geometric), median, minimum and maximum.
Commercially Confidential Information


Novartis
Confidential
Page 96
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
11.5.3
Pharmacokinetic / pharmacodynamic relationships
PK/PD analysis (incl. free CFZ533 and total soluble CD40 in plasma) will be explored 
graphically. Modeling of PK/PD data using a population approach may be performed as 
appropriate and will be reported if necessary in a separate, standalone modeling and simulation 
report.
11.5.4
Other assessments
11.6
Analysis of exploratory variables
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 97
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
11.7
Sample size calculation
The sample size is based on the number of patients required to meet the efficacy criteria 
comparing CFZ533 to placebo in the primary analysis of the ratio from baseline in UPCR at 
Week 25. The efficacy criteria are:

Statistically significant decrease in UPCR at week 25 of the treatment period compared to 
placebo (at the one-sided 10% level)

Estimated mean reduction in UPCR at week 25 of at least 20% more than on placebo (i.e. 
ratio of UPCR for CFZ533:placebo ≤0.80 or equivalently difference in log UPCR for 
CFZ533 – placebo ≤-0.223).
Commercially Confidential Information


Novartis
Confidential
Page 98
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
With complete data from 51 patients (34 patients on CFZ533 and 17 patients on placebo), there 
will be approximately 80% power to achieve the efficacy criteria assuming a true reduction of 
36% in UPCR on CFZ533 treatment compared to placebo. This calculation assumes that the 
standard deviation of the change from baseline in UPCR at 24 weeks is 0.7.
In order to account for a dropout rate of 15%, approximately 60 patients will be enrolled 
(40 patients on CFZ533 and 20 patients on placebo).
The sample size will be re-assessed based on interim analysis performed approx. 1 to 3 months
before the completion of enrollment of 60 patients. The sample size may be increased based on 
the results of the analysis, up to a maximum of 75 randomized patients.
The sample size calculations were performed using a custom-made R package run in R version 
2.13.0.
11.8
Power for analysis of key secondary variables
Not applicable
11.9
Interim analyses
Commercially Confidential Information


Novartis
Confidential
Page 99
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations 
Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles 
laid down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g. 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis by the time of 
Last Patient Last Visit to be a reviewer and signatory for the clinical study report. 
12.3
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results.
12.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed or overseen by 
Novartis Pharma Auditing and Compliance Quality Assurance (or CRO working on behalf of 
Novartis), a group independent from those involved in conducting, monitoring or performing 
Commercially Confidential Information


Novartis
Confidential
Page 100
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
quality control of the clinical trial. The clinical audit process uses a knowledge/risk based 
approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal standard operating procedures (SOPs), and are performed according to 
written Novartis processes.
13
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.
13.1
Protocol Amendments
Any change to the protocol can only be made in a written protocol amendment that must be 
approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation.
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 9 (Safety Monitoring) must be followed and the Study Lead 
informed.


