Clinical trial NCT04311632
Conditions: Kidney Transplantation
Sponsor: ITB-Med LLC
Start date: 2021-05-26; Completion date: 2023-10-03
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of escalating doses of TCD601 when compared to rATG in de novo renal transplant patients.

Detailed description:

Arms: arm 1: TCD601 administered with the standard of care (SoC) consisting of concentration-controlled tacrolimus (TAC) combined with mycophenolate mofetil (MMF) and corticosteroids (CS). arm 2: TCD601 administered with the standard of care (SoC) consisting of concentration-controlled tacrolimus (TAC) combined with mycophenolate mofetil (MMF) and corticosteroids (CS). arm 3: ATG administered with the standard of care (SoC) consisting of concentration-controlled tacrolimus (TAC) combined with mycophenolate mofetil (MMF) and corticosteroids (CS).
Interventions: intervention 1: TCD601 intervention 2: Tacrolimus (TAC) intervention 3: Corticosteroids (CS) intervention 4: Mycophenolate Mofetil (MMF) intervention 5: ATG
Intervention descriptions: intervention 1: Investigational Product intervention 2: Standard of Care Concomitant Immunosuppression intervention 3: Standard of Care Concomitant Immunosuppression intervention 4: Standard of Care Concomitant Immunosuppression intervention 5: Standard of Care induction therapy in solid organ transplantation

Protocol documents:
Prot_000.pdf: 
Clinical Protocol TCD601B102 
 
A 12-Month, Randomized, Controlled, Open-Label, Dose Escalation Study 
evaluating Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics 
(PD) of an anti-CD2 monoclonal antibody, TCD601(siplizumab) compared to anti-
thymocyte globulin (rATG), as induction therapy in de novo Renal Transplant 
Recipients 
 
NCT Number:  NCT04311632 
 
Release Date:  02-Mar-2022 


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TCD601(siplizumab) 
Clinical Protocol TCD601B102 
A 12-Month, Randomized, Controlled, Open-Label, Dose Escalation 
Study evaluating Safety, Tolerability, Pharmacokinetics (PK) and 
Pharmacodynamics (PD) of an anti-CD2 monoclonal antibody, 
TCD601(siplizumab) compared to anti-thymocyte globulin (rATG), as 
induction therapy in de novo Renal Transplant Recipients 
Document Type: 
Clinical Study Protocol 
IND Number: 
144519 
EUDRACT Number: 
2020-000419-56 
Current Version: 
2.0 
Protocol History 
Protocol incorporating Amendment No. 01, v2.0 
Protocol v1.0; Released 27Sep2020 
Clinical Trial Phase: 
IIA 
Release Date: 
02-Mar-2022
Property of ITB-MED LLC Confidential 
 This document contains proprietary and confidential material belonging to ITB-MED.  Its 
contents may not be used, divulged, published, or otherwise disclosed without the consent of 
ITB-MED 


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Table of Contents 
Table of Contents .................................................................................................................2 
List of Tables .......................................................................................................................8 
List of Figures ......................................................................................................................9 
List of Abbreviations .........................................................................................................10 
Protocol History .................................................................................................................13 
Protocol Synopsis ..............................................................................................................14 
1 
Introduction ........................................................................................................................20 
1.1 
Background ............................................................................................................20 
1.1.1 
Transplant Induction Therapy ...............................................................21 
1.1.2 
CD2 Biology ..........................................................................................22 
1.1.3 
TCD601 (siplizumab): Mechanism of Action .......................................22 
1.1.4 
Relevant Data Summary ........................................................................23 
1.1.4.1 
In Vitro Pharmacology .................................................................23 
1.1.4.2 
Toxicology Data...........................................................................23 
1.1.4.3 
Teratogenicity and Reproductive Toxicology Data .....................24 
1.1.4.4 
Human Safety and Tolerability Data ...........................................25 
1.1.4.5 
Human Pharmacokinetic Data .....................................................25 
1.1.4.6 
Human Pharmacodynamic Data ..................................................26 
1.2 
Study Purpose ........................................................................................................27 
2 
Objectives and Endpoints ..................................................................................................28 
3 
Study Design ......................................................................................................................29 
3.1 
General Overview ..................................................................................................29 
4 
Study Design Rationale .....................................................................................................32 
4.1 
Dose/Regimen and Treatment Duration Rationale ................................................33 
4.1.1 
Siplizumab Tissue Distribution / Effect Compartment .........................35 
4.2 
Rationale for Active Control ..................................................................................36 
4.3 
Rationale for Background Immunosuppression .....................................................37 
4.4 
Purpose and Timing of Interim Analyses/Design Adaptations ..............................37 
4.5 
Risks and Benefits ..................................................................................................38 
4.5.1 
Siplizumab .............................................................................................38 


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4.5.1.1 
Infusion and Inflammatory Reactions and Cytokine Release ......39 
4.5.1.2 
Immunosuppression and Infections .............................................40 
4.5.1.3 
Lymphoproliferative Disorders ....................................................41 
4.5.1.4 
Other Hypothetical Risks .............................................................42 
4.5.2 
Risks of ATG Induction Therapy ..........................................................43 
4.5.3 
Risks of SARS-CoV-2 (COVID-19) .....................................................44 
4.5.4 
Risk Mitigation Strategy .......................................................................46 
5 
Population ..........................................................................................................................49 
5.1 
Inclusion Criteria ...................................................................................................49 
5.2 
Exclusion Criteria ..................................................................................................49 
6 
Treatments .........................................................................................................................51 
6.1 
Method of Treatment Assignment .........................................................................51 
6.2 
Investigational Product ..........................................................................................52 
6.2.1 
Identification of Investigational Product ...............................................52 
6.2.2 
Management of Investigational Product ................................................52 
6.2.3 
Investigational Product Dosing Regimen ..............................................53 
6.2.4 
Preparation of Siplizumab .....................................................................53 
6.2.5 
Premedication for Siplizumab Infusion .................................................53 
6.2.6 
Siplizumab Administration ....................................................................54 
6.2.7 
Provisional Dose Levels ........................................................................54 
6.2.8 
Dose Escalation Guidelines ...................................................................54 
6.3 
ATG: Standard of Care Control .............................................................................56 
6.3.1 
ATG Dose and Duration ........................................................................56 
6.3.2 
Preparation of ATG ...............................................................................56 
6.3.3 
Premedication for ATG Infusion ...........................................................56 
6.3.4 
Administration of ATG Infusion ...........................................................56 
6.3.5 
Management of ATG Therapy ..............................................................56 
6.4 
Concomitant Immunosuppression .........................................................................56 
6.4.1 
MMF Administration ............................................................................57 
6.4.2 
TAC Administration ..............................................................................58 
6.4.3 
Corticosteroid Administration ...............................................................58 


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6.5 
Infectious Prophylaxis Treatment ..........................................................................58 
6.6 
Other Concomitant Treatments ..............................................................................60 
6.7 
Treatment of Adverse Events .................................................................................60 
6.7.1 
Treatment of Acute Rejection Episodes ................................................60 
6.7.2 
Management of BK Viremia .................................................................60 
6.7.3 
Management of Delayed Graft Function (DGF) ...................................61 
6.7.4 
Primary Graft Non-Function (PGNF) ...................................................61 
6.7.5 
Management of EBV-PTLD .................................................................62 
6.8 
Treatment Exposure and Compliance ....................................................................62 
6.9 
Prohibited Treatment .............................................................................................62 
7 
Informed Consent Procedures............................................................................................63 
8 
Visit Assessments ..............................................................................................................63 
8.1 
Subject Identification .............................................................................................64 
8.2 
Screen Failure Assessments ...................................................................................64 
8.3 
Efficacy / Pharmacodynamic Assessments ............................................................64 
8.4 
Safety Assessments ................................................................................................64 
8.4.1 
Physical Examination ............................................................................64 
8.4.2 
Vital Signs .............................................................................................65 
8.4.3 
Height and Weight .................................................................................65 
8.4.4 
Laboratory Evaluations .........................................................................65 
8.4.4.1 
Hematology ..................................................................................66 
8.4.4.2 
Clinical Chemistry .......................................................................66 
8.4.4.3 
Lipid Panel ...................................................................................66 
8.4.4.4 
Urine Dipstick ..............................................................................66 
8.4.4.5 
Pregnancy .....................................................................................66 
8.4.4.6 
Renal Function .............................................................................66 
8.4.4.7 
Coagulation Studies .....................................................................66 
8.4.4.8 
EBV-DNA PCR ...........................................................................66 
8.4.4.9 
CMV DNA PCR ..........................................................................67 
8.4.4.10 Donor Specific Antibodies (DSA) ...............................................67 
8.4.4.11 Immunogenicity ...........................................................................67 


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8.4.4.12 Viral Testing and Surveillance.....................................................67 
8.4.5 
EBV-PTLD Surveillance .......................................................................67 
8.4.6 
Imaging: PTLD Surveillance .................................................................69 
8.4.7 
Renal Biopsy .........................................................................................69 
8.4.8 
Treated Biopsy Proven Acute Rejection ...............................................69 
8.4.9 
Graft Loss ..............................................................................................69 
8.4.10 
Death .....................................................................................................70 
8.5 
Pharmacokinetic Assessments ...............................................................................70 
8.6 
Assessment of Treatment Exposure and Compliance ............................................70 
8.7 
Exploratory Biomarker Assessments .....................................................................71 
9 
Study Discontinuation and Completion .............................................................................71 
9.1 
Discontinuation ......................................................................................................71 
9.1.1 
Safety Stopping Rules ...........................................................................71 
9.1.2 
Discontinuation of Study Treatment .....................................................72 
9.1.3 
Withdrawal of Informed Consent ..........................................................73 
9.1.4 
Lost to Follow-up ..................................................................................73 
9.1.5 
Early Study Termination by the Sponsor ..............................................73 
9.2 
Study Completion ..................................................................................................73 
9.3 
Subject Replacement ..............................................................................................74 
10 Safety Monitoring and Reporting ......................................................................................74 
10.1 
Definition of Adverse Events and Reporting Requirements ..................................74 
10.1.1 
Adverse Events ......................................................................................74 
10.1.2 
Serious Adverse Events .........................................................................75 
10.1.3 
Adverse Events of Special Interest ........................................................76 
10.1.4 
SAE Reporting ......................................................................................76 
10.1.5 
Pregnancy Reporting .............................................................................77 
10.1.6 
Early Phase Safety Monitoring ..............................................................77 
10.1.7 
Reporting of Study Treatment Errors ....................................................77 
11 Data Monitoring Committee ..............................................................................................77 
12 Data Analysis and Statistical Methods ..............................................................................78 
12.1 
Analysis sets ...........................................................................................................78 


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12.2 
Subject Demographics and other Baseline Characteristics ....................................78 
12.3 
Treatments ..............................................................................................................79 
12.3.1 
Concomitant Immunosuppressants ........................................................79 
12.3.2 
Other Co-Medications ...........................................................................79 
12.4 
Analysis of the Primary Endpoint(s) ......................................................................79 
12.4.1 
Definition of Primary Endpoint(s) ........................................................79 
12.4.2 
Statistical Model, Hypothesis, and Method of Analysis .......................80 
12.4.3 
Handling of Missing Values/Censoring/Discontinuations ....................80 
12.5 
Analysis of Secondary Endpoints ..........................................................................80 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) ....................................80 
12.5.2 
Safety Endpoints ....................................................................................81 
12.5.3 
Pharmacokinetics ...................................................................................83 
12.5.4 
Biomarkers ............................................................................................84 
12.5.5 
PK/PD Relationships .............................................................................84 
12.6 
Analysis of Exploratory Endpoints ........................................................................84 
12.7 
Interim Analyses ....................................................................................................84 
12.8 
Dosing Decision Data Review ...............................................................................85 
12.9 
Sample Size Calculation ........................................................................................85 
13 Study Conduct ...................................................................................................................85 
13.1 
Sponsor Responsibilities ........................................................................................85 
13.2 
Investigator Responsibilities ..................................................................................85 
13.3 
Site Initiation ..........................................................................................................86 
13.4 
Data Quality Control ..............................................................................................86 
13.4.1 
Data Collection ......................................................................................86 
13.4.2 
Data Management ..................................................................................86 
13.4.3 
Monitoring Procedures ..........................................................................87 
13.4.4 
Protocol Adherence and Amendments ..................................................87 
13.4.5 
Quality Assurance .................................................................................88 
13.5 
Study Site Closure ..................................................................................................88 
13.5.1 
Records Retention .................................................................................88 
14 Ethical Considerations .......................................................................................................89 


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14.1 
Regulatory and Ethical Compliance ......................................................................89 
14.2 
Publication of Study Protocol and Results .............................................................89 
15 References ..........................................................................................................................90 
16 Appendices ........................................................................................................................93 
16.1 
Appendix 1:  Schedule of Assessments .................................................................93 
16.2 
Appendix 2:  Amendment No.1 – Summary of Changes ......................................96 
16.3 
Appendix 3: Investigator Agreement Page ..........................................................108 
16.4 
Appendix 4: US-Specific CellCept® Pregnancy and Safety Information ............109 
16.5 
Appendix 5: Guidelines for MMF Dose Reduction .............................................111 
16.6 
Appendix 6: Tacrolimus Drug-Drug Interactions ................................................112 
16.7 
Appendix 7: Updated 2018 Banff Classification .................................................114 


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List of Tables 
Table 1-1  
Peripheral CD4, CD8, and NK cell depletion following siplizumab 
(MEDI-507) administration in patients with CD2 Positive T-cell 
lymphoma in Study MI-CP099 ......................................................................... 27 
Table 2-1 
Objectives and Related Endpoints .................................................................... 28 
Table 3-1 
Dosing Regimen................................................................................................ 30 
Table 4-1 
Renal transplantation pooled analysis: Opportunistic infections ...................... 41 
Table 6-1 
Treatment Assignment ...................................................................................... 51 
Table 6-2 
Provisional dose levels ...................................................................................... 54 
Table 12-1 
Non-compartmental pharmacokinetic parameters ............................................ 83 
 


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List of Figures  
Figure 1-1 
Mean CD3 lymphocyte profile following siplizumab (MEDI-507) 
administration in study MI-CP027.................................................................... 26 
Figure 3-1 
TCD601B102 Study Design ............................................................................. 29 
Figure 3-2 
TCD601B102 Treatment Regimen ................................................................... 30 
Figure 4-1 
Mean predicted siplizumab serum concentrations in study TCD601B102: 
0.2 and 0.6 mg/kg.............................................................................................. 34 
Figure 4-2 
Mean predicted, log-transformed, siplizumab serum concentrations in 
study TCD601B102 following 0.2 and 0.6 mg/kg siplizumab 
administration ................................................................................................... 36 


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List of Abbreviations 
ABC 
Antibody Biodistribution Coefficient 
ADCC 
Antibody-Dependent Cell-mediated Cytotoxicity 
ADCP 
Antibody-Dependent Cellular Phagocytosis 
AE 
Adverse Event 
AKI 
Acute Kidney Injury 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
APC 
Antigen Presenting Cell 
aPTT 
Activated Partial Thromboplastin time 
AST 
Aspartate Aminotransferase 
ATG 
Anti-thymocyte Globulin 
ATL 
Adult T-cell Leukemia 
AUC 
Area Under the Curve 
BID 
Twice a day 
BMI 
Body Mass Index 
BMT 
Bone Marrow Transplantation 
BPAR 
Biopsy Proven Acute Rejection 
BUN 
Blood Urea Nitrogen 
CDC 
Complement-dependent cytotoxicity  
CDR 
Complementarity-determining regions 
CIT 
Cold Ischemia time 
CMV 
Cytomegalovirus  
CNI 
Calcineurin Inhibitor 
CS 
Corticosteroids 
CsA 
Cyclosporine 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTS 
Chimeric Transition Syndrome 
CV 
Coefficient of Variation 
DGF 
Delayed Graft Function 
DLT 
Dose Limiting Toxicity 
DMC 
Data Monitoring Committee 
DSA 
Donor Specific Antibodies 
EBV 
Epstein-Barr Virus 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
ELISA 
Enzyme-linked Immunosorbent assay 
EOS 
End of Study 
eTMF 
Electronic Trial Master File 
EU 
European Union 
FACS 
Fluorescence-activated Cell Sorter 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 


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FRP 
Females of reproductive potential 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transferase 
GvHD 
Graft-versus-host disease 
HbsAg 
Hepatitis B Surface Antigen 
Hbg 
Hemoglobin 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HLA 
Human Leukocyte Antigen 
HIV 
Human Immunodeficiency Virus 
IMPDH 
Inosine Monophosphate Dehydrogenase 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
IVIG 
Intravenous Immunoglobulin 
KDIGO 
Kidney Disease Improving Global Outcomes 
KDOQI 
Kidney Disease Outcomes Quality Initiative 
LGL 
Large Granular Lymphocytic Leukemia  
LLOQ 
Lower Limit of Quantification 
LOCF 
Last-Observation-Carried-Forward 
LPD 
Lymphoproliferative Disorder 
MDRD 
Modification of Diet in Renal Disease 
MLR 
Mixed lymphocyte reaction 
M-M 
Michaelis-Menten 
MMF 
Mycophenolate Mofetil 
MoA 
Mechanism of Action 
MPA 
Mycophenolic acid  
NCI 
National Cancer Institute 
NSAID 
Nonsteroidal anti-inflammatory drug 
PCP 
Pneumocystis Pneumonia 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamic(s) 
PGNF 
Primary Graft Non-Function 
pMHC 
Peptide-major histocompatibility complex 
PK 
Pharmacokinetic(s) 
PPK 
Population Pharmacokinetic(s) 
PRA 
Panel Reactive Antibodies 
PRED 
Prednisolone 
PT 
Prothrombin Time 
PTT 
Partial Prothrombin Time 


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PTLD 
post-transplant lymphoproliferative disorder 
PVAN 
Polyoma Virus Associated Nephropathy 
QMS 
Quality Management System 
QNAT 
Quantitative Nucleic Acid Testing 
rATG 
rabbit anti-thymocyte globulin 
RBC 
Red Blood Cell(s) 
RO 
Receptor occupancy 
REMS 
Risk Evaluation and Mitigation Strategy 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
s.c. 
Subcutaneous 
SCr 
Serum Creatinine 
SD 
Standard deviation 
SID 
Subject Identification Number 
SMQ 
Standardized MedDRA Query 
SoC 
Standard of Care 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SVR 
Sustained Viral Response 
TAC 
Tacrolimus 
TB 
Tuberculosis  
tBPAR 
treated Biopsy Proven Acute Rejection 
TCD601 or siplizumab 
Investigational Product 
TCMR 
T-cell Mediated Rejection 
TCR 
T-cell Receptor 
TDM 
Therapeutic Drug Monitoring 
TMDD 
Target-Mediated Drug Disposition  
ULN 
upper limit of normal 
ULOQ 
upper limit of quantification 
US 
United States 
VL 
Viral Load 
WBC 
White Blood Cell(s) 
WHO 
World Health Organization  
 
 
 


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Protocol History 
Amendment 01: 
This document (TCD601B102 Protocol Version 2.0) incorporates changes and editorial updates 
to harmonize the US clinical study protocol with TCD601B101 Protocol Version 2.0, which is 
active in the EU.  Key revisions include the addition of an inclusion criterion, which requires study 
subjects to have a negative SARS-CoV-2 test at screening, an outline of the Risks associated with 
COVID-19 disease (See Section 4.5.3), and Risk Mitigation Strategies to minimize exposure to 
SARS-CoV-2 (See Section 4.5.4).  These revisions and additions are in consideration of the 
ongoing global SARS-CoV-2 pandemic and harmonize with FDA and EU guidance documents 
and updated global protocol template. 
A tabulation of all changes can be reviewed in Appendix 2 of this protocol. 


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Protocol Synopsis 
Product 
Name/Number 
TCD601 (siplizumab) 
Protocol Number 
TCD601B102 
Protocol Title 
A 12-month, randomized, controlled, open-label, dose escalation study evaluating safety, 
tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of an anti-CD2 monoclonal 
antibody, TCD601 (siplizumab), compared to anti-thymocyte globulin (rATG), as induction 
therapy in de novo renal transplant recipients 
Investigation 
Type 
Interventional; Drug (biologic) 
Purpose and 
Rationale 
The purpose of this study is to investigate the safety, tolerability, pharmacokinetics and 
pharmacodynamics of escalating doses of TCD601 (siplizumab), an anti-CD2 monoclonal 
antibody, compared to a rabbit polyclonal anti-thymocyte globulin (rATG), as induction 
therapy in de novo renal transplant patients. All subjects will receive the same standard of 
care (SoC) background immunosuppression. 
This trial will focus on profiling the safety, tolerability, PK and PD activity of siplizumab in the 
setting of standard-of-care immunosuppression in a moderate immunologic risk renal 
transplant population.  
Overall, results of this study will be used to inform the siplizumab dose and regimen 
selection for investigation in later phases of clinical development and serve as proof-of-
principal study in the replacement of SoC, polyclonal, T-cell depleting induction therapy.  
Primary Objective 
To assess the safety, tolerability, PK and PD of siplizumab compared to rATG, in de novo 
renal transplant recipients at 12 months post-transplant. 
Secondary 
Objectives 
• 
To measure changes in peripheral lymphocyte immunophenotype 
• 
To measure the time-course and duration of siplizumab induced lymphocyte depletion 
and recovery 
• 
To measure peripheral CD2-receptor occupancy following siplizumab administration 
over time 
• 
To assess the incidence of treated biopsy proven acute rejection (tBPAR) at 12 months 
• 
To assess the incidence of treatment emergent de novo, donor specific antibodies 
(DSA) at 12 months 
• 
To assess the incidence of antibody meditated rejection at 12 months 
• 
To assess renal function via eGFR using the Modification of Diet in Renal Disease 
(MDRD) equation at Months 3, 6, 12 or EOS 
Exploratory 
Objectives 
• 
 
 
 
 
 
 
 
 
 
   
 
   
 
 
 
 
 
 
Study Design 
TCD601B102 is a 12-month, multi-center, randomized, controlled, open-label, dose 
escalation study to evaluate the safety, tolerability, PK and PD of siplizumab compared to 
rATG, as induction therapy, in de novo renal transplant recipients. All subjects will receive 


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background immunosuppression with standard exposure tacrolimus (TAC), mycophenolate 
mofetil (MMF) and corticosteroids (CS). 
Following a screening period of up to 4-weeks to confirm study eligibility, up to 24 moderate 
immunological risk, de novo renal transplant candidates will be enrolled into the study.  
Eligible subjects will be sequentially assigned to one of two Cohorts (A or B) using a time-
lagged dose escalation methodology. Within each Cohort, it is planned that 12 subjects will 
be randomized to siplizumab or rATG, in an 8:4 ratio prior to renal transplantation on Study 
Day 0, as outlined below:  
   
 
Subjects randomized to siplizumab will receive two intravenous (IV) doses on Day 0 and 
Day 4 post-transplant as follows:   
Siplizumab Dosing Arms: 
 
Arm 1: 0.2 mg/kg (n=8) 
 
Arm 2: 0.6 mg/kg (n=8) 
Subjects randomized to rATG (Arm 3), will receive three intravenous (IV) doses of 1.5 mg/kg 
on Days 0, 1 and 2, regardless of Cohort assignment. 
Siplizumab and rATG will be combined with concentration-controlled TAC (BID) dosing to a 
whole blood trough concentration 4-11 ng/mL, and MMF or equivalent (BID), and should be 
started within 24 hours post-transplant. Subjects will also receive CS per local practice with 
a minimum of 5.0 mg/d prednisone or equivalent until Month 12.  
Dose Escalation Criteria: 
28 days following the last investigational product administration in the 4th siplizumab treated 
subject in each treatment Cohort and prior to dose escalation to the subsequent Cohort, a 
review of all available safety, tolerability and PD data will be conducted by ITB-MED in 
collaboration with the Investigators.  This 28-day safety period allows sufficient time for 
subjects to reach full-receptor occupancy, maximum pharmacodynamic activity, and for the 
presentation of acute, drug related toxicities. 
In the event there is no evidence of acute, dose limiting toxicity (DLT), randomization to the 
next dose level may be initiated. Alternatively, a decision to terminate the dosing arm could 
be reached.  It is also possible additional and/or intermediate dose level(s) could be added 
during the course of the study per amendment. Cohorts may be added at any dose level 
below the maximum tolerated dose in order to better understand safety, PK or PD. 
This escalation data review will be repeated prior to dose escalation/termination decisions 
for each Cohort.  The review of subject data and dose escalation may occur before all 
subjects have been randomized to a given Cohort.  If the next dose level is opened to 
subject assignment, Cohorts will be back filled to achieve a final sample size of 12 subjects. 
In addition to the review of data for dose decision purposes as noted above, an independent 
Data Monitoring Committee (DMC) will conduct an ongoing review of cumulative PK, PD, 
safety, Adverse Events (AEs) and Serious Adverse Event (SAE) data as well as EBV-viral 
load and PTLD surveillance results, including clinically relevant changes on physical exam 
and clinical laboratory assessments and ad hoc imaging. The Committee will convene on a 
quarterly basis or as described in the DMC Charter. If at any time the observed AEs meet or 


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exceed the a priori defined stopping criteria, the study will be placed on hold pending a 
review. 
Interim Analysis: 
A formal interim analysis will occur once 50% of subjects in Cohort 1 and 2 complete their 6-
month study assessment.  
This formal interim analysis will be conducted to assess the safety/tolerability (e.g., AEs, 
SAEs, clinical laboratory assessments, vital signs, PK data and PK/PD activity (e.g., 
immunophenotyping and CD2 receptor occupancy). The analysis will also include 
assessment of biopsy proven acute rejection (BPAR), graft losses deaths, and key safety 
endpoints. In the event the acute rejection rate exceeds a clinically relevant threshold set 
forth in the protocol and DMC charter, or the a priori defined stopping rules, enrollment will 
be suspended to allow for the early termination of any treatment cohort where the 
benefit/risk of siplizumab is deemed unacceptable. 
Safety stopping rules: 
In addition to the formal interim analyses and escalation data reviews for dosing decision 
purposes, the following Safety Stopping Rules will be in effect at any timepoint in the study.  
Although the stopping criteria do not incorporate an absolute requirement for causality, the 
potential relationship between an AE(s) and siplizumab will be evaluated carefully on a case-
by-case basis between ITB-MED and the Investigator. Following a review of the AE(s), a 
decision to permanently discontinue enrollment or re-initiate dosing will be made by the 
DMC. Dose limiting toxicities (DLTs) will be assessed according to the standardized toxicity 
grading scale, the National Cancer Institute (NCI) CTCAE version 5.0 (NCI 2017): 
 
One (1) subject death or graft loss within the first month with the exception 
of technical failures.  
 
One (1) subject presents with histologically confirmed EBV-PTLD. 
 
One (1) subject with Grade 3 or higher cytokine release syndrome within 24 
hours of any siplizumab administration. 
 
One (1) subject with any Grade 4 toxicity, considered drug related as 
determined by the Investigator within the first 28 days.  
 
Two (2) subjects with sustained (>7 days) Grade 3 neutropenia (neutrophil 
counts 200/mm3 to < 500 to; 0.2 to <0.5 x 10e9/L) considered related to 
siplizumab. 
 
Two (2) or more subjects presenting with Grade 3 or higher toxicity 
considered related as determined by the Investigator, including infusion 
reactions, within 24 hours of any siplizumab administration. 
 
Three (3) or more subjects per cohort presenting with Grade IIA or higher 
BPAR (T-cell mediated rejection (TCMR); central pathology) during the first 
6 months post-transplant. 
Following discharge from the hospital, subjects will have study assessments conducted 
weekly through Week 10 and then monthly from Month 3 through Month 12 or end of study 
(EOS). All subjects enrolled will be followed for a minimum of 12 months.   
Population 
Up to 24 moderate immunological risk, adult, de novo renal transplant patients 
Planned Study 
Sites 
Up to 5 study sites within the United States (US) 
Key Inclusion 
Criteria 
 
Subjects eligible for inclusion in this study have to fulfill all of the following criteria: 
• 
Able to understand the study requirements and provide written informed consent before 
any study assessment is performed. 
• 
Male or female patients ≥ 18 to 70 years of age. 
• 
Recipients of a de novo renal allograft from a heart-beating deceased, living unrelated 
or non-Human Leukocyte Antigen (HLA) identical living related donor. 


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• 
Recipients of a kidney with a cold ischemia time (CIT) < 30 hours; hypothermic machine 
perfusion within the same timeframe is acceptable. 
• 
Subjects who test negative for SARS-CoV-2 via molecular testing (PCR) 
Key Exclusion 
Criteria 
 
Subjects meeting any of the following criteria are not eligible for inclusion in this study: 
• 
Transplant recipients sero-negative for Epstein-Barr virus (EBV).  
• 
Multi-organ transplant recipients. 
• 
Subjects who have received a kidney allograft previously, e.g., re-transplant. 
• 
Recipient of a kidney from an HLA identical living related donor. 
• 
Recipient of a kidney from a donor after cardiac death. 
• 
Subjects at high immunological risk for rejection as determined by local practice [(e.g., 
presence of pre-existing DSA, recipient of high Kidney Donor Profile Index ≥ 85 kidney 
(where assessed)]. 
• 
Subjects with donor specific anti-HLA antibody as measured by complement-dependent 
cytotoxicity assay (CDC), enzyme-linked immunosorbent assay (ELISA), or flow 
cytometry within 90 days prior to transplant or as performed per the center’s local 
practice. 
• 
Complement-dependent cytotoxicity (CDC) crossmatch positive transplant (isolated 
positive B cell crossmatches are not an exclusion criterion). 
• 
ABO incompatible recipient. 
• 
History of malignancy of any organ system, except for localized excised non-
melanomatous skin lesions or carcinoma in situ of the cervix. 
• 
Subjects with clinically significant laboratory abnormality that would preclude 
participation in the study (e.g., >2.5 x Upper Limit of Normal (ULN) values for (a) liver 
function chemistries (ALT, AST, alkaline phosphatase (ALP)), (b) bilirubin, (c) 
coagulation studies (INR/PT, aPTT). 
• 
Patient with any of the following: hemoglobin (Hbg) < 8 mg/dL, WBC count ≤ 2,000/mm3 
or platelet count ≤ 75,000/mm3. 
• 
Sero-positive for Human Immunodeficiency Virus (HIV) or Hepatitis B Surface Antigen 
(HBsAg). Subjects who are sero-positive for Hepatitis C virus (HCV) are excluded 
without proof of sustained viral response (SVR) after anti-HCV treatment. 
• 
Recipient of a kidney from a donor who tests positive for HIV, HBsAg/HBc positive or 
HCV. 
• 
History of hypersensitivity to any of the study drugs or to drugs of similar chemical 
classes (e.g., siplizumab, ATG, TAC, MMF, CS). 
• 
Any additional contraindication to the use of TAC or MMF according to the national 
labeling information of these products (refer to the local product label). 
• 
Evidence of TB infection (after anti-TB treatment, patients with history of latent TB may 
become eligible according to national guidelines).  
• 
Patient with severe systemic infections, current or within the two weeks prior to 
randomization. 
• 
Subjects with any other clinically significant medical condition, active infection or 
laboratory abnormality that would, in the judgment of the investigator, interfere with the 
subject’s ability to participate in the study. 
• 
Subjects who, in the opinion of the investigator, are not capable of giving informed 
consent for the study or who are unable or unwilling to adhere to the study requirements 
outlined in the protocol. 
• 
Use of other investigational products or enrollment in another investigational drug study 
within 30 days of screening or 5 half-lives of the medication, whichever is longer. 
• 
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
human chorionic gonadotropin (hCG) laboratory test. 
• 
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 24 weeks after the study medications have been stopped.  


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Investigational 
Product 
Siplizumab 
Reference 
Product (Active 
Control) 
rabbit anti-thymocyte globulin (rATG; Thymoglobulin; Genzyme) 
Background 
Therapy 
• 
Immediate release tacrolimus (TAC) 
• 
Mycophenolate mofetil (MMF) or equivalent 
• 
Corticosteroids (CS) 
Treatment 
Regimen 
Prior to surgery, on Day 0, eligible subjects will be sequentially assigned to one of 2 Cohorts 
(A or B) and then randomized to one of two dosing arms in an 8:4 ratio (siplizumab: rATG) 
as follows:  
 
Cohort 
Arm 
Subjects (n) 
Product 
Dosing Regimen 
Cohort A 
Arm 1 
8 
Siplizumab 
0.2 mg/kg (Days 0 and 4) 
Arm 3 
4 
rATG 
1.5 mg/kg (Days 0, 1 and 2) 
Cohort B 
Arm 2 
8 
Siplizumab 
0.6 mg/kg (Days 0 and 4) 
Arm 3 
4 
rATG 
1.5 mg/kg (Days 0, 1 and 2) 
Background Treatment: 
Subjects across all treatment arms will receive triple regimen background 
immunosuppressive therapy (TAC/MMF/CS). 
Concomitant Treatments: 
• 
Premedication (prior to siplizumab and rATG infusions): diphenhydramine, paracetamol 
or acetaminophen 
• 
Cytomegalovirus (CMV), pneumocystis pneumonia (PCP) prophylaxis, per local practice  
• 
Oral Candida treatment, per local practice  
PK/PD 
Assessments   
PK: Siplizumab and TAC 
• 
Siplizumab (total and free) - Dosing on Days 0 and Day 4:  
 
Sampling pre-dose (0h), 1h, 3h, 6h, and 24h after the first dose on Day 0; 
 
Sampling pre-dose (0h), 1h, 3h, and 6h on Day 4;  
 
Additional collection on Days 2 ,3, 7, 14, 21, 28, 35, 42, 49, 56, 63*, 70*, 84*, 112*, 
140*, 168*, 196*, 224*, and 252* (*Note: collections designated with an asterisk may 
be truncated based on half-life of siplizumab and serum concentrations below limit of 
quantification) 
• 
anti-siplizumab antibodies: Days 0, 28, 56, 84, 168, and EOS   
• 
TAC: Days 0, 1, 7, 14, 21, 28, month 3, 6, 12 post-transplant and as needed following a 
change in dose based on local standard of care (SoC)   
• 
PD:   
 
PD sampling times to be linked with relevant PK timepoints 
 
Peripheral lymphocyte immunophenotyping (FACS analysis) – CD2, CD3, CD4, 
CD5, CD8, CD19, CD25, CD27, CD38, CD45RA, CD45RO, CD59, CD127, CD138, 
CD154, FoxP3, HLA-DR 
 
Peripheral CD2 receptor occupancy 
Safety 
Assessments 
• 
AEs and SAEs  
• 
Clinically significant changes in clinical chemistry, hematology, vital signs, and serology 
• 
EBV-viral load measurement via PCR 
• 
Renal function 
• 
Comprehensive Physical Examination 


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Data Analysis 
All information obtained on AEs will be displayed by treatment and subject. The number and 
percentage of subjects with AEs will be tabulated by body system and preferred term with a 
breakdown by treatment arm. A subject with multiple AEs within a body system is only 
counted once towards the total of this body system. No formal statistical analysis will be 
done for the safety and tolerability evaluation. 
Siplizumab serum concentration data will be listed by treatment, subject, 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 lower limit of 
quantification (LLOQ), which will be reported as zero. Summary statistics will include mean 
(arithmetic and geometric), standard deviation (SD), coefficient of variation (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 magnitude and duration of pharmacodynamic effect of siplizumab will be characterized 
by measuring the change in peripheral immunophenotype, including all subsets of T-, B- and 
NK-cells. Similarly, biomarkers, such as inflammatory cytokines and CD2 RO will be 
summarized by cohort, treatment and subject. Summary statistics will also be provided such 
as mean, median, SD, minimum and maximum, by treatment and by visit/time for all PD and 
biomarker data. The relationship between siplizumab concentration PK and PD 
(immunophenotype) will be explored. Modeling of PK/PD data using a population approach 
will be performed as appropriate. 
Sample Size 
Determination 
No formal sample size and power analysis has been performed. A sample size of 8 subjects 
for each arm was chosen based on practical considerations, including the need to 
adequately characterize siplizumab PK and PD activity in renal transplant patients in the 
immediate post-transplant time period while balancing the overall exposure in a mechanistic 
profiling study.  
Study Duration 
All subjects enrolled will be followed for a minimum of 12 months.   


