Clinical trial NCT03781414
Conditions: Liver Transplant Rejection
Keywords: Liver transplantation de novo recipients deceased donor CFZ533 CNI-free immunosuppression Transplant rejection
Sponsor: Novartis Pharmaceuticals
Start date: 2019-10-07; Completion date: 2023-04-20
Enrollment: 129 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a multicenter, open-label, active-controlled study to evaluate the efficacy, safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of two CFZ533 maintenance doses in de novo liver transplant recipients.

Detailed description:
The study was designed as a randomized, 36-month clinical trial comprised of:

* A screening period (up to 2 months) starting from informed consent, screening visit, and including successful liver transplantation (LTx).
* A run-in treatment period following successful transplantation that ended on the day of randomization or randomization failure, at Day 8 (with visit window of +/- 2 days) post-LTx.
* The primary treatment period (Treatment Period 1) starting at randomization Day 8 +/- 2 post-LTx up to Month 12 followed by a 12-month follow-up treatment period (Treatment Period 2) until Month 24.
* The long-term extension period (Treatment Period 3) starting post Month 24 until the end of the study (EOS).
* A minimum 12-week safety follow-up period for all patients after EOS.

The study was terminated following less favorable efficacy by Iscalimab (CFZ533) in liver transplant patients compared to tacrolimus.

Arms: arm 1: Tacrolimus (TAC) + Mycophenolate mofetil (MMF) + Corticosteroids (CS) up to End of Study (EOS). Initial TAC target trough were between 5-15 ng/mL during the run-in period. From randomization onwards, the TAC levels were adjusted as per local label. arm 2: Loading doses of 30 mg/kg IV on Day 8 (with +/- 2 days window), and 15 mg/kg IV on Day 15. The subcutaneous (SC) administration of 600 mg (2 injections of 2 mL CFZ533 at 150 mg/mL) every 2 weeks started on Day 29, in combination with MMF and CS up to EOS. arm 3: Single loading dose of 30 mg/kg IV on Day 8 (with +/- 2 days window). The SC administration of 300 mg (1 injection of 2 mL CFZ533 at 150 mg/mL) every 2 weeks started on Day 29, in combination with MMF and CS up to EOS.
Interventions: intervention 1: CFZ533 intervention 2: Tacrolimus - MMF - corticosteroids
Intervention descriptions: intervention 1: Comparison with standard of care immunosuppression intervention 2: Standard of care immunosuppresive regimen

Protocol documents:
Prot_004.pdf: 
Novartis Research and Development 
CFZ533 (Iscalimab) 
Clinical Trial Protocol CCFZ533A2202 / NCT03781414
A 12-month, open-label, multicenter, randomized, safety, 
efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) 
study of two regimens of anti-CD40 monoclonal antibody, 
CFZ533 vs. standard of care control, in adult de novo liver 
transplant recipients with a 12-month additional follow-up 
and a long-term extension (CONTRAIL I)  
Document type: 
Amended Clinical Trial Protocol 
EUDRACT number: 
2018-001836-24 
Version number: 
V04 (Clean) 
Clinical Trial Phase: 
II 
Release date: 
05-Mar-2021
Property of Novartis Pharma A.G. 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 (31-Jan-2020) 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 10 
Amendment 04 .................................................................................................................. 12 
Amendment 03 .................................................................................................................. 17 
Amendment 02 .................................................................................................................. 23 
Amendment 01 .................................................................................................................. 27 
Protocol summary .............................................................................................................. 30 
1 
Introduction ....................................................................................................................... 34 
1.1 
Background ............................................................................................................ 34 
1.2 
Purpose .................................................................................................................. 36 
2 
Objectives and endpoints ................................................................................................... 36 
3 
Study design ...................................................................................................................... 38 
4 
Rationale ............................................................................................................................ 40 
4.1 
Rationale for study design ..................................................................................... 40 
4.1.1 
Rationale for choice of background therapy ......................................... 41 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 41 
4.2.1 
Arm 2 (600 mg regimen)....................................................................... 41 
4.2.2 
Arm 3 (300 mg regimen)....................................................................... 43 
4.3 
Rationale for CFZ533 dosing to compensate for drug loss due to ascites 
drainage.................................................................................................................. 45 
4.4 
Rationale for choice of control drugs (comparator) .............................................. 47 
4.5 
Purpose and timing of interim analyses/design adaptations .................................. 47 
4.6 
Risks and benefits .................................................................................................. 48 
4.7 
Previous clinical experience with CFZ533 ............................................................ 50 
4.8 
Rationale for liver Histopathology - optional surveillance biopsies ..................... 51 
5 
Study Population ............................................................................................................... 53 
5.1 
Inclusion criteria .................................................................................................... 53 
5.2 
Exclusion criteria ................................................................................................... 53 
6 
Treatment ........................................................................................................................... 56 
6.1 
Study treatment ...................................................................................................... 56 
6.1.1 
Investigational and control drugs .......................................................... 56 
6.1.2 
Additional study treatments .................................................................. 57 
6.1.3 
Treatment arms/groups.......................................................................... 57 


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6.1.4 
Compensation for CFZ533 loss through ascites fluid drainage ............ 57 
6.1.5 
Post-Trial Access .................................................................................. 58 
6.2 
Other treatment(s) .................................................................................................. 58 
6.2.1 
Concomitant therapy ............................................................................. 58 
6.2.2 
Prohibited medication ........................................................................... 59 
6.2.3 
Induction therapy .................................................................................. 59 
6.2.4 
Rescue medication ................................................................................ 60 
6.3 
Participant numbering, treatment assignment, randomization .............................. 60 
6.3.1 
Participant numbering ........................................................................... 60 
6.3.2 
Treatment assignment, randomization .................................................. 60 
6.4 
Treatment blinding ................................................................................................ 60 
6.5 
Dose modification .................................................................................................. 61 
6.5.1 
Permitted dose adjustments and interruptions of CFZ533 study 
treatment ................................................................................................ 61 
6.5.2 
Permitted dose adjustments and interruptions of other study 
treatment ................................................................................................ 61 
6.6 
Additional treatment guidance ............................................................................... 62 
6.6.1 
Treatment compliance ........................................................................... 62 
6.6.2 
Recommended treatment of adverse events .......................................... 63 
6.7 
Preparation and dispensation ................................................................................. 64 
6.7.1 
Handling of study treatment and additional treatment .......................... 64 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 65 
7 
Informed consent procedures ............................................................................................ 68 
8 
Visit schedule and assessments ......................................................................................... 69 
8.1 
Screening ............................................................................................................... 85 
8.1.1 
Information to be collected on screening failures ................................. 85 
8.2 
Participant demographics/other baseline characteristics ....................................... 85 
8.3 
Efficacy .................................................................................................................. 86 
8.3.1 
Suspected Acute Rejection/Biopsy Proven Acute Rejection 
(BPAR) .................................................................................................. 86 
8.3.2 
Treated Biopsy Proven Acute Rejection (tBPAR) ................................ 86 
8.3.3 
Graft loss ............................................................................................... 86 
8.3.4 
Death ..................................................................................................... 87 
8.3.5 
Appropriateness of efficacy assessments .............................................. 87 
8.4 
Safety ..................................................................................................................... 87 
8.4.1 
Laboratory evaluations .......................................................................... 88 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 89 


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8.4.3 
Pregnancy and assessments of fertility ................................................. 90 
8.4.4 
Other safety evaluations ........................................................................ 91 
8.4.5 
Appropriateness of safety measurements .............................................. 93 
8.5 
Additional assessments .......................................................................................... 94 
 
 94 
8.5.2 
Pharmacokinetics .................................................................................. 94 
8.5.3 
Pharmacodynamics ............................................................................... 95 
8.5.4 
Immunogenicity .................................................................................... 95 
 
 96 
 
 96 
 
 96 
 
 96 
9 
Study discontinuation and completion .............................................................................. 97 
9.1 
Discontinuation and completion ............................................................................ 97 
9.1.1 
Study treatment discontinuation and study discontinuation.................. 97 
9.1.2 
Withdrawal of informed consent ........................................................... 98 
9.1.3 
Lost to follow-up ................................................................................... 99 
9.1.4 
Replacement of early withdrawals or discontinuations ........................ 99 
9.1.5 
Study stopping rules .............................................................................. 99 
9.1.6 
Early study termination by the sponsor ............................................... 100 
9.2 
Study completion and post-study treatment ........................................................ 100 
10 Safety monitoring and reporting ...................................................................................... 101 
10.1 
Definition of adverse events and reporting requirements .................................... 101 
10.1.1 
Adverse events .................................................................................... 101 
10.1.2 
Serious adverse events ........................................................................ 103 
10.1.3 
SAE reporting...................................................................................... 104 
10.1.4 
Pregnancy reporting ............................................................................ 105 
10.1.5 
Reporting of study treatment errors including misuse/abuse .............. 106 
10.2 
Additional Safety Monitoring .............................................................................. 106 
10.2.1 
Liver safety monitoring ....................................................................... 106 
10.2.2 
Renal safety monitoring ...................................................................... 106 
10.2.3 
Data Monitoring Committee ............................................................... 107 
10.2.4 
Steering Committee ............................................................................. 107 
11 Data Collection and Database management .................................................................... 108 
11.1 
Data collection ..................................................................................................... 108 
11.2 
Database management and quality control .......................................................... 108 
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11.3 
Site monitoring .................................................................................................... 109 
12 Data analysis and statistical methods .............................................................................. 109 
12.1 
Analysis sets ........................................................................................................ 109 
12.2 
Participant demographics and other baseline characteristics ............................... 110 
12.3 
Treatments ........................................................................................................... 110 
12.4 
Analysis of the primary endpoint ........................................................................ 111 
12.4.1 
Definition of primary endpoint ........................................................... 111 
12.4.2 
Statistical model, hypothesis, and method of analysis ........................ 111 
12.4.3 
Handling of missing values not related to intercurrent event ............. 112 
12.4.4 
Supportive analyses ............................................................................. 112 
12.5 
Analysis of secondary endpoints ......................................................................... 112 
12.5.1 
Efficacy endpoint(s) ............................................................................ 112 
12.5.2 
Safety endpoints .................................................................................. 113 
12.5.3 
Pharmacokinetics ................................................................................ 116 
12.5.4 
PK/PD relationships ............................................................................ 117 
 
 117 
12.7 
Sample size calculation........................................................................................ 120 
13 Ethical considerations and administrative procedures .................................................... 122 
13.1 
Regulatory and ethical compliance ...................................................................... 122 
13.2 
Responsibilities of the investigator and IRB/IEC ................................................ 122 
13.3 
Publication of study protocol and results............................................................. 122 
13.4 
Quality Control and Quality Assurance ............................................................... 122 
14 Protocol adherence .......................................................................................................... 123 
14.1 
Protocol amendments........................................................................................... 123 
15 References ....................................................................................................................... 124 
16 Appendices ...................................................................................................................... 128 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs ....................... 128 
16.2 
Appendix 2: Milan criteria................................................................................... 129 
16.3 
Appendix 3: Banff classification of liver allograft rejection ............................... 130 
16.4 
Appendix 4: Abbreviated MDRD formula for eGFR .......................................... 131 
16.5 
Appendix 5: American Diabetes Association criteria for Diabetes ..................... 132 
16.6 
Appendix 6a: Blood log for PK, PD, Immunogenicity and other assessments 
sampling ............................................................................................................... 133 
16.7 
Appendix 6b: Blood log for unscheduled PK sampling ...................................... 136 
 
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List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 36 
Table 6-1 
Prohibited medication ........................................................................... 59 
Table 8-1 
Assessment schedule (Treatment Period 1) .......................................... 71 
Table 8-2 
Assessment Schedule (Treatment Period 2) .......................................... 80 
Table 8-3 
Assessment Schedule (Extension Period) ............................................. 83 
Table 8-4 
Assessments & Specifications............................................................... 87 
Table 8-5 
Laboratory Assessments ........................................................................ 89 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ....................................................................................... 106 
 
 118 
Table 12-2 
Probability of success under different event rates for 48 
participants of CFZ533 arm and 32 participants of control arm ......... 120 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 40 
Figure 4-1 
Predicted median CFZ533 plasma concentration time-profile in 
liver transplant participants overlaid with measured plasma 
concentrations in kidney transplant participants (Study 
CCFZ533X2201-Part 2; interim data) .................................................. 45 
Figure 4-2 
Predicted CFZ533 exposure in case of (i) no ascites drainage (light 
grey), (ii) ascites drainage but no compensating dose (pink), and 
(iii) ascites drainage with compensating dose (blue) ............................ 47 
 
 
 120 
Figure 12-2 
Probability of success under different event rates for 48 
participants of CFZ533 arm and 32 participants of control arm ......... 121 
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List of abbreviations 
AE 
Adverse Event 
ADA 
Anti-Drug Antibodies 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AR 
Acute Rejection 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
b.i.d. 
bis in die/twice a day 
BMI 
Body Mass Index 
BPAR 
Biopsy Proven Acute Rejection 
BUN 
Blood Urea Nitrogen 
CMV 
Cytomegalovirus 
CO 
Country Organization 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CS 
corticosteroids 
CSR 
Clinical study report 
CTC 
Common Terminology Criteria 
DMC 
Data Monitoring Committee 
EBV 
Epstein Barr Virus 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eGFR 
estimated Glomerular Filtration Rate 
ELISA 
Enzyme-linked immunosorbent assay 
EOI 
End of Infusion 
EOS 
End Of Study 
eSAE 
Electronic Serious Adverse Event 
eSource 
Electronic Source 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GL 
Graft Loss 
h 
Hour 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B Virus 
HCC 
Hepatocellular carcinoma 
HCP 
Health Care Provider 
HCV 
Hepatitis C Virus 
HIV 
Human immunodeficiency virus 


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i.v. 
intravenous 
IA 
Interim analysis 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IG 
Immunoglobulin 
IMP 
Investigational Medicine Product 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LDH 
lactate dehydrogenase 
LFT 
Liver function test  
LLOQ 
lower limit of quantification 
MedDRA 
Medical dictionary for regulatory activities  
mg 
milligram(s) 
mL 
milliliter(s) 
MMF 
Mycophenolate mofetil 
MPA 
Mycophenolate Acid 
NCDS 
Novartis Clinical Data Standards 
NODM 
New Onset of Diabetes Mellitus 
p.o. 
oral(ly) 
PCP 
Pneumocystis carinii pneumonia 
PD 
Pharmacodynamic(s) 
PFS 
Pre-filled syringes 
PK 
Pharmacokinetic(s) 
PT 
prothrombin time 
pTNM 
Modified Tumor Node Metastases 
QD 
Once a day 
QMS  
Quality Management System 
QTcF 
QT interval corrected by Fridericia’s formula 
RAP 
The Report and Analysis Plan  
RBC 
red blood cell(s) 
RNA 
Ribonucleic acid 
RoW  
Rest of World 
s.c. 
subcutaneous 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-
2 
Severe acute respiratory syndrome associated coronavirus - 2 


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SBP 
Systolic Blood Pressure 
sCR 
serum creatinine 
SD 
standard deviation 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SVR12 
Sustained virologic response defined as HCV-RNA undetectable 12 weeks after 
completing HCV treatment 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TAC 
tacrolimus 
tAR 
treated Acute Rejection 
tBPAR 
treated Biopsy Proven Acute Rejection 
ULN 
upper limit of normal 
ULQ 
upper limit of quantification 
UTI 
Urinary Tract Infection 
WBC 
white blood cell(s) 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 


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Glossary of terms 
Additional 
treatment 
Medicinal products that may be used during the clinical trial as described in 
the protocol, but not as an investigational medicinal product (e.g., any 
background therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant 
Control drug 
A study drug (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g., 100 mg 
once a day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used to 
capture data transcribed from paper source forms used at the point of care 
End of the clinical 
trial 
The end of the clinical trial is defined as the last visit of the last participant or 
at a later point in time as defined by the protocol 
Enrollment 
Point/time of participant entry into the study at which informed consent must 
be obtained 
eSource (DDE) 
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines 
source documents and case report forms (eCRFs) into one application, 
allowing for the real time collection of clinical trial information to sponsors and 
other oversight authorities, as appropriate 
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation or 
the existence of the measurements associated with the clinical question of 
interest 
Investigational 
drug/ treatment 
The drug whose properties are being tested in the study 
Long-term 
extension period 
Period after Month 24 visit until end of study 
Medication 
number 
A unique identifier on the label of medication kits 
Mis-randomized 
participants 
Mis-randomized participants are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study  
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e., 
concomitant or rescue therapy) 
Participant 
A trial participant (can be a healthy volunteer or a patient) 
Participant number 
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc. 
Period 
The subdivisions of the trial design (e.g., Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis 


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Personal data 
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples 
Premature 
participant 
withdrawal 
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned 
Randomization 
number 
A unique identifier assigned to each randomized participant 
Run-in Failure 
A participant who is screened but not randomized/treated after the run-in 
period (where run-in period requires adjustment to participant’s intervention or 
other treatment) 
Screen Failure 
A participant who did not meet one or more criteria that were required for 
participation in the study 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource 
Start of the clinical 
trial 
The start of the clinical trial is defined as the signature of the informed consent 
by the first participant 
Study treatment 
Any drug or combination of drugs or intervention administered to the study 
participants as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy 
Study treatment 
discontinuation 
When the participant permanently stops taking any of the study drug(s) prior to 
the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation  
Treatment 
arm/group  
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts 
Variable (or 
endpoint) 
The variable (or endpoint) to be obtained for each participant that is required 
to address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event 
Withdrawal of 
study consent 
(WoC) 
Withdrawal of consent from the study occurs only when a participant does not 
want to participate in the study any longer and does not allow any further 
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Amendment 04 
Amendment Rationale 
The key purpose of this amendment is to increase the study duration by adding an extension 
period to collect long-term data in a controlled, clinical trial setting. Patients will stay in the 
long-term extension for at least 3 years. 
Further, this amendment clarifies that in exclusion No. 12, “any history of coagulopathy”, will 
exclude only recipients that have a history of non-liver related coagulopathy or medical 
condition requiring long-term anticoagulation.   Moreover, a new exclusion criterion No. 31 is 
added to exclude donors with confirmed history of SARS-CoV-2 infection given the unknown 
long term sequelae of SARS-CoV-2 infection in the liver. 
Finally, several sections were updated with instructions for conducting the study during a public 
health emergency as declared by Local or Regional authorities, i.e., pandemic, epidemic or 
natural disaster, that limits or prevents on-site study visits. 
This clinical study is ongoing since September 2019 and 59 subjects have been randomized as 
of 28-Feb-2021. The changes proposed by this amendment will not restrict the patient 
population or have a major impact on study results.  
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
List of abbreviations: new abbreviations added and non-applicable ones deleted 
Glossary of terms: new terms added 
Protocol summary: updated with Amendment 4 changes 
Section 1.1 – Background: updates on number of patients treated with CFZ533 according to IB 
edition 10 released in December 2020. 
Table 2-1 – Objectives and related endpoints: secondary objective updated to remove 
redundancy with key secondary objective; 
 
 
Section 3 – Study design: Study design figure updated; addition of the extension period; update 
of the treatment period for every arm up to the end of extension; clarification that from Month 
12, self-administration at home will be possible using the PFS; CFZ533 compensation 
procedure deleted to avoid redundancy with Section 6.1.4; clarification that minimum cortisone 
dose is 5mg/day prednisone or equivalent dose of another oral corticosteroid. 
Figure 3-1-Study design: Figure updated with amendment 4 changes. 
Section 4.2 – Rationale for dose/regimen and duration of treatment: end of study updated to 
consider the extension.  Updated study CCFZ533X2203 as completed. 
Section 4.3 – Rationale for CFZ533 dosing to compensate for drug loss due to ascites drainage: 
CFZ533 compensation procedure deleted to avoid redundancy with section 6.1.4. 
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Section 4.5 – Purpose and timing of interim analyses/design adaptations: Clarification that 
participants will receive study treatment for a variable duration depending on when they join 
the study and complete the extension; addition of a study analysis at the end of the extension; 
clarification that additional IAs may be conducted to support decision making concerning the 
current clinical study or project, the sponsor's clinical development projects in general or in case 
of any safety concerns; clarification that the stopping rules only apply up to Month 24 and not 
during the extension.  
Section 4.6 – Risks and benefit: Removal of a duplicated paragraph; Information that new 
mitigation procedures in case of Public Health emergency have been added to the protocol. 
Section 5 – Study population: Latin America added to the study 
Section 5.1 – Inclusion criteria: criterion 8 updated to revise ULN for total bilirubin. 
Section 5.2 – Exclusion criteria: criterion 9 updated to change < symbol to ≤ for Milan criteria; 
Exclusion criteria 12 and 17 updated to provide more clarity, exclusion criterion 31 added. 
Criteria 20 updated to clarify that bilateral tubal ligation surgery is required to consider women 
as not of child bearing potential. 
Section 6.1.3 – Treatment arms/groups: end of treatment period updated 
Section 6.1.5 – Post-trial access: Deletion of “The planned duration of treatment is the 24-month 
study period. Participants may be discontinued from treatment earlier due to unacceptable 
toxicity, graft rejection, graft loss, pregnancy, and/or treatment discontinuation at the discretion 
of the investigator or the participant. For participants who are in the opinion of the investigator 
are still deriving clinical benefit from CFZ533A2202 study, every effort will be made to 
continue provision of study treatment” as not required. 
Section 6.2.2- Prohibited medication: Clarification that non-protocol immunosuppressants are 
only allowed for participants in follow-up, up to Month 24. 
Section 6.5.2 – Permitted dose adjustments and interruptions of other study treatment: 
Clarification that corticosteroids considered for the minimal dose of 5 mg is prednisone or 
equivalent dose of another oral corticosteroid. 
Section 6.6.1 – Treatment compliance: Period for local TAC trough level assessment updated 
until end of study. 
Section 6.6.2 – Recommended treatment of adverse events: Clarification that central biopsy 
readings in case of suspicion of acute rejection are mandatory until Month 24; Clarification that 
patient discontinued due to prohibited concomitant medications will be followed-up up to 
Month 24 and not until EOS; Clarification that anti-T cell antibody therapy for rejection is 
prohibited until Month 24; clarification that participants requiring anti-T cell antibody therapy 
for rejection during the long-term extension will be discontinued from the study. 
Section 6.7.1.2 – Handling of Tacrolimus, MPA and corticosteroids: Addition of a new 
paragraph describing mitigation procedures allowed during a Public Health emergency. 
Section 6.7.2.1 – CFZ533 administration: reference to assessment tables updated to add Table 
8-3; schedule of on-site visits if patient self-administers CFZ533 using PFS clarified; 
investigator responsibility to evaluate patient’s storage capacity of study treatment; treatment 


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duration updated to consider extension period; paragraph deleted as redundant with previous 
information. 
Section 6.7.2.2 – Tacrolimus administration: Treatment duration updated to consider extension 
period 
Section 8 - Visit and assessments: Reference to Table 8-3 related to extension period added; 
Update of a paragraph regarding the mitigation procedures allowed during a Public Health 
emergency; Study participation in case of treatment discontinuation prior to or during extension 
period described. 
Table 8-1: 1 footnote added for EOS visit if extension period continues beyond Month 72; 1 
footnote updated to remove information to take an ascites aliquot from the collection bag. 
Table 8-2- Assessment schedule (Treatment period 2): EOT and end of period/EOS at M24 visit 
removed;. 
Table 8-3  – Assessment schedule (extension period): Addition of table describing assessment 
schedule during extension period. 
Section 8.3.1 – Suspected Acute Rejection/Biopsy Proven Acute Rejection (BPAR): 
Clarification that central biopsy reading of for-cause biopsies only applies up to Month 24. 
Section 8.3.3 – Graft loss: Clarification on CRF pages to be used to report graft loss according 
to time of occurrence 
Section 8.4 – Safety: Table 8-3 renumbered as Table 8-4 and references to Table 8-3 added; 
addition of a new paragraph describing mitigation procedures allowed during a Public Health 
emergency. 
Section 8.4.1 – Laboratory evaluations: Addition of a new section describing mitigation 
procedures allowed during a Public Health emergency. 
Section 8.4.3 – Pregnancy and assessment of fertility: Reference to Table 8-3 added. Visits at 
which B-hCG serum pregnancy test is to be performed has been updated. In case treatment is 
discontinued prior to Month 24 visit, then urine pregnancy tests will be performed at the 
applicable follow-up visit. A new paragraph has been added describing the mitigation 
procedures allowed during a Public Health emergency.  
Table 8-5: renumbered from Table 8-4 to Table 8-5 
Section 8.5 – Additional assessments: Language of this section is updated to describe the 
mitigation procedures allowed during a Public Health emergency. 
Section 8.5.3 - Pharmacodynamics: Reference to Appendix 6b removed as not applicable. 
 
Section 8.5.6 - CFZ533 concentration in drained ascites fluid: Clarification that it only applies 
up to Month 24; collection of ascites aliquot from the bag with highest volume deleted, as not 
aligned with local practices. 
 
 
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Section 9.1.1 – Study treatment discontinuation and study discontinuation: typos corrections; 
clarification of visit to be performed in case of treatment discontinuation; deletion of term 
“special interest” for AEs; description of visit to be completed in case of discontinuation during 
extension period. 
Section 9.1.5 – Stopping rules: Clarification that stopping rules apply up to Month 24, and not 
to the extension period. 
Section 9.2 – Study completion and post-study treatment: Update of the end of study definition; 
clarification when the study will end; update on time to start TAC after study completion. 
Section 10.1.1 - Adverse events: Period for SAE reporting updated according to last CFZ533 
dose. 
Section 10.1.3 – SAE reporting: clarified that SAE reporting will be required until 14 weeks 
after EOS visit. 
Section 10.1.4 – Pregnancy reporting: Reference to Table 8-3 added. 
Section 12 – Data analysis and statistical method: Addition of a study analysis at the end of the 
extension; sentence “PK/PD and immunogenicity analysis is up to Month 24 (Day 673)” has 
been removed. 
Section 12.1 – Analysis sets: update of the full analysis set (FAS) definition and addition of 
misrandomized definition. 
Section 12.4.4 – Supportive analyses: clarification that Kaplan-Meier graph for BPAR will 
consider BPAR censored at Month 12. 
Section 12.5.1 – Efficacy endpoint(s): Text formatting updates for more clarity. 
Section 12.5.2.1 – Renal function: Deletion of evaluation of eGFR at Month 24 as key 
secondary objective is applicable at Month 12 time point only. Deletion of the MDRD as 
formula is already described in section 16.4; clarification that the Renal function at Month 24 
measured by eGFR will follow the same analysis strategy as the Month 12 analysis. 
Section 12.5.2.3 – Other safety evaluation: Table 8-3 added as reference.  
 
 
Section 12.6 – Clarification that stopping rules are applied up to Month 24. 
Section 12.7 – Sample size calculation: Update of erroneous Figure 12-2. 
Section 15 – Reference: Article from Levey (2003) deleted and article from Levey (2006) added. 
Section 16.1 - Appendix 1: update of bilirubin range. 
Section 16.4 – Appendix 4: eGFR formula updated according to Levey et al (2006) article. 
Section 16.6 - Appendix 6a: Samples numbering updated to consider extension period. 
 
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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
Summary of previous amendments  
Amendment 3 (August 2020) 
Amendment 2 (March 2020) 
Amendment 1 (July 2019) 
 
 
 
 
 
 
 
 
 
 


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Amendment 03 
Amendment Rationale 
The key purpose of this amendment is to introduce pre-filled syringes (PFS) to allow for 
self-administration after Month 12 visit, to offer more flexibility and improve adherence. This 
will reduce the frequency of visits for patients at the sites during the second year of the study 
to only those visits that require clinical assessments. Pre-filled syringe is a new presentation of 
CFZ533 and the formulation is identical in vials and PFS. The PFS is intended to be used by 
healthcare professionals, lay caregivers assisting with the treatment administration, or adult 
patients self-administering at home. The lay caregivers and adult patients will be allowed to use 
the PFS once they are trained by the study team. 
Further, this amendment is aimed to add three inclusion/exclusion criteria: 
x To clarify when a patients must be screen failed, we included an inclusion criterion to 
mandate transplantation to occur within a defined screening period following informed 
consent signature. Re-screening up to 3 times is allowed if the wait time for transplantation 
is extended. 
x Due to the variability in the hepatocellular carcinoma (HCC) diagnosis among countries and 
sites, the explant liver graft pathology reading is added prior to randomization to standardize 
the evaluation of patients with HCC. 
x To ensure appropriate dosing of CFZ533, we added a body weight range to exclude patients 
who are underweight or obese (<30 kg or >180 kg). 
Moreover, one of the secondary objectives “To assess the safety and tolerability of CFZ533 
regimens compared to TAC control at Month 12 and Month 24” was revised to remove the 
endpoint of “AEs of special interest”. We are evaluating the whole safety profile and no 
particular AEs of special interest have been identified as of this time in the program. 
The risk and benefit assessment in relation to COVID-19 was performed, and conclusion was 
that it remains unchanged in the target population and this is added to this protocol amendment 
Section 4.6. 
Finally, there are few other key reasons for this amendment: 
x codify a number of actions recommended to ameliorate the effects of the COVID-19 
pandemic as it interferes with the normal course of this trial in the past or future 
x clarify the stopping rule for serious infections where for the purpose of this rule, serious 
infections will be considered as those, which are fatal or life-threatening 
x 
 
 
x allow more flexibility regarding CFZ533 interruption during the study 
x add information about Cytomegalovirus (CMV) treatment guidance to standardize CMV 
treatment 
x add severe acute respiratory syndrome associated coronavirus - 2 (SARS-CoV-2) treatment 
recommendation to follow local guidelines 
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• add reason for collection of race and ethnicity which is required by Health Authorities to 
identify variations in safety or efficacy due to these factors and to assess the diversity of the 
study population 
• revise criteria for the diagnosis of new onset diabetes to remove “reason for transplantation 
was not diabetes” since this will be true for all patients in the study; for assessments after 
randomization change from Day 30 to Day 29 to better match the visit schedule; and for 
HbA1c, change from Day 30 to Day 85 to assess it 3 months after transplantation 
This clinical study is ongoing since September 2019 and 20 subjects have been randomized as 
of 30-Jul-2020. The changes proposed by this amendment will not restrict the patient population 
since the added body weight range is very broad. The HCC diagnostic interpretation criteria 
will standardize the evaluation of patients with HCC. The changes proposed in this amendment 
will not have a major impact on study results.  
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
Throughout the document, changes were implemented based on a new clinical trial protocol 
template released by Novartis earlier this year: 
• Replacement of “subject” term with “participant” 
• Update of the pregnancy section to clarify safety information reporting during pregnancy 
and once baby is born 
• Describe post-trial access considered after the study 
• Describe the different informed consents in use for the study 
• Update in the adverse event section. Update in the list of information to collect, and 
clarification about abnormal laboratory values or test results to consider reporting an AE 
List of amended sections includes: 
List of abbreviations – updated with new and missing ones 
Glossary of terms – updated with new terms 
Protocol Summary Section – updated to align with changes made in this amendment. 
Table 2-1: objectives and related endpoints – removed AEs of special interest from the 
secondary endpoints pertaining to the safety and tolerability of CFZ533 objective’ for more 
clarity. 
Figure 3-1: figure was replaced to correct inversion of arrow descriptions and footnotes. Blue 
arrow referred to 15 mg/kg instead of 30 mg/kg, and white arrow the contrary. Footnote ** 
referred to one injection instead of 2 and the footnote *** to 2 injections instead of 1. 
Section 2 – heading updated from ‘objectives and related endpoints’ to ‘objectives and 
endpoints’. 


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Section 4.2.1 – removed in the description of safety follow up words “subject and graft survival” 
since these are SAEs already covered by statement “to monitor any related serious adverse 
events”. 
Section 4.6 – Risks and Benefits: updated to include assessment due to COVID-19 pandemic  
Section 5.1 – Inclusion criteria: added an inclusion criterion (criteria #11) to define period 
between ICF signature and transplantation to align with the definition of the screening period. 
Section 5.2 – Exclusion criteria: added 2 new criteria to: 
- 
Add explant liver graft pathology reading for participants with HCC prior to 
randomization (exclusion # 29) 
- 
Provide a range for patients’ body weight (exclusion # 30) 
Section 6.1.1 – Investigational and control drugs: Implementation of PFS 
Section 6.1.3 – Mention added that “PFS will be used upon availability once patient has 
completed M12 visit”. 
Section 6.1.4: Cross-reference added to section 4.3. 
Section 6.1.5 – Post Trial Access: new section added based on new Novartis clinical trial 
protocol template to discuss post-trial access. 
Section 6.2.1 – Concomitant therapy: Added recommendation to use the guideline of the 
American Society of Transplantation Infectious Diseases Community of Practice to treat 
cytomegalovirus infection in solid organ transplant recipients. Added information regarding 
treatment of SARS-CoV-2 patients. 
Section 6.2.4 – Rescue medication: For participants with history of Hepatitis C virus (HCV) 
infection, added clarification that only patients with sustained virologic response (SVR) of at 
least 12 weeks will be eligible for the study. 
Section 6.4 – Treatment blinding: wording update based on the new Novartis clinical trial 
protocol template. 
Section 6.5.1 – Permitted dose adjustments and interruptions of CFZ533 study treatment: 
Added more flexibility regarding treatment interruptions allowed in the study. 
Section 6.6.2 – Recommended treatment of adverse events: added that increases in tacrolimus 
dose to manage rejection will be captured in the CRF. 
Section 6.6 – Additional treatment guidance: sub-section number and title (6.6.3 – Emergency 
breaking of assigned treatment code) removed since it is not applicable to this study. 
Section 6.7 – Preparation and dispensation: added new information based on the new Novartis 
clinical trial protocol template. 
Sections 6.7.1 – Handling of study treatment and additional treatment: added this new section 
based on new Novartis clinical trial protocol template. 
Section 6.7.2 - Instruction for prescribing and taking study treatment: update in section number 
and title. 


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Section 6.7.2.1 – CFZ533 administration: this was Section 6.7.1.1 in prior protocol, it was 
updated to include instructions on PFS use and a mitigation plan to continue study drug at in-
home administration either by site staff or HCP in case of a new pandemic. 
Section 6.7.2.2 – Tacrolimus administration: this was Section 6.7.1.2 in prior protocol, it was 
updated to clarify that all participants need to be on a treatment regimen comprising tacrolimus 
(TAC), corticosteroids (CS) and mycophenolate mofetil (MMF) at the time of randomization. 
Section 6.7.2.3 – MMF administration: this was section 6.7.1.3 in prior protocol, it was updated 
to align with changes in Section 6.7.2.2. 
Section 6.7.2.4 – Corticosteroids administration: this was section 6.7.1.4 in prior protocol, no 
new changes introduced in this amendment. 
Section 7 – Informed consent procedures: description of the different ICF available for the study. 
Section 8 – Visit schedule and assessments: clarified that the injection schedule should be 
determined based on the randomization date; added actions to consider in case of new pandemic. 
Table 8-1 Assessment schedule: 
x Footnote 9 revised to indicate that participants who discontinue the randomized study 
treatment prior to Month 12 should continue in the study until Month 24 on standard of care 
and come for follow up visits 
Footnote 10 added to clarify that TAC trough levels are not applicable to participants in Arms 
2 & 3 from D29; TAC trough levels will continue to be applicable only for Arm 1 patients from 
D29 onwards 
x Footnote 11 added to explain types of biomarkers to be assessed 
x Footnote 12 added to ensure that after switching to PFS, CFZ533 dosing will be done after 
collection of PK labs which are required at pre-dose  
x 
 
x correction of some typographical errors 
Section 8.1 – Screening: clarification that participants awaiting organ transplantation can be re-
screened 3 times. 
Section 8.1.1-Information to be collected on screening failures: new section added, text 
implemented from the new Novartis clinical trial protocol template. 
Section 8.2 – Participant demographic/other baseline characteristics: added reason for race and 
ethnicity collection. 
Section 8.3.3 – Graft loss: clarification that graft loss will lead to study discontinuation. 
Table 8-4 – Laboratory assessments: list of surface biomarkers in the viral serology section 
updated 
Section 8.4.4 – Other safety evaluations: criteria to define new onset of diabetes mellitus 
updated to remove “reason for transplantation was not diabetes”, change D30 to D29 to match 
visit schedule, delay HbA1C to D85 to capture only information after transplantation; added 
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central pathologist review of explant biopsy for participants with HCC recurrence; This section 
is also updated with the definitions for diabetic related diagnoses are according to the American 
Diabetes Association (2013) and WHO-ADA criteria. 
Section 8.5 – Additional assessments: added flexibility to continue study assessment in case of 
a new pandemic. 
Section 8.5.3 – Pharmacodynamics: clarification that CD40 is not mandatory for Arm1 patients 
(on TAC treatment) at M4.5 visit. 
. 
 