Novartis
Confidential
Page 101
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
14
References
Aoyagi T, Yamashitaa K, Suzukia T, et al (2009) A human anti-CD40 monoclonal antibody, 
4D11, for kidney transplantation in cynomolgus monkeys : induction and maintenance therapy. 
American Journal of Transplantation 9: 1731-1741
Bakoush O, Tencer J, Tapia J, et al (2002) Higher urinary IgM excretion in type 2 diabetic 
nephropathy compared to type 1 diabetic nephropathy. Kidney International 61 (1): 203-208
Bertsias GK, Tektonidou M, Amoura Z, et al (2012) Joint European League Against 
Rheumatism and European Renal Association - European Dialysis and Transplant Association 
(EULAR/ERA-EDTA) recommendations for the management of adult and pediatric lupus 
nephritis. Annals of the Rheumatic Diseases 71 (11): 1771-17782
Boumpas DT, Furie R, Manzi S, et al (2003) A short course of BG9588 (anti-CD40 ligand 
antibody) improves serologic activity and decreases hematuria in patients with proliferative 
lupus glomerulonephritis. Arthritis and Rheumatism 48 (3): 719-727
Chamberlain C, Colman PJ, Ranger AM, et al (2017) Repeated administration of dapirolizumab 
pegol in a randomized phase I study is well tolerated and accompanied by improvements in 
several composite measures of systemic lupus erythematosus disease activity and changes in 
whole blood transcriptomic profiles. Annuals of the Rheumatic Diseases 76 (11): 1837-1844. 
Immunological Investigations 36 (3): 247-257
Chatzigeorgiou AE, Lembessis PE, Mylona-Karagianni CF, et al (2010) CD40 expression and 
its association with low-grade inflammation in a Greek population of type 1 diabetic juveniles: 
evidence for differences in CD40 mRNA isoforms expressed by peripheral blood mononuclear 
cells. Experimental and Clinical Endocrinology and Diabetes 118 (1): 38-46
Chen JM, Guo J, Wei CD, et al (2015) The association of CD40 polymorphisms with CD40 
serum levels and risk of systemic lupus erythematosus. BioMed Central Genetics 16: 121
Choo HMC, Cher WQ, Kwan YH, et al (2019) Risk factors for cytomegalovirus disease in 
systemic lupus erythematosus (SLE): a systematic review. Advances in Rheumatology, 59.
Desai-Mehta A, Lu L, Ramsey-Goldman R, et al (1996) Hyperexpression of CD40 ligand by B 
and T cells in human lupus and its role in pathogenic autoantibody production. Journal of 
Clinical Investigation 97 (9): 2063-2073
Dimitriou ID, Kapsogeorgou EK, Moutsopoulos HM, et al (2002) CD40 on salivary gland 
epithelial cells : high constitutive expression by cultured cells from Sjögren’s syndrome patients 
indicating their intrinsic activiation. Clinical and Experimental Immunology 127 (2): 386-392
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 102
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
European Association for the Study of the Liver (2017) EASL 2017 Clinical Practice Guidelines 
on the management of hepatitis B virus infection. Journal of Hepatology 67 (2): 370-398
Faurschou M, Dreyer L, Kamper AL, et al (2010) Long-term mortality and renal outcome in a 
cohort of 100 patients with lupus nephritis. Arthritis Care & Research 62 (6): 873-880
Fei Y, Wu Q, Zhang W, et al (2013) Low-dose tacrolimus in treating lupus nephritis refractory 
to cyclophosphamide: a prospective cohort study. Clinical and Experimental Rheumatology 31: 
62-68
Frieri M (2013) Mechanisms of disease for the clinician: systemic lupus erythematosus. Annals 
of Allergy, Asthma & Immunology 110 (4): 228-232
Goules A, Tzioufas AG, Manousakis MN, et al (2006) Elevated levels of soluble CD40 ligand 
(sCD40L) in serum of patients with systemic autoimmune diseases. Journal of 
Autoimmunology 26 (3):165-171
Grammer AC, Slota R, Fischer R, et al (2003) Abnormal GC reactions in systemic lupus 
erythematosus demonstrated by blockade of CD154-CD40 interactions. Journal of Clinical 
Investigations 112 (10): 1506-1520
Gurevitz SL, Snyder JA, Wessel EK, et al (2013) Systemic lupus erythematosus: a review of 
the disease and treatment options. The Consultant Pharmacist 28 (2): 110-121
Hahn BH, McMahon MA, Wilkinson A, et al (2012) American College of Rheumatology 
guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Research 
64 (6): 797-808
Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the 
classification of systemic lupus erythematosus (letter). Arthritis and Rheumatism 40 (9): 1725
Huang W, Sinha J, Newman J, et al (2002) The effect of anti-CD40 ligand antibody on B cells 
in human systemic lupus erythematosus. Arthritis and Rheumatism 46 (6): 1554-1562
ICH E2D (2004) Clinical Safety Data Management: Definitions and Standards for expedited 
reporting. Accessed from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC5
00002807.pdf  Accessed on: 02Dec2016. 
Kawai T, Andrews D, Colvin RB, et al (2000) Thromboembolic complications after treatment
with monoclonal antibody against CD40 ligand. Nature Medicine 6 (2): 114
Komura K, Fujimoto M, Matsushita T, et al (2007) Increased serum soluble CD40 levels in 
patients with systemic sclerosis. Journal of Rheumatology 34 (2): 353-358
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 103
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Ljungman P, Boeckh M, Hirsch HH, et al (2017) Definitions of Cytomegalovirus Infection and 
Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis. 64(1): 87-91
MacDonald KP, Nishioka Y, Lipsky PE, et al (1997) Functional CD40 ligand is expressed by 
T cells in rheumatoid arthritis. Journal of Clinical Investigation 100 (9): 2404-2414
Meibohm B and Zhou H (2012) Characterizing the impact of renal impairment on the clinical 
pharmacology of biologics. Journal of Clinical Pharmacology 52 (1 Suppl): 54S-62S
Mohan C, Shi Y, Laman JD, et al (1995) Interaction between CD40 and its ligand gp39 in the 
development of murine lupus nephritis. Journal of Immunology 154 (3): 1470-1480
Mok CC, Ying KY, Yim CW, et al (2016) Tacrolimus versus mycophenolate mofetil for 
induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up. 
Annals of the Rheumatic Diseases 2016; 75(1):30-6Mysliwiec J, Oklota M, Mikolajuk A, et al
(2007) Serum CD40/CD40L system in Graves’ disease and Hashimoto‘s thyroiditis related t 
soluble Fas, FasL and humoral markers of autoimmune response. Immunological Investigations 
36 (3): 247-257
National Cancer Institute Common Toxicity Criteria version 4.03 (NCI-CTCAE 2010) accessed 
at http://evs.nci.nih.gov/ftp1/CTCAE/About.html on 19.06.2018
Sfikakis PP, Boletis JN, Lionaki S, et al (2005) Remission of proliferative lupus nephritis 
following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory 
molecule CD40 ligand: an open-label trial. Arthritis and Rheumatism 52 (2): 501-513
Struemper H, Chen C, and Cai W (2013) Population pharmacokinetics of belimumab following 
intravenous administration in patients with systemic lupus erythematosus. Journal of Clinical 
Pharmacology 53 (7): 711-720
Tan EM, Cohen AS, Fries JF, et al (1982) The 1982 revised criteria for the classification of 
systemic lupus erythematosus.  Arthritis and Rheumatism 25: 1271-1277
Terrault NA, Lok AS, McMahon BJ, et al (2018) Update on prevention, diagnosis, and 
treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 67 (4): 1560-
1599
Tocoian A, Buchan P, Kirby H, et al (2015) First-in human trial of the safety, pharmacokinetics 
and immunogenicity of a PEGylated anti-CD40L antibody fragment (CDP7657) in healthy 
individuals and patients with systemic lupus erythematosus. Lupus 24 (10): 1045-1056
Vakkalanka RK, Woo C, Kirou KA, et al (1999) Elevated levels and functional capacity of 
soluble CD40 ligand in systemic lupus erythematosus sera. Arthritis and Rheumatism 42 (5): 
871-881
Waldman M and Appel GB (2006) Update on the treatment of lupus nephritis. Kidney 
International 70 (8): 1403-1412
Watanabe M, Yamashita K, Fukumori D, et al (2013) Effect of ASKP1240 (4D11), a fully 
human anti-CD40 monoclonal antibody, on a single donor-derived allogeneic islet 
transplantation in cynomolgus monkeys. XIII International Congress of The Transplantation 
Society, Session Clinical Islet Transplantation, Vancouver, BC
Commercially Confidential Information