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1 
Introduction 
1.1 
Background 
Since the first successful human kidney transplantation by Murray et al. in 1954 (Murray et al 
1958), numerous immunosuppressive regimens have been developed for clinical application.  The 
ultimate goal of immunosuppression in kidney transplantation is to prevent acute rejection and 
maintain allograft function while balancing the risk of adverse effects (Tanriover et al 2015). 
Immunosuppressive agents are categorized as (1) induction therapy that is administered in the 
perioperative period and (2) maintenance therapy that transplant recipients require for lifelong use 
(KDIGO 2009).  To maximize efficacy and minimize adverse effects, current immunosuppressive 
regimens are typically based on combinations of two or three immunosuppressive drugs with or 
without induction.  Optimal combinations of therapies must be individualized based on the risk 
and benefit for each individual recipient (Bia et al 2010).   
The contemporary standard of care (SoC) maintenance regimen is based on a calcineurin inhibitor 
(CNI), such as cyclosporine (CsA, Neoral) or tacrolimus (TAC, Prograf) which inhibits T-cell 
activation, in combination with a T-cell proliferation inhibitor. CNIs are generally considered the 
primary immunosuppressant or “corner stone” of the immunosuppressive regimen.  
Immunosuppressive drugs which are typically paired with a CNIs include antiproliferative agents 
such as mycophenolic acid (MPA) based drugs (Mycophenolate Mofetil (MMF), CellCept or 
Myfortic) which block inosine monophosphate dehydrogenase (IMPDH) or mTOR inhibitors such 
as sirolimus (rapamycin, Rapamune) or everolimus (Certican/Zortress).  In addition to a CNI (e.g., 
TAC) and an antiproliferative agent (e.g., MMF) corticosteroids are usually started in the 
peri-transplant period and continued post-transplant in a triple therapy standard of care regimen.  
CNI based standard of care regimens have resulted in excellent one-year patient and graft survival 
rates of 94.7% for deceased donor kidneys and 98.1% for living donor kidneys in the United 
States (US), with low (7-8%) one-year acute rejection rates (Hart et al 2020). However, use of 
currently available immunosuppressive drugs is still limited by mechanism-based side effects and 
poor long-term graft and patient survival.  Side effects such as hypertension, dyslipidemia and 
diabetes as well as gastro-, hematologic-, neuro- and nephrotoxicity are common and result in poor 
long-term patient survival.   
Induction therapy use varies based on recipient risk and regional preference. There are two broad 
categories of induction therapies, lymphocyte-depleting antibodies, such as polyclonal rabbit 
anti-thymocyte globulin (ATG, Thymoglobulin) and nondepleting monoclonal antibodies such as 
basiliximab (Simulect) and formerly daclizumab (Zenapax; withdrawn from US in 2009) that 
inhibit T-cell activation (Hardinger et al 2013).  In the past, the lymphocyte depleting murine 
anti-human CD3 mAb, muromonab-CD3 (Orthoclone; OKT3, withdrawn 2010) and humanized 
anti-CD52 antibody alemtuzumab (Campath / Lemtrada) have sometimes been used (off-label) in 
high-risk transplant patients.  Currently, in the US, lymphocyte-depleting antibodies are 
increasingly favored for induction (73.6% of adult renal transplants) over IL-2 receptor antagonists 
(IL2-RAs; 20.6%) (Hart et al 2020) whereas almost an inverse use of ATG and IL2-RA is seen in 
Europe (EU).   


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1.1.1 
Transplant Induction Therapy 
Basiliximab is a non-depleting, chimeric murine and human monoclonal antibody that specifically 
targets CD25, or the IL-2 receptor (IL2-RA), on the surface of T-lymphocytes.  Administration of 
basiliximab in the peri-transplant time period inhibits IL-2 mediated lymphocyte activation, a 
critical signaling pathway involved in allograft rejection.  Basiliximab is generally well tolerated 
with minimal toxicities or infusion reactions and does not result in lymphocyte depletion.  When 
combined with a CsA, MMF, and corticosteroid-based (CS) immunosuppression regimen 
clinically relevant suppression of IL2 receptor activity following basiliximab administration is 
approximately 59 ±17 days (Simulect PI 2018).  
ATG is a polyclonal mixture of chimeric (rabbit / human) immunoglobulins derived from the 
serum of rabbits inoculated with human thymocytes.  The precise mechanisms underlying the 
therapeutic efficacy of ATG are not entirely known, although T-cell depletion plays a critical role. 
Quantitative analysis by Popow and colleagues demonstrated that ATG is largely comprised of 
T-cell specific antibodies to CD2 (7.5%), CD4 (1.2%) and CD8 (14.3%).  In addition, a high 
proportion of antibodies to cell surface markers like CD11a/CD18 and CD45 that are broadly 
expressed on all leukocytes as well as antigens expressed on endothelial cells and cells of non-
hematopoietic origin like CD98, CD99, CD147 and MHC class I (Popow et al 2013).  This broad 
expression of pleiotropic antibodies has been linked to the exaggerated pharmacology and off-
target toxicities expected with ATG administration. In addition, both in vitro and in vivo studies 
have suggested a number of other possible ATG mechanisms, including lymphocyte surface 
antigen modulation and transcription factor activation. ATG may disrupt immune cell processes, 
such as cytokine production, chemotaxis, endocytosis, stimulation and proliferation, as well as 
leukocyte-endothelial cell adhesion. Finally, ATG may also promote cell death via the induction 
of apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-mediated 
cytolysis (CDC) of various immune cells (Andress et al 2014) Considering the profound 
immunologic consequences of complete, long-term, lymphocyte depletion, polyclonal induction 
with ATG is not a benign therapy.  The benefits of reduced acute rejection rates can come with the 
risks associated with over-immunosuppression and mechanism-based side effects. A course of 
ATG induction results in profound lymphocyte depletion for >12 months with slow recovery and 
inversion of CD4/CD8 populations that can take an additional 2-3 years to reach pre-transplant 
levels (Hardinger et al 2004).  Mechanistic side effects such as infusion reactions, cytokine release 
syndrome, increased risk of infections and post-transplant lymphoproliferative disorder (PTLD) 
have also been reported with ATG administration.  
Lymphocyte-depleting agents are primarily used in patients with immunologic risk factors for 
acute rejection. Whereas IL2 receptor antagonists (IL2-RA) and induction-free regimens are 
primarily utilized in patients with low immunologic risk (e.g., living donor renal transplant) 
(Hardinger et al 2013). The current Kidney Disease Improving Global Outcomes (KDIGO) 
Transplant Work Group guidelines recommend IL2-RA as a first-line induction agent in all types 
of donor-recipient profiles to reduce risk of acute rejection and allograft loss. These 
recommendations are primarily based on a meta-analysis that predominantly used 
cyclosporine-based maintenance immunosuppression (KDIGO 2009). A recent retrospective 
analysis by Tanriover and colleagues assessed the use of induction therapy in living donor renal 
recipients on immunosuppression with TAC/MPA ± prednisolone (PRED) (assessment period 


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2000–2012).  Their conclusions were (i) There was no benefit from use of IL-2RA induction versus 
no induction in patients maintained on TAC/MPA/PRED with respect to acute rejection or graft 
survival (ii) ATG use was associated with 22% (combined with steroids) and 27% (in the setting 
of steroid withdrawal) reduction in the risk of acute rejection compared with IL-2RA in this 
population. (Tanriover et al 2015). 
Overall, antibodies with a high specificity for single T-cell receptors (TCR) and low 
immunogenicity, such as siplizumab, may present an opportunity to develop very specific and 
substantial immunomodulation in the immediate post-transplant time period. Considering the 
efficacy of ATG and safety profile of basiliximab, developing a therapy that targets and modulates 
the various T-cell clones without the indiscriminate lymphocyte activation and depletion, could be 
useful in bridging the gap between these two therapies. 
1.1.2 
CD2 Biology 
Human CD2 (also known as LFA-2, for leukocyte function-associated antigen-2) is a monomeric 
transmembrane glycoprotein of 45–50 kDa. CD2 is expressed early during human thymocyte 
development and is found on about half of thymocytes, thymic B-cells, NK cells and almost all 
mature peripheral T-cells. CD2 functions as an intercellular adhesion molecule, binding to its 
ligand LFA-3 (CD58) in humans with high affinity.  Human LFA-3 is a surface glycoprotein that 
contains two extracellular Ig-like domains and is expressed on B-cells and antigen presenting cells 
(APCs); particularly macrophages.  
The CD2-CD58 complex functions as an intercellular adhesion complex, forming a conjugate and 
induced a conformation change.  The formation of the conjugate gives the T-cell receptor (TCR) 
a longer interval to scan various peptide-major histocompatibility complex (pMHC) combinations 
presented by the APCs, determine if a match has been made, and, if so, complete the intracellular 
signaling and co-stimulation necessary for T-cell activation (Springer et al 1987; Davis and van 
der Merwe 1996; Seed and Aruffo 1987). The interaction of CD58 with CD2 has been found to be 
essential for the activation of cellular immunity, such as CD8+ cytotoxic T-lymphocytes and NK 
cell-mediated cytotoxic reactions (Rölle et al 2016, Leitner et al 2015). In addition, CD2 is 
up-regulated on both activated and memory T-cells while CD58-ligation to CD2 activates NK and 
dendritic cells, lowers the threshold for T-cell activation and enhances T-cell responsiveness to 
pro-inflammatory cytokines such as IL-12 (Lo et al 2011).  Furthermore, CD2-ligation of B-cell 
specific CD58 induces the upregulation of CD40 expression, suggesting that CD2 may also play a 
role in the stimulation and/or delivery of T-cell help to B-cells.  
1.1.3 
TCD601 (siplizumab): Mechanism of Action 
Siplizumab (TCD601; previously known as MEDI-507) is a non-agonistic, humanized, anti-CD2 
monoclonal antibody of the IgG1κ class.  Siplizumab binds to a unique epitope on human CD2, 
distinct from the CD58 binding site, with high affinity (kd – 5 nM), inhibiting co-stimulation and 
T-cell activation.  In addition, the Fc portion of the siplizumab antibody binds to FcγR receptors 
on NK cells resulting in ADCC and antibody-dependent cellular phagocytosis (ADCP) mediated 
depletion of CD2+ lymphocytes.  Siplizumab also demonstrates selective immunomodulatory 
activity with depletion of memory T-cells (Tmem; high CD2 expression) and sparing of regulatory 
T-cells (Treg; low CD2 expression) in vitro and in vivo based on the differential expression of 


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CD2 on lymphocytes. Considering this activity, siplizumab is expected to modulate T-cell memory 
and immune reactivity in the setting of transplantation. For complete information on the mechanism 
of action (MoA) please refer to the latest edition of the siplizumab Investigator’s Brochure (IB). 
1.1.4 
Relevant Data Summary 
Data regarding the pharmacology, toxicology, pharmacokinetics (PK), and pharmacodynamics 
(PD) activity of siplizumab have been obtained from in vitro experiments, non-clinical studies and 
clinical trials in 779 patients.  Siplizumab only cross-reacts with one non-human primate species, 
the chimpanzee (Damschroder et al 2004). Key results relevant to this trial are highlighted in this 
section. For complete information on these studies please refer to the latest edition of the siplizumab 
Investigator’s Brochure (IB).  
1.1.4.1 
In Vitro Pharmacology 
Tissue cross-reactivity of siplizumab was assessed in human tissues.  Siplizumab binds to CD2 
bearing cells including human lymphoid tissue and T-cell rich regions of thymus, lymph node, 
spleen, tonsil, stomach as well as small and large intestine and lung tissue.  Siplizumab did not 
bind to other tissues, including reproductive organs and neural tissues, that do not present the CD2 
target.  
In pharmacology studies, siplizumab induced lymphocyte hypo-responsiveness and T- and NK 
cell depletion in a mixed lymphocyte reaction (MLR) assay at concentrations of 50 ng/mL and 
greater (Branco 1999).  Maximal depletion (via ADCC) of CD2+ lymphocytes was measured with 
siplizumab concentrations between 10 and 100 ng/mL.  In vivo activity was further investigated 
in a human-xenomouse model where weekly MEDI-507 administration for 6 months increased 
survival of mice bearing a CD2+ human adult T-cell leukemia (ATL) cell line.   
1.1.4.2 
Toxicology Data 
Toxicology studies with single and multiple doses of siplizumab were conducted in primates 
(chimpanzees) and rodent models. Studies in rodents were conducted to assess off-target 
pharmacologic toxicity. In rats, after daily administration of MEDI-507 at 35 mg/kg or 70 mg/kg 
for 10 days, no gross or microscopic changes were observed.  The lack of cross-reactivity between 
rat and human CD2 means this model cannot detect the on-target pharmacologic activity expected 
to exhibit in humans.   
To further explore the safety and pharmacologic activity of siplizumab, one single and three 
repeated dose toxicology studies were conducted in chimpanzees. All animals were administered 
one (0.143 mg/kg) to three, IV doses of 0.143, 0.43, 0.60, 1.43 or 5 mg/kg MEDI-507. Following 
doses up to 1.43 mg/kg MEDI-507, 4/7 animals presented with a transient, acute, toxic event (e.g., 
brief apnea, respiratory symptoms or seizure activity) around the time of the first infusion.  All 
animals recovered within 24 hours and symptoms did not reoccur upon re-challenge. With the 
highest dose, 5 mg/kg MEDI-507, animals (n=2) presented with symptoms of mild/moderate 
hypotension and diarrhea following the first dose.  Symptoms in both animals resolved within a 
few hours and did not recur on subsequent administrations, resembling an infusion reaction.   


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A mild, transient decrease in platelet count around the time of first infusion was noted and 
attributed to activation of the reticuloendothelial system by large numbers of antibody-coated 
lymphocytes.  In addition, a mild, transient increase in serum alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST) was noted at Day 7 that subsequently normalized by the next 
assessment on Day 42. Across all MEDI-507 treated animals, a rapid, dose-dependent depression 
in absolute lymphocyte counts and CD2-bearing lymphocyte subsets was noted by day 2; after the 
second dose. Recovery to pre-administration values occurred between 4-8 weeks after MEDI-507 
administration. One animal that received MEDI-507 developed pneumonia of the right lung and 
died on study Day 29. On autopsy, it was noted that lymphoid tissues were atrophic, consistent 
with a treatment-related effect, however a causal relationship between the infection and MEDI-507 
administration was not certain as pneumonia can occur in this animal group. For additional details, 
please refer to the siplizumab IB. 
1.1.4.3 
Teratogenicity and Reproductive Toxicology Data 
The reproductive/developmental toxicity profile of siplizumab has not been fully characterized. 
In consideration of the patient population and overall risk benefit profile, women of childbearing 
potential must utilize highly effective contraception methods to avoid becoming pregnant while 
receiving siplizumab and for 24 weeks after the last dose.  
Women who are nursing may not participate in this trial. The washout period of 24 weeks after the 
last dose is justified based on predicted PK profiles at 5 mg/kg, where siplizumab is predicted to 
be fully cleared from plasma and tissues by 12 weeks.  The additional 12 weeks is a safety margin 
to assure complete clearance of siplizumab and recovery of lymphocyte activity. 
Concomitant medications may present a separate reproductive risk and are to be used according to 
local guidelines and label.  Please refer to original package leaflets for complete information and 
guidance and the risks and potential toxicities of each concomitant medication.   
In addition, specific guidance on MPA can be located below. 
Mycophenolate (MMF; mycophenolate mofetil or MPA; mycophenolic acid) is a confirmed 
teratogen associated with an increased rate of spontaneous abortion and congenital malformation 
compared with other immunosuppressants. MPA containing products carry a warning for female 
patients in the US and EU who may become pregnant and must not be used during pregnancy 
unless there is no suitable alternative to prevent transplant rejection. Use during pregnancy is 
associated with increased risks of first trimester pregnancy loss and pregnancy should be ruled out 
by use of a sensitive serum or urine test before starting mycophenolate; confirmation immediately 
before starting the medicine is also recommended. 
Females of reproductive potential (FRP) must be counseled regarding pregnancy prevention and 
planning. Mycophenolate should not be used in women of childbearing potential unless they are 
using highly effective contraception. Some local labels for MPA recommend male contraception 
(condom). Due to the risks related to the drug’s use during pregnancy, a Risk Evaluation and 
Mitigation Strategy (REMS) program has been established in the US for products containing 
mycophenolate and details pertaining to this program are provided in Appendix 4. 


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Please refer to local labeling and guidelines for the use of MPA in women of childbearing potential, 
including use of contraception and wash-out periods following discontinuation of MPA containing 
products.  
1.1.4.4 
Human Safety and Tolerability Data 
In subjects, the safety, tolerability, PK and PD activity of siplizumab has been investigated in 
clinical trials across 4 distinct patient populations with hematologic T-cell malignancies, acute 
graft-versus-host disease (GvHD), psoriasis or following de novo renal transplantation.   
In clinical trials, single-and multiple doses of MEDI-507 from 0.0004 mg/kg to 15 mg/kg IV and 
0.1 to 10 mg subcutaneous (s.c.) have been administered to over 779 patients including 23 de novo 
renal transplant patients who have received multiple doses of 0.012 to 0.6 mg/kg. Across all patient 
populations, the most common adverse events (AEs) reported following MEDI-507 administration 
included lymphopenia (Grade 1-3) as well as a first dose effect manifesting as an infusion related 
reaction (Grade 1-2; pyrexia, chills, nausea and fatigue).   
The decrease in lymphocytes is dose-dependent and expected based on the known pharmacology 
of siplizumab. For subjects who present with infusion reactions, the events were generally mild, 
transient and resolved spontaneously or were managed with nonsteroidal anti-inflammatory drugs 
(NSAIDs) and antihistamines. Serious adverse events (SAEs) were reported more frequently in 
patients with lymphoma and GvHD; including 36 deaths related to complications of GvHD 
and  9 cases of EBV-LPD.  In renal transplant and psoriasis patients, a total of 59 SAEs were 
reported in 47 patients. There was one death in a renal transplant patient reported as a complication 
of a post-transplant cardiac procedure not related to MEDI-507 administration.   
1.1.4.5 
Human Pharmacokinetic Data 
Siplizumab pharmacokinetics have been characterized with doses from 0.06 to 4.8 mg/kg in 
patients with T-cell lymphoma, psoriasis as well as patients following de novo renal 
transplantation.  The disposition of siplizumab was mainly the consequence of its interaction 
(i) through the Fc region and FcRn receptor (a high-capacity receptor responsible for IgG 
homeostasis by recycling/salvage), and (ii) through the Complementarity – determining regions 
(CDR), to CD2 expressed on T-cells, leading to receptor mediated clearance. As with all IgG 
monoclonal antibodies, the primary route of elimination of siplizumab is via proteolytic 
catabolism, occurring at sites that are in rapid equilibrium with plasma.  Siplizumab also binds to 
Fc receptors on NK cells resulting in T- and NK-cell depletion via ADCC or ADCP mechanisms 
and subsequent clearance of drug via target-mediated drug disposition (TMDD).  In addition to 
depletion of CD2-bearing lymphocytes and proteolysis, binding and internalization of 
siplizumab-CD2 complexes all results in rapid and saturable routes of clearance.  
Siplizumab pharmacokinetics in renal transplant patients can be described by a 1-compartment 
model with 2 parallel mechanisms of clearance, linear and Michaelis-Menten (MM) elimination. 
Siplizumab binds to FcRn receptors in vitro with an EC50 of 273.3 nM (0.04 µg/mL). Upon 
saturation, linear FcRn mediated recycling and standard IgG clearance dominates as expected.  
However, at concentrations below ~1.7 μg/mL (MM KM EC50 0.34 µg/mL), TMDD elimination 


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is the dominate clearance pathway and results in an inflection point and transition to very rapid 
clearance. 
Preliminary modeling of the limited PK/PD data available in renal transplant patients and T-cell 
lymphoma patients suggests a strong population effect on the pharmacokinetics of siplizumab 
(MEDI-507).  In renal transplant patients, the apparent PK half-life (T1/2) is 8.5 days.  In lymphoma 
patients, where there is an abundance of CD2+ lymphocytes and CD2 target to which siplizumab 
can bind, a higher clearance and shorter T1/2 has been estimated of approximately 4.75 days. The 
primary difference is inflection point concentration at which linear clearance transitions to a more 
rapid clearance.  In T-cell lymphoma patients, this transition occurs at a concentration ~40-fold 
higher (15 µg/mL) than renal transplant patients (0.35 µg/mL).  
1.1.4.6 
Human Pharmacodynamic Data 
The primary PD markers measured across study populations are related to peripheral T-cell counts 
and CD2 receptor occupancy. In study MI-CP027, which enrolled de novo renal transplant 
patients, the 0.06 and 0.12 mg/kg doses were pharmacologically active with a short half-life of 
14-49 hours and loss of PD activity (rapid lymphocyte recovery) and around Day 8 as illustrated 
below (Figure 1-1).  
Figure 1-1 
Mean CD3 lymphocyte profile following siplizumab (MEDI-507) administration in 
study MI-CP027 
 
SOURCE: MI-CP027; Mean (+/- standard error) CD3 lymphocyte phenotypes by dose level at day 1 pre-infusion and 
at days 2 (P= 0.027), 3 (P= 0.016), 8 (P= 0.17), 33 (P = 0.21), and 60 (P = 0.20). 
Note: N = 4 (0.012 and 0.06 mg/kg); N = 5 (0.12) 
 
In Study MI-CP099, conducted in T-cell lymphoma patients, doses from 0.4–4.8 mg/kg of 
siplizumab were administered as 1–3 consecutive daily doses every 14 days for 1–8 cycles. As 
presented in Table 1-1, depletion of CD4, CD8 and NK cells is near complete with a 4.8 mg/kg 
administered every 2 weeks achieving ~97% suppression of circulating peripheral T-cells and 90% 
suppression NK cells.  


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Table 1-1  
Peripheral CD4, CD8, and NK cell depletion following siplizumab (MEDI-507) 
administration in patients with CD2 Positive T-cell lymphoma in Study MI-CP099 
1.2 
Study Purpose 
The purpose of this study is to investigate the safety, tolerability, pharmacokinetics and 
pharmacodynamics of escalating doses of TCD601 (siplizumab), an anti-CD2 monoclonal 
antibody, compared to a rabbit polyclonal anti-thymocyte globulin (rATG), as induction therapy 
in de novo renal transplant patients. All subjects will receive the same standard of care (SoC) 
background immunosuppression.  This trial will focus on profiling the safety, tolerability, PK and 
PD activity of siplizumab in the setting of standard-of-care immunosuppression in a moderate 
immunologic risk renal transplant population.  
Overall, results of this study will be used to inform the siplizumab dose and regimen selection for 
investigation in later phases of clinical development and serve as proof-of-principal study in the 
replacement of SoC, polyclonal, T-cell depleting induction therapy.  
Dose and regimen 
N 
CD4(%) 
CD8 (%) 
NK (%) 
Multiple Doses Q2 weeks 
 
 
 
 
0.6 mg/kg (0.2 mg/kg X 3)  
3 
88.5 
81.3 
68.3 
1.2 mg/kg (0.4 mg/kg X 3) 
4 
64.3 
76.3 
81.3 
2.4 mg/kg (0.4, 0.8, 1.2 mg/kg) 
3 
87.1 
84.9 
92.2 
3.4 mg/kg (0.4, 1.2, 1.8 mg/kg) 
3 
96.2 
75.1 
92.2 
4.8 mg/kg (0.4, 1.8, 2.6 mg/kg)  
3 
97.1 
96.4 
89.7 
Single Dose Weekly 
 
 
 
 
3.4 mg/kg  
3 
98.9 
94.2 
73.4 
4.8 mg/kg  
1 
NA 
NA 
NA 
N= subjects 
SOURCE: MI-CP099 CSR; Reported percentages are the amount of depletion i.e., 90% would represent 10% of 
baseline lymphocytes remain in the peripheral circulation.  Mean due to variability; Multiple dose arms, total dose of
0.6-4.8 mg/kg administered over 3 days in divided doses as indicated. 


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2 
Objectives and Endpoints 
Table 2-1 
Objectives and Related Endpoints  
Objective(s) 
Endpoint(s) 
Primary Objective 
Endpoints for primary objective 
To assess the safety, tolerability, PK and PD of siplizumab 
compared to rATG, in de novo renal transplant recipients at 12 
months post-transplant. 
• 
Adverse events 
• 
Serious adverse events 
• 
Clinically significant changes in clinical 
chemistry, hematology, vital signs, 
serology 
• 
siplizumab PK 
• 
Immunophenotyping 
• 
CD2 RO 
• 
eGFR via MDRD 
Secondary Objectives 
Endpoints for secondary objectives 
Exploratory Objectives 
Endpoints for exploratory objectives 
• 
To measure changes in peripheral lymphocyte 
immunophenotype 
• 
To measure the time-course and duration of siplizumab 
induced lymphocyte depletion and time to recovery 
• 
To measure peripheral CD2-receptor occupancy following 
siplizumab administration over time 
• 
To assess the incidence of treated biopsy proven acute 
rejection (tBPAR) at 12 months 
• 
To assess the incidence of treatment emergent de novo, 
donor specific antibodies (DSA) at 12 months 
• 
To assess the incidence of antibody meditated rejection at 12 
months 
• 
To assess renal function via eGFR using MDRD equation at 
Months 3, 6, 12 or EOS 
• 
Immunophenotyping via FACS 
• 
Lymphocyte counts 
• 
CD2 RO 
• 
Anti-siplizumab Ab  
• 
Incidence of BPAR 
• 
de novo-DSA / anti-HLA antibody 
measurement 
• 
incidence of AMR 
 
• 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3 
Study Design 
3.1 
General Overview 
The TCD601B102 study is a 12-month, randomized, controlled, open-label, dose escalation study 
to evaluating safety, tolerability, pharmacokinetics and pharmacodynamics of an anti-CD2 
monoclonal antibody, siplizumab, compared to anti-thymocyte globulin (rATG), as induction 
therapy in de novo renal transplant recipients. All subjects will receive background 
immunosuppression with standard exposure tacrolimus (TAC), mycophenolate mofetil (MMF) 
and corticosteroids (CS).  
Up to 24 moderate immunological risk, de novo renal candidates will be enrolled into the study.   
Figure 3-1 
TCD601B102 Study Design 
 
 
During the screening period (Day -28 to -1) and after informed consent has been signed, baseline 
subject information will be obtained in accordance with local regulations, including date of birth 
(month and year), age, sex (with childbearing status for females), race and ethnicity. In addition, 
relevant medical history (including CKD, ESRD and dialysis history) and current medical 
conditions at screening, a physical examination, vital signs, laboratory assessments, and a 
pregnancy test for female subjects of child-bearing potential will also be obtained.   


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Transplant procedures will also include information on the renal transplant procedure, recipient 
and donor transplant background, recipient and donor viral serology and recipient/donor HLA 
testing results.  
Procedures performed prior to consent as part of medical standard of care may be considered in 
the determination of subject eligibility (e.g., HLA/ABO typing, laboratory results). Additionally, 
if the screening and study Day 0 visits occur in close proximity (i.e., within a 24-hour timespan), 
screening assessments are not required to be repeated.  
Day 0 is defined as the day of transplant/day of first dose of study product. Upon confirmation of 
eligibility for the study, and no later than Day 0 (Day of Transplant), the subject will be randomized 
and assigned a treatment number within the electronic data capture (EDC) System/Interactive Web 
Response System (IWRS). Every effort should be made to randomize the subject on Day 0, but 
when logistical considerations prevent this from occurring (e.g., central pharmacy requirements), 
the subject may be randomized up to 24 hours pre-transplant.  
Eligible subjects will be sequentially assigned to one of two Cohorts (A or B) using a time-lagged 
dose escalation methodology as illustrated in Figure 3-2 below.  
Figure 3-2 
TCD601B102 Treatment Regimen  
 
Within each Cohort, it is planned that 12 subjects will be randomized between siplizumab (at two 
dose levels, increasing per Cohort as above) or rATG control, in an 8:4 ratio prior to renal 
transplantation on Study Day 0, as outlined in Table 3-1. 
Table 3-1 
Dosing Regimen  
Cohort 
Arm 
Subjects (n) 
Product 
Dosing Regimen 
Cohort A 
Arm 1 
8 
Siplizumab 
0.2 mg/kg (Days 0 and 4) 
Arm 3 
4 
rATG 
1.5 mg/kg (Day 0, 1 and 2) 
Cohort B 
Arm 2 
8 
Siplizumab 
0.6 mg/kg (Days 0 and 4) 
Arm 3 
4 
rATG 
1.5 mg/kg (Day 0, 1 and 2) 
Subjects randomized to receive siplizumab will receive two intravenous (IV) doses on Days 0 and 
Day 4 post-transplant. The first dose will be administered intravenously, peri-operatively and must 
be completed prior to revascularization and perfusion of the allograft. The second and final dose 
of siplizumab will be administered intravenously on Day 4 post-transplant (Study Day 4).  Subjects 


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randomized to the rATG control arm (Arm 3) will receive three intravenous (IV) doses of 
1.5 mg/kg on Days 0, 1 and 2, regardless of Cohort assignment. 
Siplizumab and rATG will be combined with concentration-controlled TAC (BID) dosing to a 
whole blood trough concentration 4-11 ng/mL, and MMF or equivalent (BID), and should be 
started within 24 hours post-transplant. Subjects will also receive CS per local practice with a 
minimum of 5.0 mg/d prednisone or equivalent until Month 12.  
Dose escalation from one Cohort to the next will be determined 28 days following the last 
investigational product administration in the 4th siplizumab treated subject in each treatment 
Cohort and prior to dose escalation to the subsequent Cohort, a review of all available safety, 
tolerability and PD data will be conducted by ITB-MED in collaboration with the Investigators.  
This 28-day safety period allows sufficient time for subjects to reach full-receptor occupancy, 
maximum pharmacodynamic activity, and for the presentation of acute, drug related toxicities. 
In the event there is no evidence of acute, dose limiting toxicity (DLT), randomization to the next 
dose level may be initiated. Alternatively, a decision to terminate the dosing arm could be reached.  
It is also possible for additional and/or intermediate dose level to be added during the course of 
the study per amendment (See Section 13.4.4). Cohorts may be added at any dose level below the 
maximum tolerated dose in order to better understand safety, PK or PD. 
This escalation data review will be repeated prior to dose escalation/termination decisions for each 
Cohort.  The review of subject data and dose escalation may occur before all subjects have been 
randomized to a given Cohort.  If the next dose level is opened to subject assignment, Cohorts will 
be back filled to achieve a final sample size of 12 subjects. 
Dose escalation will be based on a priori defined criteria outlined in Section 6.2.8. 
In addition to the review of data for dose decision purposes as noted above, an independent Data 
Monitoring Committee (DMC) will conduct an ongoing review of cumulative PK, PD, safety, 
Adverse Events (AEs) and Serious Adverse Event (SAE) data as well as EBV-viral load and PTLD 
surveillance results, including clinically relevant changes on physical exam and clinical laboratory 
assessments and ad hoc imaging. The Committee will convene on a quarterly basis or as described 
in the DMC Charter. If at any time the observed AEs meet or exceed the a priori-defined stopping 
criteria, the study will be placed on hold pending a review as outlined in Section 9.1.1. 
Additionally, a formal interim analysis will occur once 50% of subjects assigned to the treatment 
Cohorts complete their 6-month study assessment.   
This formal interim analysis will be conducted to assess the safety/tolerability (e.g., AEs, SAEs, 
clinical laboratory assessments, vital signs, PK data and PK/PD activity (e.g., immunophenotyping 
and CD2 receptor occupancy). The analysis will also include assessment of biopsy proven acute 
rejection (BPAR), graft losses deaths, and key safety endpoints. In the event the acute rejection 
rate exceeds a clinically relevant threshold set forth in the protocol and DMC charter, or the a 
priori defined stopping rules, enrollment will be suspended to allow for the early termination of 
any treatment cohort where the benefit/risk of siplizumab is deemed unacceptable. 
Following transplantation, subjects should be treated post-operatively per standard-of-care clinic 
practice and per the assessments outlined in the protocol. Following discharge from the hospital 


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and unless more frequent clinic visits are required for laboratory specimen collection, subjects will 
present to the clinical site for study visits weekly up to and including Week 10 and then monthly 
through Month 12 or EOS, and as outlined per the Schedule of Assessments outlined in 
Appendix 1.   
All randomized subjects are expected to continue in the study up to Month 12 regardless of being 
on or off assigned treatment. Subjects who are randomized but not transplanted or administered 
their first dose of siplizumab will be replaced. 
4 
Study Design Rationale 
The goal of induction therapy is to prevent acute rejection during the early post-transplant time 
period by providing a high degree of immunosuppression at the time of transplant surgery and 1-2 
months thereafter. Escalating doses of siplizumab will be administered in place of SoC (e.g., 
rATG) induction therapy in combination with a TAC/MMF/CS based treatment regimen.   The 
time course, depth and duration of lymphocyte depletion and immunomodulation will be profiled 
in combination with the assessment of safety, tolerability, PK and PD activity.  CD2 represents a 
unique target for induction considering the broad expression and function in T-cell activation, 
co-stimulation and alloantigen recognition. This trial will characterize the safety, tolerability, PK 
and PD activity of 0.2 mg/kg and 0.6 mg/kg siplizumab in comparison to rATG induction, in the 
setting of de novo renal transplantation.   
Siplizumab will be administered in two separate IV infusions over a ~5-day time period. The first 
infusion will be administered on study day 0 at the time of transplant (pre- or intra-operatively).  
The infusion is to be completed prior to revascularization and reperfusion of the allograft to assure 
both donor and alloreactive T-lymphocytes are suppressed and depletion is initiated in the hours 
and days post-transplant.  The second dose will be administered on post-operative Day 4. 
PK and PD data will be analyzed during the trial and the Population PK/PD model will be revised 
after each dose escalation to predict the concentration- exposure-response for the next dose as 
appropriate. Overall, the escalation scheme is designed to collect data and measure siplizumab 
concentrations that demonstrate a positive benefit/risk profile while providing approximately 
45 days of T-cell and NK-cell suppression and immunomodulation.  
The randomized, controlled, open-label, dose escalation design selected for this multicenter study 
will allow for a cautious assessment and evaluation of the multiple dose siplizumab safety, 
tolerability, PK and PD when added to TAC/MMF/CS based treatment regimen in comparison to 
standard of care induction with rATG.  
Although the ideal study would employ a double-blind, double-dummy methodology to minimize 
bias, in consideration of the inherent complexity of this study (multiple arms, frequent visits, 
siplizumab PD activity, interim assessment after each dose, the different dosing schedules of 
siplizumab and ATG and extensive investigations), it has been decided to utilize an open-label 
design. This open-label design will not only minimize the risks for subjects during the initial 
investigation of siplizumab should the need for rapid intervention arise, such as emergent SAEs, 
but also avoids the additional difficulties associated with placebo infusions in the control group. It 
is recognized that Investigator bias can affect the management of subjects receiving investigational 


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treatment; especially in an open-label study setting. In general, such scrutiny biases the study in 
favor of the control arm. As such, efforts to minimize bias for or against the siplizumab treatment 
arms will be managed through the use of a limited number of high-quality transplant centers with 
similar SoC and subject management.      
Due to the unknown tolerability and PD activity, this study will enroll a moderate immunological 
risk de novo patient population who would typically be treated with ATG induction. This 
population was selected since they typically present a lower risk of post-transplant complications, 
including delayed graft function (DGF) and provide a fair assessment of clinical activity while not 
requiring the highest level of immunosuppression. While it is recommended per current KDIGO 
guidelines, that ALL renal transplant patients receive induction with anti-IL2R therapy (KDIGO 
2009), due to the expected overlapping activity with siplizumab, inhibition of T-cell activation, 
anti-IL2R or other T-cell depleting induction (e.g., ATG) will not be allowed in combination with 
siplizumab in this trial. In the setting of acute rejection prophylaxis with induction or no induction 
in the planned study population, the risk of ‘omitting’ SoC induction is manageable. Without 
induction and SoC therapy (TAC, MMF and CS) 12-month BPAR rates of 12.4% and 13.3% for 
living and deceased donor allografts have been reported, respectively (Tanriover 2015). These 
rates (BPAR) are similar to those in patients treated with anti-IL2 induction of 11.7% and 12.4%, 
respectively in the same population (Tanriover 2016).  
Overall, safety risks will be reviewed on a regular basis by ITB-MED and an external independent 
DMC, with particular attention given to acute rejections, infusion reactions, serious infections, 
EBV-reactivation and malignancies associated to those (e.g., PTLD). 
4.1 
Dose/Regimen and Treatment Duration Rationale 
While siplizumab (MEDI-507) has been administered to 779 subjects, the characterization of PK 
and PD activity following IV administration remains incomplete.  An initial population PK/PD 
model has been developed based on data collected in previous siplizumab (MEDI-507) trials in 
renal transplant, T-cell lymphoma, aGvHD and patients with psoriasis.  
The following section supports the rationale for the investigation of two siplizumab doses via a 
two-dose regimen. 
As described in Section 1.1.4.5, siplizumab pharmacokinetics in renal transplant patients can be 
described by a 1-compartment model with 2 parallel mechanisms of clearance, linear and 
Michaelis-Menten (MM) elimination.  
Mean, predicted, time-concentration profiles of the two-dose regimen planned in renal transplant 
patients have been simulated and are presented in Figure 4-1.  