 
Section 9.1.1 – Study treatment discontinuation and study discontinuation: updated reasons for 
study treatment discontinuation to align with the new Novartis clinical trial protocol template; 
clarified that in case of pregnancy or graft loss, the participant will be discontinued from the 
study and complete Month 24 EOS visit as soon as possible. 
Section 9.1.2 – Withdrawal of informed consent: based on the new Novartis protocol template 
updated the definition of withdrawal of consent and added information regarding use of 
personal data. 
Section 9.1.5 – Study stopping rules: clarification about infection events considered for the 
stopping rule. 
Section 9.2 – Study completion and post-study treatment: clarification about SAEs reporting 
procedure during safety follow-up period. 
Section 10.1.1 – Adverse events: updated to align with the new Novartis clinical trial protocol 
template, clarified that AEs will be collected until EOS visit, after which only SAEs will be 
reported in the Novartis safety database for additional period of 12 weeks; Paragraph on 
clinically significant laboratory values identification added. 
Section 10.1.4 – pregnancy reporting: Updated to align with the new Novartis clinical trial 
protocol template, added that pregnancy follow up information will be collected at 3 time points 
after delivery for a period of 12 months. 
Section 10.2.3 – Data Monitoring Committee: updated to align with the new Novartis clinical 
trial protocol template. 
Section 11.2 – Database management and quality control: clarification of data recorded by IRT. 
Section 12.2 – Participant demographic and other baseline characteristics: addition of data to 
consider. 
Section 12.3 – Treatment: section number and title (12.3.1 - Concomitant immunosuppressant) 
deleted as there is no other sub-section 
Section 12.4.3 – Handling of missing values not related to intercurrent event: clarification of 
lost to follow-up definition. 
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Section 12.4.4 – Supportive analyses: title changed from “Sensitivity analyses”, clarification on 
the composite failure efficacy failure and analysis results presentation, and addition of analysis 
to assess impact of COVID-19 pandemic. 
Section 12.5.1 – Efficacy endpoints: additional parameters included to further subdivide types 
of treated rejections and composite of graft loss and death. 
Section 12.5.2.1 – Renal function: sentence moved up to Section 12.4.3. 
Section 12.5.2.2 – General safety: updated to align with the new Novartis clinical trial protocol 
template: clarification that all listings and tables will be presented by treatment group; addition 
of a summary of death on treatment and post treatment death report; clarification of on-
treatment period considered for CFZ533 and TAC arms; updates on the adverse events analysis; 
deletion of the new onset of diabetes mellitus as it is redundant with Section 8.4.4. 
Section 12.5.3 – Pharmacokinetics: added a comparison of PK before and after introduction of 
PFS in the study. 
Section 12.7 – Sample size calculation: Figure 12-2 was updated with correct representation of 
probability of success. 
Section 15 – References: added one reference. 
Section 16.1 – Appendix 1: updated vital signs notable criteria. 
Section 16.6 – Appendix 6a: added sample number for other assessments. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
Summary of previous amendments  
Amendment 2 (March 2020) 
Amendment 1 (July 2019) 


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Amendment 02 
Amendment Rationale 
The key purpose of this amendment is: 
To clarify that the stopping rule for biopsy proven acute rejection (BPAR) is based on moderate 
and severe events (Rejection Activity Index (RAI) ≥6) evaluated by a blinded central 
pathologist. Borderline and mild rejections generally do not present with clinically apparent 
graft malfunction and do not require additional treatment (Demetris et al 1997 and 2002). As 
stopping rules are established as a safety measure, only moderate or severe events will be 
considered. 
To change the screening period from 6 months to 2 months to adapt to sites practice and reduce 
period of eligibility assessments results. 
To increase the visit window for the randomization visit at Day 8 from ±1 to ±2 days to allow 
for more flexibility at the hospital. 
To allow combining screening and baseline visit if these visits happen within a 48 h period. 
To clarify Inclusion criteria: 
• # 6: Included are patients with Model for End stage Liver Disease (MELD) score ≤ 30 
(based on laboratory values, using the United Network for Organ Sharing (UNOS) MELD 
calculator:[ https://unos.org/resources/allocation-calculators/]). 
• #7: Included are recipients with HCV antibody positive with no detectable HCV-RNA. 
Recipients with Hepatitis B infection should have no detectable HBV-DNA. Cases of 
spontaneous HCV clearance should be discussed with sponsor. 
To clarify Exclusion criteria:  
• #9: Excluded are patients with Hepatocellular carcinoma that does not fulfill Milan 
criteria (1 nodule ≤5 cm, 2-3 nodules all <3 cm, without evidence of metastatic disease 
or vascular invasion. 
• #17: Excluded are recipients with positive HCV antibody without proof of sustained 
viral response (SVR) 12 weeks after anti HCV treatment. 
• # 18: Excluded are donor organs showing macro-vesicular steatosis > 30%. 
The drug target trough level for tacrolimus (TAC) was changed from 8 to 12 ng/mL to 5 to 
15 ng/mL to better reflect local practice and allow more flexibility at clinical sites to adjust 
TAC drug levels in subjects. This dose range is consistent with the TAC product label 
information. 
Changes to the protocol 
Throughout the document the following changes have been made: 
• Replacing remaining “patients” term with “subjects” according to the glossary term 
definition. 
• Replacing randomization visit window “+/-1 day” to “+/-2 days” 


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The following sections have been changed as follow: 
Section 1.1- Background: update on subjects treated under CFZ533 according to IB #9 release. 
Section 3- Study design: update on screening period (2 months instead of 6); clarification that 
corticosteroids can be stopped once Month 4 visit has been completed and Figure 3-1 updated. 
Section 4.1- Rationale for study design: TAC blood target trough levels change from 8-
12ng/mL to 5-15ng/mL; randomization visit window (+/-2 days) added. 
Section 4.2.1 and Section 4.2.2-Arm 2 (600mg regimen)/Arm 3 (300mg): randomization visit 
window (+/-2 days) added. 
Figure 4-2- Predicted CFZ533 exposure: randomization visit window deleted and correction of 
Arm receiving CFZ533 at Day 15 (Arm 2 not Arm 3). 
Section 4.6- Benefits and risks: wording change. 
Section 4.8- Rationale for liver histopathology: wording change. 
Section 5- Population: deletion of the percentage of expected screening failure and number of 
expected subjects to complete recruitment. 
Section 5.1- Inclusion criteria: 
• #6 updated to: “Model for End stage Liver Disease (MELD) score ≤ 30 (based on 
laboratory values, using the United Network for Organ Sharing (UNOS) MELD 
calculator: [https://unos.org/resources/allocation-calculators/])” 
• 
#7 updated to: “Recipients with no active HCV and HBV replication. Recipients with 
HCV antibody positive should have no detectable HCV-RNA. Recipients with Hepatitis B 
infection should have no detectable HBV-DNA”  
Section 5.2- Exclusion criteria:  
• #9 update to: “Hepatocellular carcinoma that does not fulfill Milan criteria (1 nodule ≤5 
cm, 2-3 nodules all <3 cm, without evidence of metastatic disease or vascular invasion, 
see Appendix 2, Mazzaferro et al 1996) at the time of transplantation.” 
• #17 updated to: “Recipients with positive HCV antibody without proof of sustained viral 
response (SVR) 12 weeks after anti HCV treatment. Recipients with donors HCV 
positive” 
• #18 updated to: “Recipients with donors with macro-vesicular steatosis > 30%.” 
Section 6.1.2- Additional study treatments: addition of “mycophenolate” with MMF and 
wording update. 
Section 6.1.3- Treatment arms: addition of the randomization visit window “+/-2 days” and 
deletion of the expected on-site visits list to perform PK/PD assessment. 
Section 6.2.1- Concomitant therapy: wording update. 
Table 6-1- Prohibited medication: typo corrected. 
Section 6.3.2- Treatment assignment, randomization: deletion of randomization visit window 
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Section 6.5.1- Permitted dose adjustment and interruption of CFZ533 study treatment: typo 
corrected 
Section 6.5.2- Permitted dose adjustment and interruption of other study treatment: clarification 
that corticosteroids can be stopped once Month 4 visit has been completed. 
Section 6.6.1- Study treatment: wording update. 
Section 6.6.2- Other treatments: wording updates. 
Section 6.7- Preparation and dispensation: wording updates. 
Section 6.7.2.1- CFZ533 administration: deletion of “which correspond to one of the three 
treatment arms. Investigator staff will identify the study drug package(s) to be used for a single 
dose administration by contacting the IRT and obtaining the medication number(s)” as was not 
accurate and redundant with other sentence in the same section; change “at time of” 
randomization to “on day of” randomization for accuracy. Addition that “HCP (if applicable) 
can prepare the medication for administration”. 
Section 6.7.2.2- Tacrolimus administration: change of TAC trough level “8-12 ng/mL” to “5-
15 ng/mL”; wording updates. 
Section 7- Informed consent procedures: sentence moved within the same section. 
Section 8- Visit schedule and assessments: 
x Wording updates. 
x 
 
 
x Clarification that randomization visit (Day 8) has visit window of +/-2 days and other 
visits are expected to occur according to the study schedule based on randomization date. 
x Clarification that even if a visit date is changed, next visit should occur according to initial 
schedule. 
x Clarification that screening and baseline visits can occur on same day, and if these visits 
occur within 48 hours assessments don’t need to be repeated. 
Table 8-1 and Table 8-2- Assessment schedule: 
x Baseline visit = pre-LTx; similar footnote to clarify that all baseline assessments are 
expected to occur prior to LTx. 
x Screening period update = -1 to -60 days. 
x Weight measurements added to visits with temperature control. 
x Uncheck of Day 22 visit for TAC dose administration in Arm 2 and 3. 
x Footnote deletions. 
x New footnote to identify assessments that can be performed at home. 
x New footnote to clarify expected local lab assessments. 
x Footnote update to clarify that central lab chemistry test expected at time of suspected 
BPAR. 
x Footnote update to clarify that ascites aliquots expected from Day 8 visit onward. 
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x New footnote to clarify that CD40 at Month 4.5 visit is not mandatory for patients in Arm 
1. 
x In Table 8-2 lines for not applicable assessments have been deleted. 
x “Day schedule” corrected. 
Section 8.1 - Information to be collected on screening failure: clarification of patients eligible 
for re-screening and clarification that AEs will be captured from baseline onward. Deletion of 
the sentence requesting all AEs to be recorded in CRF from ICF consent signature as AEs will 
be recorded from baseline only. 
Section 8.2- Subject demographics/other baseline characteristics: wording updated to viral 
serology “will be obtained”. 
Section 8.3.1- Suspected Acute rejection/BPAR: wording update and addition of a central lab 
chemistry test assessment to be performed at the time of suspected BPAR. LDH test result, if 
available locally, to be captured in the eCRF. 
Section 8.4.1- Laboratory evaluations: Clarification that patient’s eligibility will be assessed 
based on local lab results, not central ones. Only tests needed to assess patient’s eligibility are 
mandatory to be performed locally.  
Table 8-4- Laboratory assessments: clarification that qualitative viral serology apply to donors 
and recipients; 24 hour collection period for proteinuria removed; qualitative and/or quantitative 
HCV-RNA and HBV-DNA (using PCR) tests will be performed locally for those patients who 
are tested anti-HCV positive and HBsAg positive, respectively. 
Section 8.4.3- Pregnancy and assessment of fertility: clarification of visits for urine and serum 
tests and addition of urine pregnancy test allowed to be done at home for subjects in Arm 1 and 
subjects receiving treatment at home, after Month 6 visit.  
Section 8.4.4- 2WKHUVDIHW\HYDOXDWLRQSUHYLRXVIRRWQRWHV³)RUUHFXUUHQWDQGGHQRYRFDVHVĮ-
fetoprotein will be evaluated as needed“ and “Quantitative EBV and CMV viral load will be 
assessed locally if active infection is suspected” integrated in the section. 
Section 8.5.2- Pharmacokinetics: wording updates and deletion of Day 8 visit window. 
Section 8.5.3- Pharmacodynamics: deletion of Day 8 visit window. 
. 
Section 8.5.6- CFZ533 concentrations in drained ascites fluids: clarification that ascites fluid 
sample collection is expected from the date of first CFZ533 administration and onward. 
Section 9.1.5- 6WXG\VWRSSLQJUXOHVFODULILFDWLRQWKDWDWUXH%3$5LVFRQVLGHUHGDV5$,
evaluated by central reader. 
Section 10.1.1- Adverse events: screening period reduced from 6 months to 2 months. 
Section 12.4.4- Sensitivity analysis: deletion of visit window at Day 8. 
 
 
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Section 12.6- Study stopping rules: wording updates and clarification that the stopping rule will 
be based on central biopsy review when BPARs are rated moderate to severe. 
Table 12-2- Probability of success under different event rates for 48 subjects of CFZ533 arm 
and 32 subjects of control arm: table updated as was previously not correct, columns were 
inverted. 
Section 15- References updated. 
Section 16.6- Blood log for PK, PD and immunogenicity: update of the Arm 1 CD 40 samples 
numbers as were previously incorrect. 
Section 16.7: deletion of the maximum volume of ascites aliquot to be collected. 
Amendment 01 
Amendment rationale 
The key purpose for this amendment is: 
 
 
Iscalimab has shown preservation of graft quality with normal renal morphology in a sub-set of 
subjects from the kidney transplant study CCFZ533X2201 (NCT02217410) (Nashan et al. 
2018). Thus, iscalimab has the potential of offering better graft quality and thereby improve 
long-term outcomes for transplanted patients. 
In patients after orthotopic liver transplantation, liver biopsy is used to detect acute or chronic 
rejection, potential recurrence of the underlying disease, and to evaluate the degree of fibrosis 
and stage of liver disease (Jiang and Farber 2017, Sebagh and Samuel 2004). Morphology plays 
an important role in differential diagnosis and subsequent treatment of post-transplant 
complications (Demetris et al 2000, Demetris et al 2016, Ormonde et al 1999). 
Routine surveillance biopsies can support clinical decision-making and allow for the 
identification of recipients who might benefit from immunosuppression treatment adjustments 
and inform the potential for immunosuppression minimization protocols (Demetris et al 2016, 
Feng and Bucuvalas 2017, Feng et al 2018, Sebagh and Samuel 2004). It also can assess the 
impact of chronic low grade injury, and help better understand low-grade chronic inflammation 
or allograft hepatitis and progressive fibrosis (Arias et al 2017, Feng and Bucuvalas 2017, Feng 
et al 2018, Londono et al 2018). Taken altogether, routine surveillance liver biopsies provide 
essential and clinically relevant information after liver transplantation with an acceptable 
benefit-risk profile (Banff Working Group on Liver Allograft 2012, Pereira et al 2016). 
 
 
 
Changes to the protocol 
The following sections have been changed in the amended protocol: 
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Title page - Introduction of International Nonproprietary Name (INN) name, Iscalimab. 
Section 1.1 - Background: Update on patients treated with CFZ533. 
 
Section 3 - Study design: Adaptations to treatment with MMF and CS. 
Section 4.4 - Rationale for choice of control drugs (comparator): Deletion of MPA, azathioprine 
and sirolimus. 
Section 4.7 - Previous clinical experience with CFZ533: New section defined and additional 
information added from CFZ533X2201 study. 
 
 
Section 5.2 - Exclusion criteria: Exclusion #4 deleted since already covered by Inclusion #5; 
Exclusion #5, clarification added to allow EBV results up to 28 days prior to baseline visits; 
Exclusion #15, re-wording. 
Section 6.1.1 - Deletion of the note mentioning that only MMF is allowed. 
Section 6.2.2 - Clarification that non-protocol immunosuppressants are only allowed for 
patients in follow-up and who discontinued from randomized study treatment.  
Table 6-1 - Removal of mycophenolic acid and anti-viral treatment for Hepatitis C from the list 
of prohibited concomitant treatments. 
Section 6.5.1 - Permitted dose adjustments and interruptions of CFZ533 study treatment: 
clarification on missed doses permission. 
Section 6.5.2 - Permitted dose adjustments and interruptions of other study treatment:  In case 
of persistent intolerance MMF can be discontinued and patients switched to other 
mycophenolates.  Guidance for CS treatment and over-immunosuppression management was 
added. 
Section 6.7.2.4 - Corticosteroids administration up to Month 24 was removed and wording 
aligned with Section 6.5.2. 
Section 7 - Inform consent procedures: Addition of contraceptive recommendations. 
Section 8 - Update of the expected follow-up visit list to match assessment schedule. 
Table 8-1 - Update of the assessment schedule: 
 
x 
 
x A-fetoprotein reported on a separate line (previously contained in the safety laboratory test 
line). 
x Clarification of footnotes. 
Table 8-4 - Implementation of quantitative assessments for EBV and CMV if active infection 
is suspected. 
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Section 8.4.3 – Pregnancy and assessments of fertility: Recommendations for female and male 
subjects taking MMF was updated 
Section 8.4.4 - Other safety evaluations: deletion of CMV and EBV assessment by donor/ 
recipient constellation. 
Section 8.5.6 - CFZ533 concentrations in drained ascites fluid: specified volume of the ascites 
aliquot was removed. Instruction to refer to lab manual procedure. 
 
 
Section 9.1.1 - Update of the expected follow-up visit list to match assessment schedule. 
Section 9.2 - Study completion and post-study treatment: Move TAC initiation time for Arms 
2 and 3, from EOS to EOS plus 2 weeks. Change in information to be reported in safety database 
at end of safety follow-up period. 
Section 10.1.1 - Adverse Event: Clarification that AEs will not be recorded from ICF signature 
date. AEs will be recorded from date of transplantation, as screening period can last up to 6 
months prior to transplantation. 
Section 12.5.2.1 - Renal function: Null and alternative hypothesis based on eGFR value at 
randomization, not baseline. 
 
 
Section 15 - References: addition of new references. 
Section 16.6, Appendix 6a - Blood log for PK, PD 
 sampling: Blood 
collection log for Arm 1 (TAC regimen) added. 
In addition minor corrections of typos were performed and are highlighted in track change. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
 
 
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Protocol summary 
Protocol number 
CCFZ533A2202 
Full Title 
A 12-month, open-label, multicenter, randomized, safety, efficacy, pharmacokinetic (PK) 
and pharmacodynamic (PD) study of two regimens of anti-CD40 monoclonal antibody, 
CFZ533 vs. standard of care control, in adult de novo liver transplant recipients with a 
12-month additional follow up and a long-term extension (CONTRAIL I). 
Brief title 
CONTRAIL I - Study of efficacy, safety, tolerability, PK/PD of anti-CD40 monoclonal 
antibody, CFZ533, in de novo liver transplant recipients. 
Sponsor and 
Clinical Phase 
Novartis 
Phase II 
Investigation type 
Biological 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of the study is to investigate the safety, efficacy, pharmacokinetics (PK) 
and pharmacodynamics (PD) of two calcineurin inhibitor (CNI)-free regimens of 
CFZ533, compared to standard of care control, in adult de novo liver transplant 
recipients. 
This study will allow the assessment of the ability of CFZ533 to replace calcineurin 
inhibitors (CNIs) in terms of anti-rejection efficacy, while providing potentially better 
renal function with an expected similar safety and tolerability profile.  
The study results will be used to inform the CFZ533 dose and regimen selection for a 
pivotal Phase III trial in de novo liver transplant population. 
Primary 
Objective(s) 
To evaluate the rate of composite efficacy failure (Biopsy Proven Acute Rejection 
(BPAR), graft loss (GL) or death) with CFZ533 600 mg and  
300 mg regimens compared to tacrolimus (TAC) Control at Month 12  
post-transplantation. 
Secondary 
Objectives 
Key secondary: 
• To evaluate the renal function (estimated Glomerular Filtration Rate (eGFR) by 
MDRD-4 formula) with CFZ533 600 mg and 300 mg regimens compared to TAC 
Control at Month 12 post-transplantation. 
Secondary: 
• To evaluate the composite of BPAR, Death, Graft Loss and Loss to Follow-up with 
CFZ533 600 mg and 300 mg regimens compared to TAC Control at Month 12 and 
Month 24 post-transplantation. 
• To evaluate whether CFZ533 600 mg or 300 mg  regimens have lower incidence 
rates over 12 months and 24 months post-transplantation compared to the control 
arm for the following events: 
- 
BPAR 
- 
Treated Biopsy Proven Acute Rejection (tBPAR) 
- 
Acute Rejection (AR) 
- 
Treated Acute rejection (tAR) 
- 
Antibody mediated (humoral) rejection 
- 
Graft Loss (GL) 
- 
Death. 
• To evaluate eGFR and change in eGFR up to Month 24 post-transplantation. 
• To assess the safety and tolerability of CFZ533 regimens compared to control at 
Month 12 and Month 24. 
• To assess the pharmacokinetics of multiple doses of CFZ533 over the 12-month and 
24-month treatment and explore the dose-exposure relationship. 
• To assess the levels of peripheral soluble CD40 (sCD40) at baseline, over the 12-
month and 24-month treatment period (to inform target biology, target engagement). 
• To evaluate the immunogenicity of CFZ533 by analysis of anti-CFZ533 antibodies 
(over the 12-month and 24-month treatment period). 
Study design 
Study CFZ533A2202 is a randomized, 12-month, active-controlled, open-label, multi-
center, dose range finding study to evaluate the efficacy, safety, tolerability, PK and PD 


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of two CFZ533 regimens with a 12-month additional follow-up and a long-term 
extension in adult de novo liver transplant recipients. 
Study population 
The study population is adult male and female de novo liver transplant recipients of a 
primary graft from a deceased donor. It is planned to randomize at least 128 
participants. 
Key Inclusion 
criteria 
Screening period up to liver transplantation: 
• 
Written informed consent obtained before any assessment. 
• 
Male or female subjects between 18 to 70 years of age. 
• 
Recipients of a primary liver transplant from a deceased donor.  
• 
Up to date vaccination as per local immunization schedules. 
• 
Recipients tested negative for HIV. 
• 
MELD score ≤ 30 (based on laboratory values, using the United Network for Organ 
Sharing (UNOS) MELD calculator: MELD calculator: 
[https://unos.org/resources/allocation-calculators/]). 
• 
Transplantation to occur within defined screening period following informed consent 
signature. 
At randomization (Day 8±2): 
• 
Recipients with no active HCV and HBV replication. Recipients with HCV antibody 
positive should have no detectable HCV-RNA.  Recipients with Hepatitis B infection 
should have no detectable HBV DNA. Cases of spontaneous HCV clearance 
should be discussed with sponsor. 
• 
Allograft is functioning at an acceptable level by the time of randomization as 
defined by AST, ALT and Alkaline Phosphatase levels ≤ 5 times ULN and Total 
Bilirubin ≤ 2 times ULN. 
• 
Renal function (eGFR, MDRD-4 formula) ≥ 30 mL/min/1.73 m2 based on most 
recent post-transplant value prior to randomization.  
• 
Recipients who have been initiated on an immunosuppressive regimen that contains 
TAC, mycophenolate mofetil (MMF) and corticosteroids (CS) as per protocol. 
Key Exclusion 
criteria 
Screening period up to liver transplantation: 
• 
Use of other investigational drugs at screening within 30 days or  
5 half-lives of screening. 
• 
Recipients of multiple solid organ or islet cell transplants, or recipients that have 
previously received a tissue transplant, or a combined liver-kidney transplant. 
• 
Recipients of a liver from a donor after cardiac death (DCD), from a living donor, or 
of a split liver. 
• 
Recipient who tests negative for Epstein Barr virus (EBV). 
• 
Recipients receiving an ABO incompatible allograft. 
• 
History of malignancy of any organ system (except hepatocellular carcinoma (HCC) 
or 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. 
• 
Hepatocellular carcinoma that does not fulfill Milan criteria (1 nodule ≤ 5 cm,  
2-3 nodules all ≤ 3 cm, without evidence of metastatic disease or vascular invasion) 
at the time of transplantation.  
• 
Recipients transplanted for acute liver failure (does not apply to acute on chronic 
liver failure). 
• 
Any use of antibody induction therapy, or use of any immunosuppressive 
medications (or other medications prohibited by the protocol) 
• 
Participants who have received a live vaccine within four weeks prior to 
transplantation.  
• 
Recipients with donors HIV positive. 
• 
Recipients with donors HBsAg positive. 


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x 
Recipients who are HCV antibody-positive without documented sustained viral 
response (SVR) at 12 weeks after finishing anti HCV treatment (e.g., direct-acting 
antivirals). 
x 
Recipients with HCV RNA-positive donors 
x 
Recipients with donors with macrovesicular steatosis > 30%. 
x 
Pregnant or nursing (lactating) women. 
At randomization (Day 8±2): 
x 
Any post-transplant history of thrombosis, occlusion or stent placement in any 
hepatic arteries, hepatic veins, portal vein or inferior vena cava at any time during 
the run-in period prior to randomization. Absence of any graft vascular thrombosis 
or occlusion (by diagnostic method used at the site to assess vascular patency) 
must be confirmed by imaging prior to randomization. 
x 
Recipients with platelet count < 50,000/mm3.  
x 
Recipients with an absolute neutrophil count of < 1,000/mm³ or white blood cell 
count of < 2,000/mm³. 
x 
Recipients with clinically significant systemic infection requiring use of intravenous 
(IV) antibiotics.  
x 
Evidence of active tuberculosis (TB) infection (after anti-TB treatment, patients with 
history of latent TB may become eligible according to national guidelines). 
x 
Recipients who are in a critical care setting at the time of randomization requiring life 
support measures such as mechanical ventilation, dialysis, requirement of 
vasopressor agents. 
x 
Recipients who are on renal replacement therapy at randomization. 
x 
Any episode of acute rejection or suspected rejection prior to randomization. 
x 
HCC participants whose explanted liver graft pathology report shows i) pTNM stage 
beyond T2N0M0, ii) presence of mixed carcinoma, iii) microvascular  invasion 
despite pTNM stage. 
x 
Participants with body weight < 30 kg or > 180 kg 
Study treatment 
x 
Arm 1 - TAC Control:Tacrolimus + MMF + CS (n=32). 
x 
Arm 2 - CFZ533 600 mg regimen:30 mg/kg IV (Day 8), 15 mg/kg IV  
(Day 15), then CFZ533 SC 600 mg every 2 weeks from Day 29 to End of Study 
(EOS) + MMF + CS (n=48). 
x 
Arm 3 - CFZ533 300 mg regimen - 30 mg/kg IV (Day 8), and then CFZ533 300 mg 
every 2 weeks SC from Day 29 to EOS + MMF + CS (n=48). 
x 
For Arm 2 and 3, use of vials from Day 29 to Month 12, and then switch to pre-filed 
syringes once available. 
Efficacy 
assessments 
x 
BPAR (Banff classification) 
x 
tBPAR 
x 
Graft Loss (GL) 
x 
Death 
Pharmacodynamic 
Assessments 
x 
Soluble CD40 plasma concentrations (up to End of Study (EOS)). 
Pharmacokinetic 
assessments  
x 
CFZ533 plasma concentrations (up to EOS). 
x 
CFZ533 concentrations in drained ascites fluid (as appropriate up to Month24). 
Key safety 
assessments 
x 
Renal Function (eGFR). 
x 
Proportion of participants with AEs, SAEs, AEs related to study drug. 
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Data analysis 
Primary 
The efficacy analysis for the first 12 months evaluates whether at least one of the two 
CFZ533 treatment arms meets the pre-defined success criterion.  
The number of participants with composite efficacy failure is assumed to follow a 
binomial distribution, i.e.,ri ~ binomial (ni, ȟi), where ri  is the number of participants with 
composite efficacy failure in treatment arm i, ni is the number of participants in treatment 
arm i and ȟi is the probability of  composite efficacy failure.   
A CFZ533 arm is considered successful if the composite efficacy failure rate difference 
EHWZHHQWKLV&)=DUPDQGWKHFRQWURODUPLVZLWKSUREDELOLW\ 
Pr (ȟCFZ533 ̽ ȟcontrol <0.15 | data) > 80% based on the FAS. 
The required posterior probabilities will be estimated from simulations of the posterior 
distributions of ȟCFZ533 ̽ ȟcontrol and compared to the threshold for level of proof. The 
prior distributions will be assumed to be non-informative. The posterior mean composite 
efficacy failure rates for each treatment arm and for the difference in mean response 
rates between CFZ533 treatment arms and control will be presented together with 95% 
credible intervals.  
Key Secondary 
The mean change in eGFR (MDRD-4) from randomization to Month 12 between a 
CFZ533 arm and control will be evaluated as follows: The mean change for each arm 
will be obtained through covariate-adjusted treatment effects using MMRM. The model 
will contain treatment arm, visit, treatment arm*visit, and randomization GFR with 
unstructured covariance matrix. The estimand will be evaluated in the FAS population 
by comparing the difference in mean change between each CFZ533 arm and control. 
Key words 
Liver transplantation, de novo liver transplant recipient, deceased donor, CFZ533, CNI-
free immunosuppression. 
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1 
Introduction 
1.1 
Background 
Liver transplantation is now recognized as the treatment of choice for end-stage liver failure. 
Its success can be attributed largely to the generation of selective immunosuppressive agents, 
which have resulted in a dramatic reduction in the incidence of acute rejection and 
improvements in the short- and long-term outcomes of patients (Selzner et al 2010). The current 
gold standard of care is based on the triple combination regimen with tacrolimus, 
mycophenolate and corticosteroids (CS). 
Despite the ability of current immunosuppressive agents to reduce the incidence of acute 
rejection, the long-term toxicity associated with current regimens now has become a major 
challenge for liver transplant recipients and is increasingly perceived as an unmet clinical need. 
The most common side effects of these agents include: increases in the incidence of bacterial 
and viral infections, nephrotoxicity with chronic renal impairment (Zhang et al 2017) de novo 
diabetes mellitus, hyperlipidemia, arterial hypertension, cardiovascular disease, osteoporosis, 
neurotoxicity/neurocognitive impairment (Pflugrad et al 2018), hematological toxicity 
[including an increased rate of post-transplant lymphoproliferative disorder (PTLD)], the 
development of de novo or recurrent solid organ cancers and disease recurrence after liver 
transplantation. The recognition of these life-threatening side effects has now driven interest in 
the use of calcineurin inhibitors (CNI)-sparing strategies to limit CNI exposure (e.g., tacrolimus, 
cyclosporine), including CNI minimization, avoidance, and withdrawal (Flechner et al 2008). 
However, to date, the majority of these minimization strategies have failed to reduce the 
incidence and severity of long-term renal and cardiovascular disease after transplantation. 
To fulfill this important unmet medical need, an exploratory Phase II study was conducted to 
evaluate the efficacy and safety of the co-stimulation blocker belatacept in adult recipients of 
first liver transplant from a deceased donor in the context of CNI-free regimen (NCT 00555321). 
At the conclusion of this study, two of three belatacept groups had higher rates of death and 
graft loss relative to the standard-of-care control group tacrolimus + MMF. All three belatacept 
groups also had higher rates of AR, and there was an increase in viral and fungal infections, the 
majority of which were not serious. Two cases of PTLD and one case of Progressive Multifocal 
Leukoencephalopathy (PML) were reported in belatacept-treated subjects. The two belatacept 
high dose groups had substantially better mGFR than the remaining three groups, while all three 
belatacept groups had better eGFR. There was also evidence of fewer neurotoxicity events in 
the belatacept groups. 
In belatacept-treated subjects, the tendency toward more viral and fungal infections observed 
raises the possibility of over-immunosuppression in some subjects, as observed with regimens 
that include MMF. Paradoxically, the higher rates of AR would suggest under 
immunosuppression or immunomodulatory effects, not yet understood in the context of liver 
transplantation. It is also possible that the management of AR placed subjects at risk for 
subsequent infectious complications. The standard treatment for rejection may have been more 
intense 
than 
was 
needed 
in 
belatacept-treated 
subjects, 
suggesting 
that 
over-
immunosuppression may explain the infectious complications (Klintmalm et al 2014). 


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Findings from this phase II study did not allow the identification of a safe and effective dose 
or regimen for further development of belatacept in the liver transplant indication. 
The authors of the study mention that the liver may be subject to CD28- independent T cell 
activity as is surely to be expected, and they cite the potential negative effect of CD28 blockade 
on regulatory T cell activity. Recent understanding of the pathways of cell activation has 
resulted in the development of a new immunosuppressive agent that may address the challenges 
facing transplantation today and allow the substitution of existing agents by offering similar 
efficacy in terms of prevention of graft rejection but offering better renal function and good 
safety profile. 
CD40 signaling is implicated in the pathology of transplant rejection as well as a range of 
autoimmune diseases. CFZ533, is a fully human, IgG1 anti-CD40 antibody that blocks 
recombinant CD154 (rCD154)-induced activation of CD40 pathway signaling in vitro and 
in vivo. The Fc-portion of CFZ533 has a single amino acid mutation which eliminates the cell-
depleting ability of the antibody via antibody-dependent cell mediated cytotoxicity (ADCC) or 
complement-dependent cytotoxicity (CDC). It is able to block T cell-dependent antibody 
responses in humans, and prolongs allograft survival in a preclinical transplantation model 
(CFZ533 Investigator’s Brochure (IB); Cordoba et al 2015). 
Up to 15-Nov-2020 approximately 837 subjects (comprising healthy volunteers, subjects with 
various autoimmune diseases and transplant subjects, for details please refer to the Investigator 
Brochure), receiving either CFZ533 (n=approximately 608) or control drug (n=254, 125 on 
placebo and 129 on standard of care (SoC) treatment), have been enrolled in the CFZ533 clinical 
development program. 
In the First-in-human Phase 1 clinical study, single doses of IV or SC CFZ533 up to 30 mg/kg 
(inclusive) were evaluated and showed a favorable safety and tolerability profile in healthy 
volunteers and in rheumatoid arthritis (RA) subjects. Similarly, in a Phase 1 study of Japanese 
healthy volunteers, single IV (0.3, 1, 3 mg/kg), and SC (3 mg/kg) doses of CFZ533 were well 
tolerated.  Furthermore, interim Phase 2a results in primary Sjöegren’s syndrome (pSS) with 
multiple doses (8 doses over 21 weeks) of 3 mg/kg SC or 10 mg/kg IV CFZ533 or placebo 
suggest a favorable safety and tolerability profile in both dose cohorts.  Preliminary efficacy 
data from this study also suggest that multiple doses of 10 mg/kg IV CFZ533 may have 
therapeutic benefit in pSS subjects. In kidney transplantation, a Proof of Concept (PoC) trial 
(CCFZ533X2201) was conducted in de novo renal transplant recipients, to evaluate the safety, 
tolerability, pharmacokinetics, pharmacodynamics and efficacy of multiple doses of CFZ533 in 
combination with MMF and corticosteroid (CS), compared to a TAC-based regimen. The 
CFZ533 treated participants received a loading regimen of 10 mg/kg IV on Days 1, 3, 7, 15, 29, 
43 and 57, followed by a maintenance regimen at 10 mg/kg IV every four weeks, up to 12 
months post-transplantation. The 12-month data, following review by an independent 
adjudication committee, showed that in comparison to TAC-based regimen, CFZ533 regimen 
had i) a comparable efficacy on the composite endpoint of treated BPAR, graft loss, or death, 
ii) a superior renal function and iii) a favorable safety profile for up to 12 months of treatment. 
In conclusion, the data supports the potential of CFZ533 to become an effective CNI-free 
treatment, improving transplant outcomes by preventing graft rejection without nephrotoxic and 
other CNI adverse effects. For the most up-to-date information, please refer to the latest CFZ533 
Investigator’s Brochure. 


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Based on these data, a dose range finding study (CCFZ533A2201) is ongoing to evaluate the 
efficacy, safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of CFZ533, 
in de novo and maintenance kidney transplant recipients (study name: CIRRUS I; 
NCT03663335). 
Study CCFZ533A2202 represents the first clinical investigation of CFZ533 in de novo adult 
liver transplant recipients. The purpose of this study is to investigate the safety, efficacy, 
pharmacokinetics (PK) and pharmacodynamics (PD) of two CNI free regimens of CFZ533 in 
de novo liver transplant recipients, compared to a standard of care control (SoC) arm of 
tacrolimus, MMF and corticosteroids (CS). This study will allow the assessment of the ability 
of CFZ533 to replace CNIs in terms of anti-rejection efficacy, while providing potentially better 
renal function with an expected similar safety and tolerability profile. 
CNI regimens can lead to renal failure and the need for kidney transplant in many non-kidney 
transplant recipients (Ojo 2003). Stage 4 or 5 chronic kidney disease (CKD) has been reported 
in ~18% of liver transplant recipients by 5 years post-transplant and is associated with increased 
morbidity and mortality. Data from 1997 to 2008 in the Organ Procurement Transplant 
Network/United Network for Organ Sharing (OPTN/UNOS) database showed a threefold 
increased rate of kidney transplantation in subjects who previously received a liver transplant. 
It is expected that CFZ533 will provide a benefit in renal function while maintaining a 
comparable anti-rejection efficacy to CNIs. In addition, other benefits of the CNI-free regimen 
may be in the areas of new-onset diabetes, neurological/neurocognitive impairment symptoms 
and other CNI-related toxicities. 
The two CFZ533 regimens proposed for Study CCFZ533A2202 are anticipated to be favorable 
and tolerable in liver transplant subjects based on clinical results in kidney transplant 
participants exposed up to 12 months to the 10 mg/kg IV dosing regimen in the CCFZ533X2201 
trial. 
1.2 
Purpose 
To investigate the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of two 
CNI-free regimens of CFZ533, compared to standard of care control, in adult de novo liver 
transplant recipients.   
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
• 
To evaluate the rate of composite efficacy failure 
(Biopsy Proven Acute Rejection (BPAR), graft 
loss or death) with CFZ533 600 mg and 300 mg 
regimens compared to TAC Control at Month 12 
post-transplantation. 
Endpoint(s) for primary objective(s) 
Incidence of composite efficacy failure at Month 12, 
where BPAR is from biopsy data indicating a rejection 
activity index (RAI) ≥3 (Appendix 3). 
Key Secondary Objective 
• 
To evaluate the renal function (estimated 
Glomerular Filtration Rate (eGFR) by MDRD-4 
Endpoint(s) for Secondary Objective(s) 
• 
Mean change in eGFR from randomization to 
Month 12. 


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Objective(s) 
Endpoint(s) 
formula) with CFZ533 600 mg and 300 mg 
regimens compared to TAC Control at Month 12 
post-transplantation. 
Secondary Objective(s) 
x 
To evaluate the composite of BPAR, Death, Graft 
Loss and Loss to Follow-up with CFZ533 600 mg 
and 300 mg regimens compared to TAC Control at 
Month 12 and Month 24 post-transplantation. 
 
x 
To evaluate whether CFZ533 600 mg or 300 mg 
regimens have lower incidence rates over 12 and 
24 months post-transplantation compared to TAC 
control arm for the following events: 
- 
BPAR 
- 
tBPAR 
- 
AR 
- 
Treated Acute rejection (tAR) 
- 
Antibody mediated (humoral) rejection 
- 
Graft Loss 
- 
Death 
 
x 
To evaluate eGFR and change in eGFR up to 
Month 24 post-transplantation. 
x 
To assess the safety and tolerability of CFZ533 
regimens compared to TAC control at Month 12 
and Month 24.   
 
 
 
 
 
 
 
 
 
 
x 
To assess the pharmacokinetics of multiple doses 
of CFZ533 over the 12-month and 24-month 
treatment 
and 
explore 
the 
dose-exposure 
relationship. 
x 
To assess the levels of peripheral soluble CD40 at 
baseline and over the 12-month and 24-month 
treatment period (to inform target biology, target 
engagement). 
x 
To evaluate the immunogenicity of CFZ533 by 
analysis of anti-CFZ533 antibodies (over the 12-
month and 24-month treatment period). 
 
 
 
x 
BPAR as above, Death, Graft Loss and Study 
completion/disposition datasets. 
 
 
 
x 
Event rates over 12 months and 24 months post-
transplantation. 
 
 
 
 
 
 
 
 
 
x 
To evaluate eGFR values and change from 
randomization to Month 24. 
x 
Proportion of participants with: 
- 
Adverse events 
- 
Serious adverse events 
- 
AEs related to study drug 
x 
Means and mean change over time of:  
- 
Vital sign parameters 
- 
Lab parameters (Section 8.4.1) 
x 
Proportion of participants with: 
- 
Premature discontinuation from study 
- 
Premature discontinuation of study drug  
- 
Dose interruption 
- 
Dose adjustment 
 
 
x 
Free CFZ533 plasma concentrations over time 
(CFZ533-treated participants only). 
 
 
x 
Total sCD40 in plasma (all participants). 
 
 
x Semi-quantitative analysis of anti-CFZ533 
antibodies in plasma (CFZ533-treated 
participants only). 
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3 
Study design 
This study is a 12-month, multicenter, open-label, randomized study with a 12-month additional 
follow-up and a long-term extension that will consist of: 
x A screening period (up to 2 months) starting from informed consent, screening visit, and 
including successful liver transplantation (LTx).  
x Run-in treatment period following the successful transplantation that ends on the day of 
randomization or randomization failure, at Day 8 (with visit window of ±2 days) post-LTx.  
x The primary treatment period (Treatment period 1) starting at randomization  
Day 8±2 post-LTx up to Month 12 followed by a 12-month follow-up treatment period 
(Treatment period 2) until Month 24 (Figure 3-1). 
x The long-term extension period (Treatment Period 3) starting post Month 24 until the end 
of the study (EOS). 
PPD


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Participants will be consented and screened for eligibility prior to liver transplantation. 
Consented participants who have met the screening inclusion criteria, undergone a successful 
liver transplantation and been initiated on a tacrolimus-based regimen that includes 
mycophenolate mofetil (MMF) and CS according to local practice, will enter the run-in period. 
Transplanted participants who meet the additional inclusion criteria will be randomized at Day 
8±2 days post-LTx. 
At least 128 participants will be randomized at a ratio of 2:3:3 to TAC Control (Arm 1) or one 
of two regimens of CFZ533: 600 mg CFZ533 subcutaneous (SC) injections every 2 weeks 
(Arm 2) or 300 mg CFZ533 SC injections every 2 weeks (Arm 3) combined with MMF and 
CS (Figure 3-1).  
Each CFZ533 arm will have a loading period where CFZ533 will be administered IV in order 
to rapidly achieve concentrations providing complete CD40-CD40L pathway blockade in target 
tissues in conditions where CD40 expression levels may be enhanced (Section 4.2 for dose 
rationale). Participants who do not meet the randomization criteria will be designated 
randomization failures. The randomized failure participants will not be further followed-up in 
the study. 
The study treatments will be as follows: 
• Arm 1 (TAC Control) - TAC, MMF and CS will be started in the peri-transplant period and 
at randomization these will continue up to the EOS. Initial tacrolimus target trough levels 
will be between 5-15 ng/mL, based on b.i.d dosing and will be maintained throughout the 
run-in period. From randomization onwards, the TAC levels will be adjusted as per local 
label. 
• Arm 2 (CFZ533 600 mg regimen) - Loading doses will be 30 mg/kg IV on Day 8 post-
transplantation, with a second dose of 15 mg/kg IV on Day 15 and SC administration of  
600 mg every 2 weeks will begin on Day 29, with MMF and CS until the EOS. 
• Arm 3 (CFZ533 300 mg regimen) - A single loading dose of 30 mg/kg IV will be 
administered on Day 8 and SC administration of 300 mg every 2 weeks will begin on Day 
29, with MMF and CS until the EOS. 
In CFZ533 Arms 2 and 3, during the immediate peri- and post-transplant period, TAC will be 
given to provide immunological coverage but must be completely weaned off by Day 22. For 
details, please refer to Section 6.7.2.2. 
CFZ533 sub-cutaneous injections will be administered by authorized Investigator/staff at each 
study visit. After the Month 6 visit (at site), in-home administration may be allowed by a health 
care provider (HCP). After Month 12 visit, the pre-filled syringes (PFS) use will allow self-
administration at home. 
The participants in the Control arm will receive their last dose of TAC on the day of the EOS. 
From EOS onwards, participants will be treated according to local standard of care practice. 
For all participants, MMF will be initiated at the time of liver transplantation, mycophenolates 
should be maintained throughout the study with CFZ533 or TAC; however adaptations are 
possible in case of signs of over-immunosuppression (see Section 6.5.2). 


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For all participants after the last study visit (EOS), there will be a 12-week safety follow-up 
period. 
MMF and Corticosteroid doses will be administered according to local practice. Corticosteroid 
use is mandatory until Month 4 visit has been completed but the initiation and dose is according 
to local practice, with a minimum prednisone dose of 5 mg/day or equivalent dose of another 
oral corticosteroid. 
All dose changes must be recorded in the appropriate CRF. 
Figure 3-1 
Study design  
 
4 
Rationale 
4.1 
Rationale for study design 
• The design was chosen using a relatively conservative approach (delayed randomization, 
12 months treatment duration and 12 months additional follow-up on treatment) given that 
this is the first study investigating CFZ533 in the liver transplant population. 
• Due to the potential risk of serious infections and higher incidence of post-transplant 
surgical complications in the liver transplant population versus other type of transplants, 
possibly leading to death/graft loss in the immediate post-transplant period, delayed 
introduction of CFZ533 has been preferred. 
• At the time of LTx (Day 1) the TAC blood target trough levels will be 5-15 ng/mL and will 
be maintained throughout the run-in period for all participants (Arms 1, 2, 3). 


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• For the Arm 1 participants, they will continue on TAC, MMF and CS. TAC levels will be 
adjusted as per local label. 
• For the CFZ533 (Arms 2 and 3) participants; TAC dose will be progressively decreased 
until Day 21 as described thereafter. On Day 8, at the time of the first CFZ533 loading dose 
(30 mg/kg IV), the TAC dose will be reduced to achieve a TAC blood trough level of 5-8 
ng/mL. The TAC dose will be further decreased by Day 15, to target a TAC blood trough 
level below 5 ng/mL. By Day 22, TAC must be completely weaned-off. 
• The delayed randomization at Day 8±2 post-LTx was chosen to mitigate the risk of post-
surgical complications, over-immunosuppression, infections and drug-loss through 
abdominal fluid and to take advantage of the vasoconstrictive and pro-fibrotic effect of 
tacrolimus. 
• The long-term extension was added to collect long-term safety and efficacy data in a 
controlled clinical trial setting. Patients will stay in the long-term extension for at least 3 
years.  
4.1.1 
Rationale for choice of background therapy 
CFZ533 will be utilized as part of the typical triple therapy regimen in association with the anti-
proliferative agent MMF and CS in the context of a CNI-free regimen. Corticosteroids have 
been the mainstay for induction of immunosuppression since the first successful cases of solid 
organ transplantation but the doses are reduced normally during the maintenance phase to 
minimize its side effects. If medical conditions allow, some centers may tend to eliminate 
corticosteroids from the regimen, resulting in a final dual therapy regimen composed by a 
backbone immunosuppressant (TAC or CFZ533) and MMF. 
4.2 
Rationale for dose/regimen and duration of treatment 
4.2.1 
Arm 2 (600 mg regimen) 
CFZ533 treatment starts with two loading doses where CFZ533 is administered at 30 mg/kg IV 
on Day 8±2, and at 15 mg/kg IV on Day 15, followed by a subcutaneous maintenance regimen 
starting on Day 29 and up to  the EOS, where CFZ533 is administered at 600 mg every 2 weeks. 
The predicted median CFZ533 plasma concentration-time profile is presented on Figure 4-1. 
Rationale for the loading dose(s) 
CFZ533 is subject to target-mediated elimination, and the level of expression of CD40 receptors 
in target tissues has the potential to affect exposure to CFZ533, and ultimately target 
engagement. High CD40 expression may be associated with high elimination rate of CFZ533 
and loss of CD40 pathway blockade, if CD40 receptors are not fully saturated. The loading 
dose(s) are aiming to achieve, at start of treatment, full CD40 receptor saturation and minimal 
CD40-mediated elimination, in conditions where, after transplantation, CD40 expression may 
be enhanced (as after kidney transplantation - illustrated below with ASKP1240 data). 