Novartis
Confidential
Page 104
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Weening JJ, D’Agati VD, Schwartz MM, et al (2004) The classification of glomerulonephritis 
in systemic lupus erythematosus revisited. Kidney International 65: 521-530
Yang M, Li M, He W, et al (2014) Calcineurin inhibitors may be a reasonable alternative to 
cyclophosphamide in the induction treatment of active lupus nephritis: A systematic review and 
meta-analysis. Experimental and Therapeutic Medicine 7: 1663-1670
Yellin MJ, D’Agati V, Parkinson G, et al (1997) Immunohistologic analysis fo renal CD40 and 
CD40L expression in lupus nephritis and other glomerulonephritides. Arthritis and Rheumatism 
40: 124-134
Zeher M, Doria A, Lan J, et al (2011). Efficacy and safety of enteric-coated mycophenolate 
sodium in combination with two glucocorticoid regimens for the treatment of active lupus 
nephritis. Lupus; 20:1484-93. 
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 105
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
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

Complete CRFs per liver event guidance*
*Liver event guidance for CRF completion is available in the Site Operations Manual


Novartis
Confidential
Page 106
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
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

Alpha-1-antitrypsin


Novartis
Confidential
Page 107
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
16
Appendix 2: Specific Renal Alert Criteria and Actions
Table 16-1
Specific Renal Alert Criteria and Actions
The following criteria and actions (intended for subjects without significant kidney disease) 
should be followed considering both potential investigational drug related toxicity and 
abnormalities that are underlying features of proliferative lupus nephritis (e.g. proteinuria, 
hematuria, decreased renal function). 
Specific Renal Alert Criteria and Actions
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 (ACR) ≥ 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.)


Novartis
Confidential
Page 108
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
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
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
Page 109
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
17
Appendix 3: 1997 Update of the 1982 ACR Revised Criteria 
for Classification of Systemic Lupus Erythematosus
Table 17-1
ACR Revised Criteria for Classification of SLE
Criterion
Definition
1. Malar rash
Fixed erythema, flat or raised, over the malar eminences, tending to spare the 
nasolabial folds
2. Discoid rash
Erythematous raised patches with adherent keratoric scaling and follicular plugging; 
atrophic scarring may occur in older lesions
3. Photosensitivity
Skin rash as a result of unusual reaction to sunlight, by patient history or physician 
observation
4. Oral ulcers
Oral or nasopharyngeal ulceration, usually painless, observed by a physician
5. Arthritis
Non-erosive arthritis involving two or more peripheral joints, characterized by 
tenderness, swelling, or effusion
6. Serositis
a) Pleuritis -  convincing history fo pleuritic pain or rub heard by a physician or 
evidence of pleural effusion 
OR
b) Pericarditis – documented by ECG or rub or evidence of pericardial effusions
7. Renal disorder
a) Persistent proteinuria greater than 0.5 grams per day or greater than 3+ if 
quantitation not performed 
OR
b) Cellular casts – may be red cell, hemoglobin, granular, tubular, or mixed
8. Neurologic 
disorder
a) Seizures – in the absence of offending drugs or known metabolic derangements 
OR
b) Psychosis – in the absence of offending drugs or known metabolic derangements
9. Hematologic 
disorder
a) Hemolytic anemia – with reticulocytosis 
OR
b) Leukopenia – less than 4,000/mm3 total on two or more occasions
OR
c) Lymphopenia – less than 1,500/ mm3 on two or more occasions 
OR
d) Thrombocytopenia – less than 100,000 mm3 in the absence of offending drugs
10. Immunologic 
disorder
a) Anti-DNA: antibody to native DNA in abnormal titer
OR
b) Anti-Sm: presence of antibody to Sm or nuclear antigen
OR
c) Positive finding of antiphospholipid antibodies based on (1) abnormal serum level 
of IgG or IgM anti-cardiolipin antibodies; (2) a positive test result for lupus 
anticoagulant using a standard method; or (3) a false positive serologic test for 
syphilis known to be positive for at least 6 months and confirmed by Treponema 
pallidum immobilization or fluorescent treponemal antibody absorption test
11. Antinuclear 
antibody
An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent 
assay at any point in time and in the absence of drugs known to be associated with 
“drug-induced lupus” syndrome
The proposed classification os based on 11 criteria. For the purpose of identifying patients in clinical studies, a 
person shall be said to have SLE if any 4 or more of the 11 criteria are present, serially or simultaneously, during 
any interval of observation  
(Tan et al 1982, Hochberg 1997)


