Conditions: Kidney Transplantation
Keywords: renal, de novo,
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 59
Healthy volunteers: no

Brief summary:
The purpose of this study was to investigate the safety, tolerability, pharmacokinetics (PK) and potential for CFZ533 to replace calcineurin inhibitors (CNI), while providing a similar rate of acute rejection prophylaxis and renal function in a de novo renal transplant population receiving an allograft from standard criteria donors.

Detailed description:

Arms:
arm 1: CFZ533 administered with the contemporary standard of care (SoC) consists of concentration-controlled tacrolimus (Tac), combined with mycophenolate mofetil (MMF) and corticosteroids (CS). arm 2: CFZ533 administered with mycophenolate mofetil (MMF) and corticosteroids (CS) with anti-IL2 induction arm 3: Standard of care (SoC) \[concentration-controlled tacrolimus (Tac) combined with mycophenolate mofetil (MMF) and corticosteroids (CS) with anti-IL2 induction\]

Interventions: intervention 1: CFZ533 intervention 2: Tacrolimus (Tac) intervention 3: Mycophenolate mofetil (MMF) intervention 4: Corticosteroids (CS) intervention 5: anti-IL2 Induction
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol document:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
CFZ533
Clinical Trial Protocol CCFZ533X2201
A 12-month randomized, multiple dose, open-label,
studyevaluating safety, tolerability, 
pharmacokinetics/pharmacodynamics (PK/PD) and efficacy 
of an anti-CD40 monoclonal antibody, CFZ533, 
incombination with mycophenolate mofetil (MMF) and 
corticosteroids (CS), with and without tacrolimus (Tac), 
indenovorenal transplant recipients
Document type:
Amended Protocol Version
EUDRACT number
2015-000925-36
Version number:
v03(Clean)
Study phase:
II
Release date:
20-Sep-2017
Personal Data
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Notification of serious adverse events
A serious adverse event (SAE) is any event which is fatal or life-threatening, which requires 
or prolongs hospitalization, which is significantly or permanently disabling or incapacitating, 
which constitutes a congenital anomaly or a birth defect, or which is medically significant, 
may jeopardize the subject and may require medical or surgicalintervention to prevent one of 
the outcomes listed above.
Any SAEoccurring in a subject from consent until 3 months after his/her last dose of CFZ533
or 2 months after the end of study visit for patients on standard of care treatment must be 
reported either on the paper SAE report form or via the electronic SAE form within the 
clinical data capture system (where available).
For SAEs reported using the paper SAE report form, the Investigator will ensure that the form 
is completed and faxed by the Investigator to the local Novartis Drug Safety and 
Epidemiology Department within 24 hours of learning of the occurrence of the SAE even if 
the SAE does not appear to be drug-related. The original SAE form, together with the fax 
confirmation sheet, must be kept with the case report forms at the study site.
For SAEs recorded electronicallyin the Novartis clinical data capture system, information 
should be entered, saved and e-signed within 24 hours of awareness of the SAE. Thesedata 
will automatically be submitted to Novartis Chief Medical Office and Patient Safety 
Department.
More details in Section 7
Personal Data
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Table of contents
Notification of serious adverse events.................................................................................2
Table of contents.................................................................................................................4
List of tables........................................................................................................................8
List of figures......................................................................................................................8
List of abbreviations............................................................................................................9
Pharmacokinetic definitions and symbols.........................................................................14
Glossary of terms...............................................................................................................15
Protocol synopsis...............................................................................................................24
Assessment schedule –Part 1............................................................................................28
Assessment schedule –Part 2............................................................................................29
1 Introduction.......................................................................................................................32
1.1
Background............................................................................................................32
1.1.1
CD40/CD40L co-stimulation: a target for transplantation....................33
1.1.2
CFZ533: mechanism of action..............................................................34
1.2
Study purpose........................................................................................................45
2 Study objectives.................................................................................................................46
2.1
Study Part 1: PK, PD and Safety...........................................................................46
2.1.1
Primary objective..................................................................................46
2.1.2
Secondary objectives.............................................................................46
2.2
Study Part 2: CNI-free Proof-of-Concept..............................................................46
2.2.1
Primary objective..................................................................................46
2.2.2
Secondary objectives.............................................................................46
3 Investigational plan...........................................................................................................47
3.1
Study design...........................................................................................................47
3.1.1
General overview..................................................................................47
3.1.2
All cohorts.............................................................................................49
3.1.3
Part 1 –Arm 1.......................................................................................50
3.1.4
Part 2 –Arms 2A-2B.............................................................................51
3.2
Rationale for study design.....................................................................................52
3.3
Rationale for dose/regimen, duration of treatment................................................
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3.4 
Rationale for choice of comparator.......................................................................58
3.6
Risks and benefits..................................................................................................58
3.6.1
CFZ533.................................................................................................59
3.6.2 
Adjunct immunosuppression.................................................................61
3.6.3
Risk mitigation strategy........................................................................61
4 Population..........................................................................................................................63
4.1
Inclusion criteria....................................................................................................64
4.2
Exclusion criteria...................................................................................................64
5 Treatment...........................................................................................................................66
5.1 
Protocol requested treatment.................................................................................66
5.1.1
Investigational treatment.......................................................................66
5.1.2
Control and concomitant drugs.............................................................66
5.1.3
Additional study treatment....................................................................66
5.2
Treatment arms......................................................................................................66
5.3
Treatment assignment............................................................................................67
5.4
Treatment blinding.................................................................................................67
5.5
Treating the subject................................................................................................67
5.5.1
Subject numbering................................................................................67
5.5.2
Dispensing the study treatment.............................................................68
5.5.3
Handling of study treatment..................................................................68
5.5.4
Instructions for prescribing and taking study treatment........................69
5.5.5
Permitted dose adjustments and interruptions of study treatment........72
5.5.6
Recommended treatment of adverse events..........................................74
5.5.7 
Rescue medication................................................................................74
5.5.8
Concomitant treatment..........................................................................74
5.5.9
Prohibited treatment..............................................................................75
5.5.10
Discontinuation of study treatment and premature subject 
withdrawal.............................................................................................75
5.5.11
Withdrawal of consent ..........................................................................78
5.5.12
Loss to follow-up..................................................................................78
5.5.13
Replacement of early withdrawals or discontinuations........................78
5.5.14
Emergency unblinding of treatment assignment...................................78
5.5.15
Study completion and post-study treatment..........................................78
5.5.16
Early study termination.........................................................................79
6 Visit assessments...............................................................................................................
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6.1
Dietary, fluid and other restrictions.......................................................................79
6.2
Information to be collected on screening failures..................................................80
6.3 
Subject demographics/other baseline characteristics.............................................80
6.4
Treatment exposure and compliance.....................................................................80
6.5
Efficacy / Pharmacodynamic assessments.............................................................81
6.5.1
Efficacy assessments.............................................................................81
6.5.2
Pharmacodynamic assessments.............................................................82
6.6
Safety assessments.................................................................................................83
6.6.1
Physical examination............................................................................83
6.6.2
Vital signs..............................................................................................83
6.6.3
Height and weight.................................................................................84
6.6.4
Laboratory evaluations..........................................................................84
6.6.5
Electrocardiogram (ECG).....................................................................86
6.6.6
Pregnancy..............................................................................................87
6.6.7
Tuberculosis surveillance......................................................................87
6.7
Pharmacokinetic assessments................................................................................87
6.7.1
PK Blood collection and processing.....................................................87
6.7.2
Pharmacokinetic analytical methods.....................................................87
6.7.3
Pharmacokinetic parameters.................................................................87
6.8
Other assessments..................................................................................................88
7 Safety monitoring..............................................................................................................89
7.1
Adverse events.......................................................................................................89
7.2
Serious adverse event reporting.............................................................................91
7.3
Pregnancy reporting...............................................................................................92
7.4
Early phase safety monitoring...............................................................................92
8 Data review and database management.............................................................................93
8.1
Site monitoring......................................................................................................93
8.2 
Data collection.......................................................................................................93
8.3
Database management and quality control............................................................94
8.4
Data MonitoringCommittee..................................................................................94
8.5
Adjudication Committee........................................................................................95
9 Data analysis......................................................................................................................95
9.1
Analysis sets..........................................................................................................
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9.2 
Subject demographics and other baseline characteristics......................................95
9.3
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................96
9.3.1
Study medication...................................................................................96
9.3.2
Concomitant immunosuppressants........................................................96
9.3.3
Other co-medications............................................................................96
9.4
Analysis of the primary variable(s).......................................................................96
9.4.1
Variable(s).............................................................................................96
9.4.2
Statistical model, hypothesis, and method of analysis..........................97
9.4.3
Supportive analyses...............................................................................98
9.5
Analysis of secondary and exploratory variables..................................................98
9.5.1
Efficacy.................................................................................................98
9.5.2
Pharmacodynamics...............................................................................98
9.5.3
Safety.....................................................................................................99
9.5.4
Model based dose-exposure response analysis...................................102
9.5.5
Pharmacokinetics................................................................................102
9.5.6
Pharmacokinetic / pharmacodynamic interactions..............................102
9.6 
Sample size calculation........................................................................................104
9.7
Power for analysis of key secondary variables....................................................107
10 Ethical considerations......................................................................................................108
10.1 Regulatory and ethical compliance......................................................................108
10.2 Informed consent procedures...............................................................................108
10.3 Responsibilities of the investigator and IRB/IEC................................................109
10.4 Publication of study protocol and results.............................................................109
11 Protocol adherence..........................................................................................................110
11.1 Protocol Amendments.........................................................................................110
12 References.......................................................................................................................111
13 Appendix 1: SampleLog table –all matrices.................................................................114
14 Appendix 2: US-Specific CellCept(R) Pregnancy and Safety Information....................118
15 Appendix 3: Stopping rules.............................................................................................120
16 Appendix 4: Guidelines for MMF dose reduction..........................................................121
17 Appendix 5: Tacrolimus drug-drug interactions.............................................................122
18 Appendix 6: Blinding and unblinding.............................................................................
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19 Appendix 7: Clinically notable laboratory values...........................................................126
20 Appendix 8: Banff ’09 Meeting Report: Antibody Mediated Graft Deterioration and 
Implementation of Banff Working Groups 
1...................................................................127
List of tables
Table 5-1
Study stopping rules for tBPAR............................................................76
Table 9-1
Summary of historical controldata.....................................................106
Table 9-2
Two-sided 80 and 95 percent example CIs for between-treatment 
difference (CFZ533-Control regimen) of calculated eGFR 
(MDRD), assuming dropout rate = 30 percent (n = 53/group)...........107
Table 14-1
Acceptable Contraception Methods for Females of Reproductive 
Potential*.............................................................................................119
Table 18-1
Blinding levels....................................................................................125
List of figures
Figure 1-1 
Roles of CD40-CD154signaling in the T and B cell............................33
Figure 3-1
CFZ533X2201 Study design.................................................................48
Figure 3-2
Part 1 Design.........................................................................................50
Figure 9-1
Probability of stopping a cohort for various true tBPAR rates...........104
Figure 9-2
Probability of progressing for different true values of tBPAR for 
CFZ533 and control............................................................................105
Figure 9-3
Results of Bayesian meta-analysis prediction.....................................
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Cor
orat
e 
Conf
ident
ial 
Infor
mati
on
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List of abbreviations
AC
Adjudication Committee
ADCC
antibody-dependent cell-mediated cytotoxicity
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANCOVA
analysis of covariance
APC
antigen presenting cell
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATC
American Transplant Congress
b.i.d.
twice a day
BMI
Body Mass Index
BPAR
biopsy-proven acute rejection
BUN
blood urea nitrogen
CDC
complement-dependent lymphocytotoxic
CD-ROM
compact disc – read only memory
CFR
Code of Federal Regulation
CKD
Chronic Kidney Disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration Equation
CI
confidence interval
CIT
cold ischemic time
CK
creatinine kinase
CMO&PS 
Chief Medical Office & Patient Safety
CMV
cytomegalovirus
CNI
calcineurin inhibitor
CO2
carbon dioxide
CPO
Country Pharma Organization
CRF
Case Report/Record Form
CRO
Contract Research Organization


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CV
coefficient of variation
CYP3A4
cytochrome P450 3A4
DBL
database lock
DGF
delayed graft function
DMC
Data Monitoring Committee
DS&E
Drug Safety & Epidemiology
DSA
Donor specific antibodies
EBV
Epstein-Barr virus
EC
Ethics committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eGFR
estimated GFR
ELISA
Enzyme-linked immunosorbent assay
EOS
end of study
EOT
end of treatment
FAS
full analysis set
FDA
Food and Drug Administration
GC
Germinal center
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GI
gastrointestinal
γ-GT
Gamma-glutamyl transferase
h
hour
HbA1c
glycosylated hemoglobin
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIGM
Hyper-Immunoglobulin M Syndrome
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
NHP
non human primates
HR
heart rate


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HUVEC
Human umbilical vein endothelial cells
IA
Interim Analysis
IB
Investigator Brochure
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
INN
International Nonproprietary Name 
IRB
Institutional Review Board
IRT
Interactive Response Technology
IS
immunosuppressant
ITT
intent-to-treat
IV
intravenous
KLH
keyhole limpet hemocyanin
LDH
lactate dehydrogenase
LLQ
lower limit of quantification
LLN
lower limit of normal
MABEL
minimal anticipated biological effect level
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram(s)
ml
milliliter(s)
MMF
mycophenolate mofetil
MPA
mycophenolic acid
NHP
Non human primate
NI
non-inferiority
NOAEL
no observed adverse effect level
NODAT
new onset diabetes mellitus after transplantation
o.d.
once a day
PA
posteroanterior
PAD
pharmacologically active dose
PBMC
peripheral blood mononuclear cells
PCP
Pneumocystis jiroveci pneumonia


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PCR
polymerase chain reaction
PD
pharmacodynamic(s)
PI
package insert
PK
pharmacokinetic(s)
p.o.
oral
PoC
Proof of Concept
PP
per-protocol
PRA
panel reactive antibodies
PTLD
post-transplant lymphoproliferative disease
RA
Rheumatoide Arthritis
RBC
red blood cell(s)
RDC
remote data capture
REB
Research Ethics Board
RO
receptor occupancy
SA
surface area (1.73 square meters)
SAE
serious adverse event
SC
subcutaneous
SCD
standard criteria donor
SD
single-dose
sCD40
soluble CD40
sCD40L
soluble CD40 ligand (or soluble CD154)
SD
standard deviation
SMQ
standardized MedDRA query
SoC
standard of care
SOC
system organ class
Tac
tacrolimus 
TBL
total bilirubin
TDAR
T cell dependent antibody response
tBPAR
treated biopsy-proven acute rejections
TPDI
Therapeutic Protein Drug Interactions
UCL
upper confidence limit
ULN
upper limit of normal


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ULQ
upper limit of quantification
WBC
white blood cell(s)


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Pharmacokinetic definitions and symbols
AUC0-t
The area under the plasma concentration-time curve from time zero to time 
‘t’ where t is a defined time point after administration [µg*day/mL]
AUCinf
The area under the plasma concentration-time curve from time zero to 
infinity [µg*day/mL]
AUClast
The area under the plasma concentration-time curve from time zero to the 
time of the last quantifiable concentration [µg*day/mL]
AUCtau
The area under the plasma concentration-time curve from time zero to the 
end of the dosing interval tau [µg*day/mL]
AUCtau,ss
The area under the plasma concentration-time curve from time zero to the 
end of the dosing interval tau at steady state [µg*day/mL]
Cav,ss
The average steady state plasma concentration during multiple dosing
Cmax
The observed maximum plasma concentration following drug administration 
[µg/mL]
Cmax,ss
The observed maximum plasma concentration following drug administration 
at steady state [µg/mL]
Cmin,ss
The lowest plasma concentration observed during a dosing interval at steady 
state [µg/mL]
CL
The systemic clearance from plasma following intravenous administration 
[mL/day]
CL/F
The apparent systemic clearance from plasma (or serum or blood) following 
extravascular administration [mL/day]
F
Bioavailability of a compound. Fabs is the absolute bioavailability, i.e., the 
fraction (or percentage) of the administered extravascular dose systemically 
available. 
T1/2
The terminal elimination half-life [day]
Tmax
The time to reach the maximum concentration after drug administration [day]
Vz
The volume of distribution during the terminal elimination phase following 
intravenous administration [mL]
Vz/F
The apparent volume of distribution during the terminal elimination phase 
following extravascular administration [mL]
Vss
The volume of distribution at steady state following intravenous 
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Glossary of terms
Assessment
A procedure used to generate data required by the study.
Control drug
A study drug used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal 
study validity, and/or evaluate comparative effects of the 
investigational drug.
Enrollment
Point/time of subject entry into the study; the point at which 
informed consent must be obtained (i.e., prior to starting any 
of the procedures described in the protocol).
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 is synonymous with “investigational new drug” or 
“investigational medicinal product”.
Investigational treatment
All investigational drug(s) whose properties are being tested 
in the study as well as their associated treatment controls.
This includes any placebos, any active controls, as well as 
approved drugs used outside of their indication/approved 
dosage or tested in a fixed combination.
Investigational treatment generally does not include other 
treatments administered as concomitant background therapy 
required or allowed by the protocol when used within 
approved indication/dosage. 
Medication number
A unique identifier on the label of each study drug package in 
studies that dispense study drug using an IRT system.
Subject number
A number assigned to each subject who enrolls in the study. 
When combined with the center number, a unique identifier is 
created for each subject in the study.
Period
A minor subdivision of the study timeline; divides phases into 
smaller functional segments such as screening, baseline, 
titration, washout, etc.
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the 
planned completion of all study assessments.
Randomization number
A unique identifier assigned to each randomized subject, 
corresponding to a specific treatment arm assignment.
Stage
A major subdivision of the study timeline; begins and ends 
with 
major 
study 
milestones 
such 
as 
enrollment, 
randomization, completion of treatment, etc.
Study completion
Point/time at which the subject came in for a final evaluation 


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visit.
Study drug/treatment
Any drug (or combination of drugs) administered to the 
subject as part of the required study procedures; includes 
investigational drug, active drug run-ins or background 
therapy: CFZ533 + tacrolimus and CFZ533 + mycophenolate 
mofetil
Study drug discontinuation
Point/time when subject permanently stops taking study drug 
(any component of the regimen) for any reason.
Subject
An individual who has consented to participate in this study. 
The term Subject may be used to describe either a healthy 
volunteer or a patient.
Variable
Information used in the data analysis; derived directly or 
indirectly from data collected using specified assessments at 
specified time-points.


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Protocol synopsis
Protocol number
CCFZ533X2201
Title
A 12-month randomized, multiple dose, open-label, study evaluating safety, 
tolerability, pharmacokinetics/pharmacodynamics (PK/PD) and efficacy of an 
anti-CD40 monoclonal antibody, CFZ533, in combination with mycophenolate 
mofetil (MMF) and corticosteroids (CS), with and without tacrolimus (Tac), in 
de novo renal transplant recipients
Brief title
Efficacy and safety study of CFZ533 in kidney transplant patients 
Sponsor and Clinical 
Phase
Novartis
Phase II
Investigation type
Drug (biologic)
Study type
Interventional 
Purpose and 
rationale
The purpose of this adaptive, two-part study is to investigate the potential for 
CFZ533 to replace calcineurin inhibitors (CNI), while providing a similar rate 
of acute rejection prophylaxis and better renal function in a de novo renal 
transplant population receiving an allograft from standard criteria donors.. 
Part 1 of this trial will focus on profiling the multiple dose pharmacokinetics 
(PK), pharmacodynamics (PD) and tolerability for both IV and SC CFZ533 
administration 
in 
the 
setting 
of 
standard-of-care, 
CNI-based 
immunosuppression. 
Part 2 will evaluate the safety and efficacy of CFZ533 in the absence of a 
CNI in combination with adjunct MMF and basiliximab induction therapy for 
up to 12 months.
Overall, results of this study will be used to inform the CFZ533 dose and 
regimen selection for investigation in the next phase of clinical development.
Primary Objectives

Part 1: PK, PD and Safety

To assess the safety, tolerability and pharmacokinetics of multiple IV 
and SC doses of CFZ533 in combination with MMF, CS, and Tac 
(standard exposure) in de novo renal transplant patients over the 
treatment and follow-up period

Part 2: CNI-free Proof-of-Concept

To assess the potential for CFZ533 to act as the primary 
immunosuppressant in a CNI-free regimen with MMF in de novo
renal transplant patients as assessed by tBPAR at Month 3 post-
transplantation
Secondary 
Objectives

Part 1: PK, PD and Safety

To quantify the magnitude and duration of peripheral blood CD40 
occupancy (free CD40 and total CD40 on B cells) 

To quantify the change from baseline and recovery of peripheral 
blood total soluble CD40 and total soluble CD154 

To evaluate the immunogenicity of CFZ533 via the quantitative 
analysis of anti-CFZ533 antibodies

Part 2: CNI-free Proof-of-Concept

To assess the safety and tolerability of CFZ533 administered 
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a control
To assess the pharmacokinetics of multiple  IV   doses of CFZ533 
during the 12-month treatment period
To quantify the magnitude and duration of peripheral blood CD40 
occupancy (free CD40 and total CD40 on B cells) during the 
treatment period following multiple IV doses of CFZ533
To compare renal function in CFZ533 treatment arms to control at 
Month 3 post-transplantation as assessed by:
Estimated GFR using MDRD
Proportion of patients with eGFR <60 mL/min/1.73m2  
Proportion of patients with negative eGFR slope  
To evaluatethe immunogenicity of multiple IV doses of CFZ533 via 
the quantitative analysis of anti-CFZ533 antibodies
To quantify the change from baseline and recovery of peripheral 
blood total soluble CD40 during the treatment period following 
multiple IV doses of CFZ533
Study design
A randomized, two-part, 6-or 12-month, sequential, adaptive, controlled, 
open-label, multicenter, clinical proof-of-concept study to evaluate the 
efficacy, safety, tolerability, PK and PD of CFZ533 + MMF + CS, with 
standard exposure (Part 1) or no tacrolimus (Part 2,), for initial and 
maintenance prophylaxis of organ rejection in adult de novorenal transplant 
recipients as compared to standard of care.
Part 1 (PK, PD and Safety): For Arm 1, 6 patients total will be enrolled to 
receive IV induction (Day 1) and SC administration on Days 15, 29, 43 and 
71 of 3 mg/kg CFZ533 with standard-exposure tacrolimus (whole blood 
trough concentration 4-11 ng/mL), MMF and CS.
All patients enrolled into Part 1 will remain on SoC until Month 6 (EOS).
Part 2 (CNI-free PoC): Following 2:1 randomization, 45 patients will be 
enrolled in Arms 2A and 2B in a parallel manner. Arm 2A will receivemultiple 
intravenous CFZ533 10 mg/kg doses with basiliximab induction, MMF and 
CS; Arm 2B (control) will receive standard-exposure tacrolimus (whole blood 
trough concentration 4-11 ng/mL) with basiliximab induction, MMF and CS.
Population
de novoadult renal transplant patients
Inclusion criteria
(key)
Written informed consent
Male or femalepatients ≥ 18 years old
Recipients of a transplant from a heart-beating deceased, living unrelated 
or non-human leukocyte antigen (HLA) identical living related donor
Recipients of a kidney with a cold ischemia time (CIT) < 30 hours
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Exclusion criteria 
(key)

Multi-organ transplant recipients

Recipient of an organ from a non-heart beating donor 

ABO incompatible allograft or complement-dependent lymphocytotoxic 
(CDC) cross-match positive transplant

Receipt of a second kidney allograft, unless the first allograft was lost due 
to surgical complication

High immunological risk for rejection as determined by local practice for 
assessment of anti-donor reactivity (e.g., high panel reactive antibodies 
(PRA) > 20%, presence of pre-existing donor-specific antibodies (DSA))

At risk for tuberculosis (TB)

Anti-HIV positive, HBsAg-positive or anti-HCV positive

EBV negative (in Part 1 only)

History of coagulopathy or medical condition requiring long-term 
anticoagulation which would preclude renal biopsy after transplantation

Active infection

Pregnant or nursing (lactating) women

Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective 
methods of contraception during dosing and for 12 weeks after the study 
medications have been stopped
Investigational and 
reference therapy
Part 1

Arm 1, n=6: CFZ533 at 3.0 mg/kg SC (5 doses; first dose is IV, SC on 
Days 15, 29, 43 and 71) + tacrolimus (4-11 ng/mL) + MMF 1.0 g BID + CS
Part 2 

Arm 2A, n=30: Basiliximab 20 mg (Days 1, 4) + CFZ533 at 10 mg/kg IV 
(17 doses) + MMF 1.0 g BID + CS

Arm 2B Control/Standard of Care, n=15: Basiliximab 20 mg (Days 1, 4) 
+ tacrolimus (4-11 ng/mL) + MMF 1.0 g BID + CS
Concomitant treatments

CMV, PCP, HBV & BK virus prophylaxis

Oral Candida treatment
Efficacy 
assessments
Treated biopsy proven acute rejection (tBPAR), graft loss, death, estimated 
GFR 