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ASKP1240 (bleselumab) in kidney transplantation 
The risk associated with under dosing in conditions where CD40 expression is enhanced is 
illustrated through the ASKP1240 (bleselumab) program. This IgG4 anti-CD40 blocking 
antibody with similar PK and pharmacology properties as CFZ533 was investigated in kidney 
transplant participants (Phase 2). We refer to data presented at the American Transplant 
Congress in 2015 (Harland et al 2015). 
In the CNI-free and low CNI arms a fixed dose of 200 mg IV ASKP120 (corresponding to about 
2.9 mg/kg for a 70 kg bodyweight participant) was administered on Days 0, 7, 15, then every 2 
weeks (Q2W) and every 4 weeks (Q4W). The cumulative dose for ASKP1240 up to Days 29 
and 57 was 800 and 1200 mg, respectively. Most of the rejections in the CNI-free arm occurred 
before Day 60. It is hypothesized that ASKP1240 failed in the CNI-free regimen likely due to 
under dosing that failed to fully saturate increased levels of CD40 expression in tissues during 
the first 1 or 2 months, leading to an enhanced CD40 mediated clearance of ASKP1240, 
suboptimal tissue exposure and high rates of rejection. 
This hypothesis is further supported by preclinical data with ASKP1240 in transplanted 
monkeys (Ma et al 2014). After receiving the allograft kidneys, the recipient’s immune system 
was rapidly activated, resulting in an increase in CD40 expression in B cells, dendritic cells, or 
macrophages as well as on selected allograft parenchymal cells. As a result of the immune 
response against allo-antigens, the number of activated cells and unoccupied CD40 sites 
increased and would have required higher doses or more frequent administration of ASKP1240, 
a notion borne out by the increased clearance of ASKP1240 observed in transplanted animals 
(Ma et al 2014). 
Previous experience with CFZ533 in kidney transplant and RA participants 
In Part 2 of the proof of concept Study CCFZ533X2201, evaluating the safety, tolerability, 
PK/PD and efficacy of multiple doses of CFZ533 in combination with MMF and corticosteroids, 
compared to a TAC-based regimen, in de novo renal transplant recipients, a loading regimen 
was implemented (10 mg/kg IV on Day 1, 3, 7, 15, 29, 43 and 57), followed by a maintenance 
regimen at 10 mg/kg IV Q4W. Treatment with CFZ533 was well tolerated, and not associated 
with an increased risk for over-immunosuppression such as infection or neutropenia. Assuming 
a BW of 70 kg, the cumulative dose of CFZ533 was 3500 and 4900 mg up to Day 29 and 57 
post-transplant, respectively. With the exception of the first week post transplantation, the 
loading regimen led to CFZ533 plasma concentrations that were generally > 200 µg/mL for up 
to 3 months. 
Similarly, in Study CCFZ533A2202 (liver transplant), assuming an absolute bioavailability of 
about 75% for CFZ533 doses administered subcutaneously (preliminary data from the first-in-
human Study CCFZ533X2101), the cumulative dose for CFZ533 in liver transplant participants 
are expected to be 3600 and 4500 mg up to Day 29 and 57, respectively. 
The proposed IV loading - SC maintenance regimen (further details in the section below) is 
expected to provide similar plasma exposure levels, during the first 3 months, to those observed 
in Study CCFZ533X2201-Part 2 (kidney transplant). 


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In the First-in-human Phase 1 Study CCFZ533X2101, the administration of CFZ533 at  
30 mg/kg IV (single dose) in rheumatoid arthritis participants, translated into a mean Cmax of 
about 848 µg/mL and 16 weeks of target engagement as measured through PK/PD data in whole 
blood. The 30 mg/kg IV dose showed a favorable safety and tolerability profile. 
Rationale for the maintenance regimen 
In Arm 2, the 600 mg regimen is expected to provide steady state median trough CFZ533 
plasma concentration of about 200 µg/mL, which is in the upper range (Figure 4-1) of the 
CFZ533 trough concentrations measured in Study CCFZ533X2201-Part 2. In that study, 
preliminary efficacy data suggest comparable biopsy proven acute rejection (BPAR) rates in 
the CFZ533 and Standard of Care arms. 
The half-life of CFZ533 is about 2 weeks when ‘full’ CD40 saturation (minimal contribution 
of CD40 receptors to the overall clearance) is obtained, therefore supports the bi-weekly SC 
regimen. In addition, the every 2 weeks regimen in this study is expected to provide less 
between-participant variability as compared to the Q4W IV regimen in Study CCF533X2201-
Part 2 in kidney transplant. 
Rationale for the duration of the safety follow-up period (target engagement 
after the last dose) 
Based on the predicted median CFZ533 plasma concentration-time profile in liver transplant 
participants (Figure 4-1), at about 14 weeks after the last dose (Day 659, Month 23.5), CFZ533 
plasma concentrations are expected to drop below 20 μg/mL with no expected 
pharmacodynamic activity in target tissues (e.g., germinal centers; data from non-human 
primates in Investigator’s Brochure). 
A 14 weeks follow-up period after the last CFZ533 dose has been selected, and it is justified to 
monitor any related serious adverse events. 
4.2.2 
Arm 3 (300 mg regimen) 
The CFZ533 treatment starts with a loading dose where CFZ533 is administered at 30 mg/kg 
IV on Day 8±2, followed by a subcutaneous maintenance regimen starting on Day 29 and up  
to EOS, where CFZ533 is administered at 300 mg every 2 weeks. 
Rationale for testing a lower CFZ533 regimen in liver transplant participants 
The decision and rationale for testing a lower regimen for CFZ533 in liver transplant is 
motivated and guided by the following considerations: 
• High tissue penetration in liver 
As compared to kidney, a tissue with tight and size-selective capillaries where CFZ533 is 
mainly restricted to the vascular space and poorly distributed in the interstitial space, higher 
interstitial 
antibody 
concentrations 
are 
expected 
in 
liver.  
In liver, due to discontinuous capillaries, the vessel wall does not provide a clear separation of 
the vascular and interstitial space for IgGs. This would translate into a rapid equilibrium 


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between the two spaces, and interstitial concentrations that are reflected by plasma 
concentrations. 
• Immune tolerance in liver transplantation 
It is now well recognized that the liver exhibits immune tolerogenic properties that contribute 
to a unique propensity toward spontaneous acceptance in the context of transplantation and to 
a far lower risk of graft loss secondary to rejection episodes, as compared with other 
transplanted organs (Calne 2000, Clavien et al 2017, Mastoridis et al 2017, Vionnet and 
Sanchez-Fueyoc 2018). 
In addition, successful liver transplantation can be obtained with lower immunosuppressive 
requirements than other organs, and liver allografts can recover from advanced acute and 
chronic rejection episodes (Doyle et al 1996, Olausson 2007, Sugawara 2009). 
• Infection risks 
While remarkable improvements in short-term allograft and transplant recipient survival have 
been achieved in the last three decades, complications (de novo malignancies, infections, 
chronic renal failure, cardiovascular and metabolic diseases) remain associated with the chronic 
use of immunosuppressive therapies. This warrants the evaluation of lower immunosuppressive 
regimens and exposures. 
In Arm 3, the loading regimen is limited to a single intravenous dose of 30 mg/kg CFZ533 on 
Day 8, and the 300 mg regimen is expected to provide steady state median trough CFZ533 
plasma concentrations of about 100 µg/mL, which are in the lower range of the CFZ533 trough 
concentrations measured in Study CCFZ533X2201-Part 2 (Figure 4-1). 
In pSS participants (Study CCFZ533X2203, completed) CFZ533 trough levels of 
approximately 100 µg/mL were associated with clinical efficacy (clear improvement in 
European League Against Rheumatism (EULAR) Sjöegren’s Syndrome Disease Activity 
Index), and suppression of a biologically relevant biomarker CXCL13 (chemokine CXC ligand 
13 protein, a marker of germinal center activity). 
In addition, for 95% of participants, this maintenance regimen is expected to provide plasma 
concentrations that are above 40 μg/mL, a threshold that was associated with a complete 
suppression of germinal center development in cortical B cell areas of lymph nodes (26-week 
toxicity study in cynomolgus monkeys; 1 mg/kg weekly), and of T cell dependent antibody 
response (recall antibody responses to immunization challenge) in non –human primate (NHP). 


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Figure 4-1 
Predicted median CFZ533 plasma concentration time-profile in liver 
transplant participants overlaid with measured plasma concentrations 
in kidney transplant participants (Study CCFZ533X2201-Part 2; interim 
data) 
 
The lines represent the predicted time-course of the CFZ533 plasma concentration for the typical transplant 
participant in Arm 2 (after 2 loading doses IV, 600 mg regimen - continuous red line), or Arm 3 (after 1 loading dose 
IV, 300 mg  regimen – dotted light blue line). For each of these regimens, the 90% prediction intervals for the trough 
CFZ533 plasma concentration at steady state are displayed. Those predictions are for participants with body weight 
ranging from 50 to 120 kg (random distribution). The CFZ533 plasma concentrations measured in Study 
CCFZ533X2201-Part 2 in de novo transplant participants are displayed as gray dots (after a loading IV regimen, 
the maintenance regimen for CFZ533 was 10 mg/kg IV Q4W; Interim Analysis data). Predictions are based on a 
model fit to the data from the single ascending dose/First-in-human study CCFZ533X2101, and the transplant study 
(CCFZ533X2201-Part 2). 
4.3 
Rationale for CFZ533 dosing to compensate for drug loss due to 
ascites drainage 
Ascites is an accumulation of fluid in the peritoneal cavity.  
It is associated with end-stage liver disease and portal hypertension. It is expected to resolve 
with a liver transplantation, but ascites can also be removed by large volume paracentesis or 
surgical drainage. 
Ascites occurs with moderate volume (< 0.25 L/day) in the majority of liver transplant 
recipients, but a non-negligible proportion of participants (7%) present with a median volume 
of 1 L/day for a median duration of 77 days post transplantation (Cirera et al, 2000).  


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Ascites has the potential to affect CFZ533 exposure in particular if ascites are removed after 
paracentesis or surgery. The drug loss depends on the amount of ascites removed, and on the 
drug concentration in the ascites. 
In the context of this study, drained ascites will be considered relevant when the cumulative 
volume of ascites or fluid loss through paracentesis/surgical drainage collected from a 
participant reaches a cumulative volume of 4 L (similar to belatacept liver transplant study; 
Klintmalm 2014). CFZ533 compensation will be administered as described in Section 6.1.4.  
Figure 4-2 displays the predicted CFZ533 plasma exposure during 2 weeks post first dose of 
CFZ533 on Day 8: 
• in case of no ascites (light gray),  
• in case of ascites and no additional/compensating CFZ533 dose (pink), 
• in case of ascites with an additional/compensating CFZ533 dose each time the 
cumulative ascites volume reaches 4 L (blue).  
As shown in Figure 4-2 where two scenarios of ascites drainage are presented (0.5 and 4 L/day), 
the additional/compensating intravenous dose is expected to adjust the participants’ exposure 
adequately during the first days of treatment. 
After Day 29, when CFZ533 concentrations are approaching steady state, a compensating dose 
specific to the treatment arm (10 mg/kg IV and 5 mg/kg IV in Arm 2 and Arm 3, respectively) 
should bring the concentration in the range of their respective steady state exposure (not shown). 
Note: Until Month 24, each time an additional/compensating intravenous CFZ533 dose 
(10 or 5 mg/kg) will be administered; a pre-dose blood sample will be taken to assess the 
CFZ533 concentration in plasma. 


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Figure 4-2 
Predicted CFZ533 exposure in case of (i) no ascites drainage (light 
grey), (ii) ascites drainage but no compensating dose (pink), and (iii) 
ascites drainage with compensating dose (blue) 
 
The lines represent the typical CFZ533 concentration-time profiles during 2 weeks post first administration of 
CFZ533 on Study Day 8 in Arm 2 and Arm 3 in case of (i) no ascites drainage (light grey), (ii) ascites drainage but 
no compensating dose (pink), and (iii) ascites drainage with additional compensating dose(s) of 10 mg/kg IV 
CFZ533, every time the cumulative ascites volume reaches at least 4 L (blue). The areas of corresponding color 
represent the 90% percentile of the individual profiles. The vertical red arrows indicate the scheduled CFZ533 
doses (30 mg/kg IV on Study Day 8 (Arm 2 and Arm 3), and 15 mg/kg IV on Study Day 15 (Arm 2 only)). The figure 
illustrates two scenarios of ascites: in the left panels, participants are losing 0.5 L of ascites per day, resulting in the 
administration of an (additional) compensating dose on Study Day 16 (8 days post first dose on Study  
Day 8); in the right panels, participants are losing 4 L of ascites per day, resulting in daily administration of a 
compensating dose (10 mg/kg IV). Note that 2 weeks post 1st dose (Day 15), Arm 2 participants loosing 4 L/day of 
ascites (top right panel) will get, on the same day, the scheduled dose (15 mg/kg IV) and the compensating 
dose (10 mg/kg IV).   
4.4 
Rationale for choice of control drugs (comparator)  
Initial therapy following liver transplantation includes a calcineurin inhibitor, used as the base 
immunosuppressive agent in combination with CS and MMF. Maintenance therapy is often 
with (i) reduced dosage and/or (ii) reduced number of immunosuppressive drug (e.g.: 
corticosteroid elimination), the calcineurin inhibitor remains as the base immunosuppressive in 
renal or liver transplantation [EMA guideline Doc. Ref. CHMP/EWP/263148/06]. 
4.5 
Purpose and timing of interim analyses/design adaptations 
Participants participating in this study will receive study treatment for a variable duration 
depending on the date of study entry and completion of the extension. The main analysis will 
be performed at 12 months to assess efficacy and safety variables. A 24-month analysis will be 


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performed as a safety and efficacy follow-up assessment. Then, at the EOS, a final analysis will 
be performed to analyze data from the long-term extension. 
An interim analysis (IA) is planned after 80% participants have reached the Month 6 visit (or 
have prematurely discontinued the study before Month 6). All efficacy data up to the cutoff 
date, including data beyond Month 6 and participants not yet reaching Month 6 will be included. 
The Poisson model (see Section 12.4.4) will be used to evaluate the composite efficacy failure 
rate to adjust for the differential follow-up time of participants at the IA. The primary objective 
of the IA is to enable the overall benefit-risk assessment. There are no plans to stop the study 
early for good efficacy, since it is desired to collect long-term efficacy and safety data. 
Following 24-month analysis until final analysis, additional IAs may be conducted to support 
decision making concerning the current clinical study or project, the sponsor's clinical 
development projects in general or in case of any safety concerns. 
Until Month 24, the stopping rules will be evaluated by the Clinical Team as outlined in Section 
12.6. Stopping rule analysis and the Data Monitoring Committee (DMC) review will not be 
conducted during the extension period. The DMC will review data at regular intervals as 
described in Section 10.2 and the DMC charter.  
The analyses will be outlined in the Statistical Analysis Plan (SAP). 
4.6 
Risks and benefits 
Stage 4 or 5 chronic kidney disease (CKD) has been reported in ~18% of liver transplant 
recipients by 5 years post-transplant and is associated with increased morbidity and mortality. 
Data from 1997 to 2008 in the Organ Procurement Transplant Network/United Network for 
Organ Sharing (OPTN/UNOS) database showed a threefold increased rate of kidney 
transplantation in participants who previously received a liver transplant. While the causes of 
CKD in liver transplant participants are multifactorial, including pre-transplant and peri-
transplant factors like hepatitis C virus (HCV), diabetes and hepatorenal syndrome, calcineurin 
inhibitors (CNIs) appear to be significant contributing factors. In the OPTN/UNOS analysis, 
~50% of liver transplant participants who received a kidney transplant had a diagnosis 
consistent with CNI toxicity. Thus, there is a need for immunosuppressive regimens that 
provide similar anti-rejection efficacy while avoiding the nephrotoxic, cardiovascular and 
metabolic risks of CNIs in liver transplant recipients. 
To fulfill this important unmet medical need, an exploratory Phase II study was conducted to 
evaluate the efficacy and safety of the co-stimulation blocker belatacept in adult recipients of 
first liver transplant from a deceased donor (NCT 00555321).  
Belatacept is a selective T-cell co-stimulation blocker, which binds to CD 80/86 ligands of 
antigen-stimulating cells and thereby inhibits the CD-28-mediated T-cell co-stimulation. 
Findings from this phase II study did not allow the identification of a safe and effective dose or 
regimen for further development of belatacept in liver transplant indication. 
The authors of the study mention that the liver may be participant to CD28- independent T cell 
activity as is surely to be expected, and they cite the potential negative effect of CD28 blockade 
on regulatory T cell activity. 


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Novartis has performed a study-specific medical and safety risk assessment and concluded that, 
based on the current data, benefit/risk of iscalimab due to COVID-19 pandemic remains 
unchanged in the target population. Please note, that infections are already a risk in transplanted 
patients, are described as potential risk in this protocol, and will need to be actively monitored 
and managed in study participants.CFZ533 
Differently from belatacept, CFZ533 targets the CD40 receptor that is a transmembrane 
glycoprotein constitutively expressed on B cells and other antigen presenting cells (APCs) 
including monocytes, macrophages, and dendritic cells (DCs), as well as by platelets, and 
inflamed parenchyma. The binding of CD40 to its ligand CD154 results in cell-type specific 
activation outcomes, including DC maturation, monocyte survival and cytokine secretion by 
many cell types including renal epithelial cells. 
In addition, co-stimulatory CD40 pathway is required for many aspects of humoral immunity 
including germinal center (GC) formation, memory B cell development, immunoglobulin (Ig) 
isotype switching, and affinity maturation.  Pharmacological inhibition of CD40-CD154 
pathway using anti-CD4- or anti-CD154 antibodies reduced autoimmune disease pathology in 
numerous pre-clinical and clinical studies and prolonged allograft survival in NHPs (refer to 
the current [Investigator’s Brochure, Section 4]). 
The proof of concept trial CFZ533X2201 conducted in kidney transplant recipients has shown 
the ability of CFZ533, in the context of CNI-free regimen, to provide similar efficacy, better 
renal function and comparable safety profile compared to CNI-based regimen 
(TAC+MMF+CS), including absence of PTLD, PML, absence of donor specific antibodies, 
reduced frequency of new onset diabetes. 
The promising data have opened the possibility for CFZ533 to represent a viable alternative to 
CNIs in liver transplant recipients fulfilling the important unmet medical need in this participant 
population. 
Benefits: Based on the mechanism of action of CFZ533 and its use in a CNI-free setup in de-
novo transplant participants it is anticipated that the CFZ533 regimen will provide long term 
graft survival without compromising short term efficacy, with potentially better renal function, 
less development of de novo Donor-Specific Antibodies (DSA) and an improved cardiovascular 
and metabolic profile with less hyperlipidemia, hypertension and New Onset of Diabetes 
Mellitus (NODM), and less neurotoxicity compared to standard of care. 
Based on the anticipated overall risk-benefit, and because there is a large unmet need for new 
immunosuppressive treatment with less severe side effects and improved long-term graft and 
participant survival, the current study evaluating CFZ533 in de novo liver transplant participants 
is justified. 
Risks: the potential safety concerns in humans and the investigator guidance are based on data 
from the available clinical trials with CFZ533, preclinical and toxicological data, as well as 
experience with other compounds of the same class (refer to the current investigator brochure). 
Beyond the potential risks described in the Investigator Brochure (IB), there may be risks that 
may be serious and unforeseen in relation to the use of CFZ533. 
The risk to subjects in this trial will be minimized by adherence to the eligibility criteria; close 
clinical monitoring and adherence to the protocol defined stopping rules (refer to Section 12.6). 


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The list of potential risks related to CFZ533 administration, in the current Investigator Brochure 
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), 
immunogenicity, infections, therapeutic failure of vaccination during CFZ533 treatment, loss 
of efficacy or allergic/immune-mediated inflammatory reactions due to development of anti-
CFZ533 antibodies, thrombophilia and lymphoproliferative disorders (refer to the actual IB for 
more details). A serious infusion reaction that results in anaphylaxis could happen in 
monoclonal antibody therapy. 
As with any therapeutic protein, immunogenicity is always a risk, although it is important to 
note that CFZ533 is a fully human monoclonal antibody (lower risk compared to humanized or 
chimeric antibodies) with immunosuppressive properties and that will be co-administered with 
MMF, further limiting the risk for the generation anti-CFZ533 antibodies. 
During a Public Health emergency as declared by Local or Regional authorities, i.e., pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate. 
4.7 
Previous clinical experience with CFZ533 
In Study CCFZ533X2101 (First In Human (FIH)), one participant at 1 mg/kg IV (1-week full 
CD40 occupancy) developed specific antibodies to CFZ533, which were detected 6 weeks after 
CFZ533 plasma concentrations were below the limit of quantification. The presence of anti-
drug antibodies (ADAs) in this participant did not compromise exposure, and was not 
associated with an immune related safety signal. This corresponds to a ADAs incidence of 2% 
in this study. 
No immunogenicity was reported in Japanese healthy volunteers (Ethnicity Sensitivity Study 
CCFZ533X1101). 
No ADAs were detected in any of the 15 participants enrolled in Study CCFZ533X2205 
(myasthenia gravis) during the 12-week treatment and 24-week follow up period after the last 
dose of CFZ533. 
The presence of anti-CFZ533 antibodies is assessed in all CFZ533-treated participants in all 
clinical studies with CFZ533. 
A Proof of Concept trial (CCFZ533X2201) has evaluated the safety, tolerability, 
pharmacokinetics, pharmacodynamics and efficacy of multiple doses of CFZ533 in 
combination with MMF and corticosteroids, compared to a tacrolimus-based regimen, in de 
novo renal transplant recipients. CFZ533 participants received a loading regimen of 10 mg/kg 
IV on Day 1, 3, 7, 15, 29, 43 and 57, followed by a maintenance regimen at 10 mg/kg IV every 
four weeks, up to 12 months post-transplantation. 
Results at Month 12 have shown that the regimen was well tolerated and specifically not 
associated with an increased risk of over-immunosuppression such as neutropenia and the rate 
of infections was comparable (85.3% in CFZ533 vs. 88.9% in TAC). There were no 


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thromboembolic events on CFZ533 (but 1 episode with TAC). There were no deaths, no PTLD, 
no PML and no graft loss in the CFZ533 arm. A trend was observed  towards fewer participants 
in the CFZ533 group with New Onset Diabetes (12.5% in CFZ533 vs. 30.0% in TAC) and BK 
polyomavirus (BKV) positive PCR >10000 copies in serum (18.2% in CFZ533 vs 22.2% in 
TAC). Renal function (eGFR) difference of about 10 mL/min favored CFZ533 over Tacrolimus, 
while the combined endpoint (Graft Loss + tBPAR) was similar (21.2% in CFZ533, 22.2% in 
TAC).  No antibodies against CFZ533 were detected in any participant enrolled into study 
CFZ533X2201 (refer to current CFZ533 IB for more details). 
The risk of insufficient efficacy in the present study will be minimized by frequent monitoring 
of clinical laboratory data, signs and symptoms suggesting rejections and the early 
discontinuation of any treatment arm that is ineffective according to the Stopping Rules (see 
details in Section 12.6). 
4.8 
Rationale for liver Histopathology - optional surveillance 
biopsies 
Iscalimab has shown preservation of graft quality with normal renal morphology in a sub-set of 
participants from the kidney transplant study CCFZ533X2201 (NCT02217410) (Nashan et al. 
2018). 3 of 5 subjects treated with iscalimab had normal histology at Month 12 or 24 (Farkash 
et al. 2019) while none of 7 control tacrolimus-treated subjects had normal histology. Similar 
observations were made in nonhuman primates treated with iscalimab (Cordoba et al. 2015). 
Thus, iscalimab has the potential of offering better graft quality and thereby improve long-term 
outcomes for transplanted participants. This is further being studied in the ongoing kidney 
transplant trial CCFZ533A2201 (NCT03663335). 
Compared to other transplanted solid organs, the transplanted liver has some unique features. It 
has a higher regenerative capacity than most organs (Muller et al. 2004, Wadstrom et al. 2017), 
Wadstrom et al. 2017), higher tolerogenic capacity (Benitez et al. 2013, Feng and Bucuvalas 
2017, Feng et al. 2012) and liver allograft rejection does not contribute to late graft failure to 
the same extent as other solid organ allografts (Kim et al. 2018). The induced tolerance can 
even make it possible to withdraw immunosuppression in a selection of participants (Benitez et 
al. 2013, Feng et al. 2012). Despite these qualities of the transplanted liver, there is a need for 
improved liver graft histology. 
Approximately 90% of biopsy samples from adult recipients surviving more than 1 year show 
significant abnormalities (Banff Working Group on Liver Allograft 2012). These changes occur 
in patients with abnormal liver function tests (LFTs), but histological signs of chronic 
inflammation and fibrosis seem to be present in up to 85% of recipients with normal LFTs (Feng 
and Bucuvalas 2017). Even with state-of-the-art immunosuppressive therapy, only one third of 
pediatric liver transplants were free from signs of inflammation (Feng et al. 2018). Commonly 
present changes that might be clinically significant include recurrent disease, fatty liver disease, 
and biliary tract strictures, while changes attributable to classic acute or chronic rejection are 
usually seen in less than 25% of biopsy samples (Banff Working Group on Liver Allograft 
2012). 
In participants after orthotopic liver transplantation, liver biopsy is used to detect acute or 
chronic rejection, potential recurrence of the underlying disease, and to evaluate the degree of 


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fibrosis and stage of liver disease (Jiang and Farber 2017, Sebagh and Samuel 2004). 
Biochemistry tests are insensitive and unspecific for liver allograft monitoring. Therefore, 
histopathological biopsy analysis remains the most sensitive modality for evaluating graft 
parenchymal injury (Banff Working Group on Liver Allograft 2012, Ekong et al. 2008, 
Gonzalez and Washington 2016, Mells and Neuberger 2008, Sebagh and Samuel 2004). 
Morphology plays an important role in differential diagnosis and subsequent treatment of post-
transplant complications (Demetris et al. 2000, Demetris et al. 2016, Ormonde et al. 1999).  
Routine surveillance biopsy monitoring of asymptomatic long-term participants with normal or 
nearly normal liver tests is more controversial (Mells and Neuberger 2008, Pereira et al. 2016). 
Arguments against the use of routine surveillance biopsy include potential morbidity and 
mortality, costs, inconvenience, resource utilization, and the uncertain clinical significance of 
unexplained histopathological findings. However, an advantage of routine surveillance biopsies 
is that it allows early detection of clinically relevant disease (Sebagh and Samuel 2004). 
Furthermore, routine surveillance biopsies can support clinical decision-making and allow for 
the identification of recipients who might benefit from treatment adjustments of immuno-
suppressant drugs. It also can assess the impact of chronic low grade injury or alcohol use, 
categorize HCV+ recipients more accurately, and inform the potential for immune suppression 
minimization protocols (Demetris et al. 2016, Feng and Bucuvalas 2017, Feng et al. 2018, 
Sebagh and Samuel 2004). Routine biopsies can help understanding low-grade chronic 
inflammation or allograft hepatitis and progressive fibrosis (Arias et al. 2017, Feng and 
Bucuvalas 2017, Feng et al. 2018, Londono et al. 2018). New techniques based on molecular 
profiling suggest that subclinical inflammation, indicative of low-grade rejection, is more 
common than is evident from histology alone (Arias et al. 2017, Feng et al. 2018, Garcia-Carro 
et al. 2018, Loupy et al. 2017, Menon et al. 2017). Minor infiltrates could represent rejection, 
autoimmunity, viral infection, or regulatory immunological reactions (Banff Working Group 
on Liver Allograft 2012). Taken altogether, routine surveillance liver biopsies provide essential 
and clinically relevant information after liver transplantation with an acceptable benefit-risk 
profile (Banff Working Group on Liver Allograft 2012, Pereira et al. 2016).  
The relationship between histology and long-term outcomes is not as well understood for the 
liver compared to the kidney. However, there is evidence suggesting an association between 
liver histology and long-term outcome after liver transplantation (Pappo et al. 1995, Sebagh et 
al. 2003, Slapak et al. 1997). However, there is no specific study so far for the commonly used 
IS therapies and their effects on liver histopathology. Currently, there is also no information 
about potential effects of iscalimab on liver graft histology. As described above, iscalimab 
seems to improve graft quality after kidney transplantation (Cordoba et al. 2015, Farkash et al. 
2019, Nashan et al. 2018). 
 
 
 
 
 


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5 
Study Population 
The study population will consist of de novo liver transplant recipients, aged 18-70 years, 
receiving a primary allograft from a deceased donor. It is planned to randomize at least 128 
participants from multiple centers located in Europe, North America and Latin America.  
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
Screening period up to liver transplantation 
1. Written informed consent must be obtained before any assessment is performed.  
2. Male or female subject between 18-70 years of age. 
3. Recipient of a primary liver transplant from a deceased donor. 
4. Up to date vaccination as per local immunization schedules. 
5. Recipient tested negative for Human Immunodeficiency Virus (HIV). 
6. Model for End stage Liver Disease (MELD) score ≤ 30 (based on laboratory values, using 
the United Network for Organ Sharing (UNOS) MELD calculator: 
https://unos.org/resources/allocation-calculators/). 
11. Transplantation to occur within defined screening period following informed consent 
signature. 
At Randomization (Day 8±2) 
7. Recipients with no active Hepatitis C Virus (HCV) and Hepatitis B (HBV) replication. 
Recipients with HCV antibody positive should have no detectable HCV-RNA. Recipients 
with Hepatitis B infection should have no detectable HBV DNA. Cases of spontaneous 
HCV clearance should be discussed with sponsor. 
8. Allograft is functioning at an acceptable level by the time of randomization as defined by 
AST, ALT, Alkaline Phosphatase levels ≤ 5 times ULN and Total Bilirubin ≤ 2 times 
ULN. 
9. Renal function (eGFR, MDRD-4 formula) ≥ 30 mL/min/1.73m2 based on most recent 
post-transplant value prior to randomization.  
10. Recipients who have been initiated on an immunosuppressive regimen that contains TAC, 
MMF and corticosteroids as per protocol. 
5.2 
Exclusion criteria 
Participants fulfilling any of the following criteria are not eligible for inclusion in this study.  
Screening period up to liver transplantation 
1. 
Use of other investigational drugs at screening, within 30 days or 5 half-lives of screening 
(until the expected pharmacodynamics effect has returned to baseline), whichever is longer. 
2. 
Recipients of multiple solid organ or islet cell transplants have previously received a tissue 
transplant, or recipients who have a combined liver-kidney transplant. 
3. 
Recipients of a liver from a donor after cardiac death (DCD), from a living donor, or of a 
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4. 
Not-applicable 
5. 
Recipient who tests negative for Epstein Barr virus (EBV) within 28 days prior to baseline 
visit. 
6. 
Patients who have received a live vaccine within four weeks prior to transplantation. 
7. 
Recipients receiving an ABO incompatible allograft. 
8. 
History of malignancy of any organ system (except hepatocellular carcinoma or 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. 
9. 
Hepatocellular carcinoma that does not fulfill Milan criteria (1 nodule ≤5 cm, 2-3 nodules 
all ≤3 cm, without evidence of metastatic disease or vascular invasion, see Appendix 2, 
Mazzaferro et al 1996) at the time of transplantation.  
10. Participants transplanted for acute liver failure (does not apply to acute on chronic liver 
failure). 
11. Any use of antibody induction therapy or use of any immunosuppressive or other 
medications prohibited by the protocol (see Section 6.2.2). 
12. Recipients with history of non-liver related coagulopathy or medical condition requiring 
long-term anticoagulation. Participants treated with low dose aspirin and patients with 
asymptomatic liver-related coagulopathy not on treatment, may be enrolled into the study. 
13. Recipients who have any serious condition, which might significantly affect the outcome 
of the study or their ability to participate in the study. 
14. History of hypersensitivity to any constituent of the product (any of the study drugs) or its 
excipients or to drugs of similar chemical classes. 
15. Recipients with HIV positive donor.  
16. Recipients with donors HBsAg positive.  
17. Recipients who are HCV antibody-positive without documented sustained viral response 
(SVR) at 12 weeks after finishing anti HCV treatment (e.g., direct-acting antivirals).  
• Recipients with HCV RNA-positive donors 
18. Recipients with donors with macrovesicular steatosis > 30%. 
19. Pregnant or nursing (lactating) women. 
20. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
dosing and for 14 weeks after stopping of study treatment. Highly effective contraception 
methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). 
Note periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking the 
study treatment. In the case of oophorectomy alone, this is only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment. 


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• Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant 
otherwise other highly effective contraceptive methods should be used. 
• Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) 
or other forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception.  
In case of use of oral contraception women should have been stable on the same brand (or 
generic equivalent) for a minimum of 3 months before taking the study treatment. 
Women are considered post-menopausal and not of child bearing potential if they have had  
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks ago. 
In the case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment she is considered not of childbearing 
potential.  
Sexually active male participants, or the female partner, are recommended to use highly 
effective contraception during therapy with MMF and at least 90 days following discontinuation 
of mycophenolate (see additional information in Section 8.4.3).  
In case local regulations deviate from the contraception methods listed above, local regulations 
apply and will be described in the Informed Consent Form (ICF). 
At Randomization (Day 8±2) 
21. Any post-transplant history of thrombosis, occlusion or stent placement in any hepatic 
arteries, hepatic veins, portal vein or inferior vena cava at any time during the run-in period 
prior to randomization. Absence of any graft vascular thrombosis or occlusion (by 
diagnostic method used at the site to assess vascular patency) must be confirmed by 
imaging prior to randomization. 
22. Recipients with platelet count < 50,000/mm3.  
23. Recipients with an absolute neutrophil count of < 1,000/mm³ or white blood cell count  
of < 2,000/mm³. 
24. Recipients with clinically significant systemic infection requiring use of IV antibiotics. 
25. Evidence of active tuberculosis (TB) infection with appropriate documentation (after anti-
TB treatment, patients with history of latent TB may become eligible according to national 
guidelines). 
26. Recipients who are in a critical care setting at the time of randomization requiring life 
support measures such as mechanical ventilation, dialysis, requirement of vasopressor 
agents. 
27. Recipients who are on renal replacement therapy at randomization. 
28. Any episode of acute rejection or suspected rejection prior to randomization. 
29. HCC participants whose explanted liver graft pathology report shows i) pTNM stage beyond 
T2N0M0, ii) presence of mixed carcinoma, iii) microvascular  invasion despite pTNM 
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30. Participants with body weight < 30 kg or > 180 kg. 
31. Recipients with donors who had confirmed history of SARS-CoV-2 infection. 
The investigator may apply no additional exclusions, in order to ensure that the study population 
will be representative of all eligible participants. 
6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
The following drugs will be used in this study and will be administered in accordance with this 
protocol and where applicable, current local labeling. 
Investigational drug 
• CFZ533 150 mg/1 mL vials which can be used as concentrate for solution for infusion via 
IV route of administration or solution for injection for SC route of administration  
• CFZ533 300 mg/2 mL prefilled syringes (PFS) - solution for injection for SC route of 
administration. 
Both the above mentioned CFZ533 vials and PFS will be supplied centrally by Novartis.  
Participants will switch over from 150 mg/1mL vial to CFZ533 300 mg/2 mL PFS presentation 
once they have completed the M12 visit and PFS are made available. PFS is intended for self-
administration and Section 6.7.2.1 provides instructions on PFS use. 
Instructions for preparation and administration of CFZ533 vials will be described in a separate 
pharmacy manual. Instruction for administration of CFZ533 PFS will be provided in a separate 
Instructions for Use document. 
Control and other study drugs 
Concomitant immunosuppression medication will be used in this study in the combination 
described in the run-in and randomized treatment periods:  
• Tacrolimus (TAC, Prograf® or generic equivalent) as 0.5 mg. 1.0 mg or 5.0 mg 
capsules/tablets or IV formulation where required. TAC will be supplied locally as part of 
standard of care. 
• Mycophenolate mofetil (MMF, CellCept® or generic equivalent) 500 mg film-coated 
tablets, 250 mg capsules or 500 mg vial for IV administration. 
• Corticosteroids (CS) for oral and IV administration will be purchased locally. The CS dose 
must be administered according to local practice. 
MMF and CS for oral and IV administration will be supplied locally and will be used as per 
local label. TAC will be supplied locally and will be used as per local label from transplantation 
onwards (Arm 1).  


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6.1.2 
Additional study treatments 
No additional concomitant immunosuppressive drugs beyond study treatment (CFZ533, TAC, 
MMF/mycophenolates, corticosteroids) are allowed in this trial; however, treatment of acute 
rejection (e.g. bolus steroids or anti-T-cell antibodies) should be performed according to local 
practice.  
6.1.3 
Treatment arms/groups 
Participants will be assigned to one of the following three treatment arms in a 2:3:3 ratio: 
• Arm 1 - TAC Control (n=32): TAC + MMF + CS up to EOS. Initial TAC target trough 
will be between 5-15 ng/mL during the run-in period. From randomization onwards, the 
TAC levels will be adjusted as per local label. 
• Arm 2 - CFZ533 600 mg regimen (n=48): Loading doses of 30 mg/kg IV on Day 8 (with 
±2 days window), and 15 mg/kg IV on Day 15. The SC administration of 600 mg (2 
injections of 2 mL CFZ533 at 150 mg/mL) every 2 weeks will begin on Day 29, in 
combination with MMF and CS up to EOS. 
• Arm 3 - CFZ533 300 mg regimen (n=48): Single loading dose of 30 mg/kg IV on Day 8 
(with ±2 days window). The SC administration of 300 mg (1 injection of 2 mL CFZ533 at 
150 mg/mL) every 2 weeks will begin on Day 29, in combination with MMF and CS up to 
EOS. 
CFZ533 SC will be administered by authorized Investigator/staff at each study visit. After the 
Month 6 visit in-home administration may be allowed by a health care provider. PFS will be 
used upon availability once patient has completed M12 visit. 
6.1.4 
Compensation for CFZ533 loss through ascites fluid drainage 
At any time during the treatment period, when the cumulative ascites fluid drainage volume 
reaches at least 4 L, and independently of the planned dosing schedule (IV or SC; 
Section 4.3), an additional dose of CFZ533 will be administered intravenously to compensate 
for the amount of CFZ533 removed from the body through drained ascites. 
• Arm 2 (600 mg  regimen): one (additional) dose of 10 mg/kg IV CFZ533, regardless of 
the time 
• Arm 3 (300 mg  regimen) 
a. Up to Day 29: one (additional) dose of 10 mg/kg IV CFZ533, 
b. After Day 29: one (additional) dose of 5 mg/kg IV CFZ533. 
In an extreme situation (massive ascites; Cirera 2000) where participants are experiencing a 
loss of fluid of 4 L/day, this should trigger the daily administration of an additional, 
compensatory CFZ533 dose, as described above. 
Any additional IV dose of CFZ533, administered on top of the scheduled CFZ533 doses (IV, 
SC), to compensate for drug loss through ascites drainage, should be captured in the appropriate 
CRF. 
Each time an additional/compensating intravenous CFZ533 dose (10 or 5 mg/kg IV) will be 
administered; a pre-dose blood sample will be taken. 


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6.1.5 
Post-Trial Access 
Participants who complete participation in this trial and continue to derive clinical benefit from 
the treatment based on the investigator’s evaluation may receive post-trial drug access program 
or have the opportunity to enter a follow-up study. Details of the follow-up study will be 
described in a separate protocol which will require endorsement in participating countries and 
sites as per local laws and regulations. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
Cytomegalovirus prophylaxis 
Cytomegalovirus (CMV) prophylaxis or preemptive monitoring for CMV should be according 
to local practice and applied uniformly for all enrolled participants at the center. However, 
following the guideline of the American Society of Transplantation Infectious Diseases 
Community of Practice to treat CMV in solid organ transplant recipients is highly recommended 
(Razonable RR and Humar 2019). Treatment with valganciclovir, ganciclovir, cytomegalovirus 
hyperimmune globulin or valacyclovir or other approved agents are permitted and will be 
administered according to local practice. CMV prophylaxis for at least 3 months is 
recommended for CMV Donor positive, Recipient negative (D+/R-) participants. CMV 
prophylaxis is also recommended following any antibody treatment of acute rejection episodes. 
Pneumocystis jirovecii (Pneumocystis carinii pneumonia (PCP) prophylaxis 
All participants should be treated according to local practice, as part of standard of care practice 
for transplanted participants. If treatment is given, it should be recorded in the appropriate CRF. 
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. The type of HBV prophylaxis should be 
according to local practice. Prophylaxis should be recorded in the appropriate CRF. 
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. Systemic therapy is to be based on 
center practice and at the investigator’s discretion. Treatment should be recorded in the 
appropriate CRF.  
Other concomitant Medications 
The investigator must instruct the participant to notify the study site about any new medications 
he/she takes after being enrolled into the study. All medications, procedures and significant 
non-drug therapies (including physical therapy and blood transfusions) administered after the 
participant was enrolled into the study must be recorded in the appropriate CRF. 


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Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact Novartis before randomizing a 
participant or allowing a new medication to be started. If the participant is already enrolled, 
contact Novartis to determine if the participant should continue participation in the study. 
The epidemiology of COVID-19 is continuously evolving, and currently, there are no 
universally agreed treatment protocols for patients with SARS-CoV-2 infections. The 
investigator should use clinical judgement and adhere to local policies for testing and treatment 
of coronavirus infections. 
6.2.2 
Prohibited medication 
Immunosuppressants other than those specified in the protocol are NOT allowed after written 
informed consent has been obtained and up to the end of study. If the use of any non-protocol 
immunosuppressant is discovered prior to randomization, the participant must not be 
randomized and will be recorded as a screen failure. If discovered after randomization, no 
further doses are to be given, and the participant should continue on the study treatment, noting 
the protocol deviation. 
Use of treatments displayed in Table 6-1 is NOT allowed. This is in order to avoid potential 
confounding factors or interaction with investigational or control treatment medication.  
These non-protocol immunosuppressants are only allowed for those participants  who have 
discontinued the randomized study treatment and switched to standard of care treatment as per 
local practice, and are continuing in follow up until Month 24 visit. 
Table 6-1 
Prohibited medication 
Treatment Arm 
Medication 
Action to be taken 
 
 
 
 
 
All 
Cyclosporine 
Sirolimus 
Once a day tacrolimus 
formulations (e.g., Advagraf, 
Envarsus) 
Everolimus 
Azathioprine 
Campath 
Belatacept 
Alemtuzumab  
Rituximab 
Bortezomib 
Use of any antibody as an 
induction agent 
Live vaccines 
 
 
 
 
Discontinue the prohibited 
medication immediately 
Keep the participant in the study  
Report the protocol deviation 
 
 
6.2.3 
Induction therapy 
No antibody therapy is allowed. 


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6.2.4 
Rescue medication 
Rescue therapy is based on local center practice. Use of rescue medication must be recorded on 
the respective CRF. 
Treatment of HCV recurrence 
Only patients with sustained virologic response (at least SVR 12) are eligible for the study. 
Treatment for HCV recurrence is permitted, but cannot be preemptive. Investigators will be 
allowed to treat HCV only when recurrent HCV disease has been documented, based on 
histological evidence as determined by the local pathologist. Therapies used for post-
transplantation HCV recurrence will be documented on the appropriate CRF. Any HCV positive 
participants requiring treatment with a protease inhibitor should be discussed with the sponsor. 
6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
The participant number assigned to a participant at screening remains the unique identifier for 
the participant throughout the study. The participant number is composed of a site number and 
a sequential number. Once assigned to a participant, the participant number will not be re-used. 
6.3.2 
Treatment assignment, randomization 
At Day 8 (randomization) visit, all eligible participants will be randomized via Interactive 
Response Technology (IRT) to one of the treatment arms. The investigator or his/her delegate 
will contact the IRT after confirming that the participant fulfills all the inclusion/exclusion 
criteria. The IRT will assign a randomization number to the participant, which will be used to 
link the participant to a treatment arm and will specify a unique medication number for the first 
package of study treatment to be dispensed to the participant. 
A participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms. 
A separate medication list will be produced by or under the responsibility of Novartis Global 
Clinical Supply using a validated system that automates the random assignment of medication 
numbers to packs containing the study treatment. 
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office. 
6.4 
Treatment blinding 
There is no blinding, the study is open-label to participants, investigator staff, persons 
performing the assessments, and the Novartis team. Furthermore, the stopping rules (Section 
12.6) will be assessed by the sponsor team based on real time unblinded safety and efficacy 
data. 