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Figure 4-1 
Mean predicted siplizumab serum concentrations in study TCD601B102: 0.2 and 
0.6 mg/kg 
 
Figure 4-1:  Solid curves represent the mean predicted time-concentration profile of siplizumab following two simulated 
0.2 or 0.6 mg/kg siplizumab doses on Study Day 0 and 4 in de novo renal transplant patients.  
 
Siplizumab concentrations are predicted to increase in a dose proportional manner with mean 
Cmax (peak) concentrations of approximately 
 µg/mL following the second dose of 0.2 
or 0.6 mg/kg on Study Day 4. The apparent PK half-life is predicted to be ~
 days at both doses 
with peak concentrations exceeding the TMDD inflection point of ~
 µg/mL.  
Dose escalation in the TCD601B102 trial will start with 0.2 mg/kg, which is 3-fold less than the 
highest dose investigated in the setting of previous renal transplantation studies (0.6 mg/kg; 
Studies NKD03 and ITN036) and ~1.7-fold higher than the 0.12 mg/kg dose investigated in the 
MI-CP027 renal transplant induction study.  A semi-log dose escalation up to 0.6 mg/kg will allow 
for adequate characterization of the PK/PD profile and investigation of lymphocyte 
pharmacodynamics. Importantly, all of the siplizumab doses proposed in this trial have been 
administered to subjects previously with good safety and tolerability, however due to the nature of 
the renal transplant population, cautious dose escalation will be conducted to ensure subject safety 
is managed closely during this trial.   
It is planned to administer the first dose prior to revascularization of the allograft to ensure both 
donor and recipient alloreactive T-lymphocytes are rapidly suppressed and depletion is initiated 
within hours of allograft perfusion. It is expected that initial distribution within the periphery and 
various tissue compartments as well as ADCC mediated depletion of lymphocytes will result in 
enhanced siplizumab clearance following the first dose. Therefore, a second dose of siplizumab 
will be administered on Day 4 with the intent of replenishing the free-siplizumab (TCD601) to 
account for redistribution of CD2 bearing lymphocytes as well as maintain saturation of the TMDD 
clearance pathways; maintaining prolonged serum concentrations above the tissue and peripheral 
concentration threshold of µg/mL.  


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Considering the apparent 
-day half-life predicted from previous trials in renal transplant patients 
(MI-CP027) and acute GvHD (MI-CP046) following bone marrow transplantation with 
siplizumab (MEDI-507) high serum concentrations will be required to prolong the peripheral 
immune modulation and T-cell suppression during the first month post-transplant; a time when 
patients are at the highest risk of acute rejection.  Based on current modeling presented in 
Figure 4-1 it is anticipated that two doses of 0.6 mg/kg will result in ~30 days above the µg/mL 
target.  While the 0.2 mg/kg dose is not expected to provide the same duration of PK coverage, 
accounting for the post-depletion lymphocyte dynamics and redistribution from lymphoid tissues, 
the pharmacodynamic activity induced by selective T-cell depletion is expected to persist 
following siplizumab clearance.   
While the duration of activity in renal transplant recipients is yet to be determined, PK/PD 
modeling planned prior to the dose escalation step will allow for a near real-time 
exposure-response analysis during the trial and modification of the escalation scheme or dosing 
regimen per amendment.  
4.1.1 
Siplizumab Tissue Distribution / Effect Compartment 
Recent characterization of monoclonal antibody distribution by Shah and Betts allows for the 
rational targeting of various tissue compartments based on the expected distribution of therapeutic 
antibodies as a percentage of the free plasma concentration (Shah & Betts 2013).  In the setting of 
solid organ transplantation, the peripheral (vascular) compartment is not the only location of 
alloreactivity. Acute cellular rejection occurs within the parenchyma and vasculature of the 
allograft.  Similarly, allorecognition occurs, to a large extent, in lymph nodes and secondary 
lymphoid tissues; therefore, these tissues represent an equally important compartment outside of 
the peripheral vasculature to target.  For renal tissue, an antibody biodistribution coefficient (ABC) 
of 13.7% of plasma concentration (CV% (± 3.10) was reported whereas the ABC for lymph nodes 
is 8.46 ±11.4% (Shah & Betts 2013).  
Completed siplizumab (MEDI-507) studies have assessed the effect of anti-CD2 therapy on 
peripheral lymphocytes and lymphocyte subsets as well as peripheral target saturation and binding.  
It is expected that administering sufficient siplizumab to achieve adequate exposure in both the 
peripheral and relevant tissue compartments will lead to more complete immune regulation. Based 
on the expected PD activity outlined in Section 1.1.4.6, where siplizumab concentrations of 
 µg/mL are required for adequate T and NK cell modulation and depletion, peripheral siplizumab 
trough (C0) concentrations of  
 µg/mL and 
 µg/mL would result in adequate target 
engagement and lymphocyte suppression in renal tissue and lymph nodes, respectively.  
As discussed in Section 1.1.4.5, population pharmacokinetics (PPK) modeling suggests that 
concentrations of siplizumab above the MM KM of 
 µg/mL, which represents the EC50 
concentration, is necessary to maintain saturation of the TMDD pathway and linear clearance in 
renal transplant patients.  To maintain full CD2 RO, target engagement and saturate clearance 
mechanisms, the relevant concentration is 3-5-fold greater than the KM; a concentration of 
 
 µg/mL. This concentration is represented by the inflection point and transition from linear- 
to non-linear clearance, occurring around the 
 mg/mL concentration range in the simulations. 
This concentration also represents a key threshold (  µg/mL) for T-cell engagement and depletion, 


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where maintenance of trough concentrations above the threshold in the periphery are expected for 
approximately 
 following 0.6 mg/kg siplizumab (Figure 4-2).   
Figure 4-2 
Mean predicted, log-transformed, siplizumab serum concentrations in study 
TCD601B102 following 0.2 and 0.6 mg/kg siplizumab administration 
 
Figure 4-2: Horizontal dashed lines represent predicted trough concentrations at 
 ug/mL.   Solid curves 
represent the mean predicted time-concentration profile of siplizumab (semi-log scale) following two simulated 0.2 or 
0.6 mg/kg siplizumab doses on Study Day 0 and 4 in de novo renal transplant patients.  
 
Based on the known variability of siplizumab (MEDI-507) PK, and proposed target tissue 
concentrations, a mean minimum serum concentration above 
 µg/mL would be required to 
maintain tissue concentrations above the  µg/mL threshold to induce immunomodulatory activity 
in renal and lymph tissue, respectively. These concentration thresholds are represented as 
horizontal dashed lines in Figure 4-2. It is expected that following the second 0.6 mg/kg dose of 
siplizumab a short duration, above the tissue exposure threshold will be achieved.   
4.2 
Rationale for Active Control 
In the completed renal transplant siplizumab clinical trials, no controlled studies have been 
performed, therefore the comparative safety and efficacy data will allow for a better estimation of 
effect size and AE rates for future clinical trials in this population.  The use of an active control 
arm was selected to allow for enrollment and randomization of a relevant moderate immunologic 
risk patient population who would be generally treated with ATG induction therapy. In addition, 
the comparative safety, biomarker and pharmacodynamic data within the control population will 
facilitate a more comprehensive assessment of siplizumab safety and tolerability in comparison to 
SoC.  
ATG is the most frequently used depleting agent for induction therapy in solid organ 
transplantation. The use of rATG (Thymoglobulin; Genzyme) is more common in North America 
compared to Europe. In Europe ATG-F (ATG-Fresenius; Grafalon, Fresenius Biotech GmbH, 
Munich, Germany) is used for those deceased donor transplant recipients that are considered at 


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risk for DGF and may be effective in reducing ischemia reperfusion injury in this setting 
(Guirado 2018).  
The mechanism of action of both ATG products is lymphodepleting, therefore there are 
mechanistic similarities as well as differences between rATG, ATG-F and siplizumab. The ATG 
products are both generated by immunization of rabbits but use different immunogens, namely 
fresh human thymocytes for ATG and a Jurkat T-cell line for ATG-F. Furthermore, the proportion 
of antibodies directed at CD2 in ATG has been estimated as 7.5% (Popow et al 2013). However, 
ATG-F targets CD28, CD29, CD45, CD49, CD98, and CD147 but rarely targets CD3, CD4, CD44, 
and HLA-DR, thus rATG and ATG-F may have different immunosuppressive activities 
(Song et al 2020), further supporting the restriction to rATG in this clinical trial.  For these reasons 
rATG is considered an appropriate control for this induction study. 
4.3 
Rationale for Background Immunosuppression 
In adult de novo kidney transplant recipients, the use of TAC, MMF and CS is an 
approved regimen for renal transplantation across the world and is the current SoC used in more 
than 90% of kidney transplants. Over the past decade, the clinical use of CNIs, including TAC, 
has focused on minimization of the CNI to mitigate many of the associated adverse effects. Current 
clinical use of TAC with an MMF-based regimen and CS results in excellent graft and patient 
survival as well as low rates of acute rejection. When TAC is combined with an MMF-based 
regimen and induction using an IL-2 antagonist, the labeled trough concentration range for TAC 
is 4-11 ng/mL (e.g., Prograf® PI 2019); this range will be employed in this clinical study.   
Similarly, MMF or equivalent, at a dose of 1.0 g BID will be utilized per label (e.g., CellCept PI 
2019). 
For CS, all subjects should receive a minimum of 5.0 mg/d (prednisone or equivalent) from Day 0 
until Month 12 with administration according to local practice.   
The use of immediate-release generic or equivalent medications for TAC and MMF are allowed 
in the TCD601B102 study, however, substitution is not allowed for the first 12 months 
post-transplant.  All subjects who start on brand or a specific generic TAC and MMF are to be 
maintained on the same brand or generic for the duration of this trial.   
For subjects who are inadvertently switched, or in the event of a drug shortage need to change to 
another manufacturer, ITB-MED is to be informed and the site should consider more intense 
therapeutic drug monitoring (TDM) to ensure the subject achieves similar TAC concentrations.  
4.4 
Purpose and Timing of Interim Analyses/Design Adaptations 
During the conduct of this study, ITB-MED and the DMC will review safety, PK and PD results 
of the trial on an ongoing basis. A regular review of cumulative safety data, including as well as 
EBV-viral load and PTLD surveillance results, including clinically relevant changes on physical 
exam and clinical laboratory assessments and ad hoc imaging, biopsy proven acute rejection 
(BPAR), graft losses deaths, and key safety endpoints, will be conducted by ITB-MED. In the 
event safety endpoints or the acute rejection rate exceeds a clinically relevant threshold set forth 
in the protocol and DMC charter, or the a priori defined Stopping Rules as outlined in 


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Section 9.1.1 are met, enrollment will be suspended to allow for the early termination of any 
treatment cohort where the benefit/risk of siplizumab is deemed unacceptable. 
Formal analyses to assess PK, PD as well as safety will be performed as follows: 
• Escalation analysis: After the first 4 siplizumab treated subjects who have been enrolled 
in each cohort reach 28 days after the last siplizumab infusion. 
• Interim analysis: Once 50% of subjects assigned to the two treatment Cohorts complete 
their 6-month study assessment. 
The purpose of the Day 28 escalation analysis is to confirm progression to the next cohort while 
the 6-month interim analysis is to support PK/PD modeling activities and clinical trial and dose 
escalation planning.  
4.5 
Risks and Benefits 
The risks and benefits are expected to be broadly similar to that of ATG in combination with SoC 
immunosuppression. In particular, the risk of increased infections and first dose effect, will be 
minimized by adherence to the inclusion/exclusion criteria, premedication, close clinical 
monitoring and minimization of protracted siplizumab exposure during treatment period. Infection 
risk will be mitigated by following applicable national vaccination guidelines and by use of 
prophylaxis (See Section 6.5). Similarly, the risks of SARS-CoV-2 will be minimized by following 
local, national and international guidelines for immunosuppressed and solid organ transplant 
patients (See Section 4.5.3). 
The risks of insufficient efficacy (higher rate of acute rejection-tBPAR than SoC) will be 
minimized by enrolling a moderate immunologic risk patient population, frequent monitoring of 
clinical labs and signs and symptoms suggesting BPAR and the early discontinuation of any 
treatment arm that is unsafe or ineffective according to the Stopping Rules detailed in 
Section 9.1.1.   
The below sections list the possible risks related to siplizumab treatment. For further details please 
refer to Section 7 of the current IB.  
Information and guidance for the SoC treatment used in this study is provided in the local labelling 
information and should be strictly followed. 
4.5.1 
Siplizumab 
Risks of siplizumab administration include those generally associated with administration of a 
monoclonal antibody in humans. These include the possibility of a hypersensitivity reaction 
characterized by acute or delayed allergic reaction, anaphylaxis, urticaria, rash, dyspnea, 
hypotension, fever, chills, and immunogenicity. A serious infusion reaction that results in 
anaphylaxis is a rare event in monoclonal antibody therapy. Siplizumab is a fully humanized 
monoclonal antibody of the IgG1 class. This class of antibody is normally abundant in humans. 
Therefore, the antibody itself is expected to be less immunogenic in humans compared to chimeric 
or other humanized antibodies.  
Assays to detect a putative antibody response to siplizumab are included in the study design. 


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In consideration of the clinical and non-clinical toxicology study results for siplizumab 
(MEDI-507) as well as clinical studies with antibodies that target CD2, the potential risks of 
siplizumab in humans may include: 
• Infusion reactions, inflammatory reactions and cytokine release 
• Immunosuppression and infections 
• EBV-associated lymphoproliferative disorders 
• Other hypothetical risks 
These risks and an overall risk mitigation strategy are discussed below.  
4.5.1.1 
Infusion and Inflammatory Reactions and Cytokine Release 
Cytokine Release 
Siplizumab is a non-activating humanized mAb that binds to CD2+ immune cells and rapidly 
eliminates them via ADCC therefore cytokine release syndrome may be observed after 
administration. Cytokine release syndrome is an acute clinical syndrome and has been temporally 
associated with the administration of certain T-cell depleting antibodies, particularly the murine 
anti-CD3 antibody, muromonab-CD3 (Orthoclone-OKT3). Similar effects are noted with B-cell 
depleting antibodies such as rituximab (Rituxan). This syndrome has been attributed to the release 
of cytokines by activated lymphocytes or monocytes. The clinical manifestations have ranged from 
a more frequently reported mild, self-limited, “flu-like” illness to a less frequently reported severe, 
life-threatening, shock-like reaction, which may include serious cardiovascular, pulmonary and 
central nervous system manifestations. The syndrome typically begins approximately 30 to 60 
minutes after administration (but may occur later) and may persist for several hours. The frequency 
and severity of this symptom complex is usually greatest with the first dose. With each successive 
dose, both the incidence and severity of the syndrome tend to diminish. Increasing the amount of 
a dose or resuming treatment after an interruption may result in a reappearance of the syndrome.   
A cytokine release event has not been reported in any subjects receiving siplizumab alone and in 
combination with other immunosuppressants to date. However due to the target cell population, 
CRS remains a hypothetical risk. 
Infusion Reactions 
Infusion-related reactions, such a chills, pyrexia, and fatigue, have been commonly seen in 
siplizumab (MEDI-507) treated patients with cancer, GvHD, psoriasis and following organ 
transplantation. These events have been mild to moderate in severity, transient in nature, and have 
not recurred with re-challenge. Other associated events included nausea, vomiting, and 
hypotension. In the cancer studies, as prophylaxis for infusion type reactions, patients have been 
premedicated with acetaminophen and diphenhydramine before each siplizumab infusion. 
Demerol has been administered for treatment of patients with rigors. Chills without rigors have 
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Inflammatory Reactions 
Allergic reactions may present as mild pruritic rashes or they may be severe such as erythroderma, 
Stevens-Johnson syndrome, vasculitis, delayed hypersensitivity or anaphylaxis.  
Anaphylactic reactions (anaphylaxis) are serious and occasionally fatal hypersensitivity reactions. 
Allergic reactions including anaphylaxis may occur when any foreign protein is injected into the 
body. They may range from mild manifestations such as urticaria or rash to lethal systemic 
reactions. Anaphylactic reactions occur soon after exposure, usually within 10 minutes. Patients 
may experience paresthesia, hypotension, laryngeal edema, mental status changes, facial or 
pharyngeal angioedema, airway obstruction, bronchospasm, urticaria and pruritus, serum sickness, 
arthritis, allergic nephritis, glomerulonephritis, temporal arteritis or eosinophilia.  
Serious allergic events including anaphylactic or anaphylactoid reactions have been reported in 
patients re-exposed to antibodies derived from foreign protein such as OKT3 or ATG. Since it can 
be very difficult to distinguish between cytokine release syndrome and anaphylaxis, extra caution 
must be taken. Reactions occurring within 10 minutes of the start of an infusion are usually 
anaphylaxis and should preclude re-administration of the antibody. Vasculitides may occur, most 
commonly leukocytoclastic vasculitis or palpable purpura. 
4.5.1.2 
Immunosuppression and Infections 
Siplizumab is being developed for its expected immunomodulatory and T-cell depleting activity. 
CD2 ligation is linked to the functional activity of T-cell activation and co-stimulation.  T-cell 
depleting antibodies may be immunosuppressive and prolonged immunosuppression may increase 
the risk of infection, including opportunistic infections. Administration of escalating doses of 
siplizumab is expected to result in general immunosuppression due to T- and NK-cell depletion 
when full receptor occupancy has been achieved.  Siplizumab induction will be combined with 
background, CNI-based triple-therapy immunosuppression in renal transplant patients.  Subjects 
treated with siplizumab may present with an increase in the overall degree of immunosuppression 
from days to weeks depending on the dose and regimen as intended in induction treatment with 
SoC T-cell depleting antibodies.  During this time of immunosuppression subjects may be at a 
higher risk for infection.  
Vaccination of human subjects during treatment with siplizumab and prior to clearance of the 
antibody is likely to result in therapeutic failure (i.e., non-protective antibody titers) (see 
Section 6.5) Administration of live attenuated agents should be avoided while receiving 
siplizumab treatment and for up to 6 months thereafter, depending on the dose and time for 
reconstitution of immune function. 
In completed clinical trials with siplizumab there is no clear evidence for a higher rate of infections 
associated with treatment administration.  Infections were common in Post-HSCT patients with 
Garde II-IV aGvHD where an increased risk of immunosuppression related opportunistic 
infections, including viral reactivation, is common.  In study MI-CP046 (adult GvHD), infections 
were common in both MEDI-507 (19 [90%]) and placebo control arms (12 [92%]). When the 
investigator’s assessment of relatedness is considered, all of the infection events are consigned to 
background. In oncology studies, infections occurred in 3/19 (16%) T-cell lymphoma patents 


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(MI-CP099), with 5 patients (26%) testing positive for CMV antigen; three of whom discontinued 
treatment per protocol. In Study MI-CP107, 4 infection-associated SAEs (infection, respiratory 
syncytial virus, sepsis, and staphylococcal bacteremia) were reported in 4/22 (18.2%) of patients. 
One event (infection) was judged by the Investigator as being related to MEDI-507. In the CD2+ 
T-cell lymphoma patient pool, there was no dose related increase in infection rates between arms, 
although there was an increase in EBV-related events; EBV-associated lymphoproliferative 
disease was reported in 9 patients treated across the T-cell lymphoma and aGvHD populations; 
see Lymphoproliferative Disorders and other Malignancies in Section 4.5.1.3 for details.  
Assessing the rates of treatment emergent infections in a relatively healthy population, psoriasis, 
the placebo group was higher as compared to the siplizumab treated group.   
While the sample size in the renal transplant pool is limited, the reported infections were as 
expected, and none were suspected by the investigator to be due to siplizumab administration as 
presented in Table 4-1 below. 
Table 4-1 
Renal transplantation pooled analysis: Opportunistic infections 
Standard or Custom MedDRA Query 
  Preferred Term 
IV: ≤ 0.12 mg/kg 
(n=13) 
IV: > 0.12 mg/kg 
(n=10) 
Total 
(N=23) 
Opportunistic Infection (CMQ) 
  2 (15.4%) 
  4 (40.0%) 
  6 (26.1%) 
Clostridium difficile colitis 
  0 
  2 (20.0%) 
  2 (8.7%) 
Gastritis 
  1 (7.7%) 
  1 (10.0%) 
  2 (8.7%) 
Gastroenteritis 
  0 
  1 (10.0%) 
  1 (4.3%) 
Herpes esophagitis 
  1 (7.7%) 
  0 
  1 (4.3%) 
Urinary tract infection 
  0 
  1 (10.0%) 
  1 (4.3%) 
Viral infection 
  0 
  1 (10.0%) 
  1 (4.3%) 
Source: Table 2.1.5.5 (Listing ADVERSE_EVENTS in CP027 study, ListingAE_LAA in NKD03 study, listing16_2_7_1 
in ITN036 study.; Abbreviations: CMQ = Custom MedDRA Query; SMQ = Standardized MedDRA Query; Note: 
MedDRA Version 22.1. 
4.5.1.3 
Lymphoproliferative Disorders 
In patients at a high risk of lymphoproliferative disorders participating in studies with MEDI-507, 
specifically patients with CD2+ T-cell lymphoma and patients with ongoing acute GvHD 
following a bone marrow transplant, EBV-associated lymphoproliferative disorder (LPD), PTLD, 
and lymphoma have been reported. In the T-cell lymphoma trials (MI-CP099 and MI-CP107), 
EBV-LPD was reported in 5/51 (9.8%) patients including large granular lymphocytic leukemia 
(LGL; n=2), cutaneous T-cell lymphoma (n=1), peripheral T-cell lymphoma (n=1), and adult 
T-cell lymphoma (ATL; n=1). In the aGvHD studies EBV-LPD (n=1), PTLD (n=1) and 
EBV-related lymphoma (n=2) was reported in 4/48 (8.3%) patients. In addition, three cases of 
LPD have been reported in Investigator-initiated and compassionate use studies of MEDI-507 in 
patients following bone marrow transplantation.   
All of the LPD cases reported with MEDI-507 have been limited to two unique patient populations, 
both of whom had a history of malignancies and increased risk factors for EBV-LPD, 
notwithstanding their primary T-cell lymphoma and aGvHD following BMT.  While rare, 
EBV-associated secondary hematological malignancies are not unexpected in the setting of 
profound immunosuppression associated with T-cell lymphoma where B-cell lymphoma rates vary 


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from 2-15% based on patient age, ethnicity and immune status (Dojcinov et al 2018).  In the setting 
of HSCT, especially in patients who present with multiple risk factors (Curtis et al 1999; Uhlin et 
al 2014), PTLD, rates of 8% up to 40% have been reported (Juvonen et al 2003).   
In the setting of renal transplantation, siplizumab use is not expected to increase the risk of 
EBV-LPD/PTLD 
over 
ATG-based 
induction 
in 
combination 
with 
background 
immunosuppression.  Independent adjudication of all 9 EBV-LPD cases was conducted to assess 
the overall risk of EBV-LPD in the setting of renal transplantation.  While a notable risk of 
EBV-LPD in the setting of T-cell lymphoma was assessed by the committee it was stated that 
experience to date does not demonstrate that this risk exceeds that associated with ATG. 
This rate in the US has been reported to be 1.03% (Hart et al 2020) and as high as high as 2.4% 
with ATG induction (Thymoglobulin PI 2020).  The rate of EBV-LPD is known to be higher in 
patients who are EBV-seronegative with a relative risk up to 33-fold that of EBV+ recipients 
(Marks et al 2011).  Therefore, all recipients will be screened prior to administration of siplizumab, 
and EBV-seronegative subjects excluded from participating in the TCD601B102 clinical trial. In 
addition, clinicians who specialize in transplant immunosuppression, and are aware of the risks for 
EBV-LPD, will be managing patients enrolled in this study.  Regular assessments of hematology, 
EBV-viral load as well as PTLD surveillance including full physical exams at each visit as well as 
monitoring of clinical signs and symptoms will be conducted during the 12-month study. 
4.5.1.4 
Other Hypothetical Risks 
Renal Dysfunction 
In two renal transplant tolerance studies, NKD03/ITN010ST (n=5) and ITN036ST (n=5), a 
transient, acute kidney injury (AKI)-like syndrome was reported in a majority (9/10) of patients 
early in the post-transplant course. The syndrome was associated with recovery of host 
hematopoietic cells and rapid loss of donor chimerism at approximately two weeks post-transplant 
and is better described as Chimeric Transition Syndrome (CTS). Patients in these two trials 
received siplizumab (0.6 mg/kg MEDI-507 on Days -1, 0 and 1) in combination with a 
non-myeloablative, cyclophosphamide-based, conditioning regimen, thymic irradiation and 
rituximab pre- and post-transplant.  Patients also received a combined haploidentical bone marrow 
cell infusion to induce transient chimerism and a renal allograft from the same donor on Day 0.   
Patients with CTS presented with a significant increase in serum creatinine (SCr) with onset 
around post-transplant day 10-14 that peaked (SCr range 3.5 to 15.4 mg/dL) between days 10-20; 
resolving by day 30.  Renal biopsies taken during the CTS event were negative for T-cell mediated 
rejection but showed capillary endothelial injury with cellular infiltrates (CD8+ / CD68+ cells) in 
the peritubular and glomerular capillaries.  
Overall, 78% (7/9) of patients recovered normal renal function following the CTS event; 3 patients 
recovered with minimal intervention (corticosteroid pulse) while 4 patients required treatment 
(Intravenous Immunoglobulin (IVIG), ATG and/or plasma exchange).  The two remaining patients 
failed to recover full renal function; this included one patient who lost their graft at day 10 due to 
severe antibody mediated rejection as well as a patient who presented with subsequent CNI toxicity 
and later progressed graft loss associated with thrombotic microangiopathy at Month 7. 


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Renal dysfunction, including significant changes in serum creatinine or eGFR has not been 
reported in other patient populations receiving siplizumab alone or in combination with SoC 
immunosuppression, including 13 patients enrolled in study MI-CP027 following renal 
transplantation.  Patient’s serum creatinine, serum cytokines and renal injury makers will be 
measured frequently in the first few weeks post-transplant with a focus on renal injury and 
dysfunction.  In addition, urinary injury biomarkers will be collected for future analysis and 
biopsies will be evaluated for CTS in the event patients present with BPAR.    
Malignancies 
Prolonged and sustained immunosuppression may result in an increased risk of developing certain 
types of cancer. 
In the T-cell lymphoma trials one patient with LGL developed a secondary leukemia (M4 type 
leukemia) one year after completing MEDI-507 therapy was reported. In the GvHD studies a case 
of acute myeloid leukemia relapse was reported. 
In the study of renal transplant patients, one patient experienced a basal cell carcinoma of the skin 
on an area of actinic exposure reported during long-term follow-up.  
Two patients in the psoriasis studies had secondary malignancies (squamous cell carcinoma of the 
skin and myelodysplastic syndrome) following treatment with MEDI-507. Both patients had a 
prior history of these respective conditions and were entered into a MEDI-507 psoriasis study in 
violation of protocol entry criteria that excluded patients with a history of cancer (although in the 
latter case the condition was not disclosed at study enrollment). 
Adjunct Immunosuppression 
The combination of escalating doses of siplizumab in the presence of adjunct immunosuppression 
with TAC, MMF, and CS is not known. Please refer to the local labeling for the other agents for 
full disclosure of the expected risks associated with use in the setting of de novo renal 
transplantation for the investigational arms.  
4.5.2 
Risks of ATG Induction Therapy 
The following summary is taken from the most recent US FDA-approved labelling of ATG 
(Thymoglobulin, Genzyme, 2020). For the most recent guidance refer to the most recently 
approved local labeling from the appropriate authority. 
Immune-Mediated reactions 
Serious immune-mediated reactions, including anaphylaxis or severe cytokine release syndrome 
(CRS), have been reported with the use of ATG. Fatal anaphylaxis has been reported. If an 
anaphylactic reaction occurs, terminate the infusion immediately and provide emergency treatment 
as indicated per local practice and clinical expertise.  


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Infusion-Associated Reactions (IAR) (including Cytokine Release Syndrome) 
Cases consistent with cytokine release syndrome (CRS) have been reported with rapid infusion 
rates. CRS is attributed to the release of cytokines by activated monocytes and lymphocytes. 
Severe acute CRS can cause serious cardiorespiratory events and/or death. Close compliance with 
the recommended dosage and infusion time may reduce the incidence and severity of 
infusion-associated reactions (IARs). Slowing the infusion rate may minimize many of these IARs.   
Local reactions at the infusion site may include pain, swelling, and redness of the skin.  
Hematologic Effects 
Low platelet and white blood cell (WBC) counts, including low counts of lymphocytes and 
neutrophils, have been identified and are reversible following dose adjustments. Total white blood 
cell and platelet counts should be monitored. 
Infections  
ATG is routinely used in combination with other immunosuppressive agents. Infections (bacterial, 
fungal, viral and protozoal), reactivation of infection (particularly cytomegalovirus) and sepsis 
have been reported after ATG administration in combination with multiple immunosuppressive 
agents. These infections can be fatal.  
Malignancy  
Use of immunosuppressive agents, including ATG, may increase the incidence of malignancies, 
including lymphoma or lymphoproliferative disorders. These events have been associated with 
fatal outcome. 
Immunizations  
The safety of immunization with attenuated live vaccines following ATG therapy has not been 
studied; therefore, immunization with attenuated live vaccines is not recommended for patients 
who have recently received ATG.  
Laboratory Tests  
ATG may interfere with rabbit antibody-based immunoassays and with crossmatch or 
panel-reactive antibody cytotoxicity assays.  ATG has not been shown to interfere with any routine 
clinical laboratory tests that do not use immunoglobulins.  
4.5.3 
Risks of SARS-CoV-2 (COVID-19) 
The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can 
spread rapidly within healthcare settings and communities and poses a special challenge for organ 
transplantation. Ongoing community transmission has been noted on all continents except 
Antarctica. Person-to-person transmission of SARS-CoV-2 occurs during close exposure 


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(< 2 meters) to an infected person, primarily via respiratory droplets produced when the infected 
person coughs or sneezes. COVID-19 disease is a respiratory illness caused by the SARS-CoV-2 
virus with variable presentation from asymptomatic to severe. Shedding of high viral titers has 
been documented from the respiratory tract, including shedding before the onset of symptoms, and 
results in droplet transmission of SARS-CoV-2 (Zou et al 2020). Transmission via droplet spread 
can occur from both symptomatic and asymptomatic individuals (Arons et al 2020) and it appears 
that patients with COVID-19 have the highest viral loads early in the course of their infection. 
Thus, a reliance on symptom-based screening strategies alone is not sufficient to prevent or 
diagnose infection; consideration of symptoms and exposure history, along with PCR-based 
testing is imperative.  
COVID-19 Disease:  
Case series on COVID-19 disease in transplant recipients have been published, however data 
remains very limited. Imaging demonstrates pneumonia in the majority of patients that are 
hospitalized (75-100%). Patients with less severe infections may have lower rates of clinical 
abnormalities. Mild infections are common, however preliminary experience suggests that 
infection, once acquired by immunosuppressed transplant recipients, may be of greater severity 
than in normal hosts after the initial incubation period. Experience with other viruses including 
prior outbreaks of coronaviruses, also suggests that severe infections will occur in some transplant 
recipients.  
At this time, the risk factors for severe disease have been characterized by observational studies. 
An initial report by (Pereira et al 2020) showed that advanced age was associated with severe 
disease in their transplant cohort, which is not different from the disease profile in the 
immunocompetent population (Kates et al 2020) reported age >65, chronic lung disease, 
congestive heart failure, and obesity were independently associated with poor outcomes of 
COVID-19 in solid organ transplantation. It is anticipated that transplant recipients may have a 
greater viral burden and shedding resulting in greater infectivity and potential spread to other 
individuals.  
Limited data are available on optimal treatment protocols, and none have been clearly 
demonstrated to optimize outcomes. When considering potential therapies, clinicians should 
consider the need for immunosuppression reduction and presence of potential drug-drug 
interactions that may result in toxicity or therapeutic failure, e.g., beta interferon or CYP3A 
inducers/inhibitors.  
The risk of a COVID-19 infection from an infected organ donor is unknown at this time. To date, 
there has been one documented case (Kaul et al 2021) of donor-derived disease transmission in a 
bilateral lung transplant recipient. Transmission from blood banks has not been documented at this 
time. 
Guidelines on the risks and management of SARS-CoV-2 in the setting of clinical trials as well as 
that of renal transplant patients have been published by the European Medicines Agency (EMA), 
US National Institutes of Health (NIH), Transplantation Society (TTS) and American Society of 
Transplantation (AST). Treatment guidelines on the use in immunocompromised and transplant 
recipients are updated periodically as knowledge of COVID-19 disease management evolves. 