Novartis
Confidential
Page 110
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
18
Appendix 4: Classification of Lupus nephritis
Table 18-1
Classification of Lupus nephritis 
Class
Definition
I
Minimal mesangial LN
II
Mesangial proliferative LN
III
Focal LN (<50% of glomeruli)
III (A)
Active lesions
III (A/C)
Active and chronic lesions
III (C)
Chronic lesions
IV
Diffuse LN (≥50% of glomeruli)
IV (A)
Active lesions
IV (A/C)
Active and chronic lesions
IV (C)
Chronic lesions
V
Membranous LN
VI
Advanced sclerosing LN (≥90% globally sclerosed glomeruli without 
residual activity)
From ACR guidelines (Hahn et al 2012)


Novartis
Confidential
Page 111
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Commercially Confidential Information


Novartis
Confidential
Page 112
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Commercially Confidential Information


Novartis
Confidential
Page 113
Amended Protocol version v04 (Clean)
Protocol No. CCFZ533X2202
Commercially Confidential Information

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
CFZ533 (iscalimab)
Study number CCFZ533X2202
A randomized, placebo-controlled, patient and investigator 
blinded study investigating the safety, tolerability, 
pharmacokinetics and preliminary efficacy of multiple 
doses of CFZ533 in patients with moderately active 
proliferative lupus nephritis
Statistical Analysis Plan (SAP)
ClinicalTrials.gov identifier: NCT03610516
Author(s):
Document type:
SAP Documentation – NIBR 
Document status:
Final – amendment 1
Release date:
18AUG2023
Number of pages:
19
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Personal Protected Data


Novartis
For business use only
Page 2
SAP
CCFZ533X2202
Commercially Confidential Information (CCI)


Novartis
For business use only
Page 3
SAP
CCFZ533X2202
Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................3
1
Introduction .........................................................................................................................5
1.1
Scope of document ..................................................................................................5
1.2
Study reference documentation ...............................................................................5
1.3
Study objectives.......................................................................................................5
1.3.1
Primary Objectives..................................................................................5
1.3.2
Secondary Objectives..............................................................................5
1.3.3
Exploratory Objectives............................................................................5
1.4
Study design and treatment......................................................................................6
2
First interpretable results (FIR) ...........................................................................................8
3
Interim analyses...................................................................................................................9
4
Statistical methods: Analysis sets........................................................................................9
5
Statistical methods for Pharmacokinetic (PK) parameters................................................10
5.1
Variables................................................................................................................10
5.2
Descriptive analyses ..............................................................................................11
5.2.1
Graphical presentation of results...........................................................11
5.3
Pharmacokinetic/pharmacodynamics interactions.................................................12
6
Statistical methods for Pharmacodynamic (PD) parameters.............................................12
6.1
Primary estimand 1................................................................................................12
6.1.1
Definition of primary estimand 1: UPCR .............................................13
6.2
Secondary estimand 1............................................................................................14
6.2.1
Definition of secondary estimand 1: Complete renal remission 
(CRR)....................................................................................................14
6.2.2
Other secondary PD variables...............................................................15
6.3
Exploratory objectives...........................................................................................15
6.3.1
Variables ...............................................................................................15
6.3.2
Descriptive analyses..............................................................................16
7
Statistical methods for safety and tolerability data............................................................16
7.1
Other safety analyses .............................................................................................17
9
Reference list.....................................................................................................................19
List of tables
Table 1-1
Predefined steroid tapering scheme ........................................................8
Commercially Confidential Information


Novartis
For business use only
Page 4
SAP
CCFZ533X2202
Table 4-1
Protocol deviation codes and analysis sets............................................10
Table 6-1
Summary of key estimands...................................................................12


Novartis
For business use only
Page 5
SAP
CCFZ533X2202
1
Introduction 
1.1
Scope of document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CCFZ533X2202” and also 
for the requirements for the interim analyses.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
This Statistical Analysis Plan is based on the protocol version 04 dated 26JUL2021.
1.3
Study objectives
1.3.1
Primary Objectives

To evaluate the safety and tolerability of 24 weeks of treatment with CFZ533 as an add-
on therapy to standard of care in moderately active lupus nephritis (LN) patients.