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6.5 
Dose modification 
6.5.1 
Permitted dose adjustments and interruptions of CFZ533 study 
treatment 
CFZ533 interruption  
During the first 12 months of the treatment period, only 1 dose of CFZ533 can be missed. In 
case of a second dose or more SC doses need to be interrupted, the investigator should contact 
the sponsor immediately to discuss if the participant can remain on treatment or be permanently 
discontinued from randomized study treatment and managed as per local practice. 
After 12 months, 1 omitted dose within a 3 month period is allowed. The investigator will 
contact the Novartis team if more than 1 dose in 3 months is missed to discuss further 
management of this participant. 
CFZ533 dose adjustments 
CFZ533 dose adjustments are not permitted except in the case of significant ascites/fluid 
loss by drainage (more details in Section 4.3 and Section 6.1.4). 
In case of medical needs, CFZ533 SC administration may be delayed by a maximum of 7 days. 
The subsequent dose must be administered as per original schedule (not recalculated from the 
time of the last delayed dosing). 
6.5.2 
Permitted dose adjustments and interruptions of other study 
treatment 
Tacrolimus  
For Control participants (Arm 1) who are unable to tolerate the protocol-specified dosing 
scheme, dose adjustments and interruptions of tacrolimus are permitted in order to keep the 
participant on study drug. Temporary interruptions of TAC should not exceed 21 consecutive 
days. 
If TAC is discontinued for more than 21 consecutive days, and the study treatment cannot be 
maintained, the participant must be permanently discontinued from the randomized study 
treatment and be managed as per local practice.  
MMF  
For both CFZ533 and control participants who are unable to tolerate the protocol-specified 
dosing scheme, dose adjustments and interruptions of MMF are permitted in order to keep the 
participant on study drug.  
The following guidelines must be followed: 
• In the event of MMF intolerance (e.g., gastrointestinal disorders, bronchiectasis), temporary 
dose adjustment or interruption may be necessary. It is recommended to reduce the actual 
dose by 50%, for approximately 15 consecutive days. 


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• In case of persistent intolerance, MMF can be discontinued and the participant may be 
switched to other mycophenolates (e.g., Myfortic® mycophenolic acid) and remain in the 
study on randomized study treatment. Alternatively, MMF may be discontinued completely 
and participants may remain in the study on randomized study treatment.  All dose changes 
must be recorded on the appropriate CRFs. 
Corticosteroids  
Corticosteroids will be administered with dosing according to local standard practice in a way 
that is consistent across all participants enrolled at each site. Corticosteroids may be tapered, as 
per local standard practice up to a minimal daily dose of 5 mg prednisone (or equivalent dose 
of another oral corticosteroid) for the first 4 months of treatment. Corticosteroids may then be 
discontinued (after completion of Month 4 visit) according to investigator discretion. 
Corticosteroids doses should be recorded on the appropriate CRF. 
Management of signs of over-immunosuppression 
In case of suspected over-immunosuppression, reducing the CFZ533 dose is not permitted, 
since under-dosing of CFZ533 may trigger loss of immunosuppression. It is recommended to 
reduce the MMF dose by 50 % or more.  
If there still are signs of over-immunosuppression, MMF and/or corticosteroids may be further 
reduced or permanently discontinued. 
Participants on CFZ533 with signs of over-immunosuppression may continue on their 
randomized regimen. In case of persistent signs of over-immunosuppression despite 
mycophenolate discontinuation, or if the symptoms are severe, participant should be 
discontinued from CFZ533 and switched to SoC. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
The investigator must promote compliance by instructing the participant to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the participant’s 
safety and the validity of the study. The participant must also be instructed to contact the 
investigator if he/she is unable for any reason to take any of the study medications. 
All pre-transplant immunosuppressive drugs, such as TAC, MMF and CS will be recorded on 
the appropriate CRFs. 
All immunosuppressive drugs administered at the time of transplantation and post-
randomization doses of CFZ533, TAC, MMF (or substitute) and CS will be recorded on the 
appropriate CRFs.  
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 treatment is interrupted due to 
inability to tolerate oral medication and rescue therapy via a nasogastric tube is administered, 
the non-study immunosuppressive drug should be recorded on the appropriate CRF. 


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TAC trough levels during the run-in period and for participants in Arm 1 until EOS will be 
determined locally and recorded on the appropriate CRF. The local trough values will be used 
to adjust the TAC dosing as needed.  
Other drugs administered prior to and continuing at start of study treatment will be entered on 
the appropriate CRF. 
Compliance will be assessed by the investigator and/or study personnel at each visit based on 
information provided by the participant. This information should be captured in the source 
document at each visit. 
6.6.2 
Recommended treatment of adverse events  
Acute rejection 
For all acute rejection episodes, regardless of initiation of anti-rejection treatment, an allograft 
biopsy must be performed preferably within 24 hours, latest within 48 hours. Whenever possible, 
anti-rejection therapy should be postponed until a histological diagnosis of rejection is 
confirmed. These biopsies will be read by the local pathologist (as well as a central reader up 
to Month 24 visit), and the histological lesions will be graded according to the Banff criteria 
(Appendix 3). Determination of the need for treatment will be according to the local 
pathologist’s findings and the investigator’s judgement.  
All episodes of acute rejection should be treated as per local practice, using for example bolus 
steroids, increased dose of oral steroids or tacrolimus (for control participants) as first line and 
anti-T-cell antibody for steroid-resistant rejections. 
A steroid-resistant acute rejection episode will be defined when no stabilization and/or no 
improvement of liver enzymes is seen within five days after initiation of methylprednisolone, 
when the participant has received at least 3 bolus injections with a minimum of 500 mg/bolus, 
or a total of 1.5 g of methylprednisolone, or initiation of anti-T-cell antibody treatment after 
repetitive methylprednisolone. 
Whenever possible a re-biopsy should be performed to confirm an ongoing steroid-resistant 
acute rejection prior to initiating anti-T-cell antibody treatment.  
The specific anti-rejection treatment, corticosteroids and anti-T-cell antibody treatment must be 
recorded on the appropriate CRFs. Increased doses of tacrolimus applied as anti-rejection 
treatment will be recorded on the corresponding dose administration record CRF page  
Participants requiring cyclosporine, azathioprine, everolimus, sirolimus or tacrolimus (if the 
participant is on a CFZ533 arm) or any other agents for anti-rejection treatment will be 
discontinued from the randomized study treatment but will be followed until Month 24. Any 
participant requiring anti-T cell antibody therapy for rejection up to Month 24 should be 
discontinued from CFZ533 but should continue in the study on standard of care 
immunosuppression. Participants requiring any of the above treatments for rejection during the 
extension will be discontinued from the study. 
The CFZ533 dose will not be modified and no extra dosing will be administered following a 
rejection episode. 


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All episodes of acute rejection must be entered on the appropriate CRFs preferably within  
24 hours.  
6.7 
Preparation and dispensation 
Each study site will be supplied with investigational drug CFZ533, (in packaging) as described 
in Section 6.1.1. 
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the IRT and obtaining the medication number(s). The study medication has a 2-part 
label (base plus tear-off label), immediately before dispensing the medication kit to the 
participant, site personnel will detach the outer part of the label from the packaging and affix it 
to the source document. 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of CFZ533 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified in the CFZ533 Investigator’s Brochure. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Participants will be 
asked to return all unused study treatment and packaging at the end of the study or at the time 
of discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the 
investigator folder at each site. 
6.7.1.2 
Handling of Tacrolimus, MPA and corticosteroids 
If tacrolimus is sourced locally by Novartis, it must be received by a designated person at the 
study site, handled and stored safely and properly and kept in a secured location to which only 
the investigator and designated site personnel have access. Upon receipt, all study treatment 
must be stored according to the instructions specified on the label. 
MMF and CS for oral and IV administration will be supplied locally and will be used as per 
local label.  


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As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, delivery of IMP directly to a participant’s home may be permitted (if allowed by Local 
or Regional Health Authorities and Ethics Committees as appropriate) in the event the 
Investigator has decided that an on-site visit by the participant is no longer appropriate or 
possible, and that it is in the interest of the participant’s health to administer the study treatment 
even without performing an on-site visit. The dispatch of IMP from the site to the participant’s 
home remains under the accountability of the Investigator. Each shipment/provisioning will be 
for a maximum of 3-month supply. In this case, regular phone calls or virtual contacts (every 4 
weeks or more frequently if needed) will occur between the site and the participant for 
instructional purposes, safety monitoring, drug accountability, investigation of any adverse 
events, ensuring participants continue to benefit from treatment and discussion of the 
participant´s health status until the participants can resume visits at the study site. 
6.7.2 
Instruction for prescribing and taking study treatment 
6.7.2.1 
CFZ533 administration  
The CFZ533 investigational drug will be supplied centrally by Novartis Global Clinical Supply 
to the investigators as open-labeled supplies.   
For preparation of CFZ533, the pharmacist or designee at the investigator’s site will need to log 
into the IRT system to identify the medication assigned number as per treatment arm. In addition, 
the pharmacist or designee at the investigator’s site and HCP (if applicable) will prepare the 
medication for administration to participants based on a separate pharmacy manual.  
Appropriate documentation of the participant specific dispensing process must be maintained 
throughout the study. 
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label. Immediately before drug administration or dispensing the package to the in-
home health care provider, investigator staff will detach the outer part of the label from the 
packaging and affix it to the source documents (Drug Label Form) for that participant’s unique 
participant number. 
CFZ533 initial loading dose(s) will be administered as an IV infusion to the participant by 
authorized investigator staff at the visits specified in the assessment schedule. 
CFZ533 SC will be administered by authorized investigator/staff at each study visit. After the 
Month 6 visit (at site), in-home administration may be allowed by a health care provider.  
CFZ533 SC using PFS will be administered by authorized participants or person of his/her 
choice once qualified and trained or by the investigator/staff.  
In-home drug administration 
At protocol specified time points (see Table 8-1, Table 8-2 and Table 8-3), if in-home 
administration of CFZ533 supported by a locally contracted health care provider has been opted 
for, the investigator or delegated site staff will contact the participant by telephone to check 
his/her status (e.g., AEs, concomitant medications) prior to ordering the treatment. The 


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investigator or delegated site staff will then dispense via the IRT an appropriate number of 
CFZ533 treatment packages to the home health care provider. The investigator staff will detach 
the outer part of the label and affix it to the source documentation (Drug Label Form). Detailed 
instructions on the in-home administration of the study treatment will be described in the 
information for use (IFU) provided to each health care provider and made available to the site 
staff and investigator. The site personnel should review these instructions in detail. 
Home health care provider will be contracted on a per country basis, depending on local 
regulations and Novartis organization decision. The locally contracted, in-home health care 
provider will be trained by Novartis team members or delegates on the protocol and the 
instructions for use (IFU). This will be documented in a training log and stored appropriately. 
The study medication preparation and administration guidelines are described in a separate 
pharmacy manual. 
During the COVID-19 pandemic that limits or prevents on-site study visits, in-home 
administration may be considered. In-home visits would be conducted by the site staff (under 
the responsibility of the investigator), or by a health care provider (HCP) supporting this activity 
beyond Month 6 visit. In such pandemic situation home-visits performed by HCP may also be 
considered prior to completion of the Month 6 visit, if this is in agreement with the investigator. 
Use of PFS  
Once available, and after completion of their Month 12 visit, participants will receive SC 
injections using PFS. If a participant had good safety and tolerability, with no indication of 
hypersensitivity or other acute reactions from the previous doses, starting from Month 12, the 
investigator will determine if participant (or person of his/her choice) is able to administer 
treatment following completion of training. Site must document training completion and site’s 
decision. 
If participant or person of his/her choice are authorized to perform the injection at home, on-
site visits after M12 will only be conducted every 3 months, until EOS or discontinuation, 
whichever occurs earlier. The investigator or delegated site staff should contact the participant 
by telephone to check on his/her status (e.g., AEs, concomitant medications, pregnancy status) 
prior to any home dosing. 
Site will provide material for self-administration (PFS kits and transportation materials). Site 
will dispense CFZ533 from the IRT according to the participant’s storage capacity, based on 
Investigator determination, with a maximum stock to cover administration up to the next on-
site visit. The site will instruct the participant that on the days of clinic visits, CFZ533 dosing 
will be done at the site, after collection of PK samples which are required before dosing. 
The study medication transportation, home-storage, preparation and administration guidelines 
will be described in a separate manual and provided to the participants. The participants will be 
provided with a form to record each administration, the location, and who performed it. 


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Arm 2 (CFZ533 600 mg regimen) 
The first dose of CFZ533 (30 mg/kg) will be administered IV on day of randomization  
(Day 8±2). The participant will be weighed prior to randomization and this weight value will 
be used for the study medication preparation and the calculation of the dose.  
The second dose of CFZ533 15 mg/kg will be administered IV on Day 15. The most recent 
weight will serve for the dose calculation. 
From Day 29 up to  the EOS, participants randomized to Arm 2 will receive two SC injections 
of 
2 
mL 
CFZ533 
at 
150 
mg/mL 
(4 
CFZ533 
vials,  
1 mL each, or 2 CFZ533 PFS of 2mL each) every 2 weeks in combination with MMF and CS. 
Arm 3 (CFZ533 300 mg regimen) 
The first dose of CFZ533 (30 mg/kg) will be administered IV on day of randomization  
(Day 8±2). The participant will be weighed prior to randomization and this weight value will 
be used for the study medication preparation and the calculation of the dose.  
From Day 29 up to  the EOS, participants randomized to Arm 3 will receive every 2 weeks one 
SC injection of 2 mL CFZ533 at 150 mg/mL (2 CFZ533 vials, 1 mL each, or 1 CFZ533 PFS of 
2mL), in combination with MMF and CS. 
Administration 
of 
CFZ533 
should 
occur 
after 
blood 
sample 
collection 
for 
PK/PD/immunogenicity assessments at visits specified in Table 8-1, Table 8-2 and Table 8-3 
(Section 8). 
All CFZ533 investigational drug kits assigned will be recorded in the IRT system.  
All dosages prescribed and dispensed to the participants during the study must be recorded in 
the appropriate CRF, including the location of injection and person who administered it.  
6.7.2.2 
Tacrolimus administration 
All participants need to be on a treatment regimen comprising TAC, CS and MMF at the time 
of randomization.  
Initiating TAC before transplantation is permitted. 
Initiation of tacrolimus post-transplantation 
Tacrolimus will be administered as capsules orally twice daily. Tacrolimus should be initiated 
as soon as possible after transplantation and TAC blood trough levels should be targeted and 
adjusted between 5-15 ng/mL (i.e., all participants should be treated exactly according to the 
same local treatment protocol). The use of intravenous tacrolimus in the immediate post-
operative period is permitted. 
Arm 1 
Participants randomized to the Control Arm 1 will continue to receive TAC, in combination 
with MMF and corticosteroids until EOS. TAC will be administered as p.o. capsules/tablets 
b.i.d. and blood trough levels will be managed according to the local approved label. 


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Every effort should be made to keep the participants within target trough levels as per local 
label. TAC dose adjustments will be based on local laboratory trough level results. 
In the event of TAC intolerance, dose reduction of TAC may be necessary. If this occurs, the 
change in TAC regimen and the TAC dosing should be recorded on the appropriate CRF. 
Arms 2 and 3 
For the CFZ533 (Arms 2 and 3) participants; TAC dose will be progressively decreased up to 
Day 21 as described thereafter. At randomization, on the day of the first CFZ533 loading dose 
(30 mg/kg IV), the TAC dose will be reduced to achieve a TAC blood trough level of 5-8 ng/mL.  
The TAC dose will be further decreased by Day 15 to reach a TAC blood trough level below 5 
ng/mL. By Day 22, TAC must be completely weaned-off. If, at any time post Day 22 and for 
any reason, TAC is not completely withdrawn and co-administration with the randomized study 
treatment is ongoing, an immediate discussion will be needed between the Sponsor and the 
Investigator whether to keep the participant on randomized treatment; this will be assessed on 
a case-by-case basis.  
In case a participant temporarily cannot take oral TAC (e.g., in case of a surgical intervention), 
TAC intravenous administration is allowed as per local practice. TAC granules for oral 
suspension are also allowed to be used for participants who cannot swallow tablets.  
All TAC doses and changes must be recorded on the appropriate CRF. 
6.7.2.3 
MMF administration – Arms 1, 2 and 3 
MMF will be given as film-coated tablets of 500 mg or capsules of 250 mg b.i.d. For de novo 
transplant participants 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 possible. 
MMF will be initiated and administered according to the approved labeling and local practice. 
All MMF doses and changes must be recorded on the appropriate CRF.  
Dose adjustment/interruption guidance for MMF is provided in Section 6.5.2. 
6.7.2.4 
Corticosteroids administration – Arms 1, 2 and 3 
Corticosteroids will be administered immediately on or after liver transplant surgery according 
to local standard practice. CS doses should be recorded on the appropriate CRF. Dose 
adjustment/interruption guidance for CS is provided in Section 6.5.2. 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), Institutional Review Board (IRB) / Independent Ethics 
Committee (IEC)-approved informed consent. 
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 


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possible given his/her understanding. If the participant is capable of doing so, he/she must 
indicate agreement by personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the participant 
informed consent and should be discussed with the participant during the study as needed. Any 
new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an investigator 
notification or an aggregate safety finding. New information might require an update to the 
informed consent and then must be discussed with the participant. 
The following informed consent forms are included in this study: 
• Main study consent, also including: 
• A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study 
• 
 
• 
 
• As applicable, Pregnancy Outcomes Reporting Consent for female participants or the 
female partners of any male participants who took study treatment 
• As applicable, home visits consent for participants to receive CFZ533 injections at home 
Women of childbearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information. A copy of the approved version of all consent forms 
must be provided to Novartis after IRB/IEC approval. Sexually active male participants, or the 
female partner, are recommended to use highly effective contraception during therapy with 
MMF and at least 12 weeks following discontinuation of mycophenolates (see additional 
information in Section 8.4.3). 
8 
Visit schedule and assessments 
Table 8-1,Table 8-2 and Table 8-3 list all of the assessments and indicate with an “X” when the 
visits need to be performed. All data obtained from study assessments must be clearly 
documented in the participant’s source notes. 


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Electrocardiograms (ECGs) must be recorded after 10 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 samplings. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1, Table 8-2 and Table 8-3). Visit window of ±2 days is allowed for the randomization 
visit (Day 8). All other visits are expected to occur according to the study schedule based on 
the randomization date, or as close to the designated day/time as possible. If a visit is delayed 
or occur in advance, the following visit date will not be re-adjusted and will remain according 
to the initial schedule. 
The study visit names may not match the number of days from transplant depending on the 
randomization date (due to the visit window of ±2 days). The injection schedule should be 
calculated from the date of first treatment (actual randomization date).  
Screening and baseline visits may occur on same day. If these visits occur within a 48h period 
screening assessments do not need to be repeated at the baseline visit. 
Every effort should be made to take the blood samples at the protocol specified visits and times.  
Missed or rescheduled visits should not lead to automatic discontinuation.  
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowed by local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g., tele consult) or visits by site staff/ home nursing 
staff to the participant´s home, can replace on-site study visits, for the duration of the disruption 
until it is safe for the participant to visit the site again.   
All randomized participants are expected to continue in the study up to Month 24, even if they 
have discontinued the study treatment.  
Participants who discontinue CFZ533 or control regimen prior to Month 24 should be treated 
according to SoC immunosuppression and return at scheduled visits to provide follow-up 
information. Participants who discontinue treatment prior to Month 12 should attend Month 6, 
Month 8, Month 10, Month 12, Month 18 and Month 24 follow-up visits. Participants who 
discontinue after Month 12 but before Month 24 should attend the Month 18 and Month 24 
follow-up visits. 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 
participant and graft status. Participants who discontinue study treatment prior to Month 24 visit 
will not enter the extension. 
Participants who prematurely discontinue the study for any reason should be scheduled for a 
visit as soon as possible, at which time all of the assessments listed for the EOS visit will be 
performed. At this EOS visit, all dispensed investigational treatment should be reconciled, and 
the adverse events and concomitant medications recorded on the CRF. 
Participants who discontinue CFZ533 or control regimen during the extension should be 
scheduled for a visit as soon as possible to perform EOS visit assessments. 


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Table 8-1 
Assessment schedule (Treatment Period 1)  
Assessment schedule (Treatment Period 1) – Screening to Randomization  
 
Period 
Screening 
Treatment Run-in 
Visit Name 
SCR 
BSL/pre-LTx@ 
Randomization 
Month 
 
 
 
Day 
-1 to -60 
1 
8±2 
Hour (h) 
 
 
Pre 
0 
EOI + 1h 
Informed consent 
X 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
X 
 
Relevant medical 
History/current medical history 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Pregnancy test (serum) 
S# 
S# 
S 
 
 
Pregnancy test (urine) 
 
 
 
 
 
IRT visit/dispensation record 
S 
S 
 
S 
 
Transplant procedure 
 
X 
 
 
 
Liver transplant background 
recipient/donor 
 
X 
 
 
 
Hepatocellular carcinoma 
history 
 
X 
 
 
 
Recipient/donor viral serology 
X 
X 
 
 
 
Liver imaging1 
 
 
 
S 
 
Vital signs: 
 
-Height 
X 
X 
 
 
 
-Temperature/ blood pressure/ 
pulse/ weight 
X 
X 
 
X 
 


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Period 
Screening 
Treatment Run-in 
Visit Name 
SCR 
BSL/pre-LTx@ 
Randomization 
Month 
 
 
 
Day 
-1 to -60 
1 
8±2 
Hour (h) 
 
 
Pre 
0 
EOI + 1h 
Assessments and 
specifications2 
S# 
S# 
 
S 
 
ECG evaluation 
X# 
X# 
 
 
 
Local laboratory tests3 
X# 
X# 
 
X 
 
Safety laboratory tests4 
 
X 
 
X 
 
ǹ-fetoprotein assessment4 
 
X 
 
X 
 
MMF trough levels4 
 
 
 
X 
 
TAC trough levels (local) 
 
 
X 
 
 
CFZ533 Pharmacokinetics5 
 
 
X 
 
X 
Pharmacodynamics sCD406 
 
 
X 
 
 
CFZ533 Immunogenicity7 
 
 
X 
 
 
Ascites fluid drainage and 
management8 
 
As required 
Administration of CFZ533 IV 
(Arm 2) 
 
 
 
X 
 
Administration of CFZ533 IV 
(Arm 3) 
 
 
 
X 
 
Administration of TAC (Arm 2 
& Arm 3) 
 
X 
 
X 
 
CFZ533 dosage administration 
record 
 
 
 
X 
 
PPD
PPD


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Period 
Screening 
Treatment Run-in 
Visit Name 
SCR 
BSL/pre-LTx@ 
Randomization 
Month 
 
 
 
Day 
-1 to -60 
1 
8±2 
Hour (h) 
 
 
Pre 
0 
EOI + 1h 
MMF and CS dosage 
administration records (Arm 2 
& Arm 3) 
 
X 
 
X 
 
TAC, MMF and CS dosage 
administration records (Arm 1) 
 
X 
 
X 
 
Concomitant medications 
X 
X 
 
X 
 
Surgical and medical 
procedures 
X 
X 
 
X 
 
Liver allograft rejection 
 
 
 
X 
 
Hospitalization record 
 
 
 
X 
 
Graft loss 
 
 
 
X 
 
EBV and CMV viral load 
As required 
Dialysis log 
 
 
 
X 
 
AEs / SAEs 
 
As required 
Infections 
 
 
 
X 
 
Hepatocellular carcinoma 
 
 
 
X 
 
Malignancies 
 
 
 
X 
 
Withdrawal of Informed 
Consent 
 
As required 
M12 Period completion 
Not applicable 
As required 
Study completion 
As required 
PPD


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Assessment schedule (Treatment Period 1) – Day 15 to Month 12 
Period 
Treatment 
Visit Name 
Treatment Period 1 
Month 
 
1 
1.5 
2 
2.5 
3 
3.5 
4 
4.5 
5 
5.5 
6 or 
FU 
6.5 
7 
7.5 
8 or 
FU 
8.5 
9 
 
9.5 
10 
or 
FU 
10.5 
11 
11.5 
12 or 
FU 
Day 
15 
22 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
 
 
 
225 
 
 
 
281 
 
 
323 
337 
Hour (h) 
Pre 
0 
EOI 
+1h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(serum) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(urine) 
 
 
 
 
S 
 
S 
 
S 
 
S 
 
S 
 
S 
 
S0 
 
S 
 
S0 
 
S 
 
S0 
 
S 
IRT 
visit/dispensati
on record 
 
S 
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Liver allograft 
biopsy 
As required 
Vital signs: 
 
-Weight/ 
temperature 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
-Blood 
pressure/pulse 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Assessments 
and 
specifications2 
 
 
 
 
 
 
S 
 
 
 
S 
 
 
 
S 
 
 
 
S 
 
 
 
S 
 
 
 
S 
ECG 
evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
PPD
PPD


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Period 
Treatment 
Visit Name 
Treatment Period 1 
Month 
 
1 
1.5 
2 
2.5 
3 
3.5 
4 
4.5 
5 
5.5 
6 or 
FU 
6.5 
7 
7.5 
8 or 
FU 
8.5 
9 
 
9.5 
10 
or 
FU 
10.5 
11 
11.5 
12 or 
FU 
Day 
15 
22 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
 
 
 
225 
 
 
 
281 
 
 
323 
337 
Hour (h) 
Pre 
0 
EOI 
+1h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 
laboratory 
tests4 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
ǹ-fetoprotein 
assessment4 
As required 
MMF trough 
levels4 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
TAC trough 
levels (local) 
X 
 
 
X 
X
10 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
CFZ533 
Pharmaco-
kinetics5 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Pharmacodyn
amics sCD406 
 
 
 
 
X 
 
X 
 
X 
 
 
X7 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
CFZ533 
Immuno-
genicity7 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Ascites fluid 
drainage and 
management8 
As required 
Administration 
of CFZ533 IV 
(Arm 2) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Period 
Treatment 
Visit Name 
Treatment Period 1 
Month 
 
1 
1.5 
2 
2.5 
3 
3.5 
4 
4.5 
5 
5.5 
6 or 
FU 
6.5 
7 
7.5 
8 or 
FU 
8.5 
9 
 
9.5 
10 
or 
FU 
10.5 
11 
11.5 
12 or 
FU 
Day 
15 
22 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
 
 
 
225 
 
 
 
281 
 
 
323 
337 
Hour (h) 
Pre 
0 
EOI 
+1h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration 
of CFZ533 IV 
(Arm 3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration 
of CFZ533  
600 mg (Arm 
2) & 300 mg 
(Arm 3) 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X0 
X0 
X0 
X 
X0 
X0 
X
0 
X 
X0 
X0 
X0 
X 
Administration 
of TAC (Arm 2 
& Arm 3) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CFZ533 
dosage 
administration 
record 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TAC dosage 
administration. 
record (Arm 2 
& Arm 3) 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMF and CS 
dosage 
administration 
records (Arm 2 
& Arm 3) 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
TAC, MMF 
and CS 
dosage 
administration 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 


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Period 
Treatment 
Visit Name 
Treatment Period 1 
Month 
 
1 
1.5 
2 
2.5 
3 
3.5 
4 
4.5 
5 
5.5 
6 or 
FU 
6.5 
7 
7.5 
8 or 
FU 
8.5 
9 
 
9.5 
10 
or 
FU 
10.5 
11 
11.5 
12 or 
FU 
Day 
15 
22 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
 
 
 
225 
 
 
 
281 
 
 
323 
337 
Hour (h) 
Pre 
0 
EOI 
+1h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
records (Arm 
1) 
Concomitant 
medications 
Ongoing basis 
Surgical and 
medical 
procedures 
As required 
Liver allograft 
rejection 
As required 
Hospitalization 
record 
As required 
Graft loss 
As required 
EBV and CMV 
viral load 
As required 
Dialysis log 
As required 
AEs / SAEs 
As required 
Infections 
As required 
Hepatocellular 
carcinoma 
As required 
Malignancies 
As required 
Withdrawal of 
Informed 
Consent 
As required 
M12 Period 
completion9 
As required 
X 


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Protocol No. CCFZ533A2202 
 
Period 
Treatment 
Visit Name 
Treatment Period 1 
Month 
 
1 
1.5 
2 
2.5 
3 
3.5 
4 
4.5 
5 
5.5 
6 or 
FU 
6.5 
7 
7.5 
8 or 
FU 
8.5 
9 
 
9.5 
10 
or 
FU 
10.5 
11 
11.5 
12 or 
FU 
Day 
15 
22 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
 
 
 
225 
 
 
 
281 
 
 
323 
337 
Hour (h) 
Pre 
0 
EOI 
+1h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study 
completion9 
As required 
@ = all assessment must be completed prior to the liver transplantation procedure. 
S = Assessment to be recorded in source documentation, not in CRF. 
X = Assessment to be performed/evaluated and recorded in CRF if applicable. 
# = to be performed once in a 48-hour period if Screening and Transplantation (Day 1) occur in close proximity. 
EOI = End of infusion IV (administration), EOS = End of Study, EOT = End of Treatment  
0 = Assessment can be done at home for Arm 1 participants and for Arm 2 and 3 participants receiving CFZ533 at home via a health care provider. 
 
1. Graft vascular patency must be confirmed using appropriate imaging technology (e.g. Doppler ultrasound, angiography, angio MRI). Participants with any thrombosis or 
occlusion of hepatic artery, veins, portal vein or inferior vena cava or participants with no confirmatory imaging study cannot be randomized. 
2. Assessment and specification refers to the physical examination. See Table 8-4 for detailed list of expected physical examinations. 
3. Site must perform, at minimum, all assessments needed to evaluate participant’s eligibility at screening and randomization.  
4. Safety laboratory tests (central) from Baseline, Day 8±2 (Randomization), and at all visits indicated will include hematology, chemistry, coagulation and urinalysis as 
specified in Table 8-5. Α-fetoprotein will be evaluated at Baseline, Day 8±2/Randomization (for HCC subjects, only) and as needed thereafter for recurrent and de novo 
cases. MMF trough levels will be collected at all visits indicated or unscheduled visit (dose change). At the time of biopsies, a chemistry central laboratory test should be 
performed and thereafter until the final outcome. 
5. Arms 2 & 3 - CFZ533-treated participants only: a blood sample is collected pre-dose at each dose administration visit (IV or SC) during the treatment period and up 
to EOS visit as indicated. In addition, for both arms 2 & 3, a blood sample is required after the loading dose (30 mg/kg IV on Day 8±2) 1 hr. after the end of the 30-min 
infusion. For participants in the Arm 2, an additional sample is required after the loading dose on Day 15 (15 mg/kg IV) 0, 1 hr. after the end of the infusion. For more 
details on scheduled and unscheduled PK samples refer to Appendix 6a and Appendix 6b. 
6. All participants (Control and CFZ533-treated): all samples are taken at pre-dose. For details refer to Appendix 6a. 
7. Arms 2 & 3 - CFZ533-treated participants only: all samples are taken at pre-dose. For details refer to Appendix 6a. 
8. Arms 2 & 3 - CFZ533-treated participants only: at any time, if ascites fluids are drained from CFZ533-treated participants, the volume of ascites drained should be 
measured and recorded on the appropriate CRF. 
 
  


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9. All participants are expected to continue in the study up to Month 24 regardless of whether they are on or off their randomized study treatment. If subjects discontinue 
the randomized study treatment prior to Month 12 they should continue in the study to Month 24 on standard of care, and come to the follow-up visit(s). In case of early 
study discontinuation, the appropriate CRF must be completed together with all final Month 24 assessments. 
10. Participants in Arms 2 & 3 will not have TAC trough levels taken from D29. TAC trough levels will continue to be applicable only for Arm 1 patients from D29 onwards.  
 
12. After a participant is switched to PFS and he/she administers at home, the participant needs to be reminded that on the days of clinic visits, CFZ533 dosing will be 
done after collection of PK labs which are required at pre-dose. 
13. Annual extension schedule will continue if needed after Month 72 until the EOS is declared. 
PPD


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Table 8-2 
Assessment Schedule (Treatment Period 2) 
Assessment schedule (Treatment Period 2) - Month 12.5 to Month 24 
 
Period 
Treatment 
 
Visit Name 
Treatment Period 2 
 
 
Month 
12.5 
13 
13.5 
14 
14.5 
15 
15.5 
16 
16.5 
17 
17.5 
18 or 
FU 
18.5 
19 
19.5 
20 
20.5 
21 
21.5 
22 
22.5 
23 
23.5 
24 or 
FU 
Day 
 
 
 
 
 
421 
 
 
 
 
 
505 
 
 
 
 
 
589 
 
 
 
 
 
673 
Hour (h) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT 
visit/dispensation 
record  
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Pregnancy test 
(serum) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S 
Pregnancy test 
(urine) 
 
S0 
 
S0 
 
S 
 
S0 
 
S0 
 
S 
 
S0 
 
S0 
 
S 
 
S0 
 
S0 
 
 
Vital Signs: 
 
-Weight/ 
temperature 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
-Blood 
pressure/pulse 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Assessments and 
specifications2 
 
 
 
 
 
S 
 
 
 
 
 
S 
 
 
 
 
 
S 
 
 
 
 
 
S 
ECG evaluation 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Safety laboratory 
tests4 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Α-fetoprotein 
assessment4 
As required 
MMF trough levels4 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 


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Period 
Treatment 
 
Visit Name 
Treatment Period 2 
 
 
Month 
12.5 
13 
13.5 
14 
14.5 
15 
15.5 
16 
16.5 
17 
17.5 
18 or 
FU 
18.5 
19 
19.5 
20 
20.5 
21 
21.5 
22 
22.5 
23 
23.5 
24 or 
FU 
Day 
 
 
 
 
 
421 
 
 
 
 
 
505 
 
 
 
 
 
589 
 
 
 
 
 
673 
Hour (h) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TAC trough levels 
(local) 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
CFZ533 
Pharmacokinetics5, 
12 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Pharmacodynamics 
sCD406 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
CFZ533 
Immunogenicity7 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Ascites fluid 
drainage and 
management8 
As required 
Administration of 
CFZ533 600 mg 
(Arm 2) & 300 mg 
(Arm 3)12 
X0 
 
X0 
 
X0 
 
X0 
 
X0 
 
X0 
 
X0 
 
X0 
 
 
X0 
 
X0 
 
X0 
 
X0 
 
X0 
 
X0 
 
X0 
 
X0 
 
X0 
 
X0 
 
X0 
 
X0 
 
X0 
 
X0 
 
X0 
X0 
CFZ533 dosage 
administration 
record 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MMF and CS 
dosage 
administration 
records (Arm 2 & 
Arm 3) 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
TAC, MMF and CS 
dosage 
administration 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
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Period 
Treatment 
 
Visit Name 
Treatment Period 2 
 
 
Month 
12.5 
13 
13.5 
14 
14.5 
15 
15.5 
16 
16.5 
17 
17.5 
18 or 
FU 
18.5 
19 
19.5 
20 
20.5 
21 
21.5 
22 
22.5 
23 
23.5 
24 or 
FU 
Day 
 
 
 
 
 
421 
 
 
 
 
 
505 
 
 
 
 
 
589 
 
 
 
 
 
673 
Hour (h) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
records (Arm 1 
only) 
Concomitant 
medications 
Ongoing 
Surgical and 
medical procedures 
As required 
Liver allograft 
biopsy 
Not applicable 
Liver allograft 
rejection 
As required 
Hospitalization 
As required 
Graft loss 
As required 
EBV and CMV 
infections 
As required 
Dialysis log 
As required 
AEs/SAEs 
Ongoing 
Infections 
As required 
Hepatocellular 
carcinoma 
As required 
Malignancies 
As required 
Withdrawal of 
Informed Consent 
As required 
Month 24 Period 
completion9 
As required 
X 
Study completion9 
 
X 
For footnotes, see Table 8-1. 


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Table 8-3 
Assessment Schedule (Extension Period) 
Assessment schedule (Extension period) - Month 24.5 to end of extension 
Period 
Long-term Extension 
End of 
study 
Visit Name 
Treatment period 3 
EOS 
Month 
24.5 
25 
25.5 
37.5 
48.5 
26 
26.5 
38.5 
50.5 
27 
27.5 
39.5 
51.5 
28 
28.5 
40.5 
52.5 
29 
29.5 
41.5 
53.5 
30 
30.5 
42.5 
54.5 
31 
31.5 
43.5 
55.5 
32 
32.5 
44.5 
56.5 
33 
33.5 
44.5 
57.5 
34 
34.5 
46.5 
58.5 
35 
35.5 
36 
 
 
36.5 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
47.5 
48 
 
 
48.5 
49 
50 
51 
52 
53 
54 
55 
56 
57 
58 
59 
59.5 
60 
 
 
60.5 
61 
61.5 
62 
62.5 
63 
63.5 
64 
64.5 
65 
65.5 
66 
66.5 
67 
67.5 
68 
68.5 
69 
69.5 
70 
70.5 
71 
71.5 
7213 
 
IRT 
visit/dispensation 
record 
 
 
 
 
 
S 
 
 
 
 
 
S 
 
 
 
 
 
S 
 
 
 
 
 
S 
S 
Pregnancy test 
(urine) 
 
S0 
 
S0 
 
S 
 
S0 
 
S0 
 
S 
 
S0 
 
S0 
 
S 
 
S0 
 
S0 
 
S 
S 
CFZ533 injection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight/ temperature 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Assessments and 
specifications2 
 
 
 
 
 
 
 
 
 
 
 
S 
 
 
 
 
 
 
 
 
 
 
 
S 
S 
Α-fetoprotein 
assessment4 
As required 
CFZ533 Drug 
dispensation 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
TAC Drug 
dispensation 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 


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Period 
Long-term Extension 
End of 
study 
Visit Name 
Treatment period 3 
EOS 
Month 
24.5 
25 
25.5 
37.5 
48.5 
26 
26.5 
38.5 
50.5 
27 
27.5 
39.5 
51.5 
28 
28.5 
40.5 
52.5 
29 
29.5 
41.5 
53.5 
30 
30.5 
42.5 
54.5 
31 
31.5 
43.5 
55.5 
32 
32.5 
44.5 
56.5 
33 
33.5 
44.5 
57.5 
34 
34.5 
46.5 
58.5 
35 
35.5 
36 
 
 
36.5 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
47.5 
48 
 
 
48.5 
49 
50 
51 
52 
53 
54 
55 
56 
57 
58 
59 
59.5 
60 
 
 
60.5 
61 
61.5 
62 
62.5 
63 
63.5 
64 
64.5 
65 
65.5 
66 
66.5 
67 
67.5 
68 
68.5 
69 
69.5 
70 
70.5 
71 
71.5 
7213 
 
MMF and CS Drug 
dispensation 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Concomitant 
medications 
Ongoing 
Liver allograft 
rejection 
As required 
Withdrawal of 
Informed Consent 
As required 
Hospitalization 
As required 
EBV and CMV 
infections 
As required 
Dialysis log 
As required 
Hepatocellular 
carcinoma 
As required 
Malignancies 
As required 
Study completion 
As required 
X 
For footnotes, see Table 8-1.
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8.1 
Screening 
All participants who have signed informed consent but do not enter into the Run-in period will 
be classified as screen failures and need to have the screening completion CRF for the screening 
period, demographics, inclusion/exclusion, and any SAE data collected.  
Rescreening (with a maximum of three screening attempts) is only allowed for participants who 
were screen failures on the initial Screening visit (due for example, to lab values out of range 
or no donor-organ available) but not yet transplanted. No transplanted participant can be 
rescreened. Rescreened participants should be assigned a new participant ID number.  
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever, in their judgement, the test abnormality occurred prior to the informed consent 
signature.   
8.1.1 
Information to be collected on screening failures 
Participants who sign an informed consent form and subsequently found to be ineligible prior 
to randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate Case Report Form. The demographic information, informed 
consent, and Inclusion/Exclusion pages must also be completed for screen failure participants. 
No other data will be entered into the clinical database for participants who are screen failures, 
unless the participant experienced a serious adverse event during the screening phase (see SAE 
section for reporting details). If the participant fails to be randomized, the IRT must be notified 
within 2 days of the screen fail that the participant was not randomized. 
Participants who are randomized and fail to start treatment, e.g., participants randomized in 
error, will be considered an early terminator. The reason for early termination should be 
recorded on the appropriate Case Report Form. 
8.2 
Participant demographics/other baseline characteristics 
After informed consent has been signed and the participant’s eligibility to participate in the 
study has been determined, baseline participant information will be obtained in accordance with 
local regulations, including, age, sex (with childbearing status for females), race and ethnicity. 
Participant’s race and ethnicity are collected and analyzed to identify variations in safety or 
efficacy due to these factors as well as to assess the diversity of the study population as required 
by Health Authorities. 
In addition full relevant medical history/current medical conditions, information on liver 
transplant procedure, recipient and donor viral serology will be obtained. 
The hepatocellular carcinoma (HCC) CRF should be completed for participants with a 
diagnosis of HCC pre-transplant or in whom HCC is discovered incidentally in the peri-
transplant period.  
Liver Doppler Ultrasound, angiography or angio MRI must be performed and allograft vessels 
must be patent prior to randomization. 