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Cumulative cases and incidence rates are tracked and published by the World Health Organization 
(WHO) and other public and private entities and should be used to guide local management of 
patients.  
With active circulation of SARS-CoV-2 in the community, it is appropriate to counsel all 
candidates about the risk for acquisition from the community and hospital environment. 
Candidates should be educated about preventive strategies such as social distancing, masking when 
in proximity to non-household contacts, frequent hand washing, and avoidance of travel to 
high-risk areas.  
A compendium of global guidance documents is maintained by the NOTIFY library and can be 
found at the following URL: 
 https://www.notifylibrary.org/background-documents#SARSCoV-2.  
4.5.4 
Risk Mitigation Strategy 
Safety and tolerability data for doses up to 15 mg/kg IV have been collected in patients with T-cell 
lymphoma with good tolerability.  With initial administration of a biologic, the first 4 hours of 
exposure are most critical with most infusion reactions (including hypersensitivity, cytokine 
release, anaphylaxis) occurring within the first 2 hours of exposure (Tabrizi and Roskos 2007). No 
cytokine release has been detected with IV or s.c. siplizumab (MEDI-507) administration in the 
completed patient studies. Cytokine release or anaphylaxis have not been reported with similar 
compounds specifically targeting the CD2 receptor. A mild infusion reaction has been described 
in primates as well as clinical studies with siplizumab following the first dose.  This first-dose-
effect presents as mild and transient pyrexia with chills, nausea and fatigue. These infusion 
reactions are self-limiting and respond well to premedication with acetaminophen and 
diphenhydramine. Subjects will receive their first dose of siplizumab in the pre- to inter-operative 
time period, at a time when patients are under the close supervision of clinical staff in a hospital 
environment. Any infusion related reactions can be managed at that time in accordance with local 
protocols.  In the TCD601B102 study all subjects will receive premedication prior to each dose of 
siplizumab to mitigate any infusion reactions. 
Infections are a common risk for all transplant recipients. Subjects will be regularly evaluated 
while hospitalized and upon return to the clinic for signs and symptoms which might indicate a 
severe infection, i.e., fever, nausea, myalgia, headache, arthralgia, chills, diarrhea, stiff neck, and 
malaise, and will be treated as appropriate per local practice depending on the infectious agent. 
Subjects will be informed to report any of the aforementioned symptoms to the clinical staff to 
assure proper assessment and care can be administered in a timely manner. 
Considering the expected immunosuppressive nature of the compound, subjects will be screened 
for a history of latent infections. Viral reactivation will be assessed for CMV and BK virus 
according to local practice on a regular basis. Prophylaxis for CMV and pneumocystis pneumonia 
(PCP) will be administered to all subjects during the trial according to local practice. A negative 
test result for TB performed within 6 months of randomization will be required prior to enrollment. 
If there is suspicion of TB, a chest x-ray may be performed in accordance with local guidelines; 
subjects with a positive test will be excluded from participation.   


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EBV serology will serve as a key inclusion criterion, where EBV-seronegative subjects will be 
excluded from participation. EBV viral loads via EBV-PCR will be collected from all subjects 
throughout the trial and will be analyzed centrally to minimize inter-laboratory variation.  Positive 
results that demonstrate an increase over time will be communicated to the investigator for 
additional follow-up and per-protocol PTLD surveillance as described in Section 8.4.5.  
The ongoing SARS-Cov-2 pandemic represents a challenge for all renal transplant candidates and 
recipients. Due to the dynamic nature of COVID-19 infection rates, centers should continue to 
follow local and national guidelines and set policies based on the local incidence and prevalence 
of infections as well as hospital and staffing resources. This includes decisions to conduct or defer 
solid organ transplant procedures as well as the ongoing management of donors and recipients. 
Subjects eligible for the TCD601B102 study will be randomized from the pool of active candidates 
who are currently undergoing transplantation and will be receiving T-cell depleting induction and 
standard of care immunosuppression. All eligible subjects will be informed of the risks of 
SARS-COV-2 during the consent process. To decrease the risk to study subjects, all candidates 
will be screened for SARs-CoV-2 prior to enrollment and excluded if positive. 
Ongoing surveillance per standard of care will occur thereafter based on local conditions and signs 
and symptoms. In renal transplant patients who experienced COVID-19 disease, common 
presenting symptoms were fever, dry cough, and diarrhea, with most patients exhibiting 
lymphopenia and elevated C-reactive protein (CRP) (Fung and Babik 2020). Subjects will be 
counseled to report any of these physical symptoms to the clinical staff. Clinicians should also 
consider the common laboratory changes when assessing the potential for COVID-19 disease. 
Subjects who may be exposed to SARS-CoV-2 or contract active disease will be managed per 
local practice and international guidelines including recommendations for seeking treatment or 
self-quarantine. As with all infection events, SARS-CoV-2 positivity and COVID-19 disease will 
be captured in the safety database and will be evaluated by the DMC during their periodic dose 
escalation and ongoing safety review. Within the clinical trial setting, subjects may be required to 
attend in-person study visits in excess of those based on standard of care for clinical laboratory 
assessments as well as PK/PD sample collection; this may increase their risk of SARS-CoV-2 
exposure. To minimize the time patients, spend indoors and within the clinic for these assessments, 
phone contact or virtual / telehealth technology will be utilized where appropriate by the site staff. 
In addition, patients will be counseled on the importance of following proper hygiene, masking 
and social distancing practices to minimize community and hospital exposure during their standard 
of care and study specific visits. 
SARS-CoV-2 vaccines (i.e., mRNA, adenoviral vector) are under development or have been 
authorized for clinical use globally. The effectiveness of these vaccines in immunocompetent 
adults is between 76-95%, however the effectiveness in solid organ transplant recipients is 
unknown (See Section 6.5). Based on current vaccination guidelines, it is recommended that all 
transplant candidates and their household members receive SARS-CoV-2 vaccination when it 
becomes available. Ideally, transplant candidates should be targeted for vaccination while they are 
awaiting transplant or 3-6 months post-transplant in this trial, based on T-cell recovery. 
Subjects will be hospitalized for several days post-transplant. Following discharge from the 
hospital, subjects will return to the clinic for routine assessments frequently during the first 


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3-6 months per standard of care.  During these visits, safety and PK/PD assessments will be 
collected. Standard safety assessments will include vital signs, physical examinations, clinical 
laboratory evaluations (hematology, blood chemistry and urinalysis), AE and SAE monitoring as 
outlined in the Schedule of Assessments. In addition to standard clinical laboratory assessments, 
subjects will be monitored regularly for signs and symptoms of infectious, inflammatory, 
hematologic or renal toxicity / rejection.  
Subject’s serum creatinine will be assessed frequently in the first few weeks post-transplant and 
thereafter with a focus on renal injury and dysfunction.  Changes in renal function will be assessed 
via serum creatinine and estimated glomerular filtration rates (eGFR) using Modification of Diet 
in Renal Disease (MDRD) formula.  In the event subjects present with a significant increase in 
SCr and/or BPAR for-cause biopsies are to be collected for evaluation according to the standard 
Banff histology system. 
  
 
 
   
Immunophenotyping via fluorescence-activated cell sorter (FACS) analysis will be conducted 
frequently during the study to assess the potential for an increased risk of infection, changes in 
leukocyte subsets and recovery following depletion anticipated with all siplizumab dosing arms.  
Coagulopathy will be assessed using standard hematology (platelets) and coagulation studies, 
including international normalized ratio (INR)/prothrombin time (PT) and activated partial 
thromboplastin time (aPTT) according to local practice. 
Finally, considering the open-label study design, ITB-MED and an independent DMC will review 
study data, including safety events and AEs of special interest, regularly and on an ad hoc basis. 
Furthermore, a priori defined stopping criteria, infection surveillance and pharmacovigilance by 
ITB-MED as well as ongoing clinical assessments by Investigator and site staff will be employed 
to protect individual subject safety during the trial.  
Overall, the non-clinical and clinical safety results with siplizumab in human, as well as the 
comprehensive monitoring plan, a priori defined study stopping criteria and ongoing review by an 
independent DMC support the continued development of this immunomodulatory compound and 
conduct of further investigational studies.  Moreover, in consideration of the ongoing 
SARS-CoV-2 pandemic, each center will manage their ongoing transplant program and enrollment 
of patients in this trial based on the Investigator’s clinical judgement and individual patient risk 
assessment in consideration of both local and per protocol risk mitigation plans.  
The overall benefit-risk assessment including the aforementioned mitigation strategies and 
monitorable and manageable risks of administering siplizumab in this patient population is positive 
and support the conduct of this clinical trial. 


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5 
Population 
This multicenter study will be conducted in up to 8 centers worldwide. The study population will 
consist of approximately 24 male and female de novo adult renal transplant patients. The 
Investigator must ensure that all subjects being considered for the study meet the following 
eligibility criteria. Subject selection is to be established by checking through all 
inclusion/exclusion criteria at screening and confirmed prior to randomization. A relevant record 
(e.g., checklist) of the eligibility criteria must be stored with the source documentation at the study 
site. 
Deviation from any entry criterion excludes a subject from enrollment into the study. 
5.1 
Inclusion Criteria 
Subjects eligible for inclusion in this study have to fulfill all of the following criteria: 
1. Able to understand the study requirements and provide written informed consent before 
any study assessment is performed. 
2. Male or female patients ≥ 18 to 70 years of age. 
3. Recipients of a de novo renal allograft from a heart-beating deceased, living unrelated or 
non-HLA identical living related donor. 
4. Recipients of a kidney with a cold ischemia time (CIT) < 30 hours; hypothermic machine 
perfusion within the same timeframe is acceptable.  
5. Subjects who test negative for SARS-CoV-2 test via molecular testing (PCR) 
5.2 
Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this study. 
1. Transplant recipients sero-negative for Epstein-Barr virus (EBV). 
2. Multi-organ transplant recipients. 
3. Subjects who have received a kidney allograft previously e.g., re-transplant. 
4. Recipient of a kidney from an HLA identical living related donor. 
5. Recipient of a kidney from a donor after cardiac death. 
6. Subjects at high immunological risk for rejection as determined by local practice [(e.g., 
presence of pre-existing DSA, recipient of high Kidney Donor Profile Index ≥ 85 kidney 
(where assessed)]. 
7. Subjects with donor specific anti-HLA antibody as measured by complement-dependent 
cytotoxicity assay (CDC), enzyme-linked immunosorbent assay (ELISA), or flow 
cytometry within 90 days prior to transplant or as performed per the center’s local practice. 
8. Complement-dependent cytotoxicity (CDC) crossmatch positive transplant (isolated 
positive B cell crossmatches are not an exclusion criterion). 
9. ABO incompatible recipient  
10. History of malignancy of any organ system, except for localized excised 
non-melanomatous skin lesions or carcinoma in situ of the cervix. 


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11. Subjects with clinically significant laboratory abnormality that would preclude 
participation in the study (e.g., >2.5 x Upper Limit of Normal (ULN) values for (a) liver 
function chemistries (ALT, AST, ALP), (b) bilirubin, (c) coagulation studies (INR/PT, 
aPTT). 
12. Patient with any of the following: 
 
• hemoglobin (Hgb) < 8 mg/dL 
• WBC count ≤ 2,000/mm3  
• platelet count ≤ 75,000/mm3. 
13. Sero-positive for Human Immunodeficiency Virus (HIV) or Hepatitis B Surface Antigen 
(HBsAg). Subjects who are sero-positive for Hepatitis C virus (HCV) are excluded without 
proof of sustained viral response (SVR) after anti-HCV treatment. 
14. Recipient of a kidney from a donor who tests positive for HIV, HBsAg/HBc positive or 
HCV. 
15. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes 
(e.g., siplizumab, ATG, TAC, MMF, CS). 
16. Any additional contraindication to the use of TAC or MMF according to the national 
labeling information of these products (refer to the local product label). 
17. Evidence of TB infection (after anti-TB treatment, patients with history of latent TB may 
become eligible according to national guidelines).  
18. Patient with severe systemic infections, current or within the two weeks prior to 
randomization. 
19. Subjects with any other clinically significant medical condition, active infection or 
laboratory abnormality that would, in the judgment of the investigator, interfere with the 
subject’s ability to participate in the study. 
20. Subjects who, in the opinion of the investigator, are not capable of giving informed consent 
for the study or who are unable or unwilling to adhere to the study requirements outlined 
in the protocol. 
21. Use of other investigational products or enrollment in another investigational drug study 
within 30 days of screening or 5 half-lives of the medication, whichever is longer. 
22. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin (hCG) laboratory test. 
23. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
dosing and for 24 weeks after the study medications have been stopped. Highly effective 
contraception methods include: 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), or tubal ligation at least six weeks before taking study treatment. In case 
of oophorectomy alone, only when the reproductive status of the woman has been 
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• Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject. 
• Any of the following: 
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate <1%), 
for example, hormone vaginal ring or transdermal hormone contraception. 
b. Placement of long-acting reversible contraceptives an intrauterine device or 
intrauterine system. 
In case of use of oral contraception women should have been stable on the same brand 
(or generic equivalent) for a minimum of 3 months before taking study treatment. 
Additionally, total abstinence, when in line with the preferred and usual lifestyle of the subject 
may be an acceptable form of contraception.  Period abstinence is not an acceptable form of 
contraception (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal).  
Women are considered post-menopausal and not of childbearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy) or tubal ligation at least six weeks prior. In the case of oophorectomy 
alone, only when the reproductive status of the woman has been confirmed by follow up hormone 
level assessment if she considered not of childbearing potential.  
6 
Treatments 
6.1 
Method of Treatment Assignment 
Approximately 24 subjects will be randomly assigned to 1 of 2 treatment Cohorts and then, within 
each Cohort, randomized to one of two treatment arms; siplizumab or rATG active control arm in 
an 8:4 ratio as noted in the table below.  
Table 6-1 
Treatment Assignment 
Cohort 
Arm 
Subjects (n) 
Product 
Dosing Regimen 
Cohort A 
Arm 1 
8 
Siplizumab 
0.2 mg/kg (Days 0 and 4) 
Arm 3 
4 
rATG 
1.5 mg/kg (Day 0, 1 and 2) 
Cohort B 
Arm 2 
8 
Siplizumab 
0.6 mg/kg (Days 0 and 4) 
Arm 3 
4 
rATG 
1.5 mg/kg (Day 0, 1 and 2) 
The randomization schedule will be generated and verified by independent statisticians. 
Prior to surgery, on Day 0 (Day of Transplant), the Investigator or his/her designee will confirm 
that the subject meets eligibility for randomization within the EDC system.  The randomization 
mechanism for the study will be deployed by an internet-based Interactive Web Response System 
(IWRS) and accessible 24 hours a day to authorized users.  Designated study personnel will access 
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and has completed all necessary screening procedures and eligibility for the study has been 
confirmed.  
The EDC/IWRS will provide a notice and assign a unique randomization number to the subject 
being assigned to Cohort A or B and randomized to receive either siplizumab or rATG (in one of 
3 treatment arms) 
The randomization number will be linked to the subject’s assigned treatment Cohort and Arm. 
After a subject is assigned a randomization number, the number will not be reused even if the 
subject withdraws before receiving any investigational product. 
6.2 
Investigational Product 
6.2.1 
Identification of Investigational Product 
Siplizumab is a humanized IgG1κ class monoclonal antibody, supplied as 
 
 for solution.  Siplizumab 
will be supplied in 6 mL vials containing 60 mg and supplied at a concentration of 10 mg/mL.   
6.2.2 
Management of Investigational Product 
Investigational product will be provided as open-label, bulk medication.  Product packaging and 
labeling will be performed by Klifo, Glostrup, Denmark. Medication labels will be in the local 
language and comply with the legal requirements of each country.  
Investigational product must be received at the study site by the Investigator or his/her designee.  
The Investigator or his/her designee must acknowledge receipt of the investigational product 
within the EDC/IWRS.  Confirmation of product receipt and condition will be logged into the 
system and any documentation of receipt maintained in the site’s study file.  
Following confirmation of receipt, all investigational product must be stored in an appropriate 
secure area (e.g., a locked room or a locked refrigerator) and within an adequately monitored 
2 - 8°C refrigerator.  Temperature logs must be maintained to document the daily minimum, 
maximum, and actual temperature to confirm the absence or presence of a temperature excursion.  
Access to the storage area and/or storage refrigerator must be limited to those persons authorized 
by the Investigator.  The Pharmacy Manual should be referenced for additional handling and 
storage details as well as expectations for reporting temperature excursions to ITB-MED. 
The Investigator must maintain an accurate record of the dispensing of all study product in a drug 
accountability log.  A copy of the log(s) must be maintained by the Investigator, Pharmacy staff, 
or designee.  ITB-MED will retrieve copies of the logs periodically or at the end of the study for 
maintenance in the electronic trial master file (eTMF). Additionally, Investigational Product 
accountability will be noted by the Monitor during site visits and/or at the completion of the trial. 
All investigational product supplies are to be used only for this protocol and not for any other 
purpose. Unless specifically instructed by ITB-MED, the Investigator must not destroy any drug 
labels, or any partly used or unused investigational product supply. 
Only after receiving a written authorization by ITB-MED, the Investigator/designee will: (i. send 
all the unused and partly used drug supplies as well as the empty containers to the address provided 


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at the time of authorization for destruction, or ii.) have the unused and partly used drug supplies 
as well as the empty containers destroyed by the site’s pharmacist or designee, providing a drug 
destruction certificate. 
Detailed instructions for the receipt, storage, accountability, and return or destruction will be 
described in the ITB-MED provided Pharmacy Manual.  
6.2.3 
Investigational Product Dosing Regimen 
The starting dose for siplizumab will be 0.2 mg/kg with escalation to 0.6 mg/kg. 
The planned duration of investigational treatment is 5 days. Subjects will receive a total of two 
doses of siplizumab: pre- or intra-operatively on Day 0 and on Day 4. Subjects may be 
discontinued from treatment earlier at the discretion of the investigator or upon request of the 
subject. 
Siplizumab dose adjustments and/or interruptions for a given subject are not permitted.  The 
siplizumab infusion rate may be changed in the event of an infusion reaction. 
6.2.4 
Preparation of Siplizumab 
As per the treatment assigned to the subject upon randomization, the Investigator or his/her 
designee will obtain the investigational product to be administered to the subject.  The dose of 
siplizumab must be prepared by and administered by the Investigator or his/her designee who is 
properly trained in the handling and aseptic preparation of IV infusions. The subject will be 
weighed within 24 hours of each infusion administration and this weight will serve as the basis for 
final dose calculations and compounding. 
The dose will be calculated by the following formula: Dose (mg) = [subject weight (kg) x dose 
level (mg/kg)].  60 mg siplizumab/ vial 
Example 1: A subject whose weight is 70 kg in Cohort A (0.2 mg/kg) should receive 14 mg of 
siplizumab (70 kg x 0.2 mg/kg = 14 mg) and would require 1 vial of siplizumab. 
Example 2: A subject whose weight is 70 kg in Cohort B (0.6 mg/kg) should receive 42 mg of 
siplizumab (70 kg x 0.6 mg/kg = 42 mg) and would require 1 vial of siplizumab. 
Upon confirmation of subject dose, the product will be prepared from vial(s), using aseptic 
technique and administration to the subject via IV infusion using a syringe or infusion pump.   
Detailed instructions on the preparation and administration of the investigational product will be 
provided in the Pharmacy Manual and must be referenced prior to administration of product to any 
study subject. 
6.2.5 
Premedication for Siplizumab Infusion 
Prior to each infusion of siplizumab, subjects should receive premedication with 650-1000 mg 
acetaminophen (paracetamol) and an H1-antagonist (antihistamine e.g., 25 mg diphenhydramine) 
to minimize signs and symptoms of an infusion reaction. Premedication administration should 
occur at least 1 hour and no more than 5 hours prior to the start of the infusion.   


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6.2.6 
Siplizumab Administration 
Siplizumab will be administered by IV infusion to the subject by authorized site personnel on 
Day 0 and Day 4.  
The first dose of siplizumab will be administered over an hour (±5 min) by IV infusion. The 
infusion should be administered pre- or intra-operatively and timed so that the completion of the 
infusion is no earlier than 4 hours prior to revascularization and perfusion of the allograft. When 
administered intra-operatively, the infusion must be completed prior to revascularization. This 
ensures both donor and alloreactive T-lymphocytes are suppressed and depletion is initiated in the 
hours and days post-transplant. The second and final dose will be administered by IV infusion over 
an hour on Day 4. 
The compatibility of siplizumab with other IV medications is not known and must not be combined 
with other infusions or medications.  
The infusion may be given directly into a peripheral vein or a separate lumen in an indwelling, 
multi-lumen, central catheter and not administered concurrently with any other medications.   
The date, start time, completion time and volume of siplizumab administration must be recorded 
in the subject’s source documentation and applicable eCRF. 
For all subjects, regardless of the timing of the Day 0 infusion, the Day 4 infusion will be 
administered between 0800 and 1000 to facilitate future sample collection and study visits.  
No dose adjustments beyond changes based on the subject’s actual weight are permitted to the 
siplizumab dose during the study.  
In case of notable AEs and/or SAEs, including loss of efficacy and/or associated PK/PD data 
collected during the study, changes to the next planned dose level across the study may be 
considered and implemented via a protocol amendment.  
6.2.7 
Provisional Dose Levels 
Table 6-2 describes the starting dose and the dose levels that may be evaluated during this trial. 
Table 6-2 
Provisional dose levels 
Dose level 
Proposed daily dose* 
Increment from previous dose 
1  
0.2mg/kg  
(starting dose) 
2 
0.6 mg/kg  
½-log 
*It is possible for an intermediate dose level(s) to be added during the course of the study. Cohorts may 
be added at any dose level below the maximum tolerated dose in order to better understand safety, PK 
or PD. 
6.2.8 
Dose Escalation Guidelines 
Before escalating to the next dose level, an interim review of all available safety/tolerability (e.g., 
AEs, SAEs, clinical laboratory assessments, vital signs), PD (immunophenotyping), receptor 
occupancy and PK data (if available) up to a minimum of approximately 28 days post dose for at 
least 4 siplizumab treated subjects in the lower dose arm will be performed.  


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This 28-day safety period allows sufficient time for subjects to reach full-receptor occupancy, 
maximum pharmacodynamic activity and for the presentation of acute, drug related, toxicities.  
For treatment cohorts where receptor occupancy at the 28-day assessment cut-off is >99% in at 
least 2 subjects, dose escalation decisions will be deferred by a minimum of approximately 14 days 
until results of the next PD assessment have been analyzed and reviewed. If the CD2 receptor 
occupancy remains at >99% in at least 2 subjects at the second assessment time point, reevaluation 
of receptor occupancy on an approximately 14-day schedule may continue until a decision to 
escalate has occurred or stopping criteria have been satisfied.  
Where siplizumab concentrations are not quantifiable, i.e., with low doses, rapid clearance or assay 
limits, receptor occupancy or lymphocyte recovery will serve as the only measure of 
investigational treatment exposure for dose escalation decisions.  
In order to escalate to the next dose level, the data at the aforementioned review must be assessed 
as satisfactory or not clinically significant. The decision to escalate to the subsequent dose cohort 
will be made jointly between ITB-MED and the Investigator(s) following a review of all relevant 
safety and PK/PD data.   
To assure subjects are not exposed to a prolonged duration of T-cell depletion and/or sustained 
receptor occupancy and consequent immunomodulation / immunodepletion, the selection of the 
next highest dose will be guided by the following criteria: 
• Escalation will not proceed if the dose is not considered safe, regardless of the duration of 
target suppression or PD activity 
Siplizumab dose escalation will be stopped when: 
1. An average of ≥ 24 weeks (168 days) duration of T-cell depletion has been measured 
(defined as <10% of baseline (i.e., 90% depletion) in ≥2 subjects or 
2. An average of ≥ 24 weeks (168 days) duration of >99% peripheral CD2 receptor occupancy 
has been measured in ≥2 subjects or 
3. An average of >36 weeks (252 days) duration of >99% CD2 receptor occupancy and T-cell 
depletion is accurately predicted using PK/PD modeling for the next dose escalation. 
Additionally, based upon the outcome of safety and PK/PD data review during and prior to dose 
escalation, or in the case of notable adverse events or safety concerns, the following changes to 
the next planned dose level may be considered: 
• Administration of a dose level below the starting dose  
• Administration of an intermediate dose strength between the current and preceding dose  
• Repeated administration of the current dose strength  
• Termination of any further dose escalation 
Any change in dosing or clinical conduct of the study will be implemented via an amendment and 
approved by the ethics committee responsible for initial approval of this study. The local heath 
authority will also be informed of any Suspected Unexpected Serious Adverse Events (SUSARS) 
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6.3 
ATG: Standard of Care Control 
6.3.1 
ATG Dose and Duration 
rATG will be given at a dose of 1.5 mg/kg on Days 0, 1 and 2 for a total of three doses. rATG dose 
adjustments and/or interruptions for a given subject are not permitted unless warranted (see 
below).   
6.3.2 
Preparation of ATG 
As per the treatment assigned to the subject upon randomization, the Investigator or his/her 
designee will prepare the investigational product to be administered to the subject.  The dose of 
rATG must be prepared by and administered by the Investigator or his/her designee who is 
properly trained in the handling and aseptic preparation of IV infusions. The subject will be 
weighed within 24 hours of each infusion administration and this weight will serve as the basis for 
final dose calculations and compounding. 
6.3.3 
Premedication for ATG Infusion 
Prior to each infusion of rATG, subjects should receive premedication with corticosteroids, 
acetaminophen/paracetamol and/or an H1-antagonist (antihistamine) to minimize signs and 
symptoms of an infusion reaction. Premedication administration should occur 1 hour prior to the 
start of the infusion.   
6.3.4 
Administration of ATG Infusion 
rATG will be administered on Day 0, Day 1, and Day 2 per local label or as outlined in the 
pharmacy manual.  
6.3.5 
Management of ATG Therapy 
Patients should be monitored for adverse reactions during and after infusion. The total white blood 
cell and platelet counts should be monitored during and after rATG therapy. The rATG dose should 
be reduced by one-half if the white blood cell (WBC) count is between 2,000 and 3,000 cells/mm3 
or if the platelet count is between 50,000 and 75,000 cells/mm3. rATG treatment may need to be 
stopped if the WBC count falls below 2,000 cells/mm3 or if the platelet count falls below 
50,000 cells/mm3.  
6.4 
Concomitant Immunosuppression 
The following medications will be used in this study and will be administered in accordance with 
this protocol, SoC practices at the institution, and where applicable, current local labeling. Not all 
dosage forms listed are available in each country, dependent on local approval status and 
regulations.  
The use of immediate release generic TAC and MMF are allowed in this study.  Subjects should 
remain on the same concomitant immunosuppression medication throughout the duration of the 
study (12 months), i.e. If the subject starts with brand Prograf® or CellCept®, the subject should 


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remain on brand and not switch to a generic at any point throughout the 12-month study period; if 
the subject starts with generic, the subject should remain on the same generic throughout the study.  
Special attention must be taken to avoid concomitant administration of drugs, food, or beverages 
which are known to be a strong inducer or inhibitor of CYP3A4, as outlined in Appendix 5.   
All doses of TAC, MMF, and CS along with dose changes during the study must be recorded, with 
reason for administration, on the corresponding eCRF.  
In general, symptomatic treatment should be considered first to treat subjects who have difficulties 
tolerating their immunosuppressive regimen. However, for subjects who are still unable to tolerate 
the protocol-specified study treatment, dose adjustments, route adjustments, and interruptions of 
study drugs may be permitted in order to keep the subject on study treatment.  
Concomitant medications will be supplied locally and used according to the local label and will 
include: 
• Immediate release TAC as 0.5 mg, 1.0 mg, or 5.0 mg capsules 
• MMF 250 mg or 500 mg film-coated tablets, or 250 mg capsules, or 500 mg vial for IV 
• CS for oral and IV administration 
Pre-transplant immunosuppression may be administered according to center practice, but such 
practice must be applied consistently to all subjects at a given center. At randomization/enrollment, 
all subjects must follow the assigned regimen.  
6.4.1 
MMF Administration 
MMF will be administered p.o. twice per day (BID) as 2 - 500 mg tablets, 4 - 250 mg capsules, or 
where oral administration is not feasible, as 1000 mg via IV administration (2 – 500 mg vial for 
IV administration). For subjects who remain intubated >24 hours post-transplant and/or are 
otherwise unable to swallow oral medication, IV MMF may be substituted 1:1 until oral conversion 
is possible. 
The first dose of MMF will be administered no later than 24 hours after graft reperfusion of the 
allograft.  
Dose adjustment/interruption guidance for MMF is provided in Appendix 5. All MMF doses and 
changes must be recorded on the applicable electronic case report form (eCRF).  


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6.4.2 
TAC Administration 
TAC will be administered as capsules or tablets p.o. BID and adjusted to maintain serum trough 
(C0) concentrations within the target range of 4-11 ng/mL. If oral administration is not feasible or 
practical IV TAC containing the equivalent of 5 mg/mL tacrolimus administration by continuous 
intravenous infusion can be substituted per label. 
TAC should be initiated as soon as possible in the peri-transplant period and may follow local 
practice but must be initiated no later than 24 hours after reperfusion of the allograft. The lowest 
permitted dosing of TAC in this study is 0.5 mg BID or IV equivalent. If TAC is discontinued for 
more than 14 consecutive days, and the study regimen cannot be maintained, the subject may 
remain in the trial, however the new immunosuppressive regimen must be documented in the 
concomitant medications eCRF, including doses and trough concentrations where applicable. 
Subjects who discontinue their study regimen are expected to remain in the study on the local SoC 
until Month 12.  
TAC dosing will be modified by Investigators as needed and recorded on the applicable eCRF at 
each visit. In the event of TAC intolerance (e.g., nephrotoxicity, neurotoxicity) dose reduction of 
TAC may be necessary. If it occurs that the TAC trough concentration is outside the required 
target, then the Investigator will be asked to confirm the intended TAC trough and to record the 
start date and reason for dose reduction on the applicable eCRF. 
TAC is a substrate for CYP3A metabolism and therefore susceptible to drug-drug interactions that 
can raise or lower systemic concentrations, leading to toxicity or therapeutic failure.  The 
co-administration of drugs known to interfere with TAC metabolism (Appendix 6) should be 
avoided if possible. If these drugs are required, the Investigator should carefully monitor TAC 
trough concentrations and adjust them accordingly during and after the use of the interacting 
treatment.   
On days when trough concentrations are monitored, the subject will be instructed to record the 
time of the last dose on the day prior to the blood draw and to bring the morning dose to the visit 
so it may be administered after the blood sampling is completed. 
6.4.3 
Corticosteroid Administration 
CS should be administered at a minimum of 5.0 mg/day (prednisone or equivalent) from Day 0 
until Month 12 and per local standard practice in a way that is consistent in all subjects enrolled at 
the site. Dosing of CS should be recorded in the Concomitant Medications eCRF. 
6.5 
Infectious Prophylaxis Treatment 
All medications administered after the subject was enrolled into the study must be recorded on the 
appropriate eCRF. ITB-MED will provide eCRF completion guidelines with additional detail for 
recording concomitant medications. 
CMV 
CMV prophylaxis, with IV ganciclovir or oral valganciclovir, will be used in subjects (CMV 
positive and CMV negative) as per local medical practice.  


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Pneumocystis jirovecii (Pneumocystis carinii) pneumonia (PCP) 
All subjects will be started on sulfamethoxazole-trimethoprim, starting when oral medication can 
be tolerated and continued per standard institutional/local practice. The same regimen should be 
administered to all subjects at a given study center. For subjects unable to tolerate 
sulfamethoxazole-trimethoprim, atovaquone plus levofloxacin (or equivalent fluoroquinolone), 
aerosolized pentamidine or dapsone may be administered.  
Hepatitis B Virus (HBV) 
Prophylaxis for HBV reactivation during the course of this study is allowed and will be 
administered at the discretion of the Investigator.  
BK Virus 
Subjects with BK viremia or viruria should be treated according to local practice. If treatment is 
given or dose adjustments are made, e.g., MMF dose reduction, they should be recorded on the 
Concomitant Medications eCRF. 
Oral Candida 
For oral thrush (Candida), Nystatin may be used in a swish and swallow regimen; alternatively, 
clotrimazole (Mycelex®) lozenges/troches may be used. Routine use of systemic agents, e.g., 
itraconazole, voriconazole and fluconazole, will not be allowed unless subjects are systemically 
infected since azole antifungal agents may increase blood concentrations of TAC.  
Systemic therapy will be based on center practice and at the Investigator’s discretion. Treatment 
should be recorded on the Concomitant Medications eCRF.  
Immunization  
Immunization of transplant candidates for vaccine preventable diseases is recommended more than 
2 weeks prior to transplantation or starting at 1-6 months after transplantation If given prior to 
transplantation, the full immunization series should be completed before the transplant procedure. 
In certain situations, it may be appropriate to wait until 3 or more months after transplantation to 
vaccinate, such as following T- or B-cell depletion therapy. Waning vaccine titers to other routine 
immunizations have been well documented after transplantation. Lower seroconversion rates to 
influenza vaccination are well documented in the setting of mycophenolate mofetil and tacrolimus 
use (Danziger-Isakov et al 2019). Vaccination during treatment with siplizumab and prior to 
clearance of the antibody and pharmacodynamic effects are likely to result in therapeutic failure 
(i.e., non-protective antibody titers). Administration of live attenuated agents should be avoided 
while receiving siplizumab treatment and for up to 6 months thereafter, depending on the dose and 
time for reconstitution of immune function. 


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6.6 
Other Concomitant Treatments 
The Investigator should instruct the subject to notify the study site about any new medications 
taken after enrollment into the study.  All medications, procedures, and significant non-drug 
therapies (including physical therapy and blood transfusions) administered after the subject was 
enrolled into the study must be recorded on the appropriate eCRF. ITB-MED will provide eCRF 
completion guidelines with additional detail for recording concomitant medications. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the ITB-MED medical monitor or designee 
before randomizing a subject or allowing a new medication to be started. If the subject is already 
enrolled, contact ITB-MED to determine if the subject should continue participation in the study. 
No other immunosuppressive medications should be administered, other than as per protocol.  
6.7 
Treatment of Adverse Events 
Following are recommended guidelines for the management of AEs. Medications used to treat 
AEs must be recorded on the appropriate eCRF. 
6.7.1 
Treatment of Acute Rejection Episodes 
In all suspected acute rejection episodes, regardless of initiation of anti-rejection treatment, a renal 
biopsy should be performed within 48 hours.  
Acute rejections should be treated with bolus methylprednisolone (other CS are acceptable at an 
equivalent dose) according to local practice. Recommended treatment is at least 3 boluses of IV 
methylprednisolone with a minimal dose of 250 mg/bolus or at least 2 boluses of IV 
methylprednisolone with a minimal total dose of 750 mg. 
Subjects who experience steroid-resistant rejections, vascular rejections, or rejections with a Banff 
grade ≥ 2B (Appendix 6Appendix 6Appendix 6Appendix 6Appendix 6Appendix 7) may be treated 
with other anti-rejection therapies (i.e., antibody therapy).  
It is important to note that the combination of siplizumab and other T-cell depleting antibodies, 
e.g., ATG, alemtuzumab, mTOR inhibitors (sirolimus or everolimus), IVIG or costimulatory 
blockade (belatacept) have not been investigated and may result in overlapping pharmacology. In 
the setting of an acute rejection episode, the selection and use of one or more of these agents in 
combination with siplizumab is at the investigator’s discretion based on their experience.   
All episodes of acute rejection, and any medications used for suspected or confirmed acute 
rejections, must be entered on the corresponding eCRF, preferably within 24 hours. 
6.7.2 
Management of BK Viremia 
BK Polyoma virus (BKV) screening generally utilizes plasma (or whole blood) viral load (VL) 
molecular assays. Urine studies (cytology for “decoy cells,” BKV DNA or VP-1 mRNA) are less 
specific. Decoy cells are shed infected tubular and ureteric epithelial cells with an enlarged nucleus 
with a large basophilic intranuclear inclusion by urine cytology. Cytology cannot distinguish BKV 
from adenovirus and false negative tests also occur. A urinary test for BKV (cytology for decoy 


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cells or urine BKV loads over 7-log geq/mL) is adequate for screening; if negative, the risk for 
polyoma virus associated nephropathy (PVAN) is low.  
Quantitative cutoffs for presumptive diagnosis of BKV nephropathy include plasma DNA VL 
>10,000 copies/mL (whole blood polymerase chain reaction (PCR) VL >1500–3500 copies/mL), 
urine VP1 mRNA load >6.5 X 10e5 copies/ng total RNA, or urine DNA load >10e7 copies/mL; 
higher viral loads are increasingly predictive of PVAN.  
World Health Organization (WHO) standards will be utilized in the performance of BKV 
quantitative nucleic acid testing (QNAT) to ensure minimization of interlaboratory variability.  
Biopsy is suggested for confirmation if creatinine is elevated. Renal histopathology provides 
definitive diagnosis of PVAN (Fishman 2017). 
If a subject is found to have BK Viremia or PVAN, the event should be recorded in the appropriate 
eCRF as an AE or SAE, and they should be managed as per local center practice.  
6.7.3 
Management of Delayed Graft Function (DGF) 
DGF for this trial is defined as the need for dialysis performed within 7 days of transplant. 
However, in the event that a subject experiences DGF and does not undergo dialysis, DGF must 
still be reported as an AE in these subjects.  
NOTE: Patients who require dialysis (up to two sessions), with the purpose of correcting 
electrolyte abnormalities in the immediate post-transplant time period, would not meet the 
definition of DGF for purposes of this study. 
In case DGF is reported as an AE and dialysis is also reported, the end of DGF is considered the 
day the last dialysis session ends.  For all other subjects it is when the renal dysfunction is 
considered resolved by the investigator. 
In case a subject experiences DGF, the DGF is by definition starting at reperfusion after the 
transplantation procedure. If the graft dysfunction is starting later according to the Investigator, 
then this condition is considered secondary graft dysfunction.  
In case of DGF, treatment will be according to local practice. DGF treatments must maintain 
sufficient immunological coverage for the graft and may include maintaining, interrupting, or 
reducing the dose of study treatment and the use of rATG. If a polyclonal antibody or rATG is 
used prior to Day 4, the investigational product must be discontinued, and the subject will be placed 
on SoC per local practice.  
6.7.4 
Primary Graft Non-Function (PGNF) 
PGNF is defined as dialysis starting after transplantation with a continuous record of 
post-transplant dialysis until either transplantectomy, re-transplantation or death. PGNF should be 
reported on the Graft Loss eCRF. 
If a subject is placed on permanent dialysis (or re-transplanted), the Graft Loss and AE eCRFs 
should be completed, and an SAE of graft loss reported. 