To assess the effect of CFZ533 on renal proteinuria in moderately active lupus nephritis 
patients after 24 weeks of treatment as an add-on therapy to standard of care as 
compared to placebo.
1.3.2
Secondary Objectives

To assess the effect of CFZ533 on relevant renal outcomes at different time points.

To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of CFZ533 in LN 
patients, after multiple 10 mg/kg IV doses.

To evaluate the immunogenicity of CFZ533 in LN patients, after multiple 10 mg/kg IV 
doses.
1.3.3
Exploratory Objectives
Commercially Confidential Information


Novartis
For business use only
Page 6
SAP
CCFZ533X2202
1.4
Study design and treatment
This is an exploratory, randomized (2:1 active:placebo), subject- and investigator-blind,
placebo-controlled, multicenter study evaluating the safety, tolerability, pharmacokinetics and 
preliminary efficacy of multiple doses of 10 mg/kg CFZ533 administered intravenously (IV) 
in lupus nephritis patients.
The study will randomize approximately 60 subjects with moderately active lupus nephritis. 
The study comprises two periods. The 24-week treatment period will be followed by a 24-
week safety follow-up period (starting on Day 169). The duration of the study (including a 
screening period of up to 4 weeks) for each subject will be approximately 53 weeks. The 
investigational drug or placebo will be administered on top of standard of care therapy for 
lupus nephritis. The randomization will be stratified by baseline daily dose equivalent of 
prednisone (≤10 mg, >10 mg). Patients who do not receive corticosteroids at baseline will be 
included in the ≤10 mg stratum.
Subjects will be screened within 29 days of the first study drug infusion. Eligibility will be 
confirmed at the baseline visit within one week before the first dose. All baseline safety 
evaluation results must be available prior to dosing, and meeting eligibility criteria. Eligible 
subjects will enter the treatment period, and will be randomized at a 2:1 ratio to receive 
treatment with either CFZ533 or placebo. Subjects will receive the intravenous infusion on 
Day 1 within seven days of the baseline visit, followed by PK, PD, and safety assessments 
until one hour after completed infusion.
All infusions will take place in a monitored facility with assessment of vital signs ahead of the 
infusion. Subjects will be discharged 1 hour post-dose following satisfactory review of safety 
data (AE events, vital signs) by the Investigator.
Each patient will come to the study site for the follow-up evaluations on Day 169, Day 197, 
Day 225, Day 253, Day 281, Day 309, and Day 337, respectively. Patients should remain on 
their standard of care therapies. Dose of standard of care (SoC) therapies (see eligibility 
criteria and permitted co-medications) must remain unchanged during the study. However, in 
case of SoC related toxicities, doses of concomitant medications may be adjusted at the 
investigator’s discretion. For patients who are taking corticosteroids at baseline, a predefined 
steroid regimen (Table 1-1) will be implemented including a taper for patients who receive 
more than 10 mg per day at baseline. After Week 17 (Visit 106), patients should not receive a 
steroid dose higher than 10 mg per day (prednisone equivalent).
Safety assessments will include physical examinations, ECGs, vital signs, standard clinical 
laboratory evaluations (also including serum amylase and lipase), hematology (including 
blood coagulation assays), blood chemistry, urinalysis, adverse event, serious adverse event 
and AEs of special interest.
Proteinuria will be assessed using urine samples collected in the patients’ home (first morning 
void sample) and at clinic (clinic spot urine sample)
Commercially Confidential Information


Novartis
For business use only
Page 7
SAP
CCFZ533X2202
PK/PD and immunogenicity assessments at pre-dose, and during treatment and follow up
periods include (i) free CFZ533 in plasma (Ctrough or Cmin, and Cmax in steady state
conditions), total soluble CD40 in plasma, and (iii) anti-CFZ533 antibodies in plasma.
Commercially Confidential Information


Novartis
For business use only
Page 8
SAP
CCFZ533X2202
Table 1-1
Predefined steroid tapering scheme
Figure 1-1
Study design
2
First interpretable results (FIR)
Commercially Confidential Information


Novartis
For business use only
Page 9
SAP
CCFZ533X2202
3
Interim analyses 
4
Statistical methods: Analysis sets
For subjects for which the actual treatment received does not match the randomized treatment 
the treatment actually received will be used for the analysis.
The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with available PK data and no protocol
deviations with relevant impact on PK data.
The PD analysis set will include all subjects with available PD data, and experienced no 
protocol deviations with relevant impact on PD data.
Selected summaries with and without the data obtained after treatment discontinuation may also 
be presented.
The analysis sets and protocol deviation codes are related as follows:
Commercially Confidential Information