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Country specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF. 
8.3 
Efficacy 
8.3.1 
Suspected Acute Rejection/Biopsy Proven Acute Rejection (BPAR)  
All episodes of acute rejection must be recorded on the appropriate CRF. Recording should be 
done within 24 h of occurrence, to ensure timely information sharing to the DMC. The precise 
reason for suspicion of an acute rejection and the final diagnosis (either to confirm or rule out 
the diagnosis of acute rejection) and all anti-rejection therapy administered must be recorded. 
A biopsy proven acute rejection (BPAR) is defined as an acute rejection confirmed by biopsy 
with a rejection activity index (RAI) score ≥ 3, Appendix 3. For all suspected rejection episodes, 
a liver biopsy must be performed preferably within 24 hours, latest within 48 hours whenever 
clinically possible, regardless of initiation of anti-rejection treatment. 
The liver biopsies will be read by a local pathologist according to the Banff criteria (Appendix 
3) and will be used to guide participant management. The results of the biopsy read by the 
local pathologist must be recorded on the appropriate CRF.  
In addition, up to Month 24 visit completion, biopsy specimen slides from these for “cause 
biopsies” will be sent to an independent central pathologist for blinded review. The efficacy 
analysis will rely on the central pathologist’s evaluations and will be based on acute rejection 
confirmed by a biopsy. Central laboratory chemistry tests should be performed at the time of 
suspected BPAR and thereafter until the final clinical outcome. Lactate dehydrogenase (LDH) 
test results, if available locally, should also be captured in the eCRF 
Every suspected acute rejection event must be recorded on the appropriate CRF with full details 
including whether or not a liver biopsy was performed (if not, reason should be provided, e.g. 
abnormal coagulation test) and the primary clinical diagnosis. 
Suspected acute rejection episodes ultimately diagnosed to be other conditions should also be 
recorded with the final diagnosis on the appropriate CRF. 
For any diagnosis of acute rejection, the treatment given and the final clinical outcome of the 
event must be recorded on the appropriate CRF. 
8.3.2 
Treated Biopsy Proven Acute Rejection (tBPAR) 
A treated biopsy proven acute rejection will be considered BPAR as defined in Section 8.3.1 
which is treated with anti-rejection therapy. 
8.3.3 
Graft loss 
The allograft will be presumed to be lost on the day the participant becomes newly listed for a 
liver allograft or the day the participant is re-transplanted or dies due to liver failure. This, in 
addition to the reason for graft loss, will be reported on the appropriate CRF.  
Graft Loss will lead to discontinuation from the study and be reported on the appropriate CRF 
page: 


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• on Month 12 visit CRF if occurs prior this time point, 
• on Month 24 visit CRF if it occurs between Month 12 and Month 24, 
• on EOS visit CRF if it occurs during the extension, 
with Graft Loss as the reason for study discontinuation and on the appropriate CRF for dosage 
administration record if graft loss occurs while on randomized treatment. 
Graft loss is considered as a Serious Adverse Event (SAE) and should be reported as a SAE 
report to the Novartis Chief Medical Office and Patient Safety (CMO & PS) department within 
24 hours. 
8.3.4 
Death  
In the event of participant death, the SAE leading to death should be reported to the Novartis 
CMO & PS department within 24 hrs. The events leading to the death should be entered on the 
appropriate CRF capturing Adverse Events. The death as reason for discontinuing study should 
be indicated on the Study Completion CRF. 
8.3.5 
Appropriateness of efficacy assessments 
The composite efficacy endpoint of BPAR, graft loss, and death is standard in the 
transplantation indication. This approach is consistent with the most recent Health Authorities 
guidance ([CHMP/EWP/263148/06], effective February 2009). 
The endpoint represents an attempt to assess the clinical balance between having sufficient 
immunosuppression to prevent rejection while minimizing toxicity.  
8.4 
Safety 
Safety assessments are specified below with the assessment schedule (Table 8-1, Table 8-2 and 
Table 8-3) detailing when each assessment is to be performed.  
For details on AE collection and reporting, refer to section AE. 
Table 8-4 
Assessments & Specifications 
Assessment 
Specification 
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, and extremities, vascular and neurological systems. If indicated based on medical 
history and/or symptoms, rectal, external genitalia, breast, and/or pelvic exams will 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 database. Significant findings that are present 
prior to informed consent are included in the Relevant Medical History on the appropriate 
CRF. Significant findings observed after signing informed consent which meet the definition 
of an adverse event must be recorded as AE. 
Vital sign 
If possible, vital sign assessments should be performed by the same study site staff member 
using the same validated device throughout the study. This will include blood pressure and 
pulse rate measurements after 5 minutes rest in a sitting position, and body temperature 
measured as per local practice (the same method to be used consistently for all participants 
at each site). 


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Assessment 
Specification 
Height and 
weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured as specified in Table 8-1, Table 8-2 and 
Table 8-3. 
Body mass index (BMI) will be calculated using the following formula: 
BMI = Body weight (kg) / [Height (m)]2 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowed by local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g., tele consult) or visits by site staff/ home nursing 
staff to the participant´s home, can replace on-site study visits, for the duration of the disruption 
until it is safe for the participant to visit the site again. 
8.4.1 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens collected listed below. Details 
on the collection, shipment of samples and reporting of results are provided in the laboratory 
manual.  
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 be contacted. 
Clinically notable laboratory findings are defined in Appendix 1.  
In all cases, the Investigator must document in the source documents, the clinical considerations 
(i.e., result was/was not clinically significant and/or medically relevant) in allowing or 
disallowing the participant to continue in the study. 
Local laboratory results will be used to assess inclusion/exclusion criteria at Screening and 
Randomization (Day 8). It is not mandatory to perform locally all assessments listed in Table 
8-5, but at a minimum those assessments required to confirm participant’s eligibility. For 
randomization, local laboratory assessments can be performed up to 3 days prior to 
randomization. Local serum creatinine results (most recent value available by the time of 
randomization or any time thereafter if not available at the central laboratory) will be recorded 
in the appropriate CRF page. 
As per Section 4.6 during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, if participants cannot visit the site for protocol specified safety lab assessments, collection 
can be performed at home by an health care provider or an alternative lab (local) collection site 
may be used. 


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Table 8-5 
Laboratory Assessments 
Test Category 
Test Name 
Hematology 
Platelets, hematocrit, hemoglobin, red blood cell (RBC), white blood cell (WBC) and differential 
count (e.g., neutrophils, basophils, eosinophils, monocytes and lymphocytes).  
Chemistry 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, calcium, total cholesterol, chloride, 
creatinine(*), CPK, gamma-GT, (fasting plasma) glucose, HbA1c, HDL, LDL, ratio of total 
cholesterol to HDL, ratio to LDL to HDL, inorganic phosphorus,  lipase, amylase, magnesium, 
potassium, total Immunoglobulin G (IgG), total protein, AST, ALT, sodium, triglycerides, blood 
urea nitrogen (BUN) and uric acid. If the total bilirubin concentration is increased above 1.5 
times the upper limit of normal, direct and indirect reacting bilirubin should be differentiated. 
(*) Serum creatinine (local) prior to the time of randomization or anytime thereafter if not 
available at the central laboratory. 
Urinalysis 
Protein, creatinine, albumin, glucose; proteinuria and albuminuria will be estimated from spot 
protein/creatinine and albumin/creatinine ratios. 
If the (macroscopic panel) dipstick result is positive for protein, nitrite, leucocytes and/or blood 
the sample will be sent for microscopic analysis of WBC, RBC and casts. 
Coagulation 
International normalized ratio (INR), prothrombin time (PT), partial thromboplastin (PTT) and 
activated partial thromboplastin time (aPTT). 
Viral serology 
Qualitative viral serology for donors/recipients evaluated for screening and/or baseline will be 
performed by local laboratories.  
It includes:  
• 
Hepatitis serology: hepatitis B surface antigen (HBsAg), antibodies to hepatitis B virus 
(anti-HBc and anti-HBs) and antibody to hepatitis C virus (anti-HCV). 
• 
Human immunodeficiency virus (HIV). 
• 
Qualitative viral serology tests for cytomegalovirus (CMV) and Epstein Barr virus (EBV) 
(IgG and IgM).  
Quantitative viral serology test for EBV and CMV will be assessed locally if active infection is 
suspected. It is highly recommended to quantify the EBV and CMV viremia and record the 
results on the corresponding CRF pages (number of copies/mL and method used). 
Qualitative and/or quantitative HCV-RNA and HBV-DNA (using PCR) will be performed 
locally for those participants who are tested anti-HCV positive and HBsAg positive, 
respectively.  
Additional 
tests:  
Α-fetoprotein, MMF trough levels, PK, PD (soluble CD40) and immunogenicity (anti-CFZ533 
antibodies) blood samplings. 
Pregnancy 
Test 
Serum (local laboratory)/Urine. 
8.4.2 
Electrocardiogram (ECG) 
In this study, local ECG will be used. ECGs must be recorded after 10 minutes rest in the supine 
position to ensure a stable baseline. A single 12 lead ECG is collected. The Fridericia QT 
correction formula (QTcF) should be used for clinical decisions. The original ECGs 
appropriately signed, must be collected and archived at the study site. 
The ECG tracing must be labeled with study number, participant number, date and time, and 
filed in the study site source document.  


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Clinically relevant abnormalities for the baseline ECG should be recorded on the relevant 
section of the CRFs capturing medical history/current medical conditions. 
8.4.3 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have a serum β-hCG test (serum 
pregnancy test) performed locally at the screening, baseline, randomization and Month 24 visits. 
Monthly local urine pregnancy tests will be performed as indicated in Table 8-1, Table 8-2 and 
Table 8-3. To fulfill inclusion criteria the local pregnancy test must be negative at the screening, 
baseline and randomization visits. In case treatment is discontinued prior to Month 24 visit, 
urine pregnancy test will be performed during follow-up visits (Month 6, 8, 10, 12, 18 and 24, 
whichever are applicable). A positive urine pregnancy test result needs to be confirmed via a 
serum β-hCG test. 
Urine pregnancy test can be evaluated at home between on-site visits (refer to Table 8-1,  Table 
8-2 and Table 8-3) for participants in Arm 1; for Arm 2 and 3 participants same rule applies 
after the Month 6 visit, if treatment administration is performed at home via a health care 
provider. If any urine pregnancy test performed at home is positive, participant must 
immediately inform the clinical site. 
A positive urine pregnancy test requires immediate interruption of study drug until serum β-
hCG is performed and found to be negative. Additional pregnancy testing might be performed 
if requested by local requirements. Study medication should not be given to pregnant women; 
therefore, highly effective method of birth control must be used for women of childbearing 
potential (see exclusion criteria definitions, Section 5.2). 
As per Section 4.6 during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, if participants cannot visit the site for protocol specified safety lab assessments, collection 
can be performed at home by an health care provider or an alternative lab (local) collection site 
may be used. 
Recommendations for female participants taking CFZ533 
In consideration of the participant population and overall CFZ533 benefit-risk profile, women 
of childbearing potential must utilize highly effective contraception methods to avoid becoming 
pregnant while receiving CFZ533 and for 14 weeks after the last dose or until data from the 
reproductive toxicity studies suggest otherwise. Women who are nursing may not participate in 
this trial. The washout period of 14 weeks after the last dose is justified based on predicted PK 
profiles for CFZ533 in this study (rationale on Section 4.2.1, Figure 4-1). 
Recommendations for female and male participants taking MMF (Cellcept) 
MMF is a confirmed teratogen associated with an increased rate of spontaneous abortion and 
congenital malformation compared with other immunosuppressant. Therefore, investigators 
should ensure that female and male participants taking MMF understand the risk of harm to the 
baby, the need for effective contraception, and the need to consult immediately the responsible 


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investigator if there is a possibility of pregnancy or a suspected gap of contraception. For further 
recommendations and detailed information, please refer to the local product label.  
a. Recommendations for female participants 
• Female participants who could become pregnant must use an effective method of 
contraception with CellCept®. This includes before start taking CellCept®, during the 
entire treatment period with CellCept® and for 6 weeks after the last dose of 
CellCept®.  
• Two forms of contraception applied simultaneously are preferable, as this will reduce 
the risk of unintended pregnancy. 
• Female participants should not donate blood during therapy with MMF or for at least 
6 weeks following discontinuation of mycophenolate.  
b. Recommendations for male participants 
• The available evidence does not indicate an increased risk of malformations or 
miscarriage if the father takes mycophenolate. However, risk cannot be completely 
excluded.  
• Sexually active male participants, or the female partner, are recommended to use 
highly effective contraception during therapy with MMF and at least 12 weeks 
following discontinuation of mycophenolate.  
c. Additional precautions 
• Male participants should not donate blood during therapy with mycophenolate mofetil 
or for at least 6 weeks following discontinuation of mycophenolate. Men should not 
donate semen during therapy or for 90 days following discontinuation of 
mycophenolate. 
Assessments of fertility 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child-
bearing potential must also be available as source documentation in the following cases: 
1. Surgical bilateral oophorectomy without a hysterectomy  
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 
In the absence of the above medical documentation, FSH testing is required of any female 
participant regardless of reported reproductive/menopausal status at screening/baseline. 
8.4.4 
Other safety evaluations 
Renal function 
Renal function will be assessed at each visit by measuring serum creatinine and utilized to 
calculate the estimated glomerular filtration rate (eGFR) using the MDRD-4 formula.  
New onset diabetes mellitus  
New onset diabetes mellitus is defined as:  


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All of the following should be true (no diabetes mellitus pre-transplantation): 
• Diabetes was not included in the medical history. 
• Glucose (random) <11.1 mmol/L (200 mg/dL) at the time of transplantation. 
• Diabetes was not recorded as reason for any medication given prior to transplantation. 
• HbA1c <5.7% at the time of transplantation. 
And at least one of the following should be true (diabetes onset after randomization): 
• Two consecutive fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L) at any time after 
Day 29 or a random plasma glucose (RPG) ≥200 mg/dL (11.1 mmol/L). 
• HbA1c ≥6.5% (only from Day 85 forward). 
• Diabetes reported as an AE that is prevalent after Day 29.  
• Any concomitant medication with Anatomical Therapeutic Chemical (ATC) level 2 code 
“A10” (drugs used in diabetes), if prevalent after Day 29.  
Definitions for diabetic related diagnoses are according to the American Diabetes Association 
2013 and [WHO-ADA criteria].  
Hepatic Artery Thrombosis  
Hepatic Artery Thrombosis (HAT) are frequent in this population and will be recorded as 
Adverse Events or Serious Adverse Events as appropriate. The treatments given should be 
recorded on the Concomitant Medications and/or the Surgical and Medical Procedures CRF 
(e.g., re-anastomosis, stent, etc.) as appropriate.  
Malignancies 
For participants on study treatment and in follow-up, any type of malignancy (including skin 
neoplasms, leukemia, post-transplantation proliferative disorder (PTLD)) should be reported as 
a SAE and recorded on the appropriate CRFs. A SAE report should be completed for 
malignancies occurring until the last visit (for participants in follow-up) or for 14 weeks after 
the last dose of study treatment taken, (for participants in the treatment period or who completed 
the treatment period). 
Hepatocellular carcinoma (HCC) recurrence 
Participants transplanted for HCC or with HCC diagnosed at the time of transplantation should 
be monitored for HCC recurrence according to local practice. For example routine laboratory 
monitoring/tests, tumor markers, hepatic ultrasound, computed tomography scans (CAT, CT) 
or Magnetic Resonance Imaging (MRI) (especially Fe-MRI) on regular basis as per local 
practice. Α-fetoprotein will be regularly evaluated at the central laboratory, Table 8-1, Table 8-
2 and Table 8-3. 
All cases of HCC recurrence or de novo HCC, diagnosed post-randomization should be 
recorded on the appropriate CRF. Details of method of diagnosis, location (hepatic and/or 
extrahepatic) of lesions, number/size of lesions, tumoral invasion of major vessels or biliary 
system and any treatment given should be recorded on the CRFs. In addition, a SAE report 
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In the event of HCC recurrence, the slides from the explant liver graft biopsy will be sent to the 
independent central pathologist for evaluation. 
For recurrent and de novo cases of HCC, α-fetoprotein will be monitored as needed. 
Dialysis 
All instances of renal replacement therapy (including hemodialysis, hemodiafiltration, 
hemofiltration and peritoneal dialysis) occurring post transplantation should be recorded on the 
appropriate CRF giving the method used. Reason for dialysis, the start and end dates and the 
total number of sessions should also be recorded.  
Infections 
Infections should be recorded with start and end date, type of infection, and medications used 
on the CRF capturing Adverse Events. If medications are used to treat the infection, the name 
of the medication must be entered on the appropriate CRF. If the participant is hospitalized a 
SAE report must be completed and reported. 
Viral infections (CMV, EBV) 
Quantitative EBV and CMV viral load will be assessed locally if active infection is suspected. 
CMV 
Suspected CMV infections will be recorded as an infection on the CRF capturing Adverse 
Events and on the CMV-specific CRF. 
CMV-infection is identified by assessments of laboratory and/or clinical sign/symptoms: 
• Laboratory-defined CMV (Antigenemia-positive, PCR-positive). 
• CMV syndrome (Fever for the last 2 days, neutropenia, leucopenia, viral syndrome). 
• CMV disease (Organ involvement). 
EBV 
EBV infections will be recorded as an infection on the CRF capturing Adverse Event and on 
the EBV-specific CRF. 
EBV-infection should be identified by assessments of laboratory and/or clinical sign/symptoms 
and these should be entered on the EBV CRF. 
8.4.5 
Appropriateness of safety measurements 
The safety laboratory assessments selected are standard for the liver transplant population. The 
assessment of (serious) adverse events, including infections, graft loss, death, malignancies and 
details of opportunistic viral infections (CMV, EBV) allow proper assessment of safety related 
outcomes and side effects in this population. 


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8.5 
Additional assessments 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, if participants cannot visit the site for protocol specified safety lab assessments, collection 
can be performed at home by an health care provider or an alternative lab (local) collection site 
may be used.
 
 
 
8.5.2 
Pharmacokinetics 
Free CFZ533 plasma concentrations will be measured in all CFZ533-treated participants (Arms 
2 and 3 only). 
All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted 
in a forearm vein (opposite to the site of the IV administration on Day 8 or Day 15). Details of 
sample processing, handling, storage and shipment will be described in a separate laboratory 
manual. All samples will be given a unique sample and collection number. The actual sample 
collection date and time will be entered on the appropriate CRF. 
Free CFZ533 plasma concentrations will be determined using a validated target-based sandwich 
enzyme-linked immunosorbent assay (ELISA) method. The lower limit of quantification 
//24LVȝJP/LQKXPDQSODVPD7KHGDWDDQGGHWDLOVRIWKHDQDO\WLFal methods 
will be provided in a standalone Bioanalytical Data Report. Concentrations below the LLOQ 
will be reported as “zero” and missing data will be labeled as such in the Bioanalytical Data 
Report. 
For standard pharmacokinetic abbreviations and definitions see the list provided at the 
beginning of this protocol. 
The following PK parameters will be determined: Ctrough at steady state and Cmax will be 
directly derived from the bioanalytical data and listings. Additional PK parameters may be 
determined if data permit.  
No other parameters (e.g. clearance, volume of distribution, or half-life) will be derived using 
non-compartmental analysis (NCA). The pharmacokinetics of CFZ533 is non-linear and 
characterized by target-mediated disposition where CD40 binding by CFZ533 is leading to 
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CFZ533 elimination (this includes receptor-mediated endocytosis by the membrane bound 
CD40, and subsequent metabolism of the CFZ533-CD40 complexes). As such, it is expected 
that: 
• The amount of drug-target complex does influence the pharmacokinetics of CFZ533, 
• Tissue metabolism may have a significant impact on the disposition of CFZ533 (the volume 
of distribution will be dependent on clearance), 
• The volume of distribution may not be accurately inferred from plasma concentration alone, 
and the values for the volume of distribution obtained from a NCA may be incorrect, 
• Volume of distribution and clearance parameters (as inferred from NCA analysis) would 
decrease when the dose increases. 
The NCA approach is not appropriate due to violations of the assumptions that the disposition 
of the drug is linear, and that the elimination is from sites that are in rapid equilibrium with 
blood. 
For each PK samples, the actual recorded sampling time will be captured, and the elapsed time 
since the first and since the last dose will be calculated. 
8.5.3 
Pharmacodynamics 
Soluble CD40  
Blood samples collected for free (pre-treatment) or total (post-treatment) soluble CD40 in 
plasma (to inform the biology of the target and target engagement) will be obtained from all 
participants and all arms (Control and CFZ533-treated participants; all samples will be 
analyzed). Assessment is not mandatory at Month 4.5 visit for arm 1 participants on TAC 
treatment. 
All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted 
in a forearm vein (opposite to the site of the IV administration on Day 8 or Day 15). Details of 
sample processing, handling, storage and shipment will be described in a separate laboratory 
manual. All samples will be given a unique sample number (as listed in the blood log 
Appendix 6a). The actual sample collection date and time will be entered on the appropriate 
CRF. The detailed methods and analysis will be described in the Bioanalytical Data Report. 
8.5.4 
Immunogenicity 
The presence of anti-CFZ533 antibodies will be determined in all CFZ533-treated participants 
only, using a validated bridging ELISA-based assay. 
All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted 
in a forearm vein (opposite to the site of the IV administration on Day 8 or Day 15). Details of 
sample processing, handling, storage and shipment will be described in a separate laboratory 
manual. All samples will be given a unique sample number (as listed in the blood log 
Appendix 6a). The detailed methods and analysis will be described in the Bioanalytical Data 
Report. 
The actual sample collection date and time will be entered on the appropriate CRF. 


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9 
Study discontinuation and completion 
9.1 
Discontinuation and completion 
9.1.1 
Study treatment discontinuation and study discontinuation 
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration and can be initiated by either the participant or the 
investigator. Study treatment can be discontinued for different reasons including: 
x Adverse event 
x Lack of efficacy 
x Technical problems 
x Participant/guardian decision 
x Loss to follow-up 
x Death 
x Graft loss 
x Pregnancy 
x Any situation in which study participation might result in a safety risk to the participant 
x Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the participant’s overall status, prevents the participant from continuing 
participation in the study 
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see withdrawn of informed consent Section 9.1.2). Where possible, they should 
return for the assessments indicated in the assessment schedule (Table 8-1 and Table 8-2). 
Participants who discontinue treatment prior to Month 12 should attend all follow up visits 
(Month 6, Month 8, Month 10, Month 12 and Month 18) until Month 24. Participants who 
discontinue after Month 12 but before Month 24 should attend Month 18 and Month 24 follow-
up visits. Participants who discontinue treatment after Month 24 visit will leave the study and 
complete the EOS visit. 
They should remain in the study on local standard of care and return at the subsequent follow-
up scheduled visits to obtain follow-up information. 
Information will be collected on graft loss/re-transplant, rejection episodes, and vital signs, 
hospitalizations, central and/or local laboratory samples (serum creatinine), AEs/SAEs, 
malignancies, opportunistic infections (especially CMV, EBV) and immunosuppressive 
therapy. 
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The dosage administration records for CFZ533, MMF and tacrolimus will be used to record 
when a participant has discontinued study treatment. 
Appropriate CRF for Treatment Completion should also be completed, giving the date and 
primary reason for stopping the study treatment. 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant 
as specified in the lost to follow-up Section 9.1.3. This telephone contact should preferably be 
done according to the study visit schedule (Table 8-1 and Table 8-2). 
Every effort should be made to contact the participant or a knowledgeable informant by 
telephone to determine the information on survival status, graft loss/re-transplant, rejection 
episodes, malignancies, adverse events, opportunistic infections, and immunosuppressive 
therapies. Since participants will be followed even after discontinuation of study medication, 
the appropriate CRF for Study Completion should only be completed at Month 24 or earlier if 
the participant can no longer be followed, e.g., death, loss to follow-up, withdrawal of consent. 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
No study drug will be provided for participants who discontinue the study treatment.  
Pregnancy 
Participants who become pregnant while in the study must be discontinued from the study 
medication and from the study and should attend a visit at the clinical site as soon as possible. 
For participants who are discontinued prior to Month 12, assessments for Month 12 visit should 
be completed.  For participants who are discontinued after Month 12 but before Month 24, 
assessments for Month 24 visit should be completed. For participants who are discontinued 
after Month 24, assessments for EOS will be completed. Please also refer to Section 10.1.4 – 
Pregnancy reporting. 
Graft loss 
Participants who experienced graft loss will be discontinued from study treatment as well as 
from the study and should attend a visit at the clinical site as soon as possible.  For participants 
who are discontinued prior to Month 12, assessments for Month 12 visit should be 
completed.  For participants who are discontinued after Month 12 but before Month 24, 
assessments for Month 24 visit should be completed. For participants who are discontinued 
after Month 24, assessments for EOS will be completed. 
9.1.2 
Withdrawal of informed consent 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant: 
• Does not want to participate in the study anymore, 
and 
• Does not want any further visits or assessments 


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and 
• Does not want any further study related contacts 
In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her consent and 
record this information. 
Where consent to the use of personal and coded data is not required, participant therefore cannot 
withdraw consent. They still retain the right to object to the further use of personal data. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the participant’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation (including any data resulting from the analysis of a 
participant’s samples until the time of withdrawal) according to applicable law. 
For United States: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For EU and Rest of World (RoW): All biological samples not yet analyzed at the time of 
withdrawal will no longer be used, unless permitted by applicable law. They will be stored 
according to applicable legal requirements. 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed or until the time point of his/her planned end of study 
visit has passed. 
9.1.4 
Replacement of early withdrawals or discontinuations 
Participants who are prematurely withdrawn from study medication or from the study will not 
be replaced. These participants will NOT be considered lost to follow-up. 
9.1.5 
Study stopping rules 
Until Month 24,  stopping rules for the incidence of BPAR and serious infections will be applied. 
These rules are designed to ensure that they trigger if there is high probability (>90%) that the 
true BPAR (RAI ≥6, evaluated by central reader) or serious infection rate is greater than 20%. 


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Infections declared as “Life-threatening” by the investigator or with fatal outcome will be 
considered as serious infections for the purpose of this stopping rule. 
Based on this stopping rule and depending on the number of participants randomized to a 
treatment arm at a given point in time, the number of participants that experienced a BPAR or 
a serious infection in this arm that would first trigger the stopping criterion are given in 
Table 12-1. 
In case the stopping rule is reached for a treatment arm, recruitment to that arm will be stopped 
and all available data reviewed. The decision to continue or permanently stop the treatment arm 
or adjust study procedures will be taken based on a thorough evaluation of the available data. 
No stopping rules will be assessed during the long-term extension. 
9.1.6 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination: 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study. 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data.  
• Discontinuation of study drug development. 
• Practical reasons. 
• Regulatory or medical reasons (including slow enrollment). 
In taking the decision to terminate, Novartis will always consider the participant welfare and 
safety. Should early termination be necessary, participants must be seen as soon as possible and 
treated as a prematurely withdrawn participant. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the participant’s interests. The investigator or sponsor depending on the local 
regulation will be responsible for informing the Institutional Review Board/Independent Ethics 
Committee (IRBs/IECs) of the early termination of the trial. 
9.2 
Study completion and post-study treatment 
Information on the participant’s completion or discontinuation of the study and the reason for 
discontinuation of the study will be recorded on the appropriate CRF.  
In any case, the investigator or site staff must contact the IRT as soon as possible to record the 
participant’s study completion (EOS) and/or discontinuation. 
The investigator must provide follow-up medical care for all participants who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. This care may 
include initiating another immunosuppressive treatment outside of the study as deemed 
appropriate by the investigator.  
Initiation of another immunosuppressive treatment will be required for all participants 
randomized to the CFZ533 arms. In case a CFZ533 participant is switched to a TAC-based 
regimen, TAC should be initiated at the lowest daily dose, e.g., 0.5 mg b.i.d.,  4 weeks after last 


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CFZ533 dose. TAC trough levels will be measured 2 weeks after TAC initiation and dosage 
appropriately adjusted to reach and maintain a trough level at approximately 5 ng/mL. 
Subsequently, TAC trough levels will be managed as per local practice and local label. 
For all participants, a safety follow-up will be conducted during 14 weeks from the last CFZ533 
injection or 12 weeks from last TAC dose.  Any serious adverse event occurring during this 
period should be communicated to Novartis to be collected in the safety database, refer to 
Section 10.1.3. 
At the study level, study completion will occur when the last participant finishes the end of 
study visit (EOS) and any repeat assessments associated with this visit have been documented 
and followed-up appropriately by the Investigator or, in the event of an early study termination 
decision, the date of that decision.  End of Study will occur when the last participant completes 
3 years in the long-term extension period or at the time of an early study termination. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign, including abnormal laboratory findings, symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Considering that the screening period may be up to 2 months long, recording of AEs will start 
from Baseline/LTx date onwards. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product. Novartis qualified medical 
personnel will be readily available to advise on trial related medical questions or problems. 
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred. 
The investigator has the responsibility for managing the safety of individual participants and 
identifying adverse events. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms,  
• they are considered clinically significant,  
• they require therapy.  


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Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values, which are considered non-typical in participant with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
participant and identifying adverse events. Alert ranges for laboratory and other test 
abnormalities are included in Appendix 1. 
Adverse events must be recorded under the signs, symptoms or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
• the severity grade. If severity grade is selected, add the following: 
- 
mild: usually transient in nature and generally not interfering with normal activities 
- 
moderate: sufficiently discomforting to interfere with normal activities 
- 
severe: prevents normal activities 
• its relationship to the study treatment and other investigational treatment. If the event is due 
to lack of efficacy or progression of underlying illness (i.e., progression of the study 
indication) the assessment of causality will usually be ‘Not suspected.’ The rationale for 
this guidance is that the symptoms of a lack of efficacy or progression of underlying illness 
are not caused by the trial drug, they happen in spite of its administration and/or both lack 
of efficacy and progression of underlying disease can only be evaluated meaningfully by an 
analysis of cohorts, not on a single participant. 
• its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported 
• whether it constitutes a serious adverse event (SAE – See Section 10.1.2 for definition of 
SAE) and which seriousness criteria have been met 
• action taken regarding with study treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:  
• no action taken (e.g., further observation only) 
• study treatment interrupted/withdrawn 
• concomitant medication or non-drug therapy given  
• non-drug therapy given  
• participant hospitalized/participant’s hospitalization prolonged (see Section 10.1.2 for 
definition of SAE) 
• its outcome - not recovered/not resolved; recovered/resolved; recovered/resolved with 
sequelae; fatal; or unknown 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 


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Adverse event monitoring should be continued until EOS visit. After EOS, only the SAEs will 
be reported to the Novartis safety database for a period of 14 weeks from the last CFZ533 
injection. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the study drug, the interventions required to treat it, and the outcome. 
Information about adverse drug reactions already known about the investigational drug can be 
found in the Investigator’s Brochure (IB). This information will be included in the participant 
informed consent and should be discussed with the participant during the study as needed. Any 
new information regarding the safety profile of the medicinal product that is identified between 
IB updates will be communicated as appropriate, for example, via an Investigator Notification 
or an Aggregate Safety Finding. New information might require an update to the informed 
consent and has then to be discussed with the participant. 
The investigator must also instruct each participant to report any new adverse event (beyond 
the protocol observation period) that the participant, or the participant’s personal physician, 
believes might reasonably be related to study treatment. This information must be recorded in 
the investigator’s source documents; however, if the AE meets the criteria of an SAE, it must 
be reported to Novartis. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. Alert ranges for some key laboratory parameters and other test 
abnormalities are included in Appendix 1. 
10.1.2 
Serious adverse events 
A SAE is defined as any adverse event (appearance of, or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires in-patient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• initial hospitalization for the transplant procedure 


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• 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 (e.g., 
liver allograft biopsy, hospitalization for rejection treatment, revision of an incisional 
hernia, etc..) 
• 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 participant’s 
general condition 
• liver biopsy for a suspected rejection 
• treatment for acute rejection, unless the rejection is unusually severe or unusual in 
nature 
• is medically significant, e.g., defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to [Annex IV, ICH-E2D Guideline]). 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse (please refer to [ICH-E2D 
Guideline]). 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.  
All report of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure participant’s safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 14 weeks following the last administration of study 
treatment (CFZ533 participants, Arms 2 & 3) and until 12 weeks for TAC participants (Arm 1) 
must be reported to Novartis safety within 24 hours of learning of its occurrence. Detailed 


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instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. 
Any SAEs experienced after this period should only be reported to Novartis safety if the 
investigator suspects a causal relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up information to the original 
episode within 24 hours of the investigator receiving the follow-up information. A SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one must be reported separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment a CMO & PS associate may 
urgently require further information from the investigator for health authority reporting. 
Novartis may need to issue an Investigator Notification (IN) to inform all investigators involved 
in any study with the same study treatment that this SAE has been reported.  
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Note: SAEs must be reported to Novartis within 24 hours of the investigator learning of its 
occurrence/receiving follow-up information. 
10.1.4 
Pregnancy reporting 
Pregnancies 
All pre-menopausal women who are not surgically sterile will have a serum β-hCG test (serum 
pregnancy test) performed at the screening/baseline/randomization/Month 24  visits, and 
monthly local urine pregnancy tests as indicated in Table 8-1, Table 8-2 and Table 8-3. A 
positive urine pregnancy test requires immediate interruption of study drug until serum β-hCG 
is performed and found to be negative. Additional pregnancy testing might be performed if 
requested by local requirements. If pregnancy is confirmed the trial participant must be asked 
to read and sign pregnancy consent form to allow the study doctor ask about her pregnancy. 
To ensure participant’s safety, each pregnancy occurring after signing the informed consent 
must be reported to Novartis within 24 hours of learning of its occurrence by the investigator 
to the Novartis Chief Medical Office and Patient Safety (CMO&PS). Pregnancy follow-up 
should be recorded on the same form and should include an assessment of the possible 
relationship to the study treatment any pregnancy outcome. Any SAE experienced during 
pregnancy must be reported. Information will be collected at three time points after the 
estimated date of delivery and for a period of 12 months. 
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the female partner. 


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10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (European Medicines Agency (EMA) definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with a SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE CRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with a 
SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not associated 
with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
There has been no safety signal for liver toxicity with CFZ533 to date in all participants and 
healthy volunteers exposed, and from a mechanism of action standpoint there is no known effect 
on the liver (refer to the actual Investigator Brochure). Standard liver function tests will be 
obtained at regular intervals, but special measures for liver safety monitoring are not planned. 
For further information on standard liver function tests, see Appendix 1. 
10.2.2 
Renal safety monitoring 
The available data does not suggest a risk of renal injury with CFZ533. Kidney function is an 
important component in the liver transplantation indication and participant’s population. The 
nephrotoxic effects of CNIs such as TAC are directly associated with irreversible renal function 
deterioration. 
Early identification, monitoring and evaluation of renal events are part of the study purpose and 
objectives. Protocol assessments were selected to ensure participant’s safety, minimize 
potential TAC related nephrotoxicity side effects, and determine the potential of CFZ533 to 
minimize or eliminate these nephrotoxicity effects in the setting of a CNI-free regimen. 


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10.2.3 
Data Monitoring Committee 
This study will include a DMC which will function independently of all other individuals 
associated with the conduct of this clinical trial, including the site investigators participating in 
the study. The DMC will assess at defined intervals the progress of a clinical trial, safety data, 
and critical efficacy variables and recommend to the sponsor whether to continue, modify, or 
terminate a trial. 
An independent DMC will be established to monitor the safety of the treatment regimens. The 
DMC will be an independent board comprised of a group of physicians with experience in liver 
transplantation and an independent statistician. A physician is not allowed to participate in this 
clinical trial while serving on the DMC. 
The timing of the first data cutoff for DMC reviews is approximately 6 months after First Patient 
First Visit (FPFV) provided at least five participants/arm have been randomized at that time. 
All visits occurring up to and including this cut-off date for all participants will be included in 
the DMC analysis. The DMC will then meet approximately every 6 months and the cut-off date 
used for each DMC analysis shall be the last cut-off date used plus 6 months. 
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC. 
The DMC charter outlines the organization and function of the DMC, describes the selected 
efficacy and safety variables that will be reviewed at each meeting, and provides guidelines for 
stopping rules. The results of the analyses will be delivered to the DMC by an independent 
statistician. The members will be primarily responsible for the clinical interpretation of the 
results. The members will be also responsible for advising Novartis as to whether or not any 
changes need to be made to the conduct of the study. The Trial Statistician and Clinical Medical 
Experts will be available for consultation. The members will report to the DMC chair who will 
inform Novartis whether or not there is a safety concern after reviewing all the information 
received. 
Decisions based on the recommendations of the DMC will take into account the potential risks 
and benefits associated with continuing the enrolment of participants in the study, continuing 
the participants on the study drug and/or the study. Such information and recommendations will 
be used in the best interest of the participants enrolled in the trial. The final decision with respect 
to any modification of the protocol will be made by Novartis. In case of termination of the study, 
all health authorities and investigators will be notified within one working day. Study 
termination would take place in accordance with Novartis Standard Operating Procedures 
(SOPs). 
10.2.4 
Steering Committee 
The steering committee has been established comprising investigators participating in the trial, 
not being members of the DMC, and Novartis/sponsor representatives from the Clinical Trial 
Team. 
The steering committee will ensure transparent management of the study according to the 
protocol through recommending and approving modifications as circumstances require. The 


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steering committee will review initial protocol and protocol amendments as appropriate. 
Together with the clinical trial team, the steering committee will also develop recommendations 
for publications of study results including authorship rules. 
11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the CRFs. The 
CRFs have been built using fully validated secure web-enabled software that conforms to 21 
CFR Part 11 requirements, Investigator site staff will not be given access to the Electronic Data 
Capture (EDC) system until they have been trained. Automatic validation programs check for 
data discrepancies in the CRFs, allow modification and/or verification of the entered data by 
the investigator staff. 
The investigator/designee is responsible for assuring that the data entered into the CRF are 
complete, accurate, and that entry and updates are performed in a timely manner. The 
Investigator must certify that the data entered are complete and accurate. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
11.2 
Database management and quality control 
Novartis personnel (or designated Clinical Research Organization (CRO)) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 
site staff are required to respond promptly to queries and to make any necessary changes to the 
data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Medical history/current medical conditions and adverse events 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. 
Laboratory samples will processed centrally and the results will be sent electronically to 
Novartis. 
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes data about all study treatment (s) dispensed to the participant and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines.Once all the necessary 
actions have been completed and the database has been declared to be complete and accurate, 
it will be locked. Any changes to the database after that time can only be made after written 
agreement by Novartis development management. 


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11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements with the investigators and 
their staff. During the study, Novartis employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. The field monitor will visit the site to 
check the completeness of participant records, the accuracy of data capture / data entry, the 
adherence to the protocol and to Good Clinical Practice, the progress of enrollment, and to 
ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis Clinical Research Associate (CRA) organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant’s file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
The primary analysis will be performed after all participants have completed the Month 12 visit 
(or prematurely discontinued study before Month 12). Another analysis will be performed after 
all participants have completed the Month 24 visit. A final analysis will be performed at the end 
of the extension. 
12.1 
Analysis sets 
The screened set (SCR) consists of all participants who signed the informed consent. 
The full analysis set (FAS) will include all participants who are transplanted and randomized, 
excluding mis-randomized participants. Mis-randomized participants are defined as cases 
where IRT contacts were made by the Investigator/qualified site staff either prematurely or 
inappropriately for confirmation of subject’s final randomization eligibility and treatment was 


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not administered to the participant. Following the intention-to-treat (ITT) principle, participants 
will be analyzed according to their treatment assignment at randomization. 
The safety set (SAF) consists of all participants who received at least one dose of study drug 
(i.e., at least one dose of TAC after randomization in the control arm and at least one dose of 
CFZ533 in the CFZ533 arms). Participants will be analyzed according to the treatment they 
actually received. 
All safety analyses will be performed on the SAF. The safety will be presented separately for 
the treatment and follow-up periods. 
The PK analysis set will include all participants with at least one available valid (i.e., not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact on PK data. 
12.2 
Participant demographics and other baseline characteristics 
Data for background and demographic variables, including disease characteristics, will be 
summarized by treatment arm based on the FAS. Continuous variables will be presented with 
mean, median, 25th percentile, 75th percentile, 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 a category labelled “missing” when 
appropriate). 
Relevant medical histories and current medical conditions at baseline will be summarized by 
treatment arm, system organ class and preferred term. 
12.3 
Treatments 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
The duration (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; for CFZ533, the dosing interval will be added (i.e., 14 days for treatment 
administered every 2 weeks). In calculating the duration of treatment, days of temporary 
interruption of study medication for any reason will be included. Further, the frequency of dose 
changes (including dose interruption) will be presented by reason for 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 participants who prematurely discontinue study medication will 
be summarized by reason for discontinuation. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the ATC classification system, by 
treatment arm. 
The average daily dose of CFZ533, MMF, TAC and CS will be summarized by treatment arm.   


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12.4 
Analysis of the primary endpoint 
The primary objective is to evaluate the rate of composite efficacy failure (BPAR, graft loss or 
death) with CFZ533 600 mg and 300 mg compared to TAC Control at Month 12 post-
transplantation. Analysis will be on the FAS. 
In addition the number of BPAR is used to evaluate the stopping rules during the conduct of the 
study given in Section 9.1.5. 
12.4.1 
Definition of primary endpoint 
The primary efficacy endpoint is occurrence of composite efficacy failure (BPAR, graft loss, or 
death) at 12 months post-transplantation based on central pathologist evaluation. If the central 
pathologist’s evaluation is not available, the local pathologist’s reading will be used. The 
estimand is: 
1. Population: full analysis set 
2. Endpoint: composite efficacy failure at 12 months 
3. Intercurrent events: regardless of treatment or study discontinuation, loss to follow-up, or 
ascites-based dosing adjustment 
4. Summary measure: the difference in the proportion of participants with composite 
efficacy failure in a CFZ533 arm compared to control 
Note that ascites-based dosing adjustment is not considered a rescue medication because the 
occurrence of ascites is not due to lack of efficacy. Accordingly, administering CFZ533 to 
compensate for drug loss caused by ascites cannot be considered rescue medication. In addition, 
this unscheduled administration will not result in exposure higher than that seen in participants 
with no ascites. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The efficacy analysis at Month 12 evaluates whether at least one of the two CFZ533 treatment 
arms meets the pre-defined success criterion. 
The number of participants with composite efficacy failure is assumed to follow a binomial 
distribution, i.e.,𝑟𝑟i ∼Binomial(𝑛𝑛𝑖𝑖, 𝜃𝜃𝑖𝑖), where 𝑟𝑟𝑖𝑖 is the number of participants with composite 
efficacy failure in treatment group i, 𝑛𝑛𝑖𝑖 is the number of participants in treatment group 𝑖𝑖 and 
𝜃𝜃𝑖𝑖 is the probability of composite efficacy failure.   
A CFZ533 arm is considered successful if the composite efficacy failure rate difference between 
this CFZ533 arm and the control arm is less than 15% with probability >80%: 
𝑃𝑃(𝜃𝜃CFZ533 −𝜃𝜃control < 0.15|data) > 0.8. 
The required posterior probabilities will be estimated from simulations of the posterior 
distributions of 𝜃𝜃CFZ533 −𝜃𝜃control and compared to the threshold for level of proof. The prior 
distributions will be assumed to be non-informative. The posterior mean composite efficacy 
failure rates for each treatment arm and for the difference in mean response rates between 
CFZ533 treatment arms and control will be presented together with 95% credible intervals. 