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6.7.5 
Management of EBV-PTLD 
EBV-PTLD is a serious disease.  Transplant clinicians managing suspected and confirmed PTLD 
should follow local institutional guidance on the diagnosis and management of EBV-PTLD, 
including consulting with transplant infectious disease and hematology-oncology clinicians where 
relevant.   
In patients diagnosed with EBV-PLTD, therapy must be individualized.  rATG and siplizumab 
doses planned for this trial are expected to result in T- and NK-cell depletion and minimal to no 
modulation of the B-cell compartment, respectively.  Clinicians should refer to the siplizumab IB 
or local labelling for rATG when considering therapeutic options for the treatment of EBV-PTLD. 
Consensus guidelines on the diagnosis and management of EBV-LPD and PTLD in the setting of 
solid organ transplantation have been published and may be referenced (Allen and Preiksaitis 2013 
and Parker et al 2010). 
6.8 
Treatment Exposure and Compliance 
Following discharge from the hospital, the Investigator or designee will dispense the appropriate 
amount of concomitant study treatment per SoC. Drug accountability will be performed to assess 
compliance at each study visit. The Investigator should promote compliance by instructing the 
subject to take their study drugs exactly as prescribed and by stating that compliance is necessary 
for the subject’s safety and the validity of the study. The subject should be instructed to contact 
the Investigator if he/she is unable for any reason to take the study drugs as prescribed. 
All drug trough concentrations assessed in this study (siplizumab, TAC) will be measured per the 
Schedule of Assessments and the Laboratory Manual.  For all samples sent for central analysis, 
the exact time and the date of sampling, together with the exact time and date of the last study 
medication dose prior to the sampling must be accurately recorded on the central laboratory 
request form (refer to the separate Laboratory Manual). Siplizumab will be measured in serum and 
TAC will be measured in whole blood.  
On the day of a scheduled sampling, the subject will be instructed not to take his/her morning dose 
of immunosuppressant medications, to record the medication dosage and time of last dose on the 
day prior to the blood sampling, and to bring all study drugs to the visit so that a dose may be 
administered upon completion of blood sampling.  
6.9 
Prohibited Treatment 
Immunosuppressants and induction treatment other than those specified in the protocol are NOT 
allowed after informed consent up to the end of study.  If the use of any of these medications or 
other non-protocol immunosuppressants is discovered prior to randomization/enrollment, the 
subject must not be randomized and will be recorded as a screen failure. If discovered after 
randomization/enrollment, no further doses are to be given, and the subject should continue on the 
randomized/assigned treatment regimen, noting the protocol deviation.  
The exception is for the treatment of acute rejection not responding to corticosteroids. 
The use of concomitant medications that may influence tacrolimus levels should be avoided, please 
refer to Appendix 6 and local prescribing information. 


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7 
Informed Consent Procedures 
Eligible subjects may only be included in the study after providing (witnessed, where required by 
law or regulation), Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
approved informed consent. 
If applicable, in cases where the subject's representative(s) gives consent (if allowed according to 
local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written Informed Consent Form (ICF). 
Informed consent must be obtained before conducting any study-specific procedures. The process 
of obtaining informed consent must be documented in the subject source documents. 
ITB-MED will provide to investigators in a separate document a proposed ICF that complies with 
the International Conference on Harmonization Good Clinical Practice (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 ITB-MED before submission to the 
IRB/IEC. 
A copy of the approved version of all consent forms must be provided to ITB-MED after IRB/IEC 
approval. 
8 
Visit Assessments  
The Schedule of Assessments is located in Appendix 1 and lists all of the study assessments and 
when they are to be performed. All data obtained from these assessments must be supported in the 
subject’s source documentation. 
While COVID-19 disease remains a risk, efforts to minimize the time a subject spends indoors at 
the clinic may be considered. These efforts could include use of virtual or telehealth technology, 
where appropriate, to remotely capture applicable study data (e.g., overall health status, assessment 
of medication compliance, review of adverse events). The intent is to allow centers to minimize 
in-person onsite clinic visit activities to those assessments that require the subject to be physically 
present (e.g., laboratory collections or physical assessments). In the event virtual or telehealth 
technology is utilized to facilitate data collection, it should be done per institutional practice and 
local regulations. Detailed documentation of all contact and information collected virtually is to 
be recorded in the study records.  
This protocol defines 7 days to a week and 4 weeks (or 28 days) to a Study Month. For example, 
Week 2 is considered to start on Day 8 and Study Month 2 is considered to start on Day 29 (Start 
of Week 5).  
Following is a description of study assessments/procedures.  For the full Schedule and when to 
collect for each subject, refer to Appendix 1. 


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8.1 
Subject Identification 
Each subject is identified in the study by a subject identification number (SID) that is automatically 
assigned by the EDC system once the subject has signed informed consent, has at least one study 
assessment or procedure completed, and the relevant data has been entered into the eCRF/EDC by 
the designated site staff. The SID is retained as the primary identifier for the subject throughout 
his/her entire participation in the trial. The SID consists of the Site Number (assigned by ITB-
MED to the investigative site) with a sequential subject number suffixed to it, so that each subject 
is numbered uniquely across the entire database.  
8.2 
Screen Failure Assessments 
Subjects who sign an ICF and are 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 
eCRF. The demographic information, informed consent, and Inclusion/Exclusion pages must also 
be completed for screen failure subjects. No other data will be entered into the clinical database 
for subjects who are screen failures, unless the subject experienced a SAE during the screening 
phase.  
It is permissible to re-screen a subject if s/he fails the initial screening; however, each case must 
be discussed and agreed with ITB-MED on a case-by-case basis. 
8.3 
Efficacy / Pharmacodynamic Assessments 
All blood samples will be taken by either direct venipuncture or an indwelling cannula. Please 
refer to the Laboratory Manual for a detailed description of central laboratory sample processing, 
handling, storage, shipment and analytical measures. 
Immunophenotyping 
The effect of siplizumab on circulating leukocytes and T-cells will be determined using flow 
cytometry FACS. Cell subpopulations that will be analyzed may include but are not limited to 
those bearing one or more of the following cell surface or intracellular markers: CD2, CD3, CD4, 
CD5, CD8, CD19, CD25, CD27, CD38, CD45RA, CD45RO, CD59, CD127, CD138, CD154, 
FoxP3 and HLA-DR.  
Lymphocyte CD2 Receptor Occupancy 
Peripheral CD2 receptor occupancy by siplizumab will be determined by flow cytometry analysis, 
measuring free or total CD2 receptors on T-cells. 
8.4 
Safety Assessments 
8.4.1 
Physical Examination 
A comprehensive physical examination will be conducted at screening, on Day 7 and then at each 
study visit thereafter.  The examination will include a comprehensive assessment of the subject’s 
general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen 
(including spleen and liver), back, lymph nodes, extremities and vasculature. The examination will 


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also include a thorough neurological evaluation. If indicated, based on medical history and/or 
symptoms, rectal, external genitalia, breast, and pelvic exams will be performed. 
Physical examination findings will be entered in the applicable Physical Examination eCRF. 
Clinically relevant findings that are present before the subject has had at least one invasive study 
procedure completed and/or performed must be recorded on the appropriate Medical History 
eCRF. Significant findings discovered after the start of study procedures, which meet the 
definition, must be recorded as an adverse event. 
8.4.2 
Vital Signs 
Vital signs (radial pulse rate, blood pressure, respiratory rate, and body temperature) will be 
recorded as indicated in the Schedule of Assessments. Attempts should be made to assess the blood 
pressure and pulse on the same arm each time of determination and after the subject has rested in 
the sitting position (may be supine if during hospitalization) for at least five minutes. Body 
temperature should be measured as per local practice – the same method to be used consistently 
for all subjects at each site. 
8.4.3 
Height and Weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg]); in indoor clothing, 
but without shoes will be measured. 
Body mass index (BMI) will be calculated using the following formula: 
• BMI = Body weight (kg) / [Height (m)]2 
8.4.4 
Laboratory Evaluations 
Samples for the laboratory tests noted below will be collected at the time points specified in 
Schedule of Assessments.  Refer to the Laboratory Manual for detailed instructions regarding the 
timing of central laboratory specimen collection along with the handling, processing, storage, and 
shipping of samples. 
In the case where a laboratory assessment that is listed in the inclusion/exclusion criteria is outside 
of a protocol-specified range at screening and/or at the initial baseline, the assessment may be 
repeated once prior to randomization. If the repeat value remains outside of protocol-specified 
ranges, the subject is excluded from the study. 
The Investigator must document in the source documents, the clinical considerations and medical 
relevance of any values outside of the reference range. (i.e., result was/was not clinically 
significant and/or medically relevant) for all laboratory values. 
Clinically relevant deviations of laboratory test results should also 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.  
Clinically significant abnormalities should be recorded on the relevant section of the Medical 
History/Current Medical Conditions/AE eCRF page as appropriate. 


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8.4.4.1 
Hematology 
Hemoglobin, hematocrit, red blood cell (RBC), MCV, MCH, Platelet Count, white blood cell 
(WBC) and differential count (% and abs). 
8.4.4.2 
Clinical Chemistry 
Albumin, total bilirubin, calcium, creatinine, glucose, phosphorus, magnesium, potassium, ALT, 
AST, ALP, GGT, amylase, sodium, uric acid, and urea/ Blood Urea Nitrogen (BUN) will be 
measured. 
8.4.4.3 
Lipid Panel 
Cholesterol, triglycerides, LDL, HDL will be measured. 
8.4.4.4 
Urine Dipstick 
At a minimum, the following parameters will be measured: pH, protein, blood, glucose, nitrites, 
and leukocytes. 
In the event of positive findings, follow-up urinalysis should be performed per local standards.  
8.4.4.5 
Pregnancy  
Serum or urine pregnancy testing will be required for females of child-bearing potential, at 
timepoints as designated in the Schedule of Assessments. A serum or urine pregnancy test must 
be obtained up to 72 hours prior to time of transplant and the result must be available and negative 
prior to administration of investigational product.  
8.4.4.6 
Renal Function 
Renal function will be assessed by eGFR, using an automated calculation factoring serum 
creatinine, demographics and the MDRD4 formula. 
8.4.4.7 
Coagulation Studies 
Coagulation 
studies 
will 
be 
performed, 
including 
international 
normalized 
ratio 
(INR)/prothrombin time (PT) and activated partial thromboplastin time (aPTT). 
8.4.4.8 
EBV-DNA PCR 
All subjects will have quantitative EBV viral load measured in serum (or whole blood) by a 
standardized PCR-based method. All measurements will be conducted centrally by a laboratory 
utilizing World Health Organization EBV international reference standards.  
There are currently no consensus guidelines on thresholds for EBV DNAemia or viral load in adult 
renal transplant recipients, therefore any PCR positive result that is increasing from baseline or a 
previous assessment will be flagged to the investigator for local follow-up per protocol, including 
a full physical and neurological exam with careful attention to the liver, spleen, allograft and lymph 
nodes.  In addition, ad hoc abdominal and allograft ultrasound to screen for signs and symptoms 
of potential PTLD lesions will be conducted.   


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Suspicion of PTLD in the setting of increasing EBV viral load should be further evaluated as 
outlined in Section 8.4.5.    
8.4.4.9 
CMV DNA PCR 
All subjects will have quantitative CMV viral load measured by a PCR-based method, preferably 
calibrated in IU/mL.  The CMV titer in blood should be recorded on the applicable eCRF.  No 
specific viral load cutoffs are available to initiate antiviral therapy. However, persistent low-level 
viremia (<2500 IU) suggests excess immunosuppression or stimulation by other infections or 
processes (e.g., rejection). If PCR positive, then treatment should be initiated per local practice. 
8.4.4.10 Donor Specific Antibodies (DSA) 
Blood samples for DSAs (antibodies directed against antigens expressed on donor organs) will be 
collected and evaluated locally.  
8.4.4.11 Immunogenicity 
The presence of anti-siplizumab antibodies will be determined using a bridging ELISA-based 
assay. 
8.4.4.12 Viral Testing and Surveillance  
All subjects will be screened/monitored for HBV, HCV, HIV, EBV, CMV, and BK virus per local 
center practice unless more rigorous testing is required for EBV and CMV monitoring, as noted in 
Section 8.4.4.8 and 8.4.5. Results of these assessments are to be transcribed into the appropriate 
eCRF pages.  
8.4.5 
EBV-PTLD Surveillance 
Clinical manifestations of EBV infection range from asymptomatic infection to clinically 
significant and potentially life-threatening disease in transplant recipients. EBV infection can be 
either primary (new infection occurring in an immunologically naïve subject) or secondary due to 
either reactivation of latent EBV in the transplant recipient under the pressure of immune 
suppression or reinfection with a new EBV strain. In general, secondary infection tends to be mild 
or even asymptomatic. Histologic evaluation is important in defining disease status of a subject 
with suspected PTLD; manifestations can evolve in individual subjects.  
The World Health Organization has provided standardized criteria for the pathologic evaluation of 
lesions associated with EBV in solid organ transplant recipients.  
The following signs and symptoms should guide the clinician in assessing the risk of and for 
EBV-PTLD (Green and Michaels 2013):  
Signs 
• Pallor 
• Lymphadenopathy 
• Subcutaneous nodules 


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• Tonsillar enlargement or inflammation 
• Hepatosplenomegaly 
• Focal neurologic signs 
• Mass lesions found on imaging obtained for other reasons 
 
Constitutional and systemic symptoms: 
• Unexplained fever or night sweats 
• Malaise 
• Weight loss and/or anorexia 
• Sore throat 
• Swollen glands 
• Headache or focal neurologic symptoms 
 
Allograft-specific symptoms: 
• Liver: jaundice, abdominal pain 
• Intestine: abdominal pain, gastrointestinal bleeding, nausea and vomiting 
• Heart/lung: shortness of breath, cough, decreased lung function (lung alone) 
• Renal: kidney dysfunction 
 
Laboratory tests: 
• Serial increase in EBV viral load from peripheral blood 
The following assessments may be considered as part of the diagnostic work-up for suspected 
EBV-PTLD (Green and Michaels 2013):  
Routine:  
• CBC, differential, platelets 
• Serum electrolytes, calcium, BUN and creatinine 
• Liver function tests  
• Uric acid  
• Lactate dehydrogenase  
• Quantitative immunoglobulins 
• EBV serologies (anti- Epstein–Barr nuclear antigens (EBNA), viral capsid antigen (VCA) 
and early antigen (EA) 
• EBV viral load from peripheral blood 
• Stool: occult bleeding 


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• Chest radiograph (anteroposterior and lateral) 
• CT or PET scan of neck/chest/abdomen/pelvis 
• Core needle or excisional biopsy of lesion(s) with flow cytometry of lymphocytes (when 
possible)  
o EBER, CD20 histochemistry studies of pathologic samples 
In select patients, based on signs, symptoms and routine assessments, the following procedures 
may be considered:  
• Bone marrow biopsy 
• Bone scan 
• Brain CT/MRI 
• Gastrointestinal endoscopy 
• Lumbar puncture 
• Ultrasound assessment of abdomen and allograft  
Any diagnostic procedures or additional laboratory assessments that result in the diagnosis of 
EBV-PTLD must be captured on the relevant eCRFs. 
8.4.6 
Imaging: PTLD Surveillance 
When warranted based on physical examination findings and/or EBV surveillance, subjects should 
have an ultrasound performed of the abdominal cavity and allograft to rule out nodal and/or extra-
nodal EBV-LPD lesions. CT, MRI and/or PET imaging may be considered for staging and 
monitoring of biopsy confirmed PTLD.    
8.4.7 
Renal Biopsy 
Any biopsies performed according to local practice must be recorded. Biopsies will be read by the 
local pathologist according to local practice and the 2017 Banff criteria (Appendix 7). The results 
of the biopsy read by the local pathologist will be listed on the applicable eCRF.  
Additionally, for all suspected rejection episodes, regardless of initiation of anti-rejection 
treatment, a renal biopsy must be performed within 48 hrs. The results will be used for subject 
management for acute rejection. 
Please refer to the Laboratory Manual for details on biopsy handling and histology assessments. 
8.4.8 
Treated Biopsy Proven Acute Rejection 
Treated biopsy proven acute rejection (tBPAR) is any condition in which the subject receives 
anti-rejection treatment and is histologically diagnosed as acute rejection according to the 2017 
Banff criteria, including borderline rejections, as outlined in Appendix 7.  
8.4.9 
Graft Loss 
The allograft will be presumed to be lost on the day the subject starts dialysis and is not able to 
subsequently be removed from dialysis. If the subject undergoes allograft nephrectomy prior to 


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starting permanent dialysis, then the day of nephrectomy is the day of graft loss. The reason for 
graft loss will be recorded on the applicable eCRF. Graft loss is considered an SAE and should be 
reported on the AE eCRF (as serious), and the SAE reported to ITB-MED Safety within 24 hours. 
8.4.10 
Death 
In the event of subject death, the SAE leading to death should be reported to ITB-MED Safety 
within 24 hours.   
8.5 
Pharmacokinetic Assessments 
Pharmacokinetics (siplizumab / anti-siplizumab antibodies) 
PK samples will be obtained and evaluated in all subjects at all dose levels, as outlined in the 
Schedule of Assessments. The timing of the PK sample collection may be altered based on 
emergent data, but the total number of samples and total blood volume collected will not exceed 
those stated in the Laboratory Manual.  
Siplizumab concentrations will be determined by a validated ELISA method; the anticipated 
Lower Limit of Quantification (LLOQ) is 10 ng/mL and concentrations will be expressed in mass 
per volume units. Concentrations below the LLOQ will be reported as “zero” and missing data 
will be labeled as such in the Bioanalytical Data Report. 
The following PK parameters will be determined using the actual recorded sampling times and 
non-compartmental method(s): Cmax, Tmax, area under the curve (AUC) last, AUCinf, T1/2, Vz/F and 
CL/F from the serum concentration-time data. 
The linear trapezoidal rule will be used for (AUC) calculation. Regression analysis of the terminal 
plasma elimination phase for the determination of T1/2 will include at least 3 data points after Cmax. 
If the adjusted R2 value of the regression analysis of the terminal phase will be less than 0.75, no 
values will be reported for T1/2, AUCinf and CL. 
Follow instructions outlined in the Laboratory Manual regarding sample collection, numbering, 
processing and shipment. 
8.6 
Assessment of Treatment Exposure and Compliance 
PK parameters (measures of treatment exposure) will be determined in all subjects treated with 
study treatment. TAC trough concentrations will be determined locally and recorded on the 
relevant trough level eCRF.  The local trough values will be used to adjust the TAC dosing as 
needed. 
Compliance with the subject’s treatment regimen will be assessed by the Investigator and/or 
designated site personnel at each study visit and info captured in the source and relevant eCRF. 


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8.7 
Exploratory Biomarker Assessments 
 
 
 
 
 
 
  
 
 
 
 
 
 
9 
Study Discontinuation and Completion 
9.1 
Discontinuation 
9.1.1 
Safety Stopping Rules 
The following stopping rules based on potential toxicities will serve as the basis for placing 
enrollment and dose escalation on hold.  
Although the stopping criteria do not incorporate an absolute requirement for causality, the 
potential relationship between an AE(s) and siplizumab will be evaluated carefully on a case-by-
case basis between ITB-MED and the Investigator. Following a review of the AE(s), a decision to 
permanently discontinue enrollment or re-initiate dosing will be made by the DMC. Dose limiting 
toxicities (DLTs) will be assessed according to the standardized toxicity grading scale, the 
National Cancer Institute (NCI) CTCAE version 5.0 (NCI 2017). 
• One (1) subject death or graft loss within the first month with the exception of technical 
failures.  
• One (1) subject presents with histologically* confirmed EBV-PTLD. 
• One (1) subject with Grade 3 or higher cytokine release syndrome within 24 hours of any 
siplizumab administration. 
• One (1) subject with any Grade 4 toxicity, considered drug related as determined by the 
Investigator within the first 28 days.  


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• Two (2) subjects with sustained (>7 days) Grade 3 neutropenia (neutrophil counts 200/mm3 
to < 500 to; 0.2 to <0.5 x 10e9/L) considered related to siplizumab. 
• Two (2) or more subjects presenting with Grade 3 or higher toxicity considered drug related 
as determined by the Investigator, including infusion reactions, within 24 hours of any 
siplizumab administration. 
• Three (3) or more subjects per cohort presenting with Grade IIA or higher BPAR (T-cell 
mediated rejection (TCMR); central pathology) during the first 6 months post-transplant. 
*NOTE: in the case of suspected PTLD lesions where a biopsy is not possible (e.g., CNS 
symptoms), radiographic and imaging (MRI) studies may be used to stage and assess the disease.  
In addition, safety data will be regularly reviewed by ITB-MED and an independent DMC. This 
regular review of cumulative data includes near real-time assessment of acute rejection (BPAR), 
graft losses deaths, and key safety endpoints. In the event the acute rejection rate exceeds a 
clinically relevant threshold set forth in the protocol and DMC charter, or the a priori defined 
stopping rules, enrollment will be suspended to allow for the early termination of any treatment 
cohort where the benefit/risk of siplizumab is deemed unacceptable.  
9.1.2 
Discontinuation of Study Treatment 
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration. Discontinuation can be initiated by the subject, the investigator, 
or by ITB-MED. 
Possible reasons for study treatment discontinuation are: 
• AE, e.g., cytokine release syndrome, PTLD, CTS  
• Lack of Efficacy 
• Technical problem during transplant surgery 
• Primary non-function 
• Subject/Guardian Decision 
• Lost to follow-up 
• Pregnancy 
• Death 
• Graft Loss 
The Investigator should discontinue a subject from their randomized treatment regimen if he/she 
believes that continuation in the study would be detrimental to the subject’s well-being. 
Subjects who discontinue their study treatment should NOT be considered withdrawn from the 
study UNLESS they withdraw their consent to participating in all the elements of the study. Such 
subjects should remain in the study, if possible, and receive standard of care immunosuppression, 
according to local practice, and return for follow-up visits through Month 12.  
All randomized subjects are expected to continue in the study up to Month 12. If they refuse to 
return for these assessments or are unable to do so, every effort should be made to contact them to 


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determine their health status, evaluate safety (SAEs) and to request a final study visit. 
Documentation of attempts to contact the subject should be recorded in the source documentation. 
If the subject is unable to return for a final study visit, every effort to obtain the subject and graft 
status should be made and documented within the subject chart. 
9.1.3 
Withdrawal of Informed Consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject no longer wishes to participate in the study and 
does not allow further collection of personal data. 
In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) to 
understand the primary reason for the subject’s decision to withdraw his/her consent and record 
this information. Study treatment must be discontinued, and no further assessments completed. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
ITB-MED will continue to maintain, and use collected study information (including any data 
resulting from the analysis of a subject’s samples until the time of withdrawal) according to 
applicable law. 
All biological samples collected at the time of withdrawal, but not yet analyzed for subjects 
enrolled within the US, may still be used for further testing/analysis in accordance with the terms 
of this protocol and of the ICF.   
9.1.4 
Lost to Follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating an 
intention to discontinue or withdraw, the investigator must show "due diligence" by documenting 
in the source documents steps taken to contact the subject, e.g., dates of telephone calls, registered 
letters, etc. A subject should not be considered as lost to follow-up until due diligence has been 
completed or until the EOS. 
9.1.5 
Early Study Termination by the Sponsor 
The study can be terminated by ITB-MED at any time. Should this be necessary, the subject should 
be seen as soon as possible and treated as a prematurely withdrawn subject. The Investigator may 
be informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the subject’s interests. The Investigator will be responsible for 
informing IRBs and/or ECs of the early termination of the trial. 
9.2 
Study Completion 
Study completion is defined as when the last subject finishes their final study visit (Month 12) 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 
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Each subject will be required to complete the study in its entirety and thereafter no further study 
treatment will be made available to them (as applicable based on local regulations). Subjects who 
are prematurely withdrawn from the study should be treated according to local SoC per the 
Investigator’s judgment. The study will complete when the last subject completes their Study 
Completion Visit, and any repeat assessments associated with this visit have been documented and 
followed-up appropriately by the Investigator. 
9.3 
Subject Replacement 
Replacement during Dose Escalation  
Subjects will not be replaced on study. However, if a subject is considered as non-evaluable, 
enrollment of a new subject to the current cohort will be considered if there is less than the required 
number of evaluable subjects. Enrollment of new subjects may be considered until at least the 
minimum number (4) or at most the maximum number (8) of evaluable subjects is achieved within 
the cohort.  
Minimum and maximum numbers of evaluable subjects per cohort are defined in the guidelines 
for dose escalation and determination section. 
10 
Safety Monitoring and Reporting 
10.1 
Definition of Adverse Events and Reporting Requirements 
10.1.1 
Adverse Events 
The Investigator is responsible for reporting all AEs that are observed or reported during the study, 
regardless of their relationship to study medication or their clinical significance. Given the 
potential for protracted time between a subject providing informed consent and organ transplant, 
AE collection will commence once a subject has provided consent and has at least one invasive 
study procedure completed and/or performed (e.g., blood draw).  
An AE is any untoward medical occurrence in a study subject administered an investigational 
product which does not necessarily have a causal relationship with the product. An AE can 
therefore be any unfavorable and unintended sign (including a new, clinical important abnormal 
laboratory finding), symptom, or disease, temporally associated with the product, whether or not 
related to the product.  
Pre-existing diseases or conditions will not be considered an AE unless there is an increase in the 
frequency or severity, or a change in the quality of the disease or condition (worsening of a 
pre-existing condition is considered an AE).   
The occurrence of AEs must be sought by non-directive questioning of the subject at each visit 
during the study. AEs also may be detected when they are volunteered by the subject during or 
between visits or through physical examination findings, laboratory test findings, or other 
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AEs must be recorded under the signs, symptoms, or diagnosis associated with them, and 
accompanied by the following information: Assessment and grade according to the CTCAE 
criteria (version 5.0 or higher) 
• Relationship to the study 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 subject 
• Duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved 
• Whether it constitutes a SAE and which seriousness criteria have been met 
• Action taken regarding with study treatment 
• Outcome 
AEs (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. 
AE monitoring should be continued for the duration of the study; in the event a subject does not 
complete the study for any reason, AE monitoring should continue for 6 months after the last 
administration of investigational product.  
Once an AE is detected, it must be followed until its resolution or until it is judged to be permanent 
(e.g., continuing at the EOS), and assessment must be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the interventions required to 
treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the IB. 
Abnormal laboratory values or test results constitute AEs only if they are considered clinically 
significant and/or require therapy or active management.  
10.1.2 
Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that:  
• Results in death 
• Is life-threatening 
o Note: The term “life-threatening” in the definition of ‘serious” refers to an event 
in which the subject was at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it were more severe. 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 


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• Requires inpatient hospitalization or prolongation of existing hospitalization 
o Note: Inpatient hospitalization is defined as 24 hours in a hospital or an overnight 
stay.  An elective hospital admission to treat a condition present before exposure to 
the study drug, or a hospital admission for a diagnostic evaluation of an AE, does not 
qualify the condition or event as an SAE. Further, an overnight stay in the hospital 
that is only due to transportation, organization, or accommodation problems and 
without medical background does not need to be considered an SAE.  Routine 
treatment or monitoring of the studied indication, not associated with any 
deterioration in condition that has not worsened since the signing of consent is not 
considered an SAE. 
• Is an important medical event  
All reports of intentional misuse and abuse of the product are also considered SAEs irrespective if 
a clinical event has occurred. 
10.1.3 
Adverse Events of Special Interest 
The following AEs are selected as adverse events of special interest (AESI) for surveillance and 
follow-up, both serious and non-serious, based on previous experience with siplizumab, all: 
• Serious Infections 
• Opportunistic Infections, including EBV, CMV, BK virus  
• Malignancies, including LPD/PTLD  
10.1.4 
SAE Reporting 
Every SAE, regardless of causality occurring after the subject has provided informed consent and 
had at least one invasive study procedure performed and continuing until the final study visit, must 
be reported to the ITB-MED Safety Department or its designee. Reporting must take place within 
24 hours of learning of its occurrence and is done by entering the SAE into the eCRF within 
24 hours of awareness. Additionally, all AESI whether serious or not should also be reported 
following the same procedure. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-up 
to the original episode, regardless of when the event occurs. This information must be submitted 
within 24 hours of the Investigator receiving the follow-up information. An SAE that is considered 
completely unrelated to a previously reported one should be reported separately as a new event. 
Information on all SAEs (either initial or follow up) is collected and entered in the eCRF(s). 
Information may also be submitted in writing to 
 when important 
information or clinical updates are required that may not be feasible to provide within the eCRFs. 
Please refer to the Site Study Manual for detailed instructions on the reporting of SAEs.  
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment, ITB-MED Safety may urgently require further 
information from the investigator for health authority reporting. ITB-MED may need to inform all 
investigators involved in any study with the same study treatment that this SAE has been reported. 


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Suspected Unexpected Series 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. 
Any SAEs experienced after the Month 12 (EOS) visit should only be reported to ITB-MED Safety 
if the investigator suspects a causal relationship to study treatment. For subjects who terminate 
from the study prematurely, SAEs should only be reported if they occur within 6 months following 
the last administration of study treatment and a causal relationship is suspected. 
10.1.5 
Pregnancy Reporting 
To ensure subject safety, each pregnancy occurring while the subject is on study treatment must 
be reported to ITB-MED Safety within 24 hours of learning of its occurrence. The pregnancy 
should be followed to determine outcome, including spontaneous or voluntary termination, details 
of the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy follow-up should be reported to ITB-MED Safety and should include an assessment of 
the possible relationship to the investigational treatment to pregnancy outcome. Any AE or SAE 
experienced during pregnancy must also be reported. 
10.1.6 
Early Phase Safety Monitoring 
The Investigator will monitor AEs in an ongoing manner and inform ITB-MED of any clinically 
relevant observations. Any required safety reviews will be made jointly between medically 
qualified personnel between ITB-MED or it’s designee and the Investigator(s). Criteria pertaining 
to stopping the study/treatment or adapting the study design are presented above. 
ITB-MED will advise the Investigator(s) at all sites in writing (e-mail) (and by telephone if 
possible) of any new, clinically relevant safety information during the conduct of the study in a 
timely manner. 
10.1.7 
Reporting of Study Treatment Errors 
Medication errors are defined as potential, intercepted, or unintentional errors in the prescribing, 
dispensing, administration, or monitoring of a medicine while under the control of a healthcare 
professional, subject, or consumer. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on the 
appropriate eCRF irrespective of whether or not associated with an AE/SAE and reported to Safety 
only if associated with an SAE; however, the ITB-MED study team should be notified 
immediately. 
11 
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 the clinical trial, safety data, and 


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critical efficacy variables and recommend to ITB-MED whether to continue, modify or terminate 
a trial. 
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 ITB-MED and the DMC. 
12 
Data Analysis and Statistical Methods 
This section describes the statistical methods to be used to analyze safety and efficacy.  These 
methods may be revised and updated due to reasons such regulatory requirements or need for 
further clarifications.  
The final analysis plan will be documented in a formal statistical analysis plan (SAP) that must be 
finalized before database lock.  The SAP will include details on how variables will be derived, 
how missing data will be handled, and how data will be presented as well as the details on statistical 
methods to be used for safety and efficacy analyses.  The final Clinical Study Report (CSR) will 
discuss deviations from the SAP, if any. 
Any data analysis carried out independently by the investigator must be submitted to ITB-MED 
before publication or presentation. 
12.1 
Analysis sets 
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned by 
randomization. According to the intent to treat principle, subjects will be analyzed according to 
the treatment they have been assigned to during the randomization procedure. 
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment received, where treatment received is defined as 
the randomized/assigned treatment if the subject took at least one dose of that treatment or the first 
treatment received if the randomized/assigned treatment was never received. 
The PK Analysis Set will include all subjects with at least one available valid (i.e., not flagged for 
exclusion) PK concentration measurement, who received any study drug and experienced no 
protocol deviations with relevant impact on PK data. 
The PD Analysis Set will include all subjects in the Full Analysis set with available PD data and 
no protocol deviations with relevant impact on PD data. 
For all analysis sets, subjects will be analyzed according to the study treatment(s) received. 
12.2 
Subject Demographics and other Baseline Characteristics 
All data for background and demographic variables will be listed by treatment group and subject. 
Summary statistics will be provided by treatment group. 
Subject demographics will include age, sex, race, ethnicity, height, weight and BMI. 
Other baseline disease characteristics include relevant medical history, current medical conditions, 


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results of laboratory screens, transplant history, donor characteristics (e.g., age, sex, race, type, 
CIT) and any other relevant information.  
Summary statistics will be presented for the subjects in the FAS. Continuous variables will be 
presented with mean, median, 25th percentile, 75th percentile, standard deviation (SD), 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 labeled as “missing” when appropriate). 
12.3 
Treatments 
The duration (days) of study medication administration will be summarized. This will be 
calculated by subtracting the date of the last administration of study medication from the date of 
first administration and then adding the dosing interval for siplizumab, TAC, MMF or CS. 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 temporary dose 
interruption) will be presented by reason for the change. 
Average daily doses will be presented by treatment. “Zero” will be used for periods of temporary 
interruption of study medication for any reason. 
The number and percentage of subjects who prematurely discontinued study medication will be 
summarized by reason for discontinuation. 
Study treatment errors, including uses outside of what is foreseen in the protocol will be 
summarized.  AEs as a result of study treatment error will also be summarized. 
12.3.1 
Concomitant Immunosuppressants 
The average daily dose of administered TAC, MMF, and CS will be summarized by treatment arm 
for subjects on study medication. The dose of the induction agent will be summarized for each of 
days when it was administered. 
The dose of antibodies used for the treatment of acute rejection episodes will be recorded as well. 
12.3.2 
Other Co-Medications 
Concomitant medications, other than immunosuppressants and CS mentioned above, will be 
summarized by therapeutic class and preferred term by presenting the number and percentage of 
subjects using each medication for each treatment group. 
12.4 
Analysis of the Primary Endpoint(s) 
12.4.1 
Definition of Primary Endpoint(s)  
All safety data, including laboratory assessments, vital signs and AEs are considered primary 
endpoints.  
All information obtained on AEs will be displayed by treatment and subject. The number and 
percentage of subjects with AEs will be tabulated by body system and preferred term with a 


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breakdown by treatment arm. A subject with multiple AEs within a body system is only counted 
once towards the total of this body system. No formal statistical analysis will be done for the safety 
and tolerability evaluation. 
12.4.2 
Statistical Model, Hypothesis, and Method of Analysis 
All data will be summarized and presented descriptively, no formal statistical analysis or 
hypothesis testing will be conducted on the analysis sets. 
The use of the concurrent control group and supplementation with a historical control group to 
better assess the incidence of AEs and SAEs reported with a TAC/MMF/CS based SoC treatment 
regimen will be investigated.  Details on the methodology for data selection and analysis will be 
presented in the SAP. 
12.4.3 
Handling of Missing Values/Censoring/Discontinuations 
The analysis will be made on the FAS population. The following imputation method will be 
applied for subjects with missing data: 
• Patients that lose their graft will be assigned a value of zero for their missing estimated 
glomerular filtration (eGFR) value. 
• Patients that die or are lost to follow-up with a functioning graft will have an imputed value 
using the last-observation-carried-forward (LOCF) method. 
• For subjects that discontinue randomized treatment, the eGFR will be considered missing after 
applying the windows defined in Section 12.1. 
Graft loss subjects do not have a functioning graft; hence the lowest possible GFR value (zero) 
will be assigned to such subjects. In contrast, subjects that die with a functioning graft, die for 
different reasons (e.g., suicide, car accident, cancer) will have an imputed value assigned as 
described above.  
Patients who are lost to follow-up have renal function, but missing values for various reasons (e.g., 
moving from the area or not being able to make the site visit during the Month 6 or Month 12 visit 
window). Patients who have a functioning graft at the time of death or are Lost to Follow-up with 
a functioning graft will be analyzed via an imputation method that employs LOCF. 
12.5 
Analysis of Secondary Endpoints 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
Immunophenotyping 
These data will be summarized by treatment and subject. 
CD2 Receptor Occupancy 
The magnitude and duration of PD effect of siplizumab will be as measured by peripheral blood 
CD2-receptor occupancy. These data will be summarized by treatment and subject. Descriptive 


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statistics will also be provided such as mean, median, SD, minimum and maximum, by time point 
and treatment. 
12.5.2 
Safety Endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g., change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for AEs will summarize only 
on-treatment events, with a start date during the on-treatment period (treatment-emergent AEs). 
The on-treatment period lasts from the date of first administration of study treatment through the 
month 12 or EOS visit. 
Adverse Events 
All information obtained on AEs will be displayed by treatment group.  
The number (and percentage) of subjects with treatment emergent AEs (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: 
• AEs by primary System Organ Class (SOC) and Preferred Term  
• AEs rated to have relationship to study drug by SOC and Preferred Term 
• AEs by primary SOC, Preferred Term, and maximum severity 
• SAEs by SOC and Preferred Term 
• SAEs rated to have relationship to study drug by SOC and Preferred Term 
• Deaths by SOC and Preferred Term 
• AEs leading to discontinuation of a study drug by SOC and Preferred Term 
• AEs leading to dose adjustment or interruptions of a study drug by SOC and Preferred Term 
• Infections by type of infection (viral, bacterial, fungal, and others) and microorganism of 
infection 
• Serious infections by type of infection and micro-organism of infection 
• AEs by standardized MedDRA query (SMQ) levels (broad and narrow search) 
• AEs by SMQ and Preferred Term (broad and narrow search) 
Separate summaries will be provided for study medication related AEs, death, SAEs, other 
significant AEs leading to discontinuation and AEs leading to dose adjustment. 