Novartis
For business use only
Page 10
SAP
CCFZ533X2202
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PK analysis in case of these PDs: 
Exclude subject from PK 
analysis set 
INCL01
Understand the study procedures and provide 
written informed consent before any study 
related assessment is performed.
INCL04
Histological diagnosis of proliferative lupus 
nephritis World Health Organization (WHO) 
ISN/RPS (Weening et al 2004) Class III or IV 
within 5 years of screening.
Exclude subject from PK 
analysis set
INCL06
First morning void or spot urine UPCR ≥0.5 
mg/mg (56.52 mg/mmol) at Screening visit 
and Baseline visit
Exclude subject from PK 
analysis set
Subjects are excluded from PD analysis in case of these PDs:
Exclude subject from PD 
analysis set
INCL01
Understand the study procedures and provide 
written informed consent before any study 
related assessment is performed.
INCL04
Histological diagnosis of proliferative lupus 
nephritis World Health Organization (WHO) 
ISN/RPS (Weening et al 2004) Class III or IV 
within 5 years of screening.
Exclude subject from PD 
analysis set
INCL06
First morning void or spot urine UPCR ≥0.5 
mg/mg (56.52 mg/mmol) at Screening visit 
and Baseline visit
Exclude subject from PD 
analysis set
Subjects are excluded from PK and PD analysis in case of these 
PDs:
Exclude subject from PK 
and PD analysis sets
INCL01
Understand the study procedures and provide 
written informed consent before any study 
related assessment is performed.
INCL04
Histological diagnosis of proliferative lupus 
nephritis World Health Organization (WHO) 
ISN/RPS (Weening et al 2004) Class III or IV 
within 5 years of screening.
Exclude subject from PK 
and PD analysis sets
INCL06
First morning void or spot urine UPCR ≥0.5 
mg/mg (56.52 mg/mmol) at Screening visit 
and Baseline visit
Exclude subject from PK 
and PD analysis sets
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to
DBL.
5
Statistical methods for Pharmacokinetic (PK) parameters
5.1
Variables 
The following pharmacokinetic parameters will be determined for free CFZ533 in plasma (i) 
Ctrough or Cmin, and Cmax will be directly derived from the bioanalytical data and listings, 
and (ii) AUClast from the last dose at Day 141 will be determined using the actual recorded 


Novartis
For business use only
Page 11
SAP
CCFZ533X2202
sampling times and non-compartmental methods with Phoenix WinNonlin (Version 8.0 or 
higher). The linear trapezoidal rule will be used for AUClast calculation.
The pharmacokinetics of CFZ533 is non-linear and characterized by target-mediated 
disposition where CD40 binding by CFZ533 is leading to CFZ533 elimination (this includes 
receptor-mediated endocytosis by the membrane bound CD40, and subsequent metabolism of 
the CFZ533-CD40 complexes). As such, it is expected that:

The amount of drug-target complex does influence the pharmacokinetics of CFZ533,

Tissue metabolism may have a significant impact on the disposition of CFZ533 (the
volume of distribution will be dependent on clearance),

The volume of distribution may not be accurately inferred from plasma concentration
alone, and the values for the volume of distribution obtained from a non-compartmental
analysis (NCA) may be incorrect,

Volume of distribution and clearance parameters (as inferred from NCA analysis) would 
decrease when the dose increases.
The NCA approach is not appropriate due to violations of the assumptions that the disposition 
of the drug is linear, and that the elimination is from sites that are in rapid equilibrium with 
blood, therefore secondary PK parameters (e.g. clearance, volume of distribution or terminal 
elimination half-life) will not be determined in this study
For each PK and total soluble CD40 samples, the actual recorded sampling time will be 
captured, and the elapsed time since the first and since the last dose before sample collection 
will be calculated. PK samples which are collected +/- 30% of the scheduled post-dose 
timepoint will be excluded from the summary statistics.
5.2
Descriptive analyses
5.2.1
Graphical presentation of results
Arithmetic mean (SD) profiles will be generated along with overlaying individual plasma 
concentration-time profiles and individual plasma concentration-time profiles.
Commercially Confidential Information


Novartis
For business use only
Page 12
SAP
CCFZ533X2202
5.3
Pharmacokinetic/pharmacodynamics interactions
PK/PD analysis (e.g. incl. free CFZ533 and total soluble CD40 in plasma) may be explored
graphically. Modeling of PK/PD data using a population approach may be performed as
appropriate and will be reported if necessary in a separate, standalone modeling and
simulation report.
6
Statistical methods for Pharmacodynamic (PD) parameters
Baseline is defined as the last available value prior to dosing and will include Screening if no 
other value after Screening is available.
For UPCR and UACR where the analyses are split between first morning void and clinic spot 
samples then the last available value prior to dosing from the first morning void or clinic spot 
sample respectively will be used. For the analyses that use the first morning void when available 
and the clinic spot sample if it is not available then the last available first morning void prior to 
dosing will be used as the baseline, if there are no first morning void values available prior to 
dosing then the last available clinic spot sample prior to dosing will be used as the baseline for 
these analyses.
Summary of key estimands for efficacy
Estimands are defined for this trial to address the efficacy objectives of the trial and to provide 
supportive evidence for those objectives. These estimands are defined in detail in the subsequent 
sections and are summarized in Table 6-1. The analysis for other safety/efficacy/PK data are 
described in other sections of this SAP.
Table 6-1
Summary of key estimands
Estimand
Variable estimand is 
based on
Section
P1
Primary 1 – renal 
proteinuria
Ratio from baseline in 
urinary protein
creatinine ratio (UPCR) 
at Week 25
6.1
S2
Secondary 1 - renal
Proportion with 
complete renal 
remission (CRR)
6.2
6.1
Primary estimand 1
The primary estimand 1 addresses the second primary objective:

To assess the effect of CFZ533 on renal proteinuria in moderately active lupus nephritis 
patients after 24 weeks of treatment as an add-on therapy to standard of care as compared 
to placebo.
This estimand addresses the scientific question of whether treatment with CFZ533 reduces 
UPCR in moderately active lupus nephritis patients after 24 weeks of treatment without death, 
rescue medication and treatment discontinuation as an add-on therapy to standard of care.


Novartis
For business use only
Page 13
SAP
CCFZ533X2202
6.1.1
Definition of primary estimand 1: UPCR

Population: moderately active proliferative lupus nephritis patients.

Variable: Ratio from baseline in UPCR at Week 25

Treatment: CFZ+SOC, Placebo+SOC

Summary Measure: Ratio of Geometric Means of CFZ533 versus placebo.
Hypothetical strategy will be used to deal with death, rescue medication and treatment 
discontinuation inter-current events. Data from patients taking rescue medication during the 
trial (or failing to tolerate steroid taper, for patients receiving oral corticosteroid at baseline) 
will be excluded from the date of rescue medication intake or failure of the steroid taper. Data 
from patients who discontinue study treatment will also be excluded, from the date of study 
drug discontinuation. A medical assessment prior to database lock will determine which 
patients are deemed to have failed the steroid taper based on clinical relevance of the steroid 
dose taken and the potential impact on the primary endpoint.
No other inter-current events will be taken into account in the estimand.
Statistical analysis model
The ratio from baseline in UPCR will be log transformed prior to the analysis. A repeated 
measures model will be fitted with factors for treatment group (CFZ533 or placebo) and visit 
(e.g. Week 5, 9, 13 etc.). The model will also include a factor for the prednisone dose-equivalent 
at baseline (≤10 mg, >10 mg) based on the concomitant medication information in the database 
rather than the stratification factor from the randomization. Log-transformed baseline UPCR 
will be included in the model as a covariate along with the interactions between visit and all of 
the fixed effects and the log-transformed baseline by visit interaction. A normal errors model 
will be assumed with an unstructured covariance matrix to account for the correlation within
subjects. The model will be estimated using maximum likelihood techniques. If there are values 
of 0 then 0.1 will be added to all the UPCR data prior to the log transformation.
At each of the visits, the difference between the CFZ533 and placebo group will be estimated
(along with its corresponding 95% confidence interval) and then back-transformed to provide
an estimate of the ratio between treatment groups.
Sensitivity analyses will be considered if a substantial proportion of patients (i.e. more than 
15%) receive rescue medicine or discontinue from study treatment. Multiple imputation models 
may be used to assess the robustness of the missing at random assumption of the primary 
analysis.
In addition if more than 15% of patients fail to tolerate the steroid taper scheme, a supportive 
analysis of efficacy using time to lack of taper as endpoint will be conducted. Additional 
analyses including all patients regardless of their adherence to treatment will be performed.
The adequacy of the model will be assessed by inspecting residual plots.
Commercially Confidential Information


Novartis
For business use only
Page 14
SAP
CCFZ533X2202
Data will be listed by treatment and timepoint. Descriptive summary statistics will include 
mean (arithmetic and geometric), SD, and CV (arithmetic and geometric), median, minimum 
and maximum and will be presented by treatment and timepoint. Outputs will be provided for 
the raw UPCR values and also the ratio from baseline. An additional summary will also be 
provided by baseline steroid dose and also for subjects with biopsies within 2 years prior to 
randomization and 5 years prior to randomization separately.
Geometric mean (95% CI) of ratio from baseline profiles will be presented along with geometric 
mean ratio to placebo profiles. These figures will use the data obtained from the above model.
Additional profiles of geometric mean (SE) UPCR data will presented based on the raw data.
For these plots the data will be log transformed and the mean and standard error calculated, the 
standard error will be added/subtracted from the mean on the log scale and then back 
transformed to obtain the error bars for the plot.
The above outputs will also cover the outputs needed for the secondary objective to assess 
UPCR at different timepoints.
The above analyses will also be repeated using only the data from the first morning void and 
clinic spot sample separately.
6.2
Secondary estimand 1
The secondary estimand 1 addresses the secondary objective:

To assess the effect of CFZ533 on relevant renal outcomes at different time points.
This estimand addresses the scientific question of whether treatment with CFZ533 has a 
beneficial effect on renal outcomes at different timepoints without death, rescue medication and 
treatment discontinuation as an add-on therapy to standard of care.
6.2.1
Definition of secondary estimand 1: Complete renal remission (CRR)