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The posterior probability of the primary decisions rule will be derived and in addition posterior 
probabilities of the composite efficacy failure rates for each treatment arm and the treatment 
difference being above various thresholds such as 10%, 15%, and 20% will also be presented. 
12.4.3 
Handling of missing values not related to intercurrent event 
The primary analysis is based on the FAS, i.e., all observations whether on- or off-treatment. 
Since participants continue to be followed after early study drug discontinuation, the number of 
missing values is expected to be limited. Any participant who is lost to follow-up or does not 
attend the Month 12 visit after treatment discontinuation will be counted as failure. A lost-to-
follow-up participant is one who did not experience BPAR, graft loss, or death and whose last 
day of contact is prior to the day of the lower limit of the (Month 12) visit window. 
12.4.4 
Supportive analyses 
As a supportive analysis, a Poisson distribution rather than binomial will be applied for the 
number of subjects with composite failures. Specifically, the number of composite efficacy 
failure events in group 𝑖𝑖 will be assumed to follow a Poisson distribution , i.e., 
𝑦𝑦𝑖𝑖 ~ Poisson (𝜇𝜇𝑖𝑖), where 𝜇𝜇𝑖𝑖 is the expected number of events in group 𝑖𝑖, with 𝜇𝜇𝑖𝑖= 𝜆𝜆𝑖𝑖,𝑇𝑇∗𝑡𝑡𝑖𝑖,𝑇𝑇, 
𝑡𝑡𝑖𝑖,𝑇𝑇 being the total follow up time in group 𝑖𝑖 in years, thus incomplete follow up of subjects due 
to early discontinuation is adjusted for. The follow up time will be calculated as [Treatment 
start date – min (lower limit of the Month 12 visit window, lost-to-follow-up date)].  
For the purposes of analysis, time of discontinuation of study drug will be determined by date 
of last study drug administration as follows: 
• Arm 1: earliest date of discontinuation of study drug (TAC or MMF) 
• Arms 2 and 3: CFZ533 study drug discontinuation date + 14 days to account for the 
dosing interval 
If a subject discontinues before randomization, the rules of Arm 1 apply. 
The exposure-adjusted treatment difference in composite efficacy failure rates between a 
CFZ533 arm and control at Month 12 will then be evaluated as for the primary endpoint. 
In addition, Kaplan-Meier estimates of time to composite efficacy failure and BPAR censored 
at Month 12 will be respectively constructed and presented graphically. In this analysis, subjects 
who have not experienced composite efficacy failure, are lost to follow-up, or do not attend the 
Month 12 visit after treatment discontinuation will be censored with the censoring time defined 
by the last contact day. 
Impact of COVID-19 or any other pandemic on the primary endpoint will be assessed. Details 
will be presented in SAP. 
12.5 
Analysis of secondary endpoints 
12.5.1 
Efficacy endpoint(s) 
Secondary efficacy endpoints include: 
1. Composite of BPAR, graft loss, death 
2. Composite of BPAR, graft loss, death, lost to follow-up 


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3. Treated BPAR (tBPAR) 
4. Acute rejection (AR) 
5. Treated AR 
6. Antibody-mediated rejection (AMR) 
7. Steroid resistant, steroid treated, and antibody treated AR 
8. Steroid resistant, steroid treated, and antibody treated BPAR 
9. Graft loss 
10. Death 
11. Graft loss and death 
Simple event rates (proportions of events) will be presented. In addition, the event rates will be 
estimated with Kaplan-Meier estimates.  Greenwood’s formula will be used to estimate the 
variance and to derive 2-sided 95% Z-test based confidence intervals for the difference between 
a CFZ533 and control arm. 
The confidence interval will be constructed as: 
 
where   
𝑟𝑟𝑇𝑇𝑖𝑖= Kaplan-Meier estimate of the failure rate for CFZ533 arm up to 12 months, 𝑖𝑖=
1, 2, 
𝑟𝑟𝐶𝐶= Kaplan-Meier estimate of the failure rate for the control arm up to 12 months, 
SE𝑑𝑑𝑖𝑖= ටSE𝑇𝑇𝑖𝑖
2 + SE𝐶𝐶
2, 𝑖𝑖= 1, 2, 
SE𝑇𝑇𝑖𝑖=  Estimated standard error for CFZ533 arm based on Greenwood’s formula, 𝑖𝑖=
1, 2, 
SE𝐶𝐶= Estimated standard error for the control arm based on Greenwood’s formula, and 
𝛼𝛼= 0.05. 
12.5.2 
Safety endpoints 
12.5.2.1 Renal function 
The key secondary objective is to evaluate renal function (eGFR) at Month 12. GFR will be 
estimated using the MDRD formula described in Section 16.4.  
Central laboratory serum creatinine values will be used for all renal function data analysis. If 
the central lab value is missing, then the local creatinine value will be used, if available. 
The estimand is:  
1. population: Full analysis set (FAS) 
2. endpoint: change from randomization in eGFR at 12 months post-transplant 
3. intercurrent events: regardless of missing assessments, discontinuation of study 
treatment, graft loss, or loss-to-follow-up 


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4. summary measure: the difference in mean eGFR on CFZ533 at 12 months 
post-transplant as compared to control 
The mean change for each arm will be obtained through covariate-adjusted treatment effects 
using MMRM. The model will contain treatment arm, visit, treatment arm*visit, and 
randomization GFR with unstructured covariance matrix. The estimand will be evaluated in the 
FAS population by comparing the difference in mean change between each CFZ533 arm and 
control. 
Renal function at Month 24 measured by eGFR will also be evaluated following the same 
analyses strategy. 
Hypothesis testing 
The objective is to demonstrate that either CFZ533 treatment arm is superior to the control arm 
with respect to mean change in eGFR at 12 months post-transplant. 
The null hypothesis: the mean change from randomization in eGFR for a CFZ533 treatment 
arm is not superior to that in the control arm. 
The alternative hypothesis: the mean change from randomization in eGFR for a CFZ533 
treatment arm is superior to that in the control arm. 
The null hypothesis will be tested at a significance level of 10% against a one-sided alternative 
hypothesis, and the test statistic will be the estimated difference in Month 12 least squares 
means from the mixed effects model to allow for adjustment for correlations between time 
points within participants. 
Handling of missing values/censoring/discontinuations 
The primary analysis is based on the FAS, i.e., all observations whether on- or off-treatment. 
Since participants continue to be followed after early study drug discontinuation, the number of 
missing values is expected to be limited. 
1. 
For participants with graft loss or death, a value of 0 will be imputed after the time of 
graft loss. 
2. 
Participants who are lost to follow-up with a functioning graft, or have missing 
assessments will have missing values assessed via MMRM. 
Supportive analyses  
The analysis of eGFR (MDRD-4) will be repeated with assessments occurring after 
discontinuation of study medication counting as missing in the MMRM model (an 
“on-treatment” analysis). 
12.5.2.2 General safety 
For all other safety analyses, the safety set will be used. Adverse events (AEs) will be presented 
and summarized for all treatment-emergent events, with a start date after randomization, 
whether on- or off-treatment. In addition, a separate summary for death including on treatment 
and post treatment deaths will be provided. General safety summaries (tables, figures) will 


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include only data from the on-treatment period with the exception of baseline data which will 
also be summarized where appropriate (e.g. change from baseline summaries). 
For CFZ533, the on-treatment period lasts from the date of first administration of study 
treatment to 14 days after the date of the last actual administration. For TAC, it lasts to the day 
of the last actual administration. 
Adverse events 
All information obtained on adverse events will be displayed by treatment group. 
The number and percentage of participants with treatment emergent adverse events and serious 
adverse events (events started after the first dose of study medication or events present prior to 
start of treatment but increased in severity based on preferred term) will be summarized in the 
following ways: 
• by treatment, primary system organ class and preferred term. 
• by treatment, primary system organ class, preferred term and maximum severity by 
treatment, Standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation and adverse events 
leading to dose adjustment. 
In addition, the proportion of participants with infections will be summarized as follows: 
1. 
Infections by type of infection (viral, fungal, bacterial, others) and microorganism of 
infection 
2. 
Serious infections by type of infection (viral, fungal, bacterial, others) and 
microorganism of infection 
The incidence rate of infection by type and micro-organism will be tabulated for each treatment 
arm. The key safety parameter is serious infections. The number of serious infections will be 
used to evaluate the stopping rule as outlined in Section 9.1.5. 
AEs and infections data will be analyzed as a whole under the heading of AEs for each 
treatment arm. If a participant has multiple occurrences of an AE, the participant will only be 
counted once in the corresponding AE category. If participant has multiple AEs within a SOC, 
the participant will be counted only once for that SOC. If a participant has multiple severity 
ratings for an AE, the participant will be counted under the maximum rating. 
New onset of diabetes mellitus (NODM) 
The new onset diabetes mellitus is defined in Section 8.4.4 
If any of the criteria for diabetes prior transplantation is unknown (e.g., lab values) and all other 
criteria are true, the subject will be considered to have no diabetes pre-transplant. 
The proportion of participants developing new onset diabetes mellitus after transplantation 
(NODM) will be summarized by treatment arm. The probabilities of developing NODM will 
be compared between treatment arms at Month 12 and at Month 24 post-transplantation using 
logistic regression models with treatment arm and HbA1c levels at randomization as 
explanatory variables.  Death, graft loss, or loss to follow up without NODM before Month 12 


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(or 24) will not be counted as developing NODM. This analysis will be performed using 
participants in the FAS population who do not have diabetes mellitus at randomization.  
Vital signs 
Summary statistics will be provided by treatment and visit/time. 
12-lead ECG  
All ECG data will be listed by treatment arm, participant and visit/time. Summary statistics will 
be provided by treatment and visit/time. 
Clinical laboratory evaluations 
Summary statistics (mean, standard deviation, minimum, median, maximum) of quantitative 
lab variables, including change from randomization, will be provided by parameter, treatment, 
and visit.   
Renal function will be plotted over time.  
12.5.2.3 Other safety evaluations  
Immunogenicity  
Blood samples for immunogenicity testing will be collected from all CFZ533-treated 
participants only, at selected time points, as defined in the assessment schedule (Table 8-1, 
Table 8-2 and Table 8-3). The presence of anti-CFZ533 antibodies will be assessed using 
screening and confirmatory assays. An integrated PK/PD and immunogenicity approach, 
focusing on the clinical and functional consequences of ADA will be applied. The consequences 
of an immune response to CFZ533 may be correlated with a loss of exposure (free CFZ533 
measures), a loss of target engagement (sCD40 measures), and/or the appearance of immune 
related adverse events. 
All immunogenicity results will be listed by treatment arm, participant, and visit/time point. No 
summary statistics will be provided. 
12.5.3 
Pharmacokinetics 
CFZ533 plasma concentration data will be listed by treatment, participant, and visit/sampling 
time point. Descriptive summary statistics will be provided by treatment and visit/sampling 
time point, including the frequency (n, %) of concentrations below the LLOQ.  
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. 
Summary statistics and graphical analysis (e.g. Box-plot) will be provided to compare steady-
state PK before and after introduction of PFS in the study. 


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If data permit, PK parameters will be calculated as described in Section 8.5.1 and will be listed 
by treatment and participant. Descriptive summary statistics will include mean (arithmetic and 
geometric), SD, and CV (arithmetic and geometric), median, minimum and maximum. 
 
 
12.5.4 
PK/PD relationships 
The relationship between PK (CFZ533 concentration) and PD (total soluble CD40; target 
engagement) will be explored graphically. Modeling of PK/PD (e.g., BPAR or eGFR) data 
using a population approach may be performed if appropriate, and reported in a standalone 
report. 
 
 


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12.7
Sample size calculation
The sample size justification considers the probability of success of the study based on the 
success criterion for the planned sample size. The success criterion for one CFZ533 treatment 
arm (see Section 12.4.2) is reached if
ܲ(ߠCFZ533 െߠcontrol < 0.15|data) > 0.8,
where ߠis the composite efficacy failure rates, and the prior is Beta(1/3, 1/3).  
Table 12-2 and Figure 12-2 show the probability of success of the study for a sample size of 48 
participants in the CFZ533 arm and 32 participants in the control arm for a range of underlying 
event rates for composite efficacy failure and serious infections in the CFZ533 treatment arm 
and in the control arm.   A control rate of 10% at Month 12 is expected based on (Levitsky et 
al 2016), which examined a large registry of deceased donor liver transplant participants from 
Scientific Registry of Transplant Recipients (SRTR) and internal Novartis studies (RAD001 
Study H2304 and AEB071 Study B2203). 
Table 12-2 
Probability of success under different event rates for 48 participants 
of CFZ533 arm and 32 participants of control arm
ߠେ୊୞ହଷଷ
ߠୡ୭୬୲୰୭୪
Probability of success
0.07
0.070
0.971
0.07
0.103
0.986
0.07
0.135
0.993
PPD


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0.07 
0.168 
0.997 
0.07 
0.200 
0.999 
0.11 
0.070 
0.833 
0.11 
0.103 
0.904 
0.11 
0.135 
0.947 
0.11 
0.168 
0.973 
0.11 
0.200 
0.987 
0.15 
0.070 
0.594 
0.15 
0.103 
0.729 
0.15 
0.135 
0.830 
0.15 
0.168 
0.900 
0.15 
0.200 
0.944 
Figure 12-2 
Probability of success under different event rates for 48 participants 
of CFZ533 arm and 32 participants of control arm 
 
Power for key secondary variable 
The primary analysis of renal function is based on the FAS. Participants continue to be followed 
after study drug discontinuation and participants with graft loss or death will have their Month 
12 values imputed as described in Section 12.5.2.1. For treatment comparisons, there will be a 
randomized sample of 48 and 32 participants in the CFZ533 and control arms respectively after 
12 months.  Assuming a common standard deviation of 16 mL/min and one-sided α=0.10, there 
is 63, 73, or 81% power to detection a difference of 6, 7, or 8 mL/min/1.73m2 respectively.  If 
the standard deviation is 20, there is 51, 59, or 67% power respectively. 


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13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the [ICH Harmonized Tripartite Guidelines for Good Clinical Practice], with applicable 
local regulations (including [European Directive 2001/20/EC, US CFR 21]), and with the 
ethical principles laid down in the [Declaration of Helsinki]. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g., Clinicaltrials.gov, EudraCT 
etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 


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14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
References are available upon request. 
American Diabetes Association. Standards of medical care in diabetes (2013) Diabetes Care 
2013; 36: Suppl 1:S11. 
Arias M, Serón D., Herrero I. et al (2017) Subclinical Antibody-Mediated Rejection. 
Transplantation 101; S1–S18. 
Benitez C., Londono MC., Miquel R. et al. 2013. Prospective multicenter clinical trial of 
immunosuppressive drug withdrawal in stable adult liver transplant recipients. 
Banff Working Group on Liver Allograft Pathology (2012) Importance of Liver Biopsy 
Findings in Immunosuppression Management: Biopsy Monitoring and Working Criteria for 
Patients With Operational Tolerance. Liver transplantation 18;1154-70. 
Calne RY (2000) Immunological tolerance - the liver effect. Immunol. Rev. 174:280. 
Cellcept® (mycophenolate; mmf: Syntex) Liver transplant study MYCS-2646. NDA No. 50-
722/S005; approval date July 28, 2000; FDA statistical reviews. 
CHMP (1998) Committee for human medicinal products, European Agency for the 
Evaluation of Medicinal Products. Points to consider on clinical investigation of medicinal 
products used in the treatment of osteoarthritis. London, UK. 
Cirera I., Navasa M., Rimola A., Garcia-Pagan J.-C., Grande L., Garcia-Valdecasas J.-
C.,Fuster J., Bosch J., and Rodes J (2000) Ascites After Liver Transplantation. Liver 
Transplantation,Vol 6, No 2 (March), 157-162. 
Clavien PA, Muller X, de Oliveira ML, Dutkowski P, Sanchez-Fueyo A (2017) Can 
immunosuppression be stopped after liver transplantation? Lancet Gastroenterol. Hepatol. 
2:531. 
Cordoba F, Wieczorek G, Audet M, et al (2015) A novel, blocking Fc-silent anti-CD40 
monoclonal antibody prolongs non-human primate renal allograft survival in the absence of B 
cell depletion. Am. J. Transplant. 15 (11); 2825-36. 
Demetris AJ, Batts KP, Dhillon AP, et al (1997) Banff schema for grading liver allograft 
rejection: an international consensus document. Hepatology; 25(3):658-63. 
Demetris AJ, Ruppert K, Dvorchik I, et al (2002) Real-time monitoring of acute liver allograft 
rejection using Banff schema. Transplantation 74 (9), 1290-96 
Demetris AJ. et al. (2000) Update of the International Banff Schema for Liver Allograft 
Rejection: Working Recommendations for the Histopathologic Staging and Reporting of 
Chronic Rejection. Hepatology; 31(3): 792-9. 
Demetris AJ., Bellamy C., Hübscher SG, et al (2016) 2016 Comprehensive Update of the 
Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated 
Rejection. Am J Transplantation; 16: 2816–35.Doyle HR, Marino IR, Morelli F, Doria C, 
Aldrighetti L, McMichael J, et al (1996) Assessing risk in liver transplantation. Special 
reference to the significance of a positive cytotoxic crossmatch. Ann. Surg. 224:168. 


Novartis 
Confidential 
Page 125 of 136 
Amended Clinical Trial Protocol (Version No. 04 clean) 
Protocol No. CCFZ533A2202 
 
Ekong UD., Melin-Aldana H., Seshadri R. et al. (2008) Graft Histology Characteristics in 
Long-Term Survivors of Pediatric Liver Transplantation. Liver transplantation 14:1582-87. 
Farkash E., Naik A, Tedesco-Silva H et al (2019)Cni-free Therapy With Iscalimab (anti-cd40 
Mab) Preserves Allograft Histology Compared To Standard Of Care After Kidney 
Transplantation. ATC [abstract]. 
Feng S, Ekong UD, Lobritto SJ et al. (2012) Complete Immunosuppression Withdrawal and 
Subsequent Allograft Function Among Pediatric Recipients of Parental Living Donor Liver 
Transplants. JAMA: 307(3) 
Feng S, Bucuvalas J (2017) Tolerance After Liver Transplantation: Where Are We? Liver 
Transplantation 23 1601–14. 
Feng S., Bucuvalas JC., Demetris AJ. et al. (2018) Evidence of Chronic Allograft Injury in 
Liver Biopsies From Long-term Pediatric Recipients of Liver Transplants. Gastroenterology 
155:1838–51. 
Flechner SM, Kobashigawa J, Klintmalm G.(2008) Calcineurin inhibitor-sparing regimens in 
solid organ transplantation: focus on improving renal function and nephrotoxicity. Clin 
Transplant. 22(1):1-15. 
Garcia-Carro C., Dörje C., Åsberg A. et al (2018) Kidney allograft subclinical rejection 
modulates systemic inflammation measured by C-reactive protein at 1 year after 
transplantation. Clin Transplant. 32:e13196. 
Gonzalez RS, Washington K (2016) Non-Neoplastic Liver Pathology. Liver Transplatation 14 
211-31 
Harland R, Klintmalm G, Yang H et al (2015) ASKP1240 in de novo kidney transplant 
recipients. Am J Transplant; 15 (suppl 3): abstract 3012. 
Farber L and Farber JL.(2017) Pathology of Liver Transplantation, C.Doria, Contemporary 
Liver Transplantation, Organ and Tissue, Philadelphia, Springer International Publishing 
Switzerland, ch.21 355-80. 
ICH E2D (2004) Clinical Safety Data Management: Definitions and Standards for expedited 
reporting. Accessed from: 
ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002807.p
df (Accessed on: 02-Dec-2016). 
Kim WR, Lake JR, Smith JM et al (2018) OPTN/SRTR 2016 Annual Data Report: Liver 
ASTS 1-82 
Klintmalm GB, Feng S, Lake JR et al (2014) Belatacept-based immunosuppression in de novo 
liver transplant recipients: 1 –year experience from a phase II randomized study. Am J 
Transplant; Aug 14(8): 1817-27. 
Levey AS, Coresh J, Greene T, et al (2006) Using standardized serum creatinine values in the 
modification of diet in renal disease study equation for estimating glomerular filtration rate. 
Ann Intern Med; 145:247-54. 


Novartis 
Confidential 
Page 126 of 136 
Amended Clinical Trial Protocol (Version No. 04 clean) 
Protocol No. CCFZ533A2202 
 
Levitsky J, Goldberg D, Smith AR and al (2017). Acute Rejection Increases Risk of Graft 
Failure and Death in Recent Liver Transplant Recipients; Clinical Gastroenterology and 
Hepatology 15: 584-93. 
LondonoM, Souza LN, Lozano J et al (2018) Molecular profiling of subclinical inflammatory 
lesions in long-term surviving adult liver transplant recipients; J. Hepatol 69, 626–34. 
Loupy A, Haas M, Solez K et al (2017), The Banff 2015 Kidney Meeting Report: Current 
Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology; Am 
J Transplantation; 17: 28–41 
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. 
Mastoridis S, Martinez-Llordella M, Sanchez-Fueyo A (2017) Immunotolerance in liver 
transplantation, Semin. Liver Dis. 37:95. 
Mells G, Neuberger J (2008) Protocol Liver Allograft Biopsies; Transplantation 85: 1686–92. 
Menon MC., Murphy B., Heeger P.S. (2017) Moving Biomarkers toward Clinical 
Implementation in Kidney Transplantation. J Am Soc Nephrol 28: 735–747. 
Muller V., Brummer D., Kissler H. et al. (2004) Effects of Portal Vein Arterialization on 
Regeneration and Morphology in Liver Transplantation: Investigations Using the Rat Model; 
Transplantation 78: 1159–65. 
Nashan B, Tedesco H, Van den Hoogen M. et al. (2018) CFZ533, A new anti-CD40 mAB 
demonstrates comparable efficacy and better renal function versus tacrolimus in de novo CNI-
free kidney transplantation. [abstract]. 
Olausson M, Mjornstedt L, Norden G, Rydberg L,  Molne J, Backman L, et al (2007) 
Successful combined partial auxiliary liver and kidney transplantation in highly sensitized 
cross-match positive recipients. Am J. Transplant. Jan; 7(1):130-6. 
Ormonde D.G., Bastiaan de Boer W., Kierath A. et al. (1999) Banff Schema for Grading 
Liver Allograft Rejection: Utility in Clinical Practice; Liver Transpl Surg, Vol 5, No 4: 261-
268. 
Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, 
Ammatuna M, Morabito A, Gennari L (1996 Mar 14) Liver transplantation for the treatment 
of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med.; 334(11):693-9. 
Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, Arndorfer J, Christensen 
L, Merion RM (2003 Sep 4) Chronic renal failure after transplantation of a nonrenal organ. N 
Engl J Med.; 349(10):931-40. 
Pappo O., Ramos H., Starzl TE. et al. (1995) Structural Integrity and Identification of Causes 
of Liver Allograft Dysfunction Occurring More Than 5 Years After Transplantation. Am J 
Surg Pathol. 19(2): 192–206. 


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Pereira S., Cruz CM., Soares M. et al. (2016) Histology Utility in Liver Graft Surveillance: 
What About Normal. Transpl Proceed, 48, 2344-47.Pflugard H et al. Long Term Calcineurin 
Inhibitor Therapy and Brain Function in Patients After Liver Transplantation. Liver 
Transplantation 24 56-66 2018 AASLD. 
Razonable RR, Humar A (2019). Cytomegalovirus in solid organ transplant recipients 
Guidelines of the American Society of Transplantation Infectious Diseases Community of 
Practice. Clin Transplant. Feb: 33e13512.Sebagh M., Rifai K., Féray C. et al. (2003) All Liver 
Recipients Benefit From the Protocol 10-Year Liver Biopsies. Hepatology 37:1293-1301. 
Sebagh M., Samuel D. (2004) Place of the liver biopsy in liver transplantation. Journal of 
Hepatology 41 897–901. 
Selzner N, Grant DR, Shalev I and al (2010) The immunosuppressive pipeline: meeting unmet 
needs in liver transplantation. Liver Transpl. 16(12):1359-72. 
Slapak GI., Saxena R., Portmann B. et al. (1997) Graft and Systemic Disease in Long-Term 
Survivors of Liver Transplantation. Hepatology 25:195-202. 
Sugawara Y, Tamura S, Kaneko J, Togashi J, Makuuchi M, Kokudo N (2009) Positive 
lymphocytotoxic crossmatch does not adversely affect survival in living donor liver 
transplantation. Dig. Surg. 26:482. 
United Network for Organ Sharing (UNOS). MELD/PELD calculator (online access: unos.org). 
Access from [https://unos.org/resources/allocation-calculators] Accessed on: 05Mar, 2020. 
Vionnet J, Sánchez-Fueyoc A (2018) Biomarkers of immune tolerance in liver 
transplantation. Human Immunology 79:388. 
Wadstrom J., Ericzon BG., Halloran PF. et al. (2017) Advancing Transplantation: New 
Questions, New Possibilities in Kidney and Liver Transplantation. Transplantation 101: S1–
S41. 
Zhang W, Fung J. Limitations of current liver transplant immunosuppressive regimens: renal 
considerations. Hepatobiliary Pancreat Dis Int. 2017 Feb; 16(1):27-32. 


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Protocol No. CCFZ533A2202 
 
16 
Appendices 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs 
The following criteria will be used to define expanded limits and notable abnormalities of key 
laboratory tests. 
Laboratory variable 
 
 
 
Standard units   
SI units 
Liver function and related variables 
SGOT (ASAT) 
 
 
 
 
≥3 × ULN 
 
≥3 × ULN 
SGPT (ALAT) 
 
 
 
 
≥3 × ULN 
 
≥3 × ULN 
Bilirubin  
 
 
 
 
>2 × ULN 
 
>2 × ULN 
Alkaline Phosphatase 
 
 
 
≥5 × ULN  
 
≥5 × ULN 
GGT 
 
 
 
 
 
≥5 × ULN  
 
≥5 × ULN 
Renal function, metabolic and electrolyte variables 
Urea  
 
 
 
 
 
≥5 × ULN  
 
≥5 × ULN 
Creatinine  
 
 
 
 
After Day 8±2: ≥3 mg/dL 
After Day 8±2: ≥265 μmoFl/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 
Magnesium 
 
 
 
 
< 1.0 mg/dL 
 
< 0.4 mmol/L 
 
 
 
 
 
 
 
> 3.6 mg/dL 
 
> 1.5 mmol/L 
Amylase  
 
 
 
 
≥ 2 x ULN 
 
≥ 2 x ULN 
Lipase  
 
 
 
 
≥ 2 x ULN 
 
≥ 2 x ULN 
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) 
 
 
160 or higher (hypertension stage 2)  
Diastolic BP (mm/Hg) 
 
 
110 or higher (hypertension stage 2)  


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Protocol No. CCFZ533A2202 
 
16.2 
Appendix 2: Milan criteria 
The United Network of Organ Sharing (UNOS) decided to prioritize allocation of organs to 
those HCC participants who met the tumor criteria recognized in the Milan experience to have 
the best outcomes (TNM = T2N0). The Milan criteria is based on tumor burden and limit 
prioritization for OLT to those who have either a single tumor 5 cm or less in diameter with a 
single hepatocellular carcinoma, and those with no more than 3 nodules, and each 3 cm or less 
in diameter, without evidence of metastatic disease or vascular invasion. The Milan criteria 
provide a simple means of selecting participants with HCC for transplantation who are at low 
risk (˜10%) for recurrence. 
Modified Tumor Node Metastases (pTNM) Classification of HCC 
pT0 
Tumor not found 
pT1 
1 nodule ≤ 1.9 cm 
pT2 
1 nodule 2.0 – 5.0 cm; 2 or 3 nodules, all ≤ 3.0 cm 
pT3 
1 nodule > 5.0 cm; 2 or 3 nodules, at least one > 3.0 cm 
pT4a 
4 or more nodules, any size 
pT4b 
pT2, pT3 or pT4 plus gross intraphepatic portal or hepatic vein involvement as 
indicated by CT, MRI, or US 
N1 
Regional (portal hepatitis) nodes, involved 
M1 
Metastatic disease, including extrahepatic portal or hepatic vein involvement 
Stage I 
T1 
Stage II 
T2 
Stage III 
T3 
Stage IVA1 
T4a 
Stage IVA2 
T4b 
Stage IVB 
Any N1, any M1 
Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna 
M, Morabito A, Gennari L (1996 Mar 14) Liver transplantation for the treatment of small 
hepatocellular carcinomas in patients with cirrhosis. N Engl J Med.; 334(11):693-9. 
Shetty K, Timmins K, Brensinger C, Furth EE, Rattan S, Sun W, Rosen M, Soulen M, Shaked 
A, Reddy KR, Olthoff KM. (2004) Liver transplantation for hepatocellular carcinoma 
validation of present selection criteria in predicting outcome. Liver Transpl; 10(7):919-21. 


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Protocol No. CCFZ533A2202 
 
16.3 
Appendix 3: Banff classification of liver allograft rejection 
REJECTION ACTIVITY INDEX (RAI) 
Criteria which can be used to score liver allograft biopsies with acute rejection, as defined by the World 
Gastroenterology Consensus Document. 
Category 
Criteria 
Score 
Portal Inflammation 
Mostly lymphocytic inflammation involving, but not noticeably 
expanding, a minority of the triads 
1 
Expansion of most or all of the triads, by a mixed infiltrate containing 
lymphocytes with occasional blasts, neutrophils and eosinophils 
2 
Marked expansion of most or all of the triads by a mixed infiltrate 
containing numerous blasts and eosinophils with inflammatory 
spillover into the periportal parenchyma 
3 
Bile Duct 
Inflammation Damage 
A minority of the ducts are cuffed and infiltrated by inflammatory cells 
and show only mild reactive changes such as increased 
nuclear:cytoplasmic ratio of the epithelial cells 
1 
Most or all of the ducts infiltrated by inflammatory cells. More than an 
occasional duct shows degenerative changes such as nuclear 
pleomorphism, disordered polarity and cytoplasmic vacuolization of the 
epithelium 
2 
As above for 2, with most or all of the ducts showing degenerative 
changes or focal lumenal disruption 
3 
Venous Endothelial 
Inflammation 
Subendothelial lymphocytic infiltration involving some, but not a 
majority of the portal and/or hepatic venules 
1 
Subendothelial infiltration involving most or all of the portal and/or 
hepatic venules 
2 
As above for 2, with moderate or severe perivenular inflammation that 
extends into the perivenular parenchyma and is associated with 
perivenular hepatocyte necrosis 
3 
Total RAI Score = _/9 
Reference: (Demetris et al 1997) 
 
Grading of Acute Liver Allograft Rejection 
Global assessment of rejection grade made on a review of the biopsy and after the diagnosis of rejection has 
been established. 
*Global Assessment 
Criteria 
Indeterminate 
Portal inflammatory infiltrate that fails to meet the criteria for the diagnosis of acute 
rejection (see reference below) 
Mild 
Rejection infiltrate in a minority of the triads, that is generally mild, and confined within 
the portal spaces 
Moderate 
 
Rejection infiltrate, expanding most or all of the triads 
Severe 
 
As above for moderate, with spillover into periportal areas and moderate to severe 
perivenular inflammation that extends into the hepatic parenchyma and is associated 
with perivenular hepatocyte necrosis 
* Verbal description of mild, moderate or severe acute rejection could also be labeled as Grade I, II and III, 
respectively. 
Reference: (Demetris et al 1997) 


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Protocol No. CCFZ533A2202 
 
16.4 
Appendix 4: Abbreviated MDRD formula for eGFR 
The abbreviated MDRD formula used for eGFR calculation is as follows, quoted from quoted 
from Levey et al (2006): 
eGFR mL/min/1.73m2 = 175*(C-1.154)*(A-0.203)*G*R, 
where 
C is the serum concentration of creatinine mg/dL, 
A is age (years), G=0.742 when gender is female, otherwise G=1, 
R=1.212 when race is black, otherwise R=1. 


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Protocol No. CCFZ533A2202 
 
16.5 
Appendix 5: American Diabetes Association criteria for Diabetes 
As defined by the American Diabetes Association:  
Diabetes is diagnosed when any of the following are present:  
• Symptoms of diabetes, plus casual plasma glucose ≥ 200 mg/dL (11.1 mmol/L). 
• Two consecutive fasting plasma glucose (post-transplantation) ≥ 126 mg/dL (7.0 mmol/L) 
• 2-hour post-load plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during a 75 gram (g) oral 
glucose tolerance test.  
• HbA1c ≥ 6.5% post-transplantation. 
Results obtained by each method must be confirmed on a different day unless definite symptoms 
of hyper glycemia are present.  
• Impaired fasting glucose is a fasting plasma glucose 100 mg/dL (5.6 mmol/L) to 125 
mg/dL (6.9 mmol/L).  
• Impaired glucose tolerance is a 2-hour post-load plasma glucose 140 mg/dL (7.8 mmol/L) 
to 199 mg/dL (11.0 mmol/L) during a 75 g glucose tolerance test.   
Reference: Diagnosis and Classification of Diabetes Mellitus, American Diabetes Association 
(2013), Diabetes Care 2013; 36 Suppl 1:S11.  


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Protocol No. CCFZ533A2202 
 
16.6 
Appendix 6a: Blood log for PK, PD, Immunogenicity and other 
assessments sampling 
Arm 1 (TAC regimen) - Blood collection log for pharmacodynamics (sCD40 in plasma). 
Study 
Day 
Month 
PD (sCD40) 
Sample Numberd, c 
(V = 2 mL) 
Other assessments 
Sample Number 
8 
0 
400 
920 
29 
1 
401 
921 
57 
2 
402 
922 
85 
3 
403 
923 
127 
4.5 
404 
924 
169 
6 
405 
925 
225 
8 
406 
926 
281 
10 
407 
927 
337 
421 
505 
589 
673  
12 
15 
18 
21 
24 
408 
409 
410 
411 
412 
928 
929 
920 
921 
922 
Arm 2 (CFZ533 600 mg regimen) - Blood collection log for pharmacokinetics (CFZ533 in 
plasma), pharmacodynamics (sCD40 in plasma) and immunogenicity (anti-CFZ533 in plasma). 
Study 
Day 
Month 
Time 
Point 
Dose  
Reference 
ID #1 
Dose 
Reference 
ID #2 
PK 
(CFZ533) 
Sample 
Numberb 
(V = 3 
mL) 
PD  
(sCD40) 
Sample 
Numberd, c 
(V = 2 mL) 
Immuno- 
genicity 
Sample 
Numberb, c 
(V = 3 mL) 
Other 
assessments 
Sample 
Number 
8 
0 
Pre-dose 
1 
1 
100 
200 
300 
900 
 
 
1 hr post 
dose a 
1 
1 
101 
 
 
 
15 
0.5 
Pre-dose 
1 
2 
102 
 
 
 
 
 
1 hr post 
dose a 
1 
2 
103 
 
 
 
29 
1 
Pre-dose 
1 
3 
104 
201 
301 
901 
43 
1.5 
Pre-dose 
1 
4 
105 
 
 
 
57 
2 
Pre-dose 
1 
5 
106 
202 
302 
902 
71 
2.5 
Pre-dose 
1 
6 
107 
 
 
 


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Protocol No. CCFZ533A2202 
 
Study 
Day 
Month 
Time 
Point 
Dose  
Reference 
ID #1 
Dose 
Reference 
ID #2 
PK 
(CFZ533) 
Sample 
Numberb 
(V = 3 
mL) 
PD  
(sCD40) 
Sample 
Numberd, c 
(V = 2 mL) 
Immuno- 
genicity 
Sample 
Numberb, c 
(V = 3 mL) 
Other 
assessments 
Sample 
Number 
85 
3 
Pre-dose 
1 
7 
108 
203 
303 
903 
99 
3.5 
Pre-dose 
1 
8 
109 
 
 
 
113 
4 
Pre-dose 
1 
9 
110 
 
 
 
127 
4.5 
Pre-dose 
1 
10 
111 
204 
304 
904 
141 
5 
Pre-dose 
1 
11 
112 
 
 
 
155 
5.5 
Pre-dose 
1 
12 
113 
 
 
 
169 
6 
Pre-dose 
1 
13 
114 
205 
305 
905 
225 
8 
Pre-dose 
1 
17 
115 
206 
306 
906 
281 
10 
Pre-dose 
1 
21 
116 
207 
307 
907 
337 
421 
505 
589 
673  
12 
15 
18 
21 
24 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
1 
1 
1 
1 
1 
25 
31 
37 
43 
48 
117 
118 
119 
120 
121 
208 
209 
210 
211 
212 
308 
309 
310 
311 
312 
908 
909 
910 
911 
912 
a 1 Hour after the end of 30-min infusion 
b CFZ533-treated participants only 
c Samples are taken at pre-dose  
d All arms (CFZ533-treated and Control) 


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Protocol No. CCFZ533A2202 
 
Arm 3 (CFZ533 300 mg regimen) - Blood collection log for pharmacokinetics (CFZ533 in 
plasma), pharmacodynamics (sCD40 in plasma) and immunogenicity (anti-CFZ533 in plasma) 
Study 
Day 
Month 
Time 
Point 
Dose  
Reference 
ID #1 
Dose 
Reference 
ID #2 
PK 
(CFZ533) 
Sample 
Number b 
(V = 3 
mL) 
PD  
(sCD40) 
Sample 
Number 
d, c 
(V = 2 
mL) 
Immuno- 
genicity 
Sample 
Number b, c 
(V = 3 mL) 
Other 
assessments 
Sample 
Number 
8 
0 
Pre-dose 
1 
1 
150 
250 
350 
950 
 
 
1 hr post 
dose a 
1 
1 
151 
 
 
 
29 
1 
Pre-dose 
1 
2 
152 
251 
351 
951 
43 
1.5 
Pre-dose 
1 
3 
153 
 
 
 
57 
2 
Pre-dose 
1 
4 
154 
252 
352 
952 
71 
2.5 
Pre-dose 
1 
5 
155 
 
 
 
85 
3 
Pre-dose 
1 
6 
156 
253 
353 
953 
99 
3.5 
Pre-dose 
1 
7 
157 
 
 
 
113 
4 
Pre-dose 
1 
8 
158 
 
 
 
127 
4.5 
Pre-dose 
1 
9 
159 
254 
354 
954 
141 
5 
Pre-dose 
1 
10 
160 
 
 
 
155 
5.5 
Pre-dose 
1 
11 
161 
 
 
 
169 
6 
Pre-dose 
1 
12 
162 
255 
355 
955 
225 
8 
Pre-dose 
1 
16 
163 
256 
356 
956 
281 
10 
Pre-dose 
1 
20 
164 
257 
357 
957 
337 
12 
Pre-dose 
1 
24 
165 
258 
358 
958 
421 
505 
589 
673 
15 
18 
21 
24 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
1 
1 
1 
1 
30 
36 
42 
47 
166 
167 
168 
169 
259 
260 
261 
262 
359 
360 
361 
362 
959 
960 
961 
962 
a 1 Hour after the end of 30-min infusion 
b CFZ533-treated participants only 
c Samples are taken at pre-dose  
d All arms (CFZ533-treated and Control) 
# End of study 


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Protocol No. CCFZ533A2202 
 
16.7 
Appendix 6b: Blood log for unscheduled PK sampling 
Applicable when an additional/compensatory IV dose of CFZ533 is administered, 
independently of the planned dosing regimen. 
Limited to up to Month 12 
Each time an additional/compensating intravenous CFZ533 dose (10 or 5 mg/kg; see protocol 
for instructions) will be administered, a pre-dose blood sample will be taken to assess the 
CFZ533 concentration in plasma (PK sample). 
The blood collection log for these unscheduled pharmacokinetic samples (to assess CFZ533 in 
plasma) is described below. 
For each participant a unique sample number will be given and the timing of blood sample will 
be recorded. 
• Arm 2 (CFZ533 600 mg regimen) 
Unique PK sample number: 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, etc ... 
Dose Reference ID: 1, for all samples 
• Arm 3 (CFZ533 300 mg regimen) 
Unique PK sample number: 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, etc ... 
Dose Reference ID: 1, for all samples 
Ascites collection log for unscheduled ascites samples 
Limited to up to Month 12 
From Day 1 and at any time during the study, if ascites fluids are drained from CFZ533-treated 
participants, the total daily volume of drained ascites will be measured and recorded on the 
ascites page of the CRF. 
An aliquot of ascites fluid will be collected from 1 bag and stored in frozen conditions. 
For each participant a unique sample number will be given and the timing of the ascites sample 
will be recorded. 
• Arm 2 (CFZ533 600 mg regimen) 
Unique sample number: 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, etc ... 
• Arm 3 (CFZ533 300 mg regimen) 
Unique sample number: 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, etc ... 
 