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The number (and proportion) of subjects with AEs of special interest/related to identified and 
potential risks (e.g., serious infections, opportunistic infections, cytokine release syndrome, 
malignancies) will be summarized by treatment. 
Multiple Occurrences for Tables: 
In all tables about incidence rates of AEs / Infections, if a subject has multiple occurrences of an 
AE, this subject will be counted only once in the corresponding AE category. If a subject has 
multiple AEs within a system organ class, s/he will be counted only once for that class. If a subject 
has multiple severity ratings for an AE while on treatment, s/he is only counted under the 
maximum rating.  
Information pertaining to AEs noted during the study will be listed by subject, including the 
verbatim term given by the Investigator, the Preferred Term and SOC given by the MedDRA 
dictionary, start and end date, causality, Grade and relationship to study drug as assessed by the 
Investigator. 
AEs which will be counted for a specific treatment period are those which are treatment emergent. 
These events are those with an onset after the start of the treatment period, or which were present 
prior to the start of the treatment period but increased in severity, changed from being not suspected 
to being suspected of study drug relationship, or developed into SAEs after the start of the 
treatment period. 
Vital Signs 
All vital sign data will be listed by treatment, subject, and visit/time and if ranges are available, 
abnormalities will be flagged. Summary statistics will be provided by treatment and visit/time. 
Clinical Laboratory Evaluations 
Abnormalities according to clinically notable criteria will be identified. A by-subject listing of 
individual subject laboratory data will be generated. Values outside of the clinically notable limits 
will be flagged. Shift tables describing changes from randomization/enrollment based on the 
clinical notable criteria will be presented.  
Descriptive statistics (mean, SD, minimum, median and maximum) of quantitative laboratory 
variables, including change from randomization/enrollment, will be generated by visit. 
Other Safety evaluations  
BK-polyoma viremia and nephropathy  
The following variables will be analyzed descriptively: 
• occurrence of BK-polyoma viremia any time post-transplantation  
• occurrence of BK-polyoma virus nephropathy any time post-transplantation  


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EBV and CMV Surveillance 
All quantitative and qualitative EBV and CMV surveillance data (serology and DNA-PCR) will 
be listed by treatment, subject, and visit/time and if normal ranges are available, abnormalities will 
be flagged. Summary statistics including mean, SD, minimum, median and maximum as well as 
change from baseline / previous assessment including shift tables will be provided by subject and 
treatment by visit/time. 
Immunogenicity  
Anti-siplizumab antibodies will be determined at specified time points. Immunogenicity data 
consisting of anti-siplizumab antibodies information will be listed by subject and visit. 
12.5.3 
Pharmacokinetics 
Siplizumab serum concentration data will be listed by treatment, subject, 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 and reported as zero. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. Concentrations below LLOQ will be treated as zero 
in summary statistics and for PK parameter calculations. A geometric mean will not be reported if 
the dataset includes zero values. 
Table 12-1 
Non-compartmental pharmacokinetic parameters  
AUClast 
The AUC from time zero to the last measurable concentration sampling time (tlast)  
(mass x time x volume-1) 
AUCinf 
The AUC from time zero to infinity (mass x time x volume-1) 
AUCtau 
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1) 
Cmax 
The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after 
single dose administration (mass x volume-1) 
Tmax 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after 
single dose administration (time) 
Lambda_z 
Smallest (slowest) disposition (hybrid) rate constant (time-1) may also be used for terminal 
elimination rate constant (time-1) 
T1/2 
The elimination half-life associated with the terminal slope (λz) of a semi logarithmic concentration-
time curve (time). Use qualifier for other half-lives 
CL/F 
The total body clearance of drug from the plasma (volume x time-1) 
Vz/F 
The apparent volume of distribution during terminal phase (associated with λz)  
(volume) 
If data permit, PK parameters will be calculated as described in Section 8.5 and Table 12-1 and 
will be listed by treatment and subject. Concentrations below the limit of quantification will not 
be considered for the calculation of PK parameters. Descriptive summary statistics will include 
mean (arithmetic and geometric), SD, and CV (arithmetic and geometric), median, minimum and 
maximum. An exception to this is Tmax where median, minimum and maximum will be presented. 


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A dose-independent, model-based analysis of the dose / concentration-exposure relationship 
should be derived using same the approach. Such analysis may be reported in a separate standalone 
report 
12.5.4 
Biomarkers 
All biomarker data (e.g., renal injury markers, cytokine data) will be listed by treatment, subject, 
and visit/time. Summary statistics will be provided (mean, median, SD, minimum and maximum) 
by treatment and visit/time. 
In the summary tables, the frequency (n, %) of values below the LLOQ and above the upper limit 
of quantification (ULOQ), respectively, will be included. 
In case of censored values (values below the LLOQ and/or values above the ULOQ), the summary 
statistics (arithmetic mean, SD, geometric mean and CV% of geometric mean) will be calculated 
as the maximum likelihood estimates using a parametric model for data that can be right censored 
and left censored assuming the data being normally or log-normally distributed. 
12.5.5 
PK/PD Relationships 
The relationship between siplizumab concentration (PK) and PD variables will be explored 
graphically. Modeling of PK/PD data using a population approach may be performed as 
appropriate and may be reported in a separate standalone report. The broad principles outlined in 
the Food and Drug Administration (FDA) Guidance for Industry: PPK will be followed. 
12.6 
Analysis of Exploratory Endpoints 
 
 
 
12.7 
Interim Analyses 
A formal interim analysis (IA) will occur once 50% of subjects assigned to the treatment Cohorts 
complete their 6-month study assessment. In consideration of the open-label nature of the study 
design and plan for descriptive statistical analysis, additional ad hoc IA may be performed. Results 
of the IA will inform decision making on safety, dose escalation and inclusion of additional doses 
to assure adequate profiling of the siplizumab PK and PD activity.   
Details of the IA process and specific analysis will be presented in the SAP.   
In addition to the formal planned Interim Analysis, the AE and SAE rates will be monitored on a 
continuous basis to support the early discontinuation of any treatment arm that is unsafe and/or 
ineffective according to the Stopping Rules as outlined in Section 9.1.1.  


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12.8 
Dosing Decision Data Review 
Prior to dose escalation to the next Cohort all available safety, tolerability, PK and PD data from 
the previous cohort(s) will be reviewed with the Investigators and a joint decision to escalate or 
terminate the arm will be made.  
Dose escalation from one Cohort to the next will be determined at least 28 days following the last 
investigational product administration in the 4th siplizumab treated subject in each treatment 
cohort.   
The purpose of the Day 28 data review is to confirm progression to the next cohort while the 6-
month IA is to support more PK/PD modeling activities necessary to profile longitudinal 
siplizumab activity for more formal trial design and development decision making.   
Results of the Dosing Decision data review will be communicated to the DMC for information, 
consulting and/or decision purposes as well as to participating investigators for information as 
deemed appropriate. A separate, cumulative, data package will be provided to the independent 
DMC as outlined in the DMC charter.  
12.9 
Sample Size Calculation 
No formal sample size or power analysis has been performed. A sample size of 8 subjects for each 
treatment arm was chosen based on practical considerations, including the need to adequately 
characterize siplizumab PK and PD activity in renal transplant patients in the immediate 
post-transplant time period while balancing the overall exposure in a mechanistic profiling study. 
13 
Study Conduct 
13.1 
Sponsor Responsibilities 
ITB-MED is obligated to conduct the study in accordance with strict ethical principles.  ITB-MED 
will take action to ensure the accuracy and reliability of study data by selecting qualified 
investigators and sites, by reviewing protocol procedures with the Investigator and relevant study 
personnel prior to study initiation, by conducting routine monitoring visits and by utilizing robust 
data management standards.  
13.2 
Investigator Responsibilities 
The Investigator agrees to conduct this study in accordance with all laws, regulations, and 
guidelines of the pertinent regulatory authority.  While delegation of certain aspects of the study 
to sub investigators and research personnel is appropriate, the Investigator will remain personally 
accountable for closely overseeing the study and for ensuring compliance with the protocol and all 
applicable regulations and guidelines. Investigators should ensure that all persons who have been 
delegated study-related responsibilities are adequately qualified and informed about the protocol, 
study drugs and their specific duties within the context of the study. 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the IRB/IEC for the trial protocol, written ICF, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to subjects.  


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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 ITB-MED 
monitors, auditors, ITB-MED Quality Assurance representatives, designated agents of ITB-MED, 
IRBs/IECs, and regulatory authorities as required.  
If an inspection of the clinical site is requested by a regulatory authority, the investigator must 
inform ITB-MED immediately that this request has been made. 
13.3 
Site Initiation 
Study personnel may not screen or enroll subjects into the study until after receiving notification 
from ITB-MED or its designee that the study can be started.  Authorization to start the study will 
not occur until: 
• The study site has received the appropriate IRB/IEC approval for the study 
• A Clinical Trial Agreement has been executed 
• All pertinent study site personnel have received the appropriate protocol and study training 
• All regulatory/GCP documents have been submitted and approved by ITB-MED 
The regulatory documents must be received from the Investigator and reviewed and approved by 
ITB-MED or its designee before the study site can begin screening procedures and before 
ITB-MED can authorize shipment of investigational product to the site.  Copies of the 
Investigator’s regulatory documents must be retained at the study site in a secure location.  It is 
the Investigator’s responsibility to ensure that copies of all required documents are organized, 
current and available for inspection. 
13.4 
Data Quality Control 
13.4.1 
 Data Collection 
Designated investigator staff will enter the data required by the protocol into the eCRFs as soon 
as possible, but no later than 5 working days after a subject study visit. The eCRFs have been built 
using fully validated secure web-enabled software that conforms to 21 CFR Part 11 requirements, 
Investigator site staff will not be given access to the EDC system until they have been trained.  
The investigator/designee is responsible for assuring that the data entered into the eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. The Investigator 
must certify that the data entered are complete and accurate. 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 subject data for archiving at 
the investigational site. 
13.4.2 
Data Management 
ITB-MED personnel or its designee will review the data entered by investigational staff for 
completeness and accuracy. Electronic data queries stating the nature of the problem and 


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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. 
Randomization codes and data about all study treatment (s) dispensed to the subject and all dosage 
changes will be tracked using an IWRS. The system will be supplied by a vendor, who will also 
manage the database. The data will be sent electronically to ITB-MED (or a designee) at specific 
timelines. 
13.4.3 
Monitoring Procedures 
Before study initiation, ITB-MED or its designee will review the protocol and data capture 
requirements with the investigators and their study personnel. During the study, ITB-MED 
employs several methods of ensuring protocol and GCP compliance and the quality/integrity of 
the sites’ data. The monitor will visit the site to check the completeness of subject records, the 
accuracy of data capture / data entry, the adherence to the protocol and to GCP, 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 monitor during 
these visits. Continuous remote monitoring of each site’s data may be performed by ITB-MED or 
its designee.  
The investigator must maintain source documents/data for each subject in the study. Source data 
is defined in International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) GCP (1.51) as all information in original 
records and certified copies of original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data should be 
accurate, legible, contemporaneous, original, attributable, complete and consistent. 
All information within the eCRFs must be traceable to these source documents in the subject’s 
file. Any data not requiring a separate written record will be defined before study start and will be 
recorded directly within the eCRFs. The investigator must also keep the original ICF signed by the 
subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the subjects will be disclosed. 
In keeping with good clinical practice and guidance from the EMA, the principal investigator must 
clearly define the intended location of all source data by completing the Source Data Location 
Form prior to subject recruitment.  This form should be prepared by the site and should be signed 
and dated by the principal investigator or by a person whom the principal investigator has assigned 
this task.   The completed form should be filed in the Site Master File. 
13.4.4 
Protocol Adherence and Amendments 
This protocol defines the study objectives, the study procedures, and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case-by-case basis. Under no circumstances, including 


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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 ITB-MED and not use it 
for any purpose other than the study, except for the appropriate monitoring on study participants. 
Investigators should exercise due diligence to avoid protocol deviations; however, should a 
deviation occur, the principal investigator or their designee, must document the deviation from the 
approved protocol and include an explanation for the deviation, including mitigation plans to avoid 
future occurrences.  
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 ITB-MED 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by ITB-MED, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only deviations to the protocol that are required for subject safety may be implemented 
immediately.  ITB-MED and the applicable health authorities must be subsequently notified of the 
protocol deviation(s).  Additionally, the investigator must notify the reviewing IRB/IEC per the 
IRB/IEC’s protocol deviation reporting requirements. 
13.4.5 
Quality Assurance 
ITB-MED maintains a Quality Management System (QMS) that includes all activities involved in 
quality assurance and quality control, to ensure compliance with written Standard Operating 
Procedures (SOPs) as well as applicable global/local GCP regulations and ICH Guidelines. 
This study will be subject to audit by ITB-MED or its designee. Audits are conducted to assess 
GCP compliance with global and local regulatory requirements, protocols and internal SOPs. 
The investigator agrees to cooperate with the auditor during the visit and will be available to supply 
the auditor with direct access to source documents and other necessary study files as necessary to 
conduct the audit.  In the event a regulatory authority notifies the site of an upcoming inspection, 
the Investigator shall notify ITB-MED immediately.  
13.5 
Study Site Closure 
A study site’s participation in the study may be terminated at any time by ITB-MED.  At the end 
of the study, all study sites will be closed.  This will include the Investigator’s final approval and 
lock of all subject data, return of unused study material and investigational product unless 
otherwise provided in writing by ITB-MED, and final visits by the monitor.   
13.5.1 
Records Retention 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. Study documents should 
not be destroyed without prior written agreement between ITB-MED and the Investigator.  If the 


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Investigator wishes to assign the study records to another party or move them to another location, 
ITB-MED must be notified in advance.  
14 
Ethical Considerations 
14.1 
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. 
14.2 
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 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 ITB-MED clinical trial results website and all required Health Authority websites (e.g., 
Clinicaltrials.gov, EudraCT, etc.). 


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15 
References 
Allen UD, Preiksaitis JK (2013). AST Infectious Diseases Community of Practice. Epstein-Barr 
virus and posttransplant lymphoproliferative disorder in solid organ transplantation. Am J 
Transplant;13 Suppl 4:107-120. 
Andress L, Gupta A, Siddiqi N, Marfo K (2014). Rabbit anti-thymocyte globulin induction in renal 
transplantation: review of the literature. Transplant Research and Risk Management; 6:9-21.  
Arons MM, Hatfield KM, Reddy SC, et al. (2020) Presymptomatic SARS-CoV-2 infections and 
transmission in a skilled nursing facility. N Engl J Med; 382:2081-2090.   
Bia M, Adey DB, Bloom RD, Chan L, Kulkarni S, Tomlanovich S (2010). KDOQI US 
commentary on the 2009 KDIGO clinical practice guideline for the care of kidney transplant 
recipients. Am J Kidney Dis;56(2):189-218. doi: 
Branco L, Barren P, Mao SY, et al (1999). Selective deletion of antigen-specific, activated T cells 
by 
a 
humanized 
MAB 
to 
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mediated 
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NK 
cells. Transplantation.;68(10):1588-1596.  
Curtis RE, Travis LB, Rowlings PA, et al (1999). Risk of lymphoproliferative disorders after bone 
marrow transplantation: a multi-institutional study. Blood;94(7):2208-2216. 
Damschroder MM, Kozhich AA, Woods RM, et al (2004). Analysis of human and primate CD2 
molecules by protein sequence and epitope mapping with anti-human CD2 antibodies. Mol 
Immunol;41(10):985-1000. doi:10 
Davis SJ, van der Merwe PA (1996). The structure and ligand interactions of CD2: implications 
for T-cell function. Immunol Today;17(4):177-187. doi:10.1016/0167-5699(96)80617-7. 
Danziger-Isakov L, Kumar D. (2019) Vaccination of solid organ transplant candidates and 
recipients: Guidelines from the American society of transplantation infectious diseases community 
of practice. Clin Transplant;33(9): e13563. 
Dojcinov SD, Fend F, Quintanilla-Martinez L (2018). EBV-Positive Lymphoproliferations of B- 
T- and NK-Cell Derivation in Non-Immunocompromised Hosts. Pathogens;7(1):28. 
Fishman JA (2017). Infection in Organ Transplantation. Am J Transplant;17(4):856-879.  
Fung M, Babik J, (2020) COVID-19 in Immunocompromised Hosts: What We Know So Far, Clin 
Infect Dis., ciaa863.  
Green 
M, 
Michaels 
MG 
(2013). 
Epstein-Barr 
virus 
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Guirado L (2018). Does Rabbit Antithymocyte Globulin (Thymoglobuline®) Have a Role in 
Avoiding Delayed Graft Function in the Modern Era of Kidney Transplantation? J Transplant; 
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Haas M, Loupy A, Lefaucheur C, et al (2017). The Banff 2017 Kidney Meeting Report: Revised 
diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and 
prospects for integrative endpoints for next-generation clinical trials. Am J Transplant;18(2):293-
307.  
Hardinger KL, Schnitzler MA, Miller B, et al (2004). Five-year follow up of thymoglobulin versus 
ATGAM induction in adult renal transplantation. Transplantation;78(1):136-141.  
Hardinger KL, Brennan DC, Klein CL (2013). Selection of induction therapy in kidney 
transplantation. Transpl Int;26(7):662-672.  
Hart A, Smith JM, Skeans MA, et al (2020). OPTN/SRTR 2018 Annual Data Report: Kidney. Am 
J Transplant;20 Suppl s1:20-130.  
Juvonen E, Aalto SM, Tarkkanen J, et al (2003). High incidence of PTLD after non-T-cell-depleted 
allogeneic haematopoietic stem cell transplantation as a consequence of intensive 
immunosuppressive treatment. Bone Marrow Transplant;32(1):97-102.  
Kates S, Haydel M, Florman S, et al. (2020) COVID-19 in solid organ transplant: A multi-center 
cohort study. Clin Infect Dis. ciaa1097.  
Kaul DR, Valesano AL, Petrie JG, et al. (2021) Donor to recipient transmission of SARS-CoV-2 
by lung transplantation despite negative donor upper respiratory tract testing. Am J 
Transplant.21:2885–2889.  
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group (2009). KDIGO 
clinical practice guideline for the care of kidney transplant recipients. Am J Transplant;9 Suppl 
3:S1-S155.  
Leitner J, Herndler-Brandstetter D, Zlabinger GJ, Grubeck-Loebenstein B, Steinberger P (2015). 
CD58/CD2 Is the Primary Costimulatory Pathway in Human CD28-CD8+ T Cells. J 
Immunol;195(2):477-487.  
Lo DJ, Weaver TA, Stempora L, et al. (2011) Selective targeting of human alloresponsive CD8+ 
effector memory T cells based on CD2 expression. Am J Transplant. 11(1):22–33. 
Marks WH, Ilsley JN, Dharnidharka VR (2011). Posttransplantation lymphoproliferative disorder 
in kidney and heart transplant recipients receiving thymoglobulin: a systematic review. Transplant 
Proc;43(5):1395-1404. 
Murray JE, Merrill JP, Harrison JH (1958). Kidney transplantation between seven pairs of identical 
twins. Ann Surg;148(3):343-359.  
Parker A, Bowles K, Bradley JA, et al (2010). Diagnosis of post-transplant lymphoproliferative 
disorder in solid organ transplant recipients - BCSH and BTS Guidelines. Br J 
Haematol;149(5):675-692.  


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Pereira MR, Mohan S, Cohen DJ, Husain SA, Dube GK, Ratner LE et al. (2020) COVID-19 in 
solid organ transplant recipients: Initial report from the US epicenter. Am J Transplant;20(7):1800-
1808.   
Popow I, Leitner J, Grabmeier-Pfistershammer K, et al (2013). A comprehensive and quantitative 
analysis of the major specificities in rabbit antithymocyte globulin preparations. Am J 
Transplant;13(12):3103-3113.  
Rölle A, Halenius A, Ewen EM, Cerwenka A, Hengel H, Momburg F (2016). CD2-CD58 
interactions are pivotal for the activation and function of adaptive natural killer cells in human 
cytomegalovirus infection. Eur J Immunol;46(10):2420-2425.  
Roufosse C, Simmonds N, Clahsen-van Groningen M, et al (2018). A 2018 Reference Guide to 
the Banff Classification of Renal Allograft Pathology [published correction appears in 
Transplantation. 2018 Dec;102(12): e497]. Transplantation;102(11):1795-1814.   
Seed B, Aruffo A (1987). Molecular cloning of the CD2 antigen, the T-cell erythrocyte receptor, 
by a rapid immunoselection procedure. Proc Natl Acad Sci U S A;84(10):3365-3369.  
Shah DK, Betts AM (2013). Antibody biodistribution coefficients: inferring tissue concentrations 
of monoclonal antibodies based on the plasma concentrations in several preclinical species and 
human. MAbs;5(2):297-305.  
Song T, Yin S, Li X, Jiang Y, Lin T (2020). Thymoglobulin vs. ATG-Fresenius as Induction 
Therapy in Kidney Transplantation: A Bayesian Network Meta-Analysis of Randomized 
Controlled Trials. Front Immunol; 11:457. Published 2020 Apr 3.  
Springer TA, Dustin ML, Kishimoto TK, Marlin SD (1987). The lymphocyte function-associated 
LFA-1, CD2, and LFA-3 molecules: cell adhesion receptors of the immune system. Annu Rev 
Immunol; 5:223-252.  
Tabrizi MA, Roskos LK (2007). Preclinical and clinical safety of monoclonal antibodies. Drug 
Discov Today;12(13-14):540-547.  
Tanriover B, Zhang S, MacConmara M, et al (2015). Induction Therapies in Live Donor Kidney 
Transplantation on Tacrolimus and Mycophenolate with or Without Steroid Maintenance. Clin J 
Am Soc Nephrol;10(6):1041-1049.  
Tanriover B, Jaikaransingh V, MacConmara MP, et al (2016) Acute Rejection Rates and Graft 
Outcomes According to Induction Regimen among Recipients of Kidneys from Deceased Donors 
Treated with Tacrolimus and Mycophenolate. Clin J Am Soc Nephrol;11(9):1650-1661.  
Uhlin M, Wikell H, Sundin M, et al (2014). Risk factors for Epstein-Barr virus-related post-
transplant 
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Zou L, Ruan F, Huang M, et al. (2020) SARS-CoV-2 viral load in upper respiratory specimens of 
infected patients. N Engl J Med; 382: 1177-1179.   


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16 
Appendices 
16.1 
Appendix 1:  Schedule of Assessments  
 


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16.2 
Appendix 2:  Amendment No.1 – Summary of Changes 
Section/Title/Page 
Original Text 
Revision 
Reason for Change 
 
 
 
 
Synopsis 
Exploratory Objectives 
To explore changes in serum cytokines over time 
 
To explore changes in serum and plasma cytokines over time 
 
To clarify that both serum 
and plasma cytokines 
changes will be explored 
in the study. 
Synopsis 
Key Inclusion Criteria 
Not applicable 
Addition of the following inclusion criterion:  
 
Subjects who test negative for SARS-CoV-2 via molecular 
testing (PCR) 
To ensure that study 
participants are tested for 
COVID-19 prior to study 
entry and only those who 
have a negative test are 
eligible for randomization 
 
Synopsis 
Planned Study Sites 
Up to 5 study sites within the United States (US) 
and Europe (EU) 
Up to 5 study sites within the United States (US) 
Europe Sites will 
participate in the 
TCD601B101, and the 
United States are 
participating in the 
TCD601B102 study 
Synopsis, 
Data Analysis 
 
Section 6.8 
Treatment Exposure and 
Compliance, 2nd paragraph, 
last sentence 
 
Section 8.5 
Pharmacokinetic 
Assessments, 3rd paragraph 
 
 
 
Section 12.5.3 
Pharmacokinetics 
1st Paragraph 
 
Siplizumab plasma concentration data will be listed 
by treatment, subject, and visit/sampling time point. 
 
Siplizumab will be measured in plasma and TAC 
will be measured in whole blood. 
 
 
 
The following PK parameters will be determined 
using the actual recorded sampling times and non-
compartmental method(s): Cmax, Tmax, area under 
the curve (AUC) last, AUCinf, T1/2, Vz/F and CL/F 
from the plasma concentration-time data. 
 
Siplizumab plasma concentration data will be listed 
by treatment, subject, and visit/sampling time point. 
Siplizumab serum concentration data will be listed by 
treatment, subject, and visit/sampling time point. 
 
 
Siplizumab will be measured in serum and TAC will be 
measured in whole blood. 
 
 
The following PK parameters will be determined using the 
actual recorded sampling times and non-compartmental 
method(s): Cmax, Tmax, area under the curve (AUC) last, 
AUCinf, T1/2, Vz/F and CL/F from the serum concentration-
time data. 
 
 
Siplizumab serum concentration data will be listed by 
treatment, subject, and visit/sampling time point. 
To clarify that siplizumab 
concentration data will be 
measured in serum and 
not plasma. 
 
Section 2 
To the time-course and duration of siplizumab 
induced lymphocyte depletion and time to recovery 
To measure the time-course and duration of siplizumab 
induced lymphocyte depletion and time to recovery 
To include how the 
endpoint would be 


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Section/Title/Page 
Original Text 
Revision 
Reason for Change 
Objectives and Endpoints, 
Table 2-1 
assessed, which was 
inadvertently omitted in 
the original protocol 
 
Section 3.1 
General overview, 
6th paragraph 
 
 
 
Section 6.2.4 
Preparation 
of 
Siplizumab 
 
 
Section 6.3.2 
Preparation of ATG 
 
Every effort should be made to randomize the 
subject on Day 0, but when logistical considerations 
prevent this from occurring (e.g., central pharmacy 
requirements), the subject may be randomized up to 
12 hours pre-transplant. 
 
The subject will be weighed within 12 hours of each 
infusion administration and this weight will serve as 
the basis for final dose calculations and 
compounding. 
 
The subject will be weighed within 12 hours of each 
infusion administration and this weight will serve as 
the basis for final dose calculations and 
compounding. 
 
Every effort should be made to randomize the subject on Day 
0, but when logistical considerations prevent this from 
occurring (e.g., central pharmacy requirements), the subject 
may be randomized up to 24 hours pre-transplant. 
 
 
The subject will be weighed within 24 hours of each infusion 
administration and this weight will serve as the basis for final 
dose calculations and compounding. 
 
The subject will be weighed within 24 hours of each infusion 
administration and this weight will serve as the basis for final 
dose calculations and compounding. 
The change from 12 to 24-
hours was included to 
provide additional 
flexibility to sites when 
subjects may be scheduled 
for their transplant in the 
early hours of the 
morning. 
 
Section 4.5  
Risk and Benefits  
1st paragraph 
 
Not applicable 
New Text: 
Infection risk will be mitigated by following applicable 
national vaccination guidelines and by use of prophylaxis (See 
Section 6.5). Similarly, the risks of SARS-CoV-2 will be 
minimized by following local, national and international 
guidelines for immunosuppressed and solid organ transplant 
patients (See Section 4.5.3). 
 
The existing Risk and 
Benefits section of the 
protocol was expanded to 
include consideration of 
the current risk of SARS-
CoV-2. 
Section 4.5.1.3  
Lymphoproliferative 
Disorders 
3rd Paragraph  
 
 
 
Independent adjudication of all 9 EBV-LPD cases 
was conducted to assess the overall risk of EBV-
LPD in the setting of renal transplantation. While a 
notable risk of EBV-LPD in the setting of T-cell 
lymphoma was assessed by the committee it was 
stated that experience to date does not demonstrate 
that this risk exceeds that associated with ATG.  
 
In the setting of renal transplantation, siplizumab 
use is not expected to increase the risk of EBV-
LPD/PTLD 
over 
ATG-based 
induction 
in 
combination with background immunosuppression. 
Revision 
In the setting of renal transplantation, siplizumab use is not 
expected to increase the risk of EBV-LPD/PTLD over ATG-
based 
induction 
in 
combination 
with 
background 
immunosuppression.  Independent adjudication of all 9 EBV-
LPD cases was conducted to assess the overall risk of EBV-
LPD in the setting of renal transplantation.  While a notable 
risk of EBV-LPD in the setting of T-cell lymphoma was 
assessed by the committee it was stated that experience to date 
does not demonstrate that this risk exceeds that associated with 
ATG. 
Additional information 
added to harmonize the 
section on EBV-LPD risk 
with that of the global 
siplizumab development 
program.  Update includes 
overall conclusion from 
an independent committee 
who conducted a case 
adjudication and risk 
assessment of siplizumab 
in comparison to ATG. 


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Section/Title/Page 
Original Text 
Revision 
Reason for Change 
This rate in the US has been reported to be 1.03% 
(Hart et al 2020) and as high as high as 2.4% with 
ATG induction (Thymoglobulin PI 2020). The rate 
of EBV-LPD is known to be higher in patients who 
are EBV-seronegative with a relative risk up to 33-
fold that of EBV+ recipients (Marks et al 2011). 
Therefore, all recipients will be screened prior to 
administration 
of 
siplizumab, 
and 
EBV-
seronegative subjects excluded from participating 
in the TCD601B102 clinical trial. In addition, 
clinicians 
who 
specialize 
in 
transplant 
immunosuppression, and are aware of the risks for 
EBV-LPD, will be managing patients enrolled in 
this study. Regular assessments of hematology, 
EBV-viral load as well as PTLD surveillance 
including full physical exams at each visit as well 
as monitoring of clinical signs and symptoms will 
be conducted during the 12-month study. 
 
This rate in the US has been reported to be 1.03% (Hart et al 
2020) and as high as high as 2.4% with ATG induction 
(Thymoglobulin PI 2020).  The rate of EBV-LPD is known to 
be higher in patients who are EBV-seronegative with a relative 
risk up to 33-fold that of EBV+ recipients (Marks et al 2011).  
Therefore, all recipients will be screened prior to 
administration of siplizumab, and EBV-seronegative subjects 
excluded from participating in the TCD601B102 clinical trial. 
In 
addition, 
clinicians 
who 
specialize 
in 
transplant 
immunosuppression, and are aware of the risks for EBV-LPD, 
will be managing patients enrolled in this study.  Regular 
assessments of hematology, EBV-viral load as well as PTLD 
surveillance including full physical exams at each visit as well 
as monitoring of clinical signs and symptoms will be conducted 
during the 12-month study. 
 
There is no change in risk 
based on this update.  
Section 4.5.3  
Risks of SARS-CoV-2 
(COVID-19) 
Not applicable 
New Text: 
The novel coronavirus, severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2), can spread rapidly within 
healthcare settings and communities and poses a special 
challenge for organ transplantation. Ongoing community 
transmission has been noted on all continents except 
Antarctica. Person-to-person transmission of SARS-CoV-2 
occurs during close exposure (< 2 meters) to an infected 
person, primarily via respiratory droplets produced when the 
infected person coughs or sneezes. COVID-19 disease is a 
respiratory illness caused by the SARS-CoV-2 virus with 
variable presentation from asymptomatic to severe. Shedding 
of high viral titers has been documented from the respiratory 
tract, including shedding before the onset of symptoms, and 
results in droplet transmission of SARS-CoV-2 (Zou et al 
2020). Transmission via droplet spread can occur from both 
symptomatic and asymptomatic individuals (Arons et al 2020) 
and it appears that patients with COVID-19 have the highest 
viral loads early in the course of their infection. Thus, a 
reliance on symptom-based screening strategies alone is not 
sufficient to prevent or diagnose infection; consideration of 
Inclusion of additional 
text to address the current 
pandemic including 
SARS-CoV-2 and 
COVID-19 disease. 