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Safety assessments
Renal function
Adverse and serious adverse events
Infections 
Cytokines
Donor specific antibodies 
NODAT
EBV, CMV and BK virus and tuberculosis surveillance
Viral serology
Immunogenicity
ECG
Vital signs
Clinical labs
Other assessments
Pharmacokinetics: 
Free CFZ533 in plasma
Tac trough levels
MPA trough levels
Soluble CD40 and soluble CD154 in plasma
Graft survival
Patient survival
Lymph node / tissue biopsy
Data analysis
Part 1
Posterior probabilities of the tBPAR rates for the treatment regimen above 
various thresholds such as 10%, 15%, 20%, 25% will be presented as: 
Pr (θCFZ533≥ T | data) for T=0.1, 0.15, 0.2, 0.25. 
assuminga non-informative neutral prior of Beta(1/3, 1/3).
Part 2
The efficacy analysis for the first 3 months of Part 2 considers whether the 
CFZ533 treatment arm meets the pre-defined criteria forPoC declaration: Pr 
(θCFZ5331–θSoC<0.20 | data) > 60%
The required posterior probabilities will be estimated from simulations of the 
posterior distributions of θCFZ533–θSoCand compared to the thresholds for the 
levels of proof.
Key words
Safety, efficacy, pharmacokinetics, pharmacodynamics, CFZ533, de novo
renal transplant patientsCNI-free immunosuppression, CD40,B cells
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Assessment schedule –Part 1
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Assessment schedule –Part 2 
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Assessment schedule –Footnotes and Legend
X = assessment for all subjects in study regardless of on-or off-randomized study regimen, to be recorded in clinical database.
A = assessment ONLY for subjects maintaining their randomized study regimen, to be recorded in clinical database.
S = assessment to be recorded on source documentation.
m= minute; h =  hour; d = day;  EOT = End of Treatment; Study Month = 28 days;
# = only need to be performed once in a 12-hour period if Screening, Baseline and Day 1 occur in close proximity. 
(1) Informed consent should be obtained prior to performing any study-related procedures.
(2) Only for females of child-bearing potential. Pregnancy tests should be carried out according to local practice. Local result must be available and negative prior to 
randomization/enrollment.  
(3) Screening may extend up to 4 weeks prior to transplant (e.g., for scheduled living donor transplants) and ends when the subject is either randomized or becomes a 
screening failure. For every consented subject, the Screening Period Disposition CRF page must be completed to indiciatewhether the subject was randomized or 
considered a screening failure.
(4) Baseline covers the transplant period from up to 24 hours prior to surgery until randomization/enrollment or its failure.Randomization/Enrollment should occur within 
24hours of the start of the transplant surgery.
(5) Viral serology includes HCV, HIV, HBV surface antigen, CMV, EBV and BK virus. For the initial assessment, measurements made within the last 6 months will be 
accepted. Otherwise, the initial tests should be performed within one week of randomization/enrollment. 
(6) First dose of CFZ533 will be administered intravenously pre-or intra-operatively and must be completed by the time of unclamping or up to 6 hours prior to the time of 
unclamping. Other study drugs (e.g., Tac, MMF, CS) should be started within 24 hours post-transplantationor according to local practice. 
(7) First dose of basiliximabinduction should be given within 2 hours prior to transplant surgery, or according to local practice. The second dose should be given on Day 
4, or according to local practice.
(8) Local laboratory tests include: hematology, urinalysis, serum chemistries,renal function, and coagulation parameters.
(9) Obtained every 15 mins for 2 hrs after the start of the first CFZ533 IV infusion or time of SC injection.
(10) Negative test result must be available prior to randomization/enrollment. 
(11) Blood collections and safety assessments should be taken pre-dose if the sampling falls on a dosing day.
(12) Blood draws for trough concentrations should be performed before the next dose is given. In addition, they should be performed locally as shown and additionally 5±2 
days following each clinic visit in which doses are changed.
(14) All serious adverse events, serious infections and pregnancies must be reported from informed consent until 3 months after his/her last dose of CFZ533or 2 months 
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after EoS visit for patients on SoC treatment.
(15) Induction therapy (e.g., basiliximab) and pre-transplant immunosuppression (if used) should be recorded on the Concomitant Medications CRF page under the 
Immunosuppressive category.
(16) Prophylaxis for CMV, PCP, HBV, BK and oral candida to be considered per protocol Section 5.5.8, and recorded on the Concomitant Medications CRF page if administered.
(17) All patients are expected to continue in the study to Month 6 or 12 and complete the Month 6 or 12 Completion page, regardl ess of whether they are on or off study 
medication. If subjects discontinue study treatment, he/she should continue in the study on SOC per local practice and attend study visits to Month 6 or 12.  Any 
permanent discontinuation of the randomized study regimen should be recorded on the appropriate DAR CRF pages. After disconti nuation of study regimen, the 
immunosuppressive regimen prescribed should be recorded on the Concomitant Medications CRF under the Immunosuppressive category. 
(18) EOI = End of Infusion (IV) or End of Injection (SC). Blood samples obtained immediately after infusion for IV -administered CFZ533 or immediately after injection for 
SC-administered CFZ533.
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1
Introduction
1.1
Background
Over the past decades, organ allotransplantation has become a common medical procedure 
with considerable impact on extending and improving the quality of life of patients with end 
stage renal, cardiac, hepatic or pulmonary failure. To maximize efficacy and minimize 
adverse effects, current immunosuppressant (IS) regimens use combinations of IS drugs. 
Care is taken to achieve synergy or additive immunosuppressive effects via the administration 
of submaximal doses of individual agents with different mechanism of actions while avoiding 
overlapping toxicities. Most treatment regimens today include two or more primary and 
adjunct immunosuppressants with or without an induction agent. Induction agents are 
administered during the first hours to days post transplantation to suppress the recipient’s 
immune system and priming of an immune response to the allograft while the other IS agents 
are reaching effective concentrations. Induction agents include the anti-CD25 mAb 
basiliximab (Simulect®, Novartis) or polyclonal anti-T cell globulin (Thymoglobulin®, rabbit 
ATG, rATG, Genzyme). In highly sensitized patients, induction with an anti-CD52 mAb, 
alemtuzumab (Campath®, Sanofi-Aventis SA) which leads to long-term lymphocyte depletion 
has been used. Within 1-2 days following transplant, the maintenance treatment regimen is 
initiated with two or more of the following agents: a calcineurin inhibitor (CNI) such as 
cyclosporine (CsA, Neoral®, Novartis) or tacrolimus (Tac, FK506, Prograf®, Astellas), 
together with a lymphocyte proliferation inhibitor such as mycophenolic acid (MPA; 
Myfortic®, Novartis) or mycophenolate mofetil (MMF; CellCept®, Roche) or proliferation 
signal inhibitor such as everolimus (Zortress®, Certican®, Novartis) or sirolimus (Rapamune®, 
Pfizer). More recently, the T cell co-stimulation blocker belatacept (Nulojix®, BMS), a fusion 
protein, demonstrated the potential of a biologic agent to replace CNIs in a calcineurin-free 
treatment regimen with MPA. 
Although the current standard-of-care regimens provide excellent short-term efficacy with 
very low acute rejection rates, there is still an opportunity to increase long-term graft and 
patient survival. The current rate of renal allograft graft survival in the first year and 5 years 
post-transplant is 95% and 68% (Matas et al 2013), respectively, with a rapid decline 
thereafter. The estimated glomerular filtration rate at 12 months has been strongly associated 
with subsequent graft failure (Kasiske et al 2011). As such, kidney allograft function is also 
an important predictor of graft survival. Other factors, such as donor age, acute rejection and 
vascular remodeling may also play a role in overall graft survival, but the nephrotoxic effects 
of calcineurin inhibitors are directly associated with irreversible renal function deterioration 
(Naesens et al 2009). By eliminating CNIs from the treatment regimen, mechanism-based side 
effects, such as nephrotoxicity, hypertension, dyslipidemia, neurotoxicity, gastrointestinal and 
hematological toxicity, and/or diabetogenic effects may be minimized or eliminated. In the 
search for novel therapeutics, there has been an increasing interest in the role B cells, plasma 
cells and antibodies play in the immune response to an allograft, specifically acute cellular 
rejection and chronic humoral or antibody mediated rejection (Clatworthy 2011). 
By developing a specific treatment that decreases the priming of T and B cells and subsequent 
production of donor specific antibodies and eliminating CNIs, it is hypothesized that chronic 


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rejection can be minimized and long-term graft survival may be increased. Hence, there is a 
significant need for new immunosuppressant agents.
1.1.1
CD40/CD40L co-stimulation: a target for transplantation
CD40 is a transmembrane glycoprotein constitutively expressed on B cells and antigen-
presenting cells (APCs) such as monocytes, macrophages, and dendritic cells (DC). CD40 is 
also expressed on platelets, and under specific conditions can be expressed on eosinophils and 
activated parenchymal cells. Ligation of CD40 on B cells results in downstream signaling 
leading to enhanced B cell survival and important effector functions, including clonal 
expansion, cytokine secretion, differentiation, germinal center formation, development of 
memory B cells, affinity maturation, immunoglobulin (Ig) isotype switching, antibody 
production and prolongation of antigen presentation. CD154-mediated activation of the 
antigen-presenting cell (APC) also leads to induction of cytokine secretion and expression of 
surface activation molecules including CD69, CD54, CD80, and CD86 that are involved in 
the regulation of CD4+ T helper cell and CD8+ T cell cross-priming and activation.
CD154 exists in two forms – membrane-bound and soluble. Membrane-bound CD154 is a 
transmembrane glycoprotein expressed on activated CD4+, CD8+, and T-lymphocytes, 
mast cells, monocytes, basophils, eosinophils, natural killer (NK) cells, activated platelets and 
has been reported on B cells. It may also be expressed at low levels on vascular endothelial 
cells and up-regulated during local inflammation. Soluble CD154 (sCD154) is formed after 
proteolysis of membrane-bound CD154 and is shed from lymphocytes and platelets following 
cell activation. Once shed, sCD154 remains functional and retains its ability to bind to the 
CD40 receptor. 
Figure 1-1
Roles of CD40-CD154 signaling in the T and B cell
Targeting CD40-154 interactions in transplantation and autoimmune disease. CD40-CD154 
interactions are essential for APC activation, T cell priming in the context of APC-T cell interactions 
and T cell dependent humoral responses. 
NOTE: mCD154=membrane bound CD154; sCD154=soluble CD154


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The critical role of CD40/CD154 interactions in vivo are best illustrated by patients suffering 
fromHyper-Immunoglobulin M (HIGM)as a result of loss of function mutations in CD40 or 
itsligand. Patients with HIGM present with a severe impairment of Tcell dependent antibody 
responses, lack of Bcell memory,and little to no circulating IgG, IgA or IgE. In patients with 
mutations in CD40 signaling, a similar phenotype and disease presentation has been described
(vanKootenandBanchereau 2000).
 
 
Using monoclonal 
antibodies to target CD154 has been hampered by the occurrence of thromboembolic 
complications (Kawaietal2000) so an alternative approach is to target the receptor, CD40. 
1.1.2
CFZ533: mechanism of action
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CFZ533 is a fully human, Fc-silent, blocking IgG1 anti-CD40 antibody that binds to the 
CD154 binding site on CD40,preventingCD154binding andthe activation of CD40pathway 
signaling and downstream effector functions on multiple cell types expressing the receptor. 
CFZ533 harboursa mutation rendering it unable to bind Fcγreceptors or mediateantibody-
dependent cell-mediated cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC).
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CFZ533: Patients with rheumatoid arthritis (10 and 30 mg/kg IV)
Single doses of CFZ533 at 10 mg/kg in RA patients have been well-tolerated. There have 
been nodeaths,suspectedSAEs or discontinuations due to AEs. 
 
Data fromASKP1240clinical trials (FIH and kidney transplantation)
ASKP1240 is a monoclonal antibody blocking CD40 (Okimuraetal2014) with PK properties 
similar to those of CFZ533 based on data from NHP (Ma et al 2014) and healthy volunteers
(Goldwateretal2013). At ATC 2015, the preliminary data of a Ph II clinical trial was 
presented (Harlandetal2015). The study failed in the CNI-free arm, i.e. there were more 
rejections with ASKP1240 than with SoC. 
 
 
 
 In fact, many individuals lost target saturation in peripheral 
blood, i.e. ASKP1240 concentration <15 µg/mL (Goldwateretal2013
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ASKP1240 was markedly higher during the first month after transplantationreflecting an 
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enhancedexpression of CD40 receptors post-transplantation. The anti-CD40 mAb levels 
required for full RO in target tissues during the first twomonthsarelikely to be 60-80µg/mL, 
which is in accordance with observations in NHP studies (Maetal2014). 
 
 
 
 
Comparator and background medication
In adult de novokidney transplant recipients, the use of Tac, MMF, and CS is an 
approvedregimen (e.g. Prograf®PI2013) and is the current standard of care used in more 
than 80% of kidney transplants globally. When Tac is combined with an MPA-based regimen 
and with induction using an IL-2 antagonist, the labeled trough concentration range for Tacis 
4-11 ng/mL (e.g. Prograf®PI2013), and this range will be employed in this clinical study.
CFZ533 will be tested in Part 1 on top of Tac, MMF and CS, and in Part 2 in a Tac/CNI-free 
regimen with MMFand induction therapy. All concomitant medication will be used according 
to label.
Tacrolimus (Tac)
Tac is a calcineurin inhibitor that blocks T cell activation and IL-2 transcription. 
Tac(e.g.Prograf
®) is indicated for the prophylaxis of organ rejection in patients receiving 
allogeneic kidney transplants. It is recommended that Tac be used concomitantly with 
azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids. Therapeuticdrug 
monitoring is recommended for all patients receiving Tac. In kidney transplant patients, the 
initial dose of Tac (e.g. Prograf
®) may be administered within 24 hours of transplantation, but 
should be delayed until renal function has recovered. In combination with MMF/IL-2 receptor 
antagonist a starting dose of 0.1 mg/kg/day and a target trough concentration during the first 
12 months of 4-11 ng/mL is recommended. The most common adverse reactions (≥ 30%) in 
kidney transplant patients were infection, tremor, hypertension, abnormal renal function, 
constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, 
urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, 
hyperkalemia, anemia. For more information on Tac, please refer to the local package insert 
(e.g. Prograf®PI2013)
Mycophenolate mofetil (MMF)
MMF (e.g.CellCept®)is a prodrug of mycophenolic acid (MPA), a reversible inhibitor of 
inosine monophosphate dehydrogenase (IMPDH) in purine (guanine) biosynthesis which is 
necessary for the growth of T cells and B cells. Other cells are able to recover purines via a 
separate salvage pathway and are thus able to escape the effect thus MMF has potent cytostatic 
effects on lymphocytes. MMF is indicated for the prophylaxis of organ rejection in patients 
receiving allogeneic renal, cardiac or hepatic transplants. MMF should be used concomitantly 
with cyclosporine and corticosteroids. A dose of 1 g administered orally twice a day 
(dailydose of 2 g) is recommended for use in renal transplant patients. MMF (e.g. CellCept®
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carries a warning for female patients who may become pregnant. Some manufacturers of 
MMF recommend male contraception (condom). Use during pregnancy is associated with 


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increased risks of first trimester pregnancy loss and congenital malformations. Females of 
reproductive potential (FRP) must be counseled regarding pregnancy prevention and planning. 
Due to the risks related to the drug’s use during pregnancy, a Risk Evaluation and Mitigation 
Strategy (REMS) program has been established in the United States for products containing 
mycophenolate and details pertaining to this program are provided in Appendix2. 
Othercommon side effects of MMF include diarrhea, vomiting, pain, stomach area pain, 
swelling of the lower legs, ankles and feet, high blood pressure. For more information please 
refer to the local package insert(e.g.CellCept®PI2013).
Basiliximab
Basiliximab(e.g. Simulect®
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) is a chimeric CD25 monoclonal antibody of the IgG1 isotype. 
Itacts as an antagonist at the interleukin-2(IL-2) binding site of the p55 subunit (Tac antigen) 
of the high affinity IL-2 receptor (CD25) on the surface of the activated T lymphocytes. 
Basiliximab is indicated for the prophylaxis of acute organ rejection in patients receiving 
renal transplantation when used as part of an immunosuppressive regimen that contains 
cyclosporine and corticosteroids. Basiliximabis for central or peripheral IVadministration 
only. Reconstituted basiliximabshould be given either as a bolus injection or diluted to a 
volume of 25mL (10 mg vial) of 50 mL (20mg/vial) with normal saline or dextrose 5% and 
administered as an IVinfusion over 20-30 minutes. Therecommended regimen for adult 
patients is two 20 mg doses; the first dose is suggested to be given within2 hours prior to 
transplantation and the second dose is suggested to be given 4 days after transplantation. 
Bolus administration may be associated with nausea, vomiting and local reactions including 
pain.


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1.2
Study purpose
The purpose of this adaptive, two-part study is to investigate the potential for CFZ533 to 
replace calcineurin inhibitors (CNI), while providing a similar rate of acute rejection 
prophylaxis and better renal function in a de novo
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renal transplant population receiving an 
allograft from standard criteria donors. Part 1 of this trial will focus on profiling the 
multiple-dose PK, PD and tolerability for both IV and SC CFZ533 administration in the 


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setting of standard-of-care, CNI-based immunosuppression. Part 2 will evaluate the safety and 
efficacy of CFZ533 in the absence of a CNI in combination with adjunct MMF and 
basiliximab induction therapy for up to 12 months.  
Overall, results of this study will be used to inform the CFZ533 dose and regimen selection 
for investigation in the next phase of clinical development. 
2
Study objectives
2.1
Study Part 1: PK, PD and Safety 
2.1.1
Primary objective

To assess the safety, tolerability and PK of multiple IV and SC doses of CFZ533 in 
combination with MMF, CS, and Tac (standard exposure) in de novo renal transplant 
patients over the treatment and follow-up period
2.1.2
Secondary objectives

To quantify the magnitude and duration of peripheral blood CD40 occupancy (free CD40 
and total CD40 on B cells) 

To quantify the change from baseline and recovery of peripheral blood total soluble CD40 
and total soluble CD154 

To evaluate the immunogenicity of CFZ533 via the quantitative analysis of anti-CFZ533 
antibodies
2.2
Study Part 2: CNI-free Proof-of-Concept
2.2.1
Primary objective

To assess the potential for CFZ533 to act as the primary immunosuppressant in a CNI-free 
regimen with MMF in de novo renal transplant patients as assessed by tBPAR at Month 3 
post-transplantation
2.2.2
Secondary objectives

To assess the safety and tolerability of CFZ533 administered chronically in combination 
with MMF and CS up to 3 months against a control

To assess the pharmacokinetics of multiple  IV doses of CFZ533 during the 12-month 
treatment period

To quantify the magnitude and duration of peripheral blood CD40 occupancy (free CD40 
and total CD40 on B cells) during the treatment period following multiple IV doses of 
CFZ533

To compare renal function in CFZ533 treatment arm to control over 12 months
post-transplantation as assessed by:

Estimated GFR using MDRD

Proportion of patients with eGFR <60 mL/min/1.73m2

Proportion of patients with negative eGFR slope 


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To evaluate the immunogenicity of multiple IV dosesof CFZ533 via the quantitative 
analysis of anti-CFZ533 antibodies
To quantify the change from baseline and recovery of peripheral blood total soluble CD40 
during the treatment period following multiple IV dosesof CFZ533
3
Investigational plan
3.1
Study design
3.1.1
General overview
Study CCFZ533X2201 is a randomized, two-part, 6-or 12-month, sequential, adaptive, 
controlled, open-label, multicenter, clinical proof-of-concept study to evaluate the efficacy, 
safety, tolerability, PK and PD of CFZ533 + MMF + CS, with standard exposure (Part 1) or 
no Tac(Part 2), for initial and maintenance prophylaxis of organ rejection in adult denovo
renal transplant recipients as compared to standard of care.
As illustrated in Figure 3-1
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regimens in a parallel arm manner. 


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Figure 3-1
CFZ533X2201 Study design
Study Part 1 of this trial will focus on measuring the multiple-dose safety, tolerability PK and 
PD of CFZ533 when administered with the contemporary standard of care (SoC) treatment 
regimen. The SoC consists of concentration-controlled Tac, a calcineurin inhibitor (CNI), 
combined with mycophenolate mofetil (MMF) and corticosteroids (CS). Arm1 will 
investigate CFZ533 3mg/kg administered IV on Day 1, followed by subcutaneous (SC) 
administration on Days 15, 29, 43 and 71. 
 will be measured on an ongoing 
basis during this portion of the trial to confirm the exposure-PD response 
 
. After the last dose, patients enrolled in Part 1 will 
remain on their background SoC treatment regimen, to be managed per local practice. 
Patientsin Part 1 willnot be carried over to Part 2. 
Study Part 2 will continue the investigation of efficacy, safety, tolerability, PK and PD with 
the addition of induction therapy and avoidance of Tac. 
 
 
Any significant 
deviations in PK or PD effects which may require a revision in the dosing scheme 
(dose,frequency or route ofadministration) will be addressed via an amendment prior to 
initiating the affected dose(s) in Part 2. 
 
 
 
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3.1.2
All cohorts
Before any study-related evaluations are performed, the patient must give written informed 
consent. Once consent is obtained, pre-transplant screening and baseline assessments will 
occur to determine the patient’s eligibility to participate in the study starting up to 28 days 
prior to transplantation. If the screening, baseline and study Day 1 visits occur in close 
proximity of each other (i.e., within a 12 hour timespan), certain repeated assessments may be 
omitted, as noted in the Assessment schedule. Data collection from assessments performed at 
the clinical site as part of medical standard of care but prior ICF sign-off is acceptable in order 
to confirm patient eligibility for patients receiving an organ from a deceased donor, if 
assessed shortly before transplantation (i.e within 24h– matching the baseline window of Day 
-1 to Day 1) and in-line with inclusion and exclusion criteria.
Day 1 is defined as the day of randomization/enrollment and transplantation. This protocol 
defines 7 days to a week and 4 weeks (or 28 days) to a Study Month. For example, Week 2 is 
considered to start on Day 8 and Study Month 2 is considered to start on Week 5/Day 29. 
Randomization/enrollment should occur within 24 hours pre-transplant and drug 
administration will begin after randomization/enrollment. If CFZ533 is to be administered, the 
first dose of CFZ533 will be administered IV pre-transplant or intra-operatively, and must be 
completed by the time of unclamping. Other study drugs must be started within 24 hours post-
transplant or according to local practice. 
Patients 
who 
are 
randomized/enrolled 
but 
not 
transplanted 
will 
be 
replaced. 
All randomized/enrolled subjects are expected to continue in the study up to Month 6 (Part 1) 
or Month 12 (Part 2) regardless of being on or off randomized/assigned treatment. 
All subjects will be followed-up for safety (e.g., SAEs) for approximately three months after 
their last dose of CFZ533 or 2 months after the EoS visit for patients on SoC treatment.
Any treatment arm in which the rejection rate fulfills the a priori defined stopping rules 
(see Section 5.5.10) will be immediately discontinued at any time during the study. 
The transition from one arm to the next including Parts 1 to 2 will be based on a priori
defined rules as described in Section 9.4. Any changes in dosing or clinical conduct of the 
study will be implemented via an amendment, approved by the ethics committee responsible 
for approval of this study, and by the local heath authority when mandated by local regulations.
Safety assessments will include physical examinations, ECGs, vital signs, standard clinical 
laboratory evaluations (hematology, blood chemistry, urinalysis) AE and SAE monitoring as 
well as special assessments as outlined in Section 6.5.