Population: moderately active proliferative lupus nephritis 

Variable: CRR at post dose timepoints

Treatment: CFZ+SOC, Placebo+SOC

Measure of intervention effect: Proportion of CFZ533 patients with CRR at post dose 
timepoints 
CRR at a timepoint is defined as having UPCR ≤0.2 mg/mg as well as eGFR within 25% of 
baseline value and normal urine sediment. If a subject died, received rescue medication or 
discontinued from treatment then they will analyzed as not having CRR from the timepoint of 
the event. CRR status will be assessed using first morning void if available and if not then 
using the clinic spot sample.
Analysis
The proportion of patients fulfilling the definition of complete renal remission will be
summarized by treatment and visit and displayed graphically in barcharts.
Composite strategy will be used to deal with death, rescue medication and treatment 
discontinuation inter-current events. If a subject died, received rescue medication or 
discontinued from treatment then they will be analyzed as not having CRR.


Novartis
For business use only
Page 15
SAP
CCFZ533X2202
No other inter-current events will be taken into account in the estimand.
Additional analyses will be performed considering the first morning void and clinic spot 
samples separately.
6.2.2
Other secondary PD variables
For other secondary PD variables (UACR, total soluble CD40 in plasma, hematuria and cellular 
casts) data will be listed together with changes from baseline (ratio to baseline for UACR and 
total soluble CD40 in plasma) by treatment, subject, and visit/sampling time point. For 
hematuria and cellular cast data only positive results are reported therefore if a result was 
negative at baseline the baseline value will be imputed as 0.
Descriptive summary statistics will be provided by treatment and visit/sampling time point. 
Summary statistics will include mean, SD, CV, median, minimum and maximum. Geometric 
statistics will also be presented for UACR and total soluble CD40 in plasma. Mean (SD) profile 
plots (geometric mean and SE for UACR and total soluble CD40 in plasma) will be generated.
For UACR outputs will be separated out by first morning void separately, clinic spot sample 
separately and using first morning void if available and if not then using the clinic spot sample.
6.3
Exploratory objectives
6.3.1
Variables 
Commercially Confidential Information


Novartis
For business use only
Page 16
SAP
CCFZ533X2202
6.3.2
Descriptive analyses
7
Statistical methods for safety and tolerability data
Baseline is defined as the last available value prior to dosing and will include Screening if no 
other value after Screening is available.
All information obtained on adverse events will be displayed by treatment and subject.
Adverse events of special interest (AESI) are defined as any of the following adverse events:
Statistical analyses comparing the event rates of AESI’s and SAE’s in the two treatment groups 
will be performed using a Cochran Mantel-Haenszel test stratified by prednisone dose-
equivalent at baseline (≤10 mg, >10 mg).
If any abnormalities occur for a subject then all their vital signs data will be listed by treatment, 
subject, and visit/time and abnormalities (and relevant orthostatic changes) will be flagged. 
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
For business use only
Page 17
SAP
CCFZ533X2202
Summary statistics will be provided by treatment and visit/time. Abnormalities will be defined 
as values outside of the below ranges:
If any abnormalities occur for a subject then all their ECG data will be listed by treatment, 
subject and visit/time and abnormalities will be flagged. Summary statistics will be provided 
by treatment and visit/time. The criteria for abnormalities are detailed below:
ECG Parameter
Clinically Notable Criteria
PR
PR > 200 msec and increase by more than 20 msec from baseline
QRS
QRS complex > 120 msec
QTcF
Males: QTcF > 450 msec and increase of 30 msec or more from baseline
Females: QTcF > 460 msec and increase of 30 msec or more from baseline
If any abnormalities (data outside of reference range) occur for a subject then all their laboratory 
data for that parameter will be listed by treatment, subject, and visit/time and abnormalities will 
be flagged. A separate listing is provided presenting all parameters in a subject with any 
abnormal values. Summary statistics will be provided by treatment and visit/time.
Boxplots will be provided for vitals signs, ECG and lab data.
7.1
Other safety analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and subject. 
Summary statistics will be provided by treatment group.
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 if any 
abnormalities/positive result drug test occur.
Treatment
Data for study drug administration (rescue medication) and concomitant therapies will be listed 
by treatment group and subject.
Vital Sign Parameter
Reference Range
Systolic Blood Pressure
90-139 mmHg
Diastolic Blood Pressure
50-89 mmHg
Pulse Rate
45-90 bpm
Body Temperature
35.0-37.5 ºC


Novartis
For business use only
Page 18
SAP
CCFZ533X2202
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on <on-
treatment/treatment emergent> adverse events which are not serious adverse events with an 
incidence greater than X% and on <on-treatment/treatment emergent> serious adverse events 
and SAE suspected to be related to study treatment will be provided by system organ class and 
preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
Quantiferon Test
Quantiferon test data collected will be listed by treatment, patient and visit/time if positive 
results occur
Immunogenicity
All immunogenicity results will be listed by subject and visit/time and summarized by treatment 
and timepoint.
Commercially Confidential Information


Novartis
For business use only
Page 19
SAP
CCFZ533X2202
9
Reference list
Commercially Confidential Information
Commercially Confidential Information