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Section/Title/Page 
Original Text 
Revision 
Reason for Change 
symptoms and exposure history, along with PCR-based 
testing is imperative.  
 
COVID-19 Disease:  
Case series on COVID-19 disease in transplant recipients have 
been published, however data remains very limited. Imaging 
demonstrates pneumonia in the majority of patients that are 
hospitalized (75-100%). Patients with less severe infections 
may have lower rates of clinical abnormalities. Mild infections 
are common, however preliminary experience suggests that 
infection, once acquired by immunosuppressed transplant 
recipients, may be of greater severity than in normal hosts after 
the initial incubation period. Experience with other viruses 
including prior outbreaks of coronaviruses, also suggests that 
severe infections will occur in some transplant recipients.  
 
At this time, the risk factors for severe disease have been 
characterized by observational studies. An initial report by 
(Pereira et al 2020) showed that advanced age was associated 
with severe disease in their transplant cohort, which is not 
different from the disease profile in the immunocompetent 
population (Kates et al 2020) reported age >65, chronic lung 
disease, 
congestive 
heart 
failure, 
and 
obesity 
were 
independently associated with poor outcomes of COVID-19 in 
solid organ transplantation. It is anticipated that transplant 
recipients may have a greater viral burden and shedding 
resulting in greater infectivity and potential spread to other 
individuals.  
 
Limited data are available on optimal treatment protocols, and 
none have been clearly demonstrated to optimize outcomes. 
When considering potential therapies, clinicians should 
consider the need for immunosuppression reduction and 
presence of potential drug-drug interactions that may result in 
toxicity or therapeutic failure, e.g., beta interferon or CYP3A 
inducers/inhibitors.  
 
The risk of a COVID-19 infection from an infected organ donor 
is unknown at this time. To date, there has been one 
documented case (Kaul et al 2021) of donor-derived disease 


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transmission in a bilateral lung transplant recipient. 
Transmission from blood banks has not been documented at 
this time. 
 
Guidelines on the risks and management of SARS-CoV-2 in 
the setting of clinical trials as well as that of renal transplant 
patients have been published by the European Medicines 
Agency (EMA), US National Institutes of Health (NIH), 
Transplantation Society (TTS) and American Society of 
Transplantation (AST). Treatment guidelines on the use in 
immunocompromised and transplant recipients are updated 
periodically as knowledge of COVID-19 disease management 
evolves. Cumulative cases and incidence rates are tracked and 
published by the World Health Organization (WHO) and other 
public and private entities and should be used to guide local 
management of patients.  
 
With active circulation of SARS-CoV-2 in the community, it is 
appropriate to counsel all candidates about the risk for 
acquisition from the community and hospital environment. 
Candidates should be educated about preventive strategies such 
as social distancing, masking when in proximity to non-
household contacts, frequent hand washing, and avoidance of 
travel to high-risk areas.  
 
A compendium of global guidance documents is maintained by 
the NOTIFY library and can be found at the following URL: 
https://www.notifylibrary.org/background-
documents#SARSCoV-2.  
 
Section 4.5.4 
Risk Mitigation Strategy,  
2 
– 
9 
Paragraph 
consolidated and moved 
14-16 Paragraph (new text) 
 
Safety and tolerability data for doses up to 15 
mg/kg IV have been collected in patients with T-
cell lymphoma with good tolerability. With initial 
administration of a biologic, the first 4 hours of 
exposure are most critical with most infusion 
reactions (including hypersensitivity, cytokine 
release, anaphylaxis) occurring within the first 2 
hours of exposure (Tabrizi and Roskos 2007). No 
cytokine release has been detected with IV or s.c. 
siplizumab (MEDI-507) administration in the 
Infections are a common risk for all transplant recipients. 
Subjects will be regularly evaluated while hospitalized and 
upon return to the clinic for signs and symptoms which might 
indicate a severe infection, i.e., fever, nausea, myalgia, 
headache, arthralgia, chills, diarrhea, stiff neck, and malaise, 
and will be treated as appropriate per local practice depending 
on the infectious agent. Subjects will be informed to report 
any of the aforementioned symptoms to the clinical staff to 
assure proper assessment and care can be administered in a 
timely manner.  
Text consolidated and 
moved to improve flow of 
Risk mitigation section. 
 
Inclusion of text around 
SARS-CoV-2 


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completed patient studies. Cytokine release or 
anaphylaxis have not been reported with similar 
compounds specifically targeting the CD2 
receptor. A mild infusion reaction has been 
described in primates as well as clinical studies 
with siplizumab following the first dose. This first-
dose-effect presents as mild and transient pyrexia 
with chills, nausea and fatigue. These infusion 
reactions are self-limiting and respond well to 
premedication with acetaminophen and 
diphenhydramine. Subjects will receive their first 
dose of siplizumab in the pre- to inter-operative 
time period, at a time when patients are under the 
close supervision of clinical staff in a hospital 
environment. Any infusion related reactions can be 
managed at that time in accordance with local 
protocols. In the TCD601B102 study all subjects 
will receive premedication prior to each dose of 
siplizumab to mitigate any infusion reactions.  
 
Considering the expected immunosuppressive 
nature of the compound, subjects will be screened 
for a history of latent infections. Viral reactivation 
will be assessed for CMV and BK virus according 
to local practice on a regular basis. Prophylaxis for 
CMV and pneumocystis pneumonia (PCP) will be 
administered to all subjects during the trial 
according to local practice. A negative test result 
for TB performed within 6 months of 
randomization will be required prior to enrollment. 
If there is suspicion of TB, a chest x-ray may be 
performed in accordance with local guidelines; 
subjects with a positive test will be excluded from 
participation.  
EBV serology will serve as a key inclusion 
criterion, where EBV-seronegative subjects will be 
excluded from participation. EBV viral loads via 
EBV-PCR will be collected from all subjects 
throughout the trial and will be analyzed centrally 
to minimize inter-laboratory variation. Positive 
Considering the expected immunosuppressive nature of the 
compound, subjects will be screened for a history of latent 
infections. Viral reactivation will be assessed for CMV and BK 
virus according to local practice on a regular basis. Prophylaxis 
for CMV and pneumocystis pneumonia (PCP) will be 
administered to all subjects during the trial according to local 
practice. A negative test result for TB performed within 6 
months of randomization will be required prior to enrollment. 
If there is suspicion of TB, a chest x-ray may be performed in 
accordance with local guidelines; subjects with a positive test 
will be excluded from participation.   
EBV serology will serve as a key inclusion criterion, where 
EBV-seronegative 
subjects 
will 
be 
excluded 
from 
participation. EBV viral loads via EBV-PCR will be collected 
from all subjects throughout the trial and will be analyzed 
centrally to minimize inter-laboratory variation.  Positive 
results that demonstrate an increase over time will be 
communicated to the investigator for additional follow-up and 
per-protocol PTLD surveillance as described in Section 8.4.5.  
The ongoing SARS-Cov-2 pandemic represents a challenge for 
all renal transplant candidates and recipients. Due to the 
dynamic nature of COVID-19 infection rates, centers should 
continue to follow local and national guidelines and set policies 
based on the local incidence and prevalence of infections as 
well as hospital and staffing resources. This includes decisions 
to conduct or defer solid organ transplant procedures as well as 
the ongoing management of donors and recipients. 
Subjects eligible for the TCD601B102 study will be 
randomized from the pool of active candidates who are 
currently undergoing transplantation and will be receiving T-
cell 
depleting 
induction 
and 
standard 
of 
care 
immunosuppression. All eligible subjects will be informed of 
the risks of SARS-COV-2 during the consent process. To 
decrease the risk to study subjects, all candidates will be 
screened for SARs-CoV-2 prior to enrollment and excluded if 
positive. 
Ongoing surveillance per standard of care will occur thereafter 
based on local conditions and signs and symptoms. In renal 
transplant patients who experienced COVID-19 disease, 
common presenting symptoms were fever, dry cough, and 


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results that demonstrate an increase over time will 
be communicated to the investigator for additional 
follow-up and per-protocol PTLD surveillance as 
described in Section 8.4.5.  
 
Subjects will be regularly evaluated while 
hospitalized and upon return to the clinic for signs 
and symptoms which might indicate a severe 
infection, i.e., fever, nausea, myalgia, headache, 
arthralgia, chills, diarrhea, stiff neck, and malaise, 
and will be treated as appropriate per local practice 
depending on the infectious agent. Subjects will be 
informed to report any of the aforementioned 
symptoms to the clinical staff to assure proper 
assessment and care can be administered in a timely 
manner.  
 
Subjects will be hospitalized for several days post-
transplant. Following discharge from the hospital, 
subjects will return to the clinic for routine 
assessments. During these visits, safety and PK/PD 
assessments will be collected. Standard safety 
assessments will include vital signs, physical 
examinations, 
clinical 
laboratory 
evaluations 
(hematology, blood chemistry and urinalysis), AE 
and SAE monitoring as outlined in the Schedule of 
Assessments. In addition to standard clinical 
laboratory assessments, subjects will be monitored 
regularly for signs and symptoms of infectious, 
inflammatory, hematologic or renal toxicity / 
rejection as outlined below. 
 
Subject’s serum creatinine will be measured 
frequently in the first few weeks post-transplant 
and thereafter with a focus on renal injury and 
dysfunction. Changes in renal function will be 
assessed via serum creatinine and estimated 
glomerular filtration rates (eGFR) using 
Modification of Diet in Renal Disease (MDRD) 
formula. In the event subjects present with a 
diarrhea, with most patients exhibiting lymphopenia and 
elevated C-reactive protein (CRP) (Fung and Babik 2020). 
Subjects will be counseled to report any of these physical 
symptoms to the clinical staff. Clinicians should also consider 
the common laboratory changes when assessing the potential 
for COVID-19 disease. 
 
Subjects who may be exposed to SARS-CoV-2 or contract 
active disease will be managed per local practice and 
international guidelines including recommendations for 
seeking treatment or self-quarantine. As with all infection 
events, SARS-CoV-2 positivity and COVID-19 disease will be 
captured in the safety database and will be evaluated by the 
DMC during their periodic dose escalation and ongoing safety 
review. Within the clinical trial setting, subjects may be 
required to attend in-person study visits in excess of those 
based on standard of care for clinical laboratory assessments as 
well as PK/PD sample collection; this may increase their risk 
of SARS-CoV-2 exposure. To minimize the time patients, 
spend indoors and within the clinic for these assessments, 
phone contact or virtual / telehealth technology will be utilized 
where appropriate by the site staff. In addition, patients will be 
counseled on the importance of following proper hygiene, 
masking and social distancing practices to minimize 
community and hospital exposure during their standard of care 
and study specific visits. 
 
SARS-CoV-2 vaccines (i.e., mRNA, adenoviral vector) are 
under development or have been authorized for clinical use 
globally. 
The 
effectiveness 
of 
these 
vaccines 
in 
immunocompetent adults is between 76-95%, however the 
effectiveness in solid organ transplant recipients is unknown 
(See Section 6.5). Based on current vaccination guidelines, it is 
recommended that all transplant candidates and their 
household members receive SARS-CoV-2 vaccination when it 
becomes available. Ideally, transplant candidates should be 
targeted for vaccination while they are awaiting transplant or 
3-6 months post-transplant in this trial, based on T-cell 
recovery. 


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significant increase in SCr and/or BPAR for-cause 
biopsies are to be collected for evaluation 
according to the standard Banff histology system. 
In addition, urinary injury biomarkers will be 
collected for future analysis. This exploratory 
biomarker assessment will allow for an additional 
dataset which may help to better assess the type 
and gross location of renal injury, i.e., glomerular 
or tubular, should a signal for such emerge during 
the trial.  
 
Immunophenotyping via fluorescence-activated 
cell sorter (FACS) analysis will be conducted 
periodically during the study to assess the potential 
for an increased risk of infection, changes in 
leukocyte subsets and recovery following 
depletion anticipated with all siplizumab dosing 
arms.  
Coagulopathy will be assessed using standard 
hematology (platelets) and coagulation studies, 
including international normalized ratio 
(INR)/prothrombin time (PT) and activated partial 
thromboplastin time (aPTT) according to local 
practice.  
 
Finally, considering the open-label study design, 
ITB-MED and an independent DMC will review 
study data regularly and on an ad hoc basis. In 
addition to the clinical opinion of the Investigator 
and biopsy results, a priori defined stopping 
criteria and guidelines will be used to protect 
individual subject safety during the trial.  
Overall, the non-clinical results, together with 
completed single- and multiple-dose studies with 
siplizumab in humans to date, as well as the 
comprehensive monitoring plan, a priori defined 
study stopping criteria and monitoring by an 
independent DMC in the TCD601B102 study 
support the continued development of this 
Subjects will be hospitalized for several days post-transplant. 
Following discharge from the hospital, subjects will return to 
the clinic for routine assessments frequently during the first 3- 
6 months per standard of care.  During these visits, safety and 
PK/PD assessments will be collected. Standard safety 
assessments will include vital signs, physical examinations, 
clinical laboratory evaluations (hematology, blood chemistry 
and urinalysis), AE and SAE monitoring as outlined in the 
Schedule of Assessments. In addition to standard clinical 
laboratory assessments, subjects will be monitored regularly 
for signs and symptoms of infectious, inflammatory, 
hematologic or renal toxicity / rejection.  
 
 
 
Subject’s serum creatinine will be assessed frequently in the 
first few weeks post-transplant and thereafter with a focus on 
renal injury and dysfunction.  Changes in renal function will 
be assessed via serum creatinine and estimated glomerular 
filtration rates (eGFR) using Modification of Diet in Renal 
Disease (MDRD) formula.  In the event subjects present with 
a significant increase in SCr and/or BPAR for-cause biopsies 
are to be collected for evaluation according to the standard 
Banff histology system.  In addition, urinary injury 
biomarkers will be collected for future analysis.  This 
exploratory biomarker assessment will allow for an additional 
dataset which may help to better assess the type and gross 
location of renal injury, i.e., glomerular or tubular, should a 
signal for such emerge during the trial.   
Immunophenotyping via fluorescence-activated cell sorter 
(FACS) analysis will be conducted frequently during the study 
to assess the potential for an increased risk of infection, 
changes in leukocyte subsets and recovery following depletion 
anticipated with all siplizumab dosing arms.  
Coagulopathy will be assessed using standard hematology 
(platelets) and coagulation studies, including international 
normalized ratio (INR)/prothrombin time (PT) and activated 
partial thromboplastin time (aPTT) according to local practice. 
Finally, considering the open-label study design, ITB-MED 
and an independent DMC will review study data, including 


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immunomodulatory compound in further 
investigational studies.  
 
Based on the information outlined above, the risks 
of administering siplizumab in combination with 
TAC, MMF, and CS are monitorable, manageable 
and the benefit-risk assessment in the intended 
patient population remains positive. 
safety events and AEs of special interest, regularly and on an 
ad hoc basis. Furthermore, a priori defined stopping criteria, 
infection surveillance and pharmacovigilance by ITB-MED as 
well as ongoing clinical assessments by Investigator and site 
staff will be employed to protect individual subject safety 
during the trial.  
Overall, the non-clinical and clinical safety results with 
siplizumab in human, as well as the comprehensive monitoring 
plan, a priori defined study stopping criteria and ongoing 
review by an independent DMC support the continued 
development of this immunomodulatory compound and 
conduct of further investigational studies.  Moreover, in 
consideration of the ongoing SARS-CoV-2 pandemic, each 
center will manage their ongoing transplant program and 
enrollment of patients in this trial based on the Investigator’s 
clinical judgement and individual patient risk assessment in 
consideration of both local and per protocol risk mitigation 
plans.  
The 
overall 
benefit-risk 
assessment 
including 
the 
aforementioned mitigation strategies and monitorable and 
manageable risks of administering siplizumab in this patient 
population is positive and support the conduct of this clinical 
trial. 
 
Section 5.1 
Inclusion Criteria 
 
 
New Text: 
Subjects who test negative for SAR-CoV-2 test via molecular 
testing (PCR) 
Addition of SARS-CoV-2 
as an exclusion criterion 
Section 5.2 
Exclusion Criteria 
 
hemoglobin (Hbg) < 8 mg/dL 
 
hemoglobin (Hgb) < 8 mg/dL 
 
Correction to units of 
measure 
Section 6.2.1. 
Identification of 
Investigational Product 
 
Siplizumab is a humanized IgG1[kappa] class 
monoclonal antibody, supplied as a clear to 
slightly opalescent, colorless to slightly brownish, 
preservative-free solution for infusion. 
Siplizumab is a humanized IgG1[kappa] class monoclonal 
antibody, supplied as a clear to slightly opalescent, colorless 
to slightly brownish, preservative-free, concentrate for 
solution.   
Clarification that 
siplizumab is supplied as 
a concentrate for solution 
Section 6.2.2 
Management of 
Investigational Product  
 
Please refer to the Pharmacy Manual for detailed 
instructions on the receipt, storage, accountability, 
and return or destruction will be described in the 
ITB-MED provided Pharmacy Manual. 
Detailed instructions for the receipt, storage, accountability, 
and return or destruction will be described in the ITB-MED 
provided Pharmacy Manual.  
Clarification to refer to 
the siplizumab Pharmacy 
Manual for specifics on 
the preparation and 
management of 
siplizumab infusions  


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Section 6.5 
Infectious Prophylaxis 
Treatment (Immunization) 
 
New Text: 
Immunization of transplant candidates for vaccine preventable 
diseases is recommended more than 2 weeks prior to 
transplantation or starting at 1-6 months after transplantation If 
given prior to transplantation, the full immunization series 
should be completed before the transplant procedure. In certain 
situations, it may be appropriate to wait until 3 or more months 
after transplantation to vaccinate, such as following T- or B-
cell depletion therapy. Waning vaccine titers to other routine 
immunizations 
have 
been 
well 
documented 
after 
transplantation. Lower seroconversion rates to influenza 
vaccination are well documented in the setting of 
mycophenolate mofetil and tacrolimus use (Danziger-Isakov et 
al 2019). Vaccination during treatment with siplizumab and 
prior to clearance of the antibody and pharmacodynamic 
effects are likely to result in therapeutic failure (i.e., non-
protective antibody titers). Administration of live attenuated 
agents should be avoided while receiving siplizumab treatment 
and for up to 6 months thereafter, depending on the dose and 
time for reconstitution of immune function. 
Information on 
immunization of 
transplant recipients and 
candidates consolidated 
and expanded under a new 
section for clarity. 
Section 8 
Visit Assessments 
 
New Text: 
While COVID-19 disease remains a risk, efforts to minimize 
the time a subject spends indoors at the clinic may be 
considered. These efforts could include use of virtual or 
telehealth technology, where appropriate, to remotely capture 
applicable study data (e.g., overall health status, assessment of 
medication compliance, review of adverse events). The intent 
is to allow centers to minimize in-person onsite clinic visit 
activities to those assessments that require the subject to be 
physically present (e.g., laboratory collections or physical 
assessments). In the event virtual or telehealth technology is 
utilized to facilitate data collection, it should be done per 
institutional 
practice 
and 
local 
regulations. 
Detailed 
documentation of all contact and information collected 
virtually is to be recorded in the study records.  
 
Clarification on flexible 
visit scheduling during the 
ongoing SARS-CoV-2 
pandemic to minimize the 
amount of time and in-
person contact necessary 
for per protocol study 
visits. 
Section 8 
Visit Assessments 
3rd Paragraph 
This protocol defines 7 days to a week and 4 weeks 
(or 28 days) to a Study Month. For example, Week 
This protocol defines 7 days to a week and 4 weeks (or 28 days) 
to a Study Month. For example, Week 2 is considered to start 
Clarification of protocol 
definitions 


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2 is considered to start on Day 7 and Study Month 
2 is considered to start on Week 5/Day 2.  
on Day 8 and Study Month 2 is considered to start on Day 29 
(Start of Week 5).  
Section 8.4.2 
Vital Signs 
Vital signs (radial pulse rate, blood pressure and 
body temperature) will be recorded as indicated in 
the Schedule of Assessments. 
Vital signs (radial pulse rate, blood pressure, respiratory rate, 
and body temperature) will be recorded as indicated in the 
Schedule of Assessments. 
Clarification that 
respiratory rate is assessed 
Section 8.4.4.5 
Pregnancy 
Serum or urine pregnancy testing will be required 
for all females regardless of child-bearing potential, 
at timepoints as designated in the Schedule of 
Assessments. 
Serum or urine pregnancy testing will be required for females 
of child-bearing potential, at timepoints as designated in the 
Schedule of Assessments. 
Clarification to only 
conduct pregnancy testing 
in WOCBP 
Appendix 1 
Schedule of Assessments 
Not applicable 
 
The following assessments were added: 
• 
SARS-CoV-2 Molecular Testing at screen 
• 
EBV-PCR (added visit 13 and visit 17) 
 
The Schedule of 
Assessments was updated 
to reflect the addition of 
study assessments and 
procedures. 
Appendix 1 
Schedule of Assessments 
• 
Footnote (b) vitals collected pre-dose, 
immediately following the end of the infusion, 
and 6 hours after completion of infusion with 
siplizumab or ATG. Other time points 
captured as indicated.  
 
 
• 
Footnote (d) results obtained within the past 6 
months 
are 
acceptable 
for 
the 
initial 
assessment; serology samples and donor EBV 
only at screening 
 
 
• 
HIV, HbsAg, HCV serology (D and R)d 
 
• 
Footnote (f) a negative pregnancy test must be 
available prior to randomization  
 
• 
Footnote (i) Subjects randomized to ATG 
(Control) 
 
• 
Footnote (m) TCD601 PK Sampling on Day 0 
dosing (pre-dose, hrs 1, 3, 6 and 24) and Day 
4 dosing (pre-dose, hrs 1, 3 and 6). Additional 
samples include collection on post-operative 
Days 2, 3, 7, 14, 21, 28, 35, 42, 49, 56, 63*, 
• 
Footnote (b) vitals collected pre-dose, immediately 
following the end of the infusion, and 6 hours after 
completion of infusion with siplizumab or rATG. Other 
time points captured as indicated. Weight is captured pre-
dose on Days 0 and 4 for siplizumab treated subjects and 
pre-dose on Days 0,1 and 2 for rATG treated subjects 
 
• 
Footnote (d) results obtained within the past 12 months are 
acceptable for the initial assessment of EBV (donor and 
recipient) and CMV. Serological testing for BKV is not 
required at Screening. EBV, CMV and BKV viral testing 
via PCR should be conducted thereafter 
 
• 
HIV, HbsAg, HCV serology (D and R) 
 
• 
Footnote (f) a negative pregnancy test must be available 
prior to randomization (for females of childbearing 
potential) 
 
• 
Footnote (i) Subjects randomized to rATG (Control) 
 
 
• 
Footnote (m) New Text: Post-dose collection time is 
based on the START time of infusion. 
 
Updates to footnotes b, d, 
f, and i in the Schedule of 
Assessments. 


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70*, 84*, 112*, *140, 168*, 196*, 224*, and 
252* (* Note: latter collections may be 
truncated based on half-life of TCD601 and 
serum 
concentrations 
below 
limit 
of 
quantification) 
Appendix 7: 
Update 2018 Banff 
Classification 
Not applicable 
New Text: 
Category 5: IFTA 
• 
Grade I (Mild): Banff Lesion Score ci1 OR Banff Lesion 
Score ct1 
• 
Grade Il (Moderate) Banff Lesion Score ci2 OR Banff 
Lesion Score ct2 
• 
Grade III (Severe) Banff Lesion Score ci3 OR Banff 
Lesion Score ct3 
Category 6:  Other changes not considered to be caused by 
acute or chronic rejection  
• 
BK-Virus Nephropathy 
• 
Posttransplant Lymphoproliferative Disorder 
• 
Calcineurin Inhibitor Toxicity 
• 
Acute Tubular Injury 
• 
Recurrent Disease 
• 
De Novo Glomerulopathy (Other Than TG) 
• 
Pyelonephritis 
• 
Drug-Induced Interstitial Nephritis 
 
Appendix updated to 
reflect the 2018 update of 
the Banff classification 
standards 
Various 
Not defined 
Correction of minor typos and clarifications throughout the 
protocol 
Typos and minor updates 
to the text to provide 
clarification were 
included throughout the 
document and are visible 
within the redlined 
version of the protocol. 


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16.3 
Appendix 3: Investigator Agreement Page 
 
INVESTIGATOR AGREEMENT 
 
Protocol Number: TCD601B102 
Version: 2.0, Incorporating Amendment No.: 1.0 
 
I have read the Investigator’s Brochure and protocol TCD601B102, “A 12-Month, Randomized, 
Controlled, Open-Label, Dose Escalation Study evaluating Safety, Tolerability, Pharmacokinetics 
(PK) and Pharmacodynamics (PD) of an anti-CD2 monoclonal antibody, TCD601 (siplizumab) 
compared to anti-thymocyte globulin (rATG), as induction therapy in de novo Renal Transplant 
Recipients” and agree to conduct this clinical study as outlined in the protocol. I will also ensure 
that all sub-investigators and other study staff members have read and understand all aspects of 
the protocol.   
I agree to cooperate fully with ITB-MED and its designated vendors during the study.  I will carry 
out the study in accordance with FDA, EMA and ICH guidelines and applicable local and 
government regulations. 
I agree to the following: 
• To use the investigational product (siplizumab) only as specified in the protocol and 
Pharmacy Manual 
• Agree to reference the Laboratory Manual provided by ITB-MED for detailed instructions 
on sample collection, processing and analysis (where applicable) 
• Understand that changes cannot be made to the protocol and study procedures without prior 
written approval from ITB-MED 
• Understand that any violation of the protocol may lead to termination of the study 
• Agree to comply with ITB-MED and regulatory requirements for the monitoring and 
auditing of the study 
 
–––––––––––––––––––––––––––––––––––––––––– 
Principal Investigator Name 
 
––––––––––––––––––––––––––––––––––––––––––                   –––––––––––––––––––––– 
Principal Investigator Signature 
 
 
 
 
Date 
 
 
 
 
 


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16.4 
Appendix 4: US-Specific CellCept® Pregnancy and Safety 
Information  
 
• Use of CellCept® during pregnancy is associated with an increased risk of first trimester 
pregnancy loss and an increased risk of congenital malformations, especially external ear and 
other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, 
esophagus, and kidney. 
• Females of reproductive potential must be made aware of the increased risk of first trimester 
pregnancy loss and congenital malformations with MPA products and must be counseled 
regarding pregnancy prevention and planning. 
• For those females using Cellcept® at any time during pregnancy and those becoming pregnant 
within 6 weeks of discontinuing therapy, the Investigator or healthcare practitioner should 
report the pregnancy to the Mycophenolate Pregnancy Registry (1800-617-8191). The 
Investigator or healthcare practitioner should strongly encourage the subject to enroll in the 
pregnancy registry. 
• Risks and benefits of CellCept® should be discussed with the subject. When appropriate, 
consider alternative immunosuppressants with less potential for embryofetal toxicity. 
In certain situations, the subject and her healthcare practitioner may decide that the maternal 
benefits outweigh the risks to the fetus. If this drug is used during pregnancy, or if the subject 
becomes pregnant while taking this drug, the subject should be apprised of the potential hazard 
to the fetus.  
• To prevent unplanned exposure during pregnancy, females of reproductive potential should 
have a serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL immediately 
before starting CellCept®. Another pregnancy test with the same sensitivity should be done 8 
to 10 days later. Repeat pregnancy tests should be performed during routine follow-up visits. 
Results of all pregnancy tests should be discussed with the subject. 
• Females of reproductive potential taking CellCept® must receive contraceptive counseling and 
use acceptable contraception. Patients must use acceptable birth control during entire 
CellCept® therapy, and for 6 weeks after stopping CellCept®, unless the subject chooses 
abstinence (she chooses to avoid heterosexual intercourse completely). 
• Patients should be aware that CellCept® reduces blood levels of the hormones in the oral 
contraceptive pill and could theoretically reduce its effectiveness. 
 
 
 
 
 
 


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


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16.5 
Appendix 5: Guidelines for MMF Dose Reduction 
An Investigator may interrupt temporarily or reduce the dosage of MMF if in his/her opinion this 
is clinically warranted, in response to any causally associated AE (e.g., neutropenia, 
thrombocytopenia, 
leucopenia, 
hyperlipidemia, 
hypertriglyceridemia 
or 
gastrointestinal 
intolerance). The following guidelines should be followed: 
Dose reduction or temporary interruption may be performed for MMF 
Implementation of MMF dose reduction will be based on thrombocytopenia, leukopenia, 
neutropenia, or other AEs which are suspected to be related to this medication, and in the opinion 
of the Investigator, are clinically warranted. The following guidelines should be used for both dose 
reduction and, once the event has resolved, restarting or increasing the dose of MMF back to 
original levels.  
MMF Dose Reduction Guidelines 
Platelets 
• platelet count < 100,000/mm³ dose may be reduced at the discretion of the Investigator 
• platelet count < 75,000/mm³ a second dose reduction should be considered 
• platelet count < 50,000/mm³ MANDATORY interruption of medication 
WBC 
• WBC < 3500/mm³ 
dose may be reduced at the discretion of the Investigator 
• WBC < 2500/mm³ 
a second dose reduction should be considered 
• WBC < 2000/mm³      interruption of medication should be considered 
All these changes must be recorded on the MMF Dosage Administration Record eCRF. 


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16.6 
Appendix 6: Tacrolimus Drug-Drug Interactions 
Please refer to most recent national prescribing information for current labeling recommendations.  
Drug interactions 
Due to the potential for additive or synergistic impairment of renal function, care should be taken 
when administering Tac with drugs that may be associated with renal dysfunction. These include, 
but are not limited to, aminoglycosides, amphotericin B, and cisplatin. Initial clinical experience 
with the co-administration of TAC and CsA resulted in additive/synergistic nephrotoxicity. 
Drugs that may alter tacrolimus concentrations 
Since TAC is metabolized mainly by the CYP3A enzyme systems, substances known to inhibit 
these enzymes may decrease the metabolism or increase bioavailability of TAC as indicated by 
increased whole blood or plasma concentrations. Drugs known to induce these enzyme systems 
may result in an increased metabolism of TAC or decreased bioavailability as indicated by 
decreased whole blood or plasma concentrations. Monitoring of blood concentrations and 
appropriate dosage adjustments are essential when such drugs are used concomitantly. 
*Drugs that may increase tacrolimus blood concentrations 
Calcium 
Channel 
Blockers 
Antifungal 
Agents  
Macrolide 
Antibiotics 
Gastrointestinal 
Prokinetic 
Agents 
Other Drugs 
diltiazem 
nicardipine 
nifedipine 
verapamil 
clotrimazole 
fluconazole 
itraconazole 
ketoconazole** 
voriconazole 
clarithromycin 
erythromycin 
troleandomycin 
cisapride 
metoclopramide 
bromocriptine 
chloramphenicol 
cimetidine 
cyclosporine 
danazol 
ethinyl estradiol 
methylprednisolone 
lansoprazole*** 
omeprazole 
protease inhibitors 
nefazodone 
magnesium-aluminum 
hydroxide 
**In a study of 6 normal volunteers, a significant increase in Tac oral bioavailability (14±5% vs. 30±8%) was observed 
with concomitant ketoconazole administration (200 mg). The apparent oral clearance of Tac during ketoconazole 
administration was significantly decreased compared to Tac alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). 
Overall, IV clearance of Tac was not significantly changed by ketoconazole co-administration, although it was highly 
variable between patients. 
*** Lansoprazole (CYP2C19, CYP3A4 substrate) may potentially inhibit CYP3A4-mediated metabolism of Tac and 
thereby substantially increase Tac whole blood concentrations, especially in transplant patients who are intermediate 
or poor CYP2C19 metabolizers, as compared to those patients who are efficient CYP2C19 metabolizers. 
 


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*Drugs that may decrease tacrolimus blood concentrations 
Anticonvulsants 
Antimicrobials 
Herbal Preparations 
Other Drugs  
carbamazepine 
phenobarbital 
phenytoin 
rifabutin 
caspofungin 
rifampin 
St. John’s Wort 
sirolimus 
* This table is not all inclusive. 
St. John’s Wort (Hypericum perforatum) induces CYP3A4 and P-glycoprotein. Since Tac is a 
substrate for CYP3A4, there is the potential that the use of St. John’s Wort in patients receiving 
Tac could result in reduced TAC levels. 
In a single-dose crossover study in healthy volunteers, co-administration of Tac and 
magnesium-aluminum hydroxide resulted in a 21% increase in the mean Tac AUC and a 10% 
decrease in the mean Tac Cmax relative to Tac administration alone. 
In a study of 6 normal volunteers, a significant decrease in TAC oral bioavailability (14±6% vs. 
7±3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a 
significant increase in Tac clearance (0.036±0.008 L/hr/kg vs. 0.053±0.010 L/hr/kg) with 
concomitant rifampin administration. 
Interaction studies with drugs used in HIV therapy have not been conducted. However, care should 
be exercised when drugs that are nephrotoxic (e.g., ganciclovir) or that are metabolized by CYP3A 
(e.g., nelfinavir, ritonavir) are administered concomitantly with TAC. Similarly, care should be 
exercised when HCV protease inhibitors (e.g., boceprevir and telaprevir), also metabolized by 
CYP3A, are administered concomitantly with Tac. 
Tac may affect the PK of other drugs (e.g., phenytoin) and increase their concentration. Grapefruit 
juice affects CYP3A-mediated metabolism and should be avoided. 
Other Drug Interactions 
Immunosuppressants may affect vaccination. Therefore, during treatment with Tac, vaccination 
may be less effective. The use of live vaccines should be avoided; live vaccines may include, but 
are not limited to measles, mumps, rubella, oral polio, BCG, yellow fever, and TY 21a typhoid 
(Prograf® PI 2019). 