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3.1.3
Part 1 –Arm 1
Figure 3-2
Part 1 Design
Approximately 6 patients who meet the inclusion criteria will be enrolled within approx. 
12hours pre-transplant to receive IV and SC CFZ533 at 3 mg/kg on Days 1 (IV), 15, 29, 43 
and 71) with standard-exposure Tac (whole blood trough concentration 4-11 ng/mL), 
mycophenolate mofetil 1.0g BID and CS(Figure3-2). 
The first dose of CFZ533 will be administered IVpre-transplant or intra-operatively. 
Drugadministration will begin after enrollment and must be completed by the time of 
unclamping. Subsequent doses of CFZ533 will be administered SC for a period of 
approximately 3 months. 
Other study drugsmust be started within 24 hours post-transplant. 
The day of enrollment and transplant will be considered to be study Day 1. Thereafter, 
post-transplant hospitalization will occur and then patients will make weekly study visits 
during Months 1-3 (up to approximately Day 71), then approximately every other week for 
Months4-6 (up to approximately Day 155).
Cumulative efficacy and safety data will be collected on an ongoing basis during the conduct 
of the study.
PK, PD and tBPARs will be reviewed on an ongoing basis by the clinical trial team. If at any 
time the observed number of tBPARs exceeds thea priori-defined stopping criteria 
(seeSection 5.5.10) the study will be stopped.
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3.1.4
Part 2 –Arms 2A-2B
Figure 3-3
Part 2 Design
Approximately 45 patients who meet the inclusion criteria will be randomized in a 2:1 fashion 
within 24 hours pre-transplant to receive one of the 2 treatment arms (Figure 3-3):
1. Arm 2A,n=30: Basiliximab20 mg (Days 1, 4) + CFZ533 at 10 mg/kg IV (17doses)+ 
MMF 1.0g BID + CS
2. Arm 2B Control/SoC, n=15: Basiliximab20 mg (Days 1, 4) + Tac(4-11ng/mL) + MMF 
1.0 g BID + CS
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Induction therapymust be started within 2 hours prior to transplantation, or according to 
local practice. 
The first dose of CFZ533 will be administered IVpre-transplant or intra-operatively. 
Drugadministration will begin after randomization and must be completed by the time of 
unclamping. Subsequent doses of CFZ533 will be administered IV(Arm2A), over a period of 
12 months. 
Other study drugs(apart from Basiliximab) should be started within 24 hours post-transplant. 
The second dose of basiliximab will be administered on Day 4, or according to local practice.
The day of randomization and transplant will be considered to be study Day 1. 
Furthertreatment will be given on study Days3, 7, 15, 29,43, 57 and then monthly thereafter 
until Months 12 (upto approximately Day 337). Subjects will then undergo Study Completion 
evaluations.
The primary endpoint of Part 2 will be assessed to determine whether the success criteria 
(safety and tBPAR) have been met 
 
 
 
 If notableAEs or safety concerns meeting the apriori-defined stopping 
criteria (see Section 5.5.10) one of the planned dose levels may be changed or discontinued 
via amendment. 
Subjects will undergo Study Completion evaluations at the end of the trial.
3.2
Rationale for study design
The open-label, adaptive design selected for Part 1 of this prospective, multicenter study will 
allow for a cautious comparison and evaluation of the multiple dose CFZ533 safety, 
tolerability, PK and PD as added to MMF+ Tac and CS for 3 months. Part 2 expandsupon the 
knowledge gained in Part 1 to assess the clinical activity and exposure-response of CFZ533 in 
a well powered CNI-free treatment regimen with basiliximab induction + MMF and CS for 
initial and maintenance prophylaxis of organ rejection in adult de novo 
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renal transplant 
recipients.
 
 
 
Although the ideal study would employ a double-blind, double-dummy methodology to 
minimize bias, in consideration of the inherent complexity of this adaptive study 
(multiplearms, frequent visits, interim analysis and extensive investigations), it has been 
decided to utilize an open-label design. This open-label design will not only minimize the 
risks for patients during the initial investigation of CFZ533 should the need for rapid 
intervention arise, such as emergent SAEs, but it also avoids the additional difficulties and 
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errors associated with sham-dose adjustments for a Tac placebo in CFZ533 arms and placebo 
injections/infusions in the control group. It is recognized that Investigator bias can affect the 
management of patients receiving investigational treatment; especially in an open-label study 
setting. In general, such scrutiny biases the study in favor of the control arm. As such, efforts 
to minimize bias for or against the CFZ533 treatment arms will be managed through the use 
of a limited number of high-quality transplant centers with a similar standard of care and 
patient management. In order to overcome any bias introduced by the open-label design, in 
Part 2, a blinded external independent adjudication committee (AC) has been formed to
centrally evaluate all biopsies taken for suspected rejection reactions and other kidney disease 
related events in an unbiased, standardized and blinded manner. Adjudication outcome will be 
entered into the eCRF and additional outputs provided.
This first-in-transplant study will enroll a de novo patient population who receive a kidney 
from donors per the inclusion and exclusion criteria outlined in the clinical study protocol (see 
Section 4). This population was selected since they typically present the lowest risk of post-
transplant complications, including delayed graft function and provide a fair assessment of 
clinical activity while not requiring the highest level of immunosuppression. Safety risks will 
be reviewed on a regular basis by an external DMC (see Section 8.4), with particular attention 
given to serious infections and malignancies associated to those (e.g., PTLD), as well as 
thromboembolic events. 
Appropriateness of efficacy assessments 
The efficacy endpoints of treated BPAR and GFR are consistent with recent HA guidance 
(CHMP/EWP/263148/06 2009) and discussions (FDA Workshop 2012 ) on including an 
assessment of graft function as well as the traditional efficacy endpoints (e.g., tBPAR, BPAR) 
with or without clinical outcomes (i.e., Death and Graft loss). 
The composite of tBPAR, graft loss or death has been used as an endpoint in many previous 
studies in the kidney transplantation indication and has been widely accepted by health 
authorities for registration purposes in this indication.
Overall, this design is consistent with well-established precedents by global health authorities 
for clinical development of immunosuppressive regimens in kidney transplantation.
3.3
Rationale for dose/regimen, duration of treatment
The initial CFZ533 dose to be administered to de novo renal transplant patients via both IV 
and SC route is 3 mg/kg CFZ533 (Part 1).. For all CFZ533 treatment regimens, the first dose 
of CFZ533 will be administered IV prior to or during transplant surgery to ensure full CD40 
target occupancy on B cells in the periphery at the time of unclamping and revascularization 
of the transplanted organ; the timing avoids initiation of an immune reaction in the initial 
presence of the foreign antigens. The SC route is preferred for patient convenience and ease of 
administration while the IV route is reserved for high doses and administration of the initial 
dose during surgery. 
The following section discusses the overall CFZ533 dose rationale and specifics for Parts 1
and 2 in turn:


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Dose selection for Part 1: In healthy volunteers, 3mg/kg IV or SC led to full (>90%) CD40 
saturation on B cells for about 4 weeks. Nevertheless, it is recognized that differences in 
expressionlevel and/or turnover of membrane bound (Loweetal2010) and soluble targets 
(Schwabeetal 1999, Continetal 2003, Komuraetal2007) may have an impact on the 
PK/PD profile of therapeutic antibodies. To profile the multiple-dose CFZ533 PK and PD in 
de novorenal transplant patients, both IV and SC doses of 3 mg/kg CFZ533 will be 
investigated over about 2 1/2 months in Part 1 of this study. In addition, to better control for 
inter-patient variability and minimize the number of patients exposed to quadruple 
immunosuppression, it is planned to evaluate both IV and biweekly and monthly SC 
administration within the same 6 patients. A simulation of the expected CFZ533 PK and 
CD40 receptor occupancy planned for Part 1 is presented in 
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Figure 3-4.


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This CFZ533 regimen is expected to result in complete CD40 suppression in peripheral whole 
blood over the treatment interval. 
 
 
 Results from Part 1 will 
provide PK and PD data that will be used to better inform modeling and selection of IV and 
SC dosing regimens to be investigated in Part 2 of this trial.
To further minimize the risk for over immunosuppression, no basiliximab induction therapy 
will be administered to patients participating in this part of the trial. Patients will also receive 
prophylaxis for CMV and PCP and recipients with negative EBV serology will be excluded. 
Upon completion of the final CFZ533 dose administration, patients will remain on SoC to be 
managed based on defined local practices and will be monitored through Month 6 per the 
study protocol.
Dose selection for Part 2: In Part 2 of this trial, CFZ533 will be investigated at 10 mg/kg IV
(a loading regimenconsisting of 7 dosesis being used in the first 2months, then monthly 
(q4w) dosing starting on study Day 57). 
 
 
PK and PD data of ASKP1240 has been published for NHP (Ma et al 2014) and for healthy 
volunteers (Goldwater et al 2013) and some data have been revealed for a Phase 2 clinical 
trial in kidney transplant (Harland et al 2015). 
 
 
 
 
 
 
 
 
 
 
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Data from ASKP1240, a monoclonal antibody blocking CD40
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: At the American 
Transplant Congress2015, preliminary data froma Ph II trial in kidney transplantation
(Harland et al Abstract ATC 2015), suggested efficient target mediated clearance of 
ASKP1240 during the first two months post-transplantation, 
 
 
 
 
 
Part 1 PK/PD data in transplanted patients will be analyzed prior to start Part 2. Anyrelevant 
deviations in the CFZ533 PK or CD40 occupancy profile for 3mg/kg IV/SC measured in 
Part1 of thistrial 
 will be modeled to further support 
the 10mg/kg IV regimen prior to the initiation ofPart 2. Any further dose or regimen 
adjustments will be implemented via amendment. 
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3.4
Rationale for choice of comparator
In adult de novokidney transplant recipients, the use of Tac, MMF, and CS is an 
approvedregimen (e.g. Prograf®PI2013) and is the current standard of care used in more 
than 80% of kidney transplants globally. When Tac is combined with an MPA-based regimen 
and with induction using an IL-2 antagonist, the labeled trough concentration range for Tacis 
4-11 ng/mL (e.g. Prograf®PI2013), and this range will be employed in this clinical study. 
Overthe past decade, the clinical use of calcineurin inhibitors, including Tac, has focused on 
minimization of the CNI to mitigate many of the associated adverse effects. Current clinical 
use of Tac with an MPA-based regimen results in excellent graft and patient survival as well 
as low rates of acute rejection. 
3.6
Risks and benefits
In this two part trial, there is no benefit expected for patients participating in Part 1 of this 
study. The risk (particularly of increased infections) to patients in Part 1 will be minimized by 
adherence to the inclusion/exclusion criteria, close clinical monitoring and minimization of 
the overall exposure to CFZ533 
 during treatment period.In Part 2, the benefit 
of a CNI-free regimen carriesthe expectation of improved renal function and 
vascular/metabolic profile (Vincentietal2010). The risks of insufficient efficacy (higher rate 
of acute rejection-tBPAR than standard of care) will be minimized by frequent monitoring of 
clinical labs and signs and symptoms suggesting tBPAR and the early discontinuation of any 
treatment arm that is ineffective according to the Stopping Rules (see details in 
Section5.5.10
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The below sections list the risks related to CFZ533 treatment. For further details pleasesee 
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Section 7of the current Investigator’s Brochure. Informationand guidance for the standard of 
care treatment used in this study is provided inthe local labellinginformationand should be 
strictly followed.
3.6.1
CFZ533
Risks of CFZ533 administration include those generally associated with administration of a 
monoclonal antibody in humans. These include the possibility of a hypersensitivity reaction 
characterized by acute or delayed allergic reaction, anaphylaxis, urticaria, rash, dyspnea, 
hypotension, fever, chills and immunogenicity. A serious infusion reaction that results in 
anaphylaxis is a rare event in monoclonal antibody therapy. CFZ533 is a fully humanized 
monoclonal antibody of the IgG1 class. This class of antibody is normally abundant in 
humans. Therefore, the antibody itself is expected to be less immunogenic in humans 
compared to chimeric or other humanized antibodies. Assays to detect a putative antibody 
response to CFZ533 are included in the study design.
In consideration of the Phase 1 study results and non-clinicaltoxicology study results for 
CFZ533 as well as clinical studies with antibodies that target CD40 and CD154 (CD40L), the 
potential risks of CFZ533 in humans may include:
1. Infusion reactions, systemic inflammation and cytokine release
2.Immunosuppression and infections
3. Lymphoproliferative disorders
4. Other hypothetical risks
These risks and an overall risk mitigation strategy are discussed in turn below. 
3.6.1.1 Infusion reactions, systemic inflammation and cytokine release
Infusion reactions and cytokine release
CFZ533 is a human, non-agonistic, Fc silent, IgG
1
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antibody. 
 
 
clinical results with CFZ533 have not demonstrated signs or symptoms of cytokine release 
syndromeor elevation of cytokines as determined by multiplex cytokine assays.
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3.6.1.2 Immunosuppressionand infections
CFZ533 is being developed for its expected immunosuppressive activity. CD40 ligation is 
linked to the functional activity of antigen presentation, as well as Tcell priming, Bcell 
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 
 has been achieved.Patients receiving CFZ533 may be immune 
suppressed from weeks to months depending on the dose. During this time of 
immunosuppression subjects may be at a higher risk for infection.
It has been shown that patients with an X-linked genetic dysfunction in CD40-CD154 
signaling, hyper-IgM (HIGM) syndrome, are at an increased risk for recurrent bacterial 
infections and infection with intracellular pathogens such as Cryptosporidium and 
Pneumocystis jirovecipneumonia (PCP) (van Kooten and Banchereau 2000).
 
 
 
 
Considering the pharmacology of CFZ533, induction of a transient HIGM–like phenotype in 
patients receiving CFZ533 ispossible, limiting their ability to mount an immune response to 
new infectious pathogens and induction of long-lasting immune memory to new immunogens.
 
Although the ability to mount a primary immune response 
will be affected by CFZ533, the memory Bcell 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).
 
 
Similarly, cytotoxic T lymphocyte (CTL) response to viral infections may 
be reduced due to impairment of antigen presentation, but are expected to remain intact.
 
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 these above hypotheses.
3.6.1.3 Lymphoproliferative disorders
 
 
It has been shown 
pre-clinically that the Epstein-Barr virus utilizes the CD40 signaling pathway to infect Bcells 
and induce long term survival (Lougaris et al 2005
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). Therefore EBV reactivation is not 
expected.To minimize the riskin Part 1 of this trial, patients who are EBV-negative will be 
excluded. For patients in Part 2, the immunosuppressive burden is lower in the context ofa 
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CNI-free treatment regimen, and recipients with a negative or positive EBV status will be 
eligible. During the trial all patients will be monitored with regular assessments of 
hematology, EBV-status as per local practice and clinical signs and symptoms 
(seeAssessmentschedule).
3.6.1.4 Thrombosis
There is a hypothetical risk for thromboembolic complications when targeting the 
CD40-CD154 co-stimulatory pathway.This risk is based on clinical results from previous 
compounds which have targeted CD154 and resulted in a fatal hypercoagulable phenotype.
 
 
During the Phase 1 program, a focus on coagulation was 
included in the trial, including regular hematology, PT, aPTT and thromboelastography (TEG). 
In addition, there have been no reports of thromboembolic complications with the non-Fc 
silent competitor anti-CD40 antibody ASKP1240 (Astellas Pharma; Goldwateretal2013; 
Yangetal2012).
In Part 1of this study, one patient sufferedfrom deep vein thrombosis(DVT), pulmonary 
embolism (PE) and dyspnea. Venous thrombotic events are known to occur in patients after 
renal transplantation with published literature suggesting a risk of up to 8.3% 
(Andrassyetal2004). In addition, the medical history of this patient included kidney disease, 
smoking, diabetes, obesity, a sedentary lifestyle, and tacrolimus use and are all likely to be 
contributory factors to the thromboembolic events observed. Therefore, given the available 
information, the causal relationship between CFZ533 administration and these 
thromboembolic events remains unclear, however, cannot be definitively excluded, and 
therefore the incident was classified as SUSAR.  
3.6.2
Adjunct immunosuppression
The combination of CFZ533 
and adjunct immunosuppression with 
Tac
(e.g.Prograf®PI2013), MMF (e.g. CellCept® PI 2013), basiliximab (e.g. Simulect®PI 2011) 
and CSis not known. Please refer to the local labeling for the other agents for full disclosure 
of the expected risks associated with use in the setting of de novorenal transplantation for the 
investigational arms as well as control. 
3.6.3
Risk mitigation strategy
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With initial administration of a biologic, the first 4 hours of exposure are most critical with 
most infusion reactions (including hypersensitivity, cytokine release, anaphylaxis) occurring 
within the first 2 hours of exposure (Tabrizi and Roskos 2007). 
 
Cytokine 
release or anaphylaxis has not been reported with similar compounds targeting the CD40 
receptor.Patients will receive their first dose of CFZ533 in the pre-to inter-operative time 
period, a time where patients are under the close supervision of clinical staff in a hospital 
environment. Any infusion related reactions can be managed at that time in accordance with 
local protocols. 
Considering the expected immunosuppressive nature of the compound alone and in 
combination with induction and adjunct immunosuppressive agents, patients will be screened 
for a history of TB. A negative test result for TB(PPD,QuantiFeron test or chest X-ray) that 
has been performed within 6 month of randomization will be required prior to enrollment. 
Tests will be performed periodically during the trial. If there is suspicion of TB, a chest x-ray 
maybe performed in accordance with local guidelines; subjects with a positive test will be 
excluded from participation. Patients will be screened forEpstein-Barr virus and if 
sero-negative,excluded from participationin Part 1 due to the high immunosuppressive 
burden expected in this cohort. Prophylaxis for CMV and PCP will be administered to all 
patients during the trial according to local practice.
Patients will hospitalized for the first few days post-transplant and will return to the clinic 
frequently during the first month with a progressively increasing visit window as the study 
progresses to monthly visits at Month 6 through 12. During these visits safety, efficacy and 
PK/PD assessmentswill be collected. Standard safety assessments will include vital signs, 
physical examinations, ECGs, clinical laboratory evaluations (hematology, blood chemistry 
and urinalysis), AEs and SAEs monitoring as outlined in the Assessment schedule
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.In addition 
to standard clinical laboratory assessments, subjects will be monitored regularly for signs and 
symptoms of infectious, inflammatory, hematologic or renal toxicity as outlined below.
Patients will be regularly evaluated while domiciled and upon return to the clinic for signs and 
symptoms which might indicate a severe infection, i.e., fever, nausea, myalgia, headache, 
arthralgia, chills, diarrhea, stiff neck, and malaise, and treated as appropriate per local practice 
depending on the infectious agent. Patients will be informed to report any of the 
aforementioned symptoms to the clinical staff to assure proper assessment and care can be 
administered in a timely manner.
Viral reactivation will be assessed for EBV, CMVand BK according to local practice on a 
regular basis.
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In agreement with the secondary objectives, changes in renal function will be assessed via 
serum creatinine and calculated creatinine clearance (MDRD).
 
 
 
Hypercoagulability and coagulopathy will be assessed using standard coagulation studies, 
including prothrombin time (PT)and activated partial thromboplastin time (aPTT)according 
to local practice.
Finally,key safety data will be reviewed by theSponsor in a blinded manner in an ongoing 
basis. A DMC will review un-blinded study data regularly and on an ad hocbasis to assess 
whether the benefit/risk of each treatment arm remains acceptable. Aprioridefined stopping 
criteria and guidelines (Section 5.5.10) in addition to the clinical opinionof the Investigator 
and biopsy results managed per local practice will be used to protect individual patient safety 
during the trial. 
 
 
 
 
 
 Cases of serious infections 
or neoplasms willalso be monitored and reviewed on an ongoing basis. 
Based on the information outlined above, the risk of administering CFZ533 in combination 
with MMF, corticosteroids, and basiliximab as well as add on to a Tac-based standard of care 
regimen appears manageable and reasonable to investigating the clinical activity of CFZ533 
in the intended patient population.
4
Population
Parts 1 and 2 (initial PoC phase) of this multicenter study will be conducted in approximately 
20 centers worldwide. The study population of Parts 1 and 2 will consist of approximately 
51male and female de novo adult renal transplant patients.
The Investigator must ensure that all subjects being considered for the study meet the 
following eligibility criteria. No additional criteria should be applied by the Investigator, 
inorder that the study population will be representative of all eligible subjects.
Subject selection is to be established by checking through all inclusion/exclusion criteria at 
screening/baseline. A relevant record (e.g., checklist) of the eligibility criteria must be stored 
with the source documentation at the study site.
Deviationfrom any 
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4.1
Inclusion criteria
Subjects eligible for inclusion in this study have to fulfill allof the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male or female patients ≥18 years old.
3. Recipients of a kidney transplant from a heart-beating deceased, living unrelated or non-
human leukocyte antigen (HLA) identical living related donor.
4. Recipients of a kidney with a cold ischemia time (CIT)< 30 hours.
5. Able to communicate well with the Investigator, to understand and comply with the 
requirements of the study.
4.2
Exclusion criteria
Subjects fulfilling anyof the following criteria are not eligible for inclusion in this study:
1. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-
lives of enrollment, whichever is longer.
2. History of hy
persensitivity to any of the study
 drugsor to drugs of similar chemical classes.
4. Recipients of an organ from a non-heart beating donor.
5. ABO incompatible or complement-dependent lymphocytotoxic (CDC) crossmatch 
positive transplant (isolated positive Bcell crossmatches are not an exclusion criterion).
6. Subjectsreceiving a second kidney allograft, unlessthe first allograft was lost due to 
surgical complication.
7. Subjects at high immunological risk for rejection as determined by local practice for 
assessment of anti-donor reactivity (e.g., high PRA > 20%, presence of pre-existing 
10. Subjects at risk for tuberculosis (TB), specifically subjects who:
Have current clinical, radiographic or laboratory evidence of active or latent TB
Have a history of active TB
a. Within the last 2 years even if it was treated
b. Greater than 2 years ago, unless there is documentation of adequate treatment 
according to locally-accepted clinical practice

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In the opinion of the Investigator and based upon an appropriate evaluation, have a 
13. Subject with severe systemic infections, current or within the two weeks prior to 
randomization/enrollment.
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16. History of malignancy of anyorgan system (other than localized basal cell carcinoma of 
the skin), treated or untreated, within the past 5 years, regardless of whether there is 
evidence of local recurrence or metastases.
18. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
hCG laboratory test.
19. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 12 weeks after the study medications have been stopped. Highly 
effective contraception methodsinclude:
Total abstinence (when thisis 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) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment.
Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject.
Combination of any two of the following (a+b ora+c, or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate <1%), 
for example, hormone vaginal ring or transdermal hormone contraception.
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b. Placementof an intrauterine device (IUD) or intrauterine system (IUS).
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
In case of use of oral contraception women should have been stable on the same brand (or 
generic equivalent) for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 
12months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of 
oophorectomy alone, only whenthe reproductive status of the woman has been confirmed by 
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follow up hormone level assessment is she considered not of child bearing potential. 
20. Any additional contraindication to the use of Tac or mycophenolate mofetil according to 
the national labeling information of these products (see local product label).
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
Treatment
5.1
Protocol requested treatment
5.1.1
Investigational treatment
The following drugs will be used in this study and will be administered in accordance with 
this protocol and where applicable, current local labeling. Not all dosage forms listed are 
available in each country, dependent on local approval status and regulations. The treatment 
regimen to which subjects are randomized comprises of up to four components: MMF 
(all study parts), CS (all study parts), CFZ533 and/or Tac (both in Part 1; either one in Part 2 )
and basiliximab (Parts 2 only).

CFZ533 is provided as 150 mg/mL lyophilized open-label bulk medication requiring 
reconstitution. CFZ533 150 mg/mL concentrate for solution for infusion/ solution for 
injection (liquid in vial) will be introduced. Instructions for preparation and administration 
to be described in a separate pharmacy manual. 
5.1.2
Control and concomitant drugs
Concomitant medication will be used according to label.

Tac (e.g. Prograf® or Generics) as 0.5 mg, 1.0 mg or 5.0 mg capsules or tablets

Mycophenolate mofetil ( e.g. CellCept® or Generics) 250 mg or 500 mg film-coated 
tablets, or 250 mg capsules, or 500 mg vial for IV administration

Basiliximab as 20 mg lyophilized vial for IV administration following reconstitution with 
sterile water.
CS for oral and IV administration, MMF, Tac and basiliximab will be supplied locally. 
5.1.3
Additional study treatment
No additional immunosuppressive agents may be used other than what is defined as per 
protocol. Concomitant therapies are as described below in Section 5.5.8.
5.2
Treatment arms
In Part 1, subjects will be enrolled into Arm 1. In Part 2, subjects will be randomized to one of 
the Arms 2A-2B. Study treatments are defined as:
Part 1

Arm 1, n=6: CFZ533 at 3.0 mg/kg SC (5 doses; first dose IV) + Tac (4-11 ng/mL) + MMF 
1.0 g BID + CS
Part 2 


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
Arm 2A, n=30: Basiliximab 20 mg (Days 1, 4) + CFZ533 at 10 mg/kg IV (17 doses) + 
MMF 1.0 g BID + CS

Arm 2B Control/Standard of Care, n=15: Basiliximab 20 mg (Days 1, 4) + Tac
(4-11 ng/mL) + MMF 1.0 g BID + CS
5.3
Treatment assignment
Randomization/Treatment numbers will be assigned to eligible subjects in Part 2 
(see Section 5.5.1 for details) prior to surgery. If provided, the Investigator will enter the 
randomization/treatment number onto the Electronic Case report Form (eCRF).
Patients in Part 1 will be enrolled sequentially across centers and will keep their screening/ 
subject number throughout the trial. Patients in Part 2 will be randomized 2:1 to Arms 2A:2B. 
The randomization/treatment numbers will be generated using the following procedure to 
ensure that treatment assignment is unbiased and concealed from subjects and Investigator 
staff, as applicable: 

For Part 1, the Investigator or his/her designee will contact the Sponsor at screening or 
baseline and confirm the subject fulfills the population criteria. 