SAP_005.pdf: 
Clinical Development 
CFZ533A / Iscalimab 
CFZ533A2202 /  NCT03781414
A 12-month, open-label, multicenter, randomized, safety, 
efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) 
study of two regimens of anti-CD40 monoclonal antibody, 
CFZ533 vs. standard of care control, in adult de novo liver 
transplant recipients with a 12-month additional follow-up 
and a long-term extension (CONTRAIL I) 
Statistical Analysis Plan (SAP) Amendment 3 
Author: 
Statistician, 
 
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
24 November 2023 
Number of pages: 
48 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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SAP 
 
CCFZ533A2202 
 
 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted (Current) 
14 Oct 
2019 
Prior to 
DB lock 
Creation of 
final version 
N/A – First version 
N/A 
16 June 
2020 
Prior to 
DB lock 
Creation of 
Amendment 1 
Modifications reflecting 
Protocol Amendment 1 and 2 
updates. See change history 
of the protocol. 
All sections 
 
 
 
Updated supportive analyses 
for primary objective. 
Section 2.4.4 
 
 
Updated definition of AR, 
NODM, etc. 
Section 2.7.1, 5.4 
8 Oct 
2021 
Prior to 
DB lock 
Creation of 
Amendment 2 
Modifications reflecting 
Protocol Amendment 3 and 4 
updates. See change history 
of the protocol. 
All sections 
 
 
 
 
Removed description of 
compensation for CFZ533 
due to ascites. 
Section 2.1 
 
 
 
Updated the estimand 
framework and handling of 
missing data for primary and 
secondary endpoints. 
Section 2.4, 2.5 
 
 
 
Updated sensitivity and 
supplementary analyses for 
primary objective. 
Section 2.4.4 
 
 
 
Updated general rules for 
safety analysis. 
Section 2.7 
 
 
 
Updated summary of 
virology. 
Section 2.7.3 
 
 
 
Updated summary of 
pharmacokinetic endpoints 
regarding PFS application. 
Section 2.8 
 
 
 
Added COVID-19 related 
summaries and analyses at 
the end of the extension. 
Section 2.12 
 
 
 
Updated IA plans and 
reorganized sections 
regarding sample size and 
stopping rules. 
Section 2.13, 3 


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SAP 
 
CCFZ533A2202 
 
 
 
10 Apr 
2023 
Prior to 
DB lock 
Creation of 
Amendment 3 
Modified the analysis plan 
following IA due to the study 
termination. 
All sections 
 
 
 
Updated analysis visit 
window. 
Section 5.1 
 
 
 
Updated details for derivation 
of efficacy endpoints and 
statistical models. 
Section 5.4, 5.5 
 
 
 
Updated analysis for AE. 
Section 2.7.1 


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Table of contents 
Table of contents ................................................................................................................. 4 
List of abbreviations ............................................................................................................ 6 
List of tables ........................................................................................................................ 8 
List of figures ...................................................................................................................... 9 
1 
Introduction ....................................................................................................................... 10 
1.1 
Study design .......................................................................................................... 10 
1.2 
Study objectives and endpoints ............................................................................. 12 
2 
Statistical methods ............................................................................................................. 14 
2.1 
Data analysis general information ......................................................................... 14 
 
General definitions ................................................................................ 15 
 
Analysis sets .......................................................................................... 15 
 
Subgroup of interest .............................................................................. 16 
2.2 
Participant disposition, demographics and other baseline characteristics ............. 16 
 
Medical history...................................................................................... 17 
 
Participant disposition ........................................................................... 18 
2.3 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 18 
 
Study treatment / compliance ................................................................ 18 
 
Prior, concomitant and post therapies ................................................... 20 
2.4 
Analysis of the primary objective .......................................................................... 20 
 
Primary endpoint ................................................................................... 21 
 
Statistical hypothesis, model, and method of analysis .......................... 21 
 
Handling of missing values/censoring/discontinuations ....................... 22 
 
Sensitivity analyses ............................................................................... 22 
 
Supplementary analyses ........................................................................ 22 
2.5 
Analysis of the key secondary objective ............................................................... 23 
 
Key secondary endpoint ........................................................................ 23 
 
Statistical hypothesis, model, and method of analysis .......................... 24 
 
Handling of missing values/censoring/discontinuations ....................... 24 
 
Supplementary analyses ........................................................................ 24 
2.6 
Analysis of secondary efficacy objectives ............................................................. 24 
2.7 
Safety analyses....................................................................................................... 24 
 
Adverse events (AEs) ............................................................................ 25 
 
Deaths .................................................................................................... 27 
 
Laboratory data ..................................................................................... 27 


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Other safety data ................................................................................... 28 
2.8 
Pharmacokinetic endpoints .................................................................................... 28 
2.9 
PD and PK/PD analyses ........................................................................................ 29 
2.10 
Participant-reported outcomes ............................................................................... 29 
 
 30 
 
 30 
2.13 
Interim analysis ...................................................................................................... 30 
3 
Sample size calculation ..................................................................................................... 31 
3.1 
Study stopping rules .............................................................................................. 31 
3.2 
Power for primary endpoint ................................................................................... 33 
3.3 
Power for key secondary variable .......................................................................... 34 
4 
Change to protocol specified analyses .............................................................................. 35 
5 
Appendix ........................................................................................................................... 35 
5.1 
Analysis visit windows .......................................................................................... 35 
5.2 
Imputation rules ..................................................................................................... 37 
 
Study drug ............................................................................................. 37 
 
AE date imputation ............................................................................... 37 
 
Concomitant medication date imputation ............................................. 39 
5.3 
Laboratory parameters derivations ........................................................................ 40 
 
Clinically notable vital signs ................................................................. 43 
 
Steroid conversion factors ..................................................................... 43 
5.4 
Definition/Derivation of Efficacy Variables ......................................................... 43 
 
Efficacy endpoint derivations based on central readings ...................... 44 
 
Efficacy endpoint derivations based on local readings ......................... 45 
5.5 
Statistical models ................................................................................................... 47 
 
Exposure-adjusted incidence rate and 100(1 - α)% confidence 
interval................................................................................................... 47 
5.6 
Rule of exclusion criteria of analysis sets.............................................................. 47 
6 
Reference ........................................................................................................................... 48 


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List of abbreviations 
AE 
AMR 
AR 
adverse event 
antibody-mediated rejection 
acute rejection 
ATC 
Anatomical Therapeutic Classification 
BMI 
BP 
BPAR 
CMV 
CNI 
CS 
body mass index 
blood pressure 
biopsy proven acute rejection 
cytomegalovirus 
calcineurin inhibitor 
corticosteroids 
CSR 
clinical study report 
CV 
coefficient of variation 
DAR 
dose administration record 
DMC 
EBV 
Data Monitoring Committee  
Epstein Barr virus 
FAS 
full analysis set 
eCRF 
eCRS 
eGFR 
EOS 
EP 
GFR 
IA 
ITT 
i.v. / IV 
electronic Case Report Form 
eletronic Case Retrieve Strategy 
estimated glomerular filtration rate 
end of study 
endpoint 
glomerular filtration rate 
interim analysis 
Intention to treat 
intravenous 
LLOQ 
lower limit of quantification 
LTx 
MDRD 
liver transplantation 
modification of diet in renal disease 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
MMF 
MMRM 
mycophenolate mofetil 
mixed model of repeated measures 
NODM 
new onset diabetes mellitus 
PD 
pharmacodynamic 
PK 
pharmacokinetics 
PT 
preferred term or prothrombin time 
Q2W 
every 2 weeks 
RAI 
Rejection activity index 
SAF 
SAP 
s.c. / SC 
sCD40 
SCR 
SD 
safety set 
Statistical Analysis Plan 
subcutaneous 
soluble CD40 
screened set 
standard deviation 


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CCFZ533A2202 
 
 
 
SE 
SMQ 
SNOMED 
standard error 
standard MedDRA query 
systematized nomenclature of medicine 
SOC 
TAC 
tAR 
System Organ Class 
tacrolimus 
treated acute rejection 
tBPAR 
TFLs 
Tx 
UPCR 
 
treated biopsy proven acute rejection 
tables, figures, listings 
transplantation 
urine protein creatinine ratio 
 
 
 
 
 
 


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CCFZ533A2202 
 
 
 
List of tables 
Table 1-1 
Objectives and related endpoints .......................................................... 12 
Table 2-1 
Exposure duration categories for study treatment ................................. 18 
Table 2-2 
Safety topics of interests ....................................................................... 25 
Table 3-1 
Stopping rules per number of events ..................................................... 31 
Table 3-2 
Probability of success under different event rates for 48 
participants of CFZ533 arm and 32 participants of control arm ........... 34 
Table 5-1 
Analysis visit windows ......................................................................... 35 
Table 5-2 
Imputation logic for partial AE dates .................................................... 37 
Table 5-3 
Imputation logic for partial concomitant medication dates ................... 39 
Table 5-4 
Clinically notable lab abnormalities...................................................... 40 
Table 5-5 
Conversion Factors from Standard (US) into SI units .......................... 41 
Table 5-6 
Newly occurring liver enzyme abnormalities ....................................... 42 
Table 5-7 
Clinically notable vital signs ................................................................. 43 
Table 5-8 
Steroids conversion factors ................................................................... 43 
Table 5-9 
Participant Classification ...................................................................... 47 
 
 


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List of figures 
Figure 1-1 
Study design .......................................................................................... 12 
Figure 3-1 
Probability of stopping a cohort for various event rates for up to 48 
participants per arm ............................................................................... 33 
Figure 3-2 
Probability of success under different event rates for 48 
participants of CFZ533 arm and 32 participants of control arm ........... 34 
 
 


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1 
Introduction 
This document presents the detailed statistical analysis plan (SAP), for Study CFZ533A2202, 
“A 12-month, open-label, multicenter, randomized, safety, efficacy, pharmacokinetic (PK) and 
pharmacodynamic (PD) study of two regimens of anti-CD40 monoclonal antibody, CFZ533 vs. 
standard of care control, in adult de novo liver transplant recipients with a 12-month additional 
follow-up and a long-term extension (CONTRAIL I)”.   
The study was terminated in September 2022 after the planned Interim Analysis (IA) which led 
to a decision that the risk-benefit was no longer favorable to continue clinical development in 
the disease area. Given the decision to terminate the study early, an abbreviated clinical study 
report (CSR) will be created for this study. Analyses covered in the original SAP and 
Amendment 1 and 2 have been reduced or simplified accordingly. 
1.1 
Study design 
This study is a 12-month, multicenter, open-label, randomized study with a 12-month additional 
follow-up and a long-term extension that will consist of: 
• A screening period (up to 2 months) starting from informed consent, screening visit, and 
including successful liver transplantation (LTx).  
• Run-in treatment period following the successful transplantation that ends on the day of 
randomization or randomization failure, at Day 8 (with visit window of ±2 days) post-
LTx.  
• The primary treatment period (Treatment Period 1) starting at randomization Day 8±2 
post-LTx up to Month 12 followed by a 12-month follow-up treatment period 
(Treatment Period 2) until Month 24 (Figure 1-1). 
• The long-term extension period (Treatment Period 3) starting post Month 24 until the 
end of the study (EOS). 
Participants will be consented and screened for eligibility prior to liver transplantation. 
Consented participants who have met the screening inclusion criteria, undergone a successful 
liver transplantation and been initiated on a tacrolimus-based regimen that includes 
mycophenolate mofetil (MMF) and corticosteroids (CS) according to local practice, will enter 
the run-in period. Transplanted participants who meet the additional inclusion criteria will be 
randomized at Day 8±2 post-LTx.  
At least 128 participants will be randomized at a ratio of 2:3:3 to TAC Control (Arm 1) or one 
of two maintenance regimens of CFZ533: 600 mg CFZ533 subcutaneous (SC) injections every 
2 weeks (Arm 2) or 300 mg CFZ533 SC injections every 2 weeks (Arm 3) combined with MMF 
and CS (Figure 1-1).  
Each CFZ533 arm will have a loading period where CFZ533 will be administered IV in order 
to rapidly achieve concentrations providing complete CD40-CD40L pathway blockade in target 
tissues in conditions where CD40 expression levels may be enhanced (Section 4.2 in the 
Protocol for dose rationale). Participants who do not meet the randomization criteria will be 
designated screen failures. The screen-failed participants will not be further followed-up in the 
study. 


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The study treatments will be as follows: 
• Arm 1 (TAC Control): TAC, MMF, and CS will be started in the peri-transplant period 
and at randomization and will continue up to EOS. Initial tacrolimus target trough levels 
will be between 5 - 15 ng/mL based on b.i.d. dosing and will be maintained throughout 
the run-in period. From randomization onwards, the TAC levels will be adjusted as per 
local label. 
• Arm 2 (CFZ533 600 mg regimen): Loading doses will be 30 mg/kg IV on Day 8 post-
transplantation, with a second dose of 15 mg/kg IV on Day 15 and SC administration of  
600 mg every 2 weeks will begin on Day 29 with MMF and CS until the EOS. 
• Arm 3 (CFZ533 300 mg regimen): A single loading dose of 30 mg/kg IV will be 
administered on Day 8 and SC administration of  300 mg every 2 weeks will begin on 
Day 29 with MMF and CS until the EOS. 
In CFZ533 Arms 2 and 3, during the immediate peri- and post-transplant period, TAC will be 
given to provide immunological coverage but must be completely weaned off by Day 22. For 
details, please refer to Section 6.7.2.2 in the Protocol.  
CFZ533 injections will be administered by authorized Investigator/staff at each study visit. 
After the Month 6 visit (at site), in-home administration may be allowed by a health care 
provider (HCP). After Month 12 visit, the pre-filled syringes (PFS) use will allow self-
administration at home. 
The participants in the Control arm will receive their last dose of TAC on the day of the EOS. 
From EOS onwards, participants will be treated according to local standard of care practice. 
For all participants, MMF will be initiated at the time of liver transplantation, mycophenolates 
should be maintained throughout the study with CFZ533 or TAC; however adaptations are 
possible in case of signs of over-immunosuppression or intolerance (see Section 6.5.2 in the 
Protocol).  
For all participants after the last study visit (EOS), there will be a 12-week safety follow-up 
period. 
MMF and corticosteroid doses will be administered according to local practice. Corticosteroid 
use is mandatory until Month 4 has been completed but the initiation and dose are according to 


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local practice, with a minimum prednisone dose of 5 mg/day or equivalent dose of another oral 
corticosteroid. 
All dose changes must be recorded in the appropriate CRF. 
Figure 1-1 
Study design  
 
1.2 
Study objectives and endpoints 
Table 1-1 
Objectives and related endpoints  
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
• 
To evaluate the rate of composite efficacy failure 
(Biopsy Proven Acute Rejection (BPAR), graft loss 
or death) with CFZ533 600 mg and 300 mg 
regimens compared to TAC Control at Month 12 
post-transplantation. 
Endpoint(s) for Primary Objective(s)  
• 
Incidence of composite efficacy failure at Month 
12, where BPAR is from biopsy data indicating a 
rejection activity index (RAI) ≥3 (Appendix 3 in 
the Protocol). 
Key Secondary Objective 
• 
To 
evaluate 
the 
renal 
function 
(estimated 
Glomerular Filtration Rate (eGFR) by MDRD-4 
formula) with CFZ533 600 mg and 300 mg 
regimens compared to TAC Control at Month 12 
post-transplantation. 
Secondary Objective(s) 
• 
To evaluate the composite of BPAR, Death, Graft 
Loss and Loss to Follow-up with CFZ533 600 mg 
and 300 mg regimens compared to TAC Control at 
Month 12 and Month 24 post-transplantation. 
 
Endpoint(s) for Secondary Objective(s) 
• 
Mean change in eGFR from randomization to 
Month 12. 
 
 
 
• 
BPAR as above, Death, Graft Loss and Study 
completion/disposition datasets. 
 
 
 


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Objective(s) 
Endpoint(s) 
• 
To evaluate whether CFZ533 600 mg or 300 mg 
regimens have lower incidence rates over 12 and 
24 months post-transplantation compared to TAC 
control arm for the following events: 
- 
BPAR 
- 
tBPAR 
- 
AR 
- 
Treated Acute rejection (tAR) 
- 
Antibody mediated (humoral) rejection 
- 
Graft Loss 
- 
Death 
• 
To evaluate eGFR and change in eGFR to Month 
24 post-transplantation. 
• 
To assess the safety and tolerability of CFZ533 
regimens compared to TAC control at Month 12 
and Month 24.   
 
 
 
 
 
 
 
 
• 
To assess the pharmacokinetics of multiple doses 
of CFZ533 over the 12-month and 24-month 
treatment 
and 
explore 
the 
dose-exposure 
relationship. 
• 
To assess the levels of peripheral soluble CD40 at 
baseline and over the 12-month and 24-month 
treatment period (to inform target biology, target 
engagement). 
• 
To evaluate the immunogenicity of CFZ533 by 
analysis of anti-CFZ533 antibodies (over the 12-
month and 24-month treatment period). 
• 
Event rates over 12 months and 24 months post-
transplantation. 
 
 
 
 
 
 
 
• 
To evaluate eGFR values and change from 
randomization over time. 
• 
Proportion of participants with: 
- 
Adverse events 
- 
Serious adverse events 
- 
AEs related to study drug 
• 
Means and mean change over time of:  
- 
Vital sign parameters 
- 
Lab parameters (Section 8.4.1 in the 
Protocol) 
• 
Proportion of participants with: 
- 
Premature discontinuation from study 
- 
Premature discontinuation of study drug  
- 
Dose interruption 
- 
Dose adjustment 
• 
Free CFZ533 plasma concentrations over time 
(CFZ533-treated participants only). 
 
 
• 
Total sCD40 in plasma (all participants). 
 
 
• 
Semi-quantitative 
analysis 
of 
anti-CFZ533 
antibodies 
in 
plasma 
(CFZ533-treated 
participants only). 


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2 
Statistical methods 
2.1 
Data analysis general information 
Due to the early termination of the study, the analysis plan has been modified and may be 
different from the Protocol.  
The primary analysis will be performed after all participants have completed the Month 12 visit, 
or prematurely discontinued study before Month 12. These analyses will be performed by a 
Contract Research Organization, ICON. Interim analyses, detailed in Section 2.13, will be 
performed also by ICON. 
The following general data conventions will apply: 
• Cut-off day is defined as the latest study day before or up to which data will be used in the 
analysis. Note that safety data collected during the Safety Follow-up period after EOS is 
reported to Novartis/Safety and will be included in relevant analyses. 
• Descriptive statistics will be calculated based on observed values. Missing values will be 
presented separately for each parameter or category. Categorical data will be presented as 
frequencies and percentages. For continuous data, 𝑛𝑛 (sample size), mean, standard 
deviation, median, 25th and 75th percentiles, minimum, and maximum will be presented. 
• BPAR will be based on centrally blinded adjudicated data. All other efficacy 
 
 endpoints will also be based on central 
lab data. 
• AE, SAE, Infection, Serious Infection (including malignancies), CMV information, and 
EBV information will be summarized based on all eligible collected events. 
• All lab and vital sign tables will include data since baseline (liver Tx) but changes are 
calculated based on the day of randomization. All summaries are based on central lab data.   


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• Efficacy and liver function analyses are based on all available data including those after 
study medication discontinuation or as a supportive analysis based only on on-treatment 
values. Participants are censored for the time-to-event analyses if they do not have an event. 
For on-treatment analysis, the censoring day is the date of discontinuation of study treatment 
(defined in Section 2.1.1); for the all-data analysis (regardless of on-treatment or off-
treatment), the censoring day is the last contact day. 
• Listings will only be provided for variables explicitly indicated in this SAP. Listings will 
include all available data. 
Details about the definition of efficacy and safety events, data handling conventions including 
“re-aligned” visit windows, imputation of missing dates, and other details about study concepts 
and terms can be found in Section 5. Note that the visits defined in the protocol are used to 
guide investigators whereas the “re-aligned” visit windows (Table 5-1) (simply referred to as 
visit windows hereafter) will be used for the analyses. 
 
General definitions  
For the purposes of statistical analysis, “study treatments” are and will be displayed in the 
outputs as CFZ533 300mg + MMF, CFZ533 600mg + MMF, and TAC + MMF. “Baseline” is 
defined as the last assessment, including unscheduled assessments, performed prior to liver Tx. 
All assessments obtained after liver Tx are considered as post-baseline unless otherwise 
specified. Only centrally adjudicated data will be used for efficacy 
 
analyses and laboratory (including vital signs). 
In the event that a participant only takes one of the three treatments, the following definitions 
apply: 
• Start of study treatment:  
a. CFZ533 arms: day of the first loading dose of CFZ533 on Day 8±2 post-LTx. 
b. Control arm: Day 8 post LTx. 
• End of study treatment: 
a. CFZ533 arms: day of the last dose of CFZ533 +14  days. If a participant in CFZ533 
arms discontinues treatment before Day 8±2 (first dose of CFZ533), the rules of 
control arm apply. 
b. Control arm: day of the last dose of TAC.  
In calculating the duration of treatment, days of permitted interruption of study medication 
(CFZ, TAC, and MMF) for any reason will be included (see Section 6.5 in the Protocol for 
details on permitted dose interruption). The entire treatment period is divided into three parts: 
Treatment Period 1, 2, and 3 (see Section 1.1). 
 
Analysis sets 
The screened set (SCR) consists of all participants who signed the informed consent. The 
screened set includes only uniquely screened participants, i.e., in the case of re-screened 
participants, only the chronologically last screened data is counted.  Screening phase disposition 
will be based on the SCR. 


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The randomized set (RND) consists of all participants who signed the informed consent and 
were randomized, including misrandomizations. 
The full analysis set (FAS) will include all participants who were transplanted and randomized, 
excluding mis-randomized participants. Mis-randomized participants are defined as cases 
where IRT contacts were made by the Investigator/qualified site staff either prematurely or 
inappropriately to confirmation of the participant’s final randomization eligibility and treatment 
was not administered to the participant. Following the intention-to-treat (ITT) principle, 
participants will be analyzed according to their treatment assignment at randomization. 
Participant demographics, baseline characteristics, efficacy and renal function measured by 
GFR will be performed on the FAS. 
The safety set (SAF) consists of all participants in FAS who received at least one dose of study 
drug (i.e., at least one dose of TAC after randomization in the Control arm and at least one dose 
of CFZ533 in the CFZ533 arms). Participants will be analyzed according to the treatment they 
actually received. All safety analyses, including renal function parameters other than GFR, will 
be performed on the SAF using on-treatment (between start and end of treatment defined in 
Section 2.1.1) data unless otherwise specified.  
The PK analysis set (PKS) will include all participants with at least one available valid (i.e., not 
flagged for exclusion) PK concentration measurement, who received any study drug and with 
no protocol deviations that impact on PK data, e.g. if a dose was taken more than 7 days after 
the planned date. 
The total screened participants and each analysis population above will be summarized in terms 
of the frequencies and percentages. Listings of randomized participants and of the participants 
excluded from analysis sets will be provided.  
Rules for exclusion from analysis sets is in Table 5-9. 
 
Subgroup of interest 
No subgroup is defined. 
2.2 
Participant disposition, demographics and other baseline 
characteristics 
Data for background and demographic variables will be summarized by treatment arm based 
on the FAS. Continuous variables will be presented with mean, median, 25th percentile, 75th 
percentile, standard deviation, minimum, maximum, and the number of non-missing 
observations.  Categorical data will be displayed via absolute and relative frequencies for each 
category (including a category labelled “missing” when appropriate). 
The following demographics and baseline characteristics will be reported by treatment arm: 
• Recipient demographics: age, age group (< 60 years and ≥ 60 years), gender, race (Asian, 
White, Black or African American, American Indian or Alaska Native, Native Hawaiian 
or Other Pacific Islander, and Other), height, weight, body mass index (BMI), and region 
(North America, Europe, and Rest of the world). 


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• Recipient baseline characteristics: HbA1c level at the time of transplantation, renal 
function measured by eGFR (MDRD4) (< 30, [30, 55), [55, 70), [70, 90), and ≥ 90 
mL/min/1.73m2), diabetic status* (Y/N) prior to transplantation, HCV status (pos/neg), 
ratio of spot urine protein to creatinine categories**, and evidence and treatment of HCC 
prior to transplantation (Y/N). 
• Donor background information: age, gender, race, weight, allograft weight, donor 
characteristics (standard criteria donor (SCD), expanded criteria (EXD)), donor category 
(deceased heart beating, deceased non heart beating), cause of death, ABO blood 
group/type, RH type, and hypotension prior to procurement (Y/N/unknown). 
• Recipient liver transplant background information: end stage disease leading to 
transplantation, MELD score summary and by-category (≤ 14,[15, 19], [20, 24], [25, 29], 
and ≥ 30), UNOS classification (Status 1A, Status1B, and Status Non 1), CHILD 
classification (Status A, Status B, and Status C), and ABO match (Identical and 
Compatible). 
• Recipient and donor viral serology for: CMV, EBV, HCV, HBsAg Anti-Hep B Surface, 
Anti-Hep B Core, and HIV. CMV donor/recipient constellation (D+R+ / D-R- / D+R- / 
DR+) is included. 
• Liver transplantation procedure information: cold ischemia time summary and by category 
(≤ 6, (6, 12], and > 12 hours). 
* A patient is identified as not having diabetes prior to transplantation if all of the following are 
true: 
1. Diabetes was not included in the medical history. 
2. Glucose (random) < 11.1 mmol/L (200 mg/dL) at the time of transplantation. 
3. Diabetes was not recorded as reason for any medication given prior to transplantation. 
4. HbA1c < 5.7% at the time of transplantation.  
5. If any of the above criteria is unknown (e.g., lab values), the participant will be 
considered to have no diabetes pre-transplant if all other criteria are true.  
** Ratio of spot urine protein to creatinine will be categorized as < 30 mg/g, [30, 500) mg/g, 
[500, 1000) mg/g, [1000, 3000) mg/g, and ≥ 3000 mg/g. 
For variables which are collected multiple times before transplantation, the last available values 
on or prior to transplantation will be used for summary if not specified otherwise. 
Demographics, baseline characteristics, and recipient liver transplant background information, 
will be provided in the listings. 
 
Medical history 
Relevant medical history/current medical conditions will be summarized by primary system 
organ class, preferred term, and treatment arm. Frequencies and percentages of participants in 
the FAS in each treatment arm will be presented. 
Relevant ongoing medical history/current medical conditions data will be listed.   


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Participant disposition 
The number and percentage of participants who prematurely discontinued from study 
medication and from study (by primary reasons), and who completed treatment periods (12-
month and 24-month),  respectively and cumulatively, will be provided by treatment based on 
the FAS.  
A listing of participant disposition and randomization information and a listing of primary 
reasons and date/study day for premature discontinuation of the randomized study treatment 
will be provided. Discontinuation of study medication reasons are from Disposition CRFs. 
2.3 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
The SAF will be used for the analyses below. All study treatment summaries will be presented 
by treatment arm. Categorical data will be summarized as frequencies and percentages. For 
continuous data, 𝑛𝑛, mean, standard deviation, median, 25th and 75th percentiles, minimum, and 
maximum will be presented. 
 
Study treatment / compliance 
Administration of study drug (CFZ533, MMF, TAC, and CS) 
The duration of exposure (in days and participant-years) to CFZ533, MMF and TAC will be 
summarized continuously, in addtion 𝑛𝑛 and percentages of participants in each exposure 
category in days (as defined in Table 2-1) will be summarized.  
The duration of exposure will be calculated by subtracting the date of the last administration of 
study medication from the date of first administration. For CFZ533, the dosing interval will be 
considered (i.e., 14 days after the last dose of CFZ533, see Section 2.1.1).  In calculating the 
duration of treatment, days of temporary interruption of study medication (CFZ533, TAC, and 
MMF) for any reason will be included. For CS, the total duration will be the sum of each 
individual CS duration. The list of CS will undergo a medical review prior to the analysis and 
medications which are not considered CS will be removed (e.g., Basiliximab, Ceftriaxone, 
Mycophenolate (any type), and Tacrolimus (any type)). Further, the frequency of dose changes 
(including dose interruption) will be presented by reason for change. 
In addition, the dose administration records for CFZ533, MMF, TAC and CS will be provided 
in the listings. 
Table 2-1 
Exposure duration categories for study treatment 
TAC, MMF 
CFZ533 
Start 
End 
Start 
End 
Days 
0 
14 
0 
28 
15 
28 
14 
29 
42 
14 
29 
56 
43 
56 
14 
57 
70 
14 


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TAC, MMF 
CFZ533 
Start 
End 
Start 
End 
Days 
57 
84 
71 
84 
14 
85 
98 
14 
85 
112 
99 
112 
14 
113 
126 
14 
113 
140 
127 
140 
14 
141 
154 
14 
141 
168 
155 
168 
28, 14 
169 
224 
169 
224 
56 
225 
280 
225 
280 
56 
281 
336 
281 
336 
56 
337 
420 
337 
420 
84 
421 
504 
421 
504 
84 
505 
588 
505 
588 
84 
589 
672 
589 
672 
84 
673 
756 
673 
756 
84 
757 
840 
757 
840 
84 
841 
924 
841 
924 
84 
925 
1008 
925 
1008 
84 
1009 
1092 
1009 
1092 
84 
1093 
1176 
1093 
1176 
84 
1177 
1260 
1177 
1260 
84 
1261 
1344 
1261 
1344 
84 
1345 
1428 
1345 
1428 
84 
1429 
1512 
1429 
1512 
84 
1513 
1596 
1513 
1596 
84 
1597 
1680 
1597 
1680 
84 
1681 
1764 
1681 
1764 
84 
1765 
1848 
1765 
1848 
84 
1849 
1932 
1849 
1932 
84 
1933 
2016 
1933 
2016 
84 
2017 
2100 
2017 
2100 
84 
2100 
EOT 
2100 
EOT 
 
 
Dose change, interruption, and discontinuation 
The number and percentage of participants with dose changes (MMF and TAC), dose 
interruptions (only in cases of ascites drainage; see Section 4.3 in the Protocol), and permanent 
discontinuation will be summarized by reason for change.  


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Average daily dose of study drug 
The average daily dose of each study drug (CFZ533, TAC, and MMF) will be presented by 
treatment and by visit window from baseline. In calculating average dose, zero daily dose will 
be used for periods of temporary interruption.   
Corticosteroids dosage 
The average daily dose and the daily body weight-adjusted prednisone equivalent dosages 
[mg/kg/day] will be summarized using descriptive statistics by treatment. Steroids administered 
after the discontinuation of randomized study medication will be ignored. To adjust the dose, 
the body weight measured closest to the start of a steroid dose will be used. 
The averages will only include corticosteroids given for “Rejection prophylaxis” purpose.  
Steroids (p.o. or i.v.) used for the treatment of rejection episodes will be presented separately. 
Inhaled, intra-nasal, and topical corticosteroids will not be included in either analysis. 
For conversion factors to prednisone equivalent dosages see Table 5-8. 
 
Prior, concomitant and post therapies 
Prior/concomitant therapies will be summarized based on the SAF. 
All medications recorded on the concomitant medications and significant non-drug therapies 
eCRF page will be classified as prior or concomitant medications and grouped by Anatomical 
Therapeutic Classification (ATC) codes and preferred terms (PT). Number and percentage of 
participants using each medication (by ATC and PT) will be presented by treatment. 
Prior medications will be drugs taken prior to the start of study treatment regardless of whether 
they continue thereafter; any medication given at least once between the start and the end of 
study treatment was a concomitant medication, including those started before randomization 
and continued into the treatment period. The start and the end of study treatment is defined in 
Section 2.1.1. 
Immunosuppressive therapies taken after discontinuation of study drug will be summarized 
separately from study drug therapies. Immunosuppressive therapies are defined as by the 
investigator in the CRF. 
Rules for imputing incomplete dates are described in Section 5.2.   
2.4 
 Analysis of the primary objective 
The primary objective is to evaluate the rate of composite efficacy failure (BPAR, graft loss, or 
death) with CFZ533 600 mg and 300 mg Q2W maintenance regimen compared to TAC Control 
at Month 12 post-transplantation. Analysis will be on the FAS. 
The analysis of the primary objective has been modified due to the early termination of the 
study. 


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Primary endpoint 
The primary efficacy endpoint is occurrence of composite efficacy failure (BPAR, graft loss, or 
death) at 12 months post-transplantation based on central pathologist evaluation (graft loss and 
death will be from local evaluation).  The estimand is: 
• Population: defined through appropriate inclusion/exclusion criteria to reflect the 
targeted population. 
• Endpoint: composite efficacy failure at Month 12 post-transplantation, defined as 
BPAR, graft loss, or death. 
• Treatment of interest: the randomized treatment, CFZ533 300 mg + MMF, CFZ533 
600 mg + MMF, and TAC+MMF, regardless of treatment or study discontinuation, 
loss to follow-up, ascites-based dosing adjustment, or administration of CS (treatment 
policy). 
• Summary measure: the difference in the proportion of participants with composite 
efficacy failure in CFZ533 arms at 12 months post-transplantation as compared to 
control. 
BPAR is defined as an acute rejection confirmed by biopsy within 48 hours of the suspected 
rejection (preferably within 24 hours) with a rejection activity index (RAI) score ≥ 3. Events 
of rejection which were discovered incidentally during the study (e.g., via optional Month 12 
biopsy or standard of care biopsy) with no clinical suspicion of acute rejection will not be 
included in the assessment of the primary endpoint.  Note that ascites-based dosing adjustment 
is not considered a rescue medication because the occurrence of ascites is not due to lack of 
efficacy. Accordingly, administering CFZ533 to compensate drug loss caused by ascites cannot 
be considered rescue medication.  In addition, this unscheduled administration aims not to result 
in exposure higher than that seen in participants with no ascites. 
 
Statistical hypothesis, model, and method of analysis 
A Poisson distribution will be assumed for the number of participants with composite efficacy 
failures. Specifically, the number of composite efficacy failure events in group 𝑖𝑖 will be 
assumed to follow a Poisson distribution, i.e., 𝑦𝑦𝑖𝑖 ~ Poisson (𝜇𝜇𝑖𝑖), where 𝜇𝜇𝑖𝑖 is the expected 
number of events in group 𝑖𝑖, with 𝜇𝜇𝑖𝑖= 𝜆𝜆𝑖𝑖,𝑇𝑇𝑡𝑡𝑖𝑖,𝑇𝑇, with 𝑡𝑡𝑖𝑖,𝑇𝑇 being the total on-treatment time in 
group 𝑖𝑖 in years up to 𝑇𝑇= 12 months, thus incomplete follow-up of participants due to early 
discontinuation is adjusted for. The follow-up time will be calculated as [min(upper limit of the 
Month 12 visit window,  date of treatment discontinuation, date of lost-to-follow-up) – date of 
randomization]. The probability of a composite event occurring before 𝑇𝑇 can the be derived as 
𝜃𝜃𝑖𝑖= 1 −exp (−𝜆𝜆𝑖𝑖,𝑇𝑇). 
For the purposes of analysis, time of discontinuation of study drug will be determined by the 
date of last study drug administration as follows: 
• Arm 1: earliest date of discontinuation of study drug (TAC or MMF) 
• Arms 2 and 3: CFZ533 study drug discontinuation date + 14 days to account for the 
dosing interval.   


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The exposure-adjusted treatment difference in composite efficacy failure rates between a 
CFZ533 arm and Control at Month 12 will then be evaluated as for the primary estimand.  
Specifically, a CFZ533 arm will be considered successful if the annualized composite efficacy 
failure rate difference between this CFZ533 arm and the Control arm is less than 15% with 
probability greater than 80%: 
𝑃𝑃(𝜃𝜃CFZ533 −𝜃𝜃control < 0.15|data) > 0.8 
The required posterior probabilities will be estimated from simulations of the posterior 
distributions of 𝜃𝜃CFZ533 −𝜃𝜃control and compared to the threshold for the level of proof. The 
prior distributions of 𝜆𝜆𝑖𝑖,𝑇𝑇 will be assumed to be non-informative (specifically, Gamma(0.001, 
0.001)). The posterior mean composite efficacy failure rates for each treatment arm and for the 
difference in mean response rates between CFZ533 treatment arms and control will be presented 
together with 95% credible intervals. 
The posterior probability of the primary decision rule 𝑃𝑃(𝜃𝜃CFZ533 −𝜃𝜃control < 0.15|data) will 
be derived. In addition, posterior probabilities of the composite efficacy failure rates for each 
treatment arm and the treatment difference being above various thresholds such as 10%, 15%, 
and 20% will also be presented, i.e. 𝑃𝑃(𝜃𝜃CFZ533 −𝜃𝜃control < 𝜃𝜃0|data), where 𝜃𝜃0= 0.1, 0.12, 0.15, 
and 0.2. 
 
Handling of missing values/censoring/discontinuations 
Participants continued to be followed until Month 12 visit, early study drug discontinuation, or 
lost to follow-up, whichever  first. If no event is observed, the partcipant is considered as 
censored and will still contribute to the analysis as described above. 
 
Sensitivity analyses 
No sensitivity analysis is planned. 
 
Supplementary analyses 
Kaplan-Meier (KM) estimates of events rates of composite efficacy failure and BPAR censored 
at Month 12 will be respectively summarized and presented graphically. In addition, 
participants who have not experienced composite efficacy failure, are lost to follow-up, or do 
not attend the Month 12 visit after treatment discontinuation will be censored with the censoring 
time defined by the last contact day. 
For Kaplan-Meier estimates, Greenwood’s formula will be used to estimate the variance and to 
derive 2-sided 95% 𝑍𝑍-test based confidence intervals for the difference between a CFZ533 arm 
and the Control arm. The confidence interval will be constructed as: 
൫𝑟𝑟𝑇𝑇𝑖𝑖– 𝑟𝑟𝐶𝐶൯± 𝑍𝑍𝛼𝛼/2 ∗SE𝑑𝑑𝑖𝑖, 
where   
𝑟𝑟𝑇𝑇𝑖𝑖= Kaplan-Meier estimate of the failure rate for CFZ533 arm up to 12 months, 𝑖𝑖=
1, 2, 
𝑟𝑟𝐶𝐶= Kaplan-Meier estimate of the failure rate for the control arm up to 12 months, 


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SE𝑑𝑑𝑖𝑖= ටSE𝑇𝑇𝑖𝑖
2 + SE𝐶𝐶
2, 𝑖𝑖= 1, 2, 
SE𝑇𝑇𝑖𝑖=  Estimated standard error for CFZ533 arm based on Greenwood’s formula, 𝑖𝑖=
1, 2, 
SE𝐶𝐶= Estimated standard error for the control arm based on Greenwood’s formula, and 
𝛼𝛼= 0.05. 
Summaries of the composite efficacy failure and its individual components will be provided. 
Acute rejection events will be summarized by treatment and severity for central and local 
assessment, respectively. Histological evidence and pathological assessment of liver allograft 
biopsies will be provided in the listings for central and local assessment, respectively. 
2.5 
Analysis of the key secondary objective 
 
Key secondary endpoint 
The key secondary objective is to evaluate renal function (eGFR) at Month 12. GFR will be 
estimated using the MDRD formula (Levey et al 2006): 
GFR [mL/min/1.73m2] = 175 ∗(𝐶𝐶−1.154) ∗(𝐴𝐴−0.203) ∗𝐺𝐺∗𝑅𝑅,  
where  
𝐶𝐶 is the serum concentration of creatinine [mg/dL], 
𝐴𝐴 is age [years], 
𝐺𝐺= 0.742 when gender is female, otherwise 𝐺𝐺= 1, and 
𝑅𝑅= 1.212 when race is black, otherwise 𝑅𝑅= 1. 
Central laboratory serum creatinine values will be used for all renal function data analysis. 
Summary statistics for central eGFR change from randomization will be produced. 
The estimand is:  
• Population: defined through appropriate inclusion/exclusion criteria to reflect the 
targeted population. 
• Endpoint: change from randomization in eGFR at 12 months post-transplant 
• Treatment of interest: the randomized treatment, CFZ533 300mg + MMF, and 
CFZ533 600mg + MMF, TAC+MMF, regardless of treatment or study 
discontinuation, loss to follow-up, ascites-based dosing adjustment, or administration 
of CS (treatment policy). 
• Summary measure: the difference in mean eGFR on CFZ533 arms at 12 months 
posttransplantation as compared to control.  
The mean change for each arm will be obtained through covariate-adjusted treatment effects 
using MMRM where visit is treated as a categorical variable. The model will contain treatment 
arm, visit, treatment arm*visit interaction, and eGFR at randomization with unstructured 
covariance matrix. In case of a convergence issue with the MMRM model, Compound 
Symmetry structure will be used  for the covariance matrix. If convergence issue still persists, 


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an ANCOVA model will be used for Month 12 visit. The estimand will be evaluated in the FAS 
population by comparing the difference in mean change between each CFZ533 arm and control.   
 
 Statistical hypothesis, model, and method of analysis 
The objective is to demonstrate that either CFZ533 treatment arm is superior to the control arm 
with respect to mean change in eGFR at 12 months post-transplantation. 
The null hypothesis is that the mean change from randomization in eGFR for a CFZ533 
treatment arm is not superior to that in the control arm. 
The alternative hypothesis is that the mean change from randomization in eGFR for a CFZ533 
treatment arm is superior to that in the control arm. 
The null hypothesis will be tested at a significance level of 10% against a one-sided alternative 
hypothesis, and the test statistic will be the estimated treatment difference at Month 12 based 
on least squares means from either the MMRM to allow for adjustment for correlations between 
time points within participants or the ANCOVA model in case of convergence issue. 
 
Handling of missing values/censoring/discontinuations 
The primary analysis is based on the FAS. Since participants continue to be followed after early 
study drug discontinuation, the number of missing values is expected to be limited. In case of 
missing values, 
1. For participants with death, a value of 0 will be imputed after the time of death.   
2. Participants that are lost to follow-up or have missing assessments will have missing 
values assessed via MMRM assuming MAR. 
 
Supplementary analyses 
The analysis of eGFR (MDRD-4) will be repeated with assessments occurring after 
discontinuation of study medication counting as missing in the MMRM model (an 
“on-treatment” analysis). 
2.6 
Analysis of secondary efficacy objectives 
Not applicable as this is removed from the abbreviated CSR. 
2.7 
Safety analyses 
The SAF will be used for safety analyses unless otherwise specified. General safety summaries 
(tables, figures, etc.) will include only data from the on-treatment period with the exception of 
baseline data which will also be summarized where appropriate (e.g., change from baseline 
summaries), unless otherwise specified. For CFZ533 arms, the on-treatment period lasts from 
the date of first administration of study treatment to 14 days after the date of the last actual 
administration. For the Control arm, it lasts to the day of the last actual administration of TAC.  


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Adverse events (AEs) 
Adverse events (AEs) will be presented and summarized for all treatment-emergent events, with 
a start date after randomization and covering until 14 weeks after the last administration of 
CFZ533 for CFZ533 arms and 12 weeks after that of TAC for TAC arm. In addition, a separate 
summary for death will be provided. Malignancies are summarized under SAEs. 
All information obtained on adverse events will be displayed by treatment group. The number 
and percentage of participants with treatment-emergent adverse events and serious adverse 
events (events started after the first dose of study medication or events present prior to start of 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways: 
• by treatment, primary system organ class and/or preferred term 
• by treatment, primary system organ class, preferred term and/or maximum severity 
Separate summaries will be provided for AEs leading to treatment discontinuation. 
In addition, the proportion of participants with infections will be summarized as follows: 
• Infections by type of infection (viral, fungal, bacterial, others) and severity. 
• Serious infections by type of infection (viral, fungal, bacterial, others) and severity. 
The incidence rate of infection by type  (viral, bacterial, fungal, and others) will be tabulated 
for each treatment arm. The key safety parameter is serious infections. The number of serious 
infections will be used to evaluate the stopping rule as outlined in Section 9.1.5 in Protocol. 
Data collected on AE CRFs will be coded with the MedDRA dictionary that gives preferred 
term (PT) and system organ class (SOC) information. AEs and infections data will be 
analyzed as a whole under the heading of AEs for each treatment arm. If a participant has 
multiple occurrences of an AE, the participant will only be counted once in the corresponding 
AE category. If participant has multiple AEs within a SOC, the participant will be counted only 
once for that SOC. If a participant has multiple severity ratings for an AE, the participant will 
be counted under the maximum rating. 
Incidence rates of safety topics of interests from eCRS will be summarized by risk categories. 
Safety topics of interests are defined in Table 2-2. 
Table 2-2 
Safety topics of interests 
Safety topics of interests 
Search strategy 
Infections 
MedDRA search strategy SOC “Infections and infestations” 
[10021881] and HLGT “Microbiology and serology investigations” 
[10027529]. 
Malignancies including 
Lymphoproliferative disorder 
SMQ Malignant or unspecified tumours (Narrow) (20000091), SMQ 
Malignancy related therapeutic and diagnostic procedures 
(20000093) 
and SMQ Tumour markers (20000094) 
Thrombosis 
MedDRA search strategy SMQ “Embolic and thrombotic 
events (SMQ)” [20000081] and HLT “Coagulation and bleeding 
analyses” [10009728]. 