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16.7 
Appendix 7: Updated 2018 Banff Classification 
Category 1:  Normal biopsy or nonspecific changes 
Category 2:  Antibody-mediated changes 
• Active ABMR: all three features must be present for diagnosis. Biopsies showing histological 
features plus evidence of current/recent antibody interaction with vascular endothelium or 
DSA, but not both, may be designated as suspicious for acute/active ABMR. Lesions may be 
clinically acute or smoldering or may be subclinical; it should be noted if the lesion is 
C4d-positive or C4d-negative, based on the following criteria: 
1. Histologic evidence of acute tissue injury, including one or more of the following: 
o Microvascular inflammation (g >0 in the absence of recurrent or de novo 
glomerulonephritis, and/or ptc >0) 
o Intimal or transmural arteritis (v >0)1 
o Acute thrombotic microangiopathy in the absence of any other cause 
o Acute tubular injury in the absence of any other apparent cause 
2. Evidence of current/recent antibody interaction with vascular endothelium, including 
at least one of the following: 
o Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen 
sections or C4d >0 by IHC on paraffin sections) 
o At least moderate microvascular inflammation ([g + ptc] ≥2), although in the 
presence of acute TCMR, borderline infiltrate, or infection; ptc ≥2 alone is not 
sufficient, and g must be ≥1 
o Increased expression of gene transcripts in the biopsy tissue strongly associated 
with ABMR, if thoroughly validated 
3. Serologic evidence of DSAs (HLA or other antigens) 
C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 
may substitute for DSA; however thorough DSA testing, including testing for non-HLA 
antibodies if HLA antibody testing is negative, is strongly advised whenever criteria 1 and 
2 are met 
 
• Chronic active ABMR2: all three features must be present for diagnosis. As with active 
ABMR, biopsies showing histological features plus evidence of current/recent antibody 
interaction with vascular endothelium or DSA, but not both, may be designated as suspicious, 
and it should be noted if the lesion is C4d-positive or C4d-negative, based on the criteria listed: 


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1. Morphologic evidence of chronic tissue injury, including one or more of the following: 
o TG (cg >0), if no evidence of chronic thrombotic microangiopathy or chronic 
recurrent/de novo glomerulonephritis; includes changes evident by electron 
microscopy (EM) alone (cg1a) 
o Severe peritubular capillary basement membrane multilayering (requires EM)3 
o Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the 
sclerotic intima favor chronic ABMR if there is no prior history of biopsy-proven 
TCMR with arterial involvement but are not required 
2. Identical to criterion 3 for active ABMR, above, 
3. Identical to criterion 3 for active ABMR, above, including strong recommendation for DSA 
testing whenever criteria 1 and 2 are met  
 
• C4d staining without evidence of rejection 
All three features must be present for diagnosis4 
1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or 
C4d >0 by IHC on paraffin sections) 
2. Criterion 1 for active or chronic, active ABMR not met. 
3. No molecular evidence for ABMR as in criterion 2 for active and chronic, active ABMR 
4. No acute or chronic active TCMR, or borderline changes 
Category 3:  Borderline changes 
• Suspicious for acute TCMR 
o Foci of tubulitis (t>0) with minor interstitial inflammation (i0 or i1) or interstitial 
inflammation (i2, i3) with mild (t1) tubulitis; retaining the i1 threshold for borderline 
with t >0 is permitted although this must be made transparent in reports and 
publications 
o No intimal or transmural arteritis (v = 0) 
 
Category 4:  TCMR 
• Acute TCMR   
o Grade IA.  
Interstitial 
inflammation 
(>25% 
of 
nonsclerotic 
cortical 
parenchyma, i2 or i3) and foci of moderate tubulitis (t2) involving 1 or more 
tubules, not including tubules that are severely atrophic5 
o Grade IB.  
Interstitial inflammation involving >25% of nonsclerotic cortical 
parenchyma (i2 or i3) with severe tubulitis (t3) involving 1 or more tubules, not 
including tubules that are severely atrophic5 


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o Grade IIA. 
Mild to moderate intimal arteritis (v1) with or without interstitial 
inflammation and tubulitis 
o Grade IIB.  
Severe intimal arteritis (v2), with or without interstitial 
inflammation and/or tubulitis 
o Grade III. Transmural arteritis and/or arterial fibrinoid necrosis of medial smooth 
muscle cells with accompanying mononuclear cell intimal arteritis (v3), with or 
without interstitial inflammation and/or tubulitis 
• Chronic active TCMR  
o Grade IA: Interstitial inflammation involving >25% of the total cortex (ti score 2 
or 3) and >25% of the sclerotic cortical parenchyma (i-IFTA score 2 or 3) with 
moderate tubulitis (t2) involving 1 or more tubules, not including severely atrophic 
tubules5; other known causes of i-IFTA should be ruled out 
 
o Grade IB: Interstitial inflammation involving >25% of the total cortex (ti score 2 
or 3) and >25% of the sclerotic cortical parenchyma (i-IFTA score 2 or 3) with 
severe tubulitis (t3) involving 1 or more tubules, not including severely atrophic 
tubules5; other known causes of i-IFTA should be ruled out 
 
o Grade II: Chronic allograft arteriopathy (arterial intimal fibrosis with mononuclear 
cell inflammation in fibrosis and formation of neointima) 
 
Category 5: IFTA  
• 
Grade I (Mild): Banff Lesion Score ci1 OR Banff Lesion Score ct1  
• 
Grade Il (Moderate) Banff Lesion Score ci2 OR Banff Lesion Score ct2  
• 
Grade III (Severe) Banff Lesion Score ci3 OR Banff Lesion Score ct3  
Category 6:  Other changes not considered to be caused by acute or chronic rejection   
• 
BK-Virus Nephropathy  
• 
Posttransplant Lymphoproliferative Disorder  
• 
Calcineurin Inhibitor Toxicity  
• 
Acute Tubular Injury 
• 
Recurrent Disease  
• 
De Novo Glomerulopathy (Other Than TG)  
• 
Pyelonephritis 
• 
Drug-Induced Interstitial Nephritis 
 


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Legend: 
ABMR, antibody-mediated rejection; cg, glomerular double contours; DSA, donor-specific antibody; EM, 
electron microscopy; g, glomerulitis; i, inflammation; IF, immunofluorescence; IHC, immunohistochemistry; 
ptc, peritubular capillaritis; t, tubulitis; TCMR, T-cell mediated rejection; TG, transplant glomerulopathy; 
TMA, thrombotic microangiopathy; v, intimal arteritis.  
1 It should be noted that these arterial lesions may be indicative of ABMR, TCMR, or mixed ABMR/TCMR. 
The v lesions are only scored in arteries having a continuous media with two or more smooth muscle 
layers. 
2 Lesions of chronic, active ABMR can range from primarily active lesions with early TG evident only by EM 
(cg1a) to those with advanced TG and other chronic changes in addition to active microvascular 
inflammation. In the absence of evidence of current/recent antibody interaction with the endothelium, the 
term “active” should be omitted; in such cases, DSAs may be present at the time of biopsy or at any 
previous time after transplantation. 
3 Seven or more layers in one cortical peritubular capillary and five or more in two additional capillaries, 
avoiding portions cut tangentially. 
4 The clinical significance of these findings may be quite different in grafts exposed to anti–blood group 
antibodies (ABO-incompatible allografts), in which they do not appear to be injurious to the graft and may 
represent accommodation; however, with anti-HLA antibodies, such lesions may progress to chronic 
ABMR, and more outcome data are needed.  
5 A severely atrophic tubule is defined as one with each of the following 3 features: a diameter <25% of 
that of unaffected or minimally affected tubules on the biopsy, an undifferentiated-appearing, cuboidal or 
flattened epithelium, and pronounced wrinkling and/or thickening of the tubular basement membrane 
(Source: Haas et al 2017, Roufosse 2018).  
 

SAP_001.pdf: 
TCD601B102 Statistical Analysis Plan (SAP) 
A 12-Month, Randomized, Controlled, Open-Label, Dose Escalation Study 
evaluating Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics 
(PD) of an anti-CD2 monoclonal antibody, TCD601(siplizumab) compared to anti-
thymocyte globulin (rATG), as induction therapy in de novo Renal Transplant 
Recipients 
NCT Number:  NCT04311632 
Release Date:  11-Jun-2024


Protocol TCD601B102
Phase IIA
STATISTICAL ANALYSIS PLAN FOR TCD601B102 
Siplizumab 
Clinical Protocol TCD601B102 
A 12-Month, Randomized, Controlled, Open-Label, Dose Escalation Study evaluating 
Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of an anti-CD2 
monoclonal antibody, TCD601(Siplizumab) compared to anti-thymocyte globulin (rATG), 
as induction therapy in de novo Renal Transplant Recipients 
Version Number: 2.0 
Clinical Trial Phase: IIA 
Release Date: 02-Mar-2022 
Property of ITB-MED LLC 
Confidential This document contains proprietary and confidential material belonging to ITB-MED. Its contents 
may not be used, divulged, published, or otherwise disclosed without the consent of ITB-MED 
Sponsor 
ITB-MED 
US Office: ITB-MED LLC 110 East 59th St FL 28. New York, NY 10022. 
Version 1.0
June 11, 2024






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TABLE OF CONTENTS 
1. 
DOCUMENT HISTORY .............................................................................................7 
2. 
LIST OF ABBREVIATIONS.......................................................................................8 
3. 
INTRODUCTION ......................................................................................................10 
4. 
STUDY DESCRIPTION ............................................................................................10 
4.1. 
Study Objectives and Endpoints .................................................................................10 
4.2. 
Study Design ...............................................................................................................11 
4.2.1. 
TCD601B102 ..............................................................................................................11 
4.2.2. 
Dose Escalation Criteria .............................................................................................13 
4.2.3. 
Safety Stopping Rules.................................................................................................13 
5. 
INTERIM ANALYSIS ...............................................................................................14 
5.1. 
Interim Analysis Objectives .......................................................................................14 
6. 
RANDOMIZATION AND BLINDING ....................................................................15 
7. 
ANALYSIS POPULATIONS ....................................................................................15 
7.1. 
Safety Set ....................................................................................................................15 
7.2. 
Full Analysis Set .........................................................................................................15 
7.3. 
PK Analysis Set ..........................................................................................................15 
7.4. 
PD Analysis Set ..........................................................................................................15 
8. 
GENERAL CONVENTIONS ....................................................................................15 
8.0. 
Statistical Model, Hypothesis, and Method of Analysis.............................................16 
8.1. 
Sample Size Calculation .............................................................................................16 
8.2. 
Definition of Baseline .................................................................................................16 
8.3. 
Software ......................................................................................................................16 
8.4. 
Handling of Missing Values/Censoring/Discontinuations .........................................16 
9. 
DESCRIPTION OF THE ANALYSIS POPULATION.............................................17 
9.1. 
Disposition ..................................................................................................................17 
9.2. 
Demographic and Baseline Characteristics ................................................................17 
9.3. 
Other baseline characteristics .....................................................................................17 
9.4. 
Prior and Concomitant Medications ...........................................................................17 
9.4.1. 
Concomitant Immunosuppressants .............................................................................18 
9.4.2. 
Other Concomitant Medications .................................................................................18 
10. 
ANALYSIS OF PRIMARY ENDPOINTS ................................................................18 


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10.1. 
Safety Analysis ...........................................................................................................18 
10.1.1. 
Extent of Exposure .....................................................................................................18 
10.1.2. 
Adverse Events ...........................................................................................................19 
10.1.3. 
Laboratory Assessments .............................................................................................20 
10.1.4. 
Vital Signs ..................................................................................................................20 
10.1.5. 
Physical Exam ............................................................................................................20 
10.1.6. 
Graft Loss ...................................................................................................................21 
10.1.7. 
Death ...........................................................................................................................21 
10.2. 
Pharmacokinetics and Pharmacodynamics .................................................................21 
10.2.1. 
Pharmacokinetics ........................................................................................................21 
10.2.2. 
PK/PD Relationships ..................................................................................................22 
11. 
ANALYSIS OF SECONDARY ENDPOINTS ..........................................................22 
11.1. 
Immunophenotyping ...................................................................................................22 
11.2. 
Lymphocyte Count .....................................................................................................22 
11.3. 
CD2 RO ......................................................................................................................22 
11.4. 
Donor specific antibodies (DSA) results ....................................................................22 
11.5. 
Efficacy Analysis ........................................................................................................23 
11.6. 
Renal Function ............................................................................................................23 
12. 
ANALYSIS OF EXPLORATORY ENDPOINTS .....................................................23 
12.1. 
Immunogenicity ..........................................................................................................24 
12.2. 
BK-polyoma viremia and nephropathy ......................................................................24 
12.3. 
EBV Surveillance .......................................................................................................24 
12.4. 
Renal Function ............................................................................................................24 
12.4.1. 
eGFR via MDRD ........................................................................................................24 
12.4.2. 
Serum Creatinine ........................................................................................................24 
12.5. 
EBV viral load data by PCR .......................................................................................24 
12.6. 
CD2 leukocyte aurora .................................................................................................25 
12.7. 
Biomarkers ..................................................................................................................25 
12.7.1. 
Renal Injury Markers ..................................................................................................25 
12.7.2. 
Cytokines ....................................................................................................................25 
12.8. 
CMV Surveillance ......................................................................................................25 
13. 
IDENTIFICATION AND SUMMARY OF PROTOCOL DEVIATIONS ................26 
14. 
REFERENCES ...........................................................................................................26 


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15. 
APPENDICES ............................................................................................................27 
15.1. 
Appendix A  Imputation Algorithm for Partial and Missing Dates ..........................27 
15.2. 
Appendix B  Special Data Handling Instructions .....................................................28 
 
LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................8 
 












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Figure 4-2 TCD601B102 Study Design
Siplizumab Dosing Arms:
Arm 1: 0.2 mg/kg (n=8)
Arm 2: 0.6 mg/kg (n=8)
Subjects randomized to rATG (Arm 3 in the above figure), will receive three intravenous (IV) doses of 1.5 
mg/kg on Days 0, 1 and 2, regardless of Cohort assignment.


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Siplizumab and rATG will be combined with concentration-controlled TAC (BID) dosing to a whole blood 
trough concentration 4-11 ng/mL, and MMF or equivalent (BID), and should be started within 24 hours 
post-transplant. Subjects will also receive CS per local practice with a minimum of 5.0 mg/day prednisone 
or equivalent until Month 12. 
4.2.2. 
Dose Escalation Criteria 
TCD601B102 
Twenty-eight days following the last investigational product administration in the 4th Siplizumab-treated 
subject in each treatment Cohort and prior to dose escalation to the subsequent Cohort, a review of all 
available safety, tolerability and PD data will be conducted by ITB-MED in collaboration with the 
Investigators. This 28-day safety period allows sufficient time for subjects to reach full-receptor 
occupancy, maximum pharmacodynamic activity, and for the presentation of acute, drug related 
toxicities. 
In the event there is no evidence of acute, dose limiting toxicity (DLT), randomization to the next dose 
level may be initiated. Alternatively, a decision to terminate the dosing arm could be reached. It is also 
possible for additional and/or intermediate dose levels to be added during the course of the study per 
amendment. Cohorts may be added at any dose level below the maximum tolerated dose in order to 
better understand safety, PK or PD. 
This escalation data review will occur prior to dose escalation/termination decisions for each Cohort. The 
review of subject data and dose escalation may occur before all subjects have been randomized to a given 
Cohort. If the next dose level is opened to subject assignment, Cohorts will be back filled to achieve a final 
sample size of 10 subjects. 
In addition to the review of data for dose decision purposes as noted above, an independent Data 
Monitoring Committee (DMC) will conduct an ongoing review of cumulative PK, PD and safety, 
Adverse Events (AEs) and Serious Adverse Event (SAE) data. The Committee will convene on a 
quarterly basis or as described in the DMC Charter. If at any time the observed AEs meet or exceed 
the a priori-defined stopping criteria, the study will be placed on hold pending a review. 
4.2.3. 
Safety Stopping Rules 
In addition to the formal interim analyses and escalation data reviews for dosing decision purposes, 
the following Safety Stopping Rules will be in effect at any timepoint in the study.  Although the 
stopping criteria do not incorporate an absolute requirement for causality, the potential relationship 
between an AE(s) and Siplizumab will be evaluated carefully on a case-by-case basis between 
ITB-MED and the Investigator. Following a review of the AE(s), a decision to permanently 
discontinue enrollment or re-initiate dosing will be made by the DMC. Dose-limiting toxicities 
(DLTs) will be assessed according to the standardized toxicity grading scale, the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (NCI 
2017): 
 One (1) subject death or graft loss within the first month with the exception of technical 
failures. 
 One (1) subject presents with histologically confirmed EBV-PTLD. 


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 One (1) subject with Grade 3 or higher cytokine release syndrome within 24 hours of any 
Siplizumab administration. 
 One (1) subject with any Grade 4 toxicity, considered drug related as determined by the 
Investigator within the first 28 days. 
 Two (2) subjects with sustained (>7 days) Grade 3 neutropenia (neutrophil counts 200/mm3 
to <500 to; 0.2 to <0.5 × 109/L) considered related to Siplizumab. 
 Two (2) or more subjects presenting with Grade 3 or higher toxicity considered related as 
determined by the Investigator, including infusion reactions, within 24 hours of any 
Siplizumab administration. 
 Three (3) or more subjects per cohort presenting with Grade IIA or higher BPAR (T-cell 
mediated rejection [TCMR]; central pathology) during the first 6 months post-transplant. 
5. 
INTERIM ANALYSIS 
5.1. 
Interim Analysis Objectives 
A formal interim analysis was conducted when 50% of subjects in Cohort 1 and 2 completed their 
6-month study assessment according to a separate interim analysis plan (dated 03MAR2023).  This 
formal interim analysis was conducted to assess the safety/tolerability (e.g., AEs, SAEs, clinical 
laboratory assessments, vital signs, PK data and PK/PD activity [e.g., immunophenotyping and 
CD2 receptor occupancy]). The analysis also included assessment of biopsy proven acute rejection 
(BPAR), graft losses deaths, and key safety endpoints. In the event the acute rejection rate exceeds 
a clinically relevant threshold set forth in the protocol and DMC charter, or the a priori defined 
stopping rules, enrollment were to be suspended to allow for the early termination of any treatment 
cohort where the benefit/risk of Siplizumab was deemed unacceptable.   
The following treatment arms will be utilized for TCD601B102: 
 Arm 1: Siplizumab 0.2 mg/kg (n=8 in Cohort A) 
 Arm 2: Siplizumab 0.6 mg/kg (n=8 in Cohort B) 
 Arm 3: rATG, a control arm, (n=4 each in Cohort A and B) 
Subjects randomized to Siplizumab will receive two intravenous (IV) doses on Day 0 and Day 4 
post-transplant and subjects randomized to rATG (Arm 3) will receive three intravenous (IV) doses 
of 1.5 mg/kg on Days 0, 1, and 2, regardless of Cohort assignment. 
 
 
 


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6. 
RANDOMIZATION AND BLINDING 
Randomizations will be performed within each cohort:   
 A randomization ratio of 2 (active arm):1 (control arm) will be utilized for Study 
TCD601B102.   
7. 
ANALYSIS POPULATIONS 
7.1. 
Safety Set 
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment received, where treatment received is defined as 
the randomized/assigned treatment if the subject took at least one dose of that treatment or the first 
treatment received if the randomized/assigned treatment was never received. 
7.2. 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned by 
randomization. According to the intent-to-treat principle, subjects will be analyzed according to 
the treatment they have been assigned to during the randomization procedure. 
7.3. 
PK Analysis Set 
The PK Analysis Set will include all subjects with at least one available valid (i.e., not flagged for 
exclusion) PK concentration measurement, who received any study drug and experienced no 
protocol deviations with relevant impact on PK data. 
7.4. 
PD Analysis Set 
The PD Analysis Set will include all subjects in the Full Analysis set with available PD data and 
no protocol deviations with relevant impact on PD data. 
For all analysis sets, subjects will be analyzed according to the study treatment(s) received. 
8. 
GENERAL CONVENTIONS 
Unless otherwise stated, all analyses will be performed using SAS Version 9.4 or later and all 
hypothesis tests will be conducted at a two-sided significance level of 0.05.  P-values will be 
presented with 3 decimals and p-values that are less than 0.001 will be presented as <0.001. 
Continuous data will be summarized using descriptive statistics: number of observations (n), mean, 
standard deviation (SD), median, minimum, and maximum.  Frequencies and percentages will be 
used to summarize categorical (discrete) data. Presentations of categorical data will generally 
suppress percentages for items where the count is zero in order to draw attention to the nonzero 
counts.   
Unless otherwise stated, the control arm will include 8 subjects who received (rATG) in study 
TCD601B102. The active arms will include: 0.2mg/kg (8 subjects) and 0.6mg/kg (8 subjects. 
Unless otherwise stated, confidence intervals, when presented, will be constructed at the two-sided 


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95% level. For binomial variables, the 95% confidence intervals will be constructed using the 
Clopper-Pearson exact method. 
Data listings will present all data collected on case report forms (CRFs) by treatment arm, center, 
and subject number. 
8.0. 
Statistical Model, Hypothesis, and Method of Analysis 
All data will be summarized and presented descriptively, no formal inferential analysis or 
hypothesis testing will be conducted on the analysis sets. 
8.1. 
Sample Size Calculation 
No formal sample size or power analysis has been performed. A sample size of 8 subjects for each 
treatment arm was chosen based on practical considerations, including the need to adequately 
characterize Siplizumab PK and PD activity in renal transplant patients in the immediate post-
transplant time period while balancing the overall exposure in a mechanistic profiling study. 
8.2. 
Definition of Baseline 
Unless otherwise stated, the last observed measurement prior to or on the date of first study medication 
will be considered the baseline measurement. 
For eGFR analysis (See Section Error! Reference source not found.), the baseline will be based on the 
Week 4 assessment. 
8.3. 
Software 
The PK parameters will be derived using Phoenix WinNonlin® version 8.3 or higher (Certara, L.P.). SAS® 
9.4 or higher (SAS institute, Inc., Cary, NC USA) will be used for PK statistical analysis to provide tables, 
listings, and figures. 
8.4. 
Handling of Missing Values/Censoring/Discontinuations 
The following imputation method will be applied for subjects with missing data: 
Subjects who lose their graft will be assigned a value of zero for their missing estimated glomerular 
filtration (eGFR) value. 
Subjects who die or are lost to follow-up with a functioning graft will have an imputed value using the 
last-observation-carried-forward (LOCF) method. 
sing after applying 
the windows. 
Graft loss subjects do not have a functioning graft; hence the lowest possible GFR value (zero) will be 
assigned to such subjects. In contrast, subjects that die with a functioning graft, die for different reasons 
(e.g., suicide, car accident, cancer) will have an imputed value assigned as described above. 
Subjects who are lost to follow-up have renal function, but missing values for various reasons (e.g., moving 
from the area or not being able to make the site visit during the Month 6 or Month 12 visit window). 


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Subjects who have a functioning graft at the time of death or are Lost to Follow-up with a functioning 
graft will be analyzed via an imputation method that employs LOCF. 
9. 
DESCRIPTION OF THE ANALYSIS POPULATION  
Summary statistics will be presented for the subjects in the FAS.  
Continuous variables will be presented with mean, median, 25th percentile, 75th percentile, 
standard deviation (SD), minimum and maximum, and the number of non-missing observations. 
Categorical data will be displayed via absolute and relative frequencies for each category 
 
9.1. 
Disposition 
Subject disposition summaries will be presented by treatment arm and will include the number of 
subjects randomized, the number and percentage of randomized subjects in each analysis 
populations, as well as the number and percentage of subjects who complete the study. The 
summaries will also include the reasons for early discontinuation from the study.   
The table format will be similar to the disposition table presented to the DMC. 
Data for disposition variables will be presented in a listing by treatment arm and subject.  
9.2. 
Demographic and Baseline Characteristics 
Demographic summaries will be provided by treatment arm and will include age, sex, race, 
ethnicity, height, weight, and BMI. These summaries will be presented for the subjects in the Full 
Analysis Set (FAS) and Safety set (SS). 
Data for demographic variables will be presented in listings by treatment arm and subject. 
9.3. 
Other baseline characteristics 
Other baseline disease characteristics include relevant medical history, transplant history, other 
concomitant procedures, childbearing potential, donor characteristics (e.g., age, sex, race, type, 
CIT) and any other relevant information. 
Medical history and procedures will be coded by MedDRA (Medical Dictionary for Regulatory Activities, 
version 26.0 or higher). Medical history will be summarized according to System Organ Class (SOC) and 
Preferred Term (PT).  
Medical history, current medical conditions, results of laboratory screens, transplant history, donor 
characteristics will be presented in listings by treatment arm and subject respectively. 
9.4. 
Prior and Concomitant Medications 
All medications recorded on the CRFs will be coded using the WHODrug Dictionary (version 
March 2023 or higher). Prior and concomitant medications will be summarized by treatment arm 
in the Safety Set by anatomical therapeutic chemical (ATC) Class Level 4 and WHODrug base 
substance preferred name. 


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Prior medications are defined as medications with stop dates occurring before the date of first 
administration of any study treatment.  Concomitant medications are defined as medications with 
start dates occurring on or after the date of first administration of any study treatment and no more 
than 30 days after the last study visit. Medications with start and stop dates that bracket the date 
of first administration of a study treatment will be summarized as both prior and concomitant 
medications. 
Medications that were stopped prior to the date of first administration of a study treatment will be 
included in the prior medications table, and medications that were started on or after the date of 
first administration of any study treatment component will be included in the concomitant 
medications table.  All other medications will be included in both the prior and concomitant 
medications tables if the date they were started or stopped is unclear. 
Prior and concomitant medications will be summarized for the Safety Set. 
Prior and concomitant medications will be presented in listings. 
9.4.1. 
Concomitant Immunosuppressants 
The average daily dose of administered TAC, MMF, and CS will be summarized by treatment arm 
for subjects receiving study medication. The dose of the induction agent will be summarized for 
each of days when it was administered. 
The dose of antibodies used for the treatment of acute rejection episodes will be recorded as well. 
 TAC, MMF, and CS administration and average daily dose will be presented in listings. 
9.4.2. 
Other Concomitant Medications  
Concomitant medications, other than immunosuppressants and CS mentioned above, will be 
summarized by therapeutic class and preferred term by presenting the number and percentage of 
subjects using each medication for each treatment group. 
Information for other co-medications will be presented in listings. 
10. 
ANALYSIS OF PRIMARY ENDPOINTS 
10.1. 
Safety Analysis 
Safety analyses will be performed using the Safety Set.  Assessment of safety will be based on the 
incidence, severity, relatedness, and type of adverse events, as well as on clinically significant 
and presented by study drug received. 
Because there is no pre-specified safety outcome defined in terms of AEs or vital signs, any formal 
comparisons between the treatment arms with respect to specific safety parameters will be post 
hoc. 
10.1.1. 
Extent of Exposure 
Summary statistics of exposure to study drug will be tabulated by treatment arm.  The exposure 
will be summarized using duration and average dosing.  Duration of exposure is defined as last 


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dosing date  first dosing date + 40; e.g. 5 PK half-lives.  Exposure by average dose is defined as 
X/Y, where X is the total dose received and Y is planned number of doses to be given. 
The duration (days) of study medication administration will be summarized. This will be 
calculated by subtracting the date of the last administration of study medication from the date of 
first administration and then adding the dosing interval for Siplizumab, TAC, MMF or CS. 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 temporary dose 
interruption) will be presented by reason for the change. 
Average da
interruption of study medication for any reason. 
The number and percentage of subjects who prematurely discontinued study medication will be 
summarized by reason for discontinuation. 
Study treatment errors, including uses outside of what is foreseen in the protocol, will be 
summarized. AEs as a result of study treatment error will also be summarized. 
Extent of exposure data will be presented in a listing.  
10.1.2. 
Adverse Events 
Each AE and SAE term will be recorded as a verbatim term on the case report forms (CRFs).  All 
AEs and SAEs will be coded by primary system organ class (SOC) and mapped to a preferred term 
using the MedDRA dictionary (version 26.0 or higher).  The investigator will assess AE severity 
and relationship to the study treatment. 
All AEs will be listed. However, only treatment emergent adverse events (TEAEs) will be included 
in the AE summaries.  A TEAE is defined as any AE with an onset date on or after the first study 
treatment dosing date.  In addition, any AEs that the investigators deem to be treatment related, 
regardless of onset date, will also be considered TEAEs and will be included in the AE summaries. 
For the purpose of calculating treatment emergence and inclusion in summary tables, incomplete 
onset dates will be imputed using the method described in Appendix A. 
AEs will be summarized by the number and percentage of subjects in each primary SOC and 
preferred term.  Subjects will be counted only once for each primary SOC and each preferred term. 
Summary tables of AEs by primary SOC, preferred term and severity will be provided. If a subject 
has more than one AE coded to the same preferred term, the subject will be counted only once for 
that preferred term by using the event with the highest severity. Similarly, if a subject has more 
than one AE within a primary SOC category, the subject will be counted only once in that SOC 
category by using the event with the highest severity. AEs by primary SOC, preferred term and 
relationship to study drug will be provided as well. If a subject has more than one AE coded to the 
same preferred term, the subject will be counted only once for that preferred term by using the 
most related event. Similarly, if a subject has more than one AE within a primary SOC category, 
the subject will be counted only once in that primary SOC category by using the most related 
event. In addition, serious adverse events (SAEs) by primary SOC and preferred term will be 
provided. Deaths and SAEs will be summarized similarly to AEs. All adverse event tables will 
also include the total number of events, counting multiple events per subject. 
In the AE summary, preferred terms within each SOC will appear in alphabetical order. 


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Frequencies for deaths and hospitalizations will also be summarized by treatment group and 
overall. 
All information obtained on AEs will be displayed by treatment group. 
The number (and percentage) of subjects with treatment emergent AEs (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: 
 
p to study drug by SOC and Preferred Term 
 
 
 
 
 to discontinuation of a study drug by SOC and Preferred Term 
 
infection 
-organism of infection 
 
 
Separate summaries will be provided for study medication related AEs, death, SAEs, other 
significant AEs leading to discontinuation and AEs leading to dose adjustment. 
All AEs will be presented in individual by-subject data listings. Listings of any subject 
experiencing TEAEs related to study drug, and an SAE will be provided separately. 
10.1.3. 
Laboratory Assessments 
Descriptive statistics (mean, SD, minimum, median and maximum) of quantitative laboratory 
variables, including change from baseline, will be generated by visit. Summary of change from 
baseline in liver function tests, renal function tests, and other clinical chemistry and hematology 
laboratory tests will be provided for the Safety Set. Shift tables describing changes from baseline 
based on the clinical notable criteria will be presented. 
Results of laboratory tests will be presented in listings. 
10.1.4. 
Vital Signs 
All vital sign data will be listed by treatment, subject, and visit/time and if ranges are available, 
abnormalities will be flagged. Summary statistics and change from baseline will be provided by 
treatment and visit/time. Shift tables describing changes from baseline based on the clinically 
notable criteria will be presented. 


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10.1.5. 
Physical Exam 
Physical exam data for each subject will be presented in a listing, if it is available. 
10.1.6. 
Graft Loss  
Graft Loss data will be summarized by group. If the subject undergoes allograft nephrectomy prior 
to starting permanent dialysis, then the day of nephrectomy is the day of graft loss.  
10.1.7. 
Death 
Primary cause of death will be summarized by treatment arm, and death data will be presented in 
a listing. 
10.2. 
Pharmacokinetics and Pharmacodynamics 
10.2.1. 
Pharmacokinetics  
PK samples will be evaluated for the subjects in PK analysis set at all dose levels.    
Siplizumab concentrations will be determined by a validated ELISA method; the anticipated 
Lower Limit of Quantification (LLOQ) is 10 ng/mL and concentrations will be expressed in mass 
will be labeled as such in the Bioanalytical Data Report. 
The following PK parameters will be determined using the actual recorded sampling times and 
non-compartmental method(s): Cmax, Tmax, area under the curve (AUC) last, AUCinf, T1/2, Vz/F, and 
CL/F from the serum concentration-time data. 
The linear trapezoidal rule will be used for (AUC) calculation. Regression analysis of the terminal 
plasma elimination phase for the determination of T1/2 will include at least 3 data points after Cmax. 
If the adjusted R2 value of the regression analysis of the terminal phase will be less than 0.75, no 
values will be reported for T1/2, AUCinf , and CL. 
Siplizumab serum concentration data will be listed by treatment, subject, 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 and reported as zero.  
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum, and maximum. Concentrations below LLOQ will be treated as zero 
in summary statistics and for PK parameter calculations. A geometric mean will not be reported if 
the dataset includes zero values.  
Table 9-1 Non-compartmental pharmacokinetic parameters 
AUClast  
The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x 
time x volume-1)  
AUCinf  
The AUC from time zero to infinity (mass x time x volume-1)  
AUCtau  
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x 
volume-1)  




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11.3. 
CD2 RO 
The magnitude and duration of PD effect of Siplizumab will be measured by peripheral blood 
CD2-receptor occupancy.  
11.4. 
Donor specific antibodies (DSA) results 
Blood samples for DSAs (antibodies directed against antigens expressed on donor organs) will 
be collected and evaluated locally. 
11.5. 
Efficacy Analysis 
Efficacy analysis will be summarized by treatment arm for the FAS. 
 tBPAR 
Treated biopsy proven acute rejection (tBPAR) is any condition in which the subject receives 
anti-rejection treatment and is histologically diagnosed as acute rejection according to the 2017 
Banff criteria, including borderline rejections. Incidence of tBPAR at 12 months will be 
summarized. 
 AMR 
Incidence of antibody meditated rejection (AMR) at 12 months will be summarized. 
11.6. 
Renal Function 
 Change from baseline in renal function eGFR 
Renal function will be assessed by eGFR, using an automated calculation factoring serum 
creatinine, demographics and the MDRD4 formula.  
MDRD 4-variable GFR Equation as below: 
GFR in mL/min per 1.73 m2 = 175 x SerumCr-1.154 * age-0.203 * 1.212 (if patient is black)  
* 0.742 (if female) 
 Change from baseline in CKD-EPI 
The CKD-EPI equation are modeled using least squares linear regression to relate log 
transformed measured GFR to log-transformed filtration markers, age and sex with two slope 
splines for creatinine, Expressed as a single equation: 
 
-1.200*0.9938Age *1.012 [if female] 
Abbreviations / Units: 
eGFR (estimated glomerular filtration rate) = mL/min/ 1.73 m2 
Scr (serum creatinine) = mg/dL 
K = 0.7 (females) or 0.9 (males) 
-0.241 (females) or -0.302 (males) 


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min = indicates the minimum of Scr/K or 1 
max = indicates the maximum of Scr/K or 1 
The above parameters will be summarized by visit. This will also be evaluated at Months 3, 6 
and 12 (EOS) by comparing the mean eGFR values between groups. 
12. 
ANALYSIS OF EXPLORATORY ENDPOINTS 
 
 
 
 
  
 
  
 
 
 
 
  
  
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 


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13. 
IDENTIFICATION AND SUMMARY OF PROTOCOL 
DEVIATIONS 
Major protocol deviations from entry criteria and treatment compliance will be summarized as far 
as they can be extracted from numeric or coded study data.  
All protocol deviations, both minor and major, will be presented in a data listing. 
14. 
REFERENCES 
None 


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15. 
APPENDICES 
15.1. 
Appendix A  Imputation Algorithm for Partial and Missing Dates 
This section describes missing date imputation methods. 
For Adverse Events 
If onset date is completely missing, onset date is set to date of randomization. 
If (year is present and month and day are missing) or (year and day are present and month is 
missing): 
 If year = year of randomization, then set month and day to month and day of randomization 
 If year < year of randomization, then set month and day to December 31. 
 If year > year of randomization, then set month and day to January 1. 
If month and year are present and day is missing: 
 If year = year of randomization and  
o If month = month of randomization then set day to day of first dose 
o If month < month of first dose then set day to last day of month 
o If month > month of first dose then set day to first day of month 
 If year < year of randomization then set day to last day of month 
 If year > year of randomization then set day to first day of month 
For all other cases, set onset date to date of randomization. 
 
For Concomitant Medications 
Start Date: If start date is completely missing and end date is not prior to randomization, then the 
medication will be classified as concomitant. If start date is completely missing and end date is 
prior to randomization, then the medication will be classified as prior. 
If (year is present and month and day are missing) or (year and day are present and month is 
missing) then set month and day to January 1.  If year and month are present and day is missing 
then set day to first day of month. 
End Date:  If end date is completely missing then the medication will be classified as concomitant. 
If (year is present and month and day are missing) or (year and day are present and month is 
missing) then set month and day to December 31.  If year and month are present and day is missing 
then set day to last day of the month. 
Note: that if both start and end dates are missing then the medication will be classified as 
concomitant. 
 


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15.2. 
Appendix B  Special Data Handling Instructions 
In the case that data has been entered which does not follow a clear handling instruction, the 
following instructions have been agreed upon and will be followed. 
1. For cases in which the site has collected a TAC trough sample, but the patient has not yet 
received Tacrolimus, the site has been instructed to put in a most recent Tacrolimus dosing 
time of 00:00. 
2. For cases in which the subject has received Tacrolimus before collecting a TAC trough 
sample, however Time of Previous Tacrolimus Dose is unknown, then the time should be 
 
3. If a PCR viral load is below the lower limit of quantification, then the site will record this 
data as Negative, with the PCR value as Unknown.  If the PCR viral load result is negative 
or 0 at the site, then it should be recorded as Negative and 0.