For Part 2, IRT will be used. IRT is a validated system that automates the random 
assignment of treatment arms to randomization numbers in the specified ratio. The 
Investigator or his/her designee will log into the IRT system at screening or baseline and 
confirm that the subject fulfills the population criteria. The IRT will assign a 
randomization number to the patient, which will be used to link the patient to a treatment 
arm. Detailed instructions on the use of the IRT can be found in the separate IRT manual. 
5.4
Treatment blinding
This is an open-label, exploratory study and it is not planned to blind patients or site staff to 
treatment. In Part 1 since there is just one treatment arm, it will be known to the whole 
Clinical Trial Team that the subjects all received 3mg/kg CFZ533. In Part 2, core Clinical 
Trial Team members will be unblinded to continuously review safety and clinical data and 
evaluate the stopping rules. 
5.5
Treating the subject
5.5.1
Subject numbering
Subject number
Each subject is uniquely identified by a subject number assigned by Novartis or IRT system 
which is composed of a site number and a sequential numberat each site. Once assigned, the 
Subject Number will not be re-used and will be the primary identifier for the subject in the study.
For Part 1, upon signing the informed consent form, the subject is assigned the next sequential 
subject number as given by the Investigator using the next blank eCRF book available from 
the EDC system. 
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the Screening Disposition eCRF.
For Part 2, upon signing the informed consent form, the subject is assigned the next sequential 
subject number by the Investigator via Interactive Response Technology (IRT). The 
Investigator or his/her staff will log into the IRT system and provide the requested identifying 
information for the subject to register them into the IRT. The site should select the eCRF book 
with a matching Randomization Number from the EDC system to enter data.
If the subject fails to be treated for any reason, the IRT should be updated within 2 days that 
the subject was not treated, the reason will be entered into the Screening Disposition eCRF.
Randomization/treatment number
In addition to the subject number primary identifier, subjects in randomized studies will also 
be assigned a randomization/treatment number linked to treatment. Once the subject is 
deemed eligible for randomization/enrollment, the randomization/treatment number will be 
assigned. Once assigned to a subject, the randomization/treatment number will not be reused.
Patients will keep the subject number throughout the trial.
5.5.2
Dispensing the study treatment
The investigational drug, CFZ533 will be prepared by Novartis and supplied to the 
Investigators as open-labeled bulk medication.
For preparation of the study medication in Part 2, the unblinded pharmacist or designee at the 
Investigator’s site will need to log into the IRT system to receive the treatment code. In 
addition, the unblinded pharmacist or designee at the Investigator’s site will prepare the 
medication for administration to subjects based on a separate pharmacy manual.
Appropriate documentation of the subject specific dispensing process must be maintained.
Bulk medication labels will be in the local language, will comply with the legal requirements of 
each country, and will include storage conditions for the drug but no information about the subject.
Each patient will be supplied by the study site with commercial drugs. Commercial Novarti s 
drugs and/or 3rd party drugs used for this trial will be locally purchased and supplied either by 
the local CPO or by the clinical site per local regulations. In exceptional cases, central supply 
may be carried out.
5.5.3
Handling of study treatment
5.5.3.1
Handling of investigational treatment
Investigational treatment must be received at the study site by a designated person, handled 
and stored safely and properly, and kept in a secured location to which only the Investigator 
and designated staff have access. Upon receipt, the study drugs should be stored according to 
the instructions specified on the labels.
Storage conditions must be adequately monitored and appropriate temperature logs 
maintained as Source data.
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drug in a drug accountability ledger. Drug accountability will be noted by the Monitor during 
site visits and/or at the completion of the trial.
All drug supplies are to be used only for this protocol and not for any ot her purpose. 
Unless specifically instructed by Novartis, the Investigator must not destroy any drug labels, 
or any partly used or unused drug supply.
At the conclusion of the study, and, if allowed during the course of the study (e.g., an open -
label study or an unblinded monitor), the Investigator will provide a copy of the drug 
accountability ledger to the monitor.
Only after receiving a written authorization by Novartis, the Investigator/designee will send 
all the unused and partly used drug supplies as well as the empty containers to the address 
provided at the time of authorization for destruction, or have the unused and partly used drug 
supplies as well as the empty containers destroyed by the site’s pharmacist, providing a drug 
destruction certificate.
5.5.4
Instructions for prescribing and taking study treatment
The Investigator will dispense the appropriate amount of study drugs to cover each visit and 
additional drug in case of loss, breakage, or scheduling problems. Drug accountability will be 
performed to assess compliance. The Investigator should promote compliance by instructing 
the patient to take the study drug exactly as prescribed and by stating that compliance is 
necessary for the patient’s safety and the validity of the study. The patient should be 
instructed to contact the Investigator if he/she is unable for any reason to take the study drugs 
as prescribed.
If MMF, Tac and/or CS are part of the assigned regimen, they will be taken concomitantly as 
per standard of local practice. The study drugs may be taken with or without food, but in a 
consistent fashion. Special attention must be taken to avoid concomitant administration of 
drugs, food or beverages which are known to be a strong inducer or inhibitor of CYP3A4 
(see Appendix 5).
All drug trough levels assessed in this study (CFZ533, Tac, MPA) will be measured per the 
Assessment schedule or as per local practice (Tac/ MPA). For all samples sent for central 
analysis, the exact time and the date of sampling, together with the exact time and date of the 
last study medication dose prior to the sampling must be recorded on the central laboratory 
request form (refer to the separate Laboratory Manual). CFZ533 and MPA will be measured 
in plasma and Tac will be measured in whole blood samples. The patient will be instructed 
not to take his/her morning dose of immunosuppressant medications the day of a scheduled 
sampling, to record the medication dosage and time of last dose on the day prior to the blood 
sampling, and to bring all study drugs to the visit so that a dose may be administered upon 
completion of blood sampling. 
All dosages of CFZ533 (all parts), MMF and Tac and all dose changes during the study must 
be recorded, with reason for administration, on the corresponding Dosage Administration 
Record eCRF. 
All immunosuppressive drugs used and dosages administered must be recorded during the 
study. All changes to the immunosuppressive medication dosing regimen should be recorded 


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in the appropriate eCRF, along with the reason for change and dates. 
Induction therapy, pre and post-transplant immunosuppression
For patients randomized to the control arm or where Tac, MMF and/or steroids are to be 
administered per protocol, they may be administered prior to transplant according to center 
practice but such practice must be applied consistently to all subjects at a given center. 
At randomization/enrollment, all subjects must follow the assigned regimen. Pre-transplant 
immunosuppression, including induction therapy and any Tac or MMF should be recorded on 
the Concomitant medication eCRF under the Immunosuppressive category.
Basiliximab induction therapy
Subjects randomized to receive induction therapy will receive 2 x 20 mg doses of basiliximab 
administered IV. The first dose should be given within 2 hours prior to transplant surgery, and 
the second dose should be administered on Day 4 post-transplant, or according to local 
practice. 
The 20 mg vial should be reconstituted with 5 mL sterile water. The resultant solution is 
isotonic and may be injected as an IV bolus. Alternatively, the solution may be diluted to a 
volume of 50 mL with sterile saline and 5% dextrose and administered as an infusion over 
30 minutes. If venous irritation occurs following bolus administration, the next dose 
(if appropriate) should be administered as a 30 minute infusion. There is no maintenance dose, 
and no other antibodies are permitted for induction therapy. All basiliximab doses and 
changes must be recorded in the Concomitant Medications eCRF under the 
Immunosuppressive category.
CFZ533 therapy
CFZ533 will be administered by IV infusion or SC injection to the patient by authorized 
Investigator staff at each visit specified in the Assessment schedule.
The first dose of CFZ533 will be administered IV pre-transplant or intra-operatively. Drug 
administration will begin after randomization/enrollment and must be completed up to 6 hours 
prior to or at the time of unclamping.
The study medication preparation and administration guidelines are described in a separate 
pharmacy manual. The subject will be weighed at the Baseline visit and this weight value will 
be used for the initial study medication preparation and the calculation of the dose. 
Most actual weight will serve as basis for further dose calculations.
All dosages prescribed and dispensed to the subject and all dose changes during the study 
must be recorded on the CFZ533 Dose Administration Record eCRF. Patients can be released 
after each treatment if deemed appropriate by the Investigator.
MMF administration
Mycophenolate mofetil will be 2 tablets of 500 mg or 4 capsules of 250 mg b.i.d. (2 g/day). 
For patients who remain intubated >24 hours post-transplant and/or whom are otherwise 
unable to swallow oral medication, IV MMF may be substituted until oral conversion is 


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possible.
The first dose of MMF will be administered immediately after randomization/enrollment and 
no later than 24 hours after graft reperfusion of the allograft or according to local practice. 
Dose adjustment/interruption guidance for MMF is provided in Appendix 4. All MMF doses 
and changes must be recorded on the MMF Dose Administration Record eCRF (Part 1) and 
Concomitant Medications eCRF under the Immunosuppressive category (Part 2). 
Tacrolimus administration
Tac will be administered as PO capsules b.i.d. and adjusted to maintain within the target 
ranges of 4-11 ng/mL. Tac should be initiated as soon as possible and no later than 24 hours 
after reperfusion of the graft. The lowest permitted dosing of Tac in this study is 0.5 mg b.i.d. 
If Tac is discontinued for more than 21 consecutive days, and the study regimen cannot be 
maintained, the patient must be discontinued from the randomized treatment and managed per 
local practice. Subjects who discontinue their study regimen are expected to remain in the 
study on standard of care to Month 6 in Part 1 or Month 12 in Part 2. 
Tac dosing will be modified by Investigators as needed and recorded on the Tacrolimus 
Dosage Administration Record (Part 1) and Concomitant Medication (Part 2) eCRF at each 
visit. In the event of Tac intolerance (e.g., nephrotoxicity, neurotoxicity) dose reduction of 
Tac may be necessary. If it occurs that the Tac trough level is outside the required target level, 
then the Investigator will be asked to confirm the intended Tac trough level, to record the start 
date and reason for dose reduction on the Tacrolimus Dosage Administration Record (Part 1) 
and Concomitant Medication (Part 2 ) eCRF.
The co-administration of drugs known to interfere with Tac metabolism (see Appendix 5) 
should be avoided if possible. If these drugs are required, the Investigator should carefully 
monitor Tac trough levels. 
The patient will be instructed to record the time of the last dose on the day prior to the blood 
draw and to bring the morning dose to the visit so it may be administered after the blood 
sampling is completed.
Corticosteroids
CS will be administered according to local standard practice in a way that is consistent in all 
patients enrolled at each site. Dosing of CS should be recorded in the Concomitant 
Medications eCRF under the Immunosuppressive category.


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5.5.5
Permitted dose adjustments and interruptions of study treatment
In general, symptomatic treatment should be considered first to treat patients who have 
difficulties to tolerate their immunosuppressive regimen. However, for patients who are still 
unable to tolerate the protocol-specified study treatment, dose adjustments and interruptions 
of study drugs are permitted in order to keep the patient on study treatment as follows below. 
MMF/ MPA
Dose adjustment/interruption guidance for MMF is provided in Appendix 4. All MMF doses 
and changes should be recorded on the MMF Dose Administration Record eCRF (Part 1) and 
Concomitant Medications eCRF under the Immunosuppressive category (Part 2).
MMF (e.g. Cellcept) is known to cause significant gastrointestinal side effects in some 
patients. In case of acute intolerance of MMF, other medications (e.g. Myfortic) can be given 
to reach target mycophenolate trough levels when used according to drug label and as per 
local practice at the clinical sites. Each case should be discussed individually with the Sponsor.
At clinical sites where mycophenolates other than MMF (e.g. Myfortic) are being used as SoC,
these drugs can be considered instead of MMF after discussion with the Sponsor. 
Tacrolimus
Tac dosing will be modified by Investigators as needed and recorded on the Tacrolimus 
Dosage Administration (Part 1) and Tacrolimus Concomitant Medication (Part 2) eCRF at 
each visit. 
CFZ533
No dose adjustments beyond changes based on the patient’s weight are permitted to the 
CFZ533 dose during the study. 
In case of notable AEs, SAEs including loss of efficacy and/or associated PK/PD data 
collected during the study, changes to the next planned dose level may be considered and 
implemented via an amendment. 
Treatment of Acute Rejection Episodes
In all suspected acute rejection episodes, regardless of initiation of anti-rejection treatment, an 
allograft biopsy must be performed within 48 hours. Handling of biopsies is addressed in 
Section 6.5.1.
All episodes of acute rejection must be entered on the corresponding eCRF (e.g., Acute 
Rejection eCRF, Kidney Allograft Biopsy eCRF) preferably within 24 hours. Sites should 
complete a SAE form for all confirmed acute rejection events in Part 1 and 2 and inform 
Sponsor within 24h.
Acute rejections should be treated with bolus methylprednisolone (other CS are acceptable at 
an equivalent dose) according to local practice. Recommended treatment is with at least 3 
boluses of IV methylprednisolone with a minimal dose of 250 mg/bolus or at least 2 boluses 
of IV methylprednisolone with a minimal total dose of 750 mg.


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Patients who experience steroid-resistant rejections, vascular rejections or rejections with a 
Banff grade ≥ 2B (Appendix 8) should be discontinued from study treatment, converted to 
local SoC and may be treated with other anti-rejection therapies (i.e., antibody therapy).
All medications used for the treatment of suspected or confirmed acute rejections must be 
recorded on the Concomitant Medications eCRF under the Immunosuppressive category.
Management of signs of over-immunosuppression
CFZ533 was highly effective in preventing renal transplant rejection in NHP when used as
monotherapy. Combining CFZ533 with MPA and CS after basiliximab induction may 
increase the risk for over-immunosuppression (e.g. BK viremia). For CFZ533 to be effective,
full inhibition of CD40 signaling is required. Reducing the CFZ533 dose is not advisable,
since under-dosing of CFZ533 may trigger loss of immunosuppression. In case of suspected 
over-immunosuppression clinical sites should first consider reducing the MPA level by 50 % 
or more (if MPA is completely stopped, CS may be slightly increased) with a follow up 
within the next weeks as per local practice. If there still are signs of over-immunosuppression, 
they should consider removing MPA and/ or reduce CS. If there still are signs of over-
immunosuppression, or if the symptoms are severe, patient should be discontinued from 
CFZ533 and be switched to SoC.
Management of BK viremia
In case of diagnosed BK virus in urine, MPA levels should be reduced as a first measure as 
described in the Section above “Management of signs of over-immunosuppression”.
Patients are considered to have significant BK viremia when their plasma PCR results report 
≥10,000 copies/mL of BK virus (Sood et al 2012). 
If a patient is found to have BK viremia that reaches ≥10,000 copies/mL in plasma, reducing/ 
stopping of MPA should be considered as a first measure. If patients have biopsy-proven BK 
nephropathy they should be discontinued from their randomized treatment and be switched to 
standard-of-care treatment as per local center practice. 
Management of Patients with Delayed Graft Function (DGF)
DGF for this trial is defined as:

A dialysis performed within 7 days of transplant

excluding up to two dialysis sessions to correct electrolyte abnormalities (e.g., 
hyperkalemia) in the post-transplant time period
In case a patient experiences DGF, the DGF is by definition starting at reperfusion after the 
transplantation procedure. If the graft dysfunction is starting later according to the 
Investigator, then this condition is considered secondary graft dysfunction. 
DGF must be reported as an AE for patients who experience DGF without requiring dialysis. 
In case DGF is reported as an AE and dialysis is also reported, the end of DGF is considered 
the day the last dialysis session ends.
In case of DGF, treatment will be according to local practice. DGF treatments must maintain 


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sufficient immunological coverage for the graft and may include maintaining, interrupting or 
reducing the dose of study drug and the use of anti-thymocyte globulin. If a polyclonal 
antibody or anti-thymocyte globulin is used, the study treatment must be discontinued and the 
subject will be placed on standard of care per local practice. 
Primary graft non-function (PGNF) is defined as dialysis started 7 days after transplantation 
with a continuous record of post-transplant dialysis until either transplantectomy or death. 
PGNF should be reported on the Graft Loss eCRF.
If a subject is placed on permanent dialysis (or retransplanted), study treatment must be 
discontinued, the Graft Loss and Adverse Event eCRFs should be completed, and an SAE 
report of graft loss submitted. Dialysis treatments should be recorded on the Dialysis eCRF. 
Retransplantation should be recorded on the Surgical and Medical Procedures eCRF. 
5.5.6
Recommended treatment of adverse events
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies eCRF.
5.5.7
Rescue medication
Not applicable.
5.5.8
Concomitant treatment
The Investigator should instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the subject was enrolled into the study will be recorded on the Concomitant 
Medications eCRF or the Surgical and Medical Procedures eCRF respectively.
CMV prophylaxis
Cytomegalovirus (CMV) prophylaxis, with i.v. ganciclovir or oral valganciclovir, will be used 
in patients (CMV positive and CMV negative) as per local medical practice. Prophylaxis 
should be recorded on the Concomitant Medications eCRF. 
Pneumocystis jirovecii (Pneumocystis carinii) pneumonia (PCP) prophylaxis
All patients will be started on trimethoprim-sulfamethoxazole, starting when oral medication
can be tolerated and continued throughout the study. The same regimen should be 
administered to all patients at a given study center. Aerosolized pentamidine or dapsone may 
be 
administered 
to 
patients 
unable 
to 
tolerate 
trimethoprim-sulfamethoxazole. 
Prophylaxis should be recorded on the Concomitant Medications eCRF. 
Hepatitis B (HBV) prophylaxis
Prophylaxis for recurrent hepatitis B during the course of this study is allowed and will be 
administered at the discretion of the Investigator. Prophylaxis should be recorded on the 
Concomitant Medications eCRF.


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BK virus
Patients with BK viremia or viruria should be treated according to local practice. If treatment 
is given it should be recorded on the Concomitant Medications eCRF.
Oral Candida treatment
For oral thrush (Candida), Nystatin may be used in a swish and swallow regimen; 
alternatively, clotrimazole (Mycelex®) lozenges/troches may be used. Routine use of systemic 
agents, e.g., itraconazole, voriconazole and fluconazole, will not be allowed in study Part 1 
unless patients are systemically infected since azoles may increase blood concentrations of 
Tac. Systemic therapy in Part 2 is to be based on center practice and at the Investigator’s 
discretion. Treatment should be recorded on the Concomitant Medications eCRF. 
5.5.9
Prohibited treatment
Immunosuppressants other than those specified in the protocol are NOT allowed after 
informed consent up to the end of study. If the use of any of these medications or other 
non-protocol immunosuppressants is discovered prior to randomization/enrollment, the 
subject must not be randomized and will be recorded as a screen failure. If discovered after 
randomization/enrollment, no further doses are to be given, and the subject should continue 
on the randomized/assigned treatment regimen, noting the protocol deviation.
The exception is for the treatment of acute rejection not responding to corticosteroids.
5.5.10
Discontinuation of study treatment and premature subject withdrawal
Study “Stopping rules”
The following stopping rules based on potential toxicities will serve as the basis for placing 
the study on hold. Although the stopping criteria do not incorporate an absolute requirement 
for causality, the potential relationship between an AE and CFZ533 will be evaluated 
carefully on a case-by-case basis between the Sponsor and the Investigator. Following a 
review of the AE(s), a decision to permanently discontinue enrollment or re-initiate dosing 
will be made by the DMC. 

Two (2) or more patients presenting with PTLD or PML 


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In addition, specific stopping rules for the incidence of tBPAR will be applied. These rules are 
designed to ensure that aCFZ533 treatmentarm will be stopped if there is high probability 
(>90%) that the true tBPAR rate is greater than 20%. 
 
 
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In addition to the automatic hold criteria and tBPAR criteria presented above, the DMC will 
review safety data regularly as outlined in their charter (see Section 8.4) during quarterly and 
ad hoc meetings. The DMC can recommend stopping a specific study arm(s) or the entire trial 
if significant changes or effects that, in their collective opinion, are deemed unsafe or 
unethical to continue administering CFZ533.
Discontinuation of study regimen
The Dosage Administration Records for CFZ533 (all parts), MMF and Tac (Part 1 only) and 
Concomitant Medication eCRF for MMF and Tac (Part 2) will be used to record if a subject 
has permanently discontinued study treatment and why.
Possible reasons for study treatment discontinuation are:

Adverse Event

Lack of Efficacy

Technical problem during transplant surgery

Subject/Guardian Decision

Lost to follow-up

Death

Graft Loss
The Investigator should discontinue a subject from their randomized treatment regimen if, on 
balance, he/she believes that continuation would be detrimental to the subject’s well-being.
Subjects who become pregnant while taking study medication must be discontinued from 
study medication and from the study, such pregnancies should be reported as SAEs to 
Novartis DSE and entered as AEs in the eCRF, the reason for discontinuation of study 
medication should be recorded as AE and reason for discontinuation from study is pregnancy 
(see next section below). 
Subjects who discontinue study medication (CFZ533 or Tac) should remain in the study, if 
possible, and receive standard of care immunosuppression, according to local practice, until 
completing the study at Month 6 (Part 1) or Month 12 (Part 2). Visits and assessments for 
such subjects are described in the Assessment schedule. All immunosuppressants after 
discontinuation of study regimen must be recorded on the Concomitant Medication eCRF 
under the Immunosuppressive category.


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Subjects who discontinue their study treatment regimen should NOT be considered withdrawn 
from the study UNLESS they withdraw their consent to participating in all the elements of the 
study (see Section 5.5.11). Information on treatment discontinuation needs to be captured on 
the end of treatment eCRF page. Such subjects should remain in the study, if possible, and 
receive standard of care immunosuppression, according to local practice, until completing the 
study at Month 6 (Part 1) or Month 12 (Part 2). See the Assessment schedule for the required 
assessments of these subjects after discontinuation of study regimen. If they fail to return for 
these assessments for unknown reasons, every effort should be made to contact them as 
specified in Section 5.5.12.
5.5.11
Withdrawal of 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 want any further visits or assessments and does not want any further 
study related contacts and does not allow analysis of already obtained biologic material.
If a subject withdraws consent, the Investigator must make every effort to determine the 
primary reason for this decision and record this information in the eCRF. Study treatment 
must be discontinued and no further assessments conducted. All biological material that has 
not been analyzed at the time of withdrawal must not be used. Further attempts to contact the 
subject are not allowed unless safety findings require communicating or follow-up.
5.5.12
Loss to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to 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). A subject should not be considered lost to follow-up until his/her scheduled end of 
study visit would have occurred.
5.5.13
Replacement of early withdrawals or discontinuations
The sponsor allows for over-recruitment of 2 patients in Part 1 and additional 10% in Part 2, 
to compensate for potential early withdrawals or discontinuations from the study.
5.5.14
Emergency unblinding of treatment assignment
Not applicable.
5.5.15
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 (as applicable based on local regulations). 
Subjects who are prematurely withdrawn from the study should be treated according to local 
standard of care per Investigator’s judgment. The study will complete when the last subject 
completes their Study Completion visit, and any repeat assessments associated with this visit 
have been documented and followed-up appropriately by the Investigator.
For Part 2: patients who completed the study on treatment with CFZ533 should be switched to


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tacrolimus (or other SoC treatment) not earlier than 28 days after having received their last 
CFZ533 dose in order to not cause over-immunosuppression. From Days 28 to 35 after last 
dose, the concentration of tacrolimus should be at the lower recommended level before 
increasing it to the dose considered appropriate for the individual patient. Doses of MMF and 
CS may remain unchanged or be adapted accordingly.
5.5.16
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the subject 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 subject’s interests. 
The Investigator will be responsible for informing IRBs and/or ECs of the early termination of 
the trial.
6
Visit assessments
The full Assessment schedule is presented at the end of the synoptic section, above. “X” 
indicates assessments that are to be performed for all subjects. “A” indicates assessments only 
to be performed for subjects maintaining the study regimen. 
All randomized subjects are expected to continue in the study up to Month 6 (Part 1) or 
Month 12 (Part 2) regardless of being on or off randomized treatment. Subjects who 
discontinue their randomized study treatment regimen should be treated according to standard 
of care immunosuppression and return for the assessments indicated by “X” in the 
Assessment schedule. If they refuse to return for these assessments or are unable to do so, 
every effort should be made to contact them or a knowledgeable informant by telephone to 
determine the subject and graft status.
Subjects should be seen for all visits on the designated day with an allowed visit window as 
specified in the Assessment schedule.
Every effort will be made to take the PK sample at the protocol specified time. 
Other assessments (e.g., ECG, vital signs) will be taken prior to or after the PK sample. 
ECGs must be recorded after 5 minutes rest in the supine position to ensure a stable baseline. 
The preferred sequence of cardiovascular data collection during study visits is: ECG 
collection first, followed by vital signs, and blood sampling. 
At a minimum, subjects will be contacted for safety evaluations (e.g., SAEs) up to 3 months 
after his/her last dose of CFZ533, and 2 months after End of Study visit (EoS) for patients in 
the control arm for Part 2. Documentation of attempts to contact the subject should be 
recorded in the source documentation.
6.1
Dietary, fluid and other restrictions
Not applicable.