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Immunogenicity 
PT: Drug specific antibody present [10013745] 
SMQ: Hypersensitivity (Narrow), (20000214) 
Vaccination failure 
Therapeutic product ineffective (10060769) 
Therapeutic response changed (10074941) 
Therapeutic response decreased (10043414) 
Therapeutic response delayed (10053181) 
Therapy non-responder (10051082) 
Antibody test abnormal (10061425) 
Antibody test negative (10061426) 
Immunology test abnormal (10061214) 
Vaccination failure (10046862) 
Vaccine breakthrough infection (10067923) 
Absence of immediate treatment response (10081766) 
Drug effect less than expected (10083365) 
 
The AE, SAE, infections, and serious infections summarized as above will also be provided in 
corresponding listings. 
New onset of diabetes mellitus (NODM) 
New onset diabetes mellitus is defined as: 
a. All of the following should be true (no diabetes pre-transplantation): 
1. Diabetes was not included in the medical history. 
2. Glucose (random) < 11.1 mmol/L (200 mg/dL) at the time of transplantation. 
3. Diabetes was not recorded as reason for any medication given prior to transplantation. 
4. HbA1c < 5.7% at  the time of transplantation  
5. If any of the above criteria is unknown (e.g. lab values), the participant will be 
considered to have no diabetes pre-transplant if all other criteria are true;  
AND 
b. At least one of the following should be true (diabetes onset after transplantation): 
1. Two consecutive fasting plasma glucose (FPG) ≥ 126 mg/dL (7.0 mmol/L) any day 
after Day 29 or a random plasma glucose (RPG) ≥ 200 mg/dL (11.1 mmol/L). 
2. HbA1c ≥ 6.5% (only from Day 85 onward). 
3. Diabetes reported as an AE that is prevalent after Day 29. 
4. Any concomitant medication with ATC level 2 code “A10” (drugs used in diabetes), 
if prevalent after Day 29. Here “prevalent after Day 29” means the described drug has 
been consecutively used for at least 30 days since Day 29. 
Note that participants with steroid-induced diabetes are excluded. The date of onset is the 
earliest date when any of the conditions in Criterion b above is met. The proportion of 
participants developing new onset diabetes mellitus (NODM) after transplantation will be 
summarized by treatment group. Death, graft loss, or loss to follow up without NODM before 
Month 12 will not be counted as developing NODM. This analysis will be performed using 


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participants in the FAS population who do not have diabetes mellitus at the time of 
transplantation according to Criterion a.  
Disclosure reporting 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment-
emergent adverse events which are not serious adverse events with an incidence greater than 
5% and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by treatment, system organ class and preferred term on the SAF. 
If for a participant, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE’s in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
 
Deaths 
In addition to the output required for disclosure, the number of deaths will be tabulated by 
treatment.  
 
Laboratory data 
Analyses of laboratory data include data since baseline (liver Tx) but changes are calucated 
based on the day of randomization. Summary statistics (mean, standard deviation, minimum, 
median, maximum, and 25% and 75% percentiles) of quantitative lab variables, including 
change from randomization, will be provided by parameter, treatment, and visit. Similarly, 
proportion of notable abnormalities of key laboratory tests (Table 5-4) by parameter, treatment, 
and visit and its listing will be provided. Shift tables using the normal/abnormal classification 
will be used to compare randomization to the worst on-treatment value.  
The following lab parameters will be presented: liver function (AST, ALT, GGT, ALP, and 
total bilirubin), renal function (eGFR, creatinine, and urine protein/creatinine ratio), lipids, and 
hematology (WBC, neutrophils, and lymphocytes). eGFR will also be summarized by CKG 
stages (< 15, [15, 30), [30, 45), [45, 60), [60, 90), and ≥ 90) by treatment arm and by visit. 
Liver events will be presented as defined in Table 5-6. 


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Virology monitoring 
Average duration of infection-free period will be presented by treatment. The frequency of 
following categories  will also be summarized by treatment: 
• EBV: > 2000 copies/mL; 
• CMV: ≤ 5000, (5000, 1000], and > 10000 copies/mL; 
For CFZ533 participants, the counts will be provided separately for participants who remain on 
CFZ533 vs. those who switch from CFZ533 to discontinuation or to SOC. In participants who 
switch from CFZ533, summary statistics of the mean time from the end of switch to viral load 
elevation (EBV > 2000 copies/mL, CMV > 10000 copies/mL) will be provided.  A listing of 
participants above the thresholds will be provided by treatment and visit. The day of end of 
switch is the same as the day of discontinuation of CFZ533 (defined in Section 2.1.1). 
 
Other safety data 
2.7.4.1 
Immunogenicity  
Blood samples for immunogenicity testing will be collected from all CFZ533-treated 
participants only, at selected time points, as defined in the assessment schedule (Table 8-1, 8-
2, and 8-3 in the Protocol). The presence of anti-CFZ533 antibodies will be assessed using 
screening and confirmatory assays. An integrated PK/PD and immunogenicity approach, 
focusing on the clinical and functional consequences of anti-drug antibodies will be applied. 
The consequences of an immune response to CFZ533 may be correlated with a loss of exposure 
(free CFZ533 measures), a loss of target engagement (sCD40 measures), or the appearance of 
immune related adverse events.  
All immunogenicity results will be listed by treatment arm, participant, and visit. No summary 
statistics will be provided. 
2.7.4.2 
ECG and cardiac imaging data 
ECG data will be listed by treatment arm, participant, and visit.  
2.7.4.3 
Vital signs 
Vital signs will be listed by treatment arm, participant, and visit. 
2.8 
Pharmacokinetic endpoints   
CFZ533 plasma concentration data will be listed by treatment, participant, and visit/sampling 
time point using PKS.  Concentrations will be given in mass per volume units.  Descriptive 
summary statistics will be provided by treatment and visit/sampling time point, including the 
frequency (𝑛𝑛, %) of concentrations below the LLOQ.  
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum, maximum, and 25% and 75% percentiles. Concentrations below 
LLOQ will be treated as zero in summary statistics. A geometric mean will not be reported if 
the dataset includes zero values. Summary statistics and graphical analysis (e.g., box plot) will 


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be provided to compare steady-state PK before and after introduction of PFS in the study. PK 
is considered steady after 10 weeks since PFS introduction. 
If data permit, PK parameters will be calculated as described in Section 8.5.2 in Protocol and 
will be listed by treatment and participant. Descriptive summary statistics will include mean 
(arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum, maximum, 
and 25% and 75% percentiles.  
In addition, CFZ533 concentration will be measured in any collected/drained ascites. The 
detailed methods and analysis will be described in the Bioanalytical Data Report. 
In the zz.xpt file in GPSII (merge file), PK concentration (free CFZ533 in plasma) will be 
expressed in unit ‘microgram/mL’ (in addition to ‘nanogram/mL’), and time will be expressed 
in unit ‘day’ (in addition to ‘hours’). 
a. Two variables for the elapsed time (e.g. EACLTM_1 and EACLTM_2) will be 
provided: elapsed time since first dose: EACLTM_1 is calculated using the Dose 
Reference ID provided in the Blood Log under Dose Reference ID series #1, 
b. EACLTM_2 is calculated using using the Dose Reference ID provided in the Blood 
Log under Dose Reference ID series #2; e.g. for Arm 2 (600 mg Q2W regimen) a 
Dose Reference ID of 17 for pre-dose PK Sample 115 on Day 225 (17ith dose of 
CFZ533) means that the elapsed time is calculated with reference to timing of 17ith 
dose of CFZ533 (and is negative). 
The zz.xpt file in GPSII will combine PK data (free CFZ533 in plasma) as well as sCD40 data 
in plasma (PD). Similar to PK output, elapsed time variables (EACLTM_1 and EACLTM_2) 
will be generated. 
2.9 
PD and PK/PD analyses 
The relationship between PK (CFZ533 concentration in plasma; Section 2.8) and PD (total 
soluble CD40 in plasma; target engagement) will be explored graphically. All participants with 
evaluable PK and PD parameters will be included in the data analysis.  
Total soluble CD40 for all participants in the PKS will be listed by treatment, participant, and 
visit/sampling time point. Total soluble CD40 concentrations will be given in mass per volume 
units (in nanogram/mL). Descriptive summary statistics will be provided by treatment and 
visit/sampling time point, including the frequency (𝑛𝑛, %) of concentrations below the LLOQ. 
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. 
The zz.xpt file in GPSII will combine PK data (free CFZ533 in plasma) as well as sCD40 data 
in plasma (PD) (Section 2.8). 
2.10 
Participant-reported outcomes 
Not applicable. 


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2.13 
Interim analysis 
An interim analysis is planned after 80% participants have reached the Month 6 visit (or have 
prematurely discontinued the study before Month 6) where all endpoints are analyzed as in the 
full CSR using on-treatment data with exceptions as described below.  
Efficacy data of all participants available at the cutoff date, including data beyond Month 6 and 
participants not yet reaching Month 6, will be included. The primary endpoint (the composite 
efficacy failure rate) will be analyzed based on a Poisson model to adjust for different follow-
up time of participants at the cutoff date (see Section 2.4.4 for details). Other primary 
comparisons not using Poisson model, including the key secondary endpoint 
 
, will be based on data up to Month 6 
visits to maximize the sample size. All summaries by visits will include all visits, including 
those beyond Month 6. Safety analyses, including AE, SAE, infections, serious infections, death,  
and safety topics of interests, will be analyzed for participants who complete Month 6 and for 
all participants based on exposure adjusted rates, respectively.  
The primary objective of the interim analysis is to enable the overall benefit-risk assessment. 
There are no plans to stop the study early for good efficacy, since it is desired to collect long-
term efficacy and safety data.     


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3 
Sample size calculation 
3.1 
Study stopping rules 
The stopping rules will be evaluated by the clinical team and the DMC will review data at 
regular intervals as described in the Section 10.2 in the Protocol and the DMC charter. In case 
the stopping rule is reached for a treatment arm, recruitment to that arm will be stopped 
and all available data reviewed. The decision to continue or permanently stop the treatment 
arm or adjust study procedures will be taken based on a thorough evaluation of the available 
data. 
Stopping rules for the incidence of centrally read moderate to severe BPARs (RAI ≥ 6) and 
serious infections will be applied. These rules are designed to ensure that they trigger if there 
is high probability (>90%) that the true BPAR or serious infection rate is greater than 20%. 
In other words, a trial is to be stopped if: 
𝑃𝑃(𝜃𝜃𝑖𝑖> 0.2|data) > 0.9, 
where 𝜃𝜃𝑖𝑖  is referring to the event rate of arm 𝑖𝑖, and the prior is Beta(1/3, 1/3). 
Based on these stopping rules and depending on the number of participants randomized to a 
treatment arm at a given point in time, the number of participants that experienced a BPAR 
or a serious infection in this arm that would first trigger the stopping criterion are given in Table 
3-1. 
Table 3-1 
Stopping rules per number of events 
Number of participants 
randomized to the treatment 
arm (N) 
Number of participants with observed event in the 
treatment arm that would lead to stopping the treatment 
arm (n) 
Observed 
event rate 
(n/N) 
3 
2 
67% 
4 
2 
50% 
5 
3 
60% 
6 
3 
50% 
7 
3 
43% 
8 
4 
50% 
9 
4 
44% 
10 
4 
40% 
11 
5 
45% 
12 
5 
42% 
13 
5 
38% 
14 
5 
36% 
15 
6 
40% 
16 
6 
38% 
17 
6 
35% 
18 
6 
33% 
19 
7 
37% 
20 
7 
35% 
21 
7 
33% 


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Number of participants 
randomized to the treatment 
arm (N) 
Number of participants with observed event in the 
treatment arm that would lead to stopping the treatment 
arm (n) 
Observed 
event rate 
(n/N) 
22 
7 
32% 
23 
8 
35% 
24 
8 
33% 
25 
8 
32% 
26 
8 
31% 
27 
9 
33% 
28 
9 
32% 
29 
9 
31% 
30 
9 
30% 
31 
10 
32% 
32 
10 
31% 
33 
10 
30% 
34 
10 
29% 
35 
11 
31% 
36 
11 
31% 
37 
11 
30% 
38 
11 
29% 
39 
12 
31% 
40 
12 
30% 
41 
12 
29% 
42 
12 
29% 
43 
13 
30% 
44 
13 
30% 
45 
13 
29% 
46 
13 
28% 
47 
14 
30% 
48 
14 
29% 
 
Properties of stopping rule 
The stopping rules as defined in Section 3.1 are designed to ensure that enrollment in a treatment 
arm will be stopped if there is a high probability (> 90%) that the true BPAR or serious infection 
rate is greater than 20%. 
Figure 3-1 indicates the probability of stopping enrollment in a treatment arm for various 
true BPAR  or serious infection rates. The thresholds for  the stopping rules ensure that the 
chance of stopping enrollment in an arm is sufficiently high for true high BPAR or serious 
infection rates, while remaining appropriately low when the true rates are low. 


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Figure 3-1 
Probability of stopping a cohort for various event rates for up to 48 
participants per arm 
 
 
3.2 
Power for primary endpoint 
The sample size justification considers the probability of success of the study based on the 
success criterion for the planned sample size. The success criterion for one CFZ533 treatment 
arm (see Section 2.4.2) is reached if 
𝑃𝑃(𝜃𝜃CFZ533 −𝜃𝜃control < 0.15|data) > 0.8, 
where 𝜃𝜃 is the composite efficacy failure rates, and the prior is Beta(1/3, 1/3).   
Table 3-2 and Figure 3-2 show the probability of success of the study for a sample size of 48 
participants in the CFZ533 arm and 32 participants in the control arm for a range of underlying 
event rates for composite efficacy failure and serious infections in the CFZ533 treatment arm 
and in the control arm.   A control rate of 10% at Month 12 is expected based on (Levitsky et 
al 2017), which examined a large registry of deceased donor liver transplant participants from 
Scientific Registry of Transplant Recipients (SRTR) and internal Novartis studies (RAD001 
Study H2304 and AEB071 Study B2203). 


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Table 3-2 
Probability of success under different event rates for 48 participants 
of CFZ533 arm and 32 participants of control arm 
𝜃𝜃CFZ533 
𝜃𝜃control 
Probability of success 
0.07 
0.070 
0.971 
0.07 
0.103 
0.986 
0.07 
0.135 
0.993 
0.07 
0.168 
0.997 
0.07 
0.200 
0.999 
0.11 
0.070 
0.833 
0.11 
0.103 
0.904 
0.11 
0.135 
0.947 
0.11 
0.168 
0.973 
0.11 
0.200 
0.987 
0.15 
0.070 
0.594 
0.15 
0.103 
0.729 
0.15 
0.135 
0.830 
0.15 
0.168 
0.900 
0.15 
0.200 
0.944 
Figure 3-2 
Probability of success under different event rates for 48 participants 
of CFZ533 arm and 32 participants of control arm 
 
3.3 
Power for key secondary variable 
The primary analysis of renal function is based on the FAS. Participants continue to be followed 
after study drug discontinuation and participants with graft loss or death will have their Month 
12 values imputed as described in Section 2.5.3. For treatment comparisons, there will be a 


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randomized sample of 48 and 32 participants in the CFZ533 and control arms respectively after 
12 months.  Assuming a common standard deviation of 16 mL/min and one-sided 𝛼𝛼= 0.10, 
there is 63, 73, or 81% power to detect a difference of 6, 7, or 8 mL/min/1.73m2 respectively.  
If the standard deviation is 20, there is 51, 59, or 67% power respectively. The power calcuation 
is completed by nQuery 8.4 based on two-sample 𝑡𝑡-test with equal variance. 
4 
Change to protocol specified analyses 
Not applicable. 
5 
Appendix 
5.1 
Analysis visit windows 
Analysis visit windows will be used to summarize the data by visit and are defined in terms of 
weeks. These will be based on the study schedule of evaluation and comprised a set of days 
“around” the nominal visits. Analysis visit windows are non-overlapping. All together they 
cover the entire study period. They are aligned to the dosing regimen, which is every 2 weeks, 
meaning a month is targeted to cover 4 weeks or 28 days. 
As participants do not necessarily have their examinations at the exact scheduled time, it might 
be misleading if all data with the same nominal visit number are lumped together for a by-visit 
analysis. Thus, all data (including reported unscheduled assessments) are “re-aligned” 
according to the window schema given below.  Note that the visit windows defined in the 
protocol are used to guide investigators whereas the ‘re-aligned’ analysis visit windows (simply 
called visit windows in the following) will be used for the analyses.   
Table 5-1 
Analysis visit windows 
 
Visit window 
(relative to date 
of Tx) 
Relative to first treatment date 
Re-aligned visit 
Start day of Visit 
window 
Midpoint 
End day of visit 
window 
1 
Screening 
Day of informed 
consent 
 
Day of transplant -
1 
2 
Baseline 
Day of Tx 
 
Day of Tx 
3 
Randomization 
Day of Tx +1 
 
Start of study 
drug# = Day 1 
4 
Day 15 
2 
8 
11 
5 
Day 22 
12 
15 
18 
6 
Day 29 
19 
22 
29 
7 
Month 1.5 
30 
36 
43 
8 
Month 2 
44 
50 
57 
9 
Month 2.5 
58 
64 
71 
10 
Month 3 
72 
78 
85 
11 
Month 3.5 
86 
92 
99 
12 
Month 4 
100 
106 
113 


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Visit window 
(relative to date 
of Tx) 
Relative to first treatment date 
Re-aligned visit 
Start day of Visit 
window 
Midpoint 
End day of visit 
window 
13 
Month 4.5 
114 
120 
127 
14 
Month 5 
128 
134 
141 
15 
Month 5.5 
142 
148 
155 
16 
Month 6 
156 
162 
190 
17 
Month 8 
191 
218 
246 
18 
Month 10 
247 
274 
302 
19 
Month 12 
303 
330 
372 (358*) 
20 
Month 15 
373 
414 
456 
21 
Month 18 
457 
498 
540 
22 
Month 21 
541 
582 
624 
23 
Month 24 
625 
666 
708 
24 
Month 27 
709 
750 
792 
25 
Month 30 
793 
834 
876 
26 
Month 33 
877 
918 
960 
27 
Month 36 
961 
1002 
1044 
28 
Month 39 
1045 
1086 
1128 
29 
Month 42 
1129 
1170 
1212 
30 
Month 45 
1213 
1254 
1296 
31 
Month 48 
1297 
1338 
1380 
32 
Month 51 
1381 
1422 
1464 
33 
Month 54 
1465 
1506 
1548 
34 
Month 57 
1549 
1590 
1632 
35 
Month 60 
1633 
1674 
1716 
36 
Month 63 
1717 
1758 
1800 
37 
Month 66 
1801 
1842 
1884 
38 
Month 69 
1885 
1926 
1968 
39 
Month 72 
1969 
2010 
End of study 
# Day 1 = randomization day if a participant was randomized but did not receive study drug. 
*  For all Month 12 analyses, the end of visit window of Month 12 visit is Day 358, instead of Day 372. 
Under this window schema, multiple records of a participant are re-aligned into the same visit 
as follows: 
• For post-randomization continuous values (except for CFZ533, TAC, and MMF trough 
level measurements and liver tests), for a given participant, if multiple numeric 
measurements for a given variable are reported in the same visit window (e.g., Month 6), 
then the measurement closest to the target visit day will be taken; if tie, take the earlier 
measurement. For screening visit, the target day is day of transplant – 1; for baseline, day 
of transplant; for randomization, start of study drug (Day 1); for other visits, the midpoint 
of the visit window.  
• For trough levels, the last value observed within a visit window is taken. 


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• For liver tests (bilirubin, SGOT, SGPT, GGT, and alkaline phosphatase), the following 
algorithm is applied: 
a. If an acute rejection occurs within a visit window with multiple liver tests reported, 
the time of the event is the date rejection first suspected, and the liver test to be 
summarized are the closest to that event (if tie, take the earlier one) 
b. If no rejection occurs, the assessment closest to the target day is taken. 
• For categorical values, the worst value of all records observed in the visit window is used. 
For parameters which are not collected at every scheduled visit 
 
, visit windows defined in Table 5-1 will be combined using the following 
rules for an applicable visit post randomization: “lower limit”  of the combined window= “upper 
limit of prior applicable visit” + 1, “upper limit” of the combined window = “target day of 
current visit” + integer part of [(“target day of next applicable visit” – “target day of current 
visit”)/2]. For example, if a parameter is measured only at Randomization, Day 29 (Month 1), 
Month 3, Month 6, and Month 12,  the combined Day 29 (Month 1) visit window will be from 
Day 2 to Day 50 (= Day 22 + interger part of [(78 - 22)/2]), Month 3 will extend from Day 51 
to Day 120 (= Day 78 + interger part of [(162 - 78)/2]), etc.. If more than one assessment falls 
into the combined window, the rules defined above handling multiple records are applied. 
5.2 
Imputation rules 
Although not the rule, partially or completely missing dates occur.  Known dates with this issue 
are the start date on the Medical History eCRF page, start and end dates on the Concomitant 
Medications eCRF page, or Surgical and Medical Procedures page eCRF page, and occasionally 
the start and end dates on the Adverse Events eCRF. 
Any date incompletely reported is split into its day, month, and year components.  In SAS, a 
numerical date value can only be defined if all these date components are known; incomplete 
dates are to be handled as text strings (character-type variables); as such, they could not be 
easily processed.  An imputation rule for incomplete dates will be performed.   
 
Study drug 
Not applicable. 
 
AE date imputation 
This algorithm is expressed in the Variable Source Derivation column as #IMPUTAEV(event) 
where event is the partial start date of the adverse event. 
Table 5-2 explains the notation used in the logic matrix. Please note that missing start dates 
will not be imputed. 
Note, if the imputed AE (or CM) start is after AE (or CM) end date, then set AE (or CM) start 
equal to AE (or CM) end date.  Missing AE end dates will not be imputed. 
Table 5-2 
Imputation logic for partial AE dates 
 


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Day 
Month 
Year 
Partial Adverse Event (or 
Concomitant Medication) 
Start Date 
Not used 
MON 
YYYY 
Treatment Start Date 
(TRTSDT) 
Not used 
TRTM 
TRTY 
The following matrix explains the logic behind the imputation. 
 
MON 
MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY 
MISSING 
NC 
NC 
NC 
NC 
YYYY < 
TRTY 
 
( D ) 
 
( C ) 
 
( C ) 
 
( C ) 
 
YYYY = 
TRTY 
 
(B) 
 
( C ) 
 
(A) 
(A) 
 
YYYY > 
TRTY 
 
(E) 
(A) 
(A) 
(A) 
 
The following table is the legend to the logic matrix. 
Relationship 
Before Treatment 
Start  
Partial date indicates AE (or CM) start date prior to Treatment Start 
Date 
After Treatment 
Start  
Partial date indicates AE (or CM) start date after Treatment Start 
Date 
Uncertain 
Partial date insufficient to determine relationship of AE (or CM) 
start date to Treatment Start Date 
Imputation Calculation 
NC / Blank 
Uncertain 
No convention 
(A) After Treatment 
Start or Uncertain 
MAX( 01MONYYYY, TRTSDT+1 ) 
(B) Uncertain 
TRTSDT+1 
(C) Before 
Treatment Start 
15MONYYYY 
(D) Before 
Treatment Start 
01JULYYYY 


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(E) After Treatment 
Start 
01JANYYYY 
 
Concomitant medication date imputation 
Table 5-3  explains the notation used in the logic matrix. Missing end dates will not be imputed. 
Table 5-3 
Imputation logic for partial concomitant medication dates 
 
 
Day 
Month 
Year 
Partial Conmed. end Date 
Not used 
MON 
YYYY 
Last Contact Date 
(LASTDT) 
Not used 
LSTM 
LSTY 
 
 
 
MON 
MISSING 
MON < LSTM 
MON = LSTM 
MON > LSTM 
YYYY 
MISSING 
NC 
NC 
NC 
NC 
YYYY < LSTY 
 
(C) 
 
(A) 
 
(A) 
 
(A) 
 
YYYY = LSTY 
 
(B) 
 
(A) 
 
(B) 
(A) 
 
YYYY > LSTY 
 
(C) 
(A) 
(A) 
(A) 
 
 
Relationship 
Before Last contact 
date  
Partial date indicates CM end date prior to Last Contact Date 
After Last contact 
date 
Partial date indicates CM end date after Last Contact Date 
Uncertain 
Partial date insufficient to determine relationship of CM end 
date to Last Contact Date 
Imputation Calculation 
NC / Blank 
Uncertain 
No convention 
(A) Before/After 
Last contact date 
Last day MONYYYY 
(B) Uncertain 
LASTDT 


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(C) Before/After 
Last contact date 
31DECYYYY 
At the interim analysis, if the above logic is applied and the imputed end date is after the cut-off 
date, then the imputed end date will be replaced with the cut-off date. 
5.3 
Laboratory parameters derivations 
Table 5-4 presents criteria to define expanded limits and notable abnormalities of key laboratory 
tests. 
Table 5-4 
Clinically notable lab abnormalities 
Laboratory variable 
Standard units  
SI units 
Liver function and related variables 
AST (SGOT) 
≥3 × ULN 
≥3 × ULN 
ALT (SGPT) 
≥3 × ULN 
≥3 × ULN 
Bilirubin 
>2 × ULN 
>2 × ULN 
Alkaline Phosphatase 
≥5 × ULN 
≥5 × ULN 
GGT 
≥5 × ULN 
≥5 × ULN 
Renal function, metabolic and electrolyte 
variables 
Urea  
≥5 × ULN 
≥5 × ULN 
Creatinine 
After Day 8±2: ≥3 mg/dL 
After Day 8±2: ≥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 
Magnesium 
< 1.0 mg/dL 
< 0.4 mmol/L 
> 3.6 mg/dL 
> 1.5 mmol/L 
Amylase 
≥ 2 × ULN 
≥ 2 × ULN 
Lipase 
≥ 2 × ULN 
≥ 2 × ULN 
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 


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Granulocytes (poly, neutrophils) 
≤1,000/mm3 
≤1 x 109/L 
Eosinophils  
≥12% 
≥12% 
Lymphocytes  
≤1,000/mm3  
≤1× 109/L 
Conversion factors from standard (US) units into SI units are given in Table 5-5. 
Table 5-5 
Conversion Factors from Standard (US) into SI units 
Laboratory Variable 
Standard 
Unit 
Conversion 
Factor* 
SI Unit 
Platelets 
% 
1 
% 
Hematocrit 
% 
1 
% 
Hemoglobin 
g/dL 
0.6206 
mmol/L 
RBC 
106/mm3 
1 
1012/L 
WBC 
103/mm3 
1 
109/L 
Sodium 
mEq/L 
1 
mmol/L 
Potassium 
mEq/L 
1 
mmol/L 
Chloride 
mEq/L 
1 
mmol/L 
Calcium 
mg/dL 
0.2495 
mmol/L 
Magnesium 
mg/dL 
mEq/L 
0.4114 
0.5 
mmol/L 
mmol/L 
Inorganic phosphate 
mg/dL  
0.3229 
mmol/L 
Urea** 
Urea[mg/dL] 
0.1665 
mmol/L 
Creatinine 
mg/dL 
88.4 
μmol/L 
Glucose 
mg/dL 
0.05551 
mmol/L 
HbA1c 
% 
1 
% 
Uric acid 
mg/dL 
0.05948 
mmol/L 
AST (SGOT) 
U/L 
1 
U/L 
ALT(SGPT) 
U/L 
1 
U/L 
Alkaline phosphatase 
U/L 
1 
U/L 
GGT 
U/L 
1 
U/L 
Total bilirubin 
mg/dL 
17.1 
umol/L 
Total cholesterol 
mg/dL 
0.02586 
mmol/L 
High Density 
Lipoprotein(HDL) 
mg/dL 
0.02586 
mmol/L 
Low Density 
Lipoprotein(LDL) 
mg/dL 
0.02586 
mmol/L 
Triglycerides 
mg/dL 
0.01129 
mmol/L 
Creatinine phosphokinase 
(CK) 
U/L 
1 
U/L 
Lipase 
U/L 
1 
U/L 
Amylase 
U/L 
1 
U/L 
Albumin 
g/dL  
10 
g/L 
Protein 
g/dL 
10 
g/L 
Urinary protein:creatinine 
mg/g 
0.113 
mg/mmol 
Table 5-6 displays the liver events to be displayed. Refer to the internal Novartis “Analysis plan 
for liver safety data” for more information. 


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Table 5-6 
Newly occurring liver enzyme abnormalities  
Safety set 
Timepoint: Week xx/Endpoint/Any time post-baseline   
--------------------------------------------------------------------------------------------------------------------- 
                                                     Active dose A        Active dose B           Placebo 
                                                        N=xxx                N=xxx                 N=xxx 
                                                        n/m (%)              n/m (%)               n/m (%) 
--------------------------------------------------------------------------------------------------------------------- 
ALT > 3x ULN                                        xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
ALT > 5x ULN                                        xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
ALT > 8x ULN                                        xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
ALT > 10x ULN                                       xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
ALT > 20x ULN                                       xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
 
ALT or AST > 3x ULN                                 xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
ALT or AST > 5x ULN                                 xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
ALT or AST > 8x ULN                                 xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
ALT or AST > 10x ULN                                xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
ALT or AST > 20x ULN                                xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
 
ALT or AST > 3x ULN & TBL > 1.5x ULN                xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
ALT or AST > 3x ULN & TBL > 2x ULN                  xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
ALT or AST > 5x ULN & TBL > 2x ULN                  xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
ALT or AST > 8x ULN & TBL > 2x ULN                  xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
ALT or AST > 10x ULN & TBL > 2x ULN                 xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
ALT or AST > 20x ULN & TBL > 2x ULN                 xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
ALT or AST > 3x ULN & INR > 1.5x ULN                xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
 
ALP > 1.5x ULN                                      xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
ALP > 2x ULN                                        xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
ALP > 3x ULN                                        xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
ALP > 5x ULN                                        xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
 
TBL > 1x ULN                                        xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
TBL > 1.5x ULN                                      xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
TBL > 2x ULN                                        xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
TBL > 3x ULN                                        xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
 
ALP > 3x ULN & TBL > 2x ULN                         xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
ALP > 5x ULN & TBL > 2x ULN                         xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
 
ALT or AST > 3x ULN & TBL > 2x ULN 
    & ALP < 2x ULN                                  xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
 
(ALT or AST > 3x ULN & TBL > 2x ULN 
    & ALP < 2x ULN) or reported Hy’s Law case       xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
 
ALT or AST > 3x ULN & (nausea or  
    vomiting or fatique or general malaise or 
    abdominal pain or (rash and eosinophilia))      xx/xxx  (xx.x)        xx/xxx  (xx.x)       xx/xxx  (xx.x) 
--------------------------------------------------------------------------------------------------------------------- 
Newly occurring: Subjects not meeting criterion at baseline and meeting criterion post-baseline 
m = Number of subjects at risk (subjects having a baseline measurement not meeting the criterion or missing but at least one 
post-baseline measurement for the laboratory test(s) <and timeframe> under consideration)  
n = Number of subjects at risk who satisfy the criterion <at post-baseline visit, endpoint, or any time> post-baseline 
 
Notes:  
1. “Hy’s law case” is a lower level term in MedDRA (10070546) and may be reported as AE. Only new onsets will be considered.  
2. The event which combines lab information and signs/symptoms information is derived using LB and the liver events eCRF, but 
is not using the AE dataset. Even if in the FDA 2009, they added as a PT anorexia, the choice was to kept it out from our 
definition as too unspecific. 
3. Black (mandatory): Those mentioned in the FDA guidance (section 2). The last one is mandatory if liver eCRFs are used. 
4. Black (mandatory) and italic: Additional criteria mentioned in the Novartis Hepatotox guideline (section 5.1). 
 
 


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Clinically notable vital signs 
Table 5-8 presents the criteria that define notable abnormalities of vital signs data. 
Table 5-7 
Clinically notable vital signs 
Vital sign variables 
Notable criteria 
Systolic BP (mm/Hg) 
160 or higher (hypertension stage 2) 
Diastolic BP (mm/Hg) 
110 or higher (hypertension stage 2) 
 
Steroid conversion factors 
Steroids will be displayed using prednisone equivalent body weight adjusted doses. The doses 
displayed in the following table are considered equivalent. To determine prednisone 
equivalent doses, doses will be multiplied by the conversion factor shown in Table 5-8. To 
adjust the dose, the body weight measured closest to the start of a steroid dose will be used 
(from vital signs eCRF).  
Table 5-8 
Steroids conversion factors 
WHO drug code 
Preferred Term Corticosteroid 
Equivalent Dose [mg] 
Conversion Factor 
000447xx 
Prednisone  
5 
1 
000162xx 
Prednisolone 
5 
1 
000496xx  
Methylprednisolone 
4 
1.25 
012428xx 
Meprednisone 
4 
1.25 
001867xx 
Prednylidene 
5 5/7   
0.875 
000319xx 
Triamcinolone 
4 
1.25 
000146xx  
Cortisone  
25 
0.2 
000286xx 
Hydrocortisone 
20 
0.25 
002131xx 
Fludrocortisone 
2 
2.5 
000085xx 
Betamethasone 
0.75 
20/3 
000664xx  
Paramethasone 
2 
2.5 
000160xx  
Dexamethasone 
0.75 
20/3 
008827xx 
Deflazacort 
6 
5/6 
5.4 
Definition/Derivation of Efficacy Variables 
All efficacy endpoints regarding biopsy described will be summarized based on the central 
pathologists’ evaluation of all biopsy readings.  If the central pathologist’s evaluation is 
missing, then the local evaluation will be used. 
All acute rejections determined by local biopsy reading are recorded in the clinical database on 
the Liver allograft rejection and Liver allograft biopsy eCRFs. Central pathological reading will 
be electronically trasnferred. 


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Efficacy endpoint derivations based on central readings 
Humoral rejection/AMR 
 A rejection is considered as a humoral rejection if: 
• MI.MITEST = “AAMR” and MI.MIRESC = “Y” ; AND 
• Reason for biopsy = “Suspicion of rejection” on Liver Allograft Biopsy eCRF page. 
Date of AMR will be MI.MIDAT_RAW when MI.MITEST = “AAMR” and MI. MIRESC= 
“Y”. 
AR 
A rejection is considered an AR if: 
• Antibody-mediated rejection  (see above); OR 
• MI.MITEST = “ATCELL” and MI. MIRESC = “Y” ; AND 
• Reason for biopsy = “Suspicion of rejection” on Liver Allograft Biopsy eCRF page. 
Date of AR will be min(MI.MIDAT_RAW when MI.MITEST = “AAMR”, 
MI.MIDAT_RAW when  MI.MITEST = “ATCELL”) when MI. MIRESC= “Y”. 
BPAR 
A rejection is considered a BPAR if: 
• AR (see above); AND 
• MI.MITEST = “RAITOT” and MI.MIRESN ≥ 3; AND 
• Reason for biopsy = “Suspicion of rejection” on Liver Allograft Biopsy eCRF page. 
Date of BPAR will be date of MI.MIDAT_RAW when MI.MITEST = “RAITOT” and 
MI.MIRESN ≥ 3. 
Steroid resistant AR 
A rejection is considered a steroid resistant AR if 
• AR (see above); AND 
• Was the rejection steroid resistant = “Yes” from Liver Allograft Rejection eCRF page 
Date of steroid resistant AR will be the date of AR (see above). 
Antibody treated AR 
A rejection is considered an antibody treated AR if 
• AR (see above); AND 
• Was antibody treatment administered = “Yes” from Liver Allograft Rejection eCRF page 
Date of antibody treated AR will be the date of AR (see above). 


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Steroid treated AR 
A rejection is considered an steroid treated AR if 
• AR (see above); AND 
• Were steroids administered = “Yes” from Liver Allograft Rejection eCRF page 
Date of steroid treated AR will be the date of AR (see above). 
Steroid resistant BPAR 
A rejection is considered a steroid resistant BPAR if 
• BPAR (see above); AND 
• Was the rejection steroid resistant = “Yes” from Liver Allograft Rejection eCRF page 
Date of steroid resistant BPAR will be the date of BPAR (see above). 
Antibody treated BPAR 
A rejection is considered an antibody treated BPAR if 
• BPAR (see above); AND 
• Was antibody treatment administered = “Yes” from Liver Allograft Rejection eCRF page 
Date of antibody treated BPAR will be the date of BPAR (see above). 
Steroid treated BPAR 
A rejection is considered an steroid treated BPAR if 
• BPAR (see above); AND 
• Were steroids administered = “Yes” from Liver Allograft Rejection eCRF page 
Date of steroid treated BPAR will be the date of BPAR (see above). 
 
Efficacy endpoint derivations based on local readings 
AR 
A rejection is considered an AR if: 
• Primary clinical diagnosis = “Acute rejection” or “Acute  and chronic rejection from 
Liver Allograft Rejection eCRF page. 
Date of AR will be “date rejection was first suspected” from the Liver Allograft Rejection eCRF, 
or if missing, the first available date of the biopsy of the particular rejection episode from the 
Liver Allograft Biopsy eCRF page. 
Treated AR (tAR) 
A rejection is considered a tAR if:  
• Acute rejection  (see above); AND 
• Was anti-rejection therapy administered  = “yes” from Liver Allograft Rejection 
eCRF page 


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Date of tAR will be the date of the corresponding AR (note: tAR is the subset of AR). 
BPAR 
A rejection is considered a BPAR if:  
• Histological Evidence of Acute Rejection = “Yes” and of Acute and Chronic Rejection = 
“Yes” from Liver Allograft Biopsy eCRF page; AND  
• Total RAI score ≥ 3 and Reason for biopsy = “Suspicion of rejection” from Liver 
Allograft Biopsy eCRF page. 
Date of BPAR will be the date of the corresponding AR (note: BPAR is a subset of AR). 
Treated BPAR (tBPAR) 
A rejection is considered a tBPAR if:  
• Biopsy-proven acute rejection (BPAR) (see above) AND 
• Was anti-rejection therapy administered = “yes” from Liver Allograft Rejection eCRF 
page 
Date of tBPAR will be the date of the corresponding AR (note: tBPAR is the subset of AR). 
Death  
Death will be recorded at either Study Completion, Follow-up, or as the outcome of an 
AE/Infection, if it occurs.  
The date of Death will be the date of death recorded on the Disposition eCRF. 
Graft loss  
The allograft will be  presumed to be lost on the day the participant becomes newly listed for a 
liver allograft or the day the participant is re-transplanted or dies due to liver failure. 
Graft losses will be identified from Graft Loss CRF page.  
Loss to follow-up 
A lost-to-follow-up participant is one who discontinued the study and did not experience BPAR, 
graft loss, or death, and whose last day of contact is prior to the day of the lower limit of the 
(Month 12 or 24) visit window. The date of loss to follow-up is the last contact date. 
Composite efficacy failure 
The date of composite efficacy failure will be the earliest non-missing date among the individual 
components of the composite endpoint. 
For the composite endpoints and each individual endpoint, if the date of the event is not 
available, then the event will be included in listings and the simple proportion efficacy tables, 
but excluded from survival analysis. 


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5.5 
Statistical models 
Randomization seed for random functions utilized in all analyses is set to 5332202.  
For the posterior probability simulation, the number of iteration is set to 10000.  
For Kaplan-Meier estimates and related analyses, the censoring day is the last day of the 
associated analysis visit window. 
 
Exposure-adjusted incidence rate and 100(1 - α)% confidence interval 
Exposure-adjusted incidence rates is presented per 100 participant-years. Participant-years is 
calculated as a sum of individual participant durations in days divided by 365.25. 
It will be assumed that for each of 𝑛𝑛 participants in a clinical trial the time 𝑡𝑡𝑗𝑗, (𝑗𝑗= 1, … , 𝑛𝑛) to 
the first occurrence of a certain treatment emergent event is observed, or if the event was not 
experienced, the (censored) time to the end of the observation period or EOT, whichever occurs 
earlier. The sequence of first occurrences of an event will be modeled to follow approximately 
a Poisson process with constant intensity 𝜃𝜃. The rate parameter 𝜃𝜃 will be estimated as 𝜆𝜆= 𝐷𝐷/𝑇𝑇, 
where 𝑇𝑇= ∑
𝑡𝑡𝑗𝑗
𝑛𝑛
𝑗𝑗=1
 and 𝐷𝐷 is the number of participants with at least one event. Conditionally on 
𝑇𝑇, an exact 100(1 −𝛼𝛼)% confidence interval for a Poisson variable with parameter 𝜃𝜃𝜃𝜃 and 
observed value 𝐷𝐷 can be obtained based on (Garwood, 1936), from which an exact 100(1 −
𝛼𝛼)% confidence interval for 𝜆𝜆= 𝐷𝐷/𝑇𝑇 will be derived as follows (Sahai, 1993; Ulm, 1990): 
Lower confidence limit 𝐿𝐿=
0.5𝜒𝜒𝛼𝛼
2,2𝐷𝐷
𝑇𝑇
 for 𝐷𝐷> 0, and = 0 otherwise; 
Upper confidence limit 𝑈𝑈=
0.5𝜒𝜒1−𝛼𝛼
2,2𝐷𝐷+2
𝑇𝑇
. 
where 𝜒𝜒𝛼𝛼,𝑘𝑘 is the 𝛼𝛼-th quantile of the Chi-square distribution with 𝑘𝑘 degrees of freedom. 
5.6 
Rule of exclusion criteria of analysis sets  
Table 5-9 displays the criteria for exclusions from analysis sets. 
Table 5-9 
Participant Classification 
Analysis Set 
PD ID that cause 
participants to be excluded 
Non-PD criteria that cause participants 
to be excluded 
SCR 
INCL01 
Not having informed consent; 
Not having screening epoch disposition page 
FAS 
INC03, OTH03, OTH10 
Not randomized; Not transplanted; 
Mis-randomized 
SAF 
NA 
No study drug taken 


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Analysis Set 
PD ID that cause 
participants to be excluded 
Non-PD criteria that cause participants 
to be excluded 
PK 
NA 
No study drug taken; PD with relevant 
impact on PK; no valid PK concentration 
measurement 
 
6 
Reference 
Garwood, F (1936). Fiducial limits for the Poisson distribution. Biometrika, 46; 441–453. 
Levey AS, Coresh J, Greene T, et al (2006) Using standardized serum creatinine values in the 
modification of diet in renal disease study equation for estimating glomerular filtration rate. 
Ann Intern Med; 145:247-54. 
Levitsky J, Goldberg D, Smith AR, Mansfield SA, Gillespie BW, Merion RM, Lok ASF, Levy 
G, Kulik L, Abecassis M, and Shaked A (2017).  Acute Rejection Increases Risk of Graft Failure 
and Death in Recent Liver Transplant Recipients; Clinical Gastroenterology and Hepatology 
15: 584-593. 
Sahai H, Khurshid Anwer (1993). Confidence intervals for the mean of a poisson distribution: 
a review. Biom J, 35 (7); 857-867 
Ulm K (1990). A simple method to calculate the confidence interval of a standard mortality 
ratio. American Journal of Epidemiology, 131(2); 373-375