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6.2
Information to be collected on screening failures
All subjects who have signed informed consent but do not enter the next period 
(i.e., Randomized treatment to Month 6 or Month 12) will have the Study Completion eCRF 
for the screening period, demographics (giving reason for screen failure), inclusion/exclusion 
and SAE data collected. AEs that are not SAEs will be followed by the Investigator and 
collected only in the source data. All consented subjects must be entered in the IRT system at 
screening for Part 2. For subjects who are not randomized, the Screening Disposition eCRF 
must both be updated to indicate screen failure.
Rescreening is only allowed for subjects who were screen failures on the initial Screening 
visit (e.g., due to lab values out of range). Rescreened subjects should be recorded as screen 
failures under their original Subject ID number and assigned a new Subject ID nu mber in the 
database when consented for rescreening. 
All subjects who have signed informed consent and received study treatment will have all 
AEs occurring after informed consent is signed recorded on the Adverse Event eCRF until 
they completed the study.
Investigators will have the discretion to record abnormal test findings on the Medical History 
eCRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
6.3
Subject demographics/other baseline characteristics
After informed consent has been signed and the subject’s eligibility to participate in the study 
has been determined, baseline subject information will be obtained in accordance with local 
regulations, including date of birth, age, sex (with child bearing status for females), race and 
ethnicity. In addition, relevant medical history (including CKD and ESRD history) and 
current medical conditions at screening, a full physical examination, vital signs and a 
pregnancy test (for females of child-bearing potential) will also be performed. 
At Baseline/Transplantation, information on the renal transplant procedure, recipient and 
donor transplant background, recipient and donor viral serology and recipient/donor HLA 
testing results will be recorded. For randomization/enrollment of subjects in Part 1, the 
sponsor must be contacted and the sponsor will assign the treatment number. 
For randomization of subjects in Part 2, the IRT must be contacted and the IRT will assign the 
randomization number. For all subjects regardless of randomization/enrollment status, the 
Enrollment (Part 1) or IRT (Part 2) and Screening Disposition eCRF must be completed to 
document all consented subjects as either randomized or as screen failures and the reason for 
screen failure recorded in the eCRF.
6.4
Treatment exposure and compliance
CFZ533 concentrations and PK parameters (measures of treatment exposure) will be 
determined in all subjects treated with study treatment, as detailed in Section 6.7.
All pre-transplant immunosuppression administered pre-randomization/enrollment, such as 
basiliximab, Tac, MMF and/or CS, will be recorded on the Concomitant Medications eCRF 
under the Immunosuppressive category.


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All post-randomization/enrollment doses of CFZ533 (all parts), Tac and MMF (Part 1 only)
will be recorded on their respective Dose Administration Record eCRFs. For Part 2, Tac will 
be recorded on the Tac Concomitant Medications eCRF. Basiliximab (all parts), MMF (Part 2)
and/or CS
will be recorded on the Concomitant Medications eCRF under the 
Immunosuppresive category.
For all these immunosuppressive drugs, the start date, total dose, stop date and reason for dose 
administration or dose change are to be provided. If study drug is interrupted due to inability 
to tolerate oral medication and rescue therapy via a NG tube is administered, the non-study 
drug immunosuppressive should be recorded on the Concomitant Medications eCRF under 
the Immunosuppressive category.
Tac and MPA trough levels will be determined locally and recorded on the relevant trough 
level eCRF. The local trough values will be used to adjust the Tac and MPA dosing as needed.
Post-discontinuation of study regimen, for patients remaining in study to Month 6 (Part 1) or 
Month 12 (Part 2), the trough levels should be recorded on the appropriate trough level eCRF.
Other drugs administered prior to and continuing at start of study medication will be entered 
on the Concomitant Medications eCRF.
Compliance will be assessed by the Investigator and/or study personnel at each visit and 
information provided by the patient. This information should be captured in the source 
document at each visit.
6.5
Efficacy / Pharmacodynamic assessments
6.5.1
Efficacy assessments
Treated Biopsy Proven Acute Rejection (tBPAR)
A treated BPAR is any condition where the subject received anti-rejection treatment and was 
histologically diagnosed as acute rejection (according to the Banff 2009 criteria, Appendix 8
or the Banff 2013 criteria. Borderline histological findings are interpreted according to local 
medical practice and fulfill the criteria of tBPAR if anti-rejection treatment is given).
Renal biopsies will be collected for all cases of suspected acute rejection. 
Kidney allograft biopsy
For all suspected rejection episodes, regardless of initiation of anti-rejection treatment, 
an allograft biopsy must be performed according to local practice preferably within 48 hrs. 
Biopsies will be read by the local pathologist according to the updated Banff 2009 criteria 
(Appendix 8, or the Banff 2013 criteria depending on the local practice). The results of the 
biopsy read by the local pathologist will be listed on the Kidney Allograft Biopsy eCRF. 
The results will be used for subject management for acute rejection. The local pathologist will 
remain blinded to treatment. Any biopsies performed according to local practice (e.g., not for 
cause) should also be recorded. In Part 2, biopsies performed for suspected rejection and other 
kidney disease related events will also be evaluated centrally by an independent Adjudication 
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Graft loss
The allograft will be presumed to be lost on the day the subject starts dialysis and is not able 
to subsequently be removed from dialysis. If the subject undergoes allograft nephrectomy 
prior to starting permanent dialysis, then the day of nephrectomy is the day of graft loss. 
Thereason for graft loss will be recorded on the Graft Loss eCRF. This will be reported on 
the Study Completion eCRF and Treatment Phase Disposition eCRF with Graft Loss as the 
reason for study discontinuation and on the appropriate Dosage Administration Record 
eCRF(s) if death occurs while on randomized treatment. Graft loss is considered a SAEand 
should be reported on the Adverse Event eCRF (asserious) and the SAE reported to the local 
Novartis Drug Safety and Epidemiology Department local Novartis Drug Safety and 
Epidemiology (DS&E) Department within 24 hrs.
Death
In the event of subject death, the SAE leading to death should be reported to Novartis DS&E 
within 24 hrs. The events leading to the death should be entered on the Adverse Event eCRF 
and the death should be indicated on the appropriate Dosage Administration Record eCRF(s) 
(if death occurs while on randomized treatment), on the Study Completion eCRF and on the 
Treatment Phase Disposition eCRF.
6.5.2
Pharmacodynamic assessments
Soluble CD40 and soluble CD154
Peripheral blood total soluble CD40 and total soluble CD154 concentrations will be 
determined in Part 1, before, during and after administration of CFZ533. Only total soluble 
CD40 levels will be determined in Part 2.
6.5.2.1 Pharmacodynamic sample collection and processing
All blood samples will be taken by either direct venipuncture or an indwelling cannula 
inserted in a forearm vein. All samples will be given a unique sample number (as listed in 
Appendix1
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). The details of sample processing, handling, storage, and shipment will be 
described in a separate laboratory manual. 
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6.5.2.2 Pharmacodynamic analytical methods
Analytical methods will be described in a separate laboratory manual.
6.5.2.3 Pharmacodynamic parameters
Total soluble CD40 and total soluble CD154
Peripheral blood total soluble CD40 and total soluble CD154 (concentrations before, during 
or after treatment, as applicable) will be analyzed, as applicable.
6.6
Safety assessments
6.6.1
Physical examination
A complete physical examination should include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological systems. 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 on 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 AE must be 
appropriately recorded on the Adverse Event eCRF.
6.6.2 
Vital signs
Vital signs (radial pulse rate, blood pressure and body temperature) will be recorded as 
indicated in theAssessment schedule. Blood pressure and pulse rate will be assessed at the 
same arm each time of determination and after the subject has rested in the sitting position 
(may be supine if during hospitalization) for at least five minutes. Systolic and diastolic blood 
pressure will be measured three times using an automated validated device (e.g., OMRON) 
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. 
The repeat sitting measurements will be made at up to 5 minute intervals and measurements 
will be recorded on the Vital Signs eCRF. Clinically notable vital signs are defined in 
Appendix7
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Body temperature should be measured as per local practice – the same method to be used 
consistently for all patients at each site.
6.6.3
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.
Body mass index (BMI) will be calculated using the following formula:

BMI = Body weight (kg) / [Height (m)]2
Results will be recorded in the Vital Signs eCRF.
6.6.4
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 and/or at the initial baseline, the 
assessment may be repeated once prior to randomization/enrollment. If the repeat value 
remains outside of protocol-specified ranges, the subject is excluded from the study.
Results from routine blood laboratory evaluation - directly assessed before Transplantation
(i.e. within 24h prior to Tx) - can be used instead of further baseline laboratory evaluation. No 
second assessment implying second drawing of venous blood needs to be done.
In the case where a laboratory range is not specified by the protocol, but is outside the 
reference range for the laboratory at screening and/or initial baseline, a decision regarding 
whether the result is of clinical significance or not shall be made by the Investigator and shall 
be based, in part, upon the nature and degree of the observed abnormality. The assessment 
may be repeated once prior to randomization/enrollment.
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 AE 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.
Clinically notable laboratory findings are defined in Appendix 7.
6.6.4.1
Hematology
Platelets, hemoglobin, red blood cell (RBC), white blood cell (WBC) and differential count 
(e.g., neutrophils, basophils, eosinophils, monocytes, lymphocytes) will be measured.


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6.6.4.2
Clinical chemistry
Albumin, alkaline phosphatase, total bilirubin, bicarbonate/CO2, calcium, cholesterol, 
chloride, creatinine, CK, gamma-GT, glucose, HbA1c, LDH, inorganic phosphorus, lipase, 
amylase, magnesium, potassium, total protein, AST, ALT, sodium, triglycerides, BUN and 
uric acid will be measured. At timepoints on 6h, 24h, 48h and 72h samples have to be taken 
only for Mg, K, creatinine, Ca and glucose.
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal, 
direct and indirect reacting bilirubin should be differentiated.
6.6.4.3
Urinalysis
The following parameters will be measured: protein, creatinine, albumin, glucose; proteinuria 
and albuminuria per 24hr period will be estimated from spot protein/creatinine and 
albumin/creatinine ratios.
If the dipstick result is positive for protein, nitrite, leucocytes and/or blood the sample will be
sent for microscopic analysis of WBC, RBC and casts according to local practice.
Local practice for transplant patients is that no microscopic analysis of the urine is done for 
the first two weeks after transplantation. 
• Within the first two weeks after transplantation additional microscopic analysis will only 
need to be performed if the dipstick result is 3+ (or more) positive for leucocytes and/or 
blood (no WBC, RBC cast is expected to be seen with only proteinuria). 
• From visit 108 (Study Day 29) onwards a microscopic analysis should be performed, except 
if the dipstick is completely negative. 
6.6.4.4
Special clinical laboratory evaluations
The details of sample processing, handling, storage, shipment and analysis for the following 
assays will be described in a separate laboratory manual, as required.
6.6.4.5
Renal Function
Renal function will be assessed by calculated eGFR using the MDRD formula.
6.6.4.6
Coagulation studies
Coagulation studies will be performed, including prothrombin time (PT) and activated partial 
thromboplastin time (aPTT). 
6.6.4.7
Cytokine assessment
Blood samples will be collected during the study (see Assessment schedule) for cytokine 
assessment via multiplex cytokine (or similar) platform (e.g., IL-2, IL-12, IFN-gamma, IL-4, 
IL-5, IL-10, IL-13, IL-1b, IL-6, IL-8, TNF-alpha, IL2R) and analyzed centrally, triggered by 
safety signals such as for example: 

hyper acute rejection or tBPAR associated with CFZ533 administration or in close 
proximity to the administration of CFZ533 


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a febrile response around the time of CFZ533 administration as an indicator of an 
inflammation 
6.6.4.8 Donor specific antibodies(DSA)
Blood samples for donor specific antibodies (antibodies directed against antigens expressed 
on donor organs) will be collected and evaluated locally. 
6.6.4.9 Immunogenicity
The presence of anti-CFZ533 antibodies will be determined using a bridging ELISA-based 
assay.
6.6.4.11Viral tests and EBV/CMV/BK virus surveillance
All subjects will be screened/monitored for hepatitis B, hepatitis C, HIV, Epstein-Barr Virus 
(EBV), cytomegalovirus (CMV) and BK virus per local center practice.For centers where no 
protocol exists, details on the assessment requirements will be provided in the laboratory 
manual.Results of these assessments are to be transcribed into the appropriate eCRFpages.
6.6.5
Electrocardiogram (ECG)
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The Fridericia QT correction formula (QTcF) will be used for clinical decisions.
Single 12 lead ECGs are collected. The original ECGs on non-heat-sensitive paper, 
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 performedto 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.


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6.6.6
Pregnancy
Pregnancy tests will be required for all females of child-bearing potential at timepoints as 
designated in the Assessment Schedule, and defined below. 
Serum or urine pregnancy tests should be carried out according to local practice. Local result 
must be available and negative prior to randomization/enrollment. 
6.6.7
Tuberculosis surveillance
Patients should have no history of active tuberculosis (per their pre-transplant assessments). 
A tuberculosis (TB) test (e.g. QuantiFeron, PPD or chest X-ray) will be conducted during 
screening whenever local procedures will allow (e.g. for living donors). For patients enrolled 
in areas where TB is endemic or who are at higher risk of active or latent TB disease, local 
screening result should be available and negative prior to randomization/enrollment for 
recipients of transplants from living donors. For deceased donor transplants a TB test showing 
negative results performed within 6 months prior to enrollment/ randomization is acceptable. 
Samples for a TB test will be collected at baseline and at various time points throughout the 
conduct of the study as defined in the Assessment schedule. Chest X-ray to verify or monitor 
TB status of the patients is acceptable depending on local regulations.  Whenever during the 
course of the study a positive test for TB is being confirmed, the patient will be discontinued 
from study treatment and returned to SoC.
6.7
Pharmacokinetic assessments
See Sample log tables (Appendix 1).
6.7.1
PK Blood collection and processing
All blood samples will be taken by either direct venipuncture or an indwelling cannula 
inserted in a forearm vein. Details of sample processing, handling, storage and shipment will 
be described in a separate laboratory manual. All samples will be given a unique s ample 
number and a collection number (as listed in the blood log, Appendix 1). The actual sample 
collection date and time will be entered on the PK blood collection page of the eCRF. 
Sampling problems will be commented in the eCRFs.
6.7.2
Pharmacokinetic analytical methods
Analytical methods will be described in a separate laboratory manual.
6.7.3
Pharmacokinetic parameters
For standard PK abbreviations and definitions, see the list provided at the beginning of this 
protocol.
If data permit, typical exposure metrics and parameters could be determined using the actual 
recorded sampling times and non-compartmental method(s) with WinNonlin Pro or Phoenix, 
including (but not limited to): Cmax, Cmin, Ctrough, Tmax, , AUCt, from the plasma 
concentration-time data.
Concentrations below the LLQ will not be considered for PK parameter calculations. 


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Definingbioavailability using the ratio of dose-normalized AUC approach, or the ratio of 
doses that provide equal AUCs approach, could be misleading (even if identical doses are 
administered IV and SC). Indeed, a non-compartmental approach, requires linear kinetics 
even if the same IV and SC doses are used. For mAbs,subject to target mediated disposition, 
clearance and distribution are dose/concentrations-dependent. A dose-independent, 
model-based analysis of IV and SC data would be the best way to determine bioavailability in 
this study. Such analysis may be reported in a separate standalone report.
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6.8
Other assessments
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7
Safety monitoring
7.1
Adverse events
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An AE is any untoward medical occurrence (i.e., any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a subject or clinical 
investigation subject. Therefore, an AE may or may not be temporally or causally associated 
with the use of a medicinal (investigational) product.
For all subjects who have signed informed consent and are enteredinto the study will have all 
adverse events occurring after informed consent is signed recorded on the Adverse Event eCRF.
Pre-existing medical conditions/diseases (i.e., Medical History(ies)) are considered AEs if 
they worsen after providing written informed consent. Abnormal laboratory values or test 
results constitute AEs only if they induce clinical signs or symptoms, or are considered 
clinically significant, or they require therapy.
The occurrence of AEs should be sought by non-directive questioning of the subject at each 
visit during the study. AEs also may be detected when they are volunteered by the subject 
during or between visits or through physical examination, laboratory test, or other assessments.
AEs must be recorded on the Adverse Event eCRF under the signs, symptoms or diagnosis 
associated with them, and accompanied by the following information:


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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 investigational treatment (no/yes), or other study treatment (non-
investigational) (no/yes), or both or indistinguishable,
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved should be reported.
4. whether it constitutes a serious adverse event (SAE)
5. action taken regarding investigational/other study treatment
6. whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy)
7. its outcome
An SAE is defined as any AE which meets any one of the following criteria:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent form

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2.


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All AEs should be treated appropriately. Treatment may include one or more of the following: 
no action taken (i.e., further observation only); study drug dosage adjusted/temporarily 
interrupted; study drug permanently discontinued due to this AE; concomitant medication 
given; non-drug therapy given. The action taken to treat the AE should be recorded on the 
Adverse Event eCRF.
Once an AE is detected, it should 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 study drug, the interventions 
required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the informed consent 
and should be discussed with the subject during the study as needed.
7.2
Serious adverse event reporting
To ensure subject safety, every SAE, regardless of causality, occurring from after the subject 
has provided informed consent and until 3 months after his/her last dose of CFZ533 or 2 
months after the EoS visit for patients on SoC treatment must be reported to Novartis within 
24 hours of learning of its occurrence.
A SAE form for each confirmed acute rejection event should be completed since these are 
considered to be “medically significant events” for this clinical trial requiring timely and
detailed reporting. The SAE form should be completed as soon as the PI at the site confirms 
the event based on the histological report from the local pathologist together with a clinical 
assessment of the event.
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the Investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event.
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the paper Serious Adverse Event Report Form. The Investigator must assess the 
relationship to each specific component of study treatment (if study treatment consists of 
several drugs) complete the SAE Report Form in English, and send the completed, signed 
form by fax within 24 hours after awareness of the SAE to the local Novartis Drug Safety and 
Epidemiology Department. The telephone and fax number of the contact persons in the local 
department of Drug Safety and Epidemiology, specific to the site, are listed in the Investigator 
folder provided to each site. The original copy of the SAE Report Form and the fax 
confirmation sheet must be kept with the case report form documentation at the study site.
Follow-up information should be provided using a new paper SAE Report Form stating that 
this is a follow-up to a previously reported SAE.


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Follow- up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should 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 investigational treatment, a Drug Safety 
and Epidemiology Department associate may urgently require further information from the 
Investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all Investigators involved in any study with the same 
investigational 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.
7.3
Pregnancy reporting
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
Investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the investigational treatment to pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
Any SAE experienced during pregnancy must be reported on the SAE Report Form. If a 
patient of a US study center becomes pregnant, please also refer to the country-specific 
instructions in Appendix 2.
7.4
Early phase safety monitoring
The Investigator will monitor AEs 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.


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8
Data review and database management
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Novartis 
representative will review the protocol and eCRFs with the Investigators and their staff. 
During the study, the field monitor will visit the site regularly to check the completeness of 
patient records, the accuracy of entries on the eCRFs, the adherence to the protocol and to 
Good Clinical Practice, the progress of enrollment, and to ensure that study drug is being 
stored, dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field 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 eCRFs 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 eCRF entries. 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 eCRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the subjects will be disclosed.
8.2
Data collection
Designated Investigator staff will enter the data required by the protocol into the eCRFs using 
fully 
validated 
software 
that 
conforms 
to 
21 
CFR 
Part 
11
requirements. 
Designated Investigator site staff will not be given access to the EDC system until they have 
been trained. Automatic validation programs check for data discrepancies and, by generating 
appropriate error messages, allow the data to be confirmed or corrected before transfer of the 
data to Novartis or 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 a CD-ROM or paper copies of the subject data for archiving at the 
investigational site.
All data captured for this study will have an external originating source (either written or 
electronic); the eCRF is not considered as source.


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8.3
Database management and quality control
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
Novartis staff or the CRO working on behalf of Novartis will review the data entered into the 
eCRFs 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 sent (e.g., fax, e-mail) to the site. Site personnel will complete and sign the copy, 
then send it (with original signature) back to Novartis staffor CRO working on behalf of 
Novartis, who will make the correction to the database.
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 AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) terminology.
Certain laboratory samples will be processed centrally and the results will be sent 
electronically to Novartis (or a designated CRO).
Randomization codes in Part 2 will be tracked using an Interactive Response Technology 
(IRT). An internal Novartis IRT (NIRT) systemwill be used in Part 2.The data will be sent 
electronically to Novartis (or a designated CRO).
Theoccurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked 
and the treatment codes will be unblinded and made available for data analysis. Any changes 
to the database after that time can only be made by joint written agreement between the 
Global Head of Clinical Information Sciences and the Clinical Franchise Head.
8.4
Data Monitoring Committee
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A DMC will be constituted. The mission of the DMC will be to ensure the ethical conduct of 
the study and to protect the safety interests of patients in this study. The DMC will be 
responsible for reviewing the safety and efficacy results from the interim and final analyses, 
as well as overseeing the data accruing in the trial at regular intervals. It is expected that the 
DMC may consist of a nephrologist, transplant surgeon, statistician, and infectious disease 
specialist.
Details on the working procedures of the DMC are described in the DMC Charter.


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8.5
Adjudication Committee
Not requiredfor Part 1.
Since the study is open-label for investigators,for Part 2 an independent and blinded 
Adjudication Committee (AC) has been appointed in order to centrally evaluate all events 
reported as acute rejection, delayed graft function or other kidney dysfunction in an unbiased 
manner.
Details on the working procedures of the AC are described in a separateAC charter.An 
additional supportive PD analysis will be performed for BPAR and tBPAR based on 
adjudicated results. 
9
Data analysis
Data from Part 1 and Part 2 will be presented separately. 
9.1
Analysis sets
Part 1 and Part 2:
The Full Analysis Set will include all subjects that received at least one dose of study drug 
and who were transplanted.
The Safety Analysis Set will include all subjects that received at least one dose of 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 experienced 
no protocol deviations with relevant impact on PK data.
The PD Analysis Set will include all subjects in the Full Analysis set with available PD data 
and no protocol deviations with relevant impact on PD data.
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
9.2
Subject demographics and other baseline characteristics
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All data for background and demographic variables will be listed by treatment group and 
subject. Summary statistics will be provided by treatment group.
Subject demographics will include age, sex, race, ethnicity, height, weight and BMI. 
Otherbaseline disease characteristics include relevant medical history, current medical 
conditions, results of laboratory screens, transplant history, donor characteristics (e.g., age, 
sex, race, type, CIT) and any other relevant information. 
Summary statistics will be presented for the subjects in the Full Analysis Set. 
Categorical data will be displayed via absolute and relative frequencies for each category 
(including a category labeled as “missing” when appropriate).


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9.3
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment group andsubject.
9.3.1
Study medication
The duration (days) of study medication administration will be summarized. This will be 
calculated by subtracting the date of the last administration of study medication from the date 
of first administration and then adding the dosing interval for CFZ533 or Tac(i.e.,28days for 
treatment administered once every 4 weeks). In calculating the duration of treatment, daysof 
temporary interruption of study medication for any reason will be included. Further, the 
frequency of dose changes(including temporary dose interruption) will be presentedby 
reason for the change.
Average daily doses will be presented by treatment. “Zero”will be used for periods of 
temporary interruption of study medication for any reason.
The number and percentage of subjects who prematurely discontinued study medication will 
be summarized by reason for discontinuation.
9.3.2
Concomitant immunosuppressants
The average daily dose of administered MMF, Tac and CSwill be summarized by treatment 
arm for subjects on study medication. The dose of the induction agent will be summarized for 
each of days when it was administered.
The dose of antibodies used for the treatment of acute rejection episodes will be recorded as well.
9.3.3
Other co-medications
Concomitant medications, other than immunosuppressants and CS mentioned above, will be 
summarized by therapeutic class and preferred term by presenting the number and percentage 
of subjects using each medication for each treatment group.
9.4
Analysis of the primary variable(s)
9.4.1
Variable(s)
Parts 1 and 2:
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The primary variable is tBPAR after 3 months of treatment.For the analysis in Part 2,the 
total “on treatment time”in each treatment group is required. 
 
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9.4.2
Statistical model, hypothesis, and method of analysis
Handling of missing values/censoring/discontinuations
The primary analysis only considers the events “on treatment” (apply thewindowdefined in 
Section9.4.1), thus accounting for discontinuations from the randomized treatment arm or 
study.
Part 1
The number of patients with tBPAR is assumed to follow a binomial distribution, i.e.,
r
i ~ Binomial( ni, θ
i ), where r
i is the number of patients with tBPARin treatment group i, ni is 
the number of patients in treatment group i and θ
i is the probability of tBPAR.
The posterior mean tBPAR rate will be presented together with the 95% credible interval. 
Part 2
The number of patients with tBPAR is assumed to follow a binomial distribution, i.e.,
ri ~ Binomial( ni, θi ), where ri is the number of patients with tBPAR in treatment group i, ni 
is the number of patients in treatment group i and θi is the probability of tBPAR.
The primary efficacy analysis for the first 3 months of Part 2evaluates whether a CFZ533 
treatment arm meets the pre-defined success criteria.  
Pr (θCFZ5331 –θSoC <0.20 | data) > 60%.
The required posterior probabilities will be estimated from simulations of the posterior 
distributions of θCFZ533 –θSoC and compared to the thresholds for the levels of proof.
The prior distributions will be assumed to be a non-informative Beta(1/3,1/3) for CFZ533 and 
an informative prior of Beta(1, 13) for placebo. This informative prior corresponds to an 
approximate mean response rate of 7% with a 95% confidence interval of (0.2%, 24%) and 
was determined via a meta-analysis of control therapies (see Section 9.6
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).
The posterior mean tBPAR rates for each treatment group and for the difference in mean 
response rates between treatments will be presented together with 95% credible intervals. 
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9.4.3
Supportive analyses
Part 2
The tBPAR(or BPAR)rate will be analyzed at 6 months and 12 months post transplantation 
using the same method as described for the month 3 analysis inSection 9.4.2.
9.5
Analysis of secondary and exploratory variables
9.5.1
Efficacy
Other efficacy variables will be analyzed similarly to the primary efficacy endpoint, although 
without the non-inferiority test:
tBPAR at Months 3, 6 and 12
BPAR at Months 3, 6 and 12
Graft loss at Months 6 and 12
Death at Months 6 and 12
Graft loss or death at Months 6 and 12
AntibodymediatedtBPAR at Month 12
For each of the efficacy endpoints (primary and secondary), simple event rate estimates 
(proportion of events) will be obtained and each CFZ533 treatment arm event rate will be 
compared with the control arm event rates using Z-statistics based on two-sided 95% 
confidence intervals for differences in event rates.
As supportive analyses, BPAR and tBPAR will also be analyzed using the adjudicated results.
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9.5.2
Pharmacodynamics
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Total soluble CD40 and total soluble CD154
These data will be summarized by treatment and subject. Descriptive statistics will also be 
provided such as mean, median, standard deviation, minimum and maximum, by time point 
and treatment.
9.5.3
Safety
Unless otherwise specified, safety analyses include all data collected, including after 
discontinuation of randomized treatment.
9.5.3.1
Main safety endpoint: estimated GFR using the MDRD formula
The key secondary and safety variable is renal function as assessed by eGFR (MDRD 
formula). This will be evaluated at Month 12 by comparing the mean eGFR values between 
groups.
The MDRD formula is defined as follows (Levey et al 2003):
GFR [mL/min/1.73m2] = 186.3*(C-1.154)*(A-0.203)*G*R 
C is the serum concentration of creatinine [mg/dL]
A is age [years]
G=0.742 when gender is female, otherwise G=1
R=1.21 when race is black, otherwise R=1.
Local laboratory serum creatinine values will be used for all renal function data analysis. 
Serum creatinine results are in units of umol/L, so the following formula should be used to 
convert to the required unit of mg/dL:
C[mg/dL] = serum concentration of creatinine [umol/L] / 88.4.
Estimated GFR will be determined and summarized in each part of the study. 
Handling of missing values/censoring/discontinuations
The analysis will be made on the FAS population. The following imputation method will be 
applied for patients with missing eGFR values:

Patients that lose their graft will be assigned a value of zero for their missing GFR value.

Patients that die or are lost to follow-up with a functioning graft will have an imputed 
value using the last-observation-carried-forward (LOCF) method.

For patients that discontinue randomized treatment the eGFR will be considered missing 
after applying the windows defined in Section 9.4.1.


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Graft loss patients do not have a functioning graft; hence the lowest possible GFR value (zero) 
will be assigned to such patients. In contrast, patients that die with a functioning graft, die for 
different reasons (e.g., suicide, car accident, cancer). Similarly, patients who are lost to 
follow-up have renal function, but missing values for various reasons (e.g., moving from the 
area or not being able to make the site visit during the Month 6 or Month 12 visit window). 
Patients who have a functioning graft at the time of death or are Lost to Follow-up with a 
functioning graft will be analyzed via an imputation method that employs LOCF.
9.5.3.2
Other safety endpoints
Vital signs
All vital signs data will be listed by treatment, 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, 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, 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 AEs will be displayed by treatment and subject.
AEs and infections collected are to be coded with the MedDRA dictionary that gives preferred 
term and primary system organ class information. AEs and infection preferred terms are to be 
analyzed as a whole under the heading of AEs for each treatment arm. The incidence of AEs 
will be summarized by body system, severity and relationship to study drug by the following:

AEs by primary SOC and PT

AEs rated to have relationship to study drug by SOC and PT

AEs by primary SOC, PT, and maximum severity

SAEs by SOC and PT

SAEs rated to have relationship to study drug by SOC and PT

Deaths by SOC and PT

AEs leading to discontinuation of a study drug by SOC and PT

AEs leading to dose adjustment or interruptions of a study drug by SOC and PT

infections by type of infection (viral, bacterial, fungal, and others) and microorganism 
of infection

serious infections by type of infection and micro-organism of infection

new onset diabetes mellitus (as defined in Section 6.6.4.4)


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
AEs by standardized MedDRA query (SMQ) levels (broad and narrow search)

AEs by standardized MedDRA query (SMQ) and preferred term (broad and narrow search)
Multiple Occurrences for Tables:
In all tables about incidence rates of AEs / Infections, if a patient has multiple occurrences of 
an AE, this patient will be counted only once in the corresponding AE category. If a patient 
has multiple AEs within a system organ class, s/he will be counted only once for that class. If 
a patient has multiple severity ratings for an AE while on treatment, s/he is only counted 
under the maximum rating. 
Information pertaining to AEs noted during the study will be listed by patient, includ ing the 
verbatim term given by the Investigator, the PT and SOC given by the MedDRA dictionary, 
start and end date, causality, severity, and relationship to study drug as assessed by the 
Investigator.
BK-polyoma viremia and nephropathy 
The following variables will be analyzed descriptively:

occurrence of BK-polyoma viremia any time post-transplantation “on treatment”

occurrence of BK-polyoma viremiaany time after switching a patient to SoC treatment

occurrence of BK-polyoma virus nephropathy any time post-transplantation “on treatment”

occurrence of BK-polyoma viremia any time after switching a patient to SoC treatment.
The difference of the investigational regimens to the control regimen will be summarized by 
risk ratios and appropriate CIs.
EBV, CMV and TB
All EBV, CMV and TB surveillance data will be listed by treatment, subject, and visit/time 
and if normal ranges are available, abnormalities will be flagged. Summary statistics will be 
provided by treatment and visit/time.
Laboratory data 
Abnormalities according to clinically notable criteria will be identified. A by-subject listing of 
individual subject laboratory data will be generated. Values outside of the clinically notable 
limits will be flagged. Shift tables describing changes from randomization/enrollment based 
on the clinical notable criteria will be presented. 
Descriptive statistics (mean, standard deviation, minimum, median and maximum) of 
quantitative laboratory variables, including change from randomization/enrollment, will be 
generated by visit.


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New onset diabetes mellitus (NODAT)
The incidence of subjects developing new onset diabetes mellitus after transplantation 
(NODAT) will be summarized by treatment group. The probabilities of developing NODAT 
will be compared between treatment groups at 6 and 12 months post-transplant using logistic 
regression models with HbA1c levels at randomization/enrollment as predictive variables. 
Death, graft loss, or loss to follow up without NODAT before Month 12 will not be counted 
as developingNODAT. This analysis will be performed using subjects in the FAS population 
who do not have DM at randomization/enrollment.
9.5.4 
Model based dose-exposure response analysis
Not applicable.
9.5.5 
Pharmacokinetics
CFZ533 plasma concentration data will be listed by treatment, subject, and visit/sampling 
time point. Descriptive summarystatistics will be provided by treatment and visit/sampling 
time point, includingthe frequency (n, %) of concentrations below the LLOQ, which will be 
reported as zero. Summary statistics will include mean (arithmetic and geometric), SD, CV 
(arithmetic and geometric), median, minimum and maximum. Concentrations below LLOQ 
will be treated as zero in summary statistics. A geometric mean will not be reported if the 
dataset includes zero values.
If data permit, PKparameters will be calculated as described in Section6.7.3and will be 
listed by treatment and subject. Concentrations below the limit of quantification will not be 
considered for the calculation of PKparameters. Descriptivesummary statistics will include 
mean (arithmetic and geometric), SD, and CV (arithmetic and geometric), median, minimum 
and maximum. Anexception to this is Tmax where median, minimum and maximum will be 
presented.
A dose-independent, model-based analysis of IV and SC dosing may be used to determine the 
bioavailability of the SC administration in this study (see Section6.7.3for more details). 
Also,any dose(concentration)-exposure relationship should be derived using same the 
approach. Such analysis willbe reported in a separate standalone report.
9.5.6
Pharmacokinetic / pharmacodynamic interactions
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The relationship between CFZ533 concentration (PK)and PD variables will be explored 
graphically. Modeling of PK/PD data using a population approach may be performed as 
appropriate and will be reported in a separate standalone report.The broad principles outlined 
in the FDA Guidance for Industry: Population Pharmacokinetics will be followed.


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Drug-drug interactions
This study is also collecting data to document potential Therapeutic Protein Drug Interactions 
(TPDI) when CFZ533 is given in combination with mycophenolate mofetil and Tacin 
denovokidney transplant patients.
To evaluate the potential for CFZ533 to cause TPDI via indirect (target binding) mechanisms, 
an exploratory population pharmacokinetic (PPK) approach may be conducted,aiming to 
identify unexpected TPDIs with planned co-therapies (monitoring trough concentrations of 
Tac and MPA), and to provide a first risk assessment in de novo
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transplant patients. 
Thisapproach is aiming to evaluate CFZ533 (i) as a perpetrator, with potential interactions 
with drugs specific to the target indication (mycophenolate mofetil and Tac), or (ii) as a 
victim drug, treating concomitant medications as covariates, by assessing a drug interaction 
effect on clearance.This exploratory approach should be generating hypothesis, with findings 
to be confirmed through a prospective pooled PPK approach based on data collected in Phase 
III and Phase II, to ensure unbiased and conclusive analysis results.
Such exploratory analysis applying a population pharmacokinetic approach may be reported 
in a separate standalone modeling report.


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9.6
Sample size calculation
All Parts: 
The stopping rules as defined in Section 5.5.10 are designed to ensure that a CFZ533 
treatment arm will be stopped if there is a high probability (>90%) that the true tBPAR rate is 
greater than 20%. 
Figure 9-1 indicates the probability of stopping for an arm for various true tBPAR rates and 
shows that the stopping rules ensure that the chance of stopping an arm are sufficiently high 
for true high tBPAR rates while remaining appropriately low when the true rates are low.
Figure 9-1
Probability of stopping a cohort for various true tBPAR rates
Part 2
Operating characteristics
The sample size justification for Part 2 considers the probability of progressing further 
development or not progressing based on the planned safety stopping rules and the success 
criteria for the planned sample size. 
The safety stopping rules (see Section 5.5.10) ensure that the study will not continue if:
Pr (θCFZ533 >0.20 | data) > 90%


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The success criteria (see Section 9.4.2) are met if:
Pr (θCFZ533 – θSoC <0.20 | data) > 60%.
Figure 9-2 shows the chances of continuing development (i.e., of not meeting the safety 
stopping rules and meeting the success criteria) on the y-axis for a range of true values of the 
tBPAR rate for CFZ533 (x-axis) and for three possible control rates (blue and grey curves). 
The probability of moving is high when CFZ533 has a low true tBPAR rate and is comparable 
to control. For example, if the true CFZ533 rate is less than 20% and the true control rate is 
around 10%, there is a greater than 80% probability of progressing to Part 3.
Conversely, when the true tBPAR rate for CFZ533 is high, the probability of not continuing is 
high. For example, there is an approximately 80% probability of not progressing when the 
true CFZ533 rate is more than 25% greater than the true control rate. 
Figure 9-2
Probability of progressing for different true values of tBPAR for 
CFZ533 and control


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These calculations assume that the primary efficacy variable, rate of tBPAR, follows a 
binomial distribution. The prior distribution for the control tBPAR rate, Beta(1, 13is 
estimated from a Bayesian meta-analysis of tBPAR rates from four previous studies using a 
control treatment similar to the one used in this study. The four studies were selected from the 
studies used in a previous Novartis generated meta-analysis studies and are summarized in 
Table 9-1.
Table 9-1
Summary of historical control data
Study
Treatment 
Number of 
patients with 
tBPAR
Total number 
of patients
tBPAR rate
1 - Vincenti et al 2007
B+Tac+MMF+CS
24
346
0.069
2 - Silva et al 2007
B+Tac XL+MMF+CS
17
214
0.079
3 - Silva et al 2007
B+Tac+MMF+CS
8
212
0.038
4 - Scholten et al 2006
B+Tac+ MMF(0.5g)+CS
4
63
0.063
B=basiliximab
Prediction of the control rate for a future trial resulting from the Bayesian meta-analysis is 
shown in Figure 9-3.
Figure 9-3
Results of Bayesian meta-analysis prediction
Figure 9-3 shows estimates of response rate and 95% credible intervals for each study based on study 
data alone (dashed lines) and from the meta-analysis (solid lines). The overall prediction for response
rate in a future study is shown in red together with the mean and 95% credible interval from the 
posterior distributions and n*, the prior number of observations that these data would contribute to a 
future analysis.


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To allow for a simple randomization ratio for allocation of patients to treatment groups, it was 
decided to reduce the control arm to 15 patients, compared to 30 for the CFZ533 arms. Thus a 
prior beta distribution of Beta (1, 13) was chosen, which has a mean value of 7 with 95% CI 
(0.2, 24) and an approximate weight of 14 patients.
9.7
Power for analysis of key secondary variables
Table9-2provides 80% and 95% CIs for between-treatment difference (CFZ533-control 
regimen) based on an assumed SD and difference for eGFR
MDRD. Since this is an exploratory 
phase 2 trial, evidence of renal benefit will be based on a 80% CI. In line with the 
SYMPHONY study (Ekbergetal2007), a difference of 6.5 mL/min/1.73m
2 between 
treatment regimens is considered to be the lower limit of clinically relevant benefit.
Table 9-2
Two-sided 80 and 95 percent example CIs for between-treatment 
difference (CFZ533-Control regimen) of calculated eGFR (MDRD), 
assuming dropout rate = 30 percent (n = 53/group)
Observed Standard 
Deviation
Observed difference in eGFRMDRD
CFZ533 –control
80% CI
95% CI
16
4.0
(-0.0, 8.0)
(-2.2,10.2)
5.0
(1.0, 9.0)
(-1.2, 11.2)
6.0
(2.0, 10.0)
(-0.2, 12.2)
7.0
(3.0, 11.0)
(0.8, 13.2)
8.0
(4.0, 12.0)
(1.8, 14.2)
18
4.0
(-0.5, 8.5)
(-3.0,11.0)
5.0
( 0.5, 9.5)
(-2.0,12.0)
6.0
( 1.5,10.5)
(-1.0,13.0)
7.0
( 2.5,11.5)
( 0.0,14.0)
8.0
( 3.5,12.5)
( 1.0,15.0)
20
4.0
(-1.0, 9.0)
(-3.7, 11.7)
5.0
(-0.0, 10.0) 
(-2.7, 12.7)
6.0
(1.0, 11.0)
(-1.7, 13.7)
7.0
(2.0, 12.0)
(-0.7, 14.7)
8.0
(3.0, 13.0)
(0.3, 15.7)
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10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented 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.
10.2
Informed consent procedures
Corporate Confidential Information
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative of the subject. 
In cases where the subject’s representative gives consent, the subject should be informed 
about the study to the extent possible given his/her understanding. If the subject is capable of 
doing so, he/she should 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 (i.e., all of the procedures described in the protocol). 
The process of obtaining informed consent should be documented in the subject source 
documents.
Novartis will provide to Investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 


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considered appropriate for this study. Any changes to the proposed consent form suggested by 
the Investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential should be informed that taking the study drug 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 for the duration 
of the study. If there is any question that the subject will not reliably comply, they should not 
be entered in the study.
In the event that Novartis wants to perform testing on the samples that are not described in 
this protocol, additional Institutional Review Board and/or Ethics Committee approval will be 
obtained.
10.3
Responsibilities of the investigator and IRB/IEC
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC/REB, must be given to 
Novartis before study initiation. 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 Clinical 
Quality Assurance representatives, designated agents of Novartis, IRBs/IECs/REBs, 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.
10.4
Publication of study protocol and results
Corporate Confidential Information
Novartis assures that 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.


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11
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 should an 
Investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If the 
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/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.
11.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for subject safety may be implemented prior to 
IRB/IEC/REB approval. 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, Novartis should be notified of this action and the Health Authorities 
(where required) and the IRB/IEC/REB at the study site should be informed within 
10 working days or less, if required by local regulation.


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References
Available upon request.
Andrassy J, Zeier M, Andrassy K (2004) Do we need screening for thrombophilia prior to 
kidney transplantation? Nephrol Dial Transplant: 19(Suppl 4): iv64.
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Diabetes Care;33(Suppl 1):S62-9.
Astragraf XL™ (tacrolimus extended release capsules) package insert, NDA 204096: Astellas, 
approved July 19, 2013 
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14th February 2014)
CellCept® (mycophenolate mofetil 500 mg tablets) package insert, NDA 050722: Roche, 
revised label approved September 27, 2013, original June 19, 1997 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050722s030s031,050723s029s030
,050758s028s029,.pdf (Accessed on 14th February 2014)
CHMP guideline on clinical investigation of immunosuppressants in solid organ 
transplantation (2009) 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC5
00003593.pdf (accessed 14th February 2014)
Clatworthy MR (2011) Targeting B cells and antibody in transplantation. Am J 
Transplant;11:1359-67.
Contin C, Pitard V, Delmas Y, et al (2003) Potential role of soluble CD40 in the humoral 
immune response impairment of uraemic patients. Immunology;110(1):131-40.
DerSimonian R and Laird N (1986) Meta-analysis in clinical trials. Controlled Clinical 
Trials;7:177-88.
Ekberg H, Tedesco-Silva H, Demirbas A, et al (2007) Reduced exposure to calcineurin 
inhibitors in renal transplantation. N Engl J Med;357(25):2562-75.
FDA Workshop, 2012: Endpoints in Clinical Trials of Kidney Transplantation. Transcript at 
http://www.fda.gov/Drugs/NewsEvents/ucm305308.htm
Food and Drug Administration CDER Statistical Review of BLA 125288/S-0000 (June 15, 
2011) http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/125288Orig1s000StatR.pdf 
(Accessed on 14th February 2014)
Goldwater R, Keirns J, Blahunkab P, et al (2013) A phase 1, randomized ascending single-
dose study of antagonist anti-human CD40 ASKP1240 in healthy subjects. Am J 
Transplant;13:1040-6.
Harland R, Klintmalm G, Yang H, et al. (2015) ASKP1240 in De Novo Kidney Transplant 
Recipients. Am J Transplant;15(S3):Abstract # 3012


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Hochberg Y (1988) A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika;75(4):800-2.
Kaplan EL and Meier P (1958). Nonparametric estimation from incomplete observations. J 
Am Statist Assoc;53(282):457-81.
Kasiske BL, Israni AK, Snyder JJ, et al (2011) The relationship between kidney function and 
long-term graft survival after kidney transplant. Am J Kidney Dis;57(3):466-75.
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. J Rheumatology;34(2):353-8.
Levey A, Coresh J, and Balk E (2003) National Kidney Foundation Practice Guidelines for 
Chronic Kidney Disease: Evaluation, Classification, and Stratification. Ann Intern 
Med;139:137-147.
Lougaris V, Badolato R, Ferrari S, et al (2005) Hyper immunoglobulin M syndrome due to 
CD40 deficiency: clinical, molecular, and immunological features. Immunol Rev;203:48-66.
Lowe PJ, Tannenbaum S, Wu K, et al (2010) On setting the first dose in man: quantitating 
biotherapeutic drug-target binding through pharmacokinetic and pharmacodynamic models. 
Basic & Clinical Pharmacology & Toxicology;106(3):195-209.
Ma A, Dun H, Song L, et al (2014) Pharmacokinetics and pharmacodynamics of ASKP1240, 
a fully human anti-CD40 antibody, in normal and renal transplanted Cynomolgus monkeys. 
Transplantation;97(4):397-404
Matas AJ, Smith JM, Skeans MA, et al (2013) OPTN/SRTR Annual Data Report: Kidney. 
Am J Transplant;13(Suppl 1):11-46.
Naesens M, Kuypers DR and Sarwal M (2009) Calcineurin inhibitor nephrotoxicity. Clin J 
Am Soc Nephrol;4(2):481-508.
Nulojix® (belatacept) package insert, BLA 125288: Bristol Myers Squibb, revised label 
approved April 8, 2013, original June 15, 2011. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125288s030lbl.pdf (Accessed on 
14th February 2014)
Okimura K, Maeta K, Kobayashi N, et al. (2014) Characterization of ASKP1240, a fully 
human antibody targeting human CD40 with potent immunosuppressive effects. Am J 
Transplant;14(6):1290-1299
Prograf® (tacrolimus capsules) package insert, NDA 050708: Astellas, revised label 
September 4, 2013, approved April 8, 1994. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050708s043,050709s036lbl.pdf 
(Accessed on 14th February 2014)


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Scholten EM, Rowshani AT, Cremers S, et al (2006) Untreated rejection in 6-month protocol 
biopsies is not associated with fibrosis in serial biopsies or with loss of graft function. J Am 
Soc Nephrol;17:2622-32.
Schwabe RF, Engelmann H, Hess S, et al (1999) Soluble CD40 in the serum of healthy 
donors, patients with chronic renal failure, haemodialysis and chronic ambulatory peritoneal 
dialysis (CAPD) patients. Clin Exp Immunol;117(1):153-8.
Simulect® (basiliximab) package insert, BLA 103764: Novartis, revised label approved 
September 2005, original May 12, 1998. 
http://www.pharma.us.novartis.com/product/pi/pdf/simulect.pdf (Accessed on 14th February 
2014)
Silva HT, Yang HC, Abouljoud M, et al (2007) One-year results with extended-release 
tacrolimus/ MMF, tacrolimus/MMF and cyclosporine/MMF in de novo kidney transplant 
recipients. Am J Transplant;7:595-608.
Sis B, Mengel M, Haas M, et al (2010) Banff 09 meeting report: antibody mediated graft 
deterioration and implementation of Banff working groups. Am J Transplant;10:464-71.
Solez K, Colvin RB, Racusen LC, et al (2008) Banff 07 classification of renal allograft 
pathology: updates and future directions. Am J Transplant;8:753-60.
Sood P, Senanayake S, Sujeet K, et al (2012) Management and outcome of BK viremia in 
renal transplant recipients: a prospective single-center study. Transplantation;94(8):814-21.
Tabrizi MA and Roskos LK (2007) Preclinical and clinical safety of monoclonal antibodies. 
Drug Discov Today;12(13-14):540-7.
van Kooten C and Banchereau J (2000). CD40-CD40 ligand. J Leukoc Biol;67(1):2-17.
Vincenti F, Charpentier B, Vanrenterghem Y, et al (2010). A phase III study of belatacept-
based immunosuppression regimens versus cyclosporine in renal transplant recipients 
(BENEFIT study). Am J Transplant;10:535-46.
Vincenti F, Mendez R, Pescovitz M, et al (2007) A phase I/II randomized open-label 
multicenter trial of efalizumab, a humanized anti-CD11a, anti-LFA-1 in renal transplantation. 
Am J Transplant;7:1770-7.
Vincenti F, Ramos E, Brattstrom C, et al (2001) Multicenter trial exploring calcineurin 
inhibitors avoidance in renal transplantation. Transplantation;71(9):1282-7.
Yang H, Vincenti F, Klintmalm G, et al (2012) A phase 1b, randomized, double-blind, 
parallel group, placebo-controlled, single-dose, pharmacokinetic, pharmacodynamic, Safety 
and tolerability study of ASKP1240 in de novo kidney transplantation [abstract]. 
Transplant;94(10S):80.


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Appendix 1: Sample Log table –all matrices
Blood Log (Part 1):
Corporate Confidential 
Information
Corporate 
Confidential 
Information


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Blood Log (Part 2):
Corporate 
Confidential 
Information
Corporate 
Confidential 
Information


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Appendix 2:
US-Specific CellCept(R) Pregnancy and Safety 
Information

Use of CellCept® during pregnancy is associated with an increased risk of first trimester 
pregnancy loss and an increased risk of congenital malformations, especially external ear 
and other facial abnormalities including cleft lip and palate, and anomalies of the distal 
limbs, heart, esophagus, and kidney.

Females of reproductive potential must be made aware of the increased risk of first 
trimester pregnancy loss and congenital malformations with MPA products and must be 
counseled regarding pregnancy prevention and planning.

For those females using Cellcept® at any time during pregnancy and those becoming 
pregnant within 6 weeks of discontinuing therapy, the Investigator or healthcare 
practitioner should report the pregnancy to the Mycophenolate Pregnancy Registry 
(1-800-617-8191). The Investigator or healthcare practitioner should strongly 
encourage the patient to enroll in the pregnancy registry.

Risks and benefits of CellCept® should be discussed with the patient. When appropriate, 
consider alternative immunosuppressants with less potential for embryofetal toxicity. 
In certain situations, the patient and her healthcare practitioner may decide that the 
maternal benefits outweigh the risks to the fetus. If this drug is used during pregnancy, or 
if the patient becomes pregnant while taking this drug, the patient should be apprised of 
the potential hazard to the fetus. 

To prevent unplanned exposure during pregnancy, females of reproductive potential 
should have a serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL 
immediately before starting CellCept®. Another pregnancy test with the same sensitivity 
should be done 8 to 10 days later. Repeat pregnancy tests should be performed during 
routine follow-up visits. Results of all pregnancy tests should be discussed with the patient.

Females of reproductive potential taking CellCept® must receive contraceptive counseling 
and use acceptable contraception (see Table 14-1 for Acceptable Contraception Methods). 
Patients must use acceptable birth control during entire CellCept® therapy, and for 
6 weeks after stopping CellCept®, unless the patient chooses abstinence (she chooses to 
avoid heterosexual intercourse completely).

Patients should be aware that CellCept® reduces blood levels of the hormones in the oral 
contraceptive pill and could theoretically reduce its effectiveness.


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Table 14-1
Acceptable Contraception Methods for Females of Reproductive 
Potential*
Option 1
Methods to Use Alone
Intrauterine device (IUD)
Tubal sterilization
Patient’s partner had a vasectomy
OR
Option 2
Choose One Hormonal 
Method AND One Barrier 
Method
Hormone Methods
choose 1
Barrier Methods
choose 1
Estrogen and 
Progesterone
Oral contraceptive pill
Transdermal patch
Vaginal ring
Progesterone-only
Injection
Implant
AND
Diaphragm with spermicide
Cervical cap with spermicide
Contraceptive sponge
Male condom
Female condom
OR
Option 3
Choose One Barrier Method 
From Each Column (must 
choose two methods)
Barrier Methods
choose 1
Barrier Methods
choose 1
Diaphragm with 
spermicide
Cervical cap with 
spermicide
Contraceptive sponge
AND
Male condom
Female condom
*Females of reproductive potential include girls who have entered puberty and all women who have a 
uterus and have not passed through menopause.


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Appendix 3:
Stopping rules 
Transition rules are based on both efficacy and safety results from Part 2. In Part 2, treatment 
arms are as follows:

A: CFZ533 10mg/kg (IV);

B is Control
Then the rules are as follows:

If A is terminated for any reason, then STOP the study.
The following rules are for terminating treatment group(s) from Part 2:
For safety:

Terminate the treatment group if there are two (2) or more patients presenting with 
PTLD or PML in that group.

For toxicities, AEs / infections, and causalities, case-by-case review is needed to 
determine any treatment group(s) should be terminated.
For efficacy (based on the number of patients with tBPAR):

If no tBPAR for SoC, then any group with tBPAR ≥ 7 will be terminated.

If one tBPAR for SoC, then any group with tBPAR ≥ 8 will be terminated.

If more than one tBPAR for SoC, then any group with tBPAR ≥ 9 will be terminated.


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Appendix 4:
Guidelines for MMF dose reduction
An Investigator may interrupt temporarily or reduce the dosage of study medication MMF 
if in his/her opinion this is clinically warranted, in response to any causally associated AE 
(e.g., neutropenia, thrombocytopenia, leucopenia, hyperlipidemia, hypertriglyceridemia or 
gastrointestinal intolerance). The following guidelines should be followed:
Dose reduction or temporary interruption may be performed for MMF
Implementation of dose reduction will be based on thrombocytopenia, leukopenia, 
neutropenia, or other AEs which are suspected to be related to study medication, and in the 
opinion of the Investigator, are clinically warranted. The following guidelines should be used 
for both dose reduction and, once the event has resolved, restarting or increasing the dose of 
MMF back to original levels. 
Dose Reduction Guidelines
Platelets

platelet count < 100,000/mm³dose may be reduced at the discretion of the Investigator

platelet count < 75,000/mm³ a second dose reduction should be considered

platelet count < 50,000/mm³ MANDATORY interruption of medication
WBC

WBC < 3500/mm³
dose may be reduced at the discretion of the Investigator

WBC < 2500/mm³
a second dose reduction should be considered

WBC < 2000/mm³ MANDATORY interruption of medication
All these changes must be recorded on the MMF Dosage Administration Record eCRF.


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Appendix 5:
Tacrolimus drug-drug interactions
Please refer to most recent national prescribing information for current labeling 
recommendations. 
Drug interactions
Due to the potential for additive or synergistic impairment of renal function, care should be 
taken when administering Tac with drugs that may be associated with renal dysfunction. 
These include, but are not limited to, aminoglycosides, amphotericin B, and cisplatin. Initial 
clinical experience with the co-administration of Tac and cyclosporine resulted in 
additive/synergistic nephrotoxicity.
Drugs that may alter tacrolimus concentrations
Since Tac is metabolized mainly by the CYP3A enzyme systems, substances known to inhibit 
these enzymes may decrease the metabolism or increase bioavailability of Tac as indicated by 
increased whole blood or plasma concentrations. Drugs known to induce these enzyme 
systems may result in an increased metabolism of Tac or decreased bioavailability as 
indicated by decreased whole blood or plasma concentrations. Monitoring of blood 
concentrations and appropriate dosage adjustments are essential when such drugs are used 
concomitantly.


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*Drugs that may increase tacrolimus blood concentrations
Calcium
Channel
Blockers
Antifungal
Agents 
Macrolide
Antibiotics
Gastrointestinal
Prokinetic
Agents
Other Drugs
diltiazem
nicardipine
nifedipine
verapamil
clotrimazole
fluconazole
itraconazole
ketoconazole**
voriconazole
clarithromycin
erythromycin
troleandomycin
cisapride
metoclopramide
bromocriptine
chloramphenicol
cimetidine
cyclosporine
danazol
ethinyl estradiol
methylprednisolone
lansoprazole***
omeprazole
protease inhibitors
nefazodone
magnesium-aluminum 
hydroxide
**In a study of 6 normal volunteers, a significant increase in Tac oral bioavailability (14±5% vs. 30±8%) 
was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of 
Tac during ketoconazole administration was significantly decreased compared to Tac alone 
(0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of Tac was not significantly 
changed by ketoconazole co-administration, although it was highly variable between patients.
*** Lansoprazole (CYP2C19, CYP3A4 substrate) may potentially inhibit CYP3A4-mediated metabolism 
of Tac and thereby substantially increase Tac whole blood concentrations, especially in transplant 
patients who are intermediate or poor CYP2C19 metabolizers, as compared to those patients who are 
efficient CYP2C19 metabolizers.
*Drugs that may decrease tacrolimus blood concentrations
Anticonvulsants
Antimicrobials
Herbal Preparations
Other Drugs 
carbamazepine
phenobarbital
phenytoin
rifabutin
caspofungin
rifampin
St. John’s Wort
sirolimus
* This table is not all inclusive.
St. John’s Wort (Hypericum perforatum) induces CYP3A4 and P-glycoprotein. Since Tac is a 
substrate for CYP3A4, there is the potential that the use of St. John’s Wort in patients 
receiving Tac could result in reduced Tac levels.
In a single-dose crossover study in healthy volunteers, co-administration of Tac and 
magnesium-aluminum hydroxide resulted in a 21% increase in the mean Tac AUC and a 10% 
decrease in the mean Tac Cmax relative to Tac administration alone.
In a study of 6 normal volunteers, a significant decrease in Tac oral bioavailability (14±6% vs. 
7±3%) was observed with concomitant rifampin administration (600 mg). In addition, there 
was a significant increase in Tac clearance (0.036±0.008 L/hr/kg vs. 0.053±0.010 L/hr/kg) 
with concomitant rifampin administration.


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Interaction studies with drugs used in HIV therapy have not been conducted. However, care 
should be exercised when drugs that are nephrotoxic (e.g., ganciclovir) or that are metabolized 
by CYP3A (e.g., nelfinavir, ritonavir) are administered concomitantly with Tac. Similarly, 
care should be exercised when HCV protease inhibitors (e.g., boceprevir and telaprevir), also 
metabolized by CYP3A, are administered concomitantly with Tac.
Tac may affect the PK of other drugs (e.g., phenytoin) and increase their concentration. 
Grapefruit juice affects CYP3A-mediated metabolism and should be avoided.
Other Drug Interactions
Immunosuppressants may affect vaccination. Therefore, during treatment with Tac, 
vaccination may be less effective. The use of live vaccines should be avoided; live vaccines 
may include, but are not limited to measles, mumps, rubella, oral polio, BCG, yellow fever, 
and TY 21a typhoid (Prograf® PI 1994) 


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Appendix 6:
Blinding and unblinding
Randomization data are kept strictly confidential. Prior to final clinical database lock, 
unblinding is allowed only for authorized personnel as described in the table below.
Table 18-1
Blinding levels
Time or Event
Role
1
2
3
4
5
6
7
Drug Supply
UI
UI
UI
UI
UI
UI
UI
Randomization Office
UI
UI
UI
UI
UI
UI
UI
Subject
B
B
UI
UI
UI
UI
UI
Treating Physician
B
B
UI
UI
UI
UI
UI
Primary Investigator
B
B
UI
UI
UI
UI
UI
Study Monitor
B
B
UI
UI
UI
UI
UI
Clinical Trial Leader
B
B
B
UI
UI
UI
UI
Data Manager
B
B
UI
UI
UI
UI
UI
PK Bioanalytics
B
UI
UI
UI
UI
UI
UI
PK Expert
B
B
B
UI
UI
UI
UI
Statistician
B
B
B
UI
UI
UI
UI
Translational Medicine Expert
B
B
B
UI
UI
UI
UI
Modeler
B
B
B
UI
UI
UI
UI
Programmer 
B
B
B
UI
UI
UI
UI
Data Monitoring Committee
B
B
B
UI
UI
UI
UI
UG Allowed to be unblinded on treatment group level
UI
Allowed to be unblinded on individual patient level
B
Remains blinded
1
Generation of randomization list, QC and lock randomization list
2
Patient allocation to treatment
3
Treatment administration
4
Safety emergency event (unblinding of a single subject)
5
Interim analysis (all patients included in the analysis have completed the study)
6
Interim analysis (some patients included in the analysis have not yet completed the study)
7
Database lock


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Appendix 7: Clinically notable laboratory values
Laboratory variable
Standard units SI units
Liver function and related variables
SGOT (ASAT)
≥3 × ULN
≥3 × ULN
SGPT (ALAT)
≥3 × ULN
≥3 × ULN
Bilirubin
≥3 × ULN
≥3 × ULN
Renal function, metabolic and electrolyte variables
Urea 
5 ULN 
5 ULN
Creatinine 
After Wk4: ≥3 mg/dL
After Wk4: ≥265 μmol/L
OR
OR
>30% above value
>30% above value
from preceding visit
from preceding visit
Uric acid 
M ≥12 mg/dL
M ≥714 μmol/L
F ≥9 mg/dL
F ≥535 μmol/L
Glucose 
<45 mg/dL
<2.5 mmol/L
>250 mg/dL
>13.9 mmol/L
Cholesterol 
≥350 mg/dL
≥9.1 mmol/L
Triglycerides 
≥750 mg/dL
≥8.5 mmol/L
CK (MB) 
None
None
Potassium 
≤3.0 mEq/L
≤3 mmol/L
≥6.0 mEq/L
≥6 mmol/L
Calcium 
≤6 mg/dL
≤1.5 mmol/L
≥13 mg/dL
≥3.2 mmol/L
Hematology variables
Hemoglobin
<7 g/dL
<4.39 mmol/L
Platelets (thrombocytes)
<50 k/mm3
<50 × 109/L
≥700 k/mm3
≥700 × 109/L
Leukocytes (WBCs)
≤2.0 k/mm3
≤ 2.0 × 109/L
≥16 k/mm3
≥16 × 109/L
Hematology variables: differential
Granulocytes (poly, neutrophils)
≤1,000/mm3
≤1 x 109/L
Eosinophils 
≥12%
≥12%
Lymphocytes 
≤1,000/mm3
≤1× 109/L
Vital sign variables
Notable criteria
Systolic BP (mm/Hg)
outside of 90≤ SBP ≥200 mm/Hg
Diastolic BP (mm/Hg)
outside 50≤ DBP ≥120 mm/Hg


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20
Appendix 8: Banff ’09 Meeting Report: Antibody Mediated 
Graft Deterioration and Implementation of Banff Working 
Groups 1 

Normal

Antibody-mediated rejection – due to circulating anti-donor antibodies, C4d, and allograft 
pathology:
C4d deposition without morphologic evidence of acute rejection – C4d, anti-donor 
antibodies, no signs of acute or chronic rejection, no ATN-like minimal inflammation.
Acute antibody-mediated rejection – C4d, anti-donor antibodies, and acute tissue injury, 
such as: (“suspicious for” if antibody not demonstrated)

Type I – ATN-like minimal inflammation

Type II – Capillary involvement and/or thromboses

Type III – Arterial changes

Chronic antibody-mediated rejection – evidence of chronic tissue such as glomerular 
double contours, peritubular capillary basement membrane multilayering, interstitial 
fibrosis/tubular atrophy (IFTA), or fibrous intimal thickening in arteries. Borderline 
changes “suspicious” for acute T cell-mediated cellular rejection. No intimal arteritis 
present, but there are foci of mild tubulitis with mild interstitial infiltration. Threshold for 
rejection diagnosis is not met.

T cell mediated rejection

Type IA - Significant interstitial infiltration (> 25% of parenchyma) and foci of 
moderate tubulitis (> 4 mononuclear cells/tubular cross section or group of 10 tubular 
cells).

Type IB - Significant interstitial infiltration (> 25% of parenchyma) and foci of severe 
tubulitis (> 10 mononuclear cells/tubular cross section or group of 10 tubular cells).

Type IIA - Mild to moderate intimal arteritis

Type IIB - Severe intimal arteritis comprising > 25% of the lumenal area

Type III - Transmural (full vessel wall thickness) arteritis and/or arterial fibrinoid 
change and necrosis of medial smooth muscle cells (with accompanying lymphocytic 
inflammation)

Interstitial fibrosis and tubular atrophy**

Grade I - Mild interstitial fibrosis and tubular atrophy without (a) or with (b) specific 
changes suggesting chronic rejection

Grade II - Moderate interstitial fibrosis and tubular atrophy (a) or (b)

Grade E III - Severe interstitial fibrosis and tubular atrophy and tubular loss (a) or (b)


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
Other: Changes not considered to be due to rejection (e.g., post-transplant 
lymphoproliferative disorder, nonspecific changes, acute tubular necrosis, etc.), 
specifically:

Chronic hypertension - Arterial/fibrointimal thickening with reduplication of elastica, 
usually with small artery and arteriolar hyaline changes.

Calcineurin toxicity - Arteriolar hyalinosis with peripheral hyaline nodules and/or 
progressive increase in the absence of hypertension or diabetes. Tubular cell injury 
with isometric vacuolization.

Chronic obstruction - Marked tubular dilatation. Large Tamm-Horsfall protein casts 
with extravasation into interstitium, and/or lymphatics.

Acute bacterial pyelonephritis - Intratubular and peritubular neutrophils with 
destruction of the tubular epithelium.

Viral infection - Viral inclusions on histology and immunohistology and/or electron 
microscopy.
*The recommended format of report is a descriptive narrative signet followed by numerical 
codes (Banff ‘09) in parentheses. Categorization should in the first instance be based solely on 
pathologic changes, and then integrated with clinical data as a second step. More than one 
diagnostic category may be used if appropriate.
**Glomerular and vascular lesions help define type of chronic nephropathy; chronic/recurrent 
rejection can be diagnosed if typical vascular lesions are seen. Grades I, II and III may include 
nonspecific vascular and glomerular sclerosis, but severity is graded by tubulointerstitial 
features.
1 (Sis et al 2010)

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
CFZ533
CCFZ533X2201
A 12-month randomized, multiple dose, open-label, study 
evaluating safety, tolerability, 
pharmacokinetics/pharmacodynamics (PK/PD) and efficacy 
of an anti-CD40 monoclonal antibody, CFZ533, in 
combination with mycophenolate mofetil (MMF) and 
corticosteroids(CS), with and without tacrolimus (Tac), in 
de novorenal transplant recipients
Statistical Analysis Plan (SAP)–Part 2
Document type:
Part 2 -SAP Documentation –NIBR 
Document status:
FinalAmendment 2
Release date:
16-Jan-2018
Number of pages:
26
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May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents.................................................................................................................3
List of tables........................................................................................................................4
1 Introduction.........................................................................................................................5
1.1
Scope of document..................................................................................................5
1.2
Study reference documentation...............................................................................5
1.3
Study objectives.......................................................................................................5
1.3.1
Primary objective....................................................................................5
1.3.2
Secondary objectives...............................................................................5
1.4
Study design and treatment......................................................................................6
1.4.1
General overview....................................................................................6
1.4.2
Part 2 –Arms 2A-2B...............................................................................7
1.4.3
Study “stopping” rules............................................................................8
2 First interpretable results (FIR).........................................................................................10
4 Statistical methods: Analysis sets......................................................................................10
5 Statistical methods for Pharmacokinetic (PK) parameters................................................11
5.1
Variables................................................................................................................11
5.2
Descriptive analyses..............................................................................................11
5.2.1
Graphical presentation of results...........................................................12
6 Statistical methods for Pharmacodynamic (PD) parameters.............................................12
6.1
Primary objective...................................................................................................12
6.1.1
Variables...............................................................................................12
6.1.2
Descriptive analyses..............................................................................12
6.1.3
Statistical model, assumptions and hypotheses.....................................12
6.1.4
Supportive analyses...............................................................................13
6.1.5
Adjudication analyses...........................................................................14
6.2
Secondary and exploratory objectives...................................................................14
6.2.1
Variables...............................................................................................14
6.2.2
Descriptive analyses..............................................................................17
6.2.3
Statistical model, assumptions and hypotheses.....................................18
7 Statistical methods for safety and tolerability data............................................................19
7.1.1
Variables...............................................................................................19
7.1.2
Descriptive analyses..............................................................................19
Special clinical laboratory evaluations..............................................................................
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Tuberculosis surveillance..................................................................................................24
Pregnancy test....................................................................................................................24
7.1.3
Graphical presentation..........................................................................25
9 Reference list.....................................................................................................................26
List of tables
Figure 1-1CCFZ533X2201 study design.................................................................................7
Figure 1-2Part 2 Design............................................................................................................8
Table 1-1 Studystopping rules for tBPAR..............................................................................9
Table 7-1 Demographic variables and disease characteristics...............................................
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1
Introduction 
1.1
Scope of document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CCFZ533X2201” Part 2 
only.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
This SAP has been developed using Clinical Trial Protocol version v02 (incorporating 
Amendment 02) dated 11 April 2016.
1.3
Study objectives
1.3.1
Primary objective

To assess the potential for CFZ533 to act as the primary immunosuppressant in a 
CNI-free regimen with MMF in de novo renal transplant patients as assessed by 
tBPAR at Month 3 post-transplantation.
1.3.2
Secondary objectives

To assess the safety and tolerability of CFZ533 administered chronically in 
combination with MMF and CS up to 3 months against a control

To assess the PK of multiple IV doses of CFZ533 during the 12-month treatment 
period

To quantify the magnitude and duration of peripheral blood CD40 occupancy (free 
CD40 and total CD40 on B cells) during the treatment period following multiple IV 
doses of CFZ533

To compare renal function in CFZ533 treatment arms to control at Month 3 post-
transplantation as assessed by:

Estimated GFR

Proportion of patients with eGFR < 60 mL/min/1.73 m2

Proportion of patients with negative eGFR slope

To evaluate the immunogenicity of multiple IV doses of CFZ533 via the quantitative 
analysis of anti-CFZ533 antibodies

To quantify the change from baseline and recovery of peripheral blood total soluble 
CD40 during the treatment period following multiple IV doses of CFZ533.
The assessment of safety and tolerability and comparison of renal function will also be 
assessed at Month 12.


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1.4
Study design and treatment
1.4.1
General overview
Study CCFZ533X2201 is a randomized, three-part, 6-or 12-month, sequential, adaptive, 
controlled, open-label, multicenter, clinical proof-of-concept study to evaluate the efficacy, 
safety, tolerability, PK and PD of CFZ533 + MMF + CS, with standard exposure (Part 1) or 
no Tac (Part 2, 3), for initial and maintenance prophylaxis of organ rejection in adult de novo
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renal transplant recipients as compared to standard of care. As illustrated in Figure 1-1, each 
study part will evaluate a set of CFZ533 doses or treatment regimens in a parallel arm manner.


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Figure1-1
CCFZ533X2201 study design
Study Part 2 will continue the investigation of efficacy, safety, tolerability, PK and PD with 
the addition of induction therapy and avoidance of Tac. The initial 3 months of Part 2 will 
serve as the CNI-free, clinical proof-of-concept (PoC), portion of this trial. During the PoC 
portion of this study, the ability of CFZ533 toassume the role of the primary 
immunosuppressant in a regimen of CFZ533+MMF and CS will be evaluated.
1.4.2
Part 2 –Arms 2A-2B
Approximately 45 patients who meet the inclusion criteria will be randomized in a 2:1 fashion 
within 12 hours pre-transplant to receive one of the 2 treatment arms:
1.  Arm 2A, n = 30: Basiliximab 20 mg (Days 0, 4) + CFZ533 at 10 mg/kg IV (17 doses) + 
MMF 1.0 g BID + CS
2.  Arm 2B Control/SoC, n = 15: Basiliximab 20 mg(Days 0, 4) + Tac (4-11 ng/mL) + MMF 
1.0 g BID + CS
Induction therapy must be started within 2 hours prior to transplantation, or according to local 
practice.
The first dose of CFZ533 will be administered IV pre-transplant or intra-operatively. Drug 
administration will begin after randomization and must be completed by thetime of 
unclamping or up to 6 hours prior to the time of unclamping. Subsequent doses of CFZ533 
will be administered IV (Arm 2A), over a period of 12 months.
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Other study drugs must be started within 24 hours post-transplant. The second dose of 
basiliximabwill be administered on Day 4, or according to local practice.
The day of randomization and transplant will be considered to be study Day 1. 
 
 
Patientswill then undergo Study Completion 
evaluations.
The primary endpoint of Part 2 will be assessed to determine whether the success criteria 
(safety and tBPAR) have been met when all patients have completed the Month 3 visit. If it is 
found that the data up to the Month 3 visit is inconclusive, a reevaluation (interim analysis) 
will occur after the Month 6 visit.
If the stopping rules are not met and the primary endpoint of Part 2 is fulfilled at Month 3, 
Part 3 (exposure-response profiling) will be initiated following consultation of the DMC. 
Cumulative efficacy and safety data will be collected on an ongoing basis during the conduct 
of the study.
Figure1-2
Part 2 Design
1.4.3
Study “stopping” rules
The following stopping rules based on potential toxicities will serve as the basis for placing 
the study on hold. Although the stopping criteria do not incorporate an absolute requirement 
for causality, the potential relationship between an AE and CFZ533 will be evaluated 
carefully on a case-by-case basis between the Sponsor and the Investigator. Following a 
review of the AE(s), a decision to permanently discontinue enrollment or re-initiate CFZ533 
dosing will be made by the DMC.
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
Two (2) or more patients presenting with post-transplant lymphoproliferative disease 
or progressive multifocal leukoencephalopathy in the CFZ533 treatment arm.
In addition, specific stopping rules for the incidence of tBPAR will be applied. These rules are 
designed to ensure that an arm will be stopped if there is high probability (> 90%) that the true 
tBPAR rate is greater than 20%. Based on this stopping rule, the maximum number of patients 
with tBPAR for various different illustrative sample sizes would be as follows:
Table 1-1
Study stopping rules for tBPAR
Total number of 
patients (N)
Number of patients with tBPAR that would lead 
to stopping the treatment arm (n)
Observed tBPAR rate (n/N)
3
2
0.67
4
2
0.50
5
3
0.60
6
3
0.50
7
3
0.43
8
4
0.50
9
4
0.44
10
4
0.40
11
5
0.45
12
5
0.42
13
5
0.38
14
5
0.36
15
6
0.40
16
6
0.38
17
6
0.35
18
6
0.33
19
7
0.37
20
7
0.35
21
7
0.33
22
7
0.32
23
8
0.35
24
8
0.33
25
8
0.32
26
8
0.319
27
9
0.33
28
9
0.32
29
9
0.31
30
9
0.30
In addition to the automatic hold criteria and tBPAR criteria presented above, the DMC will 
review safety data regularly as outlined in their charter during quarterly and ad hoc meetings. 
The DMC can recommend stopping a specific study arm(s) or the entire trial if significant 
changes or effects that, in their collective opinion, are deemed unsafe or unethical to continue 
administering CFZ533.


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2
First interpretable results (FIR)
First interpretable results (FIR) willbe provided for this trial.
4
Statistical methods: Analysis sets
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For patientsfor which the actual treatment received does not match the randomized treatment,
the treatment actually received will be used for the analysis.
The Full Analysis Set will include all patientsthat received at least one dose of study drug and 
who were transplanted.
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The modified Full Analysis Set (mFAS) will include all patients that received at least one 
dose of study drug and who were transplanted that also meet the following conditions:
Donor age < 65 years
Cold ischemic time (CIT) < 18 hours
HLA mismatches at DR locus
HLA total mismatches< 5
The Safety Analysis Set will include all patientsthat received at least one dose of study drug.
All patientsthat receive their transplant along with any patientwho receive study drug but 
have no transplant will be combined.
The PK analysis set will include all patientswith at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and experienced 
no protocol deviations with relevant impact on PK data.
The PD analysis set will include all patientsin the Full Analysis Set with any available PD 
data and no protocol deviations with relevant impact on PD data.
The protocol deviation codes are described in detail in the data management plan.
5
Statistical methods for Pharmacokinetic (PK) parameters
5.1
Variables 
If data permit, typical exposure metrics and parameters could be determined using the actual 
recorded sampling times and non-compartmental method(s) with WinNonlin Pro or Phoenix, 
including (but not limited to): Cmax, Cmin, Cmin,ss, Tmax, from the plasma concentration-
time data.
5.2
Descriptive analyses
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CFZ533 plasma concentration data will be listed by treatment, transplant status (if required), 
patient, and visit/sampling time point. Tac and MPA trough levels will be measured and listed 
by treatment, visit and patient.Ifdata permit, PK parameters will be calculated and listed by 
treatment and patient. Concentrations below the limit of quantification will not be considered 
for the calculation of PK parameters. Descriptive summary statistics will include mean 
(arithmetic and geometric), SD, and CV (arithmetic and geometric), median, minimum and 
maximum. An exception to this is Tmax where median, minimum and maximum will be 
presented. 


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5.2.1
Graphical presentation of results
The CFZ533 plasma concentration data (PK) will be presented graphically in a plot of the 
mean concentration (unit: µg/mL; log scale) overtime(unit: day; elapsed time since first 
dose),overlaying individual profiles over time with an overlaid mean and individual time-
concentration profiles by patient. 
6
Statistical methods for Pharmacodynamic (PD) parameters
6.1
Primary objective
6.1.1
Variables 
The primary variable is tBPAR after 3 months of treatment.
6.1.2
Descriptive analyses
The tBPAR data will be listed by treatment.  The data will be summarized and will include the 
number (percentage) of patientsthat have a tBPAR. 
6.1.3
Statistical model, assumptions and hypotheses
The number of patients with tBPAR is assumed to follow a binomial distribution, i.e.,
r
i ~ Binomial(ni, θ
i)
where ri is the number of patients with tBPAR in treatment group i, n
i is the number of patients
in treatment group i and θ
i is the probability of tBPAR.
The efficacy analysis for the first 3 months of Part 2 considers whether a CFZ533 treatment 
arm meets the pre-defined criteria for initiation of Part 3.
The pre-defined success criteria is considered to be a tBPAR rate difference between the 
CFZ533 arm and the control group of less than 20 percentage points with at least 60% level of 
proof.
Pr (θ
CFZ533 –θSoC <0.20 
| data) > 60%
The required posterior probabilities will be estimated from simulations of theposterior 
distributions of θCFZ533 -θ
SoC
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and compared to the thresholds for the levels of proof.
The prior distributions will be assumed to be a non-informative Beta(1/3, 1/3) for CFZ533 
and an informative prior of Beta(1, 13) for SoC. This informative prior corresponds to an 
approximate mean response rate of 7% with a 95% confidence interval of (0.2%, 24%) and 
was determined via a meta-analysis of control therapies.
The posterior mean tBPAR rates for each treatment group and for the difference in mean 
response rates between treatments will be tabulatedtogether with the 95% credible intervals, 
the number of patients with tBPAR and the posterior probabilities of being above the 
thresholds, 10%, 15%, 20%, 25%.


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6.1.3.1
Graphical presentation of results
A plot of the posterior probability distribution for the tBPAR rate and a bar chart 
corresponding to the posterior probability thresholds will be provided.
6.1.4
Supportive analyses
Kaplan-Meier estimates
In this analysis, patients who have not experienced tBPAR, will be censored with the 
censoring time as defined by the last contact day at or before the cut-off point (e.g., 1st IA 
Month 3 visit, 2nd IA Month 6 visit). The patients will be considered as completed at the date 
of their corresponding analysis cut-off point. In addition to the Kaplan-Meier plot, a log-rank 
test shall be performed to obtain estimates with CI’s for each treatment arm and the difference 
between treatment arms.
During data review, it was noticed that some patients were switched from the randomized 
treatment to another regimen. Therefore in future IA’s, more focus shall be placed on the 
Kaplan-Meier analysis.
Supportive Bayesian analysis
In addition the Bayesian analysis will be repeated with a model using a Poisson distribution to 
account for the patients that may switch treatment or discontinue early from the study. The 
following parametrization will be used:
The number of tBPAR events in group i is assumed to follow a Poisson distribution, i.e.
yi = Poisson(µi),
where µi is the expected number of events in group i, with 
µi = λi,T * ti.T,
with ti,T being the total follow up time in group i (times censored at treatment switch or 
discontinuation) up to analysis time point T and λi being the event rate in group i up to the 
analysis time point T. For sensitivity analysis of the primary analysis the analysis time point T 
is week 12 (i.e. week 13 visit, month 3 after transplantation). The probability of an tBPAR 
event occurring up to the analysis time point can then derived as θi = 1-exp(-λi * T).
The pre-defined success criteria is considered to be a difference in the probability of tBPAR
between the CFZ533 arm and the control group of less than 20 percentage points with at least 
60% level of proof.
Pr (θCFZ533 – θSoC <0.20 | data) > 60%
The required posterior probabilities will be estimated from simulations of the posterior 
distributions of θCFZ533 – θSoC and compared to the thresholds for the levels of proof.
The prior distributions will be assumed to be a non-informative Beta(1/3,1/3) for θCFZ533 and 
an informative prior of Beta(1, 13) for θSoC. 
The same outputs and presentations of the results as for the primary analysis will be provided. 
The analysis will be repeated for the adjudicated data when applicable.


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6.1.5
Adjudication analyses
Additional outputs will be provided for the adjudicated tBPAR data. The outputs to be 
provided include a listing of the data and summary statistics table, the primaryand supportive
Bayesian analysis tables and corresponding figures, and the Kaplan Meier analysis.
Adjudicated outputs will only be provided if all events can be assessed by the adjudication 
committee.
6.2
Secondary and exploratory objectives
6.2.1
Variables 
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Composite failure is a secondary variable where patients are defined to be failures if they 
experience any one of the following events
tBPAR
graft loss
death
A date is defined for all events (e.g. borderline rejection, acute rejection) on the rejection level. 
In case of several events of the same type (e.g. two acute rejections) the earliest will be chosen 
for the analysis on the patientlevel.  
The main part of the information for the efficacy evaluation comes from the Rejection eCRF 
page as well as the Biopsy eCRF page. For the derivation of the efficacy variables the 


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information from both pages need to be merged. The Rejection eCRF page is linked with the 
Biopsy eCRF page by the date of the (first) biopsy. Follow-up biopsies of the same rejection 
episode may be taken and are linked with the first biopsy by the date.
Borderline rejection
A biopsy is considered ‘borderline’ if, from the Biopsy eCRF page based on the pathologist’s 
assessment, “Borderline changes = Yes” on the Biopsy eCRF page. 
Acute rejection
Acute rejections are identified in the database from the Rejection eCRF page. One of the 
following conditions must be met:

Primary final clinical diagnosis indicates an acute rejection (either “acute rejection” or 
“acute and chronic rejection”)

OR Antibody mediated rejection = “Yes” from the Kidney allograft biopsy eCRF page 

OR Acute T-cell mediated rejection = “Yes” from the Kidney allograft biopsy eCRF page
The date of event is the “Date rejection was first suspected” from Rejection eCRF page, or if 
missing the date of the first biopsy of the particular rejection episode.
Treated acute rejection
Treated acute rejections are a subset of acute rejections.
A treated acute rejection is defined if the following criteria are fulfilled:

Acute rejection and

“Was anti-rejection therapy administered = Yes” from the Rejection eCRF page.  
The date of event is the “Date rejection was first suspected” from Rejection eCRF page, or if 
missing the date of the first biopsy of the particular rejection episode.
Treatments for acute rejection will be categorized into 3 groups: Steroids, Antibodies, and 
Other using the CRF information from the Rejection eCRF page (Were steroids administered? 
Was antibody treatment administered?).  
Biopsy-proven acute rejection (BPAR)
A rejection is considered a biopsy-proven acute rejection if the following criterion is fulfilled:
“Acute T-cell mediated rejection = Yes” or “Antibody mediated rejection = Yes” or 
Borderline changes = “Yes” from the Biopsy eCRF page 
The date of event is the “Date rejection was first suspected” from corresponding Rejection 
eCRF page, or if missing the date of the first biopsy of the particular rejection episode.
The BPAR episode can be classified into rejection types: t-cell mediated, antibody mediated, 
or a combination of those. 


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Acute antibody-mediated rejection (AMR)
A rejection is identified as an antibody-mediated rejection (also known as humoral rejections) 
if the following criterion is fulfilled:

“Antibody mediated rejection = Yes”  from the Biopsy eCRF page
The date of event is the “Date rejection was first suspected” from Rejection eCRF page, or if 
missing the date of the first biopsy of the particular rejection episode.
Treated biopsy-proven acute rejection (tBPAR)
Treated biopsy-proven rejections are a subset of biopsy-proven acute rejections. 
A treated biopsy-proven acute rejection is defined if the following criteria are fulfilled:

Biopsy-proven acute rejection and

“Was anti-rejection therapy administered = Yes” from the Rejection eCRF page.  
The date of event is the “Date rejection was first suspected” from Rejection eCRF page, or if 
missing the date of the first biopsy of the particular rejection episode.
Note that careful data cleaning is necessary to align the answer to “Was anti-rejection therapy 
administered?” with the concomitant medication eCRF page.
Steroid-treated biopsy proven acute rejection
Steroid-treated biopsy proven acute rejections are a subset of treated biopsy proven acute 
rejections. A steroid-treated biopsy proven acute rejection is defined if the following criteria 
are fulfilled:

Treated biopsy proven acute rejection and 

“Were steroids administered = Yes” on the Rejection eCRF.  
The date of event is the “Date rejection was first suspected” from Rejection eCRF page, or if 
missing the date of the first biopsy of the particular rejection episode.
Steroid-resistant biopsy proven acute rejection
Steroid-resistant biopsy proven acute rejections are a subset of steroid-treated biopsy proven 
acute rejections. A steroid-resistant biopsy proven acute rejection is defined if the following 
criteria are fulfilled:

Steroid-treated biopsy proven acute rejection and

“Was the rejection steroid resistant? = Yes” from the Rejection eCRF page 
The date of event is the “Date rejection was first suspected” from Rejection eCRF page, or if 
missing the date of the first biopsy of the particular rejection episode.
Antibody-treated biopsy proven acute rejection
Antibody-treated biopsy proven acute rejections (BPAR with T-cell depleting therapy) are a 
subset of treated biopsy proven acute rejections. It is a clinically significant sub-component of 
treated BPAR as a marker of severity. An antibody-treated biopsy proven acute rejection is 
defined if the following criteria are fulfilled. 


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Treated biopsy proven acute rejection and 
“Was antibody treatment administered = Yes”  from the Rejection eCRF page
The date of event is the “Date rejection was first suspected”from Rejection eCRF page, or if 
missing the date of the first biopsy of the particular rejection episode.
Sub-clinical biopsy proven acute rejection
A sub-clinical biopsy proven acute rejection is defined as a BPAR withoutclinical suspicion 
of a rejection i.e. a biopsy was performed without the suspicion of an acute rejection (e.g. 
center-driven local-routine biopsy, protocol driven biopsy, etc.) but the result of that biopsy 
shows histological evidence of an acute rejection (Banff classification):
BPAR and
“Clinical suspicion of an acute rejection = No” on the Kidney Allograft Rejection eCRFor 
Reason for biopsy = “Routine biopsy per local practice” from the Biopsy page.. 
The date of event is the date of biopsy. 
Graft Loss (GL)
The allograft will be presumed to be lost based on whichever of the following occurs first: the 
day the patientstarts dialysis and is not able to subsequently be removed from dialysis, the 
day of transplantectomy, or the day irreversible loss of graft perfusion is demonstrated by 
appropriate imaging techniques. Primary graft non-function is a subset of graft loss.
A patientwill be considered to have graft loss if in the Graft Loss eCRF page the following 
condition is met:
“Has subject suffered a graft loss = Yes”
The date of graft loss is specified on the Graft Loss eCRF page.  The date returned to regular 
dialysis or date of transplantectomy will be used if earlier. 
Death
The endpoint death is derived from the Death eCRF page where also the date of deathis 
captured.
6.2.2
Descriptive analyses
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Rates of graft loss and death will also be summarized.


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6.2.3
Statistical model, assumptions and hypotheses
Graft loss, death, graft loss or death andantibody-treated biopsy proven acute rejectionswill 
be analyzed in a similar way to the tBPAR and time to tBPAR, although without the non-
inferiority test.Other efficacy variables displayed in Table 6-1 will be presented within 
frequency tables to show the proportion of events and the CFZ533 treatment arm event rate 
will be compared with the control arm event rate using Z-statistics based on two-sided 
confidence intervals for differences in event rates.  
6.2.3.1 Graphical presentation of results
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The free CD40 and total CD40 on whole blood B cells data will be presented graphically to 
show the arithmetic mean (SD) of free and total CD40 on whole blood B cells compared to 
mean pre-dose over time (%), overlaid patient profiles of free CD40 and total CD40 on whole 
blood B cells compared to mean pre-doseover timeand overlaid profilesof free CD40 on 
whole blood B cellsbased on total CD40 (%).Arithmetic mean (SD) of free CD40 on whole 
blood B cells based on total CD40 (%), arithmetic mean (SD) free CD40 decrease on B cells 
compared to mean pre-dose (%) and arithmetic mean (SD) free CD40 decrease on B cells 
compared to mean pre-dose (based on total CD40 available on B cells) (%) will also be 
presented.  Additional overlaying individual profile plots of free CD40 decrease on B cells 
compared to mean pre-dose (%) and free CD40 decrease on B cells compared to mean pre-
dose (based on total CD40 available on B cells) (%) will also be presented.
Total soluble CD40 and total soluble CD154 data will be presented graphically in the form of 
individual patient panel plots by parameter, arithmetic mean (SD) over time plotsand a panel 
plot presenting the soluble CD40, soluble CD154 for each patient separately.
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7
Statistical methods for safety and tolerability data
7.1.1
Variables 
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as patientdemographics, baseline characteristics, and 
treatment information.
The following B-cell subsets are also used as safety markers: mature B cells, naive B cell, 
transitional B cells, memory B cells, plasma cells, plasma blasts.Overlaid patient profiles for 
each of these markers over time shall be presented graphically.
7.1.2
Descriptive analyses
Patientdemographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and 
patient. Patientdemographics will include age, sex, race, ethnicity, height, weight and BMI. 
Other baseline characteristics that shall be listed include relevant medical history, current 
medical conditions, results of laboratory screens, transplant history, donor characteristics (e.g., 
age, sex, race, type, CIT) and any other relevant information.
Summary statistics will be presented for the patientsin the Full analysis set.Continuous 
variables will be presented with mean, median, standard deviation, minimum and maximum, 
and the number of non-missing observations.
Categorical data will be displayed via absolute and relative frequencies for each category 
(including acategory labeled as “missing” when appropriate).
Table 7-1
Demographic variables and disease characteristics
Variable
Recipient demographics:
Age (continuous and categorized (< 50, ≥ 50) and (< 65, ≥ 65))
Gender
Race
Ethnicity
Vital signs at baseline:
Height
Body weight
BMI 
Pulse (bpm)
Systolic blood pressure, Diastolic blood pressure (mmHg)
Donor demographics:
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Age (continuous and categorized (< 50, ≥ 50) and (< 65, ≥ 65))


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Variable
Gender
Race
Ethnicity
Donor characteristics:
Donor category (living related, living unrelated, deceased heart 
beating)
Hypotension prior to procurement (no, yes, unknown)
Donor and recipient serology: 
EBV, CMV (negative, positive, not done) 
HCV Ab, HBsAG, HBsAb, HCV RNA (negative, positive, not done)
Recipient background information: 
End stage disease leading to transplantation
Current dialysis (yes/no)
Time since continuous dialysis first started
Number of previous kidney transplantations
Number of previous blood transfusions
Total number of HLA mismatches across Loci A, B, and DR 
(categorical: 0, 1, 2) 
Recipient/donor gender combination
Recipient/donor race combination
Transplantation procedure:
Cold ischemia time (deceased donors only: continuous and 
categorized: < 12 hours, ≥ 12 to 24 hours, ≥ 24 to 30 hours, > 30 
hours)
Study medication
Data for CFZ533 administration and concomitant therapies will be listed by treatment group 
and patient. The duration (days) of CFZ533 study medication administration will be 
summarized and listed. The duration will be calculated by subtracting the date of the last 
administration of study medication from the date of first administration and then adding the 
dosing interval for CFZ533. In calculating the duration of treatment, days of temporary 
interruption of study medication for any reason will be included, i.e, any days of interruptions 
will not be excluded from the duration of treatment. Further, the frequency of dose changes 
(including temporary dose interruption) will be presented by reason for the change.
Average daily doses of each treatment will be presented in a summary table and will be listed 
by treatment and patient. “Zero” will be used for periods of temporary interruption of study 
medication for any reason.
The number and percentage of patients who prematurely discontinued study medication will 
be summarized by reason for discontinuation.
If the number of events allow, Kaplan-Meier (KM) estimates of time to discontinuation of 
study medication curve will be constructed and presented graphically. In this analysis, patients


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who have not discontinued study medication will be censored with the censoring time as 
defined by the last contact day.
Concomitant immunosuppressants
The dose of administered Basiliximab, MMF, Tac and CS will be listed by treatment and
patient.
The dose of antibodies used for the treatment of acute rejection episodes will be summarized 
by treatment and listed by treatment and patient.
Other co-medications
Concomitant medications, other than immunosuppressants and CS mentioned above, will be 
listed by patient and summarized by therapeutic class and preferred term by presenting the 
number and percentage of patients using each medication for each treatment group.
Calculated eGFR 
The main safety endpoint is calculated eGFR. 
Patients will be considered as “on treatment”, whilst they are taking their assigned 
randomized treatment. If a patient switches to an alternative treatment or stops taking their 
assigned randomized treatment, this data will be excluded from the summaries, figures and 
analysis for eGFR data.
Calculated eGFR as determined by the central lab will be summarized by visit. The calculated 
eGFR will be presented graphically to show the overlaid patient profiles and mean profile 
over time.
The following imputation method will be applied at each relevant timepoint for patients with 
missing eGFR values:
1. Patients that lose their graft before the timepoint in question will be assigned a value of 
zero for their missing eGFR value.
2. Patients that die or are lost to follow-up with a functioning graft before the timepoint in 
question will have an imputed value using the last-observation-carried-forward (LOCF) 
method.
Graft loss patients do not have a functioning graft, hence the lowest possible eGFR value 
(zero) will be assigned to such patients with missing eGFR values. In contrast, patients that 
die with a functioning graft, die for different reasons such as suicide, car accidents, cancer, 
therefore if they have a missing eGFR value, an imputed value using the LOCF method will 
be used. Similarly, patients who are lost to follow-up and have renal function, but are missing 
a Month 6 or Month 12 value for various reasons (e.g. moving from the area or not being able 
to make the site visit during the Month 6 or Month 12 visit) will have an imputed value using 
LOCF method for any missing eGFR value.
The mean eGFR results will be estimated from a longitudinal repeated measures mixed 
effects model using all the individual data collected until the timepoint of interest (1st IA 
Month 3 visit, 2nd IA Month 6 visit) whilst the patient is on treatment. From the model, 
estimates of the average at the timepoint of interest, treatment difference and 90% confidence 


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intervals will be obtained. The model will include fixed effects for treatment, time, donor age, 
donor type (living or deceased) and donor characteristic, treatment by time interaction and 
donor type by treatment by time interaction. An unstructured variance-covariance structure 
shall be used, however in the case that the model fails to converge, alternative structures 
would be tested. The estimates of the adjusted means and two-sided 90% CIs obtained from 
the model will be plotted over time.
The donor characteristic is a category that could have the result of “standard” or “expanded”.
Vital signs
All vital signs data will be listed by treatment, patient, 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, patient 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, patient, and visit/time and if normal ranges are 
available abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a patient with any abnormal values. Summary statistics will be provided by 
treatment and visit/time.
Special clinical laboratory evaluations
Coagulation parameters prothrombin time and partial thromboplastin time will be listed by 
treatment, patient and visit/time. The coagulation parameters will also be presented 
graphically to show the overlaid patient profiles and mean profile over time for each 
parameter separately. Additionally overlaid patient profiles and mean profile over time will be 
presented graphically for platelets.
Cytokine assessments via multiplex cytokine including TNFa, IFNg, IL1b, IL2, IL4, IL8,
IL10, IL12p, IL70 and IL13 will be listed by treatment, patient, and visit/time. The cytokine 
assessments will also be presented graphically to show the overlaid patient profiles and mean 
profile over time for each parameter separately.
Donor specific antibodies will be listed by patient and visit.
Immunogenicity data consisting of anti-CFZ533 antibodies information will be listed by 
patient and visit.
Virology monitoring results for hepatitis B, hepatitis C, HIV, Epstein-Barr Virus (EBV), 
cytomegalovirus (CMV) and BK virus will be listed by patient, and visit/time and if normal 
ranges are available, abnormalities will be flagged. The frequency of EBV, CMV and BK 
virus will also be summarized by treatment.


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Adverse events
All information obtained on adverse events will be displayed by treatment and patient.
AEs and infections collected are to be coded with the MedDRA dictionary that gives preferred 
term and primary system organ class information. AEs and infection preferred terms are to be 
analyzed as a whole under the heading of AEs. Depending on the number of AEs in Part 2, the 
incidence of AEs will be summarized by body system, severity and relationship to study drug 
by the following where possible:

AEs by primary SOC and PT

AEs rated to have relationship to study drug by SOC and PT

AEs by primary SOC, PT, and maximum severity

SAEs by SOC and PT

SAEs rated to have relationship to study drug by SOC and PT

Deaths by SOC and PT

AEs leading to discontinuation of a study drug by SOC and PT

AEs leading to dose adjustment or interruptions of a study drug by SOC and PT

Infections by type of infection (viral, bacterial, fungal, and others) and microorganism of 
infection

Serious infections by type of infection and micro-organism of infection

New onset diabetes mellitus

AEs by standardized MedDRA query (SMQ) levels (broad and narrow search)

AEs by standardized MedDRA query (SMQ) and preferred term (broad and narrow 
search)
In all tables about incidence rates of AEs / Infections, if a patient has multiple occurrences of 
an AE, this patient will be counted only once in the corresponding AE category. If a patient 
has multiple adverse events within a system organ class, s/he will be counted only once for 
that class. If a patient has multiple severity ratings for an AE while on treatment, s/he is only 
counted under the maximum rating. In the tables, only adverse events occurring at or after 
first drug intake are included.
Information pertaining to AEs noted during the study will be listed by patient, including the 
verbatim term given by the investigator, the PT and SOC given by the MedDRA dictionary, 
start and end date, causality, severity, and relationship to study drug as assessed by the 
investigator.
BK-polyoma viremia and nephropathy
The following variables will be summarized by treatment and listed by treatment group and 
patient:
Occurrence of BK-polyoma viremia any time post-transplantation
Occurrence of BK-polyoma virus nephropathy any time post-transplantation
The difference of the investigational regimens to the control regimen will be summarized by 
risk ratios and appropriate CIs.


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Tuberculosis surveillance
Tuberculosis (TB) test data collected will be listed by patientand visit.
Pregnancy test
Pregnancy test results for all females will be listed by patientand visit.
Desirability of outcome ranking (DOOR)
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Composite endpoint:
a) Survived;without graft loss and without tBPAR
b) Survived; without graft loss and with tBPAR
c) Survived; with graft loss and without tBPAR
d) Survived; with graft loss and with tBPAR
e) death
Long term renal function:
a) Normal creatinine; without BK and without tBPAR


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b) Normal creatinine; with BK and without tBPAR
c) Normal creatinine; without BK and with tBPAR
d) Normal creatinine; with BK and with tBPAR
e) Elevated creatinine; without BK and without tBPAR
f) Elevated creatinine; with BK and without tBPAR
g) Elevated creatinine; without BK and with tBPAR
h) Elevated creatinine; with BK and with tBPAR
Where Normal creatinine is the most recent creatinineno higher than 25% above Nadir and 
Elevated creatinine is the most recent creatinine greater than 25% above Nadir
7.1.3
Graphical presentation 
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Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created.
A figure to represent the desirability of outcome ranking will be created.


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9
Reference list
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Levey A, Coresh J, and Balk E (2003) National Kidney Foundation Practice Guidelines for 
Chronic Kidney Disease: Evaluation, Classification, and Stratification.Ann Intern 
Med;139:137